Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34Am Page I

Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page i

Fluorine in Organic Chemistry

Richard D. Chambers FRS Emeritus Professor of Chemistry University of Durham, UK Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iv

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To my wife Anne and our grandchildren, Daniel, Benjamin, Alexandra, and Jack, who give us so much pleasure Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page vii

Contents

Foreword xv by Professor George A. Olah Preface xvii

1 GENERAL DISCUSSION OF ORGANIC FLUORINE CHEMISTRY 1 I General introduction 1 A Properties 1 B Historical development 2 II Industrial applications 3 A Introduction 3 B Compounds and materials of high thermal and chemical stability 3 1 Inert fluids 4 2 Polymers 5 C Biological applications 5 1 Volatile anaesthetics 6 2 Pharmaceuticals 7 3 Imaging techniques 7 4 Plant protection agents 9 D Biotransformations of fluorinated compounds 9 E Applications of unique properties 12 1 Surfactants 12 2 Textile treatments 12 3 Dyes 12 III Electronic effects in fluorocarbon systems 13 A Saturated systems 14 B Unsaturated systems 14 C Positively charged species 15 D Negatively charged species 15 E Free radicals 16 IV Nomenclature 16 A Systems of nomenclature 17 B Haloalkanes 18 References 19

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2 PREPARATION OF HIGHLY FLUORINATED COMPOUNDS 23 I Introduction 23 A Source of fluorine 23 II Fluorination with metal fluorides 23 A Swarts reaction and related processes (halogen exchange using HF) 24 1 Haloalkanes 25 2 Influence of substituent groups 26 B Alkali metal fluorides 27 1 Source of fluoride ion 28 2 Displacements at saturated carbon 29 3 Displacements involving unsaturated carbon 30 Alkene derivatives 30 Aromatic compounds 31 C High-valency metal fluorides 31 1 Cobalt trifluoride and metal tetrafluorocobaltates 32 III Electrochemical fluorination (ECF) 33 IV Fluorination with elemental fluorine 35 A Fluorine generation 35 B Reactions 35 C Control of fluorination 36 1 Dilution with inert gases 36 D Fluorinated carbon 39 E Fluorination of compounds containing functional groups 39 V Halogen fluorides 40 References 41

3 PARTIAL OR SELECTIVE FLUORINATION 47 I Introduction 47 II Displacement of halogen by fluoride ion 47 A Silver fluoride 47 B Alkali metal fluorides 47 C Other sources of fluoride ion 49 D Miscellaneous reagents 50 III Replacement of hydrogen by fluorine 51 A Elemental fluorine 51 1 Elemental fluorine as an electrophile 52 B Electrophilic fluorinating agents containing O–F bonds 56 C Electrophilic fluorinating agents containing N–F bonds 58 D Xenon difluoride 60 E Miscellaneous 60 IV Fluorination of oxygen-containing functional groups 62 A Replacement of hydroxyl groups by fluorine 62 1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent 62 2 Diethylaminosulphur trifluoride (DAST) and related reagents 63 3 Fluoroalkylamine reagents (FARs) 65 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page ix

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B Replacement of ester and related groups by fluorine 66 C Fluorination of carbonyl and related compounds 66 1 Sulphur tetrafluoride and derivatives 66 D Cleavage of ethers and epoxides 69 V Fluorination of sulphur-containing functional groups 71 VI Fluorination of nitrogen-containing functional groups 73 A Fluorodediazotisation 73 B Ring opening of azirines and aziridines 74 C Miscellaneous 75 VII Addition to alkenes and alkynes 76 A Addition of hydrogen fluoride 76 B Direct addition of fluorine 77 C Indirect addition of fluorine 79 D Halofluorination 80 E Addition of fluorine and oxygen groups 82 F Other additions 82 References 83

4 THE INFLUENCE OF FLUORINE OR FLUOROCARBON GROUPS ON SOME REACTION CENTRES 91 I Introduction 91 II Steric effects 91 III Electronic effects of polyfluoroalkyl groups 92 A Saturated systems 92 1 Strengths of Acids 92 2 Bases 93 B Unsaturated systems 94 1 Apparent resonance effects 94 2 Inductive and field effects 97 IV The perfluoroalkyl effect 97 V Strengths of unsaturated fluoro-acids and -bases 98 VI Fluorocarbocations 99 A Effect of fluorine as a substituent in the ring on electrophilic aromatic substitution 99 B Electrophilic additions to fluoroalkenes 101 C Relatively stable fluorinated carbocations 102 1 Fluoromethyl cations 104 D Effect of fluorine atoms not directly conjugated with the carbocation centre 105 VII Fluorocarbanions 107 A Fluorine atoms attached to the carbanion centre 108 B Fluorine atoms and fluoroalkyl substituents adjacent to the carbanion centre 111 C Stable perfluorinated carbanions 112 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page x

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D Acidities of fluorobenzenes and derivatives 113 E Acidities of fluoroalkenes 115 VIII Fluoro radicals 115 A Fluorine atoms and fluoroalkyl groups attached to the radical centre 115 B Stable perfluorinated radicals 117 C Polarity of radicals 117 References 118

5 NUCLEOPHILIC DISPLACEMENT OF HALOGEN FROM FLUOROCARBON SYSTEMS 122 I Substituent effects of fluorine or fluorocarbon groups on the SN2 process 122 A Electrophilic perfluoroalkylation 126 II Fluoride ion as a leaving group 128 A Displacement of fluorine from saturated carbon – SN2 processes 128 1 Acid catalysis 129 2 Influence of heteroatoms on fluorine displacement 131 B Displacement of fluorine and halogen from unsaturated carbon – addition–elimination mechanism 131 1 Substitution in fluoroalkenes 132 2 Substitution in aromatic compounds 133 References 135

6 ELIMINATION REACTIONS 137 I b-Elimination of hydrogen halides 137 A Effect of the leaving halogen 137 B Substituent effects 138 C Regiochemistry 139 D Conformational effects 140 E Elimination from polyfluorinated cyclic systems 142 II b-Elimination of metal fluorides 144 III a-Eliminations: generation and reactivity of fluorocarbenes and polyfluoroalkylcarbenes 147 A Fluorocarbenes 147 1 From haloforms 147 2 From halo-ketones and –acids 149 3 From organometallic compounds 149 4 From organophosphorous compounds 151 5 Pyrolysis and fragmentation reactions 151 B Polyfluoroalkylcarbenes 154 C Structure and reactivity of fluorocarbenes and polyfluoroalkylcarbenes 156 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xi

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1 Fluorocarbenes 156 2 Polyfluoroalkylcarbenes 158 References 159

7 POLYFLUOROALKANES, POLYFLUOROALKENES, POLYFLUOROALKYNES AND DERIVATIVES 162 I Perfluoroalkanes and perfluorocycloalkanes 162 A Structure and bonding 162 1 Carbon–fluorine bonds 162 2 Carbon–carbon bonds 162 B Physical properties 163 C Reactions 163 1 Hydrolysis 163 2 Defluorination and functionalisation 164 3 Fragmentation 166 D Fluorous biphase techniques 166 II Perfluoroalkenes 167 A Stability, structure and bonding 167 B Synthesis 169 C Nucleophilic attack 171 1 Orientation of addition and relative reactivities 172 2 Reactivity and regiochemistry of nucleophilic attack 172 3 Products formed 176 0 4 Substitution with rearrangement – SN2 processes 176 5 Cycloalkenes 183 6 Fluoride-ion-induced reactions 185 7 Addition reactions 186 8 Fluoride-ion-catalysed rearrangements of fluoroalkenes 187 9 Fluoride-ion-induced oligomerisation reactions 188 10 Perfluorocycloalkenes 190 D Electrophilic attack 191 E Free-radical additions 196 1 Orientation of addition and rates of reaction 197 2 Telomerisation 202 3 Polymerisation 203 F Cycloadditions 205 1 Formation of four-membered rings 205 2 Formation of six-membered rings – Diels–Alder reactions 209 3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions 212 4 Cycloadditions involving heteroatoms 214 G Polyfluorinated conjugated dienes 214 1 Synthesis 214 2 Reactions 216 3 Perfluoroallenes 218 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xii

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III Fluoroalkynes and (fluoroalkyl)alkynes 218 A Introduction and synthesis 218 B Reactions 222 1 Perfluoro-2-butyne 222 Formation of polymers and oligomers 222 Reactions with nucleophiles 223 Fluoride-ion-induced reactions 223 Cycloadditions 224 Free-radical additions 226 References 227

8 FUNCTIONAL COMPOUNDS CONTAINING OXYGEN, SULPHUR OR NITROGEN AND THEIR DERIVATIVES 236 I Oxygen derivatives 236 A Carboxylic acids 236 1 Synthesis 236 2 Properties and derivatives 238 3 Trifluoroacetic acid 240 4 Perfluoroacetic anhydride 241 5 Peroxytrifluoroacetic acid 242 B Aldehydes and ketones 243 1 Synthesis 243 2 Reactions 243 Addition to C5O 246 Reactions with fluoride ion 251 C Perfluoro-alcohols 254 1 Monohydric alcohols 254 2 Dihydric alcohols 255 3 Alkoxides 257 D Fluoroxy compounds 258 E Perfluoro-oxiranes (epoxides) 259 F Peroxides 264 II Sulphur derivatives 265 A Perfluoroalkanesulphonic acids 265 B Sulphides and polysulphides 270 C Sulphur(IV) and sulphur(VI) derivatives 272 D Thiocarbonyl compounds 272 III Nitrogen derivatives 275 A Amines 275 B N–O compounds 277 1 Nitrosoalkanes 277 2 Bistrifluoromethyl nitroxide 278 C Aza-alkenes 278 D Azo compounds 284 E Diazo compounds and diazirines 284 References 287 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiii

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9 POLYFLUOROAROMATIC COMPOUNDS 296 I Synthesis 296 A General considerations 296 B Saturation/re-aromatisation 297 C Substitution processes 298 1 Replacement of H by F 298 þ 2 Replacement of 2N2 by F: the Balz–Schiemann reaction 300 3 Replacement of 2OH or 2SH by F 300 4 Replacement of Cl by F 300 II Properties and reactions 306 A General 306 B Nucleophilic aromatic substitution 307 1 Benzenoid compounds 307 Orientation and reactivity 310 Mechanism 311 2 Heterocyclic compounds 315 Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds 315 Polysubstitution 320 Acid-induced processes 321 3 Fluoride-ion-induced reactions 325 Polyfluoroalkylation 325 Other systems 332 4 Cyclisation reactions 332 C Reactions with electrophilic reagents 336 D Free-radical attack 338 1 Carbene and nitrene additions 338 E Reactive intermediates 341 1 Organometallics 341 Lithium and magnesium derivatives 342 Copper compounds 346 2 Arynes 346 3 Free radicals 349 4 Valence isomers 351 Nitrogen derivatives 353 References 358

10 ORGANOMETALLIC COMPOUNDS 365 I General methods and synthesis 365 A From iodides, bromides and hydro compounds 365 1 Perfluoroalkyl derivatives 365 2 Derivatives of unsaturated systems 366 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiv

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B From unsaturated fluorocarbons 367 1 Fluoride-ion-initiated reactions 367 II Lithium and magnesium 368 A From saturated compounds 368 B From alkenes 369 C From trifluoropropyne 370 D From polyfluoro-aromatic compounds 371 III Zinc and mercury 371 A Zinc 371 B Mercury 373 1 Perfluoroalkyl derivatives 373 2 Unsaturated derivatives 374 3 Cleavage by electrophiles 375 IV Boron and aluminium 376 A Boron 376 1 Perfluoroalkyl derivatives 376 2 Unsaturated derivatives 377 B Aluminium 380 V Silicon and tin 381 A Silicon 381 B Tin 385 VI Transition metals 387 A Copper 388 B Other metals 388 References 395

Index 399 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:06pm page xv

Foreword by Professor George A. Olah Nobel Laureate

Chambers’ book Fluorine in Organic Chemistry was published 30 years ago and became a classic of the field. A revised and updated edition is a significant and authoritative contribution by one of the leaders of organic fluorine chemistry. Organic fluorine chemistry has grown enormously in significance and scope in the intervening three decades, not in small measure by the contribution of the author and his colleagues. The new edition will be of great value and help not only to those interested in fluorine chemistry, but also to the wider chemical community. When considering a new edition of a ‘classic’ of chemical literature, it is most appropriate to maintain broadly the layout and aims of the original book, concentrating on methodology, mechanism and the unique chemistry of highly fluorinated compounds. Understandably, therefore, it is outside the scope to discuss medicinal and biochemical aspects. Readers interested in these topics are advised to use the extensive reviews that are available elsewhere.

xv Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:06pm page xvii

Preface

This book is a revision and update of one that was first published in 1973, followed by two small reprintings. The original was prompted by Professor George Olah, during a year that I spent as a Visiting Lecturer in Cleveland. My aim for the original edition was to present an overview of organofluorine chemistry, in a way that corresponded with modern organic chemistry. Of course this involved including a mechanistic basis of the subject, which was still evolving at the time; to my knowledge, this was the first broad attempt to do so. The original book appears to have served a useful purpose because, for a number of years now, friends in the field have encouraged me to write an update. In the intervening years since the first edition the subject has grown enormously, and any idea of a single-author comprehensive volume would now be a preposterous under- taking. Consequently, I have concentrated attention on illustrating the principles of the subject, and especially those concerning highly fluorinated compounds, where the chemistry is quite unusual. Inevitably, important areas are omitted: for example the impact of fluorine as a label in biochemistry, which is outside my expertise. However, I hope that there are enough key references to important areas that I have neglected. Inevitably, my choice of illustrative examples is subjective and I apologise in advance for all the beautiful examples that have not been included. The considerable task of producing the manuscript would not have been completed without the continued help of a long-term friend and collaborator, Dr. John Hutchinson, to whom I am deeply indebted. Also, my sincere thanks to the Leverhulme Trust for an Emeritus Fellowship, during the tenure of which the book was written. Thanks also to my colleague, Dr Graham Sandford, for invaluable help and discussions, and to Dr Darren Holling, Rachel Slater and Chris Hargreaves for reading the manuscript. Last, but not least, thanks to my wife Anne for her continued forbearance. Dick Chambers

xvii Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 1

Chapter 1 General Discussion of Organic Fluorine Chemistry

I GENERAL INTRODUCTION One of the major activities of chemists in industry and academia is the search for ‘special- effect’ chemicals, i.e. systems with new chemistry and with novel properties that can be exploited by industry. There are, of course, many ways of creating novel systems but the introduction of carbon–fluorine bonds into organic compounds has led to spectacular industrial developments, together with an exciting field of organic chemistry and biochemistry. Fluorine is unique in that it is possible to replace hydrogen by fluorine in organic compounds without gross distortion of the geometry of the system but, surprisingly, compounds containing carbon–fluorine bonds are rare in nature [1, 2]. In principle, therefore, we could introduce carbon–fluorine bonds singly, or multiply, so that there is the potential for a vast extension to organic chemistry, providing that the appropriate methodology can be developed. Consequently, the study of systems containing carbon– fluorine bonds has become a very important area of research and the subject already constitutes a major branch of organic chemistry, while imposing a strenuous test on our fundamental theories and mechanisms. Moreover, as we shall see later in this chapter, the applications of fluorine-containing organic compounds span virtually the whole range of the chemical and life-science industries and it is quite clear that wherever organic chemistry, biochemistry and chemical industry progress, fluorine-containing compounds will have an important role to play. Surprisingly, this situation is still not reflected in current general textbooks; the reasons can be traced partly to the very rapid growth of the subject, as well as the difficulty that all workers experience in reaching a wider audience. Therefore, it is hoped that this book will help by presenting an outline of fluorine chemistry on a broadly mechanistic basis. This volume stems from an earlier book [3] on the subject; its aim remains to provide an overview through highlighting a variety of topics but with no attempt to provide comprehensive coverage of the literature. Where appropriate, books and reviews will be cited and the author therefore acknowledges the many sources, referred to either here or in the following text, to which this book is intended to be complementary [4–39].

A Properties Fluorocarbon systems, in general, present no peculiar handling difficulties and the familiar and powerful techniques of isolation, purification and identification in organic

2 Chapter 1 chemistry are applicable in every way. In fact, fluorocarbons themselves are characterised by high thermal stability and, indeed, elemental fluorine is so very reactive because it forms such strong bonds with other elements, including carbon. Volatilities of hydrocarbons and corresponding fluorocarbons are surprisingly similar, despite the increased molecular weight of the latter, and indicate a general feature that intermolecular bonding forces are reduced in the perfluorocarbon systems. A final, and by no means least important, similarity between hydrocarbon and fluorocarbon chemistry is that, like hydrogen-1, fluorine-19 has a nuclear spin quantum number of 1/2 and so nuclear magnetic resonance spectroscopy plays a powerful role in characterisation [40]. Indeed, the only tool that is not easily available for fluorine is the observation of fluorine isotope effects, because the longest-lived isotope is F-18, with a half-life of only 109 minutes [41] although, even with this limitation, applications as a mechanistic probe have been reported [42].

B Historical development It could be argued that fluorocarbon chemistry began with Moissan in 1890 when he claimed to have isolated tetrafluoromethane from the reaction of fluorine with carbon, but these results were in error [43, 44]. Swarts, a Belgian chemist, began his studies on the preparation of fluorocarbon compounds [45] by exchange reactions around 1890 and for about 25 years from 1900 he was virtually the only worker publishing in the field. He continued until about 1938, and during that time he contributed a great deal in outlining methods of preparation for a large number of partly fluorinated compounds. It was on the foundation of Swarts’s work that Midgley and Henne [46] in 1930 were able to apply fluoromethanes and ethanes as refrigerants, and this development gave the subject some financial impetus for progress. Tetrafluoromethane was the first perfluorocarbon to be isolated pure; it was reported in 1926 by Lebeau and Damiens [47] but not properly characterised by them until 1930 [48] and, in the same year, by Ruff and Keim [49]. Swarts made trifluoroacetic acid [50] as early as 1922 and in 1931 reported that the electrolysis of an aqueous solution of the latter gave pure perfluoroethane [51]. Nevertheless, the first liquid perfluorocarbons were not characterised until 1937, when Simons and Block found that mercury promotes reaction between carbon and fluorine [52]; they were able to isolate CF4,C2F6,C3F8,C4F10 (two isomers), cyclo-C6F12 and C6F14. It was established that these compounds are very thermally and chemically stable and this led to suggestions by Simons that these materials might be resistant to UF6, which was found to be the case. There then ensued a period of very rapid development in the synthesis of fluorocarbon materials, the goal being stable lubricants and gaskets for use in 235 the gaseous diffusion plant for concentrating the U isotope, using UF6. These wartime developments have been published in various collected forms [53–55]. Tetrafluoroethene was obtained by Ruff and Bretschneider in 1933, who decomposed tetrafluoromethane in an electric arc [56] while Locke et al. [57] developed a synthesis in 1934, which involved zinc dehalogenation of CF2Cl2CF2Cl. Then the formation of polytetrafluoroethene [58] was discovered in 1938 and in the same period chlorotrifluoroethene was found to polymerise to give a very stable inert transparent polymer. The wartime efforts involved development of these and other new materials. Nevertheless, even at the end of the Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 3

General Discussion of Organic Fluorine Chemistry 3 wartime work the subject was not well developed as an area of organic chemistry. However, its potential was recognised by a number of workers and, since then, progress has been extremely rapid. In the 1950s much progress was made on the chemistry of functional derivatives and a whole new fluorocarbon organometallic chemistry began to emerge. A major and greatly under-appreciated development of the period was the introduction of fluorinated anaesthetics which, being non-flammable, revolutionised anaesthesia. Also during this period was the development of fluorinated elastomers which, together with other fluorinated materials, were critical in the development of supersonic and space flight. It is clear, therefore, that this infant subject made crucial contributions to some of the most exciting scientific developments of the 20th century. The period from 1960 onwards saw perfluoroaromatic chemistry rapidly unfold, selective methods for fluorination develop, and fluorinated compounds play an increasingly important role in the pharmaceutical and plant-protection industries. Indeed, there have been so many interesting developments in the subject since the original edition [3] that it will be impossible to do justice to this era in one small volume. Remarkably, it has been reported that organofluorine compounds constitute 6–7% of all new compounds recorded in Chemical Abstracts up to 1990 and 7–8% of all chemical patents up to 1997 contain fluorinated compounds. This in itself is an outstanding output for the relatively limited number of workers in the field worldwide and is a tribute to their dedication [59].

II INDUSTRIAL APPLICATIONS A Introduction Even in 1992, it was estimated that business involving the sale of compounds containing carbon–fluorine bonds was worth around US$50 billion per annum [60] and it has certainly increased since then. In this chapter, only a short survey of the major industrial applications of fluorinated molecules is possible and the reader is directed to a number of books and reviews [17, 20, 29, 61–65] for further details.

B Compounds and materials of high thermal and chemical stability [29] The greater strength of the carbon–fluorine over the carbon–hydrogen bond leads to considerably enhanced thermal stability for perfluorocarbon systems over their hydrocarbon analogues, and stability towards oxidation is dramatic. Moreover, the large number of non-bonding p-electrons, which virtually shield the carbon backbone from attack in a perfluorocarbon, must contribute significantly to these properties and, at the same time, produce novel surface effects. Furthermore, perfluorinated systems are quite inert to microbiological attack and so, combining these observations, it is reasonable to conclude that perfluorocarbon surfaces provide the ultimate in organic materials for protection against chemical and atmospheric corrosion. A further unique property of perfluorocarbons is that they are both water- and hydrocarbon-repellent and the implications for fabric treatment are obvious. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 4

4 Chapter 1

1 Inert fluids The chlorofluorocarbons (CFCs) were introduced over 60 years ago as refrigerants [46] to replace gases such as ammonia and sulphur dioxide. In 1974, at the peak of production, 900 000 tonnes of CFCs, principally CF2Cl2 (CFC-12), CFCl3 (CFC-11) and CHFCl2 (CFC-22), were manufactured mainly for use as refrigerants, aerosols and foam blowing agents. However, it was eventually recognised that the inertness of volatile CFCs is itself a problem because they survive unchanged up to the stratosphere, where they dissociate under short-wavelength solar ultraviolet radiation, releasing chlorine atoms which then catalyse the decomposition of ozone to oxygen [66, 67]. Consequently, the Montreal Protocol, which was introduced in 1987 and revised in 1990 and 1992, caused the complete phase-out of production and use of the CFC range of compounds. This legislation forced refrigerant manufacturers to identify alternative ranges of non-toxic, stable chemicals which, additionally, possess low ozone depletion potentials (ODPs) and low global warming potentials (GWPs) to meet customer needs and regulatory requirements. Hydrofluorocarbons (HFCs), being free of chorine atoms, have ODPs of zero, making these products ideal systems for replacing CFCs. One of the major unsung achievements of the chemical industry has been the rapid development to large-scale production of these substitutes for CFCs; for example, CF3CFH2 (HFC-134a) is an acceptable substitute for CF2Cl2 (CFC-12) in refrigeration applications. Bromofluorocarbons possess outstanding fire-extinguishing ability: CF3Br has been used for automatic systems where the use of water is as potentially damaging as a fire, for instance in art galleries and in libraries, or in aircraft where highly efficient non-toxic agents are required. However, on an atom-to-atom basis bromine atoms are estimated to be 40 times more effective at destroying ozone than chlorine atoms, and therefore the Montreal Protocol required the complete phase-out of bromofluorocarbon use in 1994. Alternative ‘in-kind’ replacements [68] of these halon fire extinguishers are being developed and currently CHF3 (DuPont) and CF3CFHCF3 (Great Lakes), amongst others, are on the market [69], but at the time of writing the problem of finding replacements for bromofluorocarbons for application as fire-fighting agents in aircraft is largely unsolved. Perfluorocarbon fluids, such as the Flutect range (F2 Chemicals Ltd), find many uses in the electronics industry. For instance, the complete immersion of electronic components in a bath of perfluorocarbon fluid can efficiently cool overheated circuits and, by a similar process, the airtight packaging around highly valuable and sensitive equipment can be tested in complete safety for leaks. Since perfluorocarbons are inert to microbiological attack, many potential medical uses of these fluids have been investigated. The report by Clark in 1966 that perfluorocarbons can dissolve significant amounts of oxygen [70] prompted the exciting suggestion that such fluids could be used as ‘artificial blood’ [71] and the now-classic photograph of a rat breathing under liquid perfluorocarbon has been reproduced countless times. Perfluorocar- bons are immiscible with blood and do not dissolve the essential mineral nutrients required. Consequently, emulsions of perfluorocarbons with an aqueous buffer solution containing various surfactants have been formulated as potential blood substitutes. Although products have been approved and marketed, there is no commercially successful emulsion. The need to extend the liquid range of perfluorinated systems to very high molecular weights was satisfied by the important introduction of perfluoropolyethers (PFPEs) [72] Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 5

General Discussion of Organic Fluorine Chemistry 5 as high-boiling inert fluids, such as Krytoxt (DuPont), Fomblint (Ausimont) and Demnumt (Daikin), for use in demanding environments and for long-term reliability (Figure 1.1). These fluids have the longest liquid range known [73], remaining in fluid form from 1008 C to 3508 C and, consequently, are used for the lubrication of many diverse precision instruments, from the mechanisms of luxury watches to the moving parts of geostationary satellites and even for computer discs.

F CF3

O OCF2CF2CF2 OCF2 OCF2CF2 n nm F F n

Krytox® (DuPont) Demnum® (Daikin) Fomblin® (Ausimont)

Lubricants, coatings Lubricants, vacuum pump oils

Figure 1.1

2 Polymers [73a] Since the first synthesis of polychlorotrifluoroethene and the discovery of polytetrafluoroethene (PTFE) in the late 1930s, the global production of fluoropolymers has grown to over 60 000 tonnes per annum. Fluoropolymers possess a unique combination of properties [74–76] which ensure a wide range and continually growing number of applications for these materials. The fabled ‘non-stick’ properties of PTFE may be attributed to the abundance of non-bonding electron pairs and the coefficient of friction has been related to that of wet ice on wet ice. Some examples of commercial fluoropolymers are listed in Table 1.1 along with just some of the many applications. The remarkable feature of this area is that materials such as Vitont (DuPont) and related elastomers, which were once regarded as esoteric and appropriate in cost only for ‘space flight’ and related applications, have now entered widely into the automobile industry. Lumiflont (Asahi Glass Co., Japan), a high-performance paint which is fam- ously used on the Hikari ‘bullet trains’ in Japan, and various coatings for protection of concrete and stone building materials have also emerged. The gradual public realisation that the higher cost of high-performance products makes longer-term economic sense is the driving force behind the continued growth of this industry. Perfluorinated ionomer membranes [77], such as Nafiont (DuPont) and Flemiont (Daikin), are increasingly being used as cell-dividing membranes for chlor-alkali cells, replacing the mercury cells that have, understandably, led to so much public concern.

C Biological applications [29, 61, 62] The physiological properties of many biologically significant molecules can be modu- lated if fluorine or fluorinated groups are incorporated into their structure [24, 78]; factors affecting the change in biological activity of a substrate upon fluorination are complex [79]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 6

6 Chapter 1

Table 1.1 Applications of fluoropolymers

Polymer Monomer(s) Applications

PTFE CF2=CF2 Cookware coatings; Goretext (W.R. Gore Co.) waterproof clothing; electrical insulators; medical uses such as artificial blood vessels.

FEP CF2=CF2 + CF3CF=CF2 Fabrication by conventional melt processing; wire and cable insulators; heat-sealable film, tubing.

PFA CF2=CF2 + RFOCF=CF2 Injection-moulded parts for use in aggressive environments. FF Teflon AFt (DuPont) Optically clear, used in corrosive CF2=CF2+ OO environments where glass is unsuitable, e.g. in computer chip CF3 CF3 manufacture.

Cytopt (Asahi) CF2=CFO(CF2)nCF=CF2 Optically clear, used in corrosive environments, e.g. computer chip manufacture.

PCTFE CF2=CFCl Gaskets, seals, oils, coatings, transparent inert covers.

PVDF CF2=CH2 Weather-resistant coatings; cable insulation; piezo-electric devices. PVF CH2=CHF Coatings, flexible films. t VitonA (DuPont)CF2=CH2 + CF3CF=CF2 Elastomers used for sealants, O- rings, fuel-resistant seals for F aircraft and automobiles.

CF2 3 CF2ϭCF2 + F2CϭC Nafiont (DuPont) Membranes in chlor-alkali cells. (OCF2CF)nϪ O

Flemiont (Daikin) CF2CF2X

Nafion, X ¼ CO2H Flemion, X ¼ SO2H

1 Volatile anaesthetics Prior to 1956, the most common anaesthetics included diethyl ether and chloroethane, with the associated risks. Fluothanet (ICI) was the first widely used fluorine-containing volatile anaesthetic [80], and such was its success that it has been estimated that 70–80% of all anaesthesias carried out in 1980 were performed using this substance. However, Isofluranet, Sevofluranet and Desfluranet are now commercially available alternatives in the general quest for less readily metabolised systems and faster recovery times of the patients (Figure 1.2).

CF3CHClBr CF3CHClOCHF2 (CF3)2CHOCH2FCF3CHFOCHF2 Fluothane® Isoflurane® Sevoflurane® Desflurane®

Figure 1.2 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 7

General Discussion of Organic Fluorine Chemistry 7

2 Pharmaceuticals Fluorinated corticosteroids were the first successful commercial products where useful modification of biological activity was achieved by introduction of a carbon–fluorine bond. Subsequently, the interest of the pharmaceutical industry in this approach has grown substantially and many new fluorine-containing products are available or are in advanced screening stages. Simplistically, an orally administered drug must: (a) be absorbed through the gut into the bloodstream, (b) then pass through a series of phospholipid membranes (transport) before reaching the correct site of action, and (c) bind and produce the desired effect at the appropriate enzyme site. Following this stage, the drug should be metabolised neither too quickly, nor into toxic by-products. The incorporation of fluorine into a biologically active molecule may modulate all of these functions as well as the more obvious effects of enhancing the acidity or reducing the base strength of appropriate proximate functional groups. Size is not the dominant factor, although steric requirements in biology are not so easy to establish, and a range of factors arising from fluorine substitution are at work [81– 83] and will continue to be evaluated for some considerable time. Fluorine or trifluoromethyl substituents generally enhance the lipophilicity of an aromatic substrate and so increase the rate of transport of the drug to the active site. A contributing factor could be, for example, the change in acidity of the drug upon fluorination, thus enhancing the solubility. Whatever the relative importance of the contributing factors, introduction of a fluorine atom at the C-6 site in the antibacterial fluoroquinolone drugs, e.g. Ciproflaxint (Bayer), increases the rate of cell penetration by up to 70 times. Fluorine substitution in drugs may affect binding in two ways [61]. First, it is often possible to vary the dipole moment (e.g. using two fluorine substituents that are ortho, meta or para in a phenyl group); secondly, it is possible that fluorine may be displaced from the bound drug, leading to covalent binding, in a process referred to as ‘suicide inhibition’. The anti-metabolite 5-fluorouracil (5-FU) is almost certainly effective in part through this process. A further significant effect of introducing fluorine is the resulting enhanced resistance to metabolic oxidation and therefore to potentially toxic by-products, thus increasing both the effective lifetime and the safety of a drug. Some examples of fluorinated pharmaceuticals currently on the healthcare market are given in Figure 1.3. Both Ciprofloxacint (Bayer), a member of the 6-fluoroquinolone antibacterial agent range, and the controversial ‘sunshine drug’ Prozact (Eli Lilley), the leading member of a new family of selective serotonin re-uptake inhibitor (SSRI) antidepressants, are in the world top 20 best-selling pharmaceuticals and achieve annual sales in the region of US$1 billion each.

3 Imaging techniques The isotope fluorine-18 has a half-life of 109 minutes and decays by positron emission; therefore molecules containing this isotope can be monitored by positron emission tomography (PET), which is a technique that is especially useful for non-invasive in vivo study of metabolic processes [41]. For example, 2-fluorodeoxyglucose is transported into cells in the same manner as glucose but, after rapid phosphorylation, further metabolism is inhibited because of the fluorine, thus effectively trapping the radiolabelled Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 8

8 Chapter 1

O H CF3 N H F N O N O O N HO H

5-Fluorouracil OH (anti-cancer) Trifluridine® (anti-viral)

N N OH N O N N N F CO2H

F N N N H F Fluconazole® Ciprofloxacin® (anti-fungal) (antibacterial)

O CH OH H 2 OH ON HO CH3 CH3

F C 3 F O

Prozac® Betamethasone® (anti-depressant) (anti-inflammatory)

Figure 1.3 Examples of drugs containing fluorine molecule in a cell. Uptake of fluorine-18 gives a direct measure of the rate of glucose metabolism in the part of the body under study. Similarly, 18F-DOPA acts as a tracer for DOPA, which is a neurotransmitter in the brain, and the PET study of the complex metabolism and biodistribution of DOPA is hoped to provide a quantitative measure of the dopaminergic neurons in the brain [84] (Figure 1.4). Non-invasive monitoring of therapeutic agents can also be performed by 19F magnetic resonance imaging (MRI); the negligible natural fluorine background and the high sensitivity of 19F NMR spectroscopy has made possible the study of the in vivo action and metabolic pathways of fluorine-containing drugs. For instance, 19F MRI has demonstrated that 5-fluorouracil is metabolised to NH2CH2CHFCOOH. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 9

General Discussion of Organic Fluorine Chemistry 9

HO F CO2H O HO OH NH2 HO HO F OH 18F-2-Fluorodeoxyglucose 18F-6-Fluoro-DOPA (PET Scanning Agent) (NMR Scanning Agent)

Figure 1.4 Perfluorooctyl bromide is being used very successfully to enhance the contrast between healthy and diseased tissue in 1H MRI procedures and as a general imaging agent for X-ray and other forms of examination of soft tissue.

4 Plant protection agents [62] Environmental concerns have imposed massive constraints on plant protection products, and the impressive progress towards lower dose levels for effective control is another of the unrecognised success stories of the chemical industry. Fluorinated molecules have played an important role in these developments, leading to a range of successful herbi- cides, insecticides and fungicides [85]. Trifluralin (Dow), a herbicide used principally for the control of grassy weeds in a wide range of crops, has been in use for over 25 years and peak sales in the mid 1980s reached US$400 million per annum. Fusiladet is another widely successful herbicide used for the control of weeds in broad-leaf crops at low dosage rates. The pyrethroid derivative Cyhalothrint is a successful insecticide and the fungicide sector contains five significant products with fluorine incorporated in the substrate. Flutriafolt is used for protecting cereal crops and Flutolanilt is used mainly in the Far East for controlling crop diseases (Figure 1.5).

D Biotransformations of fluorinated compounds As the occurrence of fluoride ion is so widespread, it is particularly surprising that compounds containing carbon–fluorine bonds are rarely found in nature [1, 2]. Potassium monofluoroacetate occurs in several tropical and sub-tropical plants located in the southern hemisphere, such as Dichapetalum cymosum (South Africa, very toxic to animals) and Oxylobium parviform (Australia). Some plants, such as soya bean (Glycine max), are able to synthesise fluoroacetate when grown in fluoride-rich soil. A shrub occurring in Sierra Leone, Dichapetalum toxicarium (ratsbane), is also poisonous, particularly the seeds, and this has been attributed to the occurrence of v-fluoro-oleic acid,

CH2FðCH2Þ7CH5CHðCH2Þ7COOH [86]. Nucleocidin, an adenine-containing antibiotic, has been isolated from the fermentation broths of a micro-organism Streptomyces calvus [1]. The fact that only 12 compounds containing C–F bonds have been found in nature so far [87] leads to the questions of (a) whether this is a consequence of the difficulty of forming C–F bonds in the first place, and (b) whether subsequent enzymic transformations in plants and animals are inhibited by the presence of C–F bonds. Fluorine, as fluoride ion, although extremely abundant, is present in largely insoluble salts. Moreover, fluoride ion is extensively hydrated because of the strength of hydrogen bonding, and in Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 10

10 Chapter 1

n N Pr2 O O2N NO2 F C O 3 OnBu Me N O CF3

Trifluralin® Fusilade® OCN O F3C O

Cyhalothrin®

F CF3 O

i N F N O Pr NN H

Flutriafol® Flutolanil®

Figure 1.5 Examples of plant-protecting agents containing fluorine the hydrated state it is relatively unreactive as a nucleophile. It seems likely, therefore, that the dearth of C–F bonds in nature is essentially due to a combination of these effects, which inhibit C–F bond formation. However, an exception to this situation is the formation of the toxin fluoroacetate, which inhibits the Krebs cycle. Moreover, O’Hagan and co-workers have successfully identified the first fluorinase enzyme, in the bacterium Streptomyces cattleya, which catalyses the formation of a C–F bond [88] (Figure 1.6). These results then raise the issue of how the fluoride becomes an active nucleophile in this system: at this stage, the most likely scenario is that fluoride ion is drawn into lipophilic sites on the enzyme and effectively de-solvated, to make it more reactive. Exciting prospects for the future are indicated by the identification of this fluorinase system [88]. In contrast, there are now many examples in the literature to indicate that, when presented with organic compounds already labelled with fluorine, enzymes may be tolerant to the presence of fluorine, depending on the number of C–F bonds and their location [89, 90]. For example, baker’s yeast may lead to significant asymmetric reduction of carbonyl (Figure 1.7). Likewise, various kinetic resolutions of fluorinated compounds have been achieved, e.g. the acetate of 1,1,1-trifluoro-2-octanol has been transformed into (R)-1,1,1-trifluoro- 2-octanol (Figure 1.8). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 11

General Discussion of Organic Fluorine Chemistry 11

− + O H3N NH NH ½88 O 2 2 N − N N F N Fluorinase F N Me S+ N N N O O

HO OH HO OH

S-adenosylmethionine 5'-FDA

O O + OH NAD H F F

Fluoroacetate Fluoroacetaldehyde

Figure 1.6

OH ½89 CH2FCOPh 58%

FH2C Ph

R (90% ee)

Figure 1.7

OCOMe OH OCOMe ½89 Lipase MY

F3CCH2CO2Et F3CCH2CO2Et F3CCH2CO2Et

(R) 96% ee

Figure 1.8

The use of CHF [91] and CF2 [92] groups as oxygen mimics has been explored and fluoromethylenephosphonates, as phosphate mimics [93], have been employed as binding agents for a promising approach to catalytic antibodies [94] although inevitably these sites must be more sterically demanding than oxygen. Of course a fluorine atom itself is isoelectronic with an oxygen anion and, not surprisingly, fluorinated carbohydrates have been widely explored [22, 95], as have fluorinated amino-acids and peptides [31, 96]. Indeed, fluorine is advocated as a tool for exploring the conformations of amides and peptides [97]. The presence of fluorine, with the opportunity of observation by 19F NMR, free from the often complex 1H signals, can be an extremely useful probe. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 12

12 Chapter 1

It should be clear from this cursory discussion, and the publications referred to, that the roles of fluorine in drug design and in applications to biochemistry are very large and burgeoning topics that are hugely important.

E Applications of unique properties 1 Surfactants [29] The low surface energy possessed by highly fluorinated compounds has allowed the development of fluorine-containing surfactants that are especially effective in very low concentrations [98–100]. Surfactants based on straight fluorocarbon chains are the most efficient known, and a terminal trifluoromethyl group is essential to this efficiency. Fluorinated surfactants are used in fire-fighting foams, as emulsifiers for polymerisations and as additives to paints. Cationic, anionic and non-ionic surfactants containing perfluorinated groups have been marketed; examples of each are given in Figure 1.9.

F3CCF3

F3C O C8F17SO2NH(CH2)3NMe3 I C2F5 C2F5 SO3 Na Cationic Anionic

C8F17CH2CH2O(CH2CH2O)nH

Non-ionic

Figure 1.9 Fluorinated surfactants

2 Textile treatments [29] Polyacrylates bearing pendant perfluoroalkyl groups are extremely difficult to wet, due to the very low surface energy of the partially fluorinated polymer. When surfaces of materials are coated with such polymers, their oil and water repellencies are greatly enhanced and this has been used to great effect in the textile-finishing area. Products such as Zepelt (DuPont) are used for coating fabrics, as furniture sprays, and as carpet and leather finishing agents. However, the highly successful Scotchgardt (3M) was removed from the marketplace following concerns about the appearance of perfluoro-octyl sulphonic acid in various blood samples, albeit in extremely low concentrations. How- ever, the extreme stability of the acid could lead to a build-up in biological systems. Techniques for plasma polymerisation have been progressed significantly in recent years [101] and direct formation of fluorocarbon coatings on surfaces, including textiles, holds much promise.

3 Dyes [29] Fibre-reactive dyes are water-soluble dyes containing a chromophore that is attached to a reactive group which then may be attacked by fibres containing nucleophiles to form a Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 13

General Discussion of Organic Fluorine Chemistry 13 dye–fibre bond. Fluorinated heterocycles, such as pyrimidines or triazines, are the most widely used ‘carrier systems’ for dye chromophores since the fluorine on the heterocyclic ring may be attacked by hydroxyl groups on the cellulose or cotton fibre surface, as outlined below (Figure 1.10) (see Chapter 9 for a discussion of nucleophilic aromatic

NH-Dye NH-Dye

Cl Cl Cl N Dye-NH2 N Cotton-OH N F F F N N Cotton O N

Figure 1.10 substitution of fluorine). The incorporation of trifluoromethyl groups into a chromophore can give the dye increased light fastness and improved clarity. A similar approach to conferring oil-repellency on cellulose surfaces has been described using perfluoro(isopropyl-s-triazine)s [102]. For various reasons, the superior properties of most liquid-crystalline materials contained in LCD displays depend critically on the presence of fluorinated substructures [103]. In particular, perfluorinated groups have displaced cyano groups for their role in inducing polarity.

III ELECTRONIC EFFECTS IN FLUOROCARBON SYSTEMS The electronic properties and size of fluorine relative to hydrogen and chlorine are set out in Table 1.2; at this point it is worthwhile to examine some of the possible consequences of these differences for the chemistry of fluorocarbon systems. In this way it can be emphasised, at the outset, how far-reaching these effects will be and, at the same time, it sets the scene for a rational approach to the chemistry. First, the large ionisation energy of fluorine implies that species involving electron- deficient fluorine might be less common than those involving hydrogen or chlorine. The ionisation energy of chlorine is, in fact, less than that of hydrogen and chloronium ions

Table 1.2 Electronic properties

H F Cl Ref.

Electronic configuration 1s1 ...2s22p5 ...3s23p53d0 – Electronegativity (Pauling)ÀÁ 2.20 3.98 3.16 [104] a Ionisation energyÀÁ kJmol1 1312 1681 1251 [104] Electron affinity kJmol1 b 74.0 332.6 348.5 [104] Bond energiesÀÁ of C2Xin 446.4 546.0 305.0 [19] 1 CX4 kJmol BondÀÁ energies of X2X 434 157 242 [105] kJmol1 Bond lengths of C2Xc (A˚ ) 1.091 1.319 1.767 [19] van der Waals radius (A˚ ) 1.20 1.47 1.75 [104] Preference as a leaving group Hþ F Cl – a Xþ þ e ! X b X þ e ! X c Covalent radii in CX4 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 14

14 Chapter 1

2Clþ2 (as well as 2Brþ2 or 2Iþ2) are now well established [106], whereas the analogous fluoronium species 2Fþ2 have not been observed. It is particularly interesting that the electron affinity of fluorine is actually less than that of chlorine because, here, we have the first indication of repulsion between unshared electron pairs raising the energy of the system, and it is likely that this factor accounts for the lower bond strength of F2F than Cl2Cl bonds; it will become apparent that electron-pair repulsions are very important in fluorocarbon chemistry. Overall we can expect profound differences between hydrocarbon and fluorocarbon systems arising from, in particular: (a) electronegativity differences, (b) the existence of unshared electron pairs associated with fluorine, (c) the tendency for displacement of fluorine as F from unsaturated fluorocarbons, (d) the higher bond strength of C2F than C2H and, to a lesser extent, (e) the larger size of fluorine than hydrogen [107]. Differences between fluorocarbon and chlorocarbon systems are likely to be influenced by (a) the larger steric requirements of chlorine, (b) the lower bond strength of C2Cl than C2F, and (c) the greater availability of 3d orbitals of chlorine. We can now outline, in a collective fashion, some electronic effects of fluorine that act, or have been suggested to act, in a fluorocarbon system but no attempt is made to discuss the detail of these effects at this point.

A Saturated systems (1) Inductive (through s-bonds) and field (through space) effects arise from a highly polar bond (Is), resulting in electron withdrawal to fluorine (Figure 1.11).

d + d CF

Figure 1.11 (2) ‘Double bond–no bond resonance’ (and equivalent molecular orbital descriptions) has been suggested to be involved (R) (Figure 1.12).

FFC F CF

Figure 1.12 This may be described in molecular orbital terms as interaction of s-electrons in C2F with low-lying s-orbitals in the other C2F bonds.

B Unsaturated systems

(1) Inductive (Is) effects act as in saturated systems. (2) Inductive and field effects result in the polarisation of p-electrons (Ip) (Figure 1.13).

F d -d + CC

Figure 1.13 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 15

General Discussion of Organic Fluorine Chemistry 15

(3) Coulombic or Pauli repulsion occurs between electron pairs on fluorine and p-electrons (þIp) (Figure 1.14).

F δ+ δ− CC

Figure 1.14 Thus, there is a dichotomy in behaviour of fluorine because effects 1 and 2 lead to electron withdrawal whereas 3 leads to return of electron density from fluorine. (4) ‘No-bond resonance’ (R) is illustrated in Figure 1.15.

CF3 F C CCϭ FCCϭ F

Figure 1.15

C Positively charged species

(1) Inductive electron withdrawal (Is) would tend to destabilise a carbocation (Figure 1.16).

CCF C F

1.16A 1.16B

Figure 1.16 (2) Mesomeric interaction (þM) of an unshared pair with the empty orbital on carbon, if operating, would lead to stabilisation (Figure 1.17).

+ + C F CF

1.17A

Figure 1.17 Later discussion will show that fluorine directly attached to a carbocation centre, as in 1.16A and 1.17A, overall is clearly a stabilising influence, but the effect of fluorine more remote from the centre, as in 1.16B, is strongly destabilising.

D Negatively charged species

(1) Inductive electron withdrawal (Is) would lead to stabilisation (Figure 1.18).

CCCF F

1.18A 1.18B

Figure 1.18 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 16

16 Chapter 1

(2) Repulsion between adjacent electron pairs (þIp) would be destabilising (Figure 1.19).

1.19A

Figure 1.19 It will become apparent that fluorine not directly attached to the carbanionic carbon 1.18B is strongly stabilising but, when directly attached as in 1.18A and 1.19A, it has either a moderate stabilising effect compared with hydrogen, or it definitely destabilises, depending on the stereochemistry of the carbanion. (3) A ‘negative hyperconjugation’ has been proposed (Figure 1.20). F F CCFCCϭ F F F

Figure 1.20 Again, in MO terms, this would be described as interaction of the filled p-orbital on carbon with s-orbitals associated with C2F bonds.

E Free radicals

(1) Inductive electron withdrawal (Is) will affect the polar characteristics, and hence reactivity, of a radical (Figure 1.21).

d + d - C F

Figure 1.21

(2) All substituents replacing hydrogen should lower the potential energy of a free radical; this may be represented as a resonance stabilisation (Figure 1.22).

CF CF

Figure 1.22 Even from the foregoing crude but useful generalisations, it will be appreciated how unusual the chemistry of fluorocarbon compounds is.

IV NOMENCLATURE [108, 109] The nomenclature of fluorocarbon derivatives is based on regarding them as derivatives of the corresponding hydrocarbon compounds. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 17

General Discussion of Organic Fluorine Chemistry 17

A Systems of nomenclature The number of fluorine atoms is indicated in the name and the positions are indicated by numerals or Greek letters according to normal conventions, for example as in Figure 1.23. FF

CF3 O

CF3 FF Hexafluoroacetone 1,1,4,4-Tetrafluorocyclohexane

Figure 1.23 To avoid cumbersome use of numbers, when the number of hydrogen atoms in a molecule is four or less and the ratio of hydrogen to halogen atoms is not more than 1:3, then the position of the hydrogen atoms is designated, for example, as in Figure 1.24.

CF3CFHCF3 2H-heptafluoropropane

CHClFCF2CF3 1H-1-chlorohexafluoropropane

Figure 1.24 Another system frequently used involves adding a prefix ‘perfluoro’ before the name of the corresponding hydrocarbon analogue. This indicates that all hydrogen atoms that are not part of a recognised functional group are replaced by fluorine, for example as in Figure 1.25.

CF3

F (CF ) C-OH 3 3 F N

Perfluorocyclobutane Perfluoro-t-butanol Perfluoro(4-methylpyridine)

Figure 1.25 For cyclic systems, a capital F in the centre of the ring is used frequently to denote that all unmarked bonds are to fluorine, for example as in Figure 1.26.

F Perfluorocyclohexane

Figure 1.26 There are ambiguities and limitations to the use of the ‘perfluoro’ prefix; it should not be used for some substituted derivatives, for example see Figure 1.27.

F 1,2-dichlorohexafluorocyclobutane

Figure 1.27 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 18

18 Chapter 1

A simple method for indicating the geometry of stereoisomers is indicated in Figure 1.28.

H H F F

H H

1H, 2H / - perfluorocyclohexane 1H, / 2H - perfluorocyclohexane

Figure 1.28 For highly fluorinated systems the ‘perfluoro’ system is often much less cumbersome and immediately more meaningful than the numerical system and, for this reason, it will often be used in this book. Both systems can be used, together with parentheses, to refer to individual groups (Figure 1.29).

C6H5CF2CF2CF2CF2CF3 (Perfluoro-n-pentyl)benzene

C6H5CF2CF2CFHCF2CF3 (3H-decafluoro-n-pentyl)benzene

Figure 1.29

In many cases, the abbreviations RF and ArF are used to represent perfluoroalkyl and perfluoroaryl groups respectively. A further system of nomenclature has been authorised by the ACS, whereby a capital F preceding the name of a substrate indicates perfluorination, for example as in Figure 1.30.

CF3CF2COOH F-propanoic acid F F-benzene

Figure 1.30

B Haloalkanes [109] A perverse system of nomenclature exists for the CFC, HCFC and HFC groups of compounds and, whatever objections to it may be made, it seems to be here to stay. Therefore, to avoid much frustration it is advisable to become acquainted with the rules. A series of three numbers are used (or two if the first is zero) that indicate, in order, the following: Number of carbon atoms minus one (C 1) Number of hydrogen atoms plus one (H þ 1) Number of fluorine atoms (F) Chlorine atoms are not included and, for bromine derivatives, B is added, followed by the number of bromine atoms. Also, a cyclic system has the numbers prefixed by C, for example: Tetrachlorodifluoroethane C2Cl4F2 112 Trichlorofluoromethane CCl3F11 Perfluorocyclobutane C4F8 C318 Dibromodifluoromethane CBr2F2 12B2 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 19

General Discussion of Organic Fluorine Chemistry 19

For positional isomers, the deviation from symmetrical fluorine substitution is denoted by a letter, for example: CF2H2CF2H 134 CF32CFH2 134a

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27 G.A. Olah, R.D. Chambers and G.K.S. Prakash (eds), Synthetic Fluorine Chemistry, Wiley-Interscience, New York, 1992. 28 M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd revised edition, Ellis Horwood, Chichester, 1992. 29 R.E. Banks, B.E. Smart and J.C. Tatlow (eds), Organofluorine Chemistry. Principles and Commercial Applications, Plenum, New York, 1994. 30 T. Hayashi and V.A. Soloshonok, Tetrahedron: Asymm., 1994, 5, 955. 31 V.P. Kukhar and V.A. Soloshonok, Fluorine-containing Amino Acids, John Wiley and Sons, New York, 1995. 32 M. Hudlicky and A.E. Pavlath (eds), Chemistry of Organic Fluorine Compounds II, American Chemical Society, Washington DC, 1995. 33 T.L. Gilchrist (ed.), Comprehensive Organic Functional Group Transformations, Vol. 6, Elsevier Science, Oxford, 1995. 34 B.E. Smart, Chem. Rev., 1996, 96, 1555. 35 G. Resnati and V.A. Soloshonok, Tetrahedron, 1996, 52, 1. 36 B. Baasner, H. Hegemann and J.C. Tatlow (eds), Houben-Weyl: Methods of Organic Chemis- try, Vols E10a–E10c, Organo-fluorine Compounds, Georg Thieme, Stuttgart, 1999. 37 J.H. Clark, D. Wails, and T.W. Bastock, Aromatic Fluorination, CRC Press, Boca Raton, 1996. 38 R.D. Chambers (ed.), Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermedi- ates, Springer-Verlag, Berlin, 1997. 39 R.D. Chambers (ed.), Organofluorine Chemistry: Techniques and Synthons, Springer-Verlag, Berlin, 1997. 40 W.S. Brey and M.L. Brey in Fluorine-19 NMR, ed. D.M. Grant and R.K. Harris, John Wiley and Sons, New York, 1996, p. 2063. 41 M.R. Kilbourn, Fluorine-18 Labeling of Radiopharmaceuticals, National Academy Press, Washington DC, 1990. 42 O. Matsson, S. Axelsson, A. Hussenius and P. Ryberg, Acta. Chem. Scand., 1999, 53, 670. 43 H. Moissan, Compt. Rend., 1890, 110, 276. 44 H. Moissan, Le Fluor et ses Compose´s, Steinheil, Paris, 1900. 45 F. Swarts, Bull. Acad. Roy. Belg., 1892, 24, 474. 46 T. Midgley and A.L. Henne, Ind. Eng. Chem., 1930, 22, 542. 47 P. Lebeau and A. Damiens, Compt. Rend., 1926, 182, 1340. 48 P. Lebeau and A. Damiens, Compt. Rend., 1930, 191, 939. 49 O. Ruff and R. Keim, Z. Anorg. Allg. Chem., 1930, 192, 249. 50 F. Swarts, Bull. Acad. Roy. Belg., 1922, 8, 343. 51 F. Swarts, Bull. Acad. Roy. Belg., 1931, 17, 27. 52 J.H. Simons and L.P. Block, J. Am. Chem. Soc., 1937, 59, 1407. 53 J.H. Simons (ed.), Fluorine Chemistry, Vol. 1, Academic Press, New York, 1950. 54 J.H. Simons (ed.), Fluorine Chemistry, Vol. 2, Academic Press, New York, 1954. 55 C. Slesser and S.R. Schram (eds), Preparation, Properties and Technology of Fluorine and Organic Fluoro Compounds, McGraw-Hill, New York, 1951. 56 O. Ruff and O. Bretschneider, Z. Anorg. Allg. Chem., 1933, 210, 173. 57 E.G. Locke, W.R. Brode and A.L. Henne, J. Am. Chem. Soc., 1934, 56, 1726. 58 R.J. Plunkett, US Pat. 2 230 654 (1941); Chem. Abstr., 1941, 35, 3365. 59 H. Schofield, J. Fluorine Chem., 1999, 100, 7. 60 S. Rozen in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley, New York, 1992, p. 143. 61 R.E. Banks and K.C. Lowe, Fluorine in Medicine in the 21st Century, UMIST Chemserve, Manchester, 1994. 62 R.E. Banks, Fluorine in Agriculture, Fluorine Technology Ltd, Manchester, 1994. 63 R.E. Banks, Fluorocarbons and their Derivatives, MacDonald, London, 1970. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 21

General Discussion of Organic Fluorine Chemistry 21

64 R.L. Powell in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 59. 65 M. Silvester, Speciality Chemicals, 1991, 392. 66 M.J. Molina, Angew. Chem., Int. Ed. Engl., 1996, 35, 1778. 67 F.S. Rowland, Angew. Chem., Int. Ed. Engl., 1996, 35, 1786. 68 C.S. Todd, The Use of Halons in the United Kingdom and the Scope for Substitution, HMSO, London, 1991. 69 R.E. Banks, J. Fluorine Chem., 1994, 67, 193. 70 L.C. Clark and F. Gollan, Science, 1966, 152, 1755. 71 J.G. Riess, Chem. Rev., 2001, 101, 2797. 72 R.M. Flynn in Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11, ed. M. Howe- Grant, John Wiley and Sons, New York, 1994, p. 525. 73 R.J. Lagow, T.R. Bierschenk, T.J. Juhlke and H. Kawa in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 97. 73a G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999. 74 D.P. Carlson and W. Schmeigel in Ullmanns Encyclopedia of Industrial Chemistry, Vol. A11, VCH Publishers, Weinheim, 1988, p. 393. 75 R.F. Brady, Chem. Britain, 1990, 26, 427. 76 C.A. Sperati in Properties of Fluoropolymers, ed. J. Brandrup and E.H. Immergut, Wiley, New York, 1975. 77 A. Eisenberg and H.L. Yeager, Perfluorinated Ionomer Membranes, American Chemical Society, Washington DC, 1982. 78 V.A. Soloshonok (ed.), Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, John Wiley and Sons, New York, 1999. 79 M. Schlosser in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 613. 80 D.F. Halpern in Anaesthetics Review, ed. R.E. Banks and K.C. Lowe, UMIST Chemserve, Manchester, 1994, Paper 15. 81 B.E. Smart, J. Fluorine Chem., 2001, 109, 3. 82 D. O’Hagan and H.S. Rzepa, J. Chem. Soc., Chem. Commun., 1997, 645. 83 D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320. 84 M.R. Kilbourn in Fluorine-18 in Nuclear Medicine, ed. R.E. Banks, UMIST Chemserve, Manchester, 1994. 85 S.B. Walker, Fluorine Compounds as Agrochemicals, Fluorochem Ltd, Glossop, 1989. 86 S.R.A. Peters and R.J. Hall, J. Biochem. Pharmacol., 1959, 2, 25. 87 D. O’Hagan and D.B. Harper, Nat. Prod. Rep., 1994, 11, 123. 88 D. O’Hagan, C. Schaffrath, S.L. Cobb, J.T.G. Hamilton and C.D. Murphy, Nature, 2002, 416, 279. 89 T. Kitazume and T. Yamazaki in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 91. 90 T. Fujisawa and M. Shimizu in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 307. 91 T.F. Herpin, W.B. Motherwell and M.J. Tozer, Tetrahedron: Asymm., 1994, 5, 2265. 92 D.M. LeGrand and S.M. Roberts, J. Chem. Soc., Chem. Commun., 1993, 1284. 93 D.B. Berkowitz and M. Bose, J. Fluorine Chem., 2001, 112, 13. 94 S. Cesaro-Tadic, D. Lagos, A. Honegger, J.H. Rickard, L.J. Partridge, G.M. Blackburn and A. Pluecktun, Nat. Biotechnol., 2003, 21, 679. 95 B. Novo and G. Resnati in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 349. 96 K. Uneyama in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 391. 97 C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D. Yufit, J. Fluorine Chem., 2003, 119, 9. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 22

22 Chapter 1

98 K. Shinoda, M. Hato and T. Hayaski, J. Phys. Chem., 1972, 76, 909. 99 H. Kuneida and K. Shinoda, J. Phys. Chem., 1976, 80, 2468. 100 W. Guo, T.A. Brown and B.M. Fung, J. Phys. Chem., 1991, 95, 1829. 101 J.P. Badyal, Chem. Britain, 2001, 37, 45. 102 R.D. Chambers, C. Magron, G. Sandford, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem., 1999, 97, 69. 103 P. Kirsch and M. Bremer, Angew. Chem., Int. Ed. Engl., 2000, 39, 4216. 104 B.E. Smart in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 57. 105 N.N. Greenwood and A. Earnshaw, Chemistry of the Elements, Pergamon, Oxford, 1989. 106 G.A. Olah, Halonium Ions, Wiley-Interscience, New York, 1975. 107 C.G. Beguin in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 601. 108 R.E. Banks and J.C. Tatlow in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 1. 109 R.E. Banks in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 12. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 23

Chapter 2 Preparation of Highly Fluorinated Compounds

I INTRODUCTION Two different approaches have been adopted here in describing fluorination reactions: the production of highly fluorinated systems is discussed in this chapter on the basis of a comparison of methods, whereas selective fluorinations are described in Chapter 3 in terms of the conversion of functional groups. If we wish to produce highly fluorinated systems, then the starting materials are usually hydrocarbons, polychloro compounds or, of course, highly fluorinated ‘building-blocks’ for conversion to other compounds.

A Source of fluorine Fluorine is widely distributed in nature [1] and it is estimated that, among the elements, fluorine is about thirteenth in abundance. Phosphate rock, which is processed on a multimillion-ton scale as raw material for the fertiliser industry, contains as much as 3.8% of fluorine and is a very rich source of the element. However, the fluorine recovered from this process as fluorosilicic acid is still not a commercially competitive source of fluorine compared with fluorspar (CaF2), although reserves of the latter are said to be limited and it is expected that use of fluoride in phosphate rocks will eventually be increased. For industry, the source of fluorine is essentially anhydrous hydrogen fluoride [2], which is made commercially by distillation (b.p. 19.58 C) from a mixture of fluorspar and concentrated sulphuric acid. The liquid fumes in air and great care must be taken to avoid its contact with the skin, otherwise unpleasant burns are obtained which are difficult to heal and often require a subcutaneous injection of calcium gluconate [3, 4]. Synthesis of highly fluorinated compounds, starting from hydrogen fluoride, is therefore achieved by a variety of techniques: directly by reaction of an organic compound with hydrogen fluoride or by electrolysing solutions of certain compounds in HF, or indirectly by reactions with elemental fluorine or with metallic fluorides (Figure 2.1).

II FLUORINATION WITH METAL FLUORIDES [5] There is a considerable literature [6–8] on this group of reactions, embracing an extremely wide variety of experimental conditions, and the patent literature abounds with reports of different ‘catalyst’ systems. It is possible to group some of these reactions partly on a basis of mechanism if some rather broad generalisations are made about the mechanistic pathways. The aim here is to assist in the choice of the type of reagent but it is not

24 Chapter 2

H2SO4 KF.2HF CaF2 anhydrous HF F2 m.p. ca. 100 C

Metal Fluorides Transition Metal Fluorides

Figure 2.1 intended to imply that detailed mechanisms are understood, nor should the classifications be regarded as rigid. There are three main groups, as described below.

A Swarts reaction and related processes (halogen exchange using HF) These reactions are based on hydrogen fluoride and involve, essentially, a nucleophilic displacement of halogen (for convenience, in the sense intended throughout this book, this term usually excludes fluorine). However, only the most reactive halides such as allylic and benzylic ones can be fluorinated by anhydrous HF alone [9] (Figure 2.2). HF, 40 C PhCF PhCCl3 3 70% ½9

HF, rt Ph3CCl Ph3CF 62%

CCl3 CF3 HF, catalyst 80% 300−500 C Cl N Cl N

Figure 2.2 Hydrogen fluoride acts both as a Friedel–Crafts catalyst and a fluorinating agent in a one-step preparation of trifluoromethylated aromatics [10] (Figure 2.3).

CF3 ½10 5hr, 100 C + CCl4 + HF 92%

Figure 2.3 Halogen exchange at less activated sites requires a Lewis acid catalyst and an important part of the function of the catalyst, usually a metal fluoride or a chromium species, is to assist the removal of halogen as halide ion. Therefore, these reactions could be considered to involve carbocationic intermediates (Figure 2.4).

F CCl + MFx C MFxCl CF

Figure 2.4 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 25

Preparation of Highly Fluorinated Compounds 25

It is more likely, however, that four-centre reactions occur since the metal fluorides can be used either alone or in catalytic amounts in the presence of anhydrous hydrogen fluoride. This latter process was developed by Swarts and it now usually bears his name (Figure 2.5).

Cl δ + δ − F CCl + MFx C MFx-1 CF

Figure 2.5

Generally, reactions performed in the liquid phase utilise hydrogen fluoride in combination with antimony fluoride catalysts and their efficiency stems from the greater strength of the bond from antimony to chlorine than to fluorine. Pentavalent antimony catalysts, such as SbF5 and SbF3Cl2, are more efficient than trivalent species because they are extremely strong Lewis acids. Carbocations are formed in the presence of antimony pentahalides and, indeed, one of the now-classic techniques developed by Olah and his co-workers for the generation of relatively stable carbocations involves the reaction of an organic halide with antimony pentafluoride, in solvents such as sulphur dioxide, at low temperature [11]. On the industrial scale, reactions are performed in the vapour phase and chromium(III)-based catalysts are extensively used in the production of hydrofluorocarbons (HFCs). In general, in this group of fluorination reactions, reactivities of the substrates and the nature of the products obtained can be accounted for in terms of the corresponding carbocation intermediates.

1 Haloalkanes For many years chlorofluorocarbons (CFCs) were manufactured in huge quantities by Swarts-type processes but, after the introduction of the Montreal Protocol legislation, these compounds were superseded by non-ozone depleting HFCs (see Chapter 1). Fortunately, much of the chemistry developed for the manufacture of the CFCs can be adapted for the production of HFCs [7, 12–15]. Generally, conversion of 2CCl3 groups to 2CFCl2 can be easily accomplished, reflecting both the stabilisation of the intermediate carbocations by chlorine and the relief in steric strain associated with replacement of chlorine by fluorine. Further fluorination of the 2CFCl2 group is possible but becomes progressively more difficult [3] due to the decrease in the donating ability of the chlorine. Fluorination of 2CFCl2 groups can also be achieved but RFCH2Cl moieties (where RF ¼ perfluoroalkyl) are generally very difficult to fluorinate due to the lower stability of the derived carbocation intermediates. These effects can all be seen in the two most important industrial routes to HFC-134a, now a leading refrigerant, in which chromium(III) catalysts are used in conjunction with HF for the halogen exchange steps [15] (Figure 2.6). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 26

26 Chapter 2

HF HF CCl2=CHCl CF2ClCClH2 ½15 CF3CH2Cl Cr(III) Cr(III)

CF3CH2F HFC 134a

HF AlCl3 CCl3-CCl3 CF ClCFCl CF CCl Cr(III) 2 2 3 3

Cr(III) HF

H2 / Pd

CF3CH2F CF3CFCl2 HFC 134a

Figure 2.6

2 Influence of substituent groups Groups such as alkyl [16] and aryl [17], double bonds [18], oxygen [19] and sulphur [20] (that are known to stabilise carbocations), when attached to the carbon centres that are undergoing halogen exchange, activate the process (Figure 2.7). i PhCCl2CCl3 PhCF2CCl3 + PhCFClCCl3 ½17 60% 6% i, SbF3 / SbCl5, 150 C

i CCl CClCCl 2 3 CF3CCl CCl2 + CF2ClCClCCl2 ½18

43% 28% i, SbF3, 150 C

i CH3CCl2CH3 CH3CF2CH3 + CH3CFClCH3 ½16

85% 10% i, SbF3 / SbCl5, rt

i CCl3CF2OCH3 84% ½19 CCl3CCl2OCH3

i, SbF3, reflux

i CF −S−CH CCl3 S CH3 3 3 73% ½20

i, SbF3 / SbCl5, 90 C

Figure 2.7 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 27

Preparation of Highly Fluorinated Compounds 27

In reactions with hexachlorobutadiene, 1,4-addition of chlorine precedes fluorination and the product arises from exchange at the two reactive allylic trihalomethyl groups [21]. Perchlorocyclopentene [22] and hexachlorobenzene [23] are also extensively fluorinated by this procedure (Figure 2.8). SbF3Cl2 Cl2C CClCCl=CCl2 CCl3CClCClCCl3 ½21

CF3CClCClCF3 + CF3CClCFCF3

SbF , SbF Cl Cl 3 3 2 Cl F 72% ½22

Cl Cl Cl ½23 SbF5, 160 C Cl F + F Cl Cl 30% 20%

Figure 2.8 The fluorination of hexachloroacetone by HF over chromia catalysts at high temperature is an efficient process for the synthesis of hexafluoroacetone [20] (Figure 2.9). O O HF, 350 C ½20 Cl3C CCl3 Chromia cat. F3CCF3

Figure 2.9 In addition to the antimony fluorides, silver, mercury, thallium, aluminium, zinc, zirconium, chromium and other fluorides [7] such as mercury(II) fluoride, vanadium pentafluoride [24] and various transition metal oxide fluorides [25] have been used in exchange processes, although much less widely.

B Alkali metal fluorides (see also Chapter 3, Section IIB) [26] This second group of reactions is related to the first in that nucleophilic displacement of a halide ion is involved, but here Lewis acid assistance by the metal fluoride is not a prime factor. Therefore, ionic fluorides are applicable where an unassisted nucleophilic displacement process is feasible, even if forcing conditions are necessary (Figure 2.10). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 28

28 Chapter 2

F F Cl CC CCF CC+ Cl Cl

Figure 2.10

1 Source of fluoride ion Fluoride ion is much smaller than chloride (ionic radii 1.47 and 1.75 A˚ , respectively [27]) and the heat of hydration of fluoride is about 134 kJmol1 greater than chloride. The order of nucleophilic strength of halide ions in aqueous solution is I Br > Cl > F, which is the opposite of the order of strengths of the bonds of the halogens to carbon. Therefore, the order of reactivity is a consequence of the greater difficulty in disturbing the hydration sphere of the smaller ions. The same order seems to be observed in most hydrogen-bonding solvents but, in dipolar aprotic solvents, the order follows that of increasing halogen bond strength to carbon, that is F > Cl > Br I [28]. Conse- quently, in order to reduce hydrogen bonding between the fluoride ion source and the solvent, and hence to increase the nucleophilic strength of fluoride, reactions are generally carried out using polar, aprotic media [29, 30] such as acetonitrile, sulpholane, N-methylpyrollidinone or glymes. These solvents dissolve sufficient metal fluoride, due to coordination of the oxygen or nitrogen donor groups present with the metal cation, and presumably the fluoride ion remains relatively unsolvated. These fluorinations are not simply solution-phase processes, because some reaction undoubtedly occurs on the surface; indeed, the surface area of the metal fluoride is extremely important to reactivity and in some cases it has been demonstrated that the amount of solid metal fluoride is important [31]. Also, in some circumstances the alkali metal fluorides can be used most effectively without a solvent [32, 33], and in these cases it is likely that an MF/MCl melt is produced as the reaction proceeds. Fluoride ion is a relatively strong base which has been used to effect a large number of base-catalysed reactions in general organic synthesis [34, 35] and so, if forcing conditions are required for a particular halogen exchange reaction, the limiting feature can be proton abstraction by fluoride ion from the solvent or the substrate. Because of the low solubility of metal fluorides in even very polar aprotic solvents, high temperatures are generally required; this restricts the use of alkali metal fluorides to relatively simple substrates. Consequently, development of more reactive forms of fluoride ion, which may be useful for introduction of fluorine into more complex molecules, is an area of continuing interest [36, 37]. Methods of activating metal fluorides (usually potassium fluoride) fall into two broad classes: (a) increasing the surface area of the metal fluoride by spray drying [38, 39], freeze drying [40], recrystallising from methanol [41] or absorbing onto a solid inert support such as calcium fluoride [42], alumina [43], graphite [44] or a polymer [45]; or, (b) increasing the solubility of the metal fluoride in aprotic solvents by the addition of co- ordinating crown ethers [46, 47] such as 18-crown-6 or a phase-transfer catalyst such as tetraphenylphosphonium bromide [48, 49] or a tetra-alkylammonium salt [50]. A search for other more soluble sources of nucleophilic fluoride continues and reagents such as tetra-alkylammonium fluorides [51, 52], various amine hydrofluorides [53, 54], diethylaminosulphur trifluoride [55] (DAST), tetrabutylammonium (triphenylsilyl)difluorosili- Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 29

Preparation of Highly Fluorinated Compounds 29 cate [56] and tris(dimethylamino)sulphonium difluorotrimethylsiliconate [57] (TAS-F) have been used for the selective introduction of fluorine into organic substrates with varying degrees of success. However, in soluble reagents such as Me4NF and other so- called ‘naked fluoride’ systems, the fluoride ion is so exceptionally reactive that competing proton abstraction from the solvent, such as acetonitrile, or halogen exchange with a chlorinated solvent takes place [51, 58]. Consequently, in the development of new fluoride-ion reagents, a balance must be achieved between having sufficiently high fluoride nucleophilicity to effect halogen exchange and, at the same time, sufficiently low fluoride-ion basicity to prevent unwanted side reactions. Indeed, it has been reported that hydrated tetrabutylammonium fluoride is beneficial in reducing elimination products in reactions with 1-bromo-octane [52] (Figure 2.11).

80 C Bu4NF + 10H2O + C8H17Br C8H17F + CH2CH-C6H13 ½52 CH3CN 91% 9%

Figure 2.11 Under most aprotic conditions a general order of reactivity of the alkali-metal fluorides is CsF > KF > NaF, LiF; that is, the fluoride with the lowest lattice energy is the most efficient fluorinating agent. This highlights the over-simplification of ignoring the role of the counter-ion in nucleophilic displacement of halide by fluoride ion. In reactions that do not involve a solvent, the lattice energy itself will be an especially important factor in the process, as for example in Figure 2.12. When the metal M is large, the lattice energy difference between the halides is most favourable for the exchange reaction [59].

MF + CCl MCl + CF

Figure 2.12 A general process that involves direct and efficient reaction of fluorspar with organic halides would be very desirable but, so far, this has not been realised, except through generation in situ of hydrogen fluoride [60].

2 Displacements at saturated carbon

Displacement of halide by fluoride ion from alkyl halides usually occurs by an SN2 process with inversion of configuration [37], and since it is well known that nucleophilic displacement of chloride from polychloroalkanes becomes progressively more difficult with increasing chlorine content, it is hardly surprising that highly fluorinated alkanes are not generally synthesised by this method. However, in favourable cases more than one fluorine atom can be introduced; some examples illustrating different conditions used in ‘Halex’ processes are given in Table 2.1. Other selective nucleophilic fluorinations are discussed later (Chapter 3, Section II). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 30

30 Chapter 2

Table 2.1 Fluorinations with alkali-metal fluorides

Compound Conditions Products Yield (%) Ref.

C6H13Cl KF; (CH2OH)2;(HOCH2CH2)2O; 175–1858 CC6H13F 54 [61] CH2Cl2 KF, HF, 3008 CCH2F2 82 [62] CHCl2COOCH3 KF, 220–2308 C CHF2COOCH3 18 [63] CH3(CH2)7Br KF, 18-crown-6, MeCN CH3(CH2)7F 92 [46] CCl3CCl2CCl3 KF, 1908 CCF3CCl2CF3 60 [64] -Methyl-2-pyrrolidone N Cl

Cl KF, 4808 C, autoclave, no solvent F F [32] N N N

3 Displacements involving unsaturated carbon Alkene derivatives: There are three processes that can lead to nucleophilic displacement of halide by fluoride ion in unsaturated systems (Figure 2.13). 1. Addition / Elimination

F + + X X F F

2. Allylic or Benzylic Substitution

X F F + X

3. Nucleophilic Substitution with Rearrangement, SN2'

F F + X X

Figure 2.13 Displacement of halide by fluoride

Only perfluorocyclopentene has been synthesised directly by this route; it can be seen that, here, allylic rearrangements can occur to make all positions potentially vinylic and therefore reactive [64]. An analogous situation applies to hexachlorobutadiene. These reactions may also be carried out with potassium fluoride that has been exposed to Sulpholan or 18-crown- 6, but then suspended in a fluorocarbon. Under these conditions, a significant proportion of hexafluoro-2-butyne is formed, presumably because the latter is extracted into the fluorocarbon, pre-empting further reaction with fluoride [65] (Figure 2.14). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 31

Preparation of Highly Fluorinated Compounds 31

KF, NMP, 200 C Cl F

NMP = N-methyl-2-Pyrrolidone

Cl F etc. Cl Cl Cl F ½65 Cl F F

− CFCl2 CHClCCl=CCl2 CF3CH=CFCF3

KF / NMP

CCl2=CClCCl=CCl2

KF/Sulpholan, Perfluorocarbon

CF3CH=CFCF3 CF3C CF3 25% 75%

Figure 2.14

Aromatic compounds: Nucleophilic displacement of halide ion from haloaromatic compounds containing other electronegative substituents is well known; this process has been widely exploited for the synthesis of fluorinated aromatic compounds (Table 2.1) and is discussed later (see Chapter 9, Section II).

C High-valency metal fluorides This group of reactions [66, 67] is distinguished from those discussed earlier on the basis that the previous examples involve overall nucleophilic displacement reactions of groups (mainly other halogen) by fluoride, frequently with some degree of assistance for the leaving group by the metal. However, with the present group, the process involves change of a higher-valency metal fluoride to a lower-valency state, and therefore the metal acts somewhat like a fluorine carrier, although it is emphasised that these reactions do not involve the formation and reaction of elemental fluorine (Figure 2.15). The high-valency metal fluorides, mainly cobalt trifluoride, bring about extensive fluorination: hydrogen is replaced by fluorine and saturation of double bonds and aromatic systems usually takes place, while chlorine is frequently retained. There is much less fragmentation during this process than during direct fluorination by elemental fluorine, because the heat of reaction with cobalt trifluoride is approximately half that of the corresponding direct fluorination process [68] (Figure 2.16). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 32

32 Chapter 2

CH+ 2MFn C F+ HF + 2MFn-1

CC + 2MFn C C + 2MFn-1 F F

Figure 2.15

∆ − −1 68 2 CoF2 + F2 2 CoF3 , H (250 C) = 234kJmol ½

C H + 2 CoF3 C F + HF + 2 CoF2

Figure 2.16 DHisca 209 to 230 compared with ca 426 to 435 kJmol-1 for direct fluorination The most important member of this group is cobalt trifluoride; the present discussion will be essentially limited to the use of this fluorinating agent, although use of a variety of other fluorides has been reported, with varying degrees of success [66, 67]. Other related high-valency metal salts such as the tetrafluorocobaltates of potassium [69, 70] and caesium [71], KAgF4 [72] and K2NiF6 [73] (compare also NiF3, Section III) are milder fluorinating agents for aromatic systems. It is also worthwhile to re-emphasise that the classifications presented here must not be regarded as rigid because, for example, antimony pentafluoride has characteristics that really span both groups. It is now reasonably well established that cobalt trifluoride fluorinations proceed via a one-electron transfer oxidative process [74, 75] as outlined in Figure 2.17.

R-H − + H CoF3 + RH R RF ½74; 75

CoF3

CoF2 + F CoF3

F R'F R' R RF rearrange

Figure 2.17 The presence of carbocationic intermediates was inferred from the isolation of other perfluorinated isomers formed via rearrangement upon fluorination of n-hexane [75]. Similar arguments have been suggested for fluorinations of aromatics [74, 76, 77], ethers [78] and amines [79].

1 Cobalt trifluoride and metal tetrafluorocobaltates Laboratory-scale fluorinations with cobalt trifluoride most commonly utilise the technique pioneered by Fowler and his co-workers [80] whereby cobalt trifluoride is formed, Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 33

Preparation of Highly Fluorinated Compounds 33 and subsequently regenerated, by passing fluorine over the difluoride under agitation. The substrate is then added in the vapour phase, in a stream of nitrogen usually at high temperatures (300–4008 C). Industrial processes [81], such as that used by F2 Chemicals Ltd for the production of a range of perfluorocarbon fluids (Flutect), are operated on a continuous process in which both fluorine and the hydrocarbon are fed simultaneously into the reactor, enabling fluorination and regeneration of the trifluoride to occur. This method is probably the best available for general synthesis of saturated fluorocarbons and both open-chain and cyclic fluorocarbons have been produced readily from appropriate aliphatic or aromatic hydrocarbons, yields usually being quite high (Table 2.2). Formation of perfluorinated ethers by cobalt trifluoride is generally a low-yielding process, because of fragmentation and partial fluorination. However, incorporation into the substrate of electron-withdrawing polyfluoroalkyl groups moderates the fluorination and allows high yields to be obtained [78].

Table 2.2 Fluorinations using cobalt trifluoride

Starting material Conditions (8 C) Product Yield (%) Ref. n-C5H12 275–325 n-C5F12 67% [80]

C2H5 C2F5

350 85% [82] F

350 F F [83]

350 [84] F F N N

Cl 350 C6F12nCln [85]

440 F 70% [78] O CF2CFHCF3 O CF2CF2CF3

ONCH3 100 ONCFF 3 [86]

III ELECTROCHEMICAL FLUORINATION (ECF) [87] Simons and his co-workers discovered a remarkable fluorination process [88–90] which is still being studied [87, 91–95]. Many organic compounds dissolve readily in anhydrous Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 34

34 Chapter 2 hydrogen fluoride to give conducting solutions and it was found that when a direct electric current was passed through a solution of this type, or through a suspension of a compound in anhydrous hydrogen fluoride to which some electrolyte had been added to give a conducting medium, hydrogen was evolved at the cathode and the organic material was fluorinated. Low voltages are used (usually 5–6 V) so that generation of elemental fluorine is not involved. However, the process is not well understood and suggestions concerning the mechanism broadly fall into two classes [94]. High-valency nickel fluorides formed at the surface of the anode are the most likely fluorinating agents [96], although formation of radical cation intermediates has been suggested [97] (Figure 2.18).

−e −H −e F ½97 RH RH R R RF

Figure 2.18 The method is similar to the use of high-valency metal fluorides because it is usual for all the hydrogen in an organic compound to be replaced by fluorine; unsaturated centres, multiple bonds or aromatic systems are saturated but some functional groups are retained, and it is this last feature that makes this method attractive. Unfortunately, however, although many examples are quoted, especially in the patent literature, the yields are frequently difficult to deduce or are very low. This is particularly the case with hydrocarbons and, in general, as the length of the hydrocarbon chain in functional compounds increases, so the yields decrease. Under its present state of development the method is only preparatively useful in limited cases, for example for carboxylic or sulphonic acids, amines and some ethers (see Table 2.3) where the yields are particularly high, or in cases where alternative methods are even more inefficient. The process is in commercial use for the production of a range of perfluorocarbons and perfluoro acids.

Table 2.3 Electrochemical fluorinations

Starting material Product Yield (%) Ref.

n-C8H18 n-C8F18 15 þ tar [89] (C2H5)3N(C2F5)3N 27 [98]

F 37 [99] NF N F

(CH3)2SCF3SF5 þ (CF3)2SF4 20 þ 2 [100] CH3COF CF3COF 85 [101] C7H15COCl C7F15COF 20 [102] CH3SO2FCF3SO2F 96 [103] C8H17SO2Cl C8F17SO2F 25 [103]

F 50 [104] O CF2CFHCF3 O CF2CF2CF3 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 35

Preparation of Highly Fluorinated Compounds 35

Work with pre-formed high-valency nickel fluorides, i.e. NiF3 and NiF4, has demonstrated the very high level of reactivity of such compounds [105–107]. These are the only reagents described so far that will bring about complete fluorination at room temperature or below (Figure 2.19), and therefore mirror ECF procedures.

RFH O R C F O C F FH i 3 7 3 7 F

RFH = -CF2CFH-CF3 − i, NiF3, anhyd.HF, 28 C to rt, 24hr

Figure 2.19 Clearly these results support the idea of forming higher nickel fluorides at the anode surface during ECF but there is also the possibility that these high-valency systems could be simply regarded as fluorine atom carriers, which would account for the high level of reactivity. For any oxidation process proceeding by the ECBECN mechanism described in Figure 2.18, it would be expected that fluorination should become progressively more difficult to achieve. However, presentation of a surface of, essentially, fluorine atoms to a substrate would circumvent this difficulty of interpretation. It is worth noting that the nickel fluoride K2NiF6 [108] decomposes on heating to give elemental fluorine.

IV FLUORINATION WITH ELEMENTAL FLUORINE [109] A Fluorine generation Since anhydrous hydrogen fluoride is not sufficiently conducting, fluorine is generated at the anode by electrolysis of KF2HF, which melts conveniently around 1008 C and the cell can therefore be run at a reasonable temperature. Considerable research has been carried out on the design of fluorine cells and this is fully discussed elsewhere [2, 110].

B Reactions Reactions between hydrocarbons and elemental fluorine are extremely exothermic because of the high heats of formation of bonds from fluorine to carbon and hydrogen (approximately 456 and 560 kJmol1, respectively) [27, 111]. The value of DH for the dissociation of fluorine is very low (ca. 157 kJmol1), so it is frequently assumed that the preferred fluorination process proceeds by a radical chain mechanism (Figure 2.20), although this may not always be the case.

−20 F2 2F K = 10

RH + F R + HF

R + F2 RF + F

Figure 2.20 Fluorinations will proceed in the dark, and the initiation process poses a question. It has been pointed out [112] that, although fluorine is not appreciably dissociated at room Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 36

36 Chapter 2

20 temperature (F2 ¼ 2F , K ¼ 10 ), the low activation energy of the hydrogen abstraction reaction would mean that even this low degree of dissociation would be sufficient to start the chain process. Nevertheless, Miller and co-workers suggested the possibility of an initiation process [113–115] in which molecular fluorine reacts with a hydrocarbon molecule to yield an alkyl radical, hydrogen fluoride and a fluorine atom (Figure 2.21).

−1 RH + F2 R + HF + F ∆H = +16.3 kJmol ½113115

Figure 2.21 This is an attractive idea and there is ample precedent for this process with other halogens [116]. In reactions of fluorine with alkenes, the thermodynamics are more convincing [112] and there appears to be some supporting experimental evidence (Figure 2.22).

∆ − −1 CC+ F2 FCC + F H = 156.9 kJmol ½112

Figure 2.22 It was shown that a mixture of tetrachloroethene and chlorine did not react until a trace of fluorine was introduced, whereupon chlorination took place [114] (Figure 2.23).

F2 (trace) ½114 CCl2=CCl2 + Cl2 CCl3-CCl3 85%

Figure 2.23 Also, it has been suggested that dimerisation of haloalkenes observed during the interaction with fluorine at low temperatures (< 508 C) arises by a free-radical chain mechanism initiated in this way [115].

C Control of fluorination A consideration of the thermodynamics of fluorination reactions shows that the overall energy released upon substituting a hydrogen by fluorine [111] (430 kJmol1) is sufficient to cause carbon–carbon bond cleavage (ca. 355 kJmol1) leading to substrate degradation. Consequently, after many early attempts to effect direct fluorination had resulted in violent reactions, it was not until effective methods were developed for dissipating the considerable heat generated that any real progress was made [117, 118].

1 Dilution with inert gases It is possible to control direct fluorination reactions in their initial stages by using fluorine extensively diluted in an inert gas, such as nitrogen or helium, long reaction times, and by cooling the reactor to low temperatures. After partial fluorination of a substrate has been achieved, further fluorination generally requires more forcing conditions, since the substrate is now less activated towards radical substitution. Therefore, the concentration of fluorine and the temperature of the reaction may be raised to effect perfluorination. The ‘LaMar’ process has been developed by Lagow and Margrave with their co-workers [111, Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 37

Preparation of Highly Fluorinated Compounds 37

117, 119, 120] to prepare many perfluoroalkanes [111, 121] and perfluoroadamantane derivatives as well as functional perfluoro compounds (Table 2.4 in Section E, below). In a related ‘aerosol fluorination’ technique [122–124], a substrate is absorbed onto fine particles of sodium fluoride which are then sprayed into a stream of dilute fluorine; many perfluorinated highly branched and cyclic alkanes have been prepared by this method. Other techniques for perfluorination with elemental fluorine make use of fluorocarbon solvents which act both as a heat sink in the early stages of fluorination and as a solvent to dissolve high concentrations of fluorine, which is helpful towards ensuring complete fluorination in the later ‘finishing’ stages [125, 126]. Perfluorination may be further aided by photolysis under UV irradiation [127] or by the addition of a highly reactive substrate, such as benzene [126], that also acts as a fluorine-atom generator (see above). Maintaining a high fluorine atom flux is at the heart of perfluorination techniques. Moderation of the early stages of direct fluorination may be achieved by further fluorination of partially fluorinated systems, where the first fluorine may be introduced by methodology that does not involve the use of elemental fluorine [128] (Figure 2.24).

RFH ½128 CH3(-OCH2CH2-)nCH3 + CF2=CFCF3 RFHCH2(-OCHCH2-)nCH2RFH

R CF CFHCF F2 FH = 2 3

RF = CF2CF2CF3 RF

RFCF2(-OCFCF2-)nCF2RF

i, ii F 91% R R R ½129, 130 FH O FH F O RF

RFH = CF2CFHCF3 RF = CF2CF2CF3

i, 50% v:v F2 in N2; ii, Room temperature, then 280 C

Figure 2.24 Using these approaches, the successful further fluorination of partly fluorinated esters has been cleverly developed into a process for the synthesis of the important copolymer component perfluoro(propyl vinyl ether), PPVE [131] (Figure 2.25). A quite different, but realistic, approach to temperature control and efficient mixing involves the use of microreactors [129, 130, 132, 133]; a simple design is shown in Figure 2.26 [129]. These techniques are under active development but microreactor designs are now available that could be used on an industrial scale for the efficient and safe use of fluorine. Polyethylene vessels may be treated with fluorine in a blow moulding process (Airopakt, Air Products) so as to provide a fluorocarbon coating [134], but it seems highly unlikely that this treatment can be regarded as simply providing a polytetrafluoroethene (PTFE) Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 38

38 Chapter 2

HOCH2CH(CH3)OC3F7 + FC(O)CF(CF3)OC3F7 ½131

C3F7OCF(CF3)C(O) OCH2CH(CH3)OC3H7

C3F7OCF(CF3)C(O) OCF2CF(CF3)OC3F7

∆

2 FC(O)CF(CF3)OC3F7

i) NaOH ii)Heat

CF2=CFOC3F7 PPVE

Figure 2.25

Figure 2.26 Reprinted with the permission of the Royal Society of Chemistry surface [135, 136]. Such containers [137] possess excellent resistance to hydrocarbon solvent penetration [135, 138], probably because of enhanced cross-linking in the surface, and have been used successfully as fuel tanks by the automobile industry for many years. Other techniques of surface fluorination and oxyfluorination have been used to modify polymer surfaces. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 39

Preparation of Highly Fluorinated Compounds 39

D Fluorinated carbon [139] Fluorination of graphite at high temperature (300–5008 C) gives a white powder which approximates to the composition (CF)n. X-ray studies indicate that the fluorine atoms are strongly bonded to carbon but are contained between the graphite layers [140]. Graphite fluorides have similar properties to PTFE and have been exploited commercially as speciality lubricants and in high-performance lithium batteries [141]. Direct fluorination of Buckminsterfullerene, C60, has been studied by several groups [142]. It is claimed that C60F48 can be isolated as an intact sphere [143] and, moreover, as a single isomer after fluorination at 2508 C. Photoelectron spectroscopy studies suggest that as the level of fluorination is raised above C60F48, carbon–carbon bond cleavage occurs, thus cracking the sphere [144, 145]. A fluoroxyfullerene, C60F17OF, has been characterised [146]. Mesophase pitch, derived from coal tar, reacts smoothly with fluorine to give pitch fluoride [147, 148] with a composition between CF1:3 and CF1:6, as a yellowish white solid which differs from graphite fluoride in that it is soluble in some fluorocarbon solvents. Consequently, thin films of pitch fluoride may be deposited on materials and the resulting surfaces have been claimed to have even lower surface energies than PTFE.

E Fluorination of compounds containing functional groups When functional groups are present, the products can be quite complex. Primary and secondary amines give NF2 and NF compounds respectively and fluorination of sulphur compounds gives products in which the sulphur has been oxidised to its maximum valency state of six [149] (Table 2.4). Hydroxy compounds can give fluoroalkyl hypofluorites (fluoroxy compounds) (see also Chapter 3, Section IIIB), the corresponding alkyl derivatives not being stable [150, 151]; bisfluoroxy derivatives have also been isolated [152–154] (Figure 2.27).

i CH3OH CF3OF ½150

− i, F2, Cu/Ag, 160 180 C

i CO2 CF2(OF)2 ½153

− i, F2, CsF, 196 C to rt

Figure 2.27

Perfluorinations of many ethers [155], cryptands [156], polyethers [119, 157], including the largest perfluoro-macrocycle [158], perfluoro [60]-crown-20 [123, 159], and the first perfluorinated sugar [160], orthocarbonates [161, 162], ketones [163, 164], esters [124, 165], phosphanes [166] and alkyl halides [167, 168] have been successfully accomplished by the LaMar or aerosol processes (Table 2.4). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 40

40 Chapter 2

Table 2.4 Fluorination using dilute fluorine

Starting material Product Yield (%) Ref.

Conditions: F2 in He or N2, 788 Ctort

(CH3)3CCH2CH2C(CH3)3 (CF3)3CCF2CF2C(CF3)3 89 [169]

C F C 96 [170] 4 4

F 26 [171] F3C

H3C F F3C

H3C

– [172] CH2CH2O CF CF O n 2 2 n

(CH3)3CCH2SH (CF3)3CCF2SF5 91 [149]

Conditions: 268 C and lower

CH2CH2O CF2CF2O [159] 20 20

Conditions: 908 Ctort

O O F2 O O O O F3C F [160] O O F3C F O CF3 O F3C Conditions: Aerosol fluorination Cl Cl

60 [173] F

O OCF3 F C 65 [124] O 3 F CF2 O CF3

V HALOGEN FLUORIDES The reactions of halogen fluorides with organic compounds have been reviewed [174, 175] but their usefulness for the preparation of highly fluorinated substrates is limited to reactions with the corresponding perhalo-organic compounds [176] (Figure 2.28). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 41

Preparation of Highly Fluorinated Compounds 41

BrF3 CBr4 CF3Br 94% ½176

IF5 CI4 CF3I 95%

Figure 2.28 Liquid-phase halogenation of hexachlorobenzene with chlorine trifluoride appears to proceed by a series of additions and vinylic and allylic substitutions until all of the hexachlorobenzene is converted into chlorofluorocyclohexenes, C6Fn(Cl10n)(n ¼ mainly 4, 5 and 6), and conversion to cyclohexane derivatives occurs only upon the passage of quite a large excess of chlorine trifluoride [177] (Figure 2.29). The cyclohexene derivatives produced mainly retain the structure 2CCl5CCl2. A mixture of iodine with iodine pentafluoride, or bromine with bromine trifluoride, will add iodine monofluoride or bromine monofluoride respectively to fluorinated alkenes; this constitutes a very convenient route to the corresponding monohalopolyfluoroalkanes [178, 179], which is of considerable importance to the surfactant business (Figure 2.30). ClF3, 240 C C6Cl6 C6F7Cl3 (2%) + C6F6Cl4 (10%) + C6F4Cl4 (4%) ½177

+ C6F5Cl5 (30%) + C6F4Cl6 (35%)

Figure 2.29

½178, 179 2I2 + IF5 + 5CF2=CF2 5CF3CF2I 86%

150 C 2I2 + IF5 + 5CF3CF=CF2 5(CF3)2CFI 99%

Figure 2.30

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94 Y.W. Alsmeyer, W.V. Childs, R.M. Flynn, G.G.I. Moore and J.C. Smeltzer in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 121. 95 K. Pohmer and A. Bulan in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 305. 96 A. Dimitrov, S. Rudiger, N.V. Ignatyev and S. Datchenkov, J. Fluorine Chem., 1990, 50, 197. 97 J. Burdon and I.W. Parsons, Tetrahedron, 1972, 28, 43. 98 E.A. Kauck and J.H. Simons, G.B. Pat. 666 733 (1952); Chem. Abtsr., 1952, 46, 6015c. 99 R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1962, 3407. 100 A.F. Clifford, H.K. El-Shamy, H.J. Emele´us and R.N. Haszeldine, J. Chem. Soc., 1953, 2372. 101 H.M. Scholberg and H.G. Bryce, US Pat. 2 717 871 (1955); Chem. Abstr., 1955, 49, 15572 h. 102 H.W. Prokop, H.J. Zhou, S.Q. Xu, C.H. Wu, S.R. Chuey and C.C. Liu, J. Fluorine Chem., 1989, 43, 257. 103 T. Gramstad and R.N. Haszeldine, J. Chem. Soc., 1956, 173. 104 R.D. Chambers, R.W. Fuss, M. Jones, P. Sartori, A.P. Swales and R. Herkelmann, J. Fluorine Chem., 1990, 49, 409. 105 N. Bartlett, R.D. Chambers, A.J. Roche, R.C.H. Spink, L. Chacon and J.M. Whalen, J. Chem. Soc., Chem. Commun., 1996, 1049. 106 J.M. Whalen, L. Chacon and N. Bartlett, Proc. Electrochem. Soc., 1997, 97-15,1. 107 J.M. Whalen, L.C. Chacon and N. Bartlett in The Oxidation of Oxygen and Related Chemistry – Selected Papers of Neil Bartlett, ed. N. Bartlett, World Scientific, Singapore, 2001, p. 395. 108 K.O. Christe, Inorg. Chem., 1986, 25, 3721. 109 K.O. Christe, N. Watanabe, T. Tojo, S. Rozen, R.J. Lagow, J. Adcock, D.T. Meshri and D.B. Hage in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 159. 110 J.F. Ellis and G.F. May, J. Fluorine Chem., 1986, 33, 133. 111 R.J. Lagow and J.L. Margrave, Prog. Inorg. Chem., 1979, 26, 161. 112 J.M. Tedder, Adv. Fluorine Chem., 1961, 2, 104. 113 W.T. Miller and A.L. Dittman, J. Am. Chem. Soc., 1956, 78, 2793. 114 W.T. Miller, S.D. Koch and F.W. McLafferty, J. Am. Chem. Soc., 1956, 78, 4992. 115 W.T. Miller and S.D. Koch, J. Am. Chem. Soc., 1957, 79, 3084. 116 W.A. Pryor, Free Radicals, McGraw-Hill, New York, 1966. 117 R.R. Lagow in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 188. 118 S. Rozen in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 167. 119 R.J. Lagow, T.R. Bierschenk, T.J. Juhlke and H. Kawa in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 97. 120 R.J. Lagow in Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 11, ed. M. Howe-Grant, John Wiley and Sons, New York, 1994, p. 482. 121 W.H. Lin and R.J. Lagow, J. Fluorine Chem., 1990, 50, 345. 122 J.L. Adcock, K. Horita and E.B. Renk, J. Am. Chem. Soc., 1981, 103, 6937. 123 J. Adcock in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 202. 124 J.L. Adcock in Synthetic Fluorine Chemistry, ed. G.A. Olah, R.D. Chambers and G.K.S. Prakash, John Wiley and Sons, New York, 1992, p. 127. 125 T.R. Bierschenk, T. Juhlke and R.J. Lagow, WO Pat. 87/02 992 (1987); Chem. Abstr., 1987, 107, 176772v. 126 T.R. Bierschenk, T. Juhlke, H. Kawa and R.J. Lagow, WO Pat. 90/03 353 A1 (1990); Chem. Abstr., 1991, 114, 231007 w. 127 T. Ono, K. Yamanouchi and K.V. Scherer, J. Fluorine Chem., 1995, 73, 267. 128 R.D. Chambers, A.K. Joel and A.J. Rees, J. Fluorine Chem., 2000, 101, 97. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 45

Preparation of Highly Fluorinated Compounds 45

129 R.D. Chambers and R.C.H. Spink, J. Chem Soc., Chem. Commun., 1999, 883. 130 R.D. Chambers, D. Holling, R.C.H. Spink and G. Sandford, Lab on a Chip, 2001, 1, 132. 131 T. Okazoe, K. Watanabe, M. Itoh, D. Shirakawa, H. Morofushi, H. Okamoto and S. Tatematsu, Adv. Sci. Synth., 2001, 343, 215. 132 K. Jahnisch, M. Baerns, V. Hessel, W. Erhfeld, V. Haverkamp, H. Lowe, C. Wille and A. Gruber, J. Fluorine Chem., 2000, 105, 117. 133 N. deMas, A. Gunther, M.A. Schmit and K.F. Jensen, Ind. Eng. Chem. Res., 2003, 42, 698. 134 M. Anand, J.P. Hobbs and I.J. Brass in Organofluorine Chemistry. Principles and Commer- cial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 469. 135 F.J. du Toit and R.D. Sanderson, J. Fluorine Chem., 1999, 98, 107. 136 A.P. Kharitonov, Pop. Plastics Packaging, 1997, 75. 137 Various authors, Ind. Res. Dev., 1978, 12, 102. 138 J.P. Hobbs, P.B. Henderson and M.R. Pascolini, J. Fluorine Chem., 2000, 104, 87. 139 D.T. Meshri and D.B. Hage in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 209. 140 N. Watanabe, T. Nakajima and H. Touhara, Graphite Fluorides, Elsevier, New York, 1988. 141 G.A. Shia and G. Mani in Organofluorine Chemistry. Principles and Commercial Applica- tions., ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 483. 142 K. Kniaz, J.E. Fischer, H. Selig, G.B.M. Vaughan, W.J. Romanow, D.M. Cox, S.K. Chowdh- ury, J.P. McCauley, R.M. Strongin and A.B. Smith, J. Am. Chem. Soc., 1993, 115, 6060. 143 A.A. Gakh, A.A. Tuinman, J.L. Adcock, R.A. Sachleben and R.N. Compton, J. Am. Chem. Soc., 1994, 116, 819. 144 A.A. Tuinman, A.A. Gakh, J.L. Adcock and R.N. Compton, J. Am. Chem. Soc., 1993, 115, 5885. 145 D.M. Cox, S.D. Cameron, A. Tuinman, A. Gakh, J.L. Adcock, R.N. Compton, E.W. Hagaman, K. Kniaz, J.E. Fischer, R.M. Strongin, M.A. Cichy and A.B. Smith, J. Am. Chem. Soc., 1994, 116, 1115. 146 A.D. Darwish, A.K. Abdul-Sada, A.G. Avent, S.M. Street and R. Taylor, J. Fluorine Chem., 2003, 121, 185. 147 H. Fujimoto, M. Yoshikawa, A. Mabuchi and T. Maeda, J. Fluorine Chem., 1992, 57, 65. 148 H. Fujimoto, A. Mabuchi, T. Maeda, Y. Matsumara, N. Watanabe and H. Touhara, Carbon, 1992, 30, 851. 149 H.N. Huang, H. Roesky and R.J. Lagow, Inorg. Chem., 1991, 30, 789. 150 K.B. Kellog and G.H. Cady, J. Am. Chem. Soc., 1948, 70, 3986. 151 J.H. Prager, J. Org. Chem., 1966, 31, 392. 152 P.G. Thompson, J. Am. Chem. Soc., 1967, 89, 1811. 153 R.L. Cauble and G. Cady, J. Am. Chem. Soc., 1967, 89, 1962. 154 F.A. Hohorst and J.M. Shreeve, J. Am. Chem. Soc., 1967, 89, 1809. 155 D.F. Persico, H.N. Huang, R.J. Lagow and L.C. Clark, J. Org. Chem., 1985, 50, 5156. 156 W.D. Clark, T-Y. Lin, S.D. Maleknia and R.J. Lagow, J. Org. Chem., 1990, 55, 5933. 157 K.S. Sung and R.J. Lagow, J. Am. Chem. Soc., 1995, 117, 4276. 158 M. Biollaz and J. Kalvoda, Helv. Chim. Acta, 1977, 60, 2703. 159 H-C. Wei and R.J. Lagow, J. Chem. Soc., Chem. Commun., 2000, 2139. 160 T.-Y. Lin, H-C. Chang and R.J. Lagow, J. Org. Chem., 1999, 64, 8127. 161 W-H. Lin, W.D. Clark and R.J. Lagow, J. Org. Chem., 1989, 54, 1990. 162 J.L. Adcock, M.L. Robin and S. Zuberi, J. Fluorine Chem., 1987, 37, 327. 163 J.L. Adcock and M.L. Robin, J. Org. Chem., 1983, 48, 2437. 164 J.L. Adcock and H. Luo, J. Org. Chem., 1992, 57, 4297. 165 J.L. Adcock and R.J. Lagow, J. Am. Chem. Soc., 1974, 96, 7588. 166 J.J. Kampa, J.W. Nail and R.J. Lagow, Angew. Chem., Int. Ed. Engl., 1995, 34, 1241. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 46

46 Chapter 2

167 J.L. Adcock, W.D. Evans and L. Heller-Grossman, J. Org. Chem., 1983, 48, 4953. 168 J.L. Adcock and W.D. Evans, J. Org. Chem., 1984, 49, 2719. 169 E.K.S. Liu and R.J. Lagow, J. Fluorine Chem., 1979, 14, 71. 170 R.E. Aikman and R.J. Lagow, J. Org. Chem., 1982, 47, 2789. 171 G. Robertson, E.K.S. Liu and R.J. Lagow, J. Org. Chem., 1978, 43, 4981. 172 G.E. Gerhardt and R.J. Lagow, J. Org. Chem., 1978, 43, 4505. 173 J.L. Adcock, H. Luo and S.S. Zuberi, J. Org. Chem., 1992, 57, 4749. 174 W.K.R. Musgrave, Adv. Fluorine Chem., 1960, 1,1. 175 L.S. Boguslavskaya and N.N. Chuvatkin in New Fluorinating Agents in Organic Synthesis, ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 140. 176 A.A. Banks, H.J. Emele´us, R.N. Haszeldine and V. Kerrigan, J. Chem. Soc., 1948, 2188. 177 R.D. Chambers, J. Heyes and W.K.R. Musgrave, Tetrahedron, 1963, 19, 891. 178 R.D. Chambers, W.K.R. Musgrave and J. Savory, J. Chem. Soc., 1961, 3779. 179 M. Hauptschein and M. Braid, J. Am. Chem. Soc., 1961, 83, 2383. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 47

Chapter 3 Partial or Selective Fluorination

I INTRODUCTION Whereas the previous chapter dealt largely with the synthesis of highly fluorinated systems, here we will be concerned with methods available for introducing mainly one, or two, fluorine atoms at specific points in a molecule, although many of these processes can, of course, be applied to already partly fluorinated systems in order to introduce more fluorine. The merits and importance of introducing a single fluorine atom into biologically significant compounds was discussed in Chapter 1, and many reviews are available concerning the synthesis of selectively fluorinated compounds [1–20]; the reader is directed to these for comprehensive literature coverage. The following discussion is intended to illustrate the types of reagents required to effect replacement of a wide range of functional groups.

II DISPLACEMENT OF HALOGEN BY FLUORIDE ION A Silver fluoride Much early work [21] involved the use of silver(I) fluoride, conveniently prepared from the oxide or carbonate with 40% hydrogen fluoride, for the exchange of single halogen atoms in alkyl halides [22] and other systems [23]. The use of calcium fluoride as a solid, inert support may increase the reactivity of silver fluoride [24] (Figure 3.1).

Br F

i 84% ½24 CH3(CH2)15 CO2Me CH3(CH2)15 CO2Me

i AgF, CH3CN, H2O, 80 C, 2hr

i C8H17I C8H17F 80%

i AgF, CaF2, 75 C, 10min

Figure 3.1

B Alkali metal fluorides (see also Chapter 2, Section IIB) Potassium fluoride is used most frequently as a balance between reactivity and economy, because efficiency decreases in the series CsF > KF > NaF. Different forms of KF are available and a number of ‘catalysts’ have been used to enhance the reactivity of KF in

48 Chapter 3 aprotic solvents (see Chapter 2, Section IIB). Acid fluorides, alkyl fluorides and fluoroaromatics are obtained from the corresponding chlorides by reaction with potassium fluoride (Figure 3.2). Surprisingly, although it is usually stressed (as we have done in Chapter 2) that a metal fluoride should be dry, because fluoride ion is deactivated by its co-ordination sphere in aqueous solution, the addition of small amounts of water is necessary to obtain halogen exchange [25]. Alternatively, phase-transfer agents or crown polyethers may achieve the same result. It is the author’s view that these additions are necessary to remove other metal halide impurities from the surface of the fluoride,

i CH3COCl CH3COF 76% ½29

i, KF, CH3COOH, 100 C

i C6H5CHCHSO2Cl C6H5CHCHSO2F 51% ½30

i, KF, xylene, reflux

i or ii ½25 MF + n-C8H17Br n-C8H17F + MBr

i, MF = KF plus small amounts water, 85 C 60% ii, MF = Bu4NF.3H2O, 60 C 71%

i ½25 MF + BrCH2COOEt FCH2COOEt + MBr 70%

i, MF = CsF + 10% Bu4NF, 40 C

O(CH ) F ½27 O(CH2)3OMs 2 3

i 92%

Me Bu NN i, KF, BF4 , H2O (5 equiv), 100 C

i BrCH2CH2OH FCH2CH2OH 72% ½28

i CH3CH2CHBrCOOEt CH3CH2CHFCOOEt 78%

i, KF, Hexadecyltributylphosphonium bromide, heat

Figure 3.2 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 49

Partial or Selective Fluorination 49 because electron spectroscopy for chemical analysis (ESCA) results have demonstrated [26] that the other metal halide impurities are concentrated on the surface of the fluoride, even in samples that are ‘pure’ by bulk analysis. More remarkable is the fact that, using an ionic liquid as solvent, addition of five equivalents of water gave high reactivity and no elimination product [27]. A semi-molten mixture of potassium fluoride in hexadecyltributylphosphonium bromide (m.p. 56–588 C) is surprisingly effective [28] (Figure 3.2).

C Other sources of fluoride ion The low solubility, highly hygroscopic nature and low reactivity of alkali metal fluorides, and the sometimes harsh reaction conditions required for these fluorides to effect halogen exchange, have prompted a search for a source of fluoride ion that is easily handled, highly reactive, selective and soluble in organic solvents; several reagents possessing organic, lipophilic counter-ions have been developed for this task with varying degrees of success [18]. Maximum fluoride ion nucleophilicity is achieved if the reagents are free from moisture; tetrabutylammonium fluoride (TBAF), obtained commercially as the trihydrate, can be partially dried either by heating at 408 C under high vacuum [31] or, chemically, by reaction with hexamethyldisilazane [32], but prolonged heating of TBAF causes decomposition to occur via a Hofmann elimination pathway [33]. However, tetramethyl- ammonium fluoride [34] and adamantyltrimethylammonium fluoride [35] are more stable and they can be obtained in an anhydrous state by heating under vacuum after recrystallisation from propanol. Fluoride ion sources have been described that contain more elaborate counter-ions including tris(dimethylamino)sulphonium difluorotrimethylsiliconate (TAS-F) [12], a phosphazenium fluoride [36], cobaltocenium fluoride [37] and ‘Proton Sponge’ (PS) [38] (Table 3.1).

Table 3.1 Halogen exchange by various sources of fluoride ion

Substrate Reagent/Conditions Product Yield (%) Ref.

CH2 ¼CHCH2Br Bu4NF, 258 CCH2 ¼CHCH2F 85 [33]

O a þ O THF=HMPT ,958 C, Bu4N HF2 [39] Cl F Ph Ph

RX 2Bu4NFnH2O RF [40] (R ¼ alkyl, X ¼ Cl, Br) CH3CN

PhCH2Br Ph4PHF2 PhCH2F 100 [41] CH3CN, 508 C b PhCH2Cl Cp2CoF PhCH2F 95 [37] THF, rt

c C2H5I TAS-F C2H5F 85 [12] CH3CN, rt Contd Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 50

50 Chapter 3

Table 3.1 Contd

Substrate Reagent/Conditions Product Yield (%) Ref.

þ CH3ðCH2Þ7Br Bu4N Ph3SiF2 CH3ðCH2Þ7F 85 [42] CH3CN, 808 C O O PS=HFd CH3CN, rt 76 [38] Ph Cl Ph F

O O Pyridine9HF [43] 08 C Ph Cl Ph F a HMPT, hexamethylphosphoric triamide.

b c d Cp2CoF TAS-F PS / HF

+ − [(Me2N)3S] [(CH3)3SiF2] Me2N NMe2

Co F . HF

Hydrogen fluoride under vigorous conditions may be used in favourable circumstances, for example to make fluoromethyl ethers [44] (Figure 3.3a).

OH OCCl3 OCF3 ½44

i + CCl4

Cl Cl Cl i, HF, 150 C 70%

Figure 3.3a

Aromatic systems need to be activated towards nucleophilic attack to enable halogen exchange to occur (see Chapter 9) and the sulphonyl group has been employed as a disposable activating group [45] (Figure 3.3b). Addition of triphenyltin fluoride is claimed to be beneficial [46].

D Miscellaneous reagents Alkyl bromides are effectively transformed into alkyl fluorides by both chlorine monofluoride [47] (Figure 3.4) and the less reactive bromine trifluoride [48–50]. Since tertiary Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 51

Partial or Selective Fluorination 51

R Cl R F

i ½45 Cl SO2Cl Cl SO2F

ii, iii R = H, Me R F

i, KF, Ph4PBr ii, NaOH Cl iii, H2SO4, heat

Figure 3.3b

0 C CH3CH2CH2Br + ClF CH3CH2CH2F + CH3CHFCH3 ½47 30% 70%

rt CH2Cl CH2Br + BrF3 CH2Cl CH2F 80% ½48, 49

Figure 3.4 bromides react the most readily, and rearrangement occurs on reaction with primary alkyl bromides, a carbocationic mechanism has been proposed. The use of p-iodotoluene difluoride for replacement of iodine by fluorine has beeen described as a nucleophilic displacement of IF2, as a good leaving group, in a pre-formed iodoalkane difluoride [51]. Note that iodine is displaced in preference to p-TsO in this system (Figure 3.5a).

i RCH2 IF2 RCH2I RCH2F ½51 74% F R = p-TsO

i, p-MeC6H4IF2, Et3N.4HF, CH2Cl2

Figure 3.5a

However, a Pummerer-type process is involved in the introduction of two fluorine atoms into phenylsulphanated lactams [52] (Figure 3.5b, p. 52). The reaction of fluorine or xenon difluoride with iodoalkanes gives fluoroalkanes by similar processes [53, 54].

III REPLACEMENT OF HYDROGEN BY FLUORINE [55, 56] A Elemental fluorine From the previous discussion on extensive fluorination (Chapter 2, Section IV) it might be assumed that, in general, it will be very difficult to effect the selective replacement of hydrogen by fluorine in preparatively useful reactions. This has been the perceived wisdom in the past but the situation is changing rapidly [56]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 52

52 Chapter 3

O O IFO PhS PhS PhS ½52 N ArIF2 N ArIF2 N

O O PhS PhS N N F F F F

Figure 3.5b

The first indication that fluorine could be used as a selective fluorinating agent was reported by Bockemu¨ller in 1933 concerning reactions with butyric acid [57]. Fluorin- ation only occurs at the b- and g- positions, demonstrating that the regioselectivity of the process can be heavily influenced by the presence of an electron-withdrawing group in the substrate. This demonstrates the electrophilic nature of fluorine, although low- temperature fluorination of hydrocarbons is still much less selective than the corresponding chlorinations [58]. However, hydrogen atoms attached to tetrahedral carbon, through orbitals with a high p contribution, can be selectively replaced by fluorine when the reaction is carried out using a polar solvent such as chloroform or nitromethane [11, 59–61]. Even tertiary hydrogens in steroids may be selectively replaced using fluorine [62, 63] (Figure 3.6). It has been demonstrated that acetonitrile can be an effective solvent for these reactions, crucially allowing reactions to be carried out at higher temperatures [64, 65] (Figure 3.7).

1 Elemental fluorine as an electrophile The question arises as to whether these reactions involve molecular fluorine as an electrophile or electrophilic fluorine atoms. In principle, nucleophilic attack on fluorine could be promoted in a number of ways. Interaction of the leaving group, which in this case is fluoride, with a protonic or Lewis acid has been demonstrated [66] (Figure 3.8) and we will see that reagents containing bonds from fluorine to oxygen or, especially, to nitrogen (which provide excellent leaving groups) are particularly effective. For some reactions with saturated hydrocarbons, an electrophilic process involving a non-classical three-centre, two-electron transition state similar to other electrophilic substitutions at s-bonds [67] has been suggested [11, 65] (Figure 3.9). The facts that the stereochemistry is retained [11, 65] and products of elimination or rearrangement are not observed, as well as the result of ab initio calculations relating to the fluorination of methane [68], provide support for this argument. Moreover, there is a very close parallel between the products arising from reactions of elemental fluorine and of Selectfluort (see Section IIIC) with alkanes and cycloalkanes [64, 65]. There is an even stronger case for Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 53

Partial or Selective Fluorination 53

i ½62, 63 + OR OR OR F F

60% 10% − R = CO-C6H4NO2

− i, F2, N2, 70 C, CHCl3, CFCl3 (1:1)

OAc OAc

H F AcO AcO 50%

− i, F2 in N2(10% v/v), C6H5-NO2, 78 C, CFCl3, CHCl3

Figure 3.6

H F

i 54%, 68% conversion ½11, 64, 65

H H

i, F2 in N2 (10% v/v), CH3CN, 0 C

Figure 3.7

Nu: + F F HNuc H + HF ½66

COOH COOH F i

F F

i, F2/N2, 98% H2SO4, room temp.

Figure 3.8 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 54

54 Chapter 3

H H F ½11, 65

F F HCCl3

OCOC6H4NO2 OCOC6H4NO2

i 60%

Me F Me

− i, F2, N2, 70 C, CHCl3, CFCl3 (1:1)

Figure 3.9

N–F reagents acting as electrophiles, because radical clock experiments with these systems do not support a radical process [69, 70]. Consequently, in a given situation, the question as to whether a fluorination involves fluorine atoms (which themselves are very electrophilic, and such processes will therefore have polar characteristics) or nucleophilic attack on a molecule of elemental fluorine is difficult to assess. Both processes almost certainly occur, depending on the system and conditions. The changing perspective on the viability of fluorine as a reagent is illustrated by the fact that many selective fluorinations of substrates [8] containing carbon centres of high electron density have now been described, including a variety of enolate derivatives [71, 72], stabilised carbanions [73, 74], steroids [75] and 1,3-dicarbonyl derivatives [76] (Table 3.2) as well as some aromatic compounds [77]. Fluorinated aminoacids have been obtained by direct fluorination [78] (Figure 3.10).

Table 3.2 Selective fluorinations with elemental fluorine

Substrate Conditions Product Yield (%) Ref.

OSiMe O 3 F ,N 2 2 F 788 C, CFCl3 78 [71]

OSiMe O 3 F ,N 2 2 57 [79] 788 C, CFCl3 OEt OEt F

NO NO 2 i) OH 2 84 [74] OH ii) F2,N2,58 C, H2O OH O2N O2N H F

Contd Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 55

Partial or Selective Fluorination 55

Table 3.2 Contd

Substrate Conditions Product Yield (%) Ref.

O O O O F ,N 90 [76] OEt 2 2 OEt 108 C, HCOOH F

OH O O OHC O O F2,N2 F 71 [80] 408 C, CH3CN O O O O

R COOMe COOMe COOH F2 RCHF F RCHF F ½78 H NHCOPh NHCOPh NHCOPh

R = Alkyl or aryl COOH RCHF F

NH2

Figure 3.10

It has been established that elemental fluorine can be used to functionalise saturated sites in a two-step process using BF3 and this is one of the more direct methodologies, for this purpose, that has been described so far [65] (Figure 3.11). H F ½65 i ii

Stereochemistry H Retained H H

iii i, F2, CH3CN, 0 C ii, BF3.Et2O O iii, CH CN, H O 3 2 H N Me

Figure 3.11 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 56

56 Chapter 3

B Electrophilic fluorinating agents containing O–F bonds [81, 82]

Several organic hypofluorites, including trifluoromethyl (CF3OF) [83–85], perfluoroethyl (C2F5OF) [86], trifluoroacetyl (CF3COOF) [87] and acetyl hypofluorite (CH3COOF) [88, 89], are now known which have found applications as fluorinating agents [90–94] (Figure 3.12).

Nu: + FOCF3 NuF + OCF3

R' R' i, ii R' OSiMe3 iii R COOR'' R COOR'' ½89 OR'' H R F

i, LDA R = R' = n-Pr, R'' = Me, 90% ii, Me 3SiCl R = Ph, R' = Et, R'' = Me, 80% iii, MeCOOF

Figure 3.12

The ability of fluorine to act as an electrophile in these systems is achieved not so much by the withdrawal of electronic charge from fluorine but by the creation of excellent leaving groups attached to fluorine. If a good leaving group is not incorporated in this way, the hypofluorites can act as sources of positively charged alkoxonium ions, as in the cases of methyl and tert-butyl hypofluorite [95, 96] (Figure 3.13), rather than as electrophilic fluorinating reagents.

F OMe i 60-70% ½95 R1 R2 R1 R2

− i, MeOF, CH3CN, 40 C Room Temp

δ + δ − i ½96 C H -C CH C6H5-CH=CH2 6 5

δ − δ + F Ot-Bu i, t-BuOF, CH3CN

C6H5-CHFCH2Ot-Bu

Figure 3.13 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 57

Partial or Selective Fluorination 57

However, single-electron transfers promoted by photolysis, are the most likely processes when CF3OF is used as the fluorinating reagent [93]. Examples of the use of hypofluorites for conversion of C2HtoC2F bonds are given in Table 3.3.

Table 3.3 Fluorinations using O–F reagents

Substrate Reagent/Conditions Product Yield (%) Ref.

NO FNO 2 i) MeONa, MeOH 2 85 [97] ii) AcOF, CFCl3,08 C

O O F i) LDA, THF 86 [98] ii) AcOF, 788 C

O O OO AcOF, 72 [99] OEt CFCl3, CHCl3, 758 C OEt F

Caesium fluoroxysulphate (CsSO4F) [94] is a solid electrophilic fluorinating agent that is very easily prepared [100] (Figure 3.14) but, unfortunately, is very prone to rapid uncontrolled decomposition. However, it has been used for the fluorination of hydrocarbons [101] and aromatics [102–104] (Figure 3.15).

H2O ½100 Cs2SO4 + F2 CsSO3OF

Figure 3.14

i C6H5R FC6H4R ½102104

i, CsSO3OF, BF3, CH3CN

i p-XC6H4SnMe3 p-XC6H4F

− i, CsSO3OF, CH3CN, 4 to 0 C X = H, 69%; = Cl, 87%; = Me 86%

Figure 3.15 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 58

58 Chapter 3

C Electrophilic fluorinating agents containing N–F bonds [105–107] There is now available a range of stable, easily handled, solid electrophilic fluorinating agents of the N–F type. These remarkable reagents are generally prepared by reaction of a neutral base [108] or a salt [109] with fluorine (Figure 3.16).

(CF3SO2)2NH + F2 (CF3SO2)2NF + HF ½108

CH2Cl CH2Cl N N i BF4 2BF4 ½109 N N − i, F2, N2, NaBF4, CH3CN, 35 C F Selectfluor®

Figure 3.16

Reported reagents of this class include N-fluorobis(trifluoromethanesulphonyl)imide [110, 111], N-fluoro-N-alkyl-sulphonamides [112], dihydro-N-fluoro-2-pyridone [113], N-fluoropyridinium salts [114–116], N-fluoroquinuclidinium [117] and related salts [118, 119], N-fluoroperfluoroalkyl sulphonamides [120, 121] and N-fluorosultams [122], some of which are commercially available (e.g. Selectfluort, Air Products). Many fluorinations of resonance-stabilised carbanions [119], phosphonates [123], 1,3-dicarbonyls [124, 125], enol acetates [115], enol silyl ethers [119], enamines [119], aromatics (Chapter 9), double bonds and compounds containing carbon–sulphur bonds [126] have been performed under mild conditions (Table 3.4) and even enantioselective fluorinations of enolates are possible when appropriate homochiral N-fluorosultams are used [127, 128], or other homochiral substrates [129]. Considerable encouragement is given by reports of relatively high enantioselectivity in some processes where N–F compounds have been used in the presence of various chiral catalysts [130, 131], although the latter are currently used in significant proportions.

Table 3.4 Fluorinations using electrophilic N–F fluorinating reagents

Substrate Reagent/Conditions Product Ref.

O Me Me O Ph Ph [122] OMe N F OMe F CH3 S CH3 O O LDA, THF, 788 Ctort O O À n-Pr P OEt PhSO2Þ2NF n-Pr P OEt [123] OEt LDA, THF OEt FF

Contd Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 59

Partial or Selective Fluorination 59

Table 3.4 Contd

Substrate Reagent/Conditions Product Ref.

O O À OO CF3SO2Þ2NF [124] CH2Cl2,rt

O O CH2Cl OO N Ph NMe2 Ph NMe2 [125] − 2BF4 F N F

CH3CN, rt

OSiMe3 O − OTf F N [115] F

CH2Cl2, reflux

AcO U CH2Cl AcO U O O N F [126] − 2BF4 AcO S-Ar N AcO S-Ar F

Et3N, CH3CN, rt

O O F CO2Et [127] CO2Et N F S O O

NaH, Et2O, rt

It is frequently overlooked that, following fluorination, some of these systems, e.g. Selectfluort, are extremely acidic and may, consequently, ionise the carbon–fluorine bond just formed, leading to a carbocation and subsequent reaction with the solvent (see Section IIIA) [65]. These fluorinations are generally considered to proceed by nucleophilic attack on fluorine, rather than via an electron-transfer mechanism [115], as determined from radical Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 60

60 Chapter 3 clock experiments [69, 70]. Consistent with this view, ionic liquids have been used as solvents for fluorinations of aromatic systems with Selectfluort [132, 133] and supercritical carbon dioxide has been used with 2,2’-bipyridinium fluorides [134].

D Xenon difluoride [135–137] This reagent acts as a source of electrophilic fluorine but the nature of the products can depend on the acidity of the glass surface of the vessel used. Otherwise a single electron transfer process may intervene [138] (Figure 3.17).

X X i F ½139

i, XeF2, BF3.OEt2 X = O, CH2

OSiMe3

i) Aprotic conditions ½138 ii) Protic conditions XeF2 XeF2 i ii

O O O O F F O ++

Figure 3.17

Xenon difluoride has also been used for the fluorination of enol derivatives [5] and 1,3-dicarbonyl compounds [140], and fluorination of activated aromatic substrates is possible in the presence of a Lewis acid [141].

E Miscellaneous

Fluorinations using perchloryl fluoride (FClO3) have been reported [17, 142] but, since the perchloric acid that is formed as a side-product gives an explosive mixture with organic compounds, this approach to selective fluorinations is not recommended. Fluorination of hydrocarbons, such as adamantane, is possible using a mixture of nitrosonium tetrafluoroborate and pyridineHF [143] (Figure 3.18). Oxidative fluorination of phenols in amineHF solution gives difluorodienones [144] (Figure 3.19). Fluorination of aromatic substrates has been reported [145]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 61

Partial or Selective Fluorination 61

R C H 3 i R CF ½143 R3CH R3C 3

− NO + R3CNO i, NO BF4, Py.HF

Figure 3.18

OH O

i 30% ½144

i, PbO2, Py.HF

Figure 3.19

Oxidative fluorination of toluene derivatives to the corresponding fluoromethylben- zenes is possible using appropriate lead or nickel complexes in liquid hydrogen fluoride, but fluorination becomes more difficult as the reaction progresses because fluorine substituents increase the oxidation potential of the substrate [146] (Figure 3.20). Conse- quently, it seems unlikely that the ECF process (Chapter 2, Section III) could proceed to perfluorination by an analogous mechanism.

− + Pb(OAc)4 H ArCH3 (ArCH3) ArCH2 ½146 HF, −e −e

etc Ar CF2H ArCH2F ArCH2

Ar = p-C6H4NO2

Figure 3.20

a-Fluoro sulphides may be prepared by reaction of the parent sulphides with either XeF2 [147], an N–F-type reagent [148], or anodic fluorination in Et3N3HF as the electrolytic medium [149, 150]. A Pummerer-type mechanism has been proposed (Figure 3.21a). F F H − S S H S C S R R CH3 R CH3 H R CH2F

Figure 3.21a

Similarly, a-fluoro sulphoxides are prepared by fluorination using DAST [151]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 62

62 Chapter 3

Remarkably, iodine pentafluoride in Et3N3HF acts, in some cases, like an electrophilic fluorinating agent, replacing C2H in preference to oxygen functions [152] (Figure 3.21b).

COCH2SEt ½152 COCF2SEt i, ii + IF5 FF FF 82%

i, iii CH3COCH2COOEt + IF5 CH3COCHFCOOEt

71% i, Et3N.3HF ii, heptane 74 C iii, heptane 40 C

Figure 3.21b

IV FLUORINATION OF OXYGEN-CONTAINING FUNCTIONAL GROUPS A Replacement of hydroxyl groups by fluorine 1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent The low boiling point and the health hazard associated with anhydrous hydrogen fluoride makes it very difficult to handle in the laboratory, even though it is used extensively by industry. Various amine/hydrogen fluoride complexes, which are markedly less volatile and less acidic than hydrogen fluoride, have been prepared and used as fluorinating agents [15, 153]. The most commonly used base/HF systems are triethylamine tris(hydrogenfluoride) and pyridinium poly(hydrogenfluoride) (PPHF, Olah’s reagent). Secondary and tertiary alcohols can be converted to the corresponding fluorides by reaction with pyridineðHFÞn [43] (Figure 3.22). Preferential fluorination of tertiary alcohols over OH F i 99% ½43

i, Pyridine.(HF)n, 20 C, 2 hr

OH F

i 95%

i, Pyridine.(HF)n, 20 C, 1 hr

Figure 3.22 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 63

Partial or Selective Fluorination 63 secondary hydroxyl groups is possible, due to the much higher reactivity of tertiary hydroxyl groups towards pyridineðHFÞn [154] (Figure 3.23).

i ½154

OH O F O HO HO

− i, Pyridine.(HF)n, 35 C, CH2H2

Figure 3.23

Proton SpongeHF (Figure 3.24) is a particularly useful system which is an effective fluoride-ion donor for appropriate fluorinations [38, 155]; it is likely that the proton in this system is much less involved in H-bonding to fluoride than is the proton in hydrogen fluoride.

Me2N NMe2 Proton Sponge. HF (PS.HF) ½38 F

F3C C2F3 i C3F6 PS.HF + CF2CFCF3 (CF3)2CF F3C F 72% i, CH3CN, rt

H H N i N Cl F + PS.HCl N N 79% i, PS.HF, CH3CN, rt

Figure 3.24

A combination of IF5 with Et3N3HF appears to be effective in replacing hydroxyl [152] (Figure 3.25).

2 Diethylaminosulphur trifluoride (DAST) and related reagents [156–158] DAST was first used as an alternative fluorinating agent to sulphur tetrafluoride, by Middleton [159]. Although DAST, prepared by the reaction of SF4 with diethylamino- trimethylsilane [160] (Figure 3.26), can be used in normal laboratory glassware at Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 64

64 Chapter 3

i, ii p-CH -C H -CH OH + IF 3 6 4 2 5 p-CH3-C6H4-CH2F ½152 83% i, Et3N.3HF ii, CH2Cl2

Figure 3.25

SF4 + Et2NSiMe3 Et2NSF3 + Me3SiF ½159 DAST

Figure 3.26 atmospheric pressure, care must be exercised since it may decompose violently above 508 C [161]. Consequently, more stable analogues such as the morpholino [162] and piperidino derivativesÀ have been used and a methoxyethyl derivative has become commercially available, MeOCH2CH2Þ2NSF3 (Deoxo-Fluort, Air Products Company) [163]. Primary, secondary, tertiary and allylic hydroxyl groups are replaced by fluorine in excellent yields [12, 164] via a process involving an intermediate alkoxysulphur difluoride, the presence of which is supported by both spectroscopic [165] and chemical evidence [166] (Figure 3.27).

F ½165, 166 ROH + Et2NSF3 ROSF2NEt2 RF + FSONEt2

Figure 3.27

For most substrates SN2 replacement of hydroxyl by fluorine occurs with complete inversion of configuration [12] although retention of stereochemistry is observed when neighbouring groups containing either C5C double bonds, oxygen or nitrogen become involved in the reaction centre [17]. Allylic alcohols may be converted to mixtures of 0 isomeric allyl fluorides by either an SNiorSN2 process [12] (Figure 3.28).

NEt F 2 ½12 F S O

R SNi

F R

F NEt2 F S O SN2'

Figure 3.28 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 65

Partial or Selective Fluorination 65

Table 3.5 Replacement of hydroxyl groups by fluorine

Substrate Reagents/Conditions Product Yield (%) Ref. n-C8H17OH DAST n-C8H17-F 90 [159] CH2Cl2, 708 Ctort

PhCH2CH2OH Deoxo-Fluort PhCH2CH2F 85 [163] CH2Cl2, rt, 16 h HO F DAST O O F CH2Cl2, 408 Ctort F 71 [167] HO HO HO HO OMe OMe À À Et2OÞ2POCHðOHÞPh DAST Et2OÞ2POCHFPh 53 [168] CH2Cl2,rt

H C O SPh H C O F 3 DAST 3 CH2Cl2,08 C [169] O OH O SPh O O

Such is the versatility of DAST and related reagents that many fluorinated derivatives of natural products, including steroids, carbohydrates, nucleosides, prostaglandins and vitamin D analogues, amongst others, have been successfully synthesised [10, 16, 17] (Table 3.5). Generally, sulphur tetrafluoride can only be used for fluorodehydroxylations of acidic alcohols, otherwise extensive decomposition to side-products predominates. However, b-fluoroamino acids can be prepared by such a process [7].

3 Fluoroalkylamine reagents (FARs) [170]

Fluoroalkylamine reagents (FARs) such as the Yarovenko reagent [171], Et2NCF2CFClH, and Ishikawa’s reagent [172], Et2NCF2CFHCF3, have been used to fluorinate alcohols, carboxylic acids and hydroxyamino acids [173–175] (Figure 3.29), most probably by a process outlined in Figure 3.30. More recently, the adduct to tetrafluoroethene, Me2NCF2CF2H, has been shown to be a viable alternative reagent [176]. Enantio-controlled processes have been developed [177]; polymer-supported [178] FARs and other related systems such as PhCF22NMe2 have also been studied [179], and reactions in supercritical carbon dioxide have been reported [180]. 2,2-Difluoro-1,3-dimethylimidazoline (DFI) has recently been prepared and is very useful for replacing OH in alcohols by F. Carbonyl is converted to CF2 with accompanying elimination in some cases, whereas carboxyl is not converted to CF3 [181] (Figure 3.31). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 66

66 Chapter 3

O O ½173175 i

HO F 57%

i, Et2NCF2CFClH, CH2Cl2

O O i 45% HO OMe F OMe

i, Et2NCF2CFHCF3, CH2Cl2, 18 hr

Figure 3.29

F F F Et Et Et −F NCCFHCF3 NCCFHCF3 NCCFHCF3 Et Et Et F O O RH R H

−H

F Et Et Et −F NCCFHCF3 NCCFHCF3 NC CFHCF3 Et Et Et O O O R R

+ RF F

Figure 3.30

B Replacement of ester and related groups by fluorine Fluoride-ion substitution of an acetyl group has, generally, been limited to the preparation of glycosyl fluorides [182] (Figure 3.32). However, displacement of sulphur ester groups such as tosylate [183], mesylate [184] and triflate [185] groups are of much greater synthetic importance. These excellent leaving groups are readily displaced by an active source of fluoride ion; this process represents an efficient method for the overall transformation of hydroxyl groups to fluorinated derivatives (Figure 3.33).

C Fluorination of carbonyl and related compounds 1 Sulphur tetrafluoride and derivatives Sulphur tetrafluoride, a colourless gas (b.p. 388 C) with toxicity of the same order as phosgene, has been commercially available since a practical method for its synthesis was Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 67

Partial or Selective Fluorination 67

COCl2 KF ½181 N N N N N N Me Me Me Me Me Me O Cl F F Cl

DFI

i, ii n-C8H17OH n-C8H17F 87%

i, iii p-HOC6H4-NO2 p-FC6H4-NO2 62%

O FF F

i, iv

21% 72% i, DFI ii, CH3CN, 25 C iii, CH3CN, 85 C iv, Glyme, 85 C

Figure 3.31 O AcO ½182 O i AcO O O OCOCH3 F O O O O

i, HF, CH3NO2, Ac2O, 0 C, 3 hr

Figure 3.32 developed [186, 187] (Figure 3.34), although it is difficult to purify [188]. Its most general function is to exchange C5O for CF2 and it is usefully applied to the conversion of aldehydes and ketones to the corresponding difluorides, and of carboxylic acids (via the acid fluoride) to trifluoromethyl derivatives. Many examples have been documented and reviewed [2, 7, 156, 189] (Figure 3.35). The observation that anhydrides are not as reactive as carboxylic acids led to the use of acid catalysts with sulphur tetrafluoride; reactions are frequently carried out in the presence of anhydrous hydrogen fluoride, while BF3, AsF3,PF5 and TiF4 are also potent catalysts [190]. Conversions can be achieved in the presence of a wide range of other functional groups, for example bromo, chloro and unsaturated functions, although under some circumstances halogen exchange occurs [191]. Exchange of C5O for CF2 occurs in many classes of carbonyl compounds [2, 7, 156, 189], such as amides, esters, 1,2-dicarbonyls, hydroxy ketones, lactones, acid halides, carboxylic acids, some quinones Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 68

68 Chapter 3

i n-C8H17OSO2C6H4CH3 n-C8H17F 59% ½183

i, KF, PEG 400, 27hr, 50 C

OSO2CH3 F i OCH3 OCH3 83%: 96% e.e. ½184

O O

i, KF, HCONH2, 60 C, 20 torr

O O F i 65% ½185 OSO CF Cl 2 3 Cl

i, Bu4NF, THF, 4 hr

Figure 3.33

CH3CN, 70 C 3 SCl2 + 4 NaF SF4 + S2Cl2 + 4 NaCl 90% ½186

3SCl2 + 4Py.(HF)n SF4 + S2Cl2 ½187

Figure 3.34

SF4, 150 C C6H5CHO C6H5CHF2 81%

SF4, 170 C HOOCC CCOOH CF3C CCF3 80%

Figure 3.35 and fluoroformates (Table 3.6). Quite reasonably, the mechanism has been formulated as in Figure 3.36 [190]. Conversion of benzene-1,3,5-tricarboxylic acid to the corresponding tris (trifluoromethyl) compound provided a new source of bulky ligands for the organometallic chemist [192] (Figure 3.37). The intervention of a radical process has been suggested to account for the anomalous reaction with anthrone, leading to exchange of hydrogen for fluorine rather than attack at the carbonyl group [193] (Figure 3.38). Aminosulphur trifluorides, which are easier to handle than SF4, can also be used for the conversion of most aldehydes and ketones to difluoromethylene derivatives; numerous examples have been documented [12] (Table 3.6). A similar reaction mechanism to that for SF4 may be assumed. Molybdenum hexafluoride [201], chlorine monofluoride [49] and phenylsulphur trifluoride [202] have all been used to perform similar transformations in a limited number of cases. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 69

Partial or Selective Fluorination 69

δδδ δ XFn SF4 CO CO XFn CO XFn ½190

FSF3

CF C OSF2 C OSF3 + XFn F F F F

+ SOF2 + XFn FXF− n 1 XFn = Lewis Acid

Figure 3.36

COOH CF3 CF3 Li etc ½192

HOOC COOH F3C CF3 F3C CF3

Figure 3.37

O O

i 82% ½193

FF i, SF4, HF, CH2Cl2

Figure 3.38

D Cleavage of ethers and epoxides [157] The reaction between epoxides and HF gives fluorohydrins and, generally, other products resulting from extensive polymerisation. However, the acidity and reactivity of HF may be decreased by the addition of a base, either an amine or KF, or by complexation with a Lewis acid, such as borontrifluoride etherate [174]. Consequently, pyridineHF, Et3N3HF [203] and i-Pr2NH3HF [204] efficiently cleave epoxides to give excellent yields of fluorohydrins (Figure 3.39).

O F H H ½204 i-Pr2NH.HF OH

Figure 3.39

The regioselectivity of the reaction is dependent on the hydrofluorinating reagent used.

PyridineðHFÞn is highly acidic and the reaction proceeds by protonation of the ring oxygen, followed by fluoride ion attack on the carbon atom upon which the developing Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 70

70 Chapter 3

Table 3.6 Fluorination of carbonyl and related groups

Substrate Reagent, conditions Product Yield (%) Ref.

C6H5CHO SF4, 1508 C, 6 h C6H5CF2H 81 [194] C6H5CHO Deoxo-Fluort,rt C6H5CF2H 95 [163]

O O O F SF4, 1308 C F F [195] O O F O

CO2H CF3

SF4, 1008 C 25 [196] N N

CO2H CF3 F F CO2H SF4, HF, 2008 C O 76 [197]

CO2H F CF F CO2H 3

HO2CCO2H F3CCF3

SF4, HF, 1408 C 18 [198]

HO2CCO2H F3C CF3

O HF C OMe 2 O H OMe O

DAST, CH2Cl2,rt 45 [199] O O O O

C6H5COCH2F DAST, benzene, 508 CC6H5CF2CH2F 82 [200]

positive charge is most readily stabilised. Conversely, i-Pr2NH3HF is not sufficiently acidic to protonate the ring oxygen significantly and so ring opening occurs by fluoride- ion attack at the least hindered carbon atom in an SN2 process [205] (Figure 3.40). Larger oxygen-containing rings can also be cleaved [206] (Figure 3.41). Recently, silicon tetrafluoride [207] and tetrabutylphosphonium fluoride [208] have been used to prepare fluorohydrins from epoxides. Generation of a superacid is required for the ring opening of a perfluorinated oxirane [209] (Figure 3.42). Silyl ethers may be cleaved by either Bu4NF=CH3SO2F [210] or ArPF4 [211] to give alkyl fluorides. Fluoroformates decarboxylate, on heating in the presence of an acid catalyst, to give the corresponding fluoride [212, 213] (Figure 3.43). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 71

Partial or Selective Fluorination 71

O OH F ½205 + OBu OBu OBu F OH

Reagent : i-Pr2N.3HF Ratio : 6 1 Yield, 81% Pyridine.HF 1 4 68%

Figure 3.40

F F CF ½206 HF, 95 C 3 O

COF FF

Figure 3.41 O F CF3 i (CF3)3COH 56% ½209

FCF3

i, HF, SbF5, 100 C

Figure 3.42

OCOF F ½212, 213 i

− i, AlF3, HF, 200 300 C

OCOF F Me Me Me Me i ½214

i, HF, 130 C 69-75%

Figure 3.43

V FLUORINATION OF SULPHUR-CONTAINING FUNCTIONAL GROUPS

Several methods concerning the formation of CF, CF2 and CF3 groups by fluorodesulphurisation [215, 216] processes have been reported (Table 3.7). Generally, these fluorinations are achieved by first activating the C2SorC5S bonds by complexation of the sulphur atom with a thiophilic reagent, such as an iodonium-ion source, followed by nucleophilic attack at the carbon atom, now a site of developing positive charge, by fluoride ion (Figure 3.44). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 72

72 Chapter 3

Table 3.7 Fluorodesulphurisation reactions

Substrate Reagents/Conditions Product Yield (%) Ref.

BnO BnO p-MeC6H4-IF2 [217] O O BnO BnO F BnO CH2Cl2, 788 Ctort BnO BnO BnO S-Ar

CF CF PyridineðHFÞ , NBSa 2 3 SS n [218] CF 78Ctort 3 n-Pr n-Pr

CF2Ph SS

Ph F2,I2,CH3CN, rt [219] Br

CF2H BrF 70 [220] SS 3

C6H11 H

S S Me F O b O DAST ,CH2Cl2,rt [221]

PyridineðHFÞn, NBS C(SEt)3 CF3 [222] S 788 Ctort S

S Br CF3 Br SEt BrF3,08 C [223]

PhCH2 PhCH2 Bu N þ H F N SMe 4 2 3 N [224] CF3 NBS, rt MeO S MeO a NBS, N-bromosuccinimide. b DAST, diethylaminosulphur trifluoride. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 73

Partial or Selective Fluorination 73

I I CSR CSR CF

Figure 3.44

More recently, dithionylium salts (3.45A) have been explored for reactions with diols, amines and even azide [225], in the presence of fluoride sources, and an electrophilic brominating agent 5,5-dimethylhydantoin (DBH) to effect desulphurisation. High yields are obtained under very mild conditions (Figure 3.45).

S i-iv ½225 RCF2N3 RCF3SO3 S 89% 3.45A i, Me3SiN3, CH2Cl2, 0 C ii, Bu4NF, THF, 0 C iii, Et3N.3HF iv, DBH

Figure 3.45

VI FLUORINATION OF NITROGEN-CONTAINING FUNCTIONAL GROUPS A Fluorodediazotisation [226] In the classic Balz–Schiemann reaction [227, 228], arylamines are converted to fluoroaromatics via the corresponding diazonium tetrafluoroborate salts. The leaving group, molecular nitrogen, is lost on pyrolysis and the mechanism appears to involve formation of an aryl cation, which then abstracts fluoride ion from the tetrafluoroborate counter-ion (Figure 3.46). Variations of this procedure include the use of nitrite esters [229] as alternative nitrosating agents and the decomposition of hexafluorophosphate [230] and hexafluoroantimonate [231] diazonium salts. Photolysis [232], rather than pyrolysis, has been successfully used for the decomposition stage. When anhydrous HF, or the less volatile pyridineðHFÞn, is used as the reaction medium, isolation of the intermediate is unnecessary because decomposition of the diazonium salt occurs in situ. Many fluorinated aromatics can be prepared (Table 3.8) and, indeed, fluorobenzene is manufactured on a multi-ton scale using this methodology. Benefits arising from the use of ionic liquids have been claimed [233]. i, ii heat ½227, 228 ArNH2 Ar N2 BF4 Ar F

i, HCl, NaNO2 ii, HBF4

Figure 3.46 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 74

74 Chapter 3

HO R ½234 R COOH R O OH R COOH H

H2NH N2 H FH O (HF)nF

Figure 3.47

By a similar process, amino acids have been converted to a-fluorocarboxylic acids by fluorodediazotisation processes [234] and, generally, retention of configuration is observed due to neighbouring group participation of the adjacent carboxyl group (Figure 3.47 and Table 3.8).

B Ring opening of azirines and aziridines Aziridines may be ring-opened regioselectively by either HF or amineHF mixtures to give b-fluoroamine derivatives [239, 240]. The mechanism, either SN1orSN2, and consequently the stereochemical outcome of the reaction are greatly influenced by the precise nature of both the aziridine and the fluorinating agent used. For example, phenyl- substituted aziridines can be considered to react via the most stable carbocation in an SN1 process, which accounts for the mixture of stereoisomers obtained [239] (Figure 3.48). 1-Azirines also may be ring-opened in a similar manner [241].

Table 3.8 Fluorodediazotisation

Substrate Reagents/Conditions Product Yield (%) Ref.

Me Me i, NaNO2, HCl NH F 2 ii, HBF4 [235] iii, Heat

Me Me

H2N CO2Et FCO2Et i, NaNO2, HBF4 39 [236] ii, hn, HBF4, 508 C NNH NNH

NH2 F

NaNO2, pyridineHF 93 [237] N N

H3C COOH R COOH NaNO2, pyridineHF 76 [238]

H2NH FH Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 75

Partial or Selective Fluorination 75

H H2 N H N NH2 ½239 H H H H H

Ph Me Ph Me Ph Me

F NH2 F NH2 Ph H + HMe Ph Me

69% 8%

Figure 3.48

C Miscellaneous Nucleophilic substitution of nitro [242, 243] and trimethylammonium groups [244] by fluoride ion has been employed for the preparation of a number of fluoroaliphatic and fluoroaromatic substrates (Figure 3.49).

KF, sulpholan (NO2)3CF (NO2)2CF2 59% ½242, 243

NO 2 NO2

i 70% ½242, 243

NO2 F

i, Me4NF, DMSO, 100 C, 4 hr

18 N(CH3)3 F

i 91% ½244 ClO4

NO NO2 2 i, Cs18F, DMSO, 120 C

Figure 3.49

Hydrazones can be converted into gem-difluorides upon reaction with either fluorine [245], bromine monofluoride (generated in situ) [246] or ‘iodine monofluoride’ [247], and the reaction of diazoketones with fluorine results in similar transformations [248] (Figure 3.50). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 76

76 Chapter 3

O O OO i 70% ½248 EtO OEt EtO OEt FF N2 − i, F2, CFCl3, 70 C

CH i 3 60% ½246 CF2CH3 NNH2

i, Pyridine.(HF)n, NBS, CH2Cl2

‘IF’

CH3 80% ½247

CF2CH3 NNH2

Figure 3.50

VII ADDITIONS TO ALKENES AND ALKYNES [249] A Addition of hydrogen fluoride Addition of hydrogen fluoride to alkenes proceeds, as might be expected, via trans addition in a typical Markovnikov process, with the complicating effect of cationic polymerisation of the alkenes [250] (see also Chapter 7). However, side-products resulting from polymerisation of the alkene may be reduced by performing the reaction in a lower-acidity amineHF mixture [43] (Figure 3.51).

HF, −45 C CH3 CHCH2 CH3CHFCH3 62% ½250

i F 65% ½43

i, Pyridine.(HF)n, THF, 0 C

Figure 3.51

Reactions with less nucleophilic, halogenated alkenes require more vigorous conditions and a Lewis acid catalyst is generally added to prepare commercially significant fluoro- haloalkanes [251, 252] (Figure 3.52). Addition to acetylenes occurs under a variety of conditions; the reaction of acetylene with hydrogen fluoride is important for the manufacture of vinyl fluoride, although the Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 77

Partial or Selective Fluorination 77

HF, TaF 5 CHClCCl2 CH2Cl CCl2F 89% ½251, 252

BF3, 25 C CF CHCl CF CH Cl 90% 2 HF 3 2

Figure 3.52 addition proceeds further to give some difluoroethane [253]. With pyridineHF the reaction goes via the expected intermediate fluoroalkene to give difluoroalkanes only [43] (Figure 3.53). i ½43 C4H9C CH C4H9CF2CH3 70% i, Pyridine.(HF)n, THF, 0 C

Figure 3.53

The addition of hydrogen fluoride to electron-deficient alkenes and alkynes can be achieved in certain cases via an indirect process in which reaction of the alkene or alkyne with fluoride ion leads to a carbanion that abstracts a proton from the solvent. This method, however, is limited to cases where other reactions of the carbanion are hindered or less favourable [254, 255] (Figure 3.54). F F CF3 i C6H5 O C6H5 O 71% ½254

OR OR R = methyl i, Bu4NF, THF, 0 C, MeC6H4SO3H

i F CO2Me MeOOCC CCOOMe ½255 MeO2C H 90% i, Bu4NH2F3, CH2Cl CH2Cl, 60 C

Figure 3.54

Hydrofluorination of corresponding C5N bonds of isocyanates and diazoketones gives carbamyl fluorides and a-fluoroketones repectively [43].

B Direct addition of fluorine It was first shown that the addition of fluorine to haloalkenes can be controlled if the temperature is lowered, competition between fluorine addition and dimer formation being dependent on the conditions [256] (Figure 3.55). Russian workers subsequently reported controlled addition to vinyl acetate [257] and fumaric acid [258], to give difluoroethyl acetate and monofluoroacetaldehyde, respectively. Selective fluorination of many alkanes [8, 259], such as acenaphthene [260], Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 78

78 Chapter 3

− F2, 75 C CF3CF=CFCF3 CF3CF2CF2CF3 + [CF3CF2CF(CF3)]2 ½256 CFCl3

Figure 3.55

1,1-diphenylethene [261] and many steroids [236], is now possible in sometimes surprisingly high yield by passing fluorine diluted with an inert gas through a solution of the unsaturated compound (Table 3.9).

Table 3.9 Direct fluorination of alkenes

Substrate Reagent, conditions Product Yield (%) Ref.

O O F2,N2 CFCl3, CHCl3, EtOH 35 [259] 758 C FF

65 [237]

O O F F

O F O F2,N2 F N CFCl3, CHCl3, EtOH N 41 [262] 788 C Boc Boc

AcO O AcO O F

F2,Ar 40 [263] CFCl3, 788 C AcO AcO F OAc OAc

Unlike other halogenation reactions, direct fluorinations of alkenes give products resulting predominantly from syn addition, and a mechanism suggesting a four-centred intermediate formed by a concerted pathway was first proposed to account for this [238]. Further experimental [259] and theoretical work [235] provide evidence for an electrophilic mechanism involving a tight ion-pair (3.56A) as an intermediate. Collapse of this ion-pair 3.56A gives the syn-1,2-difluoride, whilst loss of a proton forms a fluoroalkene which may then undergo further fluorination to yield a trifluoride (Figure 3.56). Three products are observed in the fluorination of 1,1-diphenylethene [238] (Figure 3.57). A carbocationic intermediate is further supported by observed rearrangements [236] (Figure 3.58). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 79

Partial or Selective Fluorination 79

F δ F F δ F F F F F ½235, 259

H H H H 3.56A

−H

F F F2 F F

Figure 3.56

F2, N2 Ph2CCH2 Ph2CFCH2F + Ph2CCHF + Ph2CFCF2H ½238 14% 78% 8%

Figure 3.57

O O ½236

F , N 2 2 F

AcO Cl Cl

O F O F F F

Figure 3.58

C Indirect addition of fluorine Reaction of alkenes with an electrophilic fluorinating agent such as caesium fluoroxysulphate, in the presence of fluoride ion, can result in addition of fluorine to the double bond [264] (Figure 3.59). Carbocationic species are also considered to be intermediates in reactions between iodobenzene difluoride and alkenes [265, 266]. Tetrafluorination of alkynes is possible using nitrosonium tetrafluoroborate and pyridineðHFÞn [267] (Figure 3.60). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 80

80 Chapter 3

Ph Ph F i ½264 H H syn:anti Ph F Ph 65 : 35

i, CsSO3OF, HF, CH2Cl2, 20 C

Figure 3.59 i 75% ½267 PhC CPh PhCF2CF2Ph

i, NO BF4, Pyridine.(HF)n

Figure 3.60

Of course, most reactive metal fluorides, such as cobalt trifluoride [268] and vanadium pentafluoride, will react with alkenes but the reactions can be very difficult to control, except for haloalkenes [269]. Much easier control is possible with xenon fluorides [137], the reactivity decreasing in the series XeF6 > XeF4 > XeF2. Since the first report of the use of xenon difluoride for the addition of fluorine to double bonds, many studies have been published and reviewed [54, 135] (Figure 3.61).

HF, CH2Cl2 PhCHCHPh + XeF2 PhCHFCHFPh 90% ½270

cis erythreo:threo = 53 : 47 trans 62 : 38

HF, CH2Cl2 F + XeF2 F + F F 87 13

Figure 3.61

The reaction is non-stereoselective, contrary to direct fluorination, and it is found that only slight changes in either the reaction conditions or the structure of the substrate can give rise to differing amounts of syn or anti addition. The addition of a Lewis acid, usually HF [270] or BF3 Et2O [271], to the reaction mixture gives much higher yields of the desired difluoroalkanes, and both ionic and single-electron transfer pathways have been suggested [272, 273].

The very reactive species PbðOCOCH3Þ2F2, formed in situ by the reaction of lead tetra- acetate with hydrogen fluoride [274], has been used very effectively for adding fluorine to alkenes, especially in the synthesis of the biologically important 6a-fluoro steroidal hormones [275].

D Halofluorination The combination of a source of electrophilic halogen together with a fluoride ion reagent permits efficient halofluorination of nucleophilic carbon–carbon double bonds; products resulting from addition in a trans stereochemistry are usually obtained (Figure 3.62). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 81

Partial or Selective Fluorination 81

Hal Hal Hal F

Figure 3.62

A wide variety of reagent systems have been developed to carry out this synthetically useful reaction (Table 3.10). The intermediate halonium ion may undergo well-established carbocationic rearrangements, for instance in the halofluorination of norbornadiene [276] (Figure 3.63). The reaction has been used extensively for the introduction of fluorine into steroids [277], where a curious anomaly arises between BrF and IF addition. As indicated, stereospecific anti addition occurs in most reactions but syn addition of BrF or IF to carbohydrates has been observed [278]. Halofluorination of alkynes proceeds as expected, although further reaction of the resulting alkene derivative can occur.

Table 3.10 Halofluorination of alkenes and alkynes

Substrate Reagent/Conditions Product Yield (%) Ref.

a F NIS , pyridineHF 65 [43]

b C H DBH , KF2H2O 4 9 87 (9:1) [279] C4H9 Br H2SO4,CH2Cl2 F + C4H9 F Br

Me Me − 60 [280] NIBF4 F

2 I

CH2Cl2,08 C F Br2, AgNO3 pyridineHF 85 [43]

Br a NIS, N-iodosuccinimide. b DBH, 1,3-dibromo-5,5-dimethylhydantoin. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 82

82 Chapter 3

i 53% ½276 Br F

i, NBS, Et3N.3HF, CH2Cl2, 0 C

38% Br

5% Br

Figure 3.63

E Addition of fluorine and oxygen groups Evidence has been presented that hypofluorites (see Section IIIB) can act as sources of electrophilic fluorine for reactions with electron-rich double bonds [11, 93]. Syn addition usually occurs and a tight ion-pair intermediate similar to that postulated to occur in the direct fluorination of alkenes can be envisaged. However, electron-transfer processes have been invoked [93] to explain some anomalous results and cannot be discounted [281] (Figure 3.64).

H3C H3C H3C O O O ½281 i AcO AcO Y+AcO Y

X AcO AcO X AcO

X=F, Y=OCF , 11% − X=F, Y=OCF , 31% 3 i, CF3OF, CFCl3, 70 C 3 X=Y=F, 22% X=Y=F, 12%

Figure 3.64

Additions of hypofluorites to unsaturated sites have been performed [17] on a wide variety of substrates [282, 283] (Figure 3.65). CsSO3OF reacts with alkenes to give fluoroalkyl sulphates [284].

F Other additions In a similar process to halofluorination, sulphur- [285], selenium- [286] and nitrogen- containing [43] groups and fluorine may be added to hydrocarbon double bonds by reaction of an alkene with an electrophilic reagent of the heteroatom species in conjunction with a fluoride-ion source (Figure 3.66). As expected, Markovnikov addition in trans stereochemistry occurs mainly. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 83

Partial or Selective Fluorination 83

F OMe ½282 i 40%

− i, CH3OF, CH3OH, CH3CN, 40 C

OAc OAc ½283

AcO AcO OCF F 3 − i, CF3OF, CFCl3, 75 C 59%

Figure 3.65

Ph i Ph SCH3 ½285 H H 90% F CH3 CH3

− i, (CH3)2SSCH3 BF4, Et3N.3HF, CH2Cl2, rt

i SePh ½286 F MeO MeO 53%

i, PhSeCl, AgF, CH3CN

F i 65% ½43

NO2

i, NO2BF4, Pyridine.HF, 0 C

Figure 3.66

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249 P. Wolfram in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b/Part 1, Organo- fluorine Compounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 308. 250 A.V. Grosse and C.B. Linn, J. Org. Chem., 1938, 3, 26. 251 A.L. Henne and R.C. Arnold, J. Am. Chem. Soc., 1948, 70, 758. 252 A.E. Feiring, J. Fluorine Chem., 1979, 14,7. 253 F.W. Swarmer, US Pat. 2 830 100 (1958); Chem. Abstr., 1958, 52, 19943a. 254 T. Kitazume and T. Onogi, Synthesis, 1988, 614. 255 J. Cousseau and P. Albert, Bull. Chim. Soc. Fr., 1986, 910. 256 W.T. Miller, J.O. Stoffer, G. Fuller and A.C. Currie, J. Am. Chem. Soc., 1964, 86, 51. 257 A.Y. Yakubovich, S.M. Rozenshtein and V.A. Ginberg, USSR Pat. 162 825 (1965); Chem. Abstr., 1965, 62, 451g. 258 A.Y. Yakubovich, V.A. Ginsberg, S.M. Rozenshtein and S.M. Smirnov, USSR Pat. 165 162 (1965); Chem. Abstr., 1965, 62, 9018g. 259 S. Rozen and M. Brand, J. Org. Chem., 1986, 51, 3607. 260 R.F. Merritt and F.A. Johnson, J. Org. Chem., 1966, 31, 1859. 261 R.F. Merritt, J. Org. Chem., 1966, 31, 3871. 262 A. Toyota, M. Aizawa, C. Habutani, M. Katagiri and C. Kaneko, Tetrahedron, 1995, 51, 8783. 263 T. Ido, C.N. Wan, J.S. Fowler and A.P. Wolf, J. Org. Chem., 1977, 42, 2341. 264 S. Stavber and M. Zupan, J. Org. Chem., 1987, 52, 919. 265 W. Carpenter, J. Org. Chem., 1966, 31, 2688. 266 T.B. Patrick, J.J. Scheibel, W.E. Hall and Y.H. Lee, J. Org. Chem., 1980, 45, 4492. 267 C. York, G.K.S. Prakash and G.A. Olah, J. Org. Chem., 1994, 59, 6493. 268 A. Bergami and J. Burdon, J. Chem. Soc., Perkin Trans. 1, 1975, 2237. 269 G.G. Furin and V.V. Bardin in New Fluorinating Agents in Organic Synthesis, ed. L. German and S. Zemskov, Springer-Verlag, Berlin, 1989, p. 117. 270 M. Zupan and A. Pollak, Tetrahedron Lett., 1974, 1015. 271 S.A. Shackelford, R.R. McGuire and J.L. Pflug, Tetrahedron Lett., 1977, 363. 272 M. Zupan, M. Metelko and S. Stavber, J. Chem. Soc., Perkin Trans. 1, 1993, 2851. 273 S. Stavber, T. Sotler, M. Zupan and A. Popovic, J. Org. Chem., 1994, 59, 5891. 274 J. Bornstein, M.R. Borden, F. Nunes and H.I. Tarlin, J. Am. Chem. Soc., 1963, 85, 1609. 275 A. Bowers, P.G. Holton, E. Denot, M.C. Loza and R. Urquiza, J. Am. Chem. Soc., 1962, 85, 1050. 276 G. Alvernhe, D. Anker, A. Laurent, G. Haufe and C. Beguin, Tetrahedron, 1988, 44, 3551. 277 A. Bowers, E. Denot and R. Becerra, J. Am. Chem. Soc., 1960, 82, 4007. 278 K.R. Wood, P.W. Kent and D. Fisher, J. Chem. Soc., 1966, 912. 279 D.Y. Chi, D.O. Kiesewetter, J.A. Katzenellenbogen, M.R. Kilbourn and M.J. Welch, J. Fluorine Chem., 1986, 31, 99. 280 R.D. Evans and J.H. Schauble, Synthesis, 1987, 551. 281 G.C. Butchard and P.W. Kent, Tetrahedron, 1979, 35, 2439. 282 S. Rozen, O. Lerman, M. Kol and D. Hebel, J. Org. Chem., 1985, 50, 4753. 283 D.H.R. Barton, L.J. Danks, A.K. Ganguly, R.H. Hesse, G. Tarzia and M.M. Pechet, J. Chem. Soc., Perkin Trans. 1, 1976, 101. 284 N.S. Zefirov, V.V. Zhdankin, A.S. Kozmin, A.A. Fainzilberg, A.A. Gakh, B.I. Ugrak and S.V. Romaniko, Tetrahedron, 1988, 44, 6505. 285 G. Haufe, G. Alvernhe, D. Anker, A. Laurent and C. Saluzzo, Tetrahedron Lett., 1988, 29, 2311. 286 J.R. McCarthy, D.P. Matthews and C.L. Barney, Tetrahedron Lett., 1990, 31, 973. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 91

Chapter 4 The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres

I INTRODUCTION Part of the interest in fluorocarbon systems lies in a comparison of the chemistry, and particularly reaction mechanisms, of fluorocarbon derivatives with those of the corresponding hydrocarbon compounds. Indeed, such comparisons pose quite a strenuous test on our theories of organic chemistry. As will be seen, our understanding of the influence of carbon–fluorine bonds on reaction mechanisms has made considerable progress. Nevertheless, it must be emphasised that fluorocarbon derivatives present much more complicated systems than their corresponding hydrocarbon compounds because, in addition to effects arising from different electronegativities, the effect of the lone pairs of electrons of fluorine that are not involved in s-bonds must be taken into consideration. Furthermore, the relative importance of these effects seems to be very dependent on the centre to which the fluorine is attached. In this chapter we assess the effect of fluorine on some charged and neutral systems largely at a qualitative level, where this effect can be relatively well defined. Indeed, it could be argued that models of reactivity that are to be useful over a variety of related reagents, in various concentrations and solvents, are by necessity only qualitative.

II STERIC EFFECTS Replacing hydrogen in an organic molecule by fluorine does not significantly alter the geometry of many systems, but this does not necessarily mean that fluorine and hydrogen ˚ ˚ are isosteric. A comparison of the van der Waals radii, rvðHÞ 1.20 A, rvðFÞ 1.47 A and ˚ rv(O) 1.52 A [1], suggests that fluorine is isosteric with oxygen, and this fact has long been recognised for the development of bioisosteric compounds in medicinal chemistry [2]. The C–F bond length (1.38 A˚ ) is slightly longer than C–H (1.09 A˚ ); in very crowded systems this can be significant. For example, phenyl ring rotation of the cyclophane system (Figure 4.1) is slower when X ¼ F than when X ¼ H, because of the larger steric requirement of fluorine over hydrogen [3]. Substituent steric effects are generally regarded in terms of Taft Es or Charlton n parameters [4], and a number of these values for fluorinated groups, along with those for some hydrocarbon groups, are listed in Table 4.1. These data suggest, for instance, that CF3 groups are much more sterically demanding than methyl substituents and that they

92 Chapter 4

½3 X

Figure 4.1 are more demanding than isopropyl groups. Indeed, van der Waals volumes, ˚ 3 ˚ 3 CH3 ¼ 16:8 A compared to CF3 ¼ 42:6 A , further illustrate this point [5] (Figure 4.2). ½5 H F H H F F

16.8A3 42.6A3

Figure 4.2

Table 4.1 Steric parameters [4]

Substituent Taft Es Charton n

H þ1.24 0 F þ0.78 — OH þ0.69 — CH3 0 0.52 CH2CH3 0.07 0.56 CHðCH3Þ2 0.47 0.76 CðCH3Þ3 1.54 1.24 CH2F 0.24 0.62 CHF2 0.67 0.68 CF3 1.16 0.91

III ELECTRONIC EFFECTS OF POLYFLUOROALKYL GROUPS [6] In this section we will deal with the effects of a polyfluoroalkyl group as a whole attached to a saturated, and therefore not formally charged, carbon atom. The effect of fluorine and fluorinated groups directly bonded to reaction centres such as intermediate carbocation and carbanion sites will be treated in separate sections.

A Saturated systems 1 Strengths of acids As fluorine is the most electronegative element, it could be expected that the introduction of a fluorine atom or polyfluoroalkyl group into the carbon chain of an organic acid, such Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 93

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 93

Table 4.2 pKa values of some organic acids and alcohols [7]

Carboxylic acid pKa Alcohol pKa

CH3COOH 4.76 CH3CH2OH 15.9 CH2FCOOH 2.59 CF3CH2OH 12.4 CH2ClCOOH 2.86 CCl3CH2OH 12.2 CHF2COOH 1.34 ðCF3Þ2CHOH 9.3 CHCl2COOH 1.35 ðCH3Þ3COH 19.2 CF3COOH 0.52 ðCF3Þ3COH 5.1 CCl3COOH 0.56 ðCHF2Þ2CðOHÞ2 8.9 CF3CH2CH2COOH 4.15 ðCF3Þ2CðOHÞ2 6.5 CF3CH5CHCOOH 3.48 ðCF3Þ2CðOHÞCF2NO2 3.9

as an alcohol or carboxylic acid, would increase the acidity of the system and, indeed, this is the case. The pKa values [7] of a number of fluorine-containing acids, along with related systems for comparison, are collated in Table 4.2; these data suggest that the effect of introducing one fluorine atom is very close to that of a single chlorine atom (compare CH2FCOOH and CH2ClCOOH). A single fluorine substituent increases the acidity of acetic acid by ca. 100 times while trifluoroacetic acid is ca. 1000 times stronger. As expected, the inductive effect of trifluoromethyl falls off rapidly with distance, although the presence of a double bond helps to relay the effect. Various workers have drawn attention to the fact that, in aqueous solution, it is the entropy rather than the enthalpy that is more significant in determining the differences between the strengths of acids. This is a consequence of ordering of solvent which is greater as the acids become stronger. However, this is equally a consequence of inductive/field effects of groups. It is not surprising that, in the gas phase, acidities are determined by differences in enthalpies [8, 9]. It is still worth noting, however, that perfluoroalkanecarboxylic acids are much weaker than the strong inorganic acids: for example, the Hammett acidity function Ho for CF3COOH is 3:03 while Ho for sulphuric acids is 11:1. The strong inductive effect of fluoroalkyl groups has a corresponding additive acidifying effect on alcohols (Table 4.2). For instance, perfluoro-t-butanol is of the same order of acidity as acetic acid. The hydrates of fluoroketones are also remarkably acidic [10]. Perfluoroalkyl groups attached to phosphorus and sulphur [11] lead to a considerable increase in the strength of derived acids, as comparedÀ with the corresponding alkyl derivatives. Bis(trifluoromethyl)phosphinic acid, CF3Þ2POOH, is as strong as perchloric acid and is the strongest phosphorus acid known [12], while trifluoromethanesulphonic (triflic) acid, CF3SO3H, is the strongest readily available monobasic organic acid (H0 13:8) (compare conc. H2SO4, H0 11:1).

2 Bases Fluoroalkyl groups correspondingly lower the strengths of bases. Table 4.3 shows the dissociation constants of some amines, together with hydrocarbon derivatives for comparison. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 94

94 Chapter 4

Table 4.3 pKb values of some amines

Amine pKb

CH3CH2NH2 10.6 CF3CH2NH2 5.7 CCl3CH2NH2 5.4 C6H5NH2 4.6 C6F5NH2 0:36

À The observations that secondary amines, RFÞ2NH, do not react with boron trifluoride, hydrogen chloride or trifluoroacetic acid [13] also serve to indicate a lack of basic properties. Similarly, tertiary perfluoroalkylamines are quite without basic properties. Moreover, the oxygen atoms in perfluoroalkyl ethers and ketones are poor donors; this is exemplified by the fact that hexafluoroacetone cannot be protonated by superacids in solution. Such findings parallel similar observations with unsaturated derivatives where the base strength is considerably reduced in, for example, perfluoropyridine or perfluoroquinoline [14] in comparison with the parent compounds. The data, so far, clearly illustrate a very strong inductive effect (I) by polyfluoroalkyl groups in saturated systems, and the reduced donor properties of the hetero atom in nitrogen or oxygen derivatives probably partly arise from some rehybridisation (greater s character of orbitals containing the electrons not involved in s-bonds) when strongly electronegative substituents are attached [15].

B Unsaturated systems The deactivating effect and meta-orientating influence of trifluoromethyl in electrophilic aromatic substitution, together with a corresponding activating influence on nucleophilic aromatic substitution [16], are well known. Of course, these are just the results we would expect upon introducing a strongly electron-withdrawing group, but a more precise description of the mechanism of electron withdrawal by polyfluoroalkyl groups in these systems has been a source of debate. It has become normal to discuss the effects of substituents on benzene systems in terms of the Hammett equation, log k=k0 ¼ sr, where s measures the effect of a substituent on the reaction centre. Also, this simple concept has been elaborated, leading to correspondingly modified constants (s0, sþ, s) catering for the electronic nature of different reactions; some of the data relating to polyfluoroalkyl groups are contained in the following discussion (Table 4.4).

1 Apparent resonance effects (see also Section VIIB)

The overall effect of substituents may be separated into inductive (sI) and resonance (sR) contributions, where s ¼ sI þ sR. Some of the data derived on this basis are given in Table 4.4: they indicate an apparent resonance contribution by various polyfluoroalkyl groups. The problem of describing such a resonance contribution then arises, and it is immediately tempting to draw an analogy with hydrocarbon systems and invoke ‘fluorine Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 95

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 95

Table 4.4 Substituent constants for some fluorinated groups

Substituent sm sp sI sR

CH2F 0.12 0.11 0.12 0.02 CHF2 0.29 0.32 0.32 0.06 CF3 0.43 0.54 0.42 0.10 ÀCF2CF3 0.47 0.52 0.41 0.11 CF2Þ2CF3 0.47 0.52 0.39 0.11 CFðÞ CF3 2 0.37 0.53 0.48 0.04 SF5 0.63 0.86 0.56 0.27 NCFðÞ3 2 0.47 0.53 0.44 0.06 OCF3 0.47 0.27 0.50 0.23 hyperconjugation’ or ‘carbon–fluorine double-bond no-bond resonance’. These are two terms which have been used to refer to an effect that was originally suggested [17] to account for the dipole moments of p-amino- and p-dimethylaminobenzotrifluoride, which are larger than the sums of the composite bond moments. The type of interaction that was envisaged is shown in Figure 4.3. F F F F F C C F

etc.

Figure 4.3

The concept of fluorine negative hyperconjugation (FNHC), which in its simplest form can be written as indicated in Figure 4.4, has had a controversial history although there can be little doubt about the firm theoretical requirement for such an effect [18–20]. Problems have arisen because there are few rate-constant measurements that require FNHC, in addition to inductive field effects, to account for the observations [21], although structural evidence for 4.5A and 4.5B (Figure 4.5) now illustrates the effect well [22, 23]. F F CC CC

Figure 4.4

CF3 − − + F + CF3O TAS ½22 TAS ½23

F3C 4.5A 4.5B + + TAS = (Me2N)3S

Figure 4.5 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 96

96 Chapter 4

In molecular orbital terms, the unshared p-electrons at the carbanion site are donated into the s orbital of the adjacent C–F bond when the orbitals are in an anti-periplanar configuration which ensures maximum orbital overlap [19, 20]. Trends in the C–F bond lengths and strengths in the fluoromethane series, in which the C–F bonds strengthen and shorten with increasing fluorination, have been explained in terms of resonance effects, but theoretical work suggests that Coulombic interactions and hybridisation changes could also explain these observations [24]. However, the unusually long C–F bond and short C–O bond measured for the trifluoromethoxide ion [22] (Figure 4.6) suggests that the C–O bond possesses some double-bond character and, similarly, the high barrier to rotation of a-fluoroamines indicates some C–N double- bond character [25].

F − − F F COF CO ½22 F F

Figure 4.6

Stabilities of perfluorinated carbanionsÀ have also been described using FNHC; a re- examination [26, 27] of the acidity of CF3Þ3CH compared with the bicyclic compound (Figure 4.7), in which FNHC in the carbanion would result in theÀ formation of an internal alkene contrary to Bredt’s rule, found that the unconstrained CF3Þ3CH undergoes H/D exchange much more rapidly. If FNHC is the dominant process involved, then we would expect sR for CF3 to be greater than for CF22CF3 but this is not the case (Table 4.4). Calculations suggest [28] that perfluoroalkyl negative hyperconjugation can also occur, as indicated in Figure 4.8, although this seems unlikely given the destabilising effect of fluorine directly attached to carbanion centres (Section VI).

−H+ F F − H

Figure 4.7

− − CF3 CCFCCC3

Figure 4.8

Another probe technique that has been used is to compare the effects of trifluoromethyl, at the meta and para positions, in both phenol and benzoic acid [29]. Only in the case where the substituent is in the para position in phenol is it directly conjugated with the ionising centre and therefore allowing a resonance effect to be important. Values of pKa for the phenols led to the following substituent parameters: sð p-CF3Þ¼þ0:54 and sðm-CF3Þ¼þ0:43, the ratio sð p-CF3Þ=sðm-CF3Þ being 1.25, and this is essentially Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 97

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 97 the same as the ratio for the corresponding trifluoromethylbenzoic acids. This suggests that the electronic effects of CF3 operating in the phenol system are the same as those operating in the benzoic acid system and not, therefore, in accord with a resonance effect. Also, other fluorinated groups have apparent resonance effects (Table 4.4) that would be difficult to defend on the basis of any negative hyperconjugation scheme. For many processes it is not really necessary to invoke the concept of fluorine hyperconjugation to account for the observations and the most easily appreciated description of many, but by no means all, of the results available involves polarisation of the p-electron system.

2 Inductive and field effects It is generally recognised that the inductive effect should be subdivided into a polarisation effect on the s-bond framework and also on the p-electrons, and it has been indicated that a major effect of strongly electron-withdrawing groups like perfluoroalkyl is by a through-space polarisation of the aromatic p-electrons (direct field effect). The Ip effect of trifluoromethyl would result in polarisation of the p-system and perhaps approach a situation similar to that which exists in pyridine (Figure 4.9a).

CF3 CF3 δ+ δδ δ δ+ δ N δ+ + δδ+ + +

δ+ δ+

Figure 4.9a

This kind of description allows for a similar effect to be produced by other perfluoroalkyl groups (see Table 4.4), as well as the other fluorinated groups listed. Similar conclusions to those drawn here are described in a much more detailed review and analysis [30] of results available. Electrostatic interactions have been revealed as important in influencing the ‘gauche effect’, whereby, in 1,2-disubstituted ethanes (4.9bA), the gauche conformer (4.9bB)is populated to a larger extent than the anti conformer (4.9bC) [31, 31a] (Figure 4.9b).

H H H H Y Y H X X X

H H H Y 4.9bA 4.9bB 4.9bC

Figure 4.9b

IV THE PERFLUOROALKYL EFFECT Saturated, strained, small ring systems are uniquely stabilised by the introduction of perfluoroalkyl groups, as compared with the corresponding hydrocarbon derivatives, and this has allowed the study, for instance, of many long-lived valence-bond isomers Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 98

98 Chapter 4 of aromatic and heterocyclic systems [32] (see Chapter 9). This stabilising influence, denoted the ‘perfluoroalkyl effect’ [33], is considered to be kinetic rather than thermodynamic in nature [34]. The introduction of electron-withdrawing perfluoroalkyl groups into unsaturated systems lowers frontier orbital energies [35], as deduced by theory [36] and photoelectron spectroscopy [37] for a series of fluorinated alkenes, and manifestations of this effect are seen in much of the chemistry of such systems.

V STRENGTHS OF UNSATURATED FLUORO-ACIDS AND -BASES Since fluoroalkyl groups are uniformly acid-strengthening and the order of magnitude of the effect, relative to other haloalkyl groups, is consistent with electronegativities F > Cl, etc., it may be expected that the same situation occurs when fluorine is attached to unsaturated carbon. Inspection of the data in Table 4.5 quickly indicates a more complicated situation because, while fluorine substitution increases the acidity relative to the hydrocarbon analogue, the acidities are lower than the corresponding chlorocarbon compounds in the cases of the acrylic acids and phenols.

Table 4.5 Strengths of unsaturated carboxylic acids and phenols [1, 7]

Compound pKa

CH25CHCOOH 4.25 CF25CFCOOH 1.8 CCl25CClCOOH 1.21 C6H5OH 10.0 C6F5OH 5.5 C6Cl5OH 5.26 C6H5COOH 4.21 C6F5COOH 1.75

The fluorine atoms in these locations are not only inductively electron-withdrawing but interactions of the p-electron lone pairs of fluorine with the electron-rich double bond or aromatic ring can lead to a net electron donation; this effect has been studied by photoelectron spectroscopy [38, 39] (Figure 4.10). This Ip effect is discussed more fully in relation to fluorocarbanions (Section VII).

O O

F F4 ½38, 39

Figure 4.10 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 99

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 99

It has been concluded from pKa measurements and fluorine NMR data on pentafluoro- biphenyl derivatives, for example C6F5C6H4CO2H, C6F5C6H4F etc., that the pentafluorophenyl group inductively withdraws electrons more strongly than phenyl but much less strongly than trifluoromethyl, whilst pentafluorophenyl and pentachlorophenyl have a similar capacity for electron withdrawal [40].

VI FLUOROCARBOCATIONS In this section we will be mainly concerned with situations where fluorine atoms are bonded to carbon, which has some formal charge F2Cþ2, either directly or by conjugation, but we will also make reference to the effect of a fluorine atom in the situation F2C2Cþ2. As a guide we can consider boron compounds as a useful qualitative model for carbocations, because of the isoelectronic relationship of a carbocation to boron, and we note immediately that comparative chemistry of boron halides is most commonly discussed in terms of 2p–p overlap being more effective with fluorine than with the other halogens [41]. For the 2B2C2C2F situation, we note that fluoroalkyl derivatives of tricovalent boron are extremely unstable with respect to migration of fluorine from a-or b-carbon atoms to boron. Thus the fluorine atoms in these positions are enhancing the electrophilic nature of boron and we might reasonably predict the same situation for a carbocation. This is indeed the case and, at the outset, two major effects of fluorine towards positively charged carbon centres can be envisaged; fluorine directly bonded to a positively charged carbon atom is stabilising, via p–p interactions, whilst fluorine that is b-to a positively charged carbon atom is inductively strongly destabilising (Figure 4.11). F

CF C F CC

Stabilising Destabilising

Figure 4.11

A Effect of fluorine as a substituent in the ring on electrophilic aromatic substitution The course of electrophilic aromatic substitution can be represented as shown in Figure 4.12; on the basis of inductive effects of the halogens alone, we would expect the order of reactivity to be X5H > Br > Cl > F. E EH

E + H

X X X

Figure 4.12 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 100

100 Chapter 4

Table 4.6 Relative rates of para-chlorination and bromination of halobenzenes and halodurenes [42]

Substituent (X) H F Cl Br

Partial rate factor, fp, for para-chlorination of C6H5X 1 6.3 0.4 0.25 Relative rates of bromination of X Me Me 1a 4.62 0.145 0.062

Me Me a After statistical correction.

Generally, however, the reverse is the case (F > Cl > Br) (Table 4.6) and, as fluorine can in some cases increase the reactivity of an aromatic system relative to hydrogen, these data give a clear indication of resonance interaction between fluorine and the charged transition state (Figure 4.13) which is reflected in the negative (i.e. electron-donating) þ sp value (Table 4.7). EEHH

F F+

Figure 4.13

Whether fluorine can activate or deactivate an aromatic ring relative to hydrogen depends on the nature of the attacking electrophile. When the reagent is less reactive (late transition state) such as in molecular chlorinations and brominations [42, 43] (Table 4.6), resonance stabilisation of the Wheland-like transition state becomes far more important and so fluorine activates the system. On the other hand, nitration of fluorobenzene is slower than the corresponding reaction with benzene. Some s values [44] for the halogens are listed in Table 4.7 and the following general þ principles may be drawn from the data [43]. The sm and sm values indicate that fluorine influences the reaction centre mainly by the I effect, but as the values follow the inverse order of electronegativity it can be concluded that the þM effect may also be in operation

Table 4.7 s Values for halogen substituents on an aromatic ring [43, 44]

þ þ so sm sm sp sp F 0.93 0.335 0.35 0.06 0:075 Cl 1.28 0.375 0.40 0.225 0.115 Br 1.35 0.39 0.405 0.23 0.15 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 101

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 101 at the meta position. Ortho halogens also activate in the order F > Cl > Br although the so values are potentially influenced by steric effects

B Electrophilic additions to fluoroalkenes [45] The orientations and rates of addition of electrophiles to partially fluorinated alkenes follow the arguments developed in the preceding sections. For example, the rates of addition of trifluoroacetic acid to 2-halopropenes (Table 4.8) are in the order F > Cl > Br and provide evidence of the enhanced stabilisation of a carbon atom bearing a positive charge by 2p–2p interaction with fluorine [46] (Figure 4.14). + + H + H2C CFCH3 H3CHC CH3 3C C CH3 ½46 F F +

− CF3COO

CH3

H3CC OCOCF3 F

Figure 4.14

Table 4.8 First-order rate constants for reaction of trifluoroacetic acid with CH25CXCH3 at 258 C [46]

5 1 X10kðs Þ kX=kH

H 4.81 1 F 340 71 Cl 1.70 0.35 Br 0.395 0.082

The orientation of electrophilic addition to trifluoropropene was originally thought to be a reflection of the relative stabilities of the intermediate carbocations 4.15A and 4.15B (Figure 4.15), but it was subsequently found that trifluoropropene is dimerised, rather than protonated in highly acidic media [47, 48]. Deuterium labelling studies indicated that the reaction proceeds via initial fluoride ion abstraction to yield an intermediate allyl cation [49] (Figure 4.16).

+ + CF3CHCH3 CF3CH2CH2

4.15A 4.15B

Figure 4.15 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 102

102 Chapter 4

FSO3H F H − F CCHCH + FSO HF 3 2 + 3 F H

CF3CH=CH2 − (H shift) ½49 H CF 3 − F3C H F FSO3 HF CH3 H CF3 F H CH3

Figure 4.16

A similar mechanism has been advanced for the dimerisation of hexafluoropropene [50] (Figure 4.17) and other fluorinated propenes [45, 51] to analogous dimers.

F3C F SbF5 ½50 CF3CFCF2 F CF(CF3)2

Figure 4.17

C Relatively stable fluorinated carbocations The now-classic technique pioneered by Nobel Laureate George Olah and co-workers [52, 53] for preparing relatively stable long-lived carbocations, and their direct observation in solution by NMR, has been applied to the study of a number of classes of fluorinated carbocationic species [52–55], including alkyl, aryl, allyl and tropylium cations (Table 4.9). In general, a halogenated precursor is dissolved in either neat SbF5 or an SbF5=SO2 mixture, at or below room temperature [56] (Figure 4.18). F i H CCHC H CCHC 3 3 3 3 SbF6 ½56 F F − i, SbF5, 60 C, SO2

Figure 4.18

The 19F NMR spectrum of the dimethylfluorocarbocation [56] shows that the fluorine is de-shielded by a massive 260 ppm from the covalent starting material and this observation argues quite commandingly for p(p–p) resonance stabilisation of the carbocation by fluorine (Figure 4.19).

F F

Figure 4.19 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 103

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 103

Table 4.9 Stable fluorinated carbocations observed in solution by NMR spectroscopy

Carbocation Ref. Carbocation Ref.

FF CH3 CF2 [61] [62]

FF F

FF H3CCHC 3 [56] [50]

F Ar F F

CF2 [57] [63] (CF3)2CFCH2CF CH CFCH2CF3

F C [64] [59] CH3 F7

F Ph F

C [57] 2+ [65] Ar Ar Ph F

þ ðC6F5Þ3C [66] [67]

C6F5

The difluorobenzyl cation (Figure 4.20) is stable under conditions in which the benzyl cation undergoes rapid polymerisation [57] and 13C and 19F NMR studies [58] have shown that, as the electron demand of the aromatic ring increases (i.e. R is electron-withdrawing), the p( p–p) donation of fluorine to the carbocation centre also increases, leaving the electron density at Cþ relatively constant for a variety of aromatic substituents. F

CF Cl CF2 C F 2 i ½57

R R R − SbF5Cl i, SbF5, 75 C, SO2

Figure 4.20 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 104

104 Chapter 4

Other Lewis acids, such as BF3 Et2O, have been used to induce ionisation [59, 60] whilst protonation of suitably fluorinated unsaturated substrates may also lead to carbocationic species (Figure 4.21). FF

F BF3.Et2O ½59

CH3CN F7

FSO3H, SbF5 ½60

−78 C HH

Figure 4.21

The protonation of fluorobenzene outlined above suggests that fluorine para to the methylene group stabilises the arenium ion more effectively than if fluorine is at the ortho position, whilst at positions meta to the methylene group fluorine is probably destabilising relative to hydrogen. Consequently, the trifluorobenzenium ion 4.22A is particularly stable whilst the corresponding tetrafluorobenzenium ion 4.22B is of reduced stability [52] (Figure 4.22).

HH HH FF FF ½52 4.22A F 4.22B

F F

Figure 4.22

Of the several fluorine-containing dications that have been reported, the contiguous diallylic dication shown in Figure 4.23 (4.23A), as determined by NMR experiments, is unique. Furthermore, it seems to be the case that if fluorine atoms are sited at the centres of highest charge density, then very long conjugated systems are possible [68] (4.23B)

1 Fluoromethyl cations Gas-phase hydride affinity measurements suggest that the order of stability for the þ þ þ þ fluoromethyl cations is CH3 < CF3 < CH2F < CHF2 , indicating that the introduction of fluorine increases the stability of the cations relative to hydrogen [54]. The trifluoro- þ methyl cation CF3 has been generated and observed by IR spectroscopy upon photolysis of CF3I in an argon matrix at very low temperatures [69]. However, attempts to observe þ CF3 in solution by ionisation of trifluorohalomethanes [32] only resulted in the Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 105

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 105

H F F

(CF3)2CFCH2

CH2CF(CF3)2 ½68 F F H 4.23A

H (CF ) CFCH 3 2 2 CH2CF3

F F n n = 1−3 4.23B

Figure 4.23

þ production of CF4, even though CF3 is observed as a fragment ion in the mass spectra of many organofluorine compounds.

D Effect of fluorine atoms not directly conjugated with the carbocation centre Even though fluoroalkyl substituents are inductively electron-withdrawing, several cationic species have been studied in which a trifluoromethyl group is attached directly to the positively charged carbon centre [55]. The destabilising influence of a trifluoromethyl group is manifested in a comparison of the reaction rates for the solvolysis [70], via SN1 processes, of the tosylates 4.24A and 4.24B in which the replacement of hydrogen by CF3 leads to a rate retardation of ca.103 (Figure 4.24). Surprisingly, the introduction of a second trifluoromethyl, as in 4.24C, leads to only a slight reduction in the rate of solvolysis and this has been attributed to the fact that the positive charge in intermediate 4.24B is largely delocalised into the aromatic ring and so the introduction of a second electron-withdrawing substituent, as in 4.24C, has little effect on the stability of the resulting carbocation. When such delocalisation is not possible, however, the effect of attaching CF3 groups adjacent to the carbocation site on the rate of solvolysis is additive; for instance, compare the rates of solvolysis [71] for 4.25A, 4.25B and 4.25C in Figure 4.25. Resonance-stabilised long-lived carbocations such as 4.26A and 4.26B have been generated from precursor alcohols in superacidic solution [72] but, if conjugative stabilisation is absent as in 4.26C, then only protonated alcohols are observed. Similarly, ketones with up to three a-fluorine atoms can be protonated giving, for example, 4.26D, whilst hexafluoroacetone is not protonated in a superacidic medium [73] (Figure 4.26). Direct observation of a number of bridged halonium ions (X ¼ Br, Cl, I) is possible [74] when, for example, 2,3-dihalo-2,3-dimethylbutanes are ionised in SbF5=SO2 mixtures; however, as yet, no analogous fluoronium ions have been observed in solution (Figure 4.27). Indeed, 13C NMR studies suggest that ionisation of 2,3-difluoro-2,3-dimethylbutane gives a rapidly equilibrating mixture in which methyl 1,2-shifts, rather than fluorine shifts, occur [75] (Figure 4.28). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 106

106 Chapter 4

OTos OTos OTos

HHHCF3 F3CCF3 ½70

OMe OMe OMe

4.24A 4.24B 4.24C

Relative rates 4000 5.2 - 2.4 1 of Solvolysis

HCF3 HCF3

OMe OMe

4.24B

Figure 4.24

AnO SO 2 F3CH2CO R 1 R1 R1 ½71 CF3CH2OH R 2 R2 R2

Relative Rate

12 4.25A R1 = R2 = H 10 6 4.25B R1 = CF3, R2 = H 10

4.25C R1 = R2 = CF3 1

Figure 4.25

CF3 CF3 H H H C C O O CH ½73 3 C F3CCH3 F CCH H 3 3

4.26A4.26B 4.26C 4.26D

Figure 4.26 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 107

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 107

H C CH H CCH 3 3 i 3 3 ½74 H3CCH3 H CCH X Y 3 X 3

X = Cl, Y = F, Cl − i, SbF5, SO2, 60 C X = Br, Y = F, Br X = I, Y = F

Figure 4.27

H3C CH3 i H3C CH3 H3C CH3 H3C CH3 H3C CH3 H3C F ½75 F F F H3C

− i, SbF5, SO2, 90 C

Figure 4.28

However, mass-spectral breakdown patterns of PhOCH2CH2F suggest that a cyclic fluoronium ion can be observed as an ion-neutral complex in the gas phase [76], whilst þ calculations indicate that the fluoronium ion is more stable than the isomeric CH2CH2F ion [54]. Participation by fluorine remote from the reaction centre has been postulated to account for the product obtained from the reaction between 5-fluoro-1-pentyne and trifluoroacetic acid [46] (Figure 4.29).

H CF COO 3 OCOCF 3 ½46 FF F

CF3COOH

F3COCO OCOCF3 H3C F

Figure 4.29

Of course a bridged system must be involved, at least in the transition state, between boron and carbon in the decomposition of diazonium salts (Figure 4.30) and, indeed, transfer from trifluoromethyl has been observed [77] (Figure 4.30).

VII FLUOROCARBANIONS The term ‘carbanion’ is used in the present context as a general description of systems with negative charge on carbon, although this may be only fractional. It should also be remembered that the nature of the species will be dependent on the counter-ion and on the solvent [78]. Much of our information concerning substituent effects on fluorocarbanions comes from studies of the rates of base-catalysed hydrogen, deuterium and tritium Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 108

108 Chapter 4

δδ − − N2 Ar-N2 BF4 Ar----F----BF3 ArF + BF3

N2 CF3 CF3 ½77

40C

F CF2

F COOEt F CF2

Et2O

HCO3

Figure 4.30 exchange reactions and, consequently, the substituent effects refer strictly to the transition state 4.31B (Figure 4.31), although the effects are usually considered to apply also to the intermediate carbanion 4.31C.

δ − δ + C H C H Base C + H-Base

4.31A 4.31B 4.31C

Product 4.31D

Figure 4.31

If a substituent lowers the activation energy for production of 4.31B, then we assume that the energy of 4.31C is also lowered. However, it must be remembered that 4.31C may still have a very short lifetime, i.e. it is kinetically unstable with respect to initial state 4.31A or some product 4.31D, even though we may refer to the effect of a substituent as being strongly stabilising. The effect of ‘internal return’, i.e. return from 4.31B to 4.31A, or from 4.31C to 4.31B, is also a complicating factor which affects the interpretation of kinetic acidities. Sometimes equilibrium data are available and, obviously, this reflects substituent effects on the energy of 4.31A and 4.31C directly.

A Fluorine atoms attached to the carbanion centre Superficially, we would expect the high electronegativity of fluorine to stabilise a carbanion centre, but measurements of acid strengths and exchange rates for a variety Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 109

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 109

Table 4.10 Base-catalysed deuterium exchange in haloforms [80]

Haloform Rate of exchangea (105k)(l:mol1s1)

CHF3 Too slow to measure in this medium CHCl3 820 CHBr3 101 000 CHI3 105 000 CHCl2F16 CHBr2F 3600 CHI2F 8800

a 08 C in water. of halogenated compounds, discussed below, suggest that the inductive effect (Is) of fluorine is not the dominant factor in determining the stability of the carbanions formed [79]. Base-catalysed H/D exchange experiments for a series of haloforms [80] (Table 4.10) demonstrate that carbanion formation is stabilised by halogen in the order I > Br > Cl > F. When these results are combined with acidity measurements which show that CF3H ðpKa 31Þ is little more acidic than methane (pKa 40) [81], we can conclude that, in these systems, fluorine attached to a carbanion centre is stabilising with respect to hydrogen but destabilising compared with the effects of other halogens. Similar conclusions can be drawn from pKa measurements of a number of halobis(trifluoromethyl) methanes [82]. On the other hand, the pKa values of a series of substituted nitromethanes [83] (Table 4.11) suggest that, whilst chlorine bonded directly to the carbanion centre increases acidity relative to hydrogen, fluorine decreases acidity and, therefore, decreases the stability of the corresponding carbanion. To rationalise these two contradictory results we must consider not only the stabilising inductive effect of fluorine (Is), but also destabilising interactions between the electron pairs on fluorine and the non-bonding electron pair at the negatively charged carbon atom (Ip) which, for the halogens, follows the order F > Cl > Br > I [84] (Figure 4.32).

½84 − Iσ H2CFStabilising Iπ H2CFDestabilising

Figure 4.32

Table 4.11 Apparent ionisation constants of substituted nitromethanes (in water, at 258 C) [83]

XYCHNO2 pKa XYCHNO2 pKa

Y ¼ COOC2H5 Y ¼ NO2 X ¼ Cl 4.16 X ¼ Cl 3.80 X ¼ H 5.75 X ¼ H 3.57 X ¼ F 6.28 X ¼ F 7.70 Y ¼ Cl X ¼ Cl 5.99 X ¼ H 7.20 X ¼ F 10.14 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 110

110 Chapter 4

The net stabilising or destabilising influence of fluorine attached to a carbanion centre is, therefore, a result of these two effects. A consideration of the geometry of carbanions formed at both planar and tetrahedral carbon, as depicted in Figure 4.33, illustrates that Ip repulsion is greater at a planar carbon since, in this situation, the repelling non- bonding electron pairs on carbon are closer in space to electron pairs on fluorine [79] (Figure 4.33).

90 ½79

CF109 CF109 109

Tetrahedral (sp3) C Planar (sp2) C

Figure 4.33

Consequently, for the haloform case (Table 4.10), since Ip repulsion for chlorine is less than that for fluorine, chlorine as a substituent facilitates carbanion formation much more than fluorine. The enhanced acidities of bromoform and iodoform have been attributed to the release of steric strain on deprotonation, while the increased availability of d-orbitals and the easier polarisation of these larger atoms [85] are effects that are at a minimum for fluorine (Figure 4.34).

CBr C Br ½85

Figure 4.34

The carbanion centres in nitro derivatives described in Table 4.11 are more planar in character due to conjugative stabilisation of the negative charge by the nitro group, and the fact that here fluorine destabilises the carbanions relative to hydrogen as a consequence of Ip repulsion dominating over Is stabilisation. Also, the nature of other groups attached to the central carbon affects the level of conjugation of the negative charge with the nitro group and, consequently, the stereochemistry of the carbanion site. A propensity of fluorocarbanions to adopt pyramidal structures in which Ip repulsions are minimised is supported by calculations [86] from which it was deduced that for 1 the CH2F carbanion a pyramidal structure is 55 kJmol more stable than the planar form. Furthermore, calculations concerning a-fluorocyclopropyl anions [87] suggest that a non-planar conformation is adopted and that the barrier to inversion is significantly higher for a monofluorinated ring (175 kJmol1) than for the cyclopropyl anion (73 kJmol1). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 111

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 111

B Fluorine atoms and fluoroalkyl substituents adjacent to the carbanion centre When a fluorine atom is located b- to a carbanion centre, F2C2C, we would expect the high electronegativity of fluorine to give rise to a very dominant stabilising effect (Is), since, in this situation, there is no opportunity for Ip repulsion. Indeed, b-fluorine substituents are very strongly stabilising but the basis of the effect has been a subject of varied interpretation. Attempts to determine the effect on carbanion formation of halogen atoms attached to the adjacent carbon are generally complicated by a competing b-elimination process [88] (Figure 4.35). However, Andreades [89] found that, for a series of monohydrofluorocar- bons, the exchange process proceeds much more rapidly than elimination; the forward (kH) and reverse (kD) reactions were studied (Figure 4.36; Table 4.12). These observed relative reactivities and derived acidities indicate that the stabilities of perfluorocarbanions are in the order tertiary > secondary > primary and, therefore, that b-fluorine (F2C2C)is much more effective at carbanion stabilisation than a-fluorine (F2C) [79]. A further demonstration of these effects is observed for ðCF3Þ3CH, which is 50 orders of magnitude more acidic than methane. Furthermore, pentafluorocyclopentadiene [90] is only slightly more acidic than cyclopentadiene (pKa 15) whereas pentakis(trifluoromethyl)cyclopentadiene ðpKa < 2Þ is even more acidic than conc. nitric acid [32, 32a]!

D2O −Hal DCC Hal C C Hal CC ½88

Figure 4.35

k H RF H + CH3OD RF D + CH3OH

kD ½89

(NaOCH3)

Figure 4.36

The enhanced stability of b-fluoro carbanions (Figure 4.37) has been attributed to fluorine negative hyperconjugation (FNHC; see Section IIIB). For instance, negative hyperconjugation (see Section III) has been invoked to explain the enhanced reactivity (100-fold) [27] and the higher gas-phase acidity (by 5.4 pKa units) [91] of 4.38A over the

Table 4.12 Deuterium exchange and acidities of monohydroperfluoroalkanes [89]

Compound CF3HCF3ðCF2Þ5CF2H ðCF3Þ2CFH ðCF3Þ3CH

Derived ion CF3 CF3ðCF2Þ5CF2 ðCF3Þ2CF ðCF3Þ3C Relative reactivity 1 6 2 105 109

Approx. pKa 31 30 20 11 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 112

112 Chapter 4

F F CCF CC F F F

Figure 4.37 bridgehead compound 4.38B in which negative hyperconjugation in the derived carbanion is unfavourable. Elongated b-C2F bonds and shortened Ca2Cb bonds in 4.38C, as measured by X-ray crystallography, provides direct experimental evidence [23] (Figure 4.38).

CF3 ½27 F + (CF3)3CH F (Me2N)3S CF H 3

4.38A 4.38B 4.38C

Figure 4.38

The stereochemical course of hydrogen–deuterium exchange in homochiral PhEtHC CF3 has been studied [15] and, like systems containing other carbanion- stabilising groups, the extent of racemisation of the product varies with solvent.

C Stable perfluorinated carbanions [92–94] Inevitably, the successful generation of long-lived carbocations by the protonation of alkenes in superacid solution prompted attempts to generate observable perfluorocarbanions by the reaction of fluoride ion with perfluoroalkenes (‘Mirror-image chemistry’). Although fluoroalkenes can oligomerise in the presence of fluoride ion, there are now reported examples [79, 95] of fluorocarbanions that can be observed directly by NMR and, in some cases, obtained as crystalline solids [96]. Their generation is achieved by reaction of either a fluoroalkene [97] or an allene [98] with a fluoride-ion source, usually CsF or TAS-F [99], in a suitable solvent at room temperature. Various tertiary perfluorocarbanions have been directly observed but carbanions with a-fluoro substituents are usually too unstable, due to Ip repulsion (Figure 4.39). The anion 4.39A shown in Figure 4.39 is an exception [100]. Fluoride-ion-promoted carbon–carbon bond cleavage enabled the preparation of the cyclic carbanion shown in Figure 4.40 [23]. Sigma-complexes, observed by NMR, are analagous to the well-known Wheland intermediates in hydrocarbon chemistry, is possible upon the addition of CsF to perfluoro-s- triazine derivatives [101] (Figure 4.41) but direct observation of similar s-complexes derived from less-activated perfluoroaromatic systems has not yet been reported. Deprotonation of hydroperfluorocarbons provides an alternative route to perfluorocarbanions and, for example, several perfluoropentadienide [90, 102–104] (Figure 4.42) and benzylic [105] carbanions have been prepared by this method. A cyclopentadienide ion can also be prepared by reaction of a diene with Bu4NI via a single-electron transfer pathway [104] (Figure 4.43). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 113

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 113

F3C i F3C + ½97 CCF2 CCF3 Cs F C 3 F3C i, CsF, tetraglyme

F i FFFF + FFCs+ ½95

i, CsF, tetraglyme

CF3 F3C i F3C CF3 • + (Me2N)3S ½98 F3C CF3 CF3 CF3

+ − i, (Me2N)3S Me3SiF2 (TAS-F), THF

FFCs+ ½100

4.39A

Figure 4.39

F F CF3 CF3 THF F TAS-F F ½23 F F F C F C (Me N) S+ 3 F 3 F 2 3

Figure 4.40

N NNN ½101 F Cs+

N F N F

Figure 4.41

D Acidities of fluorobenzenes and derivatives Inductive effects of ortho substituents are important in governing the acidity of a C–H bond in substituted benzenes [106], and a variety of data indicate that the acidifying influence of fluorine falls off in the order ortho meta > para; this is illustrated by Table 4.13 [107]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 114

114 Chapter 4

CF3 CF3 H CF3 CF3 CF3 CF3 H2O ½103, 104 H3O

CF3 CF3 CF3 CF3

Figure 4.42

CF CF3 CF3 3 CF CF 3 3 CF3 CF3 Bu4NI ½104 Bu4N CF3I CF CF 3 3 CF3 CF3

Figure 4.43

Table 4.13 Relative rates of base-catalysed deuterium exchange [107]

Rate, relative to

Compound Benzene Toluene

[2-D] Fluorobenzene 6:3 105 — [3-D] Fluorobenzene 107 — [4-D] Fluorobenzene 11.2 — [3-D] Benzotrifluoridea 580 — 2,5-Difluoro[Me-D1]toluene — 350

a Trifluoromethyl [3-D] benzene.

Also, the order of acidity of the dihalobenzenes, m-C6H4F2 > m-C6H4ClF > m-C6H4Cl2, obtained from exchange data on the monodeutero derivatives [88], indicates the greater acidifying influence of ortho-fluorine than of ortho-chlorine and is a further illustration of the significance of inductive effects. Polyfluorobenzenes are very acidic, as evidenced by the fact that pentafluorobenzene and 1,2,4,5-tetrafluorobenzene, for example, are metallated with butyl lithium rather than undergoing nucleophilic substitution [108]; see Chapter 9, Section IIE. This is illustrated by the data in Table 4.14, which contains a comparison of rates of exchange of tritium and of nucleophilic substitution.

Table 4.14 Rates of tritium exchange and of nucleophilic substitution by sodium methoxide [109]

104k ðÞl:mol1s1

Displacement at Polyfluorobenzene Exchange at 408 C 508 C

Pentafluorobenzene 1360 1.05 1,2,3,4-Tetrafluorobenzene 0.0053 0.018 1,2,4,5-Tetrafluorobenzene 58 < 104 1,2,3,5-Tetrafluorobenzene 5.6 0.049 1,3-Difluorobenzene 0.0061 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 115

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 115

Also relating to these data is the observation that substitution accompanies metallation in the reaction of 1,2,3,4-tetrafluorobenzene with butyl lithium [108]. Fluorine substituents in the ring also enhance the acidity of hydrogen at benzylic positions [82]; for example, the acidity of 2,5-difluorotoluene relative toÀ toluene is shown in Table 4.13. Indeed, a comparison of the equilibrium acidities of C6F5Þ2CH2 andðÞ C6F5 3CH with the values for diphenylmethane and triphenylmethane indicates that substitution of each phenyl group by pentafluorophenyl results in an enhancement of acidity by 5–6 pK units; this effect has also been attributed, principally, to a strong inductive influence by polyfluoroaryl groups [110].

E Acidities of fluoroalkenes Studies on the influence of halogen on the acidity of hydrogen in 1-chloro-2-fluoroethene showed that the kinetic acidity of the hydrogen a- to chlorine is greater than that for hydrogen a- to fluorine, in accordance with lower Ip repulsions for chlorine a- to the carbanion centre [79]. Similarly, the pKa values for a range of halogenated ethenes [26] (Table 4.15) demonstrate that a-halogen substituents facilitate vinyl carbanion formation in the same order as in the haloform series, i.e. Br > Cl > F. Calculations suggest that negative hyperconjugation is also a factor in vinylic systems although the vinyl anions are thermodynamically unstable relative to the formation of ethyne and fluoride ion [111].

Table 4.15 Acidities of halogenated alkenes [26]

Carbon acid pKa

CCl25CHBr 24.6 CCl25CHCl 25.0 CF25CHCl 25.3 CCl25CHF 26.3 CF25CHF 27.2

VIII FLUORO RADICALS [112, 113] A Fluorine atoms and fluoroalkyl groups attached to the radical centre The organic chemist is interested in the separate effects of fluorine substituents on (a) the rate constants for formation of radicals and (b) the effect on the subsequent reactivity of these radicals; but it is not always easy to disentangle this information from experimental observations. Do fluorine substituents have an effect on thermodynamic stabilisation, or not? We might expect fluorine to have a similar stabilising influence to that of oxygen on the formation of radicals (Figure 4.44). However, we have already noted the schizophrenic nature of fluorine in carbanions, where inductive electron withdrawal wrestles with Ip electron repulsion, and it is a similar situation with radicals. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 116

116 Chapter 4

OCH2 OCH2

Figure 4.44

Stabilities of methyl and fluoromethyl radicals have been calculated [114] to be in the l l l l order CF3 < CH3 < CF2H < CFH2 and the relative rates of formation of such radicals, measured in b-scission reactions of a series of t-butoxy radical derivatives, as shown in Figure 4.45, lend support to this conclusion [115].

O + CH3 RCH k 3 CH3 CH3 1 ∆ RCOCO2 RCO ½115

k2 CH3 2 CH3 O + R

H3CCH3

Figure 4.45

Methyl radicals are essentially planar but ESR measurements [116], supported by theoretical calculations [114], show that fluoromethyl radicals deviate from planarity to l increasingly pyramidal structures upon further fluorination, with CF3 measured to be 49.18 from planarity. The barriers to inversion of fluoromethyl radicals increase in the l l l order CFH2 < CF2H < CF3 while fluorocyclopropyl radicals (Figure 4.46) adopt a fixed pyramidal conformation at the radical centre [117], as determined by ESR at 1088 C. The tendency for fluorine to induce pyrimidalisation of radical centres has also been used to account for the stereochemistry of products [118].

½117

H3CCH3

Figure 4.46

Electronegative groups lower orbital energies and therefore, in principle, the high electronegativity of fluorine should lower the orbital energy of an attached carbon radical centre. Additionally, conjugative interactions between the singly occupied orbital of the carbon and the lone pairs on fluorine would be a stabilising interaction, which would simultaneously render the carbon atom more nucleophilic (Figure 4.47). The fact that further stabilisation by fluorine substitution is negligible, after the first substituent, suggests that Ip repulsion becomes more important as we increase the charge on carbon and this also accounts for the tetrahedral nature of the trifluoromethyl radical. This is exactly analogous to the effect of fluorine substituents on carbanions, where electron-pair repulsions are minimised in a pyramidal conformation (Figure 4.48). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 117

The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 117

H H CF CF H H

Figure 4.47

H H CF CF F F

Figure 4.48

B Stable perfluorinated radicals The effect of fluorine substituents that are not directly attached to the radical centre is more difficult to define, although calculations [114, 119] suggest an order of stability l l l l l CH3CH2 > FCH2CH2 > F2CHCH > CH3 > CF3CH2 which is, intuitively, the opposite of the order which might be anticipated. Obviously, polyfluoroalkyl substituents will be strongly electron-withdrawing, making the radical more electrophilic in character and in some cases steric crowding is so severe at multi-substituted radical centres that the radicals are kinetically very stable. An example is the ‘Scherer radical’ [120] (Figure 4.49), which is stable at room temperature, even in the presence of oxygen. CF CF F 3 F 3 F C CF 3 3 F2 F3C C2F5 ½120 F3C F F3C F F CF3 CF3

Figure 4.49

Likewise, the radical shown in Figure 4.50 is a stable perfluorovinyl system [121].

CF(CF3)3 F2

(CF3)3CFC CCF(CF3)3 CC ½121 F (CF3)3CF

Figure 4.50

C Polarity of radicals It is increasingly apparent that polar characteristics of radicals are important in organic synthesis [122] and the effect of fluorine on the polarity of radicals is very significant. Reactions of perfluoroalkyl radicals with a series of substituted p-styrenes [123] (Figure 4.51) shows that the rate constant for radical addition to alkenes increases as the alkene becomes more electron-rich (Table 4.16) and, in similar additions, perfluoroalkyl radicals reacted 40 000 times faster with 1-hexene than the corresponding alkyl radicals. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 118

118 Chapter 4

C8F17 ½123 + C8F17 R R

Figure 4.51

Table 4.16 Relative rates of addition of perfluoro-octyl radicals to para-substituted styrenes [123]

rel R kadd

OCH3 1.41 CH3 1.33 H 1.0 Cl 0.77 CF3 0.53

Likewise, perfluorinated radicals react more rapidly with electron-rich alkenes (X¼H) than with electrophilic alkenes (X¼F) in some intramolecular processes [124] (Figure 4.52). Similarly, rates of hydrogen abstraction by perfluoroalkyl radicals from a series of aromatic thiols were greatest from the most nucleophilic thiol [125]; clearly, taken together, these data show that perfluoroalkyl radicals are highly electrophilic in character, in comparison with alkyl radicals, which are of course more nucleophilic. X XX X X XCX2H H CF2 + X F CF2 F F2C CF 2 ½124 4.52A 4.52B

5 −1 X = F, kA 4.9 x 10 s , Only 3-4% 4.52A formed

7 −1 6 −1 X = H, kA 1.06 x 10 s , kB 3.5 x 10 s

Figure 4.52

REFERENCES 1 B.E. Smart in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 57. 2 C.W. Thornber, Chem. Soc. Rev., 1979, 8, 563. 3 S.A. Sherrod, R.L.d. Costa, R.A. Barnes and V. Boekelheide, J. Am. Chem. Soc., 1974, 96, 1565. 4 R. Gallo, Prog. Phys. Org. Chem., 1983, 14, 115. 5 D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320. 6 M. Schlosser, Angew. Chem., Int. Ed. Engl., 1998, 110, 1497. 7 R. Stewart, The Proton: Applications to Organic Chemistry, Academic Press, London, 1985. 8 G.V. Calder and T.J. Barton, J. Chem. Educ., 1971, 48, 338. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 119

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94 R.D. Chambers and J.F.S. Vaughan in Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer Verlag, Berlin, 1997, p. 1. 95 R.D. Chambers, R.S. Matthews, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin 1, 1980, 435. 96 W.B. Farnham, D.A. Dixon and J.C. Calabrese, J. Am. Chem. Soc., 1988, 110, 2607. 97 A.E. Bayliff and R.D. Chambers, J. Chem. Soc., Perkin 1, 1988, 201. 98 W.B. Farnham, W.J. Middleton, W.C. Fultz and B. E. Smart, J. Am. Chem. Soc., 1986, 108, 3125. 99 B.E. Smart, W.J. Middleton and W.B. Farnham, J. Am. Chem. Soc., 1986, 108, 4905. 100 R.D. Chambers and T. Nakamura, J. Chem. Soc., Perkin Trans. 1, 2001, 398. 101 R.D. Chambers, P.D. Philpot and P.L. Russell, J. Chem. Soc., Perkin 1, 1977, 1605. 102 R.D. Chambers and M.P. Greenhall, J. Chem. Soc., Chem. Commun., 1990, 1128. 103 E.D. Laganis and D.M. Lemal, J. Am. Chem. Soc., 1980, 102, 6633. 104 R.D. Chambers, S.J. Mullins, A.J. Roche and J.F.S. Vaughan, J. Chem. Soc., Chem. Commun., 1995, 841. 105 R.D. Chambers, M.P. Greenhall and M.J. Seabury, J. Chem. Soc., Perkin 1, 1991, 2061. 106 A. Streitwieser and J.H. Hammons, Prog. Phys. Org. Chem., 1965, 3, 41. 107 A. Streitwieser and F. Mares, J. Am. Chem. Soc., 1968, 90, 644. 108 R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385. 109 A. Streitwieser, J.A. Hudson and F. Mares, J. Am. Chem. Soc., 1968, 90, 648. 110 R. Filler and C.-S. Wang, J. Chem. Soc., Chem. Commun., 1968, 287. 111 P.v.R. Schleyer and A.J. Kos, Tetrahedron, 1983, 39, 1141. 112 W.R. Dolbier, Chem. Rev., 1996, 96, 1557. 113 W.R. Dolbier in Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 97. 114 D.J. Pasto, R. Krasnansky and C. Zercher, J. Org. Chem., 1987, 52, 3062. 115 X.K. Xiang, X.Y. Li and K.Y. Wang, J. Org. Chem., 1989, 54, 5648. 116 R.W. Fessenden and R.H. Schuler, J. Chem. Phys., 1965, 43, 2704. 117 T. Kawamura, M. Tsumara, Y. Yokomichi and T. Yonezawa, J. Am. Chem. Soc., 1977, 99, 8251. 118 S.F. Wnuk, D.R. Companioni, V. Neschadimenko and M.J. Robins, J. Org. Chem., 2002, 67, 8794. 119 A. Pross and L. Radom, Tetrahedron, 1980, 36, 1999. 120 K.V. Scherer, T. Ono, K. Yamanouchi, R. Fernandez, P. Henderson and H. Goldwhite, J. Am. Chem. Soc., 1985, 107, 718. 121 B.L. Turmanskii, V.F. Chestkov, N.I. Delyagina, S.R. Sterlin, N.N. Bubnov and L.S. German, Russ. Chem. Bull., 1995, 44, 962. 122 W.B. Motherwell and D. Crich, Free Radical Chain Reactions in Organic Synthesis, Academic Press, London, 1992. 123 D.V. Avila, K.U. Ingold, J. Lusztyk, W.R. Dolbier, H.Q. Pan and M. Muir, J. Am. Chem. Soc., 1994, 116, 99. 124 X.X. Rong, H.Q. Pan and W.R. Dolbier, J. Am. Chem. Soc., 1994, 116, 4521. 125 W.R. Dolbier and X.X. Rong, Tetrahedron Lett., 1994, 35, 6225. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 122

Chapter 5 Nucleophilic Displacement of Halogen from Fluorocarbon Systems

It is the aim of this chapter to develop a model for the very broad spectrum of reactivity of fluorine-containing systems towards nucleophiles. Substituent effects of fluorine and fluorocarbon groups on the SN1 process were considered earlier, in a more general discussion of carbocations (see Chapter 4, Section VI); effects on the SN2 process will now be examined. Then the broader principles of displacement of fluorine, as fluoride ion, from carbon in different environments will be discussed to emphasise why, for example, nucleophilic displacement of fluoride ion from perfluoroalkenes occurs extremely rapidly while, in contrast, perfluoroalkanes are characterised by extreme inertness.

I SUBSTITUENT EFFECTS OF FLUORINE OR FLUOROCARBON GROUPS ON THE SN2 PROCESS

In general, substituent effects on the SN2 process are not easy to predict [1] because, in principle, electron-withdrawing or -donating groups can either accelerate or retard the process, depending on whether bond making, between carbon and nucleophile, or bond breaking, between carbon and the leaving group, is emphasised. The situation is further complicated by substituent effects either resulting in mechanistic change or creating very significant steric effects. Nevertheless, halogen substituents not directly attached to the reaction centre usually reduce SN2 reactivity in alkyl halides [2], as illustrated by the data in Table 5.1. Clearly, the effects are not large and are not very different for the individual halogens. Similarly, nucleophilic displacements from centres substituted with CF3 groups are retarded [3–5] in comparison with corresponding alkyl derivatives, due to steric hindrance and fluorine lone-pair repulsion of the incoming nucleophile, but preparatively useful

Table 5.1 Reactivities of RBr towards NaOPh (in MeOH at 208 C) [2]

R k (l:mol1s1 104)

CH3CH2 39.1 CH3CH2CH2 25.6 FCH2CH2 4.95 ClCH2CH2 5.61 BrCH2CH2 4.99

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 123 reactions are possible when a sufficiently good leaving group, such as tosyl, is employed [6] (Figure 5.1). The effect of introducing fluorine a-, b-org- to the reaction centre in solvolysis reactions can be very substantial, especially inhibiting SN1 processes [7, 8]. − − CF3CH2X + I CF3CH2I + X ½6

Figure 5.1

A single-electron transfer process may be a competing mechanism in reactions between sterically demanding nucleophiles and CF3CH2I, since side products arising from radical coupling reactions are observed [9]. In contrast, fluorine or fluorocarbon groups directly attached to the reaction centre have a much more pronounced effect [4]; for example, the hydrolytic displacement of chloride from PhCHFCl appears to be activated with respect to benzyl chloride [10], although the situation is complicated by concomitant SN1 and SN2 processes. Nucleophilic substitution of halogen in RFCF2Hal systems is very difficult, due to a combination of steric effects and shielding of the carbon skeleton by surrounding non-bonding pairs on fluorine, and there are no examples of halogen substitution by an SN2 process involving these substrates. For example, RCF2Br compounds are quite inert to halide exchange under conditions where CH3CH2Br is reactive [4]. However, in principle there are other ways in which RFHal systems could react with nucleophiles, namely: (1) Nucleophilic attack on halogen (Figure 5.2). However, this process is often very difficult to distinguish from the single-electron process, (2), shown below. Burton and co-workers have demonstrated that phosphorous nucleophiles react with CF2Br2 to give synthetically useful ylids and they suggested carbene intermediates to explain their findings [11] (Figure 5.3). Halophilic attack on polyfluorinated systems, followed by b-elimination to give intermediate polyfluorinated alkenes that are susceptible to nucleophilic attack, has also been suggested [12] (Figure 5.4).

H Nuc + I CF3 Nuc I + CF3 CF3H Solvent

Figure 5.2

R3P + CF2Br2 R3PBr + CF2Br

CF2Br CF2 + Br ½11

R3P + CF2 R3P-CF2

R3P CF2 + R3PBr Br (R3PCF2Br) Br R3P

Figure 5.3 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 124

124 Chapter 5

PhS + Br CF2CF2Br PhSBr + CF2CF2Br

½12

PhSBr PhS PhSCF2CF2Br PhSCF2CF2 CF2CF2

Figure 5.4

(2) Single-electron transfer (SET) [13, 14] (Figure 5.5).

Nuc RFI Nuc RFI

RFI RF I etc

e.g. RF RF i I NR2 + NR2 ½13, 14 NR2 I −H+

RF RF

H3O + HI O NR2

i , RFI (RF = C8F17 ), Pentane, uv

Figure 5.5

(3) A radical chain process (SRN1) (Figure 5.6).

+ Nuc + RF-I Nuc + RF-I RF I

R I + F RF Nuc Nuc-RF Nuc-RF + RF-I etc

Figure 5.6 An essential feature of this process is the reaction of a nucleophile with a fluorocarbon radical. It is important to emphasise that radicals, being electron-deficient, are electrophilic and therefore that fluorocarbon radicals are even more electrophilic. These processes are, of course, aided by ultraviolet irradiation and inhibited by radical traps, or the radicals may be intercepted, e.g. by norbornene as in the example shown in Figure 5.7a [15]. Further examples are given in Table 5.2. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 125

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 125

(CF3)2CFSPh

PhS

(CF3)2CFI (CF3)2CF Norbornene

½15 CF(CF3)2

(CF3)2CFI

I (CF3)2CF CF(CF3)2

Figure 5.7a

Table 5.2 Substitution of halogen in RCF2Hal systems

Substrate Nucleophile, conditions Product Yield (%) Ref.

CH3 þ C5F11CF2INO2ðCH3Þ2C Li C6F13 C NO2 53 [16] DMF, 3 h CH3

OO H

+ CO2Et ClCF CF I − OEt Na 50 [17] 2 2 ClCF2

CO2Et

O2N O2N N N + C5F11CF2I Bu4N 94 [18] C6F13 N N−

Electrochemistry, CH3CN H

þ CF2BrCF2Br PhO K PhOCF2CF2Br [19] HMPAa , rt

þ C6F13Br PhS K C6F13SPh 62 [20] DMF, rt

þ C6F13I PhS Bu4N C6F13SPh 76 [15] Benzene, H2O, rt

þ CF2Br2 Ph3P ðPh3PCF2BrÞ Br 100 [11] Diglyme, rt a HMPA, hexamethylphosphoric triamide. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 126

126 Chapter 5

Formally, an aromatic system acts as the nucleophile in SET processes involving haloperfluoroalkanes, although the orientation pattern indicates an aromatic sustitution by a fluorocarbon radical [21, 22] (Figure 5.7b).

OMe

i H(CF ) Cl + C H OCH 2 4 6 5 3 (CF2)4H ½21, 22

i, Na2S2O4, NaHCO3, DMSO ortho : meta : para = 50 : 35 : 15

Figure 5.7b

The processes described above invoke breakdown of intermediate radical-anions to give perfluoroalkyl radicals and halide ion; this is supported by theory [23] and ESR studies [24]. However, t-perfluoroalkyl iodides do not react with nucleophiles in this manner because it is thermodynamically more favourable for these particular intermediate radical-anions to break down into relatively stable perfluorocarbanions and iodine atoms [23] (Figure 5.8). The reaction of tertiary perfluoroalkyl iodides and hexene to give perfluoroalkenes supports this conclusion [25].

i −I C3F7C(CF3)2I [C3F7C(CF3)2I] C3F7C(CF3)2 ½23

− i, Zn, CH2CHR, AcOEt, 80 C F

CF3CF2CFC(CF3)2 CF3CF2CF2C(CF3)CF2 1 5 90%

Figure 5.8

Remarkably, electron transfer from phenylthiolate anions to perfluorodecalin occurs, to give naphthalene derivatives [26]. It is not clear why this has not proved to be a general process but it may be considered to involve a series of electron transfer steps (Figure 5.9).

A Electrophilic perfluoroalkylation

The 2CF2I group may be activated towards nucleophilic attack by enhancing the leaving group ability of iodine through expansion of its valence shell to an iodonium species, and this has culminated in the development of a range of electrophilic perfluoroalkylphenyl- iodonium triflate (FITS) reagents [27] (Figure 5.10). These remarkable electrophilic reagents have been used to carry out perfluoroalkylation of various nucleophilic systems, including carbanions, activated aromatics and enolate derivatives; examples are shown in Figure 5.11. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 127

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 127

+1e −F F F F F F F ½26

+1e

+1e etc. −F F F F F F F

PhS SPh SPh PhS SPh i F F PhS SPh SPh SPh i, PhS Na, DMEU, 70C, 10 days

Figure 5.9

i ii RFI RFI(OCOCF3)2 RF I O-Tf Ph ½27 i, 80% H2O2, (CF3CO)2O

ii, Benzene, CF3SO2OH (TfOH)

Figure 5.10

−110 C PhCH2MgCl C3F7IPh OTf PhCH2C3F7 82%

OTMS O MeCN, 45 C C F C F I OTf 8 17 + 8 17 Ph 76%

Figure 5.11

A range of related trifluoromethylating agents in which the perfluoroalkyl group is attached to a sulphonium leaving group have also been developed, as indicated in Figure 5.12. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 128

128 Chapter 5

+ DMF, 80C N O-Tf CF S N 3 H H 90% CF3

Figure 5.12

II FLUORIDE ION AS A LEAVING GROUP The wide range of reactivity of the carbon–fluorine bond, referred to at the beginning of this chapter, must obviously be attributable to variations in the mechanism of the substitution process and, in particular, to the amount of bond breaking in the transition state [28].

A Displacement of fluorine from saturated carbon – SN2 processes

In addition to the two overall nucleophilic displacement processes, SN1 and SN2, we can envisage a spectrum of transition states for the SN2 process. Various stages can be represented by 5.13A, in which there is little or no carbon–fluorine bond breaking; 5.13B, which is concerted; and 5.13C, where carbon–fluorine bond breaking is in advance of the new bond being formed (Figure 5.13).

δ + δ − δ + δ − δ + δ − Nuc CF Nuc C F Nuc C F

5.13A 5.13B 5.131C

Figure 5.13

Of course, the extreme of 5.13A would be complete bond formation with the nucleophile in an addition–elimination process, such as can occur when fluorine is bound to unsaturated carbon. Since a fluorine atom attached to carbon leads to a very polar, yet very strong, Cdþ Fd bond, we have two conflicting effects: (a) the attached carbon is electron-deficient and therefore susceptible to nucleophilic attack; (b) if the transition state involves much carbon–fluorine bond breaking, it may be of relatively high energy depending on the degree of solvation of the developing fluoride ion. Also, fluorine is not a polarisable atom and this contributes to the high energy of the process. Consequently, because carbon–chlorine bonds are weaker and more polarisable, the ratio kF=kCl, for displacement from the corresponding fluorides and chlorides, is regarded as a useful probe for indicating the amount of carbon–halogen bond breaking in the transition state. Factor (b) is the more important with alkyl fluorides since they are, for example, much less readily hydrolysed than other alkyl halides (Table 5.3), but it is also evident that the reactivity ratios are influenced considerably by the reagent. Fluoride ions (or incipient fluoride ions) form very strong hydrogen bonds, much stronger than corresponding bonds to chloride, and so a change to a more hydrogen- Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 129

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 129

Table 5.3 Relative reactivities of isoamyl halides ðCH3Þ2CHðCH2Þ2X with piperidine and sodium methoxide at 188 C [29]

Reagent X ¼ FX¼ Cl X ¼ Br X ¼ I

C5H11N 1 68.5 17 800 50 500 CH3ONa=CH3OH 1 71 3500 4500

Table 5.4 Fluorine : chlorine rate ratios for reactions of alkyl halides [28]

Halide Reagent Solvent Temp. (8 C) kF=kCl

6 Ph3CX H2O 85% aq. Me2CO 25 1:0 10 4 Ph2CHX H2O/EtOH 80% aq. EtOH 25 1:6 10 3 PhCH2XH2O 10% aq. Me2CO 50 3:2 10 2 CH3XH2OH2O 100 2:9 10 bonding solvent increases the reactivity of a carbon–fluorine bond relative to the other carbon–halogen bonds [28, 30]. Table 5.4 shows the fluoride:chloride rate ratios for some arylmethyl halides, albeit under different conditions in some cases, but the differences in ratios are sufficiently large to suggest the trend towards an increasing ratio as the process changes from SN1toSN2.

1 Acid catalysis Catalysis by protonic acids accounts for the hydrolysis of fluorides, such as trityl fluoride [31], or elimination of hydrogen fluoride from various systems (Chapter 6), frequently being autocatalytic. The hydrolysis of benzyl fluoride is roughly proportional to the Hammett acidity function Ho [32], which is consistent with the scheme indicated in Figure 5.14 [1, 33]. Indeed, the decomposition of benzyl fluoride, on storage, may be violent [34].

+ + PhCH2F + H PhCH2 FH PhCH2 + HF ½1, 33

Figure 5.14

Solvolysis of allylic fluorides may be acid-catalysed [35] and the influence of fluorine substituents at different positions is interesting. Solvolysis of 5.15A occurs where fluorine at the 1-position is able to stabilise an attached carbocation; but in the isomer 5.15B fluorine at the 2-position deactivates and solvolysis of 5.15B does not occur under conditions where 5.15A reacts (Figure 5.15). Similar hydrolysis of 1,2- diethoxytetrafluorocyclobutene leads to the well-known, very stable, ‘squarate anion’ [36] (Figure 5.16a). Hydrogen iodide is very effective in replacing fluorine by iodine in fluoroalkanes [33] (Figure 5.16b). Cleavage of a carbon–fluorine bond can be induced by reaction with a Lewis acid (see Chapter 4, Section VIC). In Friedel–Crafts alkylations, alkyl fluorides are more reactive than the chlorides [37] with, for example, aluminium halides or boron halides as catalysts (Figure 5.17). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 130

130 Chapter 5

RCHCHCHF2 H +F aq. HCOOH RCHFCHCFH R H −F 5.15A H F H2O ½35 RCHCHCHO F

RCHFCFCH2 R H 5.15B H H

Figure 5.15

OEt O OH OO H SO F 2 4 2+ ½36

OEt O OH O O

Figure 5.16a

i RF + HI RI + HF ½33 i, R = 1-heptyl, 105 C, 10hr. (85%) R = cyclohexyl, 105 C, 1hr. (90%)

Figure 5.16b

BBr3 FCH2CH2Cl C6H5CH2CH2Cl ½37 Benzene

Figure 5.17

Of course, this arises from a compensating greater strength of aluminium–fluorine or boron–fluorine bonds than the corresponding bonds to chlorine [D(A1–F) ¼ 615 kJmol1; D(A1–Cl) ¼ 494 kJmol1]. This difference also seems to be the driving force in the often very easy replacement of fluorine by chlorine, especially at allylic or benzylic positions, using aluminium chloride [38] (Figure 5.18).

0 C Cl F + AlCl3 ½38

Figure 5.18 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 131

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 131

2 Influence of heteroatoms on fluorine displacement Oxygen or, particularly, nitrogen adjacent to a carbon–fluorine bond greatly increases reactivity towards nucleophiles. Hydrolysis of a, a–difluoro ethers occurs under acid conditions [39] (Figure 5.19). Orthoesters are produced by reaction with alkoxides; such reactions may, however, occur via initial elimination of hydrogen fluoride, rather than by direct nucleophilic displacement of fluoride [40] (Figure 5.20).

H2SO4 ½39 CHF2CF2OC2H5 CHF2COOC2H5

Figure 5.19

EtOH CHClFCF2OC2H5 CHClFC(OC2H5)3 ½40 KOH

Figure 5.20

The exceptional ease of nucleophilic displacement of fluorine from ðC2H5Þ2- NCF2CFClH and similar systems has been utilised as a general method for replacement of hydroxyl by fluorine (see Chapter 3, Section IVA, Subsection 3), and probably involves an SN1 process with internal assistance to ionisation coming from the adjacent nitrogen [41] (Figure 5.21).

F − F Me −F Me etc NC CF2H NCCF2H Me Me ½41 F O RCH2 H

Figure 5.21

The presence of C2H bonds in a perfluorinated system can, of course, have a profound effect, but the subsequent increase in reactivity usually stems from an elimination–addition rather than direct nucleophilic displacement of fluoride ion (see below).

B Displacement of fluorine and halogen from unsaturated carbon – addition–elimination mechanism When fluorine is attached to an unsaturated carbon atom, then a two-step displacement process can occur where the addition step may be rate-limiting (Figure 5.22) and it is probable that the importance of influence of the C–Hal dipole, in attracting the approaching nucleophile, has been under-appreciated. If the addition stage is rate-limiting, which is usually the case, polarity of the bond to carbon is probably the most important factor governing the activation energy required, since fluorine is sometimes displaced more easily than chlorine or the other halogens. For example, benzoyl fluoride reacts more readily with hydroxide than the corresponding Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 132

132 Chapter 5 chloride [42, 43] (Table 5.5). However, the order of halogen mobility depends very much on the system and the order illustrated in Table 5.5 is Br > Cl > F.

δ X Nuc Nuc δ X Addition F F

Nuc X X + F Elimination F Nuc

Figure 5.22

Table 5.5 Isopropanolysis of acid halides at 258 C [43]

Compound k2 Halogen mobility ratio Cl ¼ 1

C3H7CO2X X ¼ F8:4 1010 1:6 104 X ¼ Cl 5:1 106 1 X ¼ Br 2:7 103 5200 C4F9CO2X X ¼ F1:6 103 4:6 102 X ¼ Cl 3:5 102 1

It is reasonable to assume, therefore, that situations occur where the activation energy associated with the elimination step is comparable with that required for the addition stage. In these situations, overall reactivity is then also influenced by the strength of the carbon–halogen bond and, consequently, the stronger carbon–fluorine bond has a greater retarding effect than bonds between carbon and the other halogens.

1 Substitution in fluoroalkenes The usually greater reactivity of vinylic fluorine than vinylic chlorine is demonstrated in methanolyses of halonitrostyrenes [44] (Table 5.6), providing support for the two-step process with a rate-limiting addition stage outlined above.

Table 5.6 Nucleophilic substitution of p-nitrohalostyrenes using NaOMe at 258 C [44]

p-NO2 C6H4 H

1 H X 104kðl:mol1s Þ

X ¼ F 7.21 X ¼ Cl 0.025 X ¼ Br 0.016 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 133

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 133

However, if both fluorine and chlorine are attached to the same vinylic carbon, the elimination stage of the mechanism becomes more important and, consequently, chlorine is selectively displaced, reflecting the greater leaving-group ability of chlorine compared with fluorine [45, 46] (Figure 5.23).

C H Cl C H O-Me C H F 6 5 MeONa 6 5 6 5 +

F3C F F3C F F3C O-Me ½45, 46

96% 4%

Figure 5.23

Displacement of vinylic chlorine is predominantly stereoselective whereas, in some cases, substitution of fluorine can give a mixture of isomeric products. It has been argued that the fluorine-containing carbanionic intermediates are more stable and longer-lived than the corresponding chlorinated derivatives, thus allowing rotation to occur in the carbanionic intermediate before elimination of the halide, and enabling the formation of geometric isomers [47, 48]. The importance of the addition step, leading to a developing carbanion in the transition state, is made evident by the very wide range of reactivity in the series CF25CF2,CF2 ¼CFCF3 CF25CðCF3Þ2, the last of these being extremely susceptible to nucleophilic attack (Figure 5.24). −F Nuc CF2C(CF3)2 Nuc CF2CF(CF3)2 Nuc CF CF(CF3)2

Figure 5.24

Reactions of polyfluoroalkenes are discussed in Chapter 7.

2 Substitution in aromatic compounds Nucleophilic substitution in highly fluorinated aromatic compounds will be dealt with in detail in Chapter 9, but it is worth noting here that, in common with most other nucleophilic aromatic substitutions [49], the processes are likely to involve two steps, with very little bond breaking in the rate-limiting transition state. In the classic work on 2,4-dinitrohalobenzenes with many nucleophiles, the ease of replacement of aromatic halogen is in the order F Cl > Br > I [49, 50], arising from a slow first step ðk1Þ and a fast second step ðk2Þ, consistent with the scheme outlined in Figure 5.25. Of course, the nitro groups are extremely important in lowering the energy of the developing carbanionic transition state, leading to the intermediate complex 5.25A. Both oxygen and nitrogen nucleophiles react more rapidly with fluoroaromatics than corresponding sulphur and carbon nucleophiles, in accordance with Hard–Soft Acid–Base principles [51]. It should be remembered, however, that the situation can become more complex with, for example, base catalysis, where the rate of the second stage becomes important; under these rather unusual conditions, an order of replacement Br > Cl > F has been observed [52]. The second step may be rate-limiting in reactions of fluoroaryl systems with neutral amines [53]. Loss of halide ion from the intermediate complex is catalysed by base and is Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 134

134 Chapter 5 much faster when fluorine is the leaving group compared with the other halogens, due to stronger hydrogen bonding between developing fluoride and the base [54] (Figure 5.26). For ortho-halonitrobenzenes, displacement of fluorine is more rapid than that of chlorine, due to lower steric requirements [55]. δ Nuc X Nuc X δ _ NO NO2 NO2 Nuc 2 k1 k2 ½49, 50 k−1

NO NO NO2 2 2

X = F, Cl, Br, I 5.25A

Figure 5.25

X NHR H2RN X NO2 NO2 NO2 RNH2 Base ½54

NO2 NO2 NO2

X = F, Cl, Br, I

Figure 5.26

Fluoroaromatics with electron-releasing substituents may be activated towards nucleophilic attack by complexation with chromium species [56] (Figure 5.27).

LiCMe2CN H3CF H3C CN CF3SO3H ½56

Cr(CO)3 Cr(CO)3

Figure 5.27

An oxidatively initiated nucleophilic substitution mechanism has been suggested to account for reactions with electron-rich aromatic substrates such as 4-fluoroanisole [57] (Figure 5.28). The foregoing discussion has outlined principles that can account for very wide differences in reactivities of the C2F bond. For example, while saturated perfluorocarbons like polytetrafluoroethene are relatively inert to nucleophiles, at the other extreme are perfluoroisobutene, which reacts with neutral methanol, and perfluoro-1,3,5-triazine, which is hydrolysed in moist air. As a note of caution, great care should be taken with the systems that are very reactive to nucleophiles and correspondingly potentially very toxic, although there is no good correlation between toxicity levels and reactivity towards nucleophiles. More will be said about some of these systems in later chapters. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 135

Nucleophilic Displacement of Halogen from Fluorocarbon Systems 135

−e ArF ArF

ArF + Nuc [NucArF] ½57 [NucArF] ArNuc + F

ArNuc + ArF ArNuc + ArF

Figure 5.28

REFERENCES 1 C.A. Bunton, Nucleophilic Substitution at a Saturated Carbon Atom, Elsevier, Amsterdam, 1963. 2 J. Hine and W.H. Brader, J. Am. Chem. Soc., 1953, 75, 3964. 3 J. Hine and R.G. Ghirardelli, J. Org. Chem., 1958, 23, 1550. 4 F.G. Bordwell and W. Brannen, J. Am. Chem. Soc., 1964, 84, 4645. 5 T. Nakai, K. Tanaka and N. Ishikawa, J. Fluorine Chem., 1977, 9, 89. 6 G.V.D. Tiers, J. Am. Chem. Soc., 1953, 75, 5978. 7 X. Creary, Chem. Rev., 1991, 91, 1625. 8 A.D. Allen and T.T. Tidwell in Advances in Carbocation Chemistry, ed. X. Creary, JAI Press, Greenwich, CT, 1989. 9 F.G. Bordwell and C.A. Wilson, J. Am. Chem. Soc., 1987, 109, 5470. 10 G. Kohnstam, D. Routledge and D.L.H. Williams, J. Chem. Soc., Chem. Commun., 1966, 113. 11 D.J. Burton, J. Fluorine Chem., 1983, 23, 339. 12 X.Y. Li, X. Jiang, H.Q. Pan, J.S. Hu and W.M. Fu, Pure Appl. Chem., 1987, 59, 1015. 13 C. Wakselman, J. Fluorine Chem., 1992, 59, 367. 14 V.I. Popov, V.N. Boiko and L.M. Yagupolskii, J. Fluorine Chem., 1982, 21, 365. 15 A.E. Feiring, J. Fluorine Chem., 1984, 24, 191. 16 A.E. Feiring, J. Org. Chem., 1983, 48, 347. 17 Q.Y. Chen and Z.M. Qiu, J. Fluorine Chem., 1987, 35, 343. 18 M. Medebielle, J. Pinson and J.M. Saveant, J. Am. Chem. Soc., 1991, 113, 6872. 19 X.Y. Li, H. Pan and X. Jiang, Tetrahedron Lett., 1984, 25, 4937. 20 C. Wakselman and M. Tordeux, J. Org. Chem., 1985, 50, 4047. 21 C.-M. Hu and W.M. Huang in Fluorine Chemistry at The Millenium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 261. 22 X.-T. Huang, Z.-Y. Long, and Q.-Y. Chen, J. Fluorine Chem., 2001, 111, 107. 23 S.M. Igumnov, I.N. Rozhkov, S.I. Pletnev, Y.A. Borisov and G.D. Rempel, Bull. Acad. Sci. USSR, 1989, 38, 2122. 24 A. Hasegawa, M. Shiotani and F. Williams, J. Chem. Soc., Faraday Discuss., 1978, 157. 25 S.I. Pletnev, S.M. Igumnov, I.N. Rozhkov, G.D. Rempel, V.I. Ponomarev, L.E. Deev and V.S. Shaidurov, Bull. Acad. Sci. USSR, 1989, 38, 1892. 26 D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59. 27 A.T. Umemoto, Chem. Rev., 1996, 96, 1757. 28 R.E. Parker, Adv. Fluorine Chem., 1963, 3, 63. 29 B.V. Tronov and E.A. Kruger, J. Russ. Phys. Chem. Soc., 1926, 58, 1270. 30 J.A. Revetllat, A. Oliva, and J. Bertran, J. Chem. Soc., Perkin Trans. II, 1984, 815. 31 A.K. Coverdale and G. Kohnstam, J. Chem. Soc., 1960, 3806. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 136

136 Chapter 5

32 C.G. Swain and E.T. Spalding, J. Am. Chem. Soc., 1960, 82, 6104. 33 M. Namavari, N. Satayamurthy, M.E. Phelps and J.R. Barrio, Tetrahedron Lett., 1990, 31, 4973. 34 S.S. Szucs, Chem. Eng. News, 1990, 68,4. 35 T.J. Dougherty, J. Am. Chem. Soc., 1964, 86, 2236. 36 J.D. Park, S. Cohen and J.R. Lacher, J. Am. Chem. Soc., 1962, 84, 2919. 37 G.A. Olah, Friedel–Crafts and Related Reactions, Wiley-Interscience, New York, 1964. 38 R.F. Merritt, J. Am. Chem. Soc., 1967, 89, 609. 39 J.A. Young and P. Tarrant, J. Am. Chem. Soc., 1950, 72, 1860. 40 P. Tarrant and H.C. Brown, J. Am. Chem. Soc., 1951, 73, 1781. 41 V.A. Petrov, S. Swearingen, W. Hong and W.C. Petersen, J. Fluorine Chem., 2001, 109, 25. 42 C.G. Swain and C.B. Scott, J. Am. Chem. Soc., 1953, 75, 246. 43 J. Miller and Q.L. Ying, J. Chem. Soc., Perkin Trans. II, 1985, 323. 44 G. Marchese, F. Naso and G. Modena, J. Chem. Soc. (B), 1969, 290. 45 D.J. Burton and H.C. Krutzsch, J. Org. Chem., 1971, 36, 2351. 46 H.F. Koch and J.G. Koch in Fluorine-containing Molecules. Structure, Reactivity, Synthesis and Applications, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH Publishers, New York, 1988, p. 99. 47 Y. Apeloig and Z. Rappoport, J. Am. Chem. Soc., 1979, 101, 5095. 48 B.E. Smart in The Chemistry of Functional Goups, Supplement D, ed. S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603. 49 J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam, 1968. 50 V.M. Vlasov, J. Fluorine Chem., 1993, 61, 193. 51 F.G. Bordwell and D.L. Hughes, J. Am. Chem. Soc., 1986, 108, 5991. 52 T.J. Broxton, D.M. Muir and A.J. Parker, J. Org. Chem., 1975, 40, 3230. 53 N.S. Nudelman, J. Phys. Org. Chem., 1989, 2,1. 54 E.T. Akinyela, I. Onyido and J. Hirst, J. Chem. Soc., Perkin Trans. II, 1988, 1859. 55 T.O. Bamkole, J. Hirst and E.J. Udoessien, J. Chem. Soc., Perkin Trans. II, 1973, 110. 56 F. Rose-Munch, L. Mignon and J.P. Sanchez, Tetrahedron Lett., 1991, 32, 6323. 57 L. Eberson, L. Jonsson and L.G. Wistrand, Tetrahedron, 1982, 38, 1087. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 137

Chapter 6 Elimination Reactions

Since eliminations cover a very wide spectrum of chemical reactions, this chapter is a selective discussion of the subject. The mechanistic basis of b-eliminations is discussed, largely with reference to dehydrohalogenation, and a variety of a-eliminations are included here. Other eliminations, such as dehalogenation, are described throughout later chapters with reference to specific syntheses.

I b-ELIMINATION OF HYDROGEN HALIDES A Effect of the leaving halogen Effects arising from the halogen atom that is eliminated during b-elimination of hydrogen halide may be summed up (Figure 6.1) as: (a) b-halogen has an acidifying influence on the adjacent hydrogen; and (b) ease of elimination will vary with the strength of the carbon–halogen bond and the ability of halogen to accommodate a negative charge. The combination of these effects is likely to be in the order F < Cl < Br. Of course, elimination will also be solvent-dependent. Clearly, b-elimination of hydrogen fluoride should proceed via a transition state that will be very carbanionic in character, and at a rate slower than corresponding hydrogen halide eliminations since carbon–halogen bond breaking is involved in the rate-determining step. These effects are well illustrated in eliminations from 2-phenylethyl derivatives [1, 2] (Table 6.1). β α CC CC + BH+ + X HX

B X = Halogen

Figure 6.1

Eliminations from fluorides are often autocatalytic [3], due to assistance in ionisation by hydrogen bonding between the leaving fluoride ion and hydrogen fluoride produced in the reaction (Figure 6.2). As a consequence, fluorides can sometimes be more stable in even slightly alkaline solution than in the pure state [3].

Table 6.1 Relative rates of elimination of HX from PhCH2CH2X [1, 2]

Substrate Reaction conditions X ¼ FX¼ Cl X ¼ Br

PhCH2CH22X EtONa, EtOH, 308 C 1 68 4100 5 7 PhCHBrCF22X EtONa, EtOH, 258 C14 10 3 10

138 Chapter 6

δ δ − + − C C FHF CC + HF2 ½3 H

Figure 6.2

Elimination of HBr in preference to HF from the cyclohexane derivative 6.3A further demonstrates the greater leaving-group ability of other halogens over fluorine [4] (Figure 6.3). Br

+ ½4 F FF 6.3A (9:1)

Figure 6.3

However, in some cases, HF is eliminated in preference to dehydrobromination, e.g. in the succinic acid series [5, 6] (Figure 6.4). In these less common processes, the transition state has significant carbanion (E1cB-like) character, and the products are probably governed by the relative stabilities of the possible carbanionic transition states, 6.5A and 6.5B (Figure 6.5), where a fluorine atom situated b to a developing carbanion centre, as in 6.5B, is more stabilising than when directly attached, as in 6.5A. This effect is also seen in eliminations from dihaloacenaphthenes [7]. Br F Br ½5, 6 HO2C CO2H HO2CCO2H

Figure 6.4

B B δ H + δ+H Br F δ− F Br δ− HO C CO2H 2 CO2H HO2C

6.5A 6.5B more stable

Figure 6.5

B Substituent effects A spectrum of transition states is possible for eliminations [8], varying from transition states with considerable double-bond character, 6.6A, through those with increasing amounts of charge developed on the b-carbon atom, 6.6B, until an E1cB mechanism is observed [9] when the b-hydrogen has been made sufficiently acidic to be removed, leaving a carbanion (Figure 6.6). Base-catalysed hydrogen/deuterium exchange is still probably the only definitive probe for the ElcB process in which H/D exchange occurs in the starting material at a rate faster Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 139

Elimination Reactions 139 than the second elimination stage (Figure 6.7), although internal return can be significant, which then leads to an under-estimation of kinetic acidity [9]. Indeed, it has been suggested that a hydrogen-bonded carbanion may be an intermediate, rather than a transition state [10]. δ− CCX CCX

H δ H + ½9 6.6A 6.6B Concerted E1cB - like

Figure 6.6

Base (−H+) + Solvent (+D ) 9 CCX CCX CCX ½ Solvent (+H+) H D Internal Return

CCXC C + X−

Figure 6.7

Highly halogenated alkanes often undergo base-catalysed H/D exchange at rates faster than elimination [11]; for example, H/D exchange for PhCHClCF2Cl has been measured 2 1 1 to be 1:65 10 l:mol s [9]. However, in a related system, PhCHClCF3, no H/D exchange is observed but isotope effects suggest that the mechanism is also a two-step E1cB process in which elimination of chloride ion from the intermediate carbanion is much faster than deuteration [12].

C Regiochemistry In concerted E2 eliminations from monofluorides the orientation of elimination is controlled by the relative acidities of b-hydrogen in a process that is consistent with a poor leaving group and a transition state with high carbanionic character of the b-carbon atom [13] (Figure 6.8). H NaOMe C4H9 H C3H7 H C3H7CH2 C CH3 + ½13 MeOH F H H H CH3 69% 21%

C3H7 CH3 + H H 9%

Figure 6.8 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 140

140 Chapter 6

The orientation of elimination of hydrogen halides from more highly fluorinated systems is also governed by the relative acidities of hydrogen atoms within the molecule, and therefore the relative stabilities of the intermediate carbanions, as well as the mobility of the leaving halogen, which is generally in the order I > Br > Cl > F. The examples in Figure 6.9 illustrate these points, in which the most acidic proton and the best halogen leaving group are eliminated preferentially [14–16]. KOH CF3CH2CHBrCH3 CF CHCHCH ½14 EtOH 3 3

CHCl2CCl2CHF2 CCl2CClCHF2 ½15

Aq. KOH ½16 CCl3CH2CF2Cl CCl2CHCF2Cl

Figure 6.9

In addition to C2H acidity, elimination may also be controlled by the mobility of fluorine from carbon, which generally decreases in the series 2CF > 2CF2 > 2CF3,as can be seen in the examples in Figures 6.10 and 6.11. Where there is a choice, the most stable fluoroalkene, in which the number of vinylic fluorines is at a minimum (see Chapter 7), is the predominant product.

CF CHFCHF CF CFCHF+ CF CHCF 3 2 3 3 2 ½17 70% 30%

Figure 6.10

RFH RF

KOtert-Bu

−10C ½18

RFH RF RFH = CF2CFHCF3 RF = CF CFCF3

Figure 6.11

D Conformational effects In many cases, elimination of hydrogen halide via an anti-coplanar transition state is observed [19] (Figure 6.12) in what is commonly regarded as the most favourable process [20, 21]. However, overall syn elimination is more common than was once thought; a variety of factors may be responsible. The ratio of products arising from syn/anti elimination can depend on the reaction medium, e.g. syn elimination appears to be enhanced by a less polar medium, and this has led to the suggestion that a concerted cyclic process involving the base may be involved [19] (Figure 6.13). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 141

Elimination Reactions 141

C5H11 H C5H11 H t-BuOK (only alkene formed) THF ½19 C5H11 F C5H11 F H

C H H C5H11 H 5 11 t-BuOK (only alkene formed) F C5H11 THF FC5H11 H

Figure 6.12

X X X X Y Y + BH + MF ½19 H F Y Y B M B = Base MB M = Metal

Figure 6.13

It has been suggested that favourable hydrogen-bonding interactions between R and trifluoromethyl in an E1cB-like transition state, 6.14B, could account for the formation of the least thermodynamically stable isomer, 6.14C, from 6.14A; 6.14C is converted to 6.14D on heating with caesium fluoride [18] (Figure 6.14).

i R F F F RCF CFHCF 2 3 6.14C ½18 F CF R CF3 6.14A 3 F 6.14B ii R = Adamantyl

R F i, KOtert-BuOH, tert-BuOH, 0 C 6.14D ii, CsF, Tetraglyme, 200 C F CF3

Figure 6.14

The preferential syn elimination of hydrogen fluoride, in preference to elimination of hydrogen bromide, from 6.15A is particularly surprising [22] (Figure 6.15). It is not clear how much the true preference for a gauche relationship between a fluorine substituent and an adjacent electron-withdrawing centre [23] will have on the ease of elimination of hydrogen fluoride, but it is clearly an area of interest. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 142

142 Chapter 6

F F HCO2Et HCOEt 2 HCO2Et i ½22 H syn Br CO Et 2 EtO2CBr EtO C Br H 2 6.15A

i, NaOH, H O anti 2

Figure 6.15

E Elimination from polyfluorinated cyclic systems Tatlow and his co-workers conducted an extremely comprehensive programme of syntheses and structure derivations of a series of fluorinated cycloalkanes [24], and concluded that the reactivity of the system, as well as the orientation of the cycloalkene produced, are similarly influenced by electronic factors which have been outlined in the preceding sections of this chapter. Anti elimination is generally the more favourable process but conformational effects may make the syn/anti rates nearly comparable. Elimination from the cyclohexanes 6.16A and 6.16B illustrates the balance between electronic and conformational effects [25]. Anti elimination is possible from 6.16A, involving removal of fluoride from >CHF rather than >CF2 since in this case electronic (the carbon–fluorine bond in CFH is weaker than in CF2) and conformational effects (H and F are anti-periplanar) are in concert (Figure 6.16). In contrast, anti elimination from 6.16B can only occur with elimination of fluoride from the more stable >CF2 position and therefore anti and syn eliminations occur together.

F F F H H aq. KOH F F F F H F F F F F 6.16A ½25 F F H F H aq. KOH F F F + F F F F F F F H

6.16B

Figure 6.16

Electronic factors dominate reactivity in the series shown in Figure 6.17; in this series, qualitatively, the order of reactivity indicated has been established [26]. There is probably a relationship between reactivity and the number of acidifying b-fluorine Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 143

Elimination Reactions 143 atoms, which decreases as shown, and this is supported by the product from the fluorocycohexane (Figure 6.18), where exclusive removal of the more acidic hydrogen occurs [26]. HH H H FF> FH >> F H ½26 H H H H

Figure 6.17

F H aq. KOH F H F ½26 H H H

Figure 6.18

In the cyclopentane series, electronic factors remain unchanged but differences in conformation effects may be significant. A coplanar arrangement of atoms in the transition state is energetically favourable; this can, of course, be accommodated in anti elimination from cyclohexane systems, but only in syn elimination from highly fluorinated cyclopentanes (Figure 6.19). However, anti elimination is still a favourable process [27] for these systems and electronic factors often outweigh conformational effects in determining the orientation of elimination.

Repulsion F F F F H Base

Base

Cyclohexane Cyclopentane

Figure 6.19

The reactions of cyclopentanes 6.20A and 6.20B with aqueous alkali both give the same cylopentene by anti and syn elimination respectively, with only traces of by-products arising from syn elimination from 6.20A or anti elimination from 6.20B (Figure 6.20). Inward syn elimination occurs from 6.20B, giving the cyclopentene in 86% yield, and this is a further indication that removal of fluoride from >CHF is easier than from >CF2 (Figure 6.20) In the cyclobutane series [28] (Figure 6.21) syn and anti eliminations from 6.21A and 6.21B proceed again at much more nearly comparable rates than from corresponding cyclohexane systems. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 144

144 Chapter 6

H HH H −HF −HF H F F F

H H H 6.20A 6.20B

Figure 6.20

H H H F aq. KOH F FF+ F ½28 F F H 6.21A cis 6.21B trans

Figure 6.21

II b-ELIMINATION OF METAL FLUORIDES b-Elimination of two halogen atoms is a frequently used process in the synthesis of alkenes and alkynes, using a variety of conditions, and examples will be given later (see Chapter 7). Normally, fluorine is not easily removed by this process, although there are a number of cases where defluorination has been achieved, for instance in the preparation of fluoroaromatic compounds (Chapter 9). However, a feature of the chemistry of fluorocarbon organometallic compounds is that decomposition by a-orb-elimination of a metal fluoride is very common. The ease with which such decompositions occur is very variable and factors such as the strength of the metal–fluorine bond being formed, the type of carbon–fluorine bond being broken, the mechanism of the process and whether the metal has an available empty orbital to aid migration of fluorine are all important in affecting the elimination. Fluorocarbon organometallic reagents will be discussed separately in Chapter 10, where these points will be illustrated; only examples of some eliminations from organolithium derivatives of polyfluoroalkanes and polyfluorocycloalkanes will be referred to here. Perfluoroalkyl-lithium derivatives are thermally unstable and their use in organic synthesis has been limited by competing b-elimination processes [29]. Pentafluoroethyl- lithium has a half-life of around 8 h at 788 C [30]. In complete contrast, perfluorinated bridgehead lithio derivatives are much more stable since, in these cases, elimination of LiF would contravene Bredt’s rule and would, therefore, be a higher-energy process. Conse- quently, perfluoroadamantyl-lithium is stable at 08 C for several days [31] (Figure 6.22).

H Li

½31 F F

Figure 6.22 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 145

Elimination Reactions 145

Nevertheless, evidence that bridgehead alkenes or diradical species are generated by decomposition of 6.23A was obtained by trapping with furan [24, 32, 33] (Figure 6.23).

F F CH3Li F furan 25−30C O ½24, 32, 33 H Li

6.23A

Figure 6.23

Surprisingly, the bicyclo[2.2.2]octane derivative (Figure 6.24) is much more stable [33] than the analogous norbornyl system 6.23A, and this has been attributed to the additional stabilising influence of the extra CF2 group, since there is no obvious stereochemical reason for the considerable difference in the rates of decomposition. This is a quite dramatic illustration of how electronic effects of groups which are apparently remote from the reaction centre can have a considerable effect on reactivity; this effect, while being well documented for other areas of organic chemistry, is not much in evidence in reactions of organic fluorine compounds.

Figure 6.24

A related b-elimination occurs when alkali-metal salts of perfluoroalkanecarboxylic acids are pyrolysed [34] (Figure 6.25). The most likely process involves decarboxylation with elimination of fluoride ion from the resultant carbanion. Indeed, the method can be very useful for the synthesis of perfluoroalkenes (Chapter 7), the most important example of which is shown in Figure 6.26 and is used in the production of fluorinated membranes [35]. F ∆ − − + , CO2 CF3CF2CF2CO2 Na F3C C CF2 ½34 F

CF3CFCF2 + NaF

Figure 6.25

Novel chemistry that was initiated by Nakai and co-workers [36, 37] involves elimination of hydrogen fluoride from the tosylate of trifluoroethanol, followed by reaction of the intermediate with appropriate electrophiles (Figure 6.27). A wide range of approaches to the synthesis of difluoromethylene derivatives has ensued. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 146

146 Chapter 6

F C CF(CF3)OCF2CF(CF3)OCF2CF2SO2F ½35

Heat, Na2CO3

CF2CFOCF2CF(CF3)OCF2CF2SO2F

Figure 6.26

− i Electrophiles CF3CH2OTs CF3CHOTs CF2 CHOTs ½36, 37 − i, LDA, THF, 78 C ii ii, n-BuLi, R3B

CF2CLiOTs R OTs CF C CF2 C Electrophiles 2 BR BR2 R R Various products.

Figure 6.27

A simple alternative approach to the synthesis of difluoromethylene compounds involves electron transfer from metals to carbon–oxygen or carbon–nitrogen double bonds [38, 39] (Figure 6.28).

− O O − O i − −F F2C ½38, 39 F CR 3 ( +1e) F3CR ( +1e) R

R = Alkyl or Aryl

i, Mg (2 equiv.), TMS-Cl (4 equiv.), 0 C, 30 min. ii, R1R2CO

OTMS ii Product F2C R

Figure 6.28

Reactions of lithium derivatives and Grignard reagents from polyfluoroalkenes or polyfluoroaromatic compounds are often complicated by eliminations but are generally much more useful in synthesis than polyfluoroalkane derivatives. Generation of arynes is discussed later (see Chapter 9). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 147

Elimination Reactions 147

III a-ELIMINATIONS: GENERATION AND REACTIVITY OF FLUOROCARBENES AND POLYFLUOROALKYLCARBENES Fluoromethylene and polyfluoroalkylmethylene units can be introduced into various molecules by a variety of processes that, overall, involve a-elimination from the original fluorocarbon system. The processes themselves are carbenoid but may not necessarily involve carbene intermediates. There are many carbenoid procedures available for the insertion of fluorine-containing units and they can be roughly divided into the following four types [40, 41]. (1) Decomposition of carbanions (Figure 6.29).

− XC CX

Figure 6.29

(2) Elimination of metal and non-metal fluorides (Figure 6.30). F

CM C + MF

Figure 6.30

(3) Fragmentation reactions (Figure 6.31).

C X C C Y XCCY+ C

Figure 6.31

(4) Decomposition of diazo compounds (Figure 6.32).

N + CN2 or C N2 C N

Figure 6.32

Examples of each of these types follow.

A Fluorocarbenes 1 From haloforms The classic work of Hine and co-workers [42, 43] established that carbenes could be generated by base hydrolysis of haloforms and that the process could be divided into two steps (Figure 6.33). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 148

148 Chapter 6

− CHXYZ + OH CXYZ + H2O ½42, 43 − CXYZ XCY+ Z

Figure 6.33

The deprotonation step was deduced from H/D exchange studies and the second stage from a steady-state treatment of the overall rates of hydrolysis. Stabilisation of the intermediate carbanions by halogen follows the order I > Br > Cl > F (Chapter 4, Section VII) and loss of halide ion in stage 2 is in the order of leaving group ability, I > Br > Cl > F. Therefore, it was possible to conclude that the effect of fluorine on the stability of carbenes is in the order F > Cl > Br > I [42]. Fluorine is relatively poor at stabilising directly attached carbanions; however, it appears to be the best of the halogens at stabilising carbenes, and consequently elimination of HZ (Figure 6.33) may become concerted if X is a sufficiently good leaving group. In eliminations of HBr from CHBrF2 no H/D exchange is observed [44], which could indicate a concerted process, but elimination of bromide ion may, in this case, be much faster than deuteration (cf. b-eliminations, Section I) and so a two-step process cannot be ruled out. A number of different bases, usually KOH or NaOH [45] with a phase-transfer catalyst [46] or crown ether [47], have been used for generating carbenes which can be trapped by nucleophilic species such as alkoxides, thiolates and, more usually, alkenes. This approach to carbene generation is still popular due to the low cost and the ease of handling the reagents used; some examples are given in Figure 6.34 [45, 46, 48].

H3C CH3 i H3C CH3 CH2Br2 + CF2Br2 + ½48 H3C CH3 H3CCH3

− + + 2KBr + CBr4 + 2H2O i, Bu4N HSO4, 60% KOH

FCl

H3C CH3 i H3C CH3 + CHFCl2 ½45 H3CCH3 H3CCH3 43% i, NaOH, tetraglyme, 95 C

Br F i ½46 + CFHBr2

+ − i, 50% NaOH, CH2Cl2, Et3N CH2Ph Cl 90%

Figure 6.34 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 149

Elimination Reactions 149

2 From halo-ketones and acids The formation of dihalocarbenes by decomposition of trihaloacetate anions is well known and is usually formulated as involving two steps (Figure 6.35) but, of course, the process could be concerted.

O ClCF C 2 ClCF2 + CO2 O

ClCF2 FCF + Cl

Figure 6.35

It is found that decarboxylation of dichlorofluoroacetate [49] gives about 70% of CCl2FH via competitive abstraction of a proton from solvent by the intermediate CCl2F anion, whereas chlorodifluoroacetate [50] gives very little CClF2H, suggesting either that chloride ion loss in this case is faster than protonation, or that the process is concerted. Decarboxylation procedures have been widely used, mainly for the preparation of fluorocyclopropyl derivatives as illustrated in Figure 6.36 [51, 52].

FF Ph H i Ph 88% CH3 ½51 H CH3 H OAc OAc − + i, ClF2CCOO Na , diglyme, reflux

FF C H 8 17 i C H 8 17 ½52

OAc H OAc

− + i, ClF2CCOO Na , diglyme, reflux

Figure 6.36

In similar processes, base-induced cleavage of halogenated ketones has been used to prepare cyclopropane derivatives [53] (Figure 6.37).

3 From organometallic compounds Trifluoromethyl-lithium, prepared by metal/halogen exchange, is unstable; its decomposition probably involves generation of difluorocarbene, which dimerises [54] (Figure 6.38). Elimination of bromine from dibromodifluoromethane is readily achieved, and various trapping experiments have been carried out with difluorocarbene from this source [55] (Figure 6.39). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 150

150 Chapter 6

O O i H C CFCl H C C CFCl CFCl 3 2 3 2 2 ½53 H i, NaH, MeOH −Cl

Cl CFCl

60%

Figure 6.37

i −LiF CF3I CF3Li CF2 F2CCF2 ½54

− i, CH3Li, 45 C

Figure 6.38

F n-BuLi −LiBr ½55 CF2Br2 CF2BrLi CF2 F

Figure 6.39

Perfluoroalkyl anions, which form carbenes upon subsequent elimination of a- fluorine, may be generated by cleavage of the carbon–tin and carbon–mercury bonds in, for example, (trifluoromethyl)trimethyltin [56] and phenyl(trifluoromethyl)mercury [57] (Figure 6.40) under very mild conditions. Carbenes may be generated from

− − − −F I Me3Sn CF3 CF3 + Me3Sn-I CF2 ½56

F F

89%

i F ½57 + PhHgCF3 F

− + i, NaI, Bu4N I , 18-crown-6, 80 C 56%

Figure 6.40 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 151

Elimination Reactions 151 perfluoroalkyl anions which, in turn, may be displaced from, for example, tin, mercury or silicon by halide ions. Here the driving force is the strength of the new bond to halogen being formed. A combination of zinc and CF2Br2 can be used to add difluorocarbene to relatively reactive alkenes [58] (Figure 6.41a). FF Ph i Ph 71% ½58 H3C H3C

i, CF2Br2, Zn, I2 (cat), rt

Figure 6.41a

Remarkably, ðCF3Þ3Bi generates difluorocarbene at low temperatures in the presence of aluminium trichloride [59] (Figure 6.41b).

i ii F (CF3)3Bi [CF2] F ½59 − i, AlCl3, 30 C ii, Cyclohexene

Figure 6.41b

4 From organophosphorous compounds Difluorocarbene can be conveniently generated at room temperature by the addition of fluoride ion to bromodifluorophosphonium bromide and, provided that the solvents are scrupulously dry, can be trapped by alkenes [60], dienes [61] and cycloalkenes [62] (Figure 6.42). The phosphonium salt may be generated in situ, allowing cyclopropanation to be carried out in a one-pot process [60] (Figure 6.43). Addition of 18-crown-6 to the reaction medium enhances the solubility of the metal fluoride and allows cyclopropanation of less nucleophilic alkenes and alkynes to be performed [63] (Figure 6.44).

5 Pyrolysis and fragmentation reactions

Pyrolytic a-elimination of HCl from CHClF2 is the basis for the manufacture of tetrafluoroethene on an industrial scale [64] (Figure 6.45). A carbene intermediate has been proposed for the formation of hexafluorobenzene by pyrolysis of CHFCl2 and CHFBr2 [65], whilst difluoroacetylene is the suggested intermediate in the corresponding pyrolysis of CFBr3 [66] (Figure 6.46). Hexafluoropropene oxide (HFPO) [67] fragments exclusively by a reversible process at high temperature to give trifluoroacetyl fluoride and difluorocarbene only [68] (Figure 6.47). Cyclopropanation of electron-deficient alkenes is also possible, as shown in Figure 6.48, but molecular rearrangements at the high temperature required for HFPO decomposition may reduce the yield of the desired product [69–72]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 152

152 Chapter 6

+ − H3C CH3 i H C CH Br + CsF + 3 3 [Ph3PCF2Br] ½60 H C CH 3 3 H3C CH3

i, diglyme, rt 79%

FF + − i FF + [Ph3PCF2Br] Br ½61 +

i, CsF, triglyme, rt

38% 22%

F + − i ½62 + [Ph3PCF2Br] Br F

i, KF, triglyme, rt 92%

Figure 6.42

FF H C 3 i H3C + Ph3P + CsF + CF2Br2 ½60 H C 3 H3C

i, diglyme, rt 66%

Figure 6.43

FF + − i PhC CH + [Ph3PCF2Br] Br ½63 Ph H i, KF, 18-crown-6, glyme, rt 79%

Figure 6.44

> 650 C CHClF2 CF2 F2CCF2 ½64 0.5 atm.

Figure 6.45 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 153

Elimination Reactions 153

i CHFCl2 C6F6 + CFCl3 + CFCl CFCl + CFCl2 CFCl2 ½65

i, Pt, 700−750 C

i CFBr3 C6F6 35% ½66

i, Pt, 640 C

Figure 6.46

O O F F 165−185 C + CF2 ½68 F3C F F3CF

Figure 6.47

FF F F i 65% ½69 H F H F F F i, HFPO, 185 C, 6 h

F F F F F F F i ½70 63% F H H F H H F i, HFPO, 175 C

CF3 F F C CF3 i 3 F • 52% ½71 F CF3 F F F i, HFPO, 175 C

Cl i F Cl F F + Cl Cl ½72 Cl Cl 50%, 1:1 i, HFPO, CaCO3, 185 C

Figure 6.48 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 154

154 Chapter 6

Pyrolysis of various phosphorane, e.g. ðCF3Þ2PF2 [73], and fluoroalkylated tin compounds [74] has been used to generate difluorocarbene. Diazirines decompose to give carbenes by either photolysis or pyrolysis [75] (Figure 6.49). F F

F N 135 C + 85% ½75 F N

Figure 6.49

Remarkably, tetrafluoroethene [76] and even PTFE [77] (Figure 6.50) may be used as sources of difluorocarbene, if sufficiently high temperatures are used. CF Cl Cl CF2 3 ½76 i FF FF + FF

i, CF2CF2, 640 C

F3CCF3 i FF+ F CF3 ½77 N N N

i, (CF2)n, 550 C isomers

Figure 6.50

Reactions of arc-generated carbon with fluorocarbons lead to CF, which reacts in ways resembling carbenes to give a variety of products [78, 79] (Figure 6.51).

C + CF4 FCCF3 CF2 CF2 ½78

F F F ½79 + CF +

N N N

Figure 6.51

However, there are still no general methods for the preparation of fluorocarbene, CFH [41].

B Polyfluoroalkylcarbenes A useful source of perfluoroalkylcarbenes is the corresponding diazoalkane, or diazirine [80, 81], which have been obtained by a variety of routes (Chapter 8). Confirmation that bis(trifluoromethyl)carbene is produced in the pyrolysis of these species comes from the observation that, at low pressures, hexafluoropropene is obtained; it results from an internal 1,2-fluoride shift in the intermediate carbene [80] (Figure 6.52). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 155

Elimination Reactions 155

F3C 250 C + N2 CF3CF=CF2 (CF3)2C=C(CF3)2 ½80 Low pressure F3C

Figure 6.52

Insertion reactions [81], alkene additions [82] and even additions to benzene and hexafluorobenzene [83] have been observed using these sources of carbenes, as shown in Figure 6.53.

ν F3C h ½81 CF3CH2 76% N2 + H

F3CF H C CH F3C 3 3 170 C H C CH + 3 3 N2 ½82 F 30% H3C CH3 H3C CH3

F C CF 3 3 ½83 150 C 20% N2 + F F F3C CF3

Figure 6.53

However, many reactions of bistrifluoromethyldiazoalkanes may involve formation of an intermediate pyrazoline followed by loss of nitrogen, rather than a carbene intermediate: a cyclic adduct has been isolated from reaction of bis(trifluoromethyl)diazomethane with but-2-yne, which then loses nitrogen on pyrolysis [80] (Figure 6.54).

H3C CH3 F3C ½80 CF N + CH3C CCH3 3 2 N F3C N CF3

400C − N2

F3CCF3

H3CCH3

Figure 6.54

Organo-metallic or -metalloid reagents provide efficient routes to fluoroalkylated carbenes; difluoromethylfluorocarbene (6.55A) is readily generated by a general route which involves the pyrolysis of fluoroalkylsilicon compounds [84] (Figure 6.55). Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 156

156 Chapter 6

ν h SbF3 HSiCl3 + C2F4 CHF2CF2SiCl3 CHF2CF2SiF3 ½84

150 C

(CH3)3CH (CH)3CCHFCHF2 F2HC C F + SiF4

61% 6.55A

Figure 6.55

The mercurial C6H5HgCFBrCF3 serves as a useful transfer agent for CF3CF [85] (Figure 6.56).

F 160 C + C6H5HgCFBrCF3 87% ½85 C H 6 6 CF3

Figure 6.56

C Structure and reactivity of fluorocarbenes and polyfluoroalkylcarbenes 1 Fluorocarbenes The existence of two possible and opposing effects arising from fluorine attached to the carbon of a carbene produces a dichotomy analogous to that which occurs in fluorocarbocations (Chapter 4, Section VI). The inductive effect of fluorine should make the carbon atom, which is already electron-deficient, even more electrophilic (6.57A in Figure 6.57), but the possibility of p-bonding (6.57B) between fluorine and a vacant orbital on carbon could also occur.

δ + δ − F C F FCF FCF

6.57A 6.57B

Figure 6.57

On the basis of spectroscopic and thermodynamic data, it has been concluded that p-bonding is significant in difluorocarbene [86] and to a degree which accounts for the fact that it is surprisingly stable and relatively unreactive compared with CH2 and other carbenes [86]. That the balance between the two effects is clearly dominated by p-bonding is illustrated by the relative reactivities of various carbenes with different alkenes; it is concluded that electrophilicity decreases in the series CH2 > CBr2 > CCl2 > CFCl > CF2 and CH2 > CHF > CF2. Indeed, CF2 is considered to be amphiphilic [87]. Of course, carbenes can exist as either a singlet or triplet in the ground state, and the calculated energy differences between these two states (DEST ¼ ET ES) for several different carbenes are given in Table 6.2. Electron-withdrawing substituents lower orbital energies and we have noted the stabilising effect of perfluoroalkyl groups on radicals Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 157

Elimination Reactions 157

Table 6.2 Calculated energy difference between singlet and triplet states of carbenes, DEST [89, 90]

1 Carbene DEST ðkJmol Þ

CH2 246 CHF 142 CF2 808 CðCF3Þ2 313

(Chapter 4) and their strongly destabilising effect on carbocations. In parallel with these observations, a trifluoromethyl group clearly enhances the stability of the triplet state (Table 6.2). Conversely, fluorine directly attached to the carbene centre strongly favours the singlet state, which, of course, contains a vacant orbital that is able to interact strongly with the non-bonding electron pairs on fluorine. However, CFCl and CFBr are also found to have singlet ground states [88]. The stereochemistry of reactions between carbenes and alkenes is determined by the states of the carbenes (when generated), whereby singlet carbenes react in a stereospecific one-step concerted process whilst triplet carbenes lead to a mixture of products via a diradical intermediate (Figure 6.58). Consequently, since fluorocarbenes are singlets in the ground state (Table 6.2), cyclopropanation of alkenes is often stereospecific [91] (Figure 6.59) (for more examples, see Sections A and B). FF R1 R2 singlet CF2 R R1 2 R3 R4 R3 R4

triplet CF2

FF FF R1 R2 Spin R4 + R R2 R 4 R Inversion R1 1 3 CF 2 R3 R4 R3 R2

Figure 6.58

FF C2H5 Me3Sn-CF3 H 74% ½91 NaI C2H5 C2H5 HC2H5

Figure 6.59

The selectivity of carbenes has been qualitatively estimated by a series of competition reactions between various carbenes and mixtures of different alkenes; it is found that electrophilic carbenes react preferentially with the most electron-rich alkene present [87, 92]. Fluorocarbenes, being less reactive, give rise to fewer products from C2H insertion reactions than CCl2 [91] (Figure 6.60). However, selectivity may be temperature- dependent [93, 94]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 158

158 Chapter 6

Cl Cl

CCl2 ½91 + O O CCl2H O (1 : 1) CF2

Figure 6.60

2 Polyfluoroalkylcarbenes Electronic effects in bispolyfluoroalkylcarbenes (6.61A) are clearly defined, in that the already electron-deficient carbon is made even more electrophilic by the strong electron withdrawal by polyfluoroalkyl groups (Figure 6.61). Polyfluoroalkylfluorocarbenes (6.61B) are, however, an intermediate situation with the possibility of compensating p-bonding, as described earlier.

δ + δ − δ − δ +

RF C RF RF C F

6.61A 6.61B

Figure 6.61

The extremely electrophilic nature of bis(trifluoromethyl)carbene has already been illustrated by the formation of addition products, even with hexafluorobenzene [83] (Section IIIB), and the high reactivity results in more side-reactions, such as insertion into C2H bonds, than with difluorocarbene (Figure 6.62).

C(CF3)2H C(CF3)2H i CF3 ½80 + + CF3 47%44% 9%

ν i, (CF3)2CN2, h

Figure 6.62

Trifluoromethylcarbene [95] also yields high proportions of insertion products in reactions with alkenes, whilst difluoromethylfluorocarbene is intermediate in reactivity because, although it undergoes a range of C2H insertion reactions, it is more selective than trifluoromethylcarbene [96]. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 159

Elimination Reactions 159

Polyfluoroalkylcarbenes have triplet ground states [89] and so reactions with alkenes give isomeric mixtures of cyclopropanes, as well as other side-products, in contrast to reactions involving difluorocarbene [80] (Figure 6.63).

F3CCF3 i F3C CH3 + H H H3CCH3 F3C CH3 ½80 H3C CH3 ν i, (CF3)2CN2, h cis trans 49% 39% 8%

Figure 6.63

REFERENCES 1 C.H. DePuy and C.A. Bishop, J. Am. Chem. Soc., 1960, 82, 2535. 2 H.F. Koch, D.B. Dahlberg, M.F. McEnfee and C.J. Klecha, J. Am. Chem. Soc., 1976, 98, 1060. 3 N.B. Chapman and J.L. Levy, J. Chem. Soc., 1952, 1677. 4 M. Hudlicky, J. Fluorine Chem., 1986, 32, 441. 5 M. Hudlicky and T.E. Glass, J. Fluorine Chem., 1983, 23, 15. 6 M. Hudlicky, J. Fluorine Chem., 1984, 25, 353. 7 E. Baciocchi, R. Ruzziconi and G.V. Sebastiani, J. Org. Chem., 1982, 47, 3237. 8 S. Alunni, V. Laureti, L. Ottavi and R. Ruzziconi, J. Org. Chem., 2003, 68, 718. 9 H.F. Koch, D.J. McLennan, J.G. Koch, W. Tumas, B. Dobson and N.H. Koch, J. Am. Chem. Soc., 1983, 105, 1930. 10 H.F. Koch in Comprehensive Carbanion Chemistry, ed. E. Buncel and T. Durst, Elsevier, Amsterdam, 1987. 11 J. Hine, R. Wiesboeck and O.B. Ramsay, J. Am. Chem. Soc., 1961, 83, 1222. 12 H.F. Koch and J.G. Koch in Carbanion Intermediates, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH, New York, 1988. 13 R.A. Bartsch and J.F. Bunnett, J. Am. Chem. Soc., 1968, 90, 408. 14 P. Tarrant, A.M. Lovelace and M.R. Lilyquist, J. Am. Chem. Soc., 1955, 77, 2783. 15 H.W. Davis and A.M. Whaley, J. Am. Chem. Soc., 1950, 72, 4637. 16 R.P. Ruh, US Pat. 2 628 988 (1953); Chem. Abstr., 1954, 48, 1407b. 17 P. Tarrant, R.W. Whitfield and R.H. Summerville, J. Fluorine Chem., 1971, 1, 31. 18 R.D. Chambers, R.W. Fuss, R.C.H. Spink, M.P. Greenhall, A.M. Kenwright, A.S. Batsanov and J.A.K. Howard, J. Chem. Soc., Perkin Trans. 1, 2000, 1623. 19 H. Matsuda, T. Hamatani, S. Matsubara and M. Schlosser, Tetrahedron, 1988, 44, 2865. 20 W.H. Saunders and A.F. Cockerill, Mechanisms of Elimination Reactions, John Wiley and Sons, New York, 1973. 21 D.J. McLennan, Tetrahedron, 1975, 31, 299. 22 M. Hudlicky, Coll. Czech. Chem. Commun., 1991, 56, 1680. 23 C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem., 2003, 119,9. 24 J.C. Tatlow, J. Fluorine Chem., 1995, 75,7. 25 R.P. Smith and J.C. Tatlow, J. Chem. Soc., 1957, 2505. 26 D.E.M. Evans, W.J. Feast, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1963, 4828. 27 J. Burdon, T.M. Hodgins, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1965, 2382. 28 G. Fuller and J.C. Tatlow, J. Chem. Soc., 1961, 3198. 29 D.J. Burton and Z.Y. Yang, Tetrahedron, 1992, 48, 189. 30 P.G. Gassman and N.J. O’Reilly, J. Org. Chem., 1987, 52, 2481. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 160

160 Chapter 6

31 J.L. Adcock and H. Luo, J. Org. Chem., 1993, 58, 1999. 32 S.F. Campbell, R. Stephens and J.C. Tatlow, Tetrahedron, 1965, 21, 2997. 33 W.B. Hollyhead, R. Stephens, J.C. Tatlow and W.T. Westwood, Tetrahedron, 1969, 25, 1777. 34 R. N. Haszeldine, Fluorocarbon Derivatives, Royal Institute of Chemistry, London, 1956. 35 M. Yamabe and H. Miyake in Organofluorine Chemistry: Principles and Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum Press, New York, 1994, p. 403. 36 N.T. Nakai, K. Tanaka and N. Ishikawa, Tetrahedron Lett., 1976, 17, 1263. 37 J.M. Percy in Organofluorine Chemistry: Techniques and Synthons, ed. R.D. Chambers, Springer, Berlin, 1997, p. 131. 38 H. Hata, T. Kobayashi, A. Amii, K. Uneyama and J.T. Welch, Tetrahedron Lett., 2002, 43, 6099. 39 K. Uneyama and H. Amii, J. Fluorine Chem., 2002, 114, 127. 40 D.J. Burton and J.L. Hahnfeld, Fluorine Chem. Rev., 1977, 8, 119. 41 B.E. Smart in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath, ACS, Washington DC, 1995, p. 767. 42 J. Hine, Divalent Carbon, Ronald, New York, 1964. 43 W.E. Parham and E.E. Schweizer, Org. Reactions, 1963, 13, 55. 44 J. Hine and P.B. Langford, J. Am. Chem. Soc., 1957, 79, 5497. 45 G.C. Robinson, Tetrahedron Lett., 1965, 1749. 46 L. Anke, D. Reinhard and P. Weyerstahl, Liebigs Ann. Chem., 1981, 591. 47 Y. Bessiere, D.N.H. Savary and M. Schlosser, Helv. Chem. Acta, 1977, 60, 1739. 48 P. Balcerzak, M. Fedorynski and A. Jonczyk, J. Chem. Soc., Chem. Commun., 1991, 826. 49 J. Hine and D.C. Duffey, J. Am. Chem. Soc., 1959, 81, 1129. 50 J. Hine and D.C. Duffey, J. Am. Chem. Soc., 1959, 81, 1131. 51 Y. Kobayashi, T. Taguchi, T. Morikawa, T. Takase and H. Takanishi J. Org. Chem., 1982, 47, 3232. 52 T. Taguchi, T. Takigawa, Y. Tawara, T. Morikawa and Y. Kobayashi, Tetrahedron Lett., 1984, 25, 5689. 53 T. Ando, H. Tamanaka, S. Terabe, A. Horike and W. Funasaka, Tetrahedron Lett., 1967, 1123. 54 O.R. Pierce, E.T. McBee and G.F. Judd, J. Am. Chem. Soc., 1954, 76, 474. 55 V. Franzen, Chem. Ber., 1962, 95, 1964. 56 D.J. Seyferth, J. Organometal. Chem., 1973, 62, 33. 57 S.F. Sellers, W.R. Dolbier, H. Koroniak and D.M. Al-Fekri, J. Org. Chem., 1984, 49, 1033. 58 W.R. Dolbier, H. Wojtowicz and C.R. Burkholder, J. Org. Chem., 1990, 55, 5420. 59 N.V. Kirii, S.V. Pazenok, Y.L. Yagupolskii, D. Naumann and W. Turra, Russ. J. Org. Chem., 2001, 37, 207. 60 D.J. Burton and D.G. Naae, J. Org. Chem., 1973, 95, 8467. 61 W.R. Dolbier and S.F. Sellers, J. Org. Chem., 1982, 47,1. 62 A. Greenberg and N. Yang, J. Org. Chem., 1990, 55, 372. 63 Y. Bessard and M. Schlosser, Tetrahedron, 1991, 47, 7323. 64 A.E. Feiring in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banke, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 339. 65 R.E. Banks, J.M. Birchall, R.N. Haszeldine, J.M. Simm, H. Sutcliffe and J.H. Umfreville, Proc. Chem. Soc., 1962, 281. 66 J.M. Birchall and R.N. Haszeldine, J. Chem. Soc., 1959, 3653. 67 H. Millauer, W. Schwertfeger and G. Siegemund, Angew. Chem. Int. Ed. Engl., 1985, 24, 161. 68 W. Mahler and P.R. Resnick, J. Fluorine Chem., 1973, 3, 451. 69 P.B. Sargent and C.G. Krespan, J. Am. Chem. Soc., 1969, 91, 415. 70 W.R. Dolbier, S.F. Sellers, B.H. Al-Sader, T. H. Fielder, S. Elsheimer and B.E. Smart, Isr. J. Chem., 1981, 21, 176. 71 P.W.L. Bosbury, R. Fields, R.N. Haszeldine and G.R. Lomax, J. Chem. Soc., Perkin Trans. 1, 1982, 2203. Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 161

Elimination Reactions 161

72 W.P. Dailey, P. Ralli, D. Wasserman and D.M. Lemal, J. Org. Chem., 1989, 54, 5516. 73 R.G. Cavell, R.C. Dobbie and W.J.R. Tyerman, Canad. J. Chem., 1967, 45, 2849. 74 J.M. Birchall, R.N. Haszeldine and D.W. Roberts, J. Chem. Soc., Chem. Commun., 1967, 287. 75 R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 758. 76 V.M. Karpov, V.E. Platonov, I.P. Chuikov and G.G. Yakobson, J. Fluorine Chem., 1983, 22, 459. 77 R.D. Chambers, R.P. Corbally, T.F. Holmes, and W.K.R. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1974, 108. 78 M. Rahman, M.L. McKee and P.P. Shevlin in Fluorine-Containing Molecules, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH, New York, 1988. 79 R. Sztyrbicka, M. Rhaman and M.E. D’Aunoy, J. Am. Chem. Soc., 1990, 112, 6712. 80 D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617. 81 J.H. Atherton and R. Fields, J. Chem. Soc. C, 1968, 2276. 82 W.P. Dailey, Tetrahedron Lett., 1987, 28, 5801. 83 D.M. Gale, J. Org. Chem., 1968, 33, 2536. 84 R.N. Haszeldine and J.G. Speight, J. Chem. Soc., Chem. Commun., 1967, 995. 85 D. Seyferth and G. J. Murphy, J. Organometal. Chem., 1973, 52, C1. 86 J.P. Simons, J. Chem. Soc., 1965, 5406. 87 R.A. Moss, Acc. Chem. Res., 1980, 13, 58. 88 R.A. Seburg and R.J. McMahon, J. Org. Chem., 1993, 58, 979. 89 D.A. Dixon, J. Phys. Chem., 1986, 90, 54. 90 K.K. Irikura, W.A. Goddard and J.L. Beauchamp, J. Am. Chem. Soc., 1992, 114, 48. 91 D. Seyferth and S.P. Hopper, J. Org. Chem., 1971, 26, 620. 92 N.G. Rondan, K.N. Houk and R.A. Moss, J. Am. Chem. Soc., 1980, 102, 1770. 93 B. Giese, W.B. Lee and J. Meister, Ann. Chem., 1980, 725. 94 K.N. Houk, N.G. Rondan and J. Mareda, J. Am. Chem. Soc., 1984, 106, 4291. 95 J.H. Atherton and R. Fields, J. Chem. Soc. C, 1967, 1450. 96 R.N. Haszeldine, R. Rowland, J.G. Speight and A.E. Tipping, J. Chem. Soc., Perkin Trans. 1, 1980, 314. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 162

Chapter 7 Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives

I PERFLUOROALKANES AND PERFLUOROCYCLOALKANES [1] A Structure and bonding [2, 3] 1 Carbon–fluorine bonds Carbon–fluorine bonds in the fluoromethane series shorten progressively upon increasing fluorination (Table 7.1), a feature that is not observed for other carbon–halogen bonds in halomethanes [2, 3]. Clearly, the carbon–fluorine bond shortening is accompanied by an increase in the bond energy of the carbon–fluorine bond, whilst the variation in bond lengths for the carbon–hydrogen bond is much smaller. In the chloromethanes the carbon– chlorine bond weakens slightly with increasing chlorine content.

Table 7.1 Bond lengths r and bond strengths B of various halomethanes [3, 4]

X ¼ FX¼ Cl

r(C2F) (A˚ ) B(C2F) (kJmol1) r(C2Cl) (A˚ ) B(C2Cl) (kJmol1)

CXH3 1.385 459.8 1.781 354.0 CX2H2 1.357 500.0 1.772 335.1 CX3H 1.332 533.5 1.758 324.7 CX4 1.319 546.0 1.767 305.8

Bond-shortening in fluoromethanes has been discussed by a number of authors. Pauling originally [5] introduced the concept of double-bond no-bond resonance (negative hyperconjugation, Chapter 4, Section IIIB) involving, in MO terms, interaction of non-bonding electron pairs of fluorine with a s orbital of a carbon–fluorine bond, to account for the effect, and this is now well established [6] (Figure 7.1).

2 Carbon–carbon bonds The weakest bonds in perfluoroalkanes are the carbon–carbon bonds, so it is of interest as to whether the strengths of these bonds are affected by the introduction of fluorine. It is

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 163

F F F FCFFCF FCF etc. ½6 F F F

Figure 7.1 found that carbon–carbon bond strengths in a series of fluoroethanes increase upon a-fluorination (Table 7.2).

Table 7.2 Carbon–carbon bond strengths and lengths in fluoroethanes [3]

Ethane r(C2F) (A˚ ) BDE(C2C) (kJmol1)

CH32CH3 1.532 378.2 CH32CH2F 1.502 381.6 CH32CHF2 1.498 400.0 CH32CF3 1.494 423.4 CF32CH2F 1.501 395.8 CF32CF3 1.545 413.0

Paradoxically, the carbon–carbon bond in hexafluoroethane is stronger than in ethane, even though it is longer; as yet, such observations remain unaccounted for.

B Physical properties Since the molecular weight of a fluorocarbon is considerably higher than that of the corresponding hydrocarbon, we might expect boiling points to be increased. It can be seen from Figure 7.2 [7] that this is not so, and that there is a remarkable similarity between the boiling points of fluorocarbons and the corresponding hydrocarbons [8], the increase in molecular weight being offset by a decrease in intermolecular bonding forces in the fluorocarbon [9]. Perfluorocarbons have the potentially valuable property of dissolving useful amounts of certain gases, including oxygen, carbon dioxide and even fluorine, and the inertness of fluorocarbons to oxidation has led to a long-term study of fluorocarbon emulsions in water for use as ‘artificial’ blood and other transport applications [10]. Although working systems have been demonstrated, drawbacks associated with reactions of the immune system have, so far, limited their successful commercial development. Fluorinated fullerenes have been studied intensively [11].

C Reactions 1 Hydrolysis Perfluorocarbons are essentially inert to hydrolysis unless heated to very high temperatures, although it has been calculated that the free energy of hydrolysis of carbon tetrafluoride is exothermic by 304 kJmol1 [12], and the inertness therefore stems from a high activation barrier. The carbon backbone in a perfluorocarbon is shielded towards attack by nucleophiles by the non-bonding electron pairs associated with the many adjacent fluorine atoms, and this is undoubtedly a major factor contributing to the relative inertness of fluorocarbons. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 164

164 Chapter 7

150

100

50 C) 0 2 468 Number of carbon atoms −50 Boiling point (

−100

−150

Fluorocarbons Hydrocarbons −200

Figure 7.2 Boiling points of alkanes

2 Defluorination and functionalisation [1] Either fusion with alkali metals or reaction with alkali-metal complexes with aromatic hydrocarbons will break down most fluorocarbon systems, due to the high electron affinities of these systems. Such reactions form the basis of some methods of elemental analysis [13], the fluorine being estimated as hydrogen fluoride after ion exchange. Surface defluorination of PTFE occurs with alkali metals and using other techniques [14]. Per- fluorocycloalkanes give aromatic compounds by passage over hot iron and this provides a potential route to a variety of perfluoroaromatic systems (Chapter 9, Section IB). Electron transfer from other, less vigorous, reducing agents (Table 7.3) can result in selective defluorination, which arises from a single-electron transfer process, under very mild conditions (Figure 7.3).

− − +e −F CF2CF2 CF2CF2 CF2CF2 CF2CF n n n-1

− +e

− − +e −F etc. CF CF CF=CF CF CF CF CF 2 2 n-1 2 2 n-1 2

Figure 7.3 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 165

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 165

Table 7.3 Defluorination of perfluorocarbons

Yield Substrate Reagents/Conditions Product (%) Ref.

Cp TiF 40 [15] FF 2 2 FF Al, HgCl2, THF, rt

Cp Co 53 [16] FF 2 FF LiðO3SCF3Þ,Et2O, rt

Ph C5O, Na 62 [17] FF 2 FF THF, rt

When the reducing agent can also act as a nucleophile, such as thiolate anion [18] (Figure 7.4) or ammonia sensitised by mercury [19] (Figure 7.5), functionalisation of the unsaturated, fluorinated intermediate can occur.

SPh SPh PhS SPh i F F ½18 PhS SPh

− + SPh SPh i, PhS Na , DMEU, 70C, 10 days

Figure 7.4

F C NC NH2 3 i 19 CF CF2 ½

F3C CF2CF3 NC CF2CF3

CF3 CN HN NH2 i ½19 F F

ν i, Hg/h , NH3

Figure 7.5 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 166

166 Chapter 7

3 Fragmentation Although perfluorocarbons are extremely thermally stable compounds, pyrolysis at elevated temperatures can lead to useful preparations of some simple alkenes [20] (Figure 7.6).

725C F CF2 C(CF3)2 + CF2 CFCF3 ½20 70% 20%

Figure 7.6

Vacuum pyrolysis of polytetrafluoroethene gives tetrafluoroethene as virtually the only product [21]; this unzipping reaction is almost unique amongst depolymerisation processes. At higher pressures the pyrolysis product contains other perfluorinated alkenes and perfluorocyclobutane, the proportions depending on the exact reaction conditions [22].

D Fluorous biphase techniques [1, 23, 24] The technique of using mixtures of perfluorocarbon and hydrocarbon solvents to aid separation and recovery of products, catalysts etc. was initiated by Horva´th and Rabai [25]. These mixtures of solvents may be largely immiscible at room temperature but will become miscible on heating, whereupon reaction will take place. On cooling, separation occurs and products may be recovered. If a component has an attached perfluoroalkyl group that is sufficiently long to render that component soluble in the perfluorocarbon (e.g. a catalyst), then recovery from the perfluorocarbon becomes easy [25] (Figure 7.7). In this example, the product aldehyde separates from the perfluorocarbon solvent [26]. However, because of the high cost of perfluorocarbons and their global warming potential, it seems unlikely that these approaches will be used in large-scale syntheses.

CO/H 2 CO/H2 CO/H2 1-octene n-nonanal 81% 1-octene Heat ½26 25 C, C7F14 25 C, C7F14 70 C, C7F14 [Rh] [Rh] [Rh]

P(4-C6H4C6F13)3 P(4-C6H4C6F13)3 P(4-C6H4C6F13)3

Figure 7.7

Curran and co-workers have introduced a promising approach to separation and purification procedures by using fluorocarbon-coated solid phases for liquid-phase chromatography. This approach depends on attaching a variety of perfluorocarbon tags to functional compounds which render the eventual substrate mixture separable over the perfluorinated stationary phase [27, 28] (Figure 7.8). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 167

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 167

1 1 1 1 1 1 A RF A RF B RF ½27, 28 i

6 6 6 6 6 6 A RF A RF B RF

Separate Mixture Mixture Components i, various chemical transformations Chromatography 1 RF etc. = Fluorinated tag

1 1 B RF Recovery of B1-B6 and RF tags 6 6 B RF Separate Components

Figure 7.8

II PERFLUOROALKENES A Stability, structure and bonding Substitution of hydrogen, in an alkene, by fluorine leads to increased reactivity for a number of processes; for example, with tetrafluoroethene, heats of addition of chlorine, hydrogenation and polymerisation are 58.5, 66.9 and 71:1 kJmol1 greater, respectively, than for the analogous reactions with ethene [3, 29]. These observations could be attributed either to an increase in the carbon–fluorine bond strength upon changing the hybridisation of the carbon atoms bonded to fluorine [30] or to p-bond destabilisation by fluorine [31]. Here it is reasonable to note the effect of fluorine and of perfluoroalkyl groups on orbital energies; in this regard, photoelectron spectroscopy is quite valuable. It is useful to emphasise, again, that electron-withdrawing groups lower orbital energies, and photoelectron spectroscopy confirms that perfluoroalkyl groups have this effect on attached p-bonds. The same technique [32, 33] also points to the ambiguous nature of a fluorine atom attached to a double bond (Chapter I, Section IIIB) where inductive electron withdrawal is offset by interaction of non-bonding electron pairs on fluorine with the p-system. Consequently, the effect of fluorine attached to a double bond on the energies of the p-orbitals is little different from that of hydrogen, whereas perfluoroalkyl is strongly stabilising. In contrast, a fluorine atom attached to a saturated site can only be a stabilising influence, so we can appreciate that there is a driving force towards decreasing the number of sites where a fluorine atom is attached to an unsaturated carbon centre. A consideration of the cyclobutene ring-opening reactions [34, 35] (Table 7.4) reveals that the changes in hybridisation of carbon bonded to fluorine are the same for both compounds T7.4A and T7.4B, and so any changes in carbon–fluorine bond energies must also be the same. Consequently, as DH for T.7.4A is more endothermic than for T7.4B, Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 168

168 Chapter 7

Table 7.4 Ring opening of cyclobutenes [34]

1 1 Substrate Product DHðkJmol Þ EaðkJmol Þ Keq at 3158 C

33.5 136.0 9000

F2C F 48.9 197.0 5:6 103 F

T7.4A F2C F

CF3 F2C CF3 F 1.7 192.5 8.4

CF 3 F2C CF3 T7.4B

this difference must be due to destabilisation of the p-system by fluorine, an effect which must increase with the number of fluorine atoms attached to the double bond. These conclusions are supported by the measurement of the p-bond dissociation energy 1 [36] of CF25CF2, which is 29 kJmol less than that for ethene. However, the situation is less clear for partly fluorinated systems such as CF25CH2, in which the p-bond is 12:5 kJmol1 more stable than in ethene [37]. cis-1,2-Difluoroethene is more thermodynamically stable by about 48 kJmol1 than the trans isomer [38]. This observation, which has been termed the cis effect, appears to be a similar phenomenon to the conformational preference of 1,2-difluoroethane for the gauche form [39]. A number of explanations and theoretical calculations have been advanced [3, 39], with non-bonded attraction and conjugative destabilisation being the most widely discussed. Of course, it could be that fluorine atoms in the trans isomer of 1,2-difluoroethene have the more destabilising influence on the p-bond. All available data appear to point to the same underlying feature, that fluorine prefers not to be attached to unsaturated carbon; this most probably stems from repulsion between electron pairs on fluorine and those of the p-systems. Earlier discussions showed that similar repulsions are important in determining the stability of fluorocarbanions (see Chapter 4, Section VIIA), and that these repulsive forces appear to be critically interdependent with stereochemistry. Similar effects on fluoroalkenes are represented in Figure 7.9. The formation of a double bond involving sp2-hybridised carbon, 7.9A, would lead to greater electron-pair repulsion than when formed from sp3- hybridised carbon (cf. 7.9A and 7.9B); the latter would lead to ‘bent bond’ formulation 7.9B. Extension of this approach leads to the conclusion that fluorine attached to a carbon– carbon triple bond would be considerably destabilising, since electron-pair repulsions with fluorine would then be at a maximum (Figure 7.10). This could partly account for the instability of fluoroalkynes, described later (Section IIIA, below). Of course, it must not Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 169

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 169 be forgotten that the electronegativity of carbon increases in the series sp3, sp2, sp and the carbon–fluorine bond strength decreases correspondingly.

2 3 7.9A, C sp 7.9B, C sp

109 90 109 109 FC F C

Figure 7.9

FC C

Figure 7.10

B Synthesis There are four main general methods [40–42] for the preparation of perfluorinated alkenes, namely dehydrohalogenation, dehalogenation, pyrolysis and halogen exchange reactions of appropriate fluorinated precursors. The overall features of the mechanisms of each of these processes have already been discussed (Chapters 6 and 7, Sections I and II). Representative examples of each of these types of synthesis are collated in Table 7.5; clearly the method of choice for the synthesis of a particular fluoroalkene will depend

Table 7.5 Synthesis of perfluoroalkenes

Reaction Ref.

Dehydrohalogenation H KOH/H O [43, 44] F 2 F Reflux/30 min.

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 170

170 Chapter 7

Table 7.5 Contd

Reaction Ref.

CF2CFHCF3 CF CFCF3

[45] NaOH 85C

F F Cl F KOH F [46] H F F

Dehalogenation Cl 200C Zn, EtOH CF2 CFCl F F 100% [47] Cl

Pyrolysis i CF2 CF2 CF2 CFCF3 [48] i, 750-800C, Atmos Press.

i (CF2 CF2)n CF2 CFCF3 32%+ CF2 CFC2F5 9%

+ CF2 C(CF3)2 53% [49]

i, 700C, Atmos Press.

− + ∆ CF3CF2CF2CO2 Na CF2 CFCF3 [50] − CO2

Halogen exchange

i F3C H CCl CClCCl CCl 59% 2 2 [51, 52] F CF3 i, KF, 200C, NMP

i Cl F 72% [51]

i, KF, NMP, 200C

i CCl2 CCl CCl CCl2 CF3C CCF3 [53] i, KF, 18-Crown-6, Perfluorocarbon Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 171

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 171 upon the availability of suitable precursors. In this section we will confine ourselves to syntheses of per- and poly-fluoroalkenes, whilst other approaches to the preparation of selectively fluorinated alkenes will be discussed in other chapters. It is important to note that most of the simple highly fluorinated, commercially significant fluoroalkenes are synthesised from materials obtained by the Swarts reaction (Chapter 2, Section IIA) involving catalysed reactions of anhydrous hydrogen fluoride with chloroalkanes [54] (Figure 7.11) or bromoalkanes.

HF 700C CHClF CF CF CHCl3 2 2 2 ½54 catalyst Pt 860C Vacuum

CF2 CFCF3

HF ∆ CH3 CCl3 CH3 CClF2 CH2 CF2 catalyst − HCl

Figure 7.11

Decarboxylation of fluoro-acids which, in turn, are prepared by electrochemical fluorination (ECF) on the industrial scale, is a useful route to longer-chain terminal fluoroalkenes [50] (Figure 7.12).

E.C.F. H2O n-C3H7COF n-C3F7COF n-C3F7COOH ½50

− ∆ − − + F n-C F COO Na C F CF CFCF + NaF 3 7 − 3 7 2= 3 CO2

Figure 7.12

Perfluorocyclopentene is exceptional in being obtained from non-fluorinated materials by a simple one-step procedure, i.e. displacement of chlorine in perchlorocyclopentene by fluoride ion [51], although some polyfluorochloro- and polyfluorohydro-alkenes can be made by analogous processes [51, 52]. If a perfluorocarbon is used as the reaction medium with potassium fluoride/18-crown-6 complex, then a variety of products may be obtained, including hexafluoro-2-butyne [53]. Many useful, higher-molecular-weight fluoroalkenes can be conveniently prepared by fluoride-ion-induced oligomerisation reactions of smaller fluoroalkenes such as tetrafluoroethene and hexafluoropropene, and these methods are discussed in Section C.

C Nucleophilic attack [55–57] Fluoroalkenes are generally much more susceptible to attack by nucleophiles than by electrophiles and, in this respect, the chemistry of polyfluoroalkenes and their Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 172

172 Chapter 7 corresponding alkenes may be said to be complementary [56]. Consequently, the term ‘mirror-image chemistry’ is appropriate to describe much of what follows (Figure 7.13).

F F F F F F − H+ Nuc + CC Nuc C C Nuc C C H F F F F F F

H − H H H H H + Nuc E + CC ECC ECCNuc H H H H H H

Figure 7.13

Nucleophilic attack on a double bond proceeds via carbanionic intermediates; a consideration of the relative stabilities of such species as models for the corresponding transition states accounts for most, but not all, of the observations concerning nucleophilic addition to fluoroalkenes. The formation and direct observation by NMR of perfluoroalkyl anions in solution e.g. 7.14A, via addition of fluoride ion to perfluorinated alkenes [58] is analogous to the observation of carbocations by protonation of alkenes. The carbanions generated can be readily trapped by electrophiles [58]: in a classical experiment Wiley [59] showed that carbanions are intermediates in nucleophilic addition to tetrafluoroethene, by trapping the intermediate with dimethylcarbonate. Later developments showed that various nucleophiles may be used, and that fluoro-esters may be employed as the trapping agent [60, 61] (Figure 7.14).

1 Orientation of addition and relative reactivities Problems of orientation of attack and reactivities of fluorinated alkenes arise in a way that is analogous but entirely complementary to the classical problems of electrophilic attack on alkenes. For example, typical of the results that we must be able to account for is the reaction of methoxide in methanol which occurs specifically at the CF25 site in perfluoropropene (Figure 7.15). Also, there is a very wide range of reactivity with perfluoroalkenes: for example, reactions of tetrafluoroethene usually require base catalysis, whereas perfluoroisobutene reacts with neutral methanol. (Caution: Like all alkylating agents, fluorinated alkenes should be treated as being potentially toxic [62, 63]. For example, perfluoroisobutene is an extreme case and should be avoided.)

2 Reactivity and regiochemistry of nucleophilic attack A great deal of chemistry involving nucleophilic attack on fluorinated alkenes may be rationalised on the basis of some simple ground rules and assumptions: (1) There is a significant ion–dipole interaction [64] that contributes to the much greater reactivity of alkenes bearing fluorine rather than chlorine at comparable sites [65], and a terminal difluoromethylene is especially reactive [66] (Figure 7.16). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 173

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 173

F C CF CF F3C 3 2 3 tetraglyme + ½58 + CsF CF2CF2CF3 Cs rt F3C F F3C 7.14A, Observable by NMR

CF3

CF2CF2CF3 CF3

− − ½59 CH3O + CF2 CF2 CH3OCF2CF2

(CH3O)2C=O

CH3OCF2CF2CO2CH3 74%

O i Nuc CF2 CF2 NucCF2CF2 NucCF2CF2 C RF ½60, 61

i, RFCOOR OR

− − − − − eg Nuc = N3 , PhO, CH3O, CH3S.

Figure 7.14

− CH3O CF2 CFCF3 CH3OCF2CFCF3

CH3OH

− CH3OCF(CF3)CF2 CH3OCF2CFHCF3 CH3O

Figure 7.15

(2) Fluorine attached to carbon, which is itself adjacent to the carbanionic site (7.16A), is carbanion-stabilising and therefore strongly activating, for example when X or Y in 7.16A is CF3. (3) When fluorine is directly attached to the carbanionic site, e.g. X or Y ¼ Fin7.16A, the result is usually activating, but much less so than in (2). Thus, we have an increase in reactivity in the series 7.17A–7.17C [67–69], and we can see that this corresponds to an increase in stabilities of the derived intermediate carbanions 7.17D–7.17F (Figure 7.17). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 174

174 Chapter 7

δ δ δ δ C F >> C Cl

F Nuc C CXY Nuc CF CXY etc. δ 2 F δ 7.16A

Figure 7.16

CF2 CF2

7.17A 7.17B 7.17C

− NucCF2CF2 <

7.17D 7.17E 7.17F

Figure 7.17

Furthermore, the rates of nucleophilic addition of diethylamine have been found to increase in the series CF25CF2 < CF25CFCl < CF25CFBr [70] (Figure 7.18), again in the order of increasing stability of the supposed intermediate carbanion.

+ + −H − +H (C2H5)2NH CF2 CFBr (C2H5)2NCF2CFBr (C2H5)2NCF2CFBrH

Figure 7.18

The order of reactivity CF25CðRFÞ2 > CFRF5CðRFÞ2 > ðRFÞ2C5CðRFÞ2 (where RF ¼ perfluoroalkyl) has been clearly established from the isomeric system, 7.19A–7.19C,in competition for reactions with methanol [68] (Figure 7.19).

− F CF2 C(RF)CF2CF3 CF3CF2(CF3)C C(CF3)CF2CF3 ½68

7.19A 7.19B

− RF = CF3CFCF2CF3 F

CF3CF C(CF3)RF

7.19C

Figure 7.19

Intermediate carbanions formed by the addition of nucleophiles to fluorinated alkenes may also be intercepted via halophilic processes [71] (Figure 7.20), as well as trapping by electrophiles (see Figure 7.14). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 175

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 175

− 71 CH3O CF2 CFBr CH3OCF2CFBr ½

CF2 CFBr

CH3OCF2CFBr2 CF2 CF

Other products

Figure 7.20

However, the type of argument outlined above is insufficient to account for the reactivity of perfluoropropene being greater than that of perfluoro-2-butene (7.21A) (Figure 7.21), because the corresponding intermediate (7.21B) could only have margin- ally different stability from the intermediate derived from perfluoropropene (7.17E). There is also the greater reactivity of 7.22A than 7.22B to account for, where any difference in stability of intermediate carbanions 7.22C and 7.22D would also be mar- ginal (Figure 7.22).

− Nuc CF3CF CFCF3 NucCF(CF3)CF(CF3) Products

7.21A 7.21B

Figure 7.21

RFCF C(RF)2 > (RF)2C C(RF)2

7.22A 7.22B RF = Perfluoroalkyl

NucCF(RF)C(RF)2 NucC(RF)2C(RF)2

7.22C 7.22D

Figure 7.22

Consequently, a frontier-orbital approach has also been used to account for reactivity and orientation of attack [72]. This approach recognises that HOMO–LUMO interaction, between nucleophile and fluorinated alkene respectively, will be important, and that replacing a fluorine atom that is directly attached to unsaturated carbon in a fluorinated alkene by trifluoromethyl reduces LUMO energy. This increased HOMO–LUMO interaction correspondingly increases reactivity, providing that the trifluoromethyl groups are on the same carbon atom of the double bond, i.e. as in 7.17A–7.17C. However, coefficients also appear to be important, and introduction of trifluoromethyl increases the coefficient in the LUMO at the adjacent carbon, i.e. as shown for 7.23A (Figure 7.23). When two trifluoromethyl groups are attached to adjacent carbon atoms (7.23B), then it is reasonable to assume that their effect on coefficients, and hence on reactivity, is opposing; consequently the reactivity order CF25CF2 < CF25CFCF3 > CF3CF5CFCF3 is observed. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 176

176 Chapter 7

F3C F3CCF3 CC CC

F3C

7.23A 7.23B

Figure 7.23

Strain is a very important factor affecting reactivity. This is probably best illustrated by the relative reactivities of the dienes 7.24A–7.24C (Figure 7.24) [73] towards methanol, giving the methoxy derivatives indicated. Diene 7.24A reacts vigorously with neutral methanol, diene 7.24B reacts only over several days, while base is required to induce reaction with diene 7.24C. Electronic effects in the dienes 7.24A–7.24C are essentially equivalent and, therefore, these considerable differences in reactivity may be taken, generally, as illustrative of the contributions that angle strain may introduce.

X X

X CF3 CF F F FF 3 F3C F3C Y Y Y

X, Y = F (7.24A) X, Y = F (7.24B) X, Y = F (7.24C) X = F, Y = OMe X = F, Y = OMe X = F, Y = OMe X = Y = OMe X = Y = OMe

Figure 7.24

3 Products formed The nature of the products formed in these processes may be regarded as being dependent upon the fate of an intermediate carbanion (7.25A in Figure 7.25): this can lead to proton abstraction from the solvent to give 7.25B; elimination of fluoride to give 7.25C; or, if the 0 opportunity is available, an SN2 process, e.g. by elimination of fluoride ion accompanied by allylic rearrangement to give 7.25D. The ratio of elimination to addition increases with the reactivity of the alkene, because the stability of the carbanion 7.25A increases and, at the same time, 7.25A becomes correspondingly less basic. Of course, the amount of alkene 7.25C also depends on whether the reaction is simply a base-catalysed process or whether a molecular equivalent of base is present. These processes are illustrated in Figure 7.26 [74, 75]. All three types of product are seen in many reactions between fluoroalkenes and nucleophiles [55, 76] (Figure 7.27). With very strong nucleophiles, polysubstitution may occur [77] (Figure 7.28). With ammonia and other nitrogen bases, a variety of unsaturated compounds may be obtained, such as nitriles and triazines [78–80] (Figure 7.29).

0 4 Substitution with rearrangement – SN2 processes Examples of substitutions that are accompanied by migration of the double bond are very common with fluoroalkenes; although in most cases it is not established whether these Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 177

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 177

Nuc-H − Nuc C C Nuc C C H + Nuc

F R F R (Base catalysed addition) 7.25A 7.25B

− −F SN2' − R = CFR'2

Nuc R' Nuc F R' R

7.25D 7.25C

Figure 7.25

− + C4H9O Na n-C4H9OH + CF2 CF2 n-C4H9OCF2CF2H 81% 0-40C ½74

Room CH OH CF C(CF ) CH OCF CH(CF ) 65% 3 2 3 2 Temp. 3 2 3 2 ½75

CH3OCF C(CF3)2 8%

Figure 7.26

i CF2 CFCF2C4F9 CH3OCF2CFHCF2C4F9 (45%, addition) ½76

+CH3OCF CFCF2C4F9 (15%, substitution)

+ CH3OCF2CF CFC4F9 (40%, SN2') − + i, CH3O Na , CH3OH, 50 C

Figure 7.27

Room 4C H Li + CF CF (C6H5)2C C(C6H5)2 ½77 6 5 2 2 Temp

Figure 7.28

0 reactions are concerted, they will be referred to as SN2 processes here [81] (Figure 7.30). That substitution occurs by attack at the CF25 group, rather than direct displacement of chloride from 2CF2Cl, has been deduced from the fact that, under equivalent conditions, C6H5CClF2, CClF5CF2CClF2 and CCl25CCl2CClF2 are unreactive [82]. In non-aqueous media the relative order of reactivity of the attacking halide ions, as nucleophiles in these processes, is F > Cl I [83]. This in itself indicates that the Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 178

178 Chapter 7

XHFC N CFHX C C CF CFX NH3 2 ½78 N N C CFHX

Vap. CF3CF CF2 NH3 CF3CHFCN ½79 Phase

Et2O ½80 (CF3)2C CF2 NH3 (CF3)2CHFCN 21% −60C

(CF3)2CHCONH2 13%

Figure 7.29

− − CH3O CF2 CFCF2Cl CH3OCF2CF CF2 Cl ½81

Figure 7.30

C6H5 k C6H5 − 1 CF2 + C2H5O CCF2OC2H5 products ½84 R R

3 −1 Rk1 x 10 s (77 C)

CF3 1.9

CF2Cl 1.8

CF2CF3 0.67

Figure 7.31 bond-making process is most important and that the reactions involve a two-step addition–elimination, rather than a concerted displacement in which the most polarisable anion would be the most reactive. The same conclusion was drawn from a comparison of the rates of reaction of various alkenes with ethoxide in ethanol under pseudo first-order conditions [84] (Figure 7.31). Rearrangement products were only obtained when R was CF2Cl, where elimination of chloride was easier, but the rate constants for the other two examples are comparable, which indicates a rate-controlling addition step (k1). In general it is very difficult to make any distinction between a concerted process and the involvement of a short-lived carbanion. For clarity a number of alkene rearrangements in the following text are written as two-step processes, but it should be emphasised that they could involve concerted mechanisms. Products arising from substitution with rearrangement are frequently encountered in reactions of cyclic fluoroalkenes and in fluoride-ion-induced rearrangements (Subsection 6, below). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 179

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 179

The literature concerning reactions between nucleophiles and fluoroalkenes is now extensive and is included in various reviews [41, 55, 57, 85–92] and books devoted to organofluorine chemistry (see the relevant chapters in the general textbooks listed in Chapter 1, Section I). Some examples of reactions between fluoroalkenes and an illustrative selection of nucleophiles are recorded in Table 7.6. The many unusual products and the wide scope of these reactions will be apparent even from such a brief overview of the subject. Examples of reactions involving bifunctional nucleophiles are also included, whereas reactions involving initial attack by fluoride ion as the nucleophile are discussed in Subsection 6, below.

Table 7.6 Reactions of fluoroalkenes with nucleophiles

Reaction Ref.

Carbon nucleophiles

C8F17

C8F17SiMe3 + F F 95% [93]

i CF2 CF2 NCCF2CF2CO2CH3 72% [60]

i, NaCN, CO2, (CH3O)2SO2

i Ph2CCN XYCCF2 Ph2C(CN)CF2CXY [94] i, Phase Transfer Conditions

Ph2C(CN)CF2CHXY Ph2C(CN)CF=CXY

i Ph-CF CFCF3 Ph2C CFCF3 PhCF C(CF3)Ph [95] i, PhLi, Et2O Ph2C C(CF3)Ph (1 : 3.3 : 2.1)

NMe2 NMe2 [96] CH CN, rt + FF 3 73%

F F

CH MgX CF CCl CH CF CCl H 3 2 2 3 2 2 [97]

CH3CF CCl2

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180 Chapter 7

Table 7.6 Contd

Reaction Ref.

Nitrogen nucleophiles F F rt F N CF CF2 + CH3NH2 F N [98] N CH H 3

78%

CF F 3 C2F5 F C2F5 NH3, Et2O [99] F C CH CN 0C 3 2 94% C2F5 F C2F5 C F F3C 2 5

Oxygen nucleophiles F C O F C 3 CF F3C O CF 3 CF3 i 3 3 + [100] C F C F C F H C2F5 2 5 2 5 2 5 C2F5 62% 28% i, NaOCl, H2O, CH3CN

F C 3 xylene F3C F CF2 + Bu3SnOMe 62% [101] 0C F3C F3C OMe

H OH H H i 78% [102] F Ph O Ph

F F i, Montmorillonite (cat), KIO3, Hexane, Reflux

O i C(CF3)2 68% [103] (CH2OH)2 CF2 C(CF3)2 O − i, CH3CN, 5 to 0 C

Phosphorous nucleophiles C F CF CF + Bu PCF CF CFP(F) Bu 3 7 2 3 3 7 3 [104] (100%, Z)

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 181

Table 7.6 Contd

Reaction Ref.

i Bu3PCF2 CFCF3 Bu3P CF CFCF3 [105] F − i, Et2O, 70 C to rt

BF3.Et2O

F CF3 ii − Bu3P CF CFCF3 BF4 IF

ii, I2, DMF, NaCO3

F [106] F + Ph3P PPh3

Sulphur nucleophiles

F3C F F C S CF K2S, DMF 3 3 [107] 62% F3C FSF3C CF3

i CF2 CFCF3 CF3CFHCF2SC( S)NMe2 29% [108] + CF3CF CFSC( S)NMe2 63% − + i, Me2N CS2 Na , DMA, 20 C

Halide ions I [109] NaI, DMF F F

Transition metal nucleophiles

− F [110] F + Re(CO)5

Re(CO)5

Reduction

i F CF3 PhCF CFCF3 9% [111] Ph H i, LiAlH4, glyme, 70 C

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 182

182 Chapter 7

Table 7.6 Contd

Reaction Ref.

Bifunctional nucleophiles

CF3

F3C CF3 C2F5 CF HO 3 i C2F5 [112] + O O F3C C2F5 OH

i, Na2CO3, tetraglyme 58%

i 77% CF3CF CFCF3 + I N N [113] CF3 NH2 N

i, K2CO3, CH2Cl2, rt CF3

OH O i, ii + F F [114]

NH2 N i, K2CO3, CH3CN ii, NEt3 59%

i Li Li CF CF [115] n n = 10−20 − i, CF2 CF2, Et2O, 110 C

SH S i CF CFCF CH(CF ) 2 3 3 2 [116] NH2 N

i, THF, i-Pr2NEt

i Me3SiOCH2(CF2)3CH2OSiMe3 F [117] OCH2(CF2)3CH2O i, CsF, Glyme, Stepwise F F

OCH2(CF2)3CH2O

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 183

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 183

Table 7.6 Contd

Reaction Ref.

N i D.B.U. + CF3CH CFCF3 [118] N

F C 3 CF2H i, Hexane, rt

D. B. U., 1, 5-diazabicyclo [3.4.D] nonene-5

5 Cycloalkenes The various reactions of cyclic polyfluoroalkenes [85] (Figure 7.32) can largely be explained on a similar basis to that described above, although the opportunity for some rather more subtle orientation effects arises. Vinylic fluorine is generally replaced in preference to other vinylic halogens, either in the same molecule or in comparable systems, e.g. in the reaction of 7.32A with a deficiency of alkoxide ion. In these cases, 0 vinylic substitution is usually preferred over SN2 processes.

Cl − Cl 85 C H O ½ F 2 5 F

F OC2H5 7.32A

Figure 7.32

With equivalent halogen atoms at the vinylic positions, the remaining substituents have a significant effect on the orientation of nucleophilic attack [85] (Figure 7.33). Attack on 7.33A occurs to give predominantly 7.33C and 7.33D; this has been interpreted as indicating that CCl2 adjacent to the intermediate carbanion is more stabilising than CF2, and similar deductions concerning CF2 and CH2 could be made from the exclusive formation of 7.34B from 7.34A (Figure 7.34). It has been suggested that an additional factor to be considered in determining the products from polyfluorocyclohexenes is the stereochemistry of the elimination step [119] (Figure 7.35). Elimination of fluoride ion may occur from the carbanion 7.35B, produced by reaction of 7.35A with methoxide ion, by an outward (displacement with rearrangement) or inward (vinylic displacement) process. In order to account for the results shown, it was suggested that anti addition of methoxide occurs and that the carbanion 7.35B partially retains its configuration [119]. Then competition occurs between an electronically favoured syn inward elimination of fluoride from 2CFOCH3, and the stereochemically favoured anti outward elimination of fluorine from 2CF2 [120] (Figure 7.36). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 184

184 Chapter 7

F F Cl Cl F F F Cl Cl OEt F Cl C2H5OH Cl Cl Cl OEt Cl KOH Cl Cl 7.33B, 10% F OEt 7.33A F Cl Cl Cl Cl

F Cl F OEt F OEt F + Cl Cl Cl Cl Cl

7.33C, 61% 7.33D, 23%

Figure 7.33

F F F F F − F F F C2H5O F OEt F F OEt 7.34A 7.34B

Figure 7.34

F R R R R MeO− ½119 F F F + F F F F OMe OMe OMe

7.35A 7.35B 7.35C 7.35D

R % %

H 49 51

CH3 54 46

62 OCH3 38

Figure 7.35 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 185

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 185

F F F F F F F F F F R F F F F MeO F F F R F MeO 7.35B

Figure 7.36

6 Fluoride-ion-induced reactions [56, 57, 121] In the preceding sections we outlined reactions of fluoroalkenes with many types of nucleophilic species, but reactions involving initial attack on fluoroalkenes by fluoride ion have been reserved for a separate discussion here. Pioneering work by Miller and co-workers [55, 83] established that carbanions can be generated by reaction of fluoride ion with fluoroalkenes and an important analogy was drawn between the role of fluoride ion in reactions with unsaturated fluorocarbons, and the proton in reactions with unsaturated hydrocarbons [83]. In spite of the obvious misgivings in trying to draw an analogy between carbanion and carbocation processes, the model has been taken a surprisingly long way [56] (Figure 7.37).

Addition

F + − E F + CC F3CC F3CCE F Compare

H − + Nuc H + CC H3CC F3CCNuc H

Substitution with Rearrangement

F F − − F + F F F F F F Compare H H + + H H H + H H H

Figure 7.37 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 186

186 Chapter 7

7 Addition reactions

þ Addition of an alkali-metal fluoride, frequently KF, CsF, ðMe2NÞ3S Me3SiF2 (soluble in organic solvents) or a tetraalkylammonium salt, to a fluoroalkene in an aprotic dipolar solvent is usually the method used to generate perfluorocarbanions. Some of these intermediates have been directly observed by NMR [58, 121]. The intermediate carbanions may be trapped by a variety of electrophiles, and some examples are given in Table 7.7.

Table 7.7 Fluoride-ion-induced addition reactions to fluoroalkenes

Reaction Ref.

CF F C CF -CF 3 3 2 3 CsF + CH3I C3F7 C CH3 79% [122] F3C F DMF CF3

O KF, DMF CF3 [123] CF2 CFCF3 + PhCOCl Ph 66% F CF3

KF − i, ii CF CF CF CF CO H CF2 CF2 3 2 3 2 2 75% CH3CN [124] i, CO2, 150 C, ii, H2SO4

F3C + − CsF [125] CF CFCF + C H N Cl F N N C6H5 2 3 6 5 2 CH CN 3 F3C 41%

CF3 CsF CF2 C(CF3)2 + C6H5SCl F3C C SC6H5 82% [126] glyme CF3

F C S CF KF, 120C 3 3 [127] CF2 CFCF3 + S 70% F3C S CF3

CsF, Br [128] FF2 FF

150C (CF ) CFI 99% CF2 CFCF3 + IF5 + I2 3 2 [129]

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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 187

Table 7.7 Contd

Reaction Ref.

CF F C CF 3 3 3 200C ++IF 79% + KF I2 5 CF3CF2 C I [130] F3C F CF3

i Hg(CF(CF ) ) 2CF2 CFCF3 + HgCl2 3 2 2 [131] i, KF, (CH2OMe)2, 50 C

i CF CFCF + SO F (CF3)2CFSO2F 2 3 2 2 [132] i, KF, CH3CN, 150 C, Autoclave

F E

i E C C E + F F E [133]

E = CO2CH3 i, CsF, tetraglyme

The related reactions of polyfluorinated carbanions with fluoroarenes (Figure 7.38) will be discussed fully in Chapter 9, Section IIB.

CF(CF3)2 F − N ½134 F + CF2 CFCF3 (CF3)2CF F N

Figure 7.38

8 Fluoride-ion-catalysed rearrangements of fluoroalkenes In the absence of electrophiles, loss of fluoride ion from intermediate carbanions may occur in a manner such as to yield the most thermodynamically stable fluoroalkene, often resulting in isomerisation of the original reactant. Fluoroalkenes with the fewest fluorine atoms attached to the double bond are generally the most thermodynamically stable (see Section IIA above). Consequently, ‘internal’ isomers are usually to be expected as the result of fluoride-ion-induced processes such as those indicated in Figure 7.39 [135, 136]. A number of remarkable fluoride-ion-induced rearrangements have been documented; one example is given in Figure 7.40. The possibility that many of these rearrangements are addition–elimination reactions 0 rather than concerted SN2 processes is supported by the isolation, in some cases, of Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 188

188 Chapter 7

CsF ½135 C F CF CF CF C F CF CFCF 95% 3 7 2 2 diglyme 3 7 3

CF3 KF, MeCN F3C CF2CF3 ½136 F CF CFCF3 18-crown-6 96% F3C F CF3

Figure 7.39

CF2 F F F2C ½137 F F F2C F F − F − F F

CF2 F2C F F2CCF2 F F

CF2 F2C i, ii F F F F2CCF2

F F − i, −F ; ii, Rearrangement

Figure 7.40 cyclised products, resulting from internal nucleophilic attack by an intermediate carbanion [138] (Figure 7.41). In many thermally induced rearrangements, it is often difficult or impossible to distinguish between a thermally induced fluorine-atom shift and the type of fluoride-induced rearrangement that we have just exemplified. However, evidence for photochemically induced 1,3-shifts of fluorine in the equilibrium between 7.42A and 7.42B is very convincing [139] (Figure 7.42).

9 Fluoride-ion-induced oligomerisation reactions Since fluoroalkenes are so susceptible to nucleophilic attack, we might have expected anionic polymerisation, initiated by fluoride ion, to occur readily. As we have noted, fluorocarbanions are readily generated by fluoride-ion attack on fluoroalkenes; these Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 189

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 189

F C CF − 2 F + CF2 CFCF2CF CF2 CF2 ½138 CF

CF3

F F

F3C F3C

Figure 7.41

CF2 hν FF FF F F ½139 7.42A ν h (Photoequilibrium) 95%

F F 7.42B

Figure 7.42 carbanions do indeed react further with the original fluoroalkenes but this results in only short-chain oligomers [56, 57, 92] rather than polymers. This occurs because the extending carbanion loses fluoride ion (Route A, Figure 7.43), rather than continuing the propagation step (Route B, Figure 7.43).

− F + F F ½56, 57, 92 etc. n + 1

B, Propagation − A, Elimination of F

F Fluoroalkenes n + 2

Figure 7.43

By contrast, anionic polymerisation of hexafluoro-2-butyne (see Section IIB) proceeds rapidly because elimination of fluoride ion from the propagating anion is difficult, in that it would require the formation of allenes. The oligomerisation of tetrafluoroethene [91, 92, 140–142] demonstrates how processes like this can be used to build up useful, synthetically more sophisticated systems from readily available fluoroalkene precursors (Figure 7.44). The product distribution Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 190

190 Chapter 7

− F CF2 CF2 CF2 CF2 CF3CF2 CF3CF2CF2CF2 A − 91, 92, 140 42 −F ½

CF3CF2CF CF2

− +F CF3CF2 SN2' CF3 CF3 − A CF C CC 3 − CF3CF CFCF3 F F C2F5 B CF 3 CF2

− F A − B F, Dimerisation

CF3 C2F5 CF3 CF3 C2F5 C F CF F 2 5 3

C2F5 Tetramer CF3

Pentamer

Figure 7.44 depends upon the reaction conditions, with higher pressures generally leading to greater proportions of higher-molecular-weight products [140, 143]. Similar fluoride-ion-induced oligomerisations of hexafluoropropene [143, 144] (in which only dimers and trimers are formed, due to increased steric hindrance in the propagation step) and chlorotrifluoroethene [145] have been described. In each of these cases, highly branched fluoroalkene systems are formed, due to the tendency of the intermediate carbanion to lose fluoride ion, giving the most thermodynamically stable fluoroalkene. ‘Mixed’ oligomers can also be produced by fluoride-ion-initiated reaction between two different fluoroalkenes [146] (Figure 7.45), in which initial fluoride-ion attack occurs on the most reactive fluoroalkene (section IIC, Subsection 2). Oligomerisation of fluoroalkenes can also be initiated by tertiary amines, such as pyridine [147], trimethylamine [148] and tetrakis(dimethylamino)ethylene [149], via processes that involve either initial ylid formation or the generation in situ of an active source of fluoride ion.

10 Perfluorocycloalkenes Perfluorocyclobutene is much more reactive than perfluoro-cyclopentene or -cyclohexene and this enhanced reactivity is obviously attributable to relief of angle strain on carbanion formation. Perfluorocyclobutene [147, 150] gives a trimer and an equimolar mixture of Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 191

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 191

− +F − CF2 CF2 − (CF3)2C CF2 (CF3)3C (CF3)3CCF2CF2 ½146

(CF3)2C CF2

− −F − (CF3)3CCF2CF2CF C(CF3)2 (CF3)3CCF2CF2CF2C(CF3)2

60%

Figure 7.45 dimers (see the preceding section) whilst perfluorocyclo-pentene and -hexene give dimers only [151] (Figure 7.46).

− F A F F FF ½151

A − −F

− − F F FF FF F F

F F

Figure 7.46

For the resultant fluorocycloalkene dimers [56, 147], the number of fluorine atoms at the double bond is not the controlling factor in determining the position of equilibrium. In Figure 7.47, only 7.47A1 is observed from perfluorocyclohexene, preserving one strain- free ring, whereas 7.47B2 is formed exclusively from perfluorocyclopentene, thereby minimising eclipsing interactions. In contrast, equivalent proportions of 7.47C1 and 7.47C2 are formed from perfluorocyclobutene as a result of the reduced angle strain in 7.47C1 over 7.47C2, which compensates for eclipsing interactions.

D Electrophilic attack [152] In general terms, highly fluorinated alkenes are relatively resistant to attack by the types of reactant that are normally considered to be electrophilic in character [55, 153–155]. When one or more perfluoroalkyl groups are attached to the double bond, then the system Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 192

192 Chapter 7

− F FF FF ½56, 147 (Not observed)

7.47A1 7.47A2

F F F F F

(Formed exclusively)

7.47B1 7.47B2

− F F F F F

(Equimolar mixture)

7.47C1 7.47C2

Figure 7.47 becomes particularly resistant to electrophilic attack, although hydrofluoroalkenes and chlorofluoroalkenes will react with quite a range of electrophilic reagents. These effects correspond to the expected influence of these groups on carbocation stability. Many reactions are known [55, 154, 155] that involve addition of, for example, halogens, interhalogen compounds, hydrogen halides and haloalkanes, sometimes in the presence of Lewis acids, to fluoroalkenes; it is quite probable that many of these involve electrophilic attack, although other possibilities often arise. A number of reactions using anhydrous hydrogen fluoride as solvent have been formulated as involving electrophilic addition of XþF. Hexafluoropropene is unreactive towards anhydrous hydrogen fluoride, even at 2008 C, but silver fluoride in anhydrous hydrogen fluoride reacts at 1258 C and it has been suggested, therefore, that an initial electrophilic addition of silver fluoride occurs [156] (Figure 7.48).

HF AgF CF2 CFCF3 AgCF(CF3)2 ½156 125C

HCF(CF3)2 AgF

Figure 7.48

Mercuric fluoride under similar conditions gives a stable mercurial and it was suggested that strong solvation of fluoride ion, to give HnFnþ1, inhibits nucleophilic attack by this fluoride ion but promotes dissociation of metal fluorides, therefore leading to attack by metal cations [156] (Figure 7.49). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 193

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 193

+ − HgF nHF HgF H F etc 2 n n+1 ½156

HF HgF 2CF CFCF Hg[CF(CF ) ] 60% 2 2 3 85C 3 2 2

Figure 7.49

A variety of interesting electrophilic addition processes have been developed, where additions (where the electrophile is, for example, Cl, Br, I, NO2, 2OCH22, CH2NH2,CH2OH etc.) to fluoroalkenes are achieved by reaction with a series of reagents (Table 7.8).

Table 7.8 Electrophilic additions to fluoroalkenes

Reaction Ref.

BF3 CF2 CCl2 + HF CF3CHCl2 + polymer [157]

H AlCl3 C10H21CH CF2 + C2H5COCl C10H21 C CO.C2H5 [158]

CF2Cl

C6H5 CF3 C6H5 CF3 + Br2 Br CCBr 86% FF [159] F F anti : syn 1:1

−20C CF2 CH2 + HI CH3-F2I + polymer [160]

i CF2 CF2 HNO3 CF3CF2NO2 93% [161]

i, HF, 20 C

i (CF ) CFNO CF2 CFCF3 HNO3 3 2 2 76% [154]

i, HF, 60 C

i FClC CFCl HNO3 NO2CFClCOOH 63% [162]

i, H2SO4, rt

i H2C CHF + CH3COCl CH3COCH2CHFCl 70% [163]

i, FeCl3, CH2Cl2, 0 C

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 194

194 Chapter 7

Table 7.8 Contd

Reaction Ref.

CF2 CFCF3 + IF5/I2 (CF3)2CFI 99% [129]

CF2 CF2 + IF5/I2 CF3CF2I 86% [129]

CF CXCF + BF /ICl/HF (CF ) CXI 60-80% 2 3 3 3 2 [164] X = H, F

F C i 3 CF2 CFCl + (CF3)2CO O 98% F C 3 [165, 166] F F i, AlClXFY, 100 C Cl F

i CF2 CFCF3 + CH2F2 FCH2CF(CF3)2 90% [167] − i, SbF5, 35 50 C

The orientations of addition (Table 7.8) are consistent with an electrophilic process (Figure 7.50), bearing in mind that fluorine attached to positively charged carbon, Cþ2F, is stabilising whereas fluorine that is b- to the carbocation centre is destabilising (Chapter 4, Section VI).

E-CCl CF Stabilising F Cl 2 2 + E F Cl

E-CF2CCl2 Destabilising

Figure 7.50

Systems with perfluoroalkyl groups directly attached to the double bond are particularly unreactive towards electrophiles but reaction of hexafluoropropene (HFP) with SbF5 leads to a perfluoroallyl cation, which then reacts with another molecule of HFP to give a dimer, probably by an electrophilic process [168] (Figure 7.51) that is analogous to that described earlier for 1,1,1-trifluoropropene [169], (Chapter 4, Section VIB). Similar addition and isomerisation reactions, which proceed via carbocationic intermediates, are given in Figure 7.52 [170–172]. Addition of sulphur trioxide is an important step in the process for the production of Nafiont membrane (see Chapter 8, Section IIA) [173]; reaction with chlorotrifluoroethene (CTFE) is not regioselective [174] (Figure 7.53). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 195

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 195

F F CF3 F F F F SbF5 C3F6 ½168 CF CFCF F + 2 3 CF2 F F F F

− F shift

F − F F CF(CF3)2 CF3-CF CFCF(CF3)2 F F

Figure 7.51

i CF2 CFCF3 CF2 CF2 F(CF2)2CF CF3 47 % ½170

i, AlCl3, 25 C

SbF5 ½171 F + CF2 CF2 F

CF2CF3

SbF5 HCF2CF2CF CF2 FCH CFCF2CF3 ½172

Figure 7.52

F F F F ½173

CF2 CF2 SO3 OSO2

½174 F F F F F Cl Cl F i CF2 CFCl SO3 OSO2 OSO2

i, CTFE bubbled through liq. SO3

Figure 7.53

However, sulphur trioxide is also a very strong Lewis acid and reaction with hexafluoropropene proceeds first by fluoride elimination from the allylic position, presumably via the perfluoroallyl cation [152] (Figure 7.54). Tetrafluoroallene is interesting in that, in addition to its susceptibility towards nucleophilic attack discussed earlier, the compound also reacts readily with anhydrous hydrogen Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 196

196 Chapter 7

F C i or ii CF2 CFCF3 SO3 CF2 CFCF2OSO2F F2C CF2 ½152 i, BF3, 50 C, 6hr, (60%); ii, B(OMe)3, 35 C, 6hr, (52%)

Figure 7.54 fluoride and other hydrogen halides, and it has been reasonably concluded that these reactions probably involve electrophilic attack [175, 176] (Figure 7.55). i CF C CF CF CH CF 99% 2 2 3 2 ½175, 176 i, anhyd. HF, −72 to 20C

Figure 7.55

E Free-radical additions [177–181] A generalised free-radical addition process can be described as in Figure 7.56, using the normal terminology for the various steps.

Initiator AB A• + B In Initiation

A• + A Addition

A + A Propagation

AB ABA A + Chain Transfer

Figure 7.56

If the A–B bond is weak and A2B is in sufficiently high proportion with respect to the alkene, then chain transfer will compete effectively with propagation, allowing overall free-radical addition of A2B to the double bond to occur preferentially (Figure 7.57).

In A B + AB

Figure 7.57

Conversely, when the rate of propagation is faster than chain transfer, products arising from telomerisation and polymerisation are formed in greater concentration. In this section, free-radical addition to fluoroalkenes will be dealt with first, in order to establish Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 197

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 197 some ground rules concerning the free-radical addition process, and will be followed by telomerisation and polymerisation.

1 Orientation of addition and rates of reaction In contrast to ionic reactions, radical additions to unsymmetrical fluoroalkenes are frequently bi-directional; factors that affect the rate and orientation of addition depend on, for example, polar effects, steric effects, radical stabilisation and the character of the attacking radical [182–185]. Free-radical addition to a double bond is a strongly exothermic process, because a p-bond is broken and a s-bond is formed and so, according to the Hammond postulate, early transition states are involved where there is limited bond breaking or making. Consequently, the influence of polar and steric effects becomes significant, in competition with the stability of the developing intermediate radical formed, in determining the orientation and relative rates of addition. Radicals with ‘nucleophilic’ character add to electrophilic alkenes more rapidly than to nucleophilic alkenes whilst, conversely, the rate of addition of electrophilic radicals to electron-rich alkenes is greater than addition to electron-deficient alkenes. To be more sophisticated, we should refer to a high-SOMO (singly occupied molecular orbital; nucleophilic) radical interacting favourably with a low-LUMO (lowest unoccupied molecular orbital; electrophilic) alkene but, for simplicity and brevity, we will continue to use these ‘short-hand’ terms [177]. For instance, compare rates of addition of perfluoroalkyl radicals to ethene and various fluorinated derivatives with their rates of H-atom abstraction from heptane (Table 7.9) [186]. Broadly, reactivity of the alkene decreases with fluorine content, with trifluoromethyl having a large effect.

Table 7.9 Relative rates of addition of perfluoroalkyl radicals to alkenes versus their rates of hydrogen-atom abstraction from heptane at 508 C [186] : : : Alkene CF3 C2F5 C3F7

CH25CH2 132 340 290 CH25CHF 30 108 40 CH25CF2 913— CHF5CF2 69— CF25CF2 87<0.3 CF25CFCF3 0.33

Addition of radicals to unsymmetrical perfluoroakenes could lead to two possible products (Figure 7.58). Earlier in this chapter we noted that nucleophiles attack the CF25 site in a fluorinated alkene exclusively and, in parallel with these observations, nucleophilic radicals, such as

l CH3S and carbon-centred radicals, give products arising predominantly from attack at this site (Path 1). Electrophilic radicals such as trifluoromethyl, on the other hand, are less selective and give a mixture of products (Paths 1 and 2) (Figure 7.58). Examples of the regiochemistry of addition of trifluoromethyl to a variety of fluorinated alkenes are given in Table 7.10. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 198

198 Chapter 7

AB 1 ACF CFCF 2 3 ACF2CFBCF3 A

A CF2 CFCF3

2 CF CFACF AB 2 3 BCF2CFACF3 A

Figure 7.58

Table 7.10 Regiochemistry of trifluoromethyl radical additions to fluoroalkenes: ratio of attack at A:B (Figure 7.58) [182, 184, 187]

Alkene Ratio

A B A:B CH25CHF 1:0.09 CH25CF2 1:0.05 CHF5CHF 1:0.05 CH25CHCH3 1:0.1 CH25CðCH3Þ2 1:0.08 CH25CHCH5CH2 1:0.01 CH25CHCF3 1:0.01 CHF5CHCF3 1:0.33 CF25CHCH3 1:50 CF25CHCF3 1:1.5 CF25CFCF3 1:0.25

A decreasing order of reactivity (towards free-radical addition of methanol) has been observed [188] in the order CF25CCl2 > CF25CFCl > CFCl5CFCl > CF25CHCl, and this is largely consistent with expected effects on the relative stabilities of intermediate radicals after attack at the CF2 sites, where there is a choice. Steric inhibition to attack accounts for the order CF25CCl2 > CFCl5CFCl. Frontier orbital theory can also be used to explain the observed rate and orientation patterns [185]. As we have seen (Section IIC, Subsection 2), vinylic fluorine substituents do not affect alkene orbital energies that much in relation to hydrogen, whereas perfluoroalkyl groups lower LUMO energies considerably. Energies of the SOMO (singly occupied molecular orbital) of radicals are increased in radicals containing electron- donating substitutents and so the SOMO (of the attacking radical)–LUMO (of the alkene) interaction is at a maximum with alkenes containing perfluoroalkyl groups in reactions with nucleophilic radicals. The coefficients of the LUMO of the alkene can be used, just as in nucleophilic substitution, to explain the orientation of radical addition. As we have seen, perfluoroalkyl groups polarise the LUMO in such a way as to increase the coefficient at the b-carbon (i.e. the CF2 sites in Table 7.11) and so SOMO–LUMO overlap is greatest at this position. Many examples of free-radical addition to fluoroalkenes have been recorded; some examples are listed in Table 7.11. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 199

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 199

Table 7.11 Free-radical additions to fluoroalkenes

Reaction Ref.

CF2CFH2 CFHCF2H g rays [189] CF2 CFH

60% 40%

CF2CFHCF3 i [45] + CF2 CFCF3

i, g rays, or peroxide

i (CH3)2CH2 + CF2 CFCF3 (CH3)2CHCF2CFHCF3 75% [45]

3% i, (t-BuO)2, 140 C CH3CH2CH2CF2CFHCF3

RFH RFH

i RFH + CF2 CFCF3 RFH RFH [45] R FH RFH i, (t-BuO) , 140 C 2 36% 59%

RFH = CF2CFHCF3

i CH3OH + CF2 CFCF3 CF3CFHCF2CH2OH 93% [190, 191]

i, (t-BuO)2, 140 C

OH i OH + CF CFCF 87% 2 3 [191] CF2CFHCF3 i, (t-BuO)2, 180 C

OH HO CF2CFHCF3

i + CF CFCF 2 3 [192]

i, (t-BuO) , 140 C OH 2 OH CF2CFHCF3

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 200

200 Chapter 7

Table 7.11 Contd

Reaction Ref.

OOCF2CFHCF3 i + CF CFCF [193–195] 2 3 70%

i, γ rays, or hν

i CH3(OCH2CH2)nOCH3 + CF2 CFCF3 [196, 197] R CH [OCH(R )CH ] OCHR i, (t-BuO)2, 140 C FH 2 FH 2 n FH

RFH = CF2CFHCF3

F F F F RF i (CH CH ) O + [(CF ) C CHCF ] R 3 2 2 3 2 2 2 F [198] H3C O CH i, γ-rays, rt 3 RF = CH(CF3)2

H F O γ ray O [194] F 83%

O O i C3H7 CH+ CF2 CFCF3 C3H7 C CF2CFHCF3 [190] 70% i, (C6H5CO2)2, 80 C, 16 h.

O O i Ph C H + CF2 CFCF3 Ph CF2CFHCF3

F [199] i, (t-BuO) , 140 C CF3 2 + F F O

CHCl + CF CFCF CCl CF CFHCF 3 2 3 3 2 3 [200]

i, 280 C, 116 h

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 201

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 201

Table 7.11 Contd

Reaction Ref.

Hg/hν SiH4 + CF2 CFCF3 CF3CHFCF2–SiH3 51% F [201]

+ F2HC SiH3 34%

CF3

H SiCl3

F hν F 80% [201] + HSiCl3

H Sn(CH3)3

F 20 C F [202] + HSn(CH3)3 94%

i (C2H5)2P(O)H + CF2 CF2 (C2H5)2P(O)CF2CF2H 33% [203] i, (t-BuO)2, 140 C

i CF2 CHCl + SF5Br F5SCF2CHClBr 73% [204] i, 100 C

An interesting process, reminiscent of the Barton reaction, occurs during the radical addition of 7.59A to HFP [205] (Figure 7.59).

H Me F H F H H ½205 i F F H H OH OH OH F CF F CF3 3 7.59A

i i, CF2 CFCF3

Me CH2CF2CFHCF3

OH OH

CF2CFHCF3 CF2CFHCF3

Figure 7.59 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 202

202 Chapter 7

2 Telomerisation [178, 206] Telomerisations [207, 208] are regarded as reactions in which a telogen (A2B) and several molecules of a monomer ðR2C5CR2Þ react to give short-chain products with, correspondingly, low molecular weights. In these reactions, the propagation step (Figure 7.56) competes with chain transfer, and a number of factors can influence the relative effectiveness of these two processes. In all telomerisations, the distribution of molecular weights increases, i.e. n increases with (a) an increasing rate of free-radical addition to the alkene, (b) a decreasing rate of the atom-transfer step, i.e. the A2B bond is stronger, (c) a higher concentration of alkene relative to the telogen and (d) temperature. As explained earlier in this chapter (Section IIA), the propagation step for the homopolymerisation of tetrafluoroethene is approximately 71 kJmol1 more exothermic than for ethene [2], in spite of adverse polar effects of fluorine substitution on the addition step. It is therefore easy to obtain telomers with tetrafluoroethene and this is also the case with, for example, trifluoroethene, chlorotrifluoroethene and 1,1-difluoroethene. Many telogens (A2B in Figure 7.56) have been used in these processes, including perfluoroalkyl iodides [209], a, v-di-iodoperfluoro- [210] and chlorofluoroalkanes [211], iodine [211], iodine monochloride [212] and perfluoroalkyl bromides [213]. All of the readily available fluorine-containing ethenes have been used as monomers in telomerisation reactions for the production of many telomers, some of which have important commercial applications, e.g. in the synthesis of high-efficiency surfactants and for fire-fighting foams [214]. With CF3I and CF25CF2, a broad range of telomers is produced unless a considerable excess of the iodide is employed [215]; but with

ðCF3Þ2CFI as telogen, where the C2I bond is more easily broken [216] (Figure 7.60), the chain length is more easily controlled.

175C (CF3)2CFI + CF2=CF2 (CF3)2CF(CF2CF2)nI ½216

(4.6 : 1) n = 1 (69%); n = 2 (18%) n = 3 (10%); n = 4 (3%)

Figure 7.60

The effect of the fluoroalkyl iodide on the telomer distribution is illustrated for CH25CF2 in Table 7.12, as well as the effect of molar ratio of telogen to alkene and of the reaction temperature. Telomers may be used for further transformations and they are often useful ‘model compounds’ for related polymers, for exploring cross-linking and other processes [217] (Figure 7.61). Telomerisation of hexafluoropropene may be achieved using fluoroalkyl iodides as telogens [218, 219]; this is rather surprising, considering that it is very difficult to achieve homopolymerisation of hexafluoropropene (Figure 7.62). It has been suggested [218] that these reactions may not be radical-chain processes but could involve successive four- centre additions of fluorocarbon iodides to the olefin (Figure 7.63). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 203

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 203

Table 7.12 Telomerisation reactions of 1,1-difluoroethene [216]

Fluoroalkyl iodide Molar ratio Temp. Time Conversion Composition of RFðCH2CF2ÞnI RFI RFI: CH2CF2 (8 C) (h) of iodide (%) (mol%)

n512 3 4 5 6

CF3I 1 : 1 200–210 41 35 46 33 14 5 1 — C2F5I 1 : 1 190 45 55 92 6 2 — — — n-C3F7I 1 : 1 200 36 88 70 25 5 — — — i-C3F7I 1 : 1 185 36 88 90 10 Trace — — — 1 : 1 220 36 90 87 13 Trace — — — 1 : 4 220 36 100 2 21 29 26 18 4

180 C (CF3)2CF(CH2CF2)nI (CF3)2CFI CH2 CF2 ½217

SbF5 / 0 C

CsF (CF ) CF(CH CF ) F (CF3)2C CHCF2(CH2CF2)n-1F 3 2 2 2 n 130 C

Figure 7.61

194 C CF =CFCF CF ICFCF CFCF I 2 3 3 3 2 3 n ½218, 219 n = 1 (47%); n = 2 (23%) n = 3 (19%); n = 4 (8%) n = 5 (4%).

Figure 7.62

CF2 I

CF2 CFCF3

Figure 7.63

3 Polymerisation [219a] Many fluorinated polymers have been prepared using free-radical processes and the intensity of interest in this field stems from the number of unique properties that are bestowed on the polymer by the presence of the carbon–fluorine bonds in a system. For example, excellent resistance to chemically aggressive environments, high thermal stability, low dielectric constant, low flammability and very low surface energies are just some of the properties of fluorinated materials that have been exploited. Uses range from Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 204

204 Chapter 7 the relatively mundane but important everyday items, like coatings for pans, to crucial materials for the development of supersonic flight and space travel, but the nature of this book dictates that only a sample of the materials available can be illustrated here. The fluorinated ethenes CF25CF2,CF25CFH, CF25CH2,CF25CFCl and CF25CFBr each form homopolymers in conventional free-radical initiation procedures [220] and it is notable that the heat of polymerisation for tetrafluoroethene is much greater than for ethene [2]. Indeed, tetrafluoroethene and trifluoropropene are relatively dangerous monomers to handle because of the risk of explosive polymerisation. In marked contrast, quite drastic conditions are required in order to form a homopolymer from hexafluoropropene (HFP) [221], although commercially successful copolymers of CF25CFCF3 with CF25CF2 (i.e. FEP) and with CF25CH2 (Vitont rubber) have been developed.

Polytetrafluoroethene (PTFE), 2ðCF2CF2Þn2 PTFE is polymerised using conventional initiators [220] to give linear polymers whose non-stick properties and chemical inertness are now familiar to all. A disadvantage of PTFE is that it has a very high melt viscosity and cannot be used for melt-processing. Consequently, copolymers of CF25CF2 and CF25CFCF3 (FEP polymers) are used for this purpose (Figure 7.64). Also, introduction of a perfluoropropoxy group is a more expensive solution to the problem, giving perfluoroalkoxy (PFA) resins.

(CF2CF2)x (CF2CF) (CF2CF2)x (CF2CF)

CF3 OC3F7

FEP PFA

Figure 7.64

Recently, amorphous fluoropolymers have been developed in order to obtain high- performance materials with optical clarity for microelectronic etching processes. It is interesting that the monomer perfluoro(2,2-dimethyl-1,3-dioxole) (PDD) (Figure 7.65) is sufficiently reactive to copolymerise with CF25CF2 to give copolymers with a high proportion of PDD. This suggests that ether groups, which are isoelectronic with fluorine, have a similar effect to fluorine on reactivity of alkenes towards radicals (Figure 7.65).

CF CF CF CF CF2 CF2 In x y OO CF2 CF2 OO

F3C CF3 F3C CF3

PDD Teflon AF®

Figure 7.65

Cytopt (Asahi Glass Co.) is a similar product and is produced by a novel cyclopolymerisation process [222] (Figure 7.66). Calculations suggest that the transition states for forming five-membered rings (Route B) are significantly lower-energy than those for forming six-membered rings (Route A) and therefore it is likely that polymerisation occurs by Route A. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 205

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 205

R RCF2 CF2 CF O(CF2)2CF CF2 F ½222 Route A O

R Route B Monomer etc.

CF2 etc. F2CR F Polymer O Monomer

Figure 7.66

Polychlorotrifluoroethene (PCTFE), 2ðCF22CFClÞn2 This material melts at 2138 C and is therefore melt-processable giving clear films.

Polyvinyl fluoride (PVF), 2ðCH22CHFÞn2 PVF films can be made that adhere to various surfaces and are particularly important as protective coatings for both indoor and outdoor applications.

Polyvinylidene fluoride (PVDF), 2ðCH2CF2Þn2 This material has excellent mechanical properties and is used extensively as weather resistant coating for aluminium and various outdoor applications. The piezoelectrical properties of the material have been exploited in a range of electronic applications [220].

Vinylidene fluoride/HFP copolymers Vitont was the first of these important systems to be developed as an elastomer suitable for use in aggressive environments. Consequently, this and related materials have made a particularly important contribution to the development of supersonic and space flight. The raw copolymer itself is quite unstable to the loss of hydrogen fluoride and the final product is a result of cross-linking and curing processes. These techniques have been the basis of much study over many years [223].

F Cycloadditions [2, 224, 225] 1 Formation of four-membered rings One of the most unusual aspects of organofluorine chemistry is the propensity for fluoroalkenes to form four-membered rings upon dimerisation. For example, tetrafluoroethene dimerises to perfluorocyclobutane, a reaction that is not observed for ethene [226] (Figure 7.67). 200C 2 CF CF F ½226 2 = 2 Autoclave

Figure 7.67 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 206

206 Chapter 7

Codimerisation occurs not only between different fluoroalkenes but also between fluoroalkenes and other unsaturated hydrocarbons. Moreover, some of these codimerisations proceed more readily than the reactions involving only fluorinated alkenes. Examples of addition reactions of fluoroalkenes are shown in Table 7.13. Rate constants have been measured for ½2p þ 2p and ½2p þ 4p cycloadditions involving fluorinated alkenes, employing gas-phase NMR techniques [227].

Table 7.13 Cycloaddition reactions of fluoroalkenes

Reaction Ref.

Cl − 130 250 C F (E/Z = 1:1) [228] CF2 CFCl Cl

CF3 F (E + Z)

CF3

CF3CF CF2 [229]

CF3 F (E + Z)

F3C

CF2

CF2 C CF2 F [175]

CF2

F H F H 150 C 40% [230] CF2 CF2 CH2 CH2 F H F H

F H F H CF CF (CH CH ) 2 2 2 2 [230] F H F CH CH2

F F H 225C 35% CF2 CF2 HC CH [231] F H F

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 207

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 207

Table 7.13 Contd

Reaction Ref.

F H F H 100 C [232] CF2 CFCl CH2 CHC6H5 F H Cl C6H5

(CF3)2CF (CF3)2CF <0C (CF3)2CFC CF [233]

F F

72% 18%

110C, 7 days F CF2 + 47% [234]

A particular driving force appears to be the presence of CF25 in the alkene; 1,2- difluoroalkenes, 2CF5CF2, are much less reactive in this context but examples have been recorded [235]. Dimerisation of tetrafluoroethene to perfluorocyclobutane takes place at 2008 C whilst the reverse reaction occurs at about 5008 C [226]. Activation energies, measured for the forward and back reactions, indicate that the dimerisation is exothermic by 209 kJmol1 [236], as compared with approximately 67 kJmol1 for the hypothetical dimerisation of ethene, and point to factors which destabilise the fluoroalkene. Similarly, when the DH values for cyclobutene ring opening for hydrocarbon and fluorocarbon systems were compared earlier in this chapter (Table 7.4), it was concluded that fluorine attached to a vinylic carbon atom raises the energy of the system, relative to that for the corresponding hydrocarbon, leading to a lower bond strength in CF25CF2 than in ethene [36, 237]. In forming a cyclobutane ring, not only are these repulsive forces removed but, if a CF25 was originally present, then stronger carbon–fluorine bonds are formed in 2CF22. Therefore, the factors that probably lead to the driving force for fluoroalkenes to dimerise as in Figure 7.68 are:

F F F 2 F F F

Figure 7.68 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 208

208 Chapter 7

(1) Ip repulsion is relieved. (2) F atoms are mutually bond strengthening in the product. (3) Substituents that stabilise di-radical intermediates will activate (see later). With few exceptions, products are formed which result from a combination of alkenes in a head-to-head manner, or a correspondingly regiospecific manner in codimerisations (see Table 7.13). Furthermore, the reactions are not stereospecific. In considering the mechanism of these reactions it is important to stress that they are [2p þ 2p] additions, which are formally forbidden as thermally induced [2ps þ 2ps] processes according to the well-established Woodward–Hoffman rules for pericyclic reactions. Consequently, it is much more likely that these reactions proceed via a pathway that involves radical intermediates, although concerted processes have been claimed [238]. A process involving di-radical intermediates provides an explanation for the products obtained in the dimerisation of 1,1-dichlorodifluoroethene (Figure 7.69). The reaction pathway is governed by the stability of the intermediate di-radical species and, because chlorine stabilises a radical centre more effectively than fluorine, i.e. compound 7.69B is more stable than 7.69A, then Pathway B, leading to the head-to-head product, is preferred.

CCl2 CF2 Pathway A

CF2 CCl2 2 CF2 CCl2 7.69A

Pathway B CF —CCl 2 2 F2 Cl2

CF2—CCl2 F2 Cl2 7.69B

Figure 7.69

The orientations of other cyclodimerisations may be accounted for in a similar manner (Table 7.13). However, as the difference in the ability of the substituents at each carbon of the alkene to stabilise a radical diminishes, then the selectivity of the process is also reduced. For example, trifluoroethene gives a mixture of products since, in this case, the stabilities of the two intermediate radicals 7.70C and 7.70D are similar (Figure 7.70). H CF2—CFH F (E + Z isomers) CF2—CFH H 7.70C 2 CF2 CFH

H CF2—CFH F (E + Z isomers) CFH—CF2 H 7.70D

Figure 7.70 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 209

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 209

The latter reaction also illustrates that these processes are not stereospecific (see also Table 7.13). Studies on the formation of four-membered rings by reaction between tetrafluoroethene and di-deuterioethene led to analogous conclusions and this is further evidence for the formation of di-radical intermediates [239, 240]. Moreover, reactions involving alkenes with geminal capto-dative substituents (e.g. 7.71A and 7.71B which are, of course, especially stabilising for radical intermediates) are both efficient and regiospecific [241] (Figure 7.71). SPh

F < i 2 >Cl ½241 CF CClSPh CH C(CN)t-Bu 2 2 > < CN 7.71A 7.71B t-Bu

i, 120 C, 10hr.

SPh F2 Cl 88% CN

t-Bu

Figure 7.71

The energy of the double bond may be raised by other means, e.g. by strain or by antiaromaticity [224]. Miller, a pioneer in the field of organofluorine chemistry, generated tetrakis(trifluoromethyl)cyclobutadiene and showed that it reacts to form a tricyclic dimer [242] which can be converted to the corresponding cubane and cuneane derivatives by ultraviolet radiation [243] (Figure 7.72). When the system is appropriately substituted, cycloaddition may even proceed via zwitterion formation [244] (Figure 7.73).

2 Formation of six-membered rings – Diels–Alder Reactions [245, 246] In this section we will consider [4 þ 2] cycloaddition reactions in which the fluoroalkene acts as the dienophile. For related reactions involving fluorinated dienes, see Section IIG. Since Diels–Alder reactions are governed by HOMO–LUMO interaction of the diene and dienophile, we should remind ourselves that vinylic fluorine does not much alter the orbital energies compared with hydrogen, whilst perfluoroalkyl groups significantly lower these orbital energies [33]. Consequently, we might expect that vinylic fluorine should have little effect on reactivity, whereas the introduction of allylic fluorine, especially via trifluoromethyl groups, should have a significant effect in comparison with the corresponding hydrocarbon analogues. We have seen (Table 7.13) that in reactions between fluoroalkenes and dienes, [2 þ 2] cycloaddition as opposed to [4 þ 2] cycloaddition is the dominant reaction [246, 247], and systematic studies performed on reactions of this type, such as that between 1,1-dichlorodifluoroethene and isoprene, provide a strong case for the intermediacy of Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 210

210 Chapter 7

F3C CF3 F3C CF3

Br Li, −20 C F ½243 F3C CF3 F3C CF3

CF3 CF3 CF3 CF3 F3C CF3 F3C CF3

CF F3C CF3 F3C 2 CF3 CF3 CF3 CF3

300 C 300 C hν hν

(CF ) 300 C 3 8 (CF3)8 (CF3)8

Figure 7.72

(CF3)2C C(CN)2 ½244 (CF3)2C C(CN)2 CH2 CHOC2H5 H2C CH.OC2H5

F3C CN

F3C CN H H

H OC2H5

95%

Figure 7.73 di-radicals [248] (Figure 7.74). A methyl group would be expected to make a greater contribution to the stability of the allyl system in 7.74B than in 7.74A; this is consistent with the product ratio observed. Nevertheless, some Diels–Alder reactions between fluoroalkenes and dienes have been recorded with significant amounts of product derived from Diels–Alder addition when the diene is in the cis conformation [246, 249] (Figure 7.75). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 211

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 211

CF2CCl2 80 C F2 + + + ½248 Cl2 CF2 — CCl2 CF2 — CCl2 7.74 B 7.74 A 1.6%

F2 Cl2 F2 Cl2 15% 83%

Figure 7.74

F2 475C F2 + CF2 CF2 + ½246, 249 F2 F2 2 : 1

Figure 7.75

The thermal addition of trifluoroethene to cyclopentadiene at and below 1228 C yields a 1,4-cycloadduct, with less than 0.1% of 1,2-cycloadduct, whereas a photosensitised reaction between these two reactants (a di-radical process) leads to a product consisting of 87% of the 1,2-cycloadduct and 13% of the 1,4-cycloadduct [250]. These contrasting results led to the conclusion that the thermally induced Diels–Alder product arises from a normal concerted process and it is probable that, in general, whilst the 1,2-cycloadditions and 1,4-Diels–Alder additions are competing processes, they are mechanistically unre- lated. Fluoroalkenes possessing perfluoroalkyl substituents, which reduce the energy of the frontier orbitals, undergo Diels–Alder reactions, as shown in Figure 7.76 [251, 252]. O O CF i 2 ½251 + CF2 CFCF3 F 35%

F F i, 120 C, 16 h., Et2O

260 C + CF CF CFCF 42% ½252 3 3 30 h CF3

F CF3

Figure 7.76 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 212

212 Chapter 7

Fluoroalkenes that have significant ring strain in the ground state undergo Diels–Alder reactions much more readily, due to the enhanced relief of this strain upon [4 þ 2] cycloaddition as opposed to [2 þ 2] addition (Table 7.14)

Table 7.14 Diels–Alder additions to fluorinated alkenes

Reaction Ref.

F F F 72% [253] 80 C F

H2 O F H2 O O O F 100% [254] FF F2

F10

Cl Cl Me Me F2 F [255] 89% 170 C, 48 h F F2 Me F

F 100C F CF + [256] 2 F

F 100C F F + 30% [257] F F

3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions A number of 1,3-dipolar cycloadditions to fluoroalkenes have been reported [245]; some examples are listed in Table 7.15. Addition of diazomethane to fluoroalkenes [72] follows the order of reactivity

ðRFÞ2C5CðRFÞ2 > ðRFÞ2C5CFRF > ðRFÞ2C5CF2,RFCF5CFRFðRF ¼ perfluoroalkyl). In reactions involving unsymmetrical fluoroalkenes the additions are highly regiospecific, with the carbon atom of the dipole becoming attached to the site most susceptible Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 213

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 213

Table 7.15 1,3-Dipolar cycloaddition reactions involving fluoroalkenes

Reaction Ref.

N H CF C F H 3 2 5 i N +CH2—N N 94% [72, 258] CF3 F CF3 C2F5 i, Et2O, rt CF3 F

N H CF C F H 3 2 5 i N +CH2—N N 93% CF C2F5 3 CF3 C2F5 i, Et2O, rt C2F5 CF3

N H N H [198] CF3 H CF CF 3 3 i CF3 CF3 +CH2—N N CF3 H H N H N i, Et2O, rt

CF3 H CF3 CF3

N CH2Ph CF3 i N N CF + PhCH N 2 2 3 87% [259] CF3 F CF3 F CF i, 190 C, 16 h 3

F N i 55% F + CH2—N N N [72]

F i, Et2O, rt, 14 days to nucleophilic attack. These concerted reactions probably proceed with some character of nucleophilic attack and the orientation of attack can be accounted for in terms of the frontier orbital approach discussed in Section IIC, Subsection 2 [72] (Figure 7.77).

(RF)2C CF(RF)

N CH2 N

Figure 7.77 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 214

214 Chapter 7

4 Cycloadditions involving heteroatoms In the light of the foregoing discussion it may be expected that fluoroalkenes participate in cycloaddition reactions with unsaturated systems containing heteroatoms [260], e.g. nitroso compounds [261], sulphur trioxide [262], sulphur dioxide [263], nitriles [264] and so on (Figure 7.78).

F3C NO ½261 F F 62% 20 C F F CF2 CF2 CF3NO

−45 to 20 C N OCF2 CF2 64% n CF3

O O S O 0 C RCF CF2 + SO3 ½262 R CCF 44% FF R = CH2ClCHClCH2-

FF i F F CF CF SO ½263 2 2 2 FCOCF2SOF SO 80% ν − O i, CF2Cl2, N2, h , 32 to 90 C

CF3 F F ½264 F CF3CN 40% N CF N 3

Figure 7.78

G Polyfluorinated conjugated dienes 1 Synthesis Many of the synthetic approaches that are used for the preparation of fluoroalkenes can be adopted for the synthesis of polyfluorodienes. Examples of other processes such as reductive coupling methods and syntheses based on organometallic precursors [265] or phosphorous ylids are also included in Table 7.16. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 215

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 215

Table 7.16 Synthesis of fluorodienes and polymers

Reaction Ref.

Dehydrohalogenation H H CF CF 3 3 CF CF i 2 3 [266] CF CF 3 3 CF CF3 2 i, t-BuOK/t-BuOH

i (CF ) CFCH CF (CF ) C CHCF 70% 3 2 2 2 2 3 2 2 2 [267]

i, CsF, 150 C, Sealed Tube

Dehalogenation Zn [268] BrCF2CClFCClFCF2Br CF2 CFCF CF2 78%

CF3 F CF3 F Cl i F 40% [269] CF3 CF2Cl CF3 F F F i, Zn, 120 C, diglyme

CF3 CF3 CF C F 3 2 5 i F F 90% CF C2F5 3 [270] CF3 CF3 Me N NMe 2 2 , CH Cl , rt i, Me N 2 2 2 NMe2

F F F i 79% [270] F F F

i, Na, Hg (0.5% w/w), water cooling

O O O

i Cl ii F [271]

(FCl)6

i, F2, CF2ClCFCl2 ii, Cu Bronze

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 216

216 Chapter 7

Table 7.16 Contd

Reaction Ref.

Decarboxylation

i − CF2 CFCF CF2 25 37% NaO2C(CF2)4CO2Na + [272] i, 450 C, 0.01 mm CF2 CF(CF2)2CO2Na

Reductive coupling Cl I i F F F 75% [273] Cl Cl

i, Cu powder, DMF, 135 C

F F I F i F F + [273]

I F F F

i, Cu powder, DMF, 135 C 50% 34%

hν F FF F [274] Anti : Syn = 20 : 1

F CF3 CF3 F CF3 F + Ph F [265, 275] F Cu Ph I F CF3

CF3 CF3 i F F F 75% [276] CF3 i, PPh3, CH3CN, 25 C

2 Reactions Fluorinated dienes, like fluoroalkenes, are very susceptible to nucleophilic attack [90, 91]; some examples of nucleophilic substitution processes are given in Table 7.17. Examples of rearrangements and other reactions are also listed. An early demonstration that Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 217

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 217

Table 7.17 Reactions of polyfluorinated dienes

Reaction Ref.

Nucleophilic attack OPh

i F F + PhOH F F 58% [73]

PhO i, KF, CH3CN, rt

CF3 CF3 DMF + K S 72% CF3 F 2 rt [73] S F CF3 (CF3)4

CF H 3 CF3 F CF F F MeOH 3 [269, 279] CF3 rt F F F CF2OMe

MeO F MeOH F MeO [73] rt F F

CF3 F

CO2Et CF3 CF3 OO i CF2 + [280] CF2 CF2 OEt FOMe Na+ F

i, Tetraglyme, rt, 17 h

CF3 CF CF O 3 3 CF3 F i 70% F + t-BuOOH O F [281] CF3 CF CF3 CF3 3 F i, BuLi, THF, −78 C to rt

Rearrangements

CF3 F F CF3 SbF5 F CF3 [269] CF3 0 to 5 C F FF F F

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 218

218 Chapter 7

Table 7.17 Contd

Reaction Ref.

FF F CF2 hν F + FF CF2 85 C, 5 h CF [282] F F 2 36% 64%

Cycloadditions F CF2 Ph Ph F CF2 F Dioxane F HC CCPh + F [283] 60 C F2C F H H

4% 38%

1,4-cycloadditions of fluorinated dienes may occur involved perfluorocyclo-1,3-hexa- diene, as shown in Figure 7.79.

CO.CH3 Heat F + CH2 CHCO.CH3 F ½277 H H

Figure 7.79

The acceptor properties of some cyclic dienes are sufficient for stable charge-transfer salts to be isolated (Figure 7.80).

+ [C Me ] Fe ½278 FF+[C5Me5]2Fe FF5 5 2

Figure 7.80

3 Perfluoroallenes Perfluoroallenes are also attacked by nucleophiles and undergo cycloaddition reactions, as shown in Table 7.18.

III FLUOROALKYNES AND (FLUOROALKYL)ALKYNES A Introduction and synthesis Fluorine directly attached to a carbon–carbon triple bond raises the energy of the system due to repulsion between the p-electrons and the non-bonding electron pairs on fluorine, as we have discussed earlier (Figure 7.10). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 219

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 219

Table 7.18 Reactions of perfluoroallenes

Reaction Ref.

F3C F CF3 F CF3 CsF F F3C F C C CF2 F [284] (CF3)2CF CF3 CF3 F3CF

72% 18%

CF2 Ph F i [285] CF2=C=CF2 + PhCHN2 F N N

i, benzene, rt 78%

H F N Ph + O N i NPh CF2=C=CF2 + [286] O N CF3 63% i, xylene, 120 C

Indeed, monofluoroethyne, obtained by the pyrolysis of monofluoromaleic anhydride, is dangerously explosive whilst difluoroethyne has not been isolated, although claims to its preparation have been reported [287] (Figure 7.81). O F F

650 C O HC CF + CO + CO2 287 1-2mm ½ F F O

Figure 7.81

However, perfluoroalkyl substituents lower the energy of the system; for example, perfluoropropyne is considerably more stable than the fluoroalkynes referred to above [288] (Figure 7.82). Perfluorodialkylalkynes, in which fluorine lone-pair–p-electron repulsions are absent, are quite stable, and the chemistry of these substrates has been well developed [41, 289– 291]. Perfluoro-2-butyne is the most important member of this class of compounds that can be obtained by a reasonably direct route [292] (Figure 7.83). Hexafluoro-2-butyne has also been obtained by routes involving fluoride-ion processes, such as by using a fluorocarbon ‘solvent’ [53] or by passing perfluorocyclobutene over a bed of caesium fluoride or potassium fluoride [293] (Figure 7.84). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 220

220 Chapter 7

i ii CF BrCH CF CF2Br2 + CH2=CF2 CF2BrCH2CF2Br 2 = 2 86% ½288

ν i, Bz2O2, 110 C; ii, C, 300C; iii, h , Br2 iii

Zn AlBr3 CF C CF CF3CBr=CFBr CF BrCHBrCF Br 3 dioxane 2 2

Figure 7.82

i CCl2=CClCCl=CCl2 CF3CCl=CClCF3 ½292 85%

i, SbF3, SbF3Cl2, 115 C ii ii, Zn, (CH3CO)2O, reflux

CF3C CCF3 63%

Figure 7.83

i ii CCl CClCCl CCl CF CH CFCF 2= = 2 3 = 3 CF3C CCF3 ½53 56% i, Fluorocarbon, sulpholan (25% v:v), KF ii, Molecular Sieve

F CF2 i F CF3C CCF3 ½293 − F CF2 F 80% 90%

− i, CsF or KF, 510 590 C, Flow system in N2

Figure 7.84

A recent direct route from CF3CH2CF2H (hydrofluorocarbon 245fa) to the lithium salt now makes the trifluoropropyne ‘building block’ very accessible for many potential developments [294] (Figure 7.85). Other syntheses of a variety of fluoroalkynes are given in Table 7.19 where, in many cases, the synthetic approaches to these compounds can be seen to be adaptations of methods for the preparation of fluoroalkenes. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 221

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 221

i, ii i, ii CF3CH2CF2H CF3CH=CHF CF3C CH ½294 i

PhCHO CF3C CCH(OH)Ph CF3C CLi 60%

Ph3SnCl i, n−BuLi ii, −LiF CF3C CSnPh3

84%

Figure 7.85

Table 7.19 Synthesis of fluoroalkynes

Reaction Ref.

i CF2=CH2 FC CH 90% [295] i, s-BuLi, −110 C to −80 C

i CF3CH=CICH3 CF3C CCH3 45% [296] i, KF, crown ether, dioxane

i HCl C F CCl CCl C3F7C CZnCl CF3C CH 3 7 2 3 [297] 77%

i, Zn, DMF, 90−100 C

RF RF hν [298] RFC CRF + RFC N N N rt N

RF = CF(CF3)2

70 C CH3(CH2)5C CSnMe3 + C6F13I C6H13C CC6H13 [299] 6 h 55%

220 C KOH C3F7I + HC CH C3F7CH=CHI C3H7C CH

i i, C3F7I, 220 C [300] KOH C3F7C CC3F7 C3F7CI=CHC3F7

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 222

222 Chapter 7

Table 7.19 Contd

Reaction Ref.

HO CF3 H CF i 3 ii p-ClC6H4 Cl p-C6H4C CCF3 [301] Cl p-ClC6H4 Cl 81% i, Ac2O, Et3N, Zn, DMF; ii, NaNH2, t-BuOH, benzene, rt

i PhC CLi + C8F17IPhOTf PhC CC8F17 [302] 66% i, THF, −78 C

B Reactions Formation of the lithium derivative of trifluoropropyne was described in the preceding section [294] and the various acetylides, RFC;CM, had been prepared previously (e.g. M ¼ Cu, Ag, Hg; RF ¼ CF3,C2F5,CF3CH2) [289]. However, most studies concerning the reactions of perfluoroalkynes [291] have centred on the use of perfluoro-2-butyne, as this is commercially available.

1 Perfluoro-2-butyne [289, 291] Formation of polymers and oligomers: When perfluoro-2-butyne is heated, either alone or with halogen compounds or a metal carbonyl, hexakis(trifluoromethyl)benzene is obtained [303–306] (Figure 7.86). This is a very interesting compound that gives stable valence isomers on irradiation with ultraviolet light (see Chapter 9, Section IIE, Subsection 4).

CF3

F3C CF3

375 C hν CF3C CCF3 Stable valence isomers ½303306

F3C CF3 CF3

Figure 7.86

A high-molecular-weight, insoluble polymer is obtained when perfluoro-2-butyne is subjected to various initiators for free-radical polymerisation (Figure 7.87). The off-white colour of this material is remarkable for a polyacetylene! [307, 308]. Indeed, it is largely ignored in discussions on polyacetylenes because, of course, the fact that it is not coloured also means that the system is not conjugated: the trifluoromethyl groups keep the p-systems out of plane relative to each other. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 223

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 223

hν CF C CCF -C(CF3)=C(CF3)- ½307, 308 3 3 n

Figure 7.87

Reactions with nucleophiles: The most striking feature about this alkyne is that it is extremely electrophilic in nature, and electrophilic additions are suppressed whilst nucleophilic additions proceed with ease in reactions with a wide range of nucleophilic species (cf. fluoroalkenes) [309, 310] (Figure 7.88). F C H NaOBu 3 ½309 n–C4H9OH + CF3C CCF3 89% 20 C n-BuO CF3

F3C O ½310 NaOH OH CF3C CCF3 + 50 C F3C

F3C

CF3

Figure 7.88

Fluoride-ion-induced reactions: A similar polymer to that in Figure 7.87 is obtained upon anionic polymerisation of hexafluoro-2-butyne initiated by fluoride ion in a solvent [311–313] (Figure 7.89). This is a clear example of an anionic polymerisation of an unsaturated fluorocarbon, although the growing anion can be trapped by a sufficiently reactive system [291, 314], such as pentafluoropyridine [315] (Figure 7.90). There is little difference between the ultraviolet spectra of 7.90A and 7.90B, confirming that conjugation in the polyene system is inhibited by steric effects.

i CF C CCF 3 3 CF3CF CCF3 ½311313 C4F6 i, CsF, Sulpholan

CF3CFC(CF3)C(CF3)CCF3

C4F6 etc.

F CF CC(CF ) 3 3 n

Figure 7.89 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 224

224 Chapter 7

CF3 F3C

7.90A ½315 F N F i CF3C CCF3 CF3F=CCF3

C(CF3)=C(CF3)nF i = F 7.90B N F N

Figure 7.90

An equivalent polymer is also obtained from perfluorobutadiene in the presence of fluoride ion; this is a further demonstration of the propensity of systems to rearrange to reduce the number of fluorine atoms attached to vinyl sites [315, 316] (Figure 7.91). i i F CF2=CF CF3C CCF3 C(CF3)=C(CF3) ½315, 316 2 n

i, CsF, Sulpholan, 100 C

Figure 7.91

Cycloadditions [40]: Perfluoro-2-butyne is a highly reactive dienophile and many [4 þ 2] cycloaddition and 1,3-dipolar addition reactions involving this alkyne have been reported (Table 7.20). Moreover, [2 þ 2] additions with hydrocarbon alkenes are possible (Table 7.20).

Table 7.20 Cycloaddition reactions with perfluoro-2-butyne

Reaction Ref.

COPh COCH3 N N i + CF3C CCF3 100% [317] CF3

i, THF, 100 C CF3

N Ph CF C CCF + PhN 50 C NN 3 3 3 80% [318]

CF3 CF3

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 225

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 225

Table 7.20 Contd

Reaction Ref.

CF3

F3C 200 C CH H3C 3 CF3C CCF3 [319] 10 h

H C 3 CH3

100 C CF3 CF3C CCF3 O 6 h

CH3 H3C CF3

OH [320] i CF3 ii

CF3 F3C

CH3 O CH2=CH2

F3C CH3 i, BF3.Et2O

ii, H2, Pt/C, 400 C

CF3

∆ F3C CF3C CCF3 [321]

Polyacetylene

Heptafluoro-2-butene, which is readily available in a laboratory synthesis from hexachlorobutadiene, may be used as a synthon for perfluoro-2-butyne in cycloaddition reactions where in situ elimination occurs [322] (Figure 7.92). Reaction with difluorocarbene leads to the formation of novel cyclopropene and bicyclobutane systems [323] (Figure 7.93), and similar reactions are observed using polyfluoroalkyne derivatives of some metals [324]. Reactions with sulphur atoms alone give a variety of cyclic products, depending on the conditions [325], but when iodine is also present the potentially aromatic compound Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 226

226 Chapter 7

CF3

F3C −HF CF CH CFCF 3 = 3 ½322

CF3

91%

CF3

Figure 7.92

F3C CF3 [CF2] [CF2] F C CF CF3C CCF3 3 3 ½323 100 C 100 C F F F F 25%

Figure 7.93

7.94B is produced which is a rare, and probably unique, example of the dithiete system [326] (Figure 7.94). SS (CF ) 3 4 ½326 CF3C CCF3 S I2 S F3C CF3 7.94A 11% 7.94B 26%

F C 3 S S CF3

S S CF F3C 3

7.94C 29%

Figure 7.94

Free-radical additions: Free-radical addition reactions involving perfluoro-2-butyne are also possible, as indicated in Figure 7.95 [327, 328]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 227

Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 227

CF3 γ O CF3 ½327 30% CH3CHO + CF3C CCF3 H CF3

220 C C3F7I + CF C CCF CF CIC(CF )C F 68% ½328 3 3 7 days 3 3 3 7

Z : E 3 : 4

Figure 7.95

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234 Chapter 7

250 P.D. Bartlett, Quart. Rev., 1970, 24, 473. 251 V.A. Albekov, A.F. Benda, A.F. Gontar, G.A. Sokolskii and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1988, 37, 777. 252 V.A. Albekov, A.F. Benda, S.G.A. Gontar, and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1988, 37, 785. 253 A.E. Bayliff, M.R. Bryce, R.D. Chambers, J.R. Kirk and G. Taylor, J. Chem. Soc., Perkin Trans. 1, 1985, 1191. 254 Y. He, C.P. Junk, J.J. Cawley and D.M. Lemal, J. Am. Chem. Soc., 2003, 125, 5590. 255 D.J. Burton and D.A. Link, J. Fluorine Chem., 1983, 22, 397. 256 B.E. Smart, J. Am. Chem. Soc., 1974, 96, 929. 257 P.B. Sargeant and C.G. Krespan, J. Am. Chem. Soc., 1969, 91, 415. 258 M.R. Bryce, R.D. Chambers and G. Taylor, J. Chem. Soc., Chem. Commun., 1983, 5. 259 Y.V. Zeifman and L.T. Lantseva, Bull. Acad. Sci., USSR, 1986, 35, 248. 260 I.L. Knunyants and G.A. Sokolski, Angew. Chem. Int. Ed. Engl., 1972, 11, 583. 261 D. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532. 262 J. Mohtasham, G.L. Gard, Z.Y. Yang and D.J. Burton, J. Fluorine Chem., 1990, 50, 31. 263 A.Y. Yakubovich, S.M. Rozenshstein, S.E. Vasyukov, B.I. Tetel’baum and V.I. Yakutin, J. Gen. Chem. USSR, 1966, 36, 740. 264 L.P. Anderson, W.J. Feast and W.K.R. Musgrave, J. Chem. Soc. (C), 1969, 2559. 265 D.J. Burton, Z.Y. Yang and P.A. Morken, Tetrahedron, 1994, 50, 2993. 266 G.S. Krashnikova, L.S. German and I.L. Knunyants, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1973, 22, 459. 267 G. Apsey, R.D. Chambers and M. Salisbury, J. Fluorine Chem., 1988, 40, 261. 268 V. Dedek and Z. Chvatal, J. Fluorine Chem., 1986, 31, 363. 269 V.A. Petrov, G.G. Belenkii and L.S. German, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1981, 30, 1920. 270 M.W. Briscoe, R.D. Chambers, S.J. Mullins, T. Nakamura, J.F.S. Vaughan and F.G. Drake- smith, J. Chem. Soc., Perkin Trans. 1, 1994, 3115. 271 Y. Lou, Y. He, J.T. Kendall and D.M. Lemal, J. Org. Chem., 2003, 68, 3891. 272 R.N. Haszeldine, J. Chem. Soc., 1954, 4026. 273 R.L. Soulen, S.K. Choi and J.D. Park, J. Fluorine Chem., 1973, 3, 141. 274 D. Lemal in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 297. 275 D.J. Burton and S.W. Hansen, J. Am. Chem. Soc., 1986, 108, 4229. 276 A.A. Stepanov, G.Y. Bekker, A.P. Kurbakova, L.A. Leites and I.N. Rozhkov, Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1981, 21, 2746. 277 R.D. Chambers, W.K.R. Musgrave and D.A. Pyke, Chem. Ind., 1964, 564. 278 M.W. Briscoe, R.D. Chambers, W. Clegg, V.C. Gibson, S.J. Mullins and J.F.S. Vaughn, J. Fluorine Chem., 1996, 76,1. 279 I. Linhart and V. Dedek, Collect. Czech. Chem. Commun., 1985, 50, 1737. 280 M.R. Bryce, R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Chem. Soc., Perkin Trans. 1, 1983, 2451. 281 R.D. Chambers, J.F.S. Vaughan and S.J. Mullins, J. Chem. Soc., Chem. Commun., 1995, 629. 282 Z. Chvatal and V. Dedek, J. Fluorine Chem., 1993, 63, 185. 283 N.B. Kazmina, A.P. Kurbakova, L.A. Leitas, B.A. Kvasov and E.J. Mysov, Zh. Org. Khim., 1986, 55, 1500. 284 P.W.L. Bosbury, R. Fields and R.N. Haszeldine, J. Chem. Soc., Perkin Trans. 1, 1978, 422. 285 G.B. Blackwell, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1983, 1. 286 G.B. Blackwell, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc., Perkin Trans. 1, 1982, 2207. 287 B.E. Smart in The Chemistry of Functional Groups. Supplement D, Fluorocarbons, ed. S. Patai and Z. Rappoport, John Wiley and Sons, New York, 1983, p. 613. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 235

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288 R.E. Banks, M.G. Barlow, W.D. Davies, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc. (C), 1969, 1104. 289 M.I. Bruce and W.R. Cullen, Fluorine Chem. Rev., 1969, 4, 79. 290 H. Muramatsu and K. Inukai, J. Synth. Org. Chem. Jpn., 1973, 31, 466. 291 E.S. Turbanova and A.A. Petrov, Russ. Chem. Rev., 1991, 60, 501. 292 A.L. Henne and W.G. Finnegan, J. Am. Chem. Soc., 1949, 71, 298. 293 R.D. Chambers, C.G.P. Jones, G. Taylor and R.L. Powell, J. Chem. Soc., Chem. Commun., 1979, 964. 294 A.K. Brisdon and I.R. Crossley, J. Chem. Soc., Chem. Commun., 2002, 2420. 295 R. Sauvetre and J.F. Normant, Tetrahedron Lett., 1982, 23, 4325. 296 J.J. Mielcarek, J.G. Morse and K.W. Morse, J. Fluorine Chem., 1978, 12, 321. 297 D.J. Burton and T.D. Spawn, J. Fluorine Chem., 1988, 38, 119. 298 R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans. 1, 1990, 983. 299 S. Matsubara, M. Mitani and K. Utimoto, Tetrahedron Lett., 1987, 28, 5857. 300 M. Hudlicky, J. Fluorine Chem., 1981, 18, 385. 301 G. Meazza, L. Capuzzi and P. Piccardi, Synthesis, 1989, 331. 302 T. Umemoto and Y. Gotoh, Bull. Chem. Soc. Jpn., 1986, 59, 439. 303 H.C. Brown, H.L. Gewanter, D.M. White and W.G. Woods, J. Org. Chem., 1960, 25, 634. 304 H.C. Brown, J. Org. Chem., 1957, 22, 1256. 305 J.F. Harris, R.J. Harder and G.N. Sausen, J. Org. Chem., 1960, 25, 633. 306 J.L. Boston, D.W.A. Sharp and G. Wilkinson, J. Chem. Soc., 1962, 3488. 307 J.F. Harris, US Pat. 2 923 746 (1960); Chem. Abstr., 1962, 54, 9799a. 308 H.C. Brown and H.L. Gewanter, J. Org. Chem., 1960, 25, 2071. 309 R.D. Chambers, C.G.P. Jones, M.J. Silvester and D.B. Speight, J. Fluorine Chem., 1984, 25, 47. 310 C.G. Krespan, Tetrahedron, 1967, 23, 4243. 311 R.D. Chambers, W.K.R. Musgrave and S. Partington, Chem. Commun., 1970, 1050. 312 W.T. Flowers, R.N. Haszeldine and P.G. Marshall, Chem. Commun., 1970, 371. 313 R.D. Chambers and C.G.P. Jones, J. Fluorine Chem., 1981, 17, 581. 314 W.T. Miller, R. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850. 315 R.D. Chambers, S. Partington and D.B. Speight, J. Chem. Soc., Perkin Trans. 1, 1974, 2673. 316 R.D. Chambers, S. Nishimura and G. Sandford, J. Fluorine Chem., 1998, 91, 63. 317 R.W. Kaesler and E. LeGoff, J. Org. Chem., 1982, 47, 4779. 318 N.P. Stepanova, N.A. Orlova, V.A. Galishov, E.S. Turbanova and A.A. Petrov, Zh. Org. Khim., 1985, 51, 979. 319 C.G. Krespan, B.C. McKusick and T.L. Cairns, J. Am. Chem. Soc., 1961, 83, 3428. 320 R.D. Chambers, A.J. Roche and M.H. Rock, J. Chem. Soc., Perkin Trans. 1, 1996, 1095. 321 W.J. Feast in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 142. 322 R.D. Chambers and A.R. Edwards, Tetrahedron, 1998, 54, 4949. 323 W. Mahler, J. Am. Chem. Soc., 1962, 84, 4600. 324 W.R. Cullen and M.C. Waldman, Inorg. Nucl. Chem. Lett., 1968, 4, 205. 325 B. Verkoczy, A.G. Sherwood, I. Safarik and O. Strausz, Can. J. Chem., 1983, 61, 2268. 326 C.G. Krespan, J. Am. Chem. Soc., 1961, 83, 3434. 327 R.D. Chambers, C.G.P. Jones and M.J. Silvester, J. Fluorine Chem., 1986, 32, 309. 328 R. Fields, R.N. Haszeldine and I. Kumadaki, J. Chem. Soc., Perkin Trans. 1, 1982, 2221. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 236

Chapter 8 Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives

This chapter contains only a brief survey of the chemistry of a range of derivatives that are of interest to the organic chemist; further aspects have been discussed in detail and may be referred to elsewhere [1, 2]. Because of the extreme electronegativity of fluorine and fluorocarbon groups, the acidities of various functions are increased by introduction of these groups. Some examples are given in Table 8.1: it is clear that fluorocarbon groups have a dramatic effect on the acidities of alcohols and carboxylic acids. Moreover, the CF3SO2 group is one of the most electron-withdrawing groups known [3] and consequently the carbon acid ðCF3SO2Þ2CH2 is more acidic than trifluoroacetic acid. Also, the sulphonamide ðCF3SO2Þ2NH is a strong acid [4]. Conversely, fluorine or fluorocarbon groups have a major effect in reducing the base strength of amines, ethers and carbonyl compounds; for example, 2,2,2-trifluoroethylamine 5 (pKb ¼ 3:3) is ca. 10 times less basic than ethylamine. Also, pentafluoropyridine is only protonated in strong acid [6], whereas hexafluoroacetone is not protonated even in superacids [7–9] and perfluorinated tertiary amines and ethers are sufficiently non-basic for them to be used as inert fluids interchangeably with perfluorocarbons.

I OXYGEN DERIVATIVES A Carboxylic acids 1 Synthesis The electrochemical fluorination process [10] (see Chapter 2, Section IVA) is particularly effective for the synthesis of polyfluoroalkanoic acids and is applied on an industrial

Table 8.1 Acidities of fluorinated systems [3, 5]

Acid pKa

CH3COOH 4.76 CF3COOH 0.52 ðCH3Þ2CHOH 16.1 ðCF3Þ2CHOH 9.3 ðCF3Þ3COH 5.4 ðCF3SO2Þ2CH2 1.0 ðCF3SO2Þ2NH 1.7

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 237 scale, although hydrolysis of chlorofluoroalkanes can also be a useful process [11, 12]. Dicarboxylic acids may be obtained by oxidation of cyclic alkenes; examples are shown in Table 8.2.

Table 8.2 Preparation of fluorinated carboxylic acids

Reaction Ref.

E C F H2O RCOCl RFCOF RFCOOH [13]

e.g. RF = CF3, C4F9

i CF3CCl3 CF3COOH [14]

i, SO3, BF3

i C8F17I C7F15COF 83% [15]

i, Fuming H2SO4, PCl5

i, ii CF2=CF2 (CF2)n(COOMe)2 [16] i, K S O , FeSO , H O 2 2 8 4 2 n = 1−11 ii, Esterification

i CF3(CF2)6I(Br) CF3(CF2)5COONa 83% [17] i, HOCH2SO2Na, NaHCO3, DMF, H2O, 90 C

i − (CF2)4(CH2CH2OH)2 (CF2)4(CH2COOH)2 69 95% [18] − i, CrO3 H2SO4

i H(CF2)6CH2OH H(CF2)6COOH 65% [19] i, HNO3, FeCl2.nH2O

hν [20] CHF2COF + Br2 BrCF2COF

i CF2ClCFClCCl3 CF2ClCFClCOOCl

ii [21] iii CF2ClCFClCOOCD3 CF2=CFCOOCD3 i, Oleum ii, CD3OD iii, Zn

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238 Chapter 8

Table 8.2 Contd

Reaction Ref.

X SbF i Cl 5 F (CF ) (COOH) 2 4 2 [22, 23] X X = Cl, F i, Alk. KMnO4

Cl Cl i ii Cl F O(CF2COOH)2 [24] O O i, SbF3.SbCl5. ii, KMnO4

2 Properties and derivatives Boiling points of perfluoroalkanoic acids are lower than for corresponding alkanoic acids, which indicates a significant reduction in intermolecular forces for the fluorocarbon acids. They are very strong in comparison with other organic acids (see Chapter 4, Section IIIA, Subsection 1) and, correspondingly, most of the metal salts, e.g. those of trifluoroacetic acid, are water- and alcohol-soluble whilst the silver salts are soluble in ether and benzene. Alkali-metal salts of higher acids are used as emulsifying agents. A range of normal functional-group chemistry may be carried out with perfluoroalkanoic acids, little modified by the perfluoroalkyl group [2, 25, 26]. Acid chlorides are readily obtained with thionyl chloride or phosphorus chlorides and may be converted to the fluorides using potassium fluoride or, where a volatile product is obtained, by exchange with benzoyl fluoride (see Chapter 3, Section IIB); anhydrides are produced by reaction of the acid with phosphorus pentoxide [27]. To illustrate some of the chemistry of perfluoroalkanoic acids, a selection of reactions is contained in Table 8.3.

Table 8.3 Reactions of perfluoroalkanoic acids and derivatives

Reaction Ref.

OH O CF3

O OH i [28]

O O

i, CF3COOH

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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 239

Table 8.3 Contd

Reaction Ref.

CF COOH + C H COX CF COX + C H COOH 3 6 5 3 6 5 [29] X = Cl, F

i CF3COONa + POCl3 CF3COCl 90% [30]

i, 100C, 24 h

[27] CF3COOH + P2O5 (CF3CO)2O

i [31] CF3COOC2H5 + NH3 CF3CONH2 99% i, (C2H5)2O, 0 C

i C2F5CONH2 C2F5Br [32] i, Br2, NaOH

i CF3COOC2H5 + NH3 CF3CONH2 99% [33] i, (C2H5)2O, 0 C

i CF3COOC4H9 + LiAlH4 CF3CH2OH 76% [34]

i, (C2H5)2O, Reflux

i ii CF3COCl CF3COCHN2 CF3CH2COOC2H5 62% 40% [35] − i, CH2N2, 0 20 C; ii, Ag2O, C2H5OH

i CF CONH CF CN 74% 3 2 3 [31] − i, P2O5, 150 200 C

Pyrolysis of alkali-metal salts does not lead to simple decarboxylation but, instead, elimination of fluoride also occurs; this is a useful synthetic method [36], commercialised in the synthesis of monomer for the manufacture of Nafiont [37] (Figure 8.1); see Chapter 7, Section IIB for the preparation of fluoroalkenes. Decomposition of sodium salts of dicarboxylic acids is more complicated [38] (Figure 8.2). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 240

240 Chapter 8

SO F2C CF2 F CF CF 3 2= 2 FCOCF2SO2F O SO2

F ½37

HFPO OCF CF(CF )OCF CF SO F 2 3 2 2 2 OCF2CF2SO2F

HFPO

Na2CO3 FCO[CF(CF )OCF ] CF SO F 3 2 2 2 2 Heat

CF2=CFOCF2CF(CF3)OCF2CF2SO2F CF CF CF HFPO = 3 2 O CF2=CF2

Co-polymer

Figure 8.1

i ii (CF ) (COONa) 2 4 2 CF2=CF(CF2)2COONa (CF2=CF-)2 ½38 61% − i, 460C, 10 2mm ii, 160−450C, 10−2mm

Figure 8.2

The Hunsdiecker method has been applied effectively for the replacement of carboxyl by bromine and iodine [39–42] (Figure 8.3) but on an industrial scale the products are more effectively obtained by other processes [43]. Routes starting from alkenes are particularly significant (Figure 8.4). It is important to note that the toxicities of these iodoalkanes appear to be increased dramatically from that of trifluoroiodomethane, which is relatively harmless (and has unwisely been considered as a fire-extinguishing agent), to those of the tertiary iodides, which are dangerously toxic [44].

AgNO3 I2 CF CO Na CF CO Ag CF I 91% ½40 3 2 3 2 Heat 3

Figure 8.3

The particular toxicity of perfluoro-t-butyl iodide is most probably related to the efficiency of the iodide as a one-electron acceptor in reactions with nucleophilic sites in the body.

3 Trifluoroacetic acid The advantages of trifluoroacetic acid as a very strong organic acid have, of course, been appreciated for a long time; they include its unusual properties as a solvent for kinetic Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 241

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 241

IF5/I2 CF2=CF2 C2F5I 86% ½45, 46

IF5/I2 CF2=CFCF3 (CF3)2CFI 99% ½45, 46

i ½47 F CF2=CFCF3 (CF3)2CFI 61%

i, KF, I2, CH3CN, 100 C

i F CF2=C(CF3)2 (CF3)3CFI 61% ½48

i, KF, I2, CH3CN, 130 C

Figure 8.4 studies, e.g. for electrophilic aromatic substitution reactions [49] or solvolysis studies [50]. The acid is a good ionising medium but appears to have a surprisingly low solvating effect, or nucleophilicity, towards cations, apparently because of the high internal stabilisation of the CF3COO ion. Conversely, the medium is highly efficient in solvating anions through hydrogen bonding. As a consequence of these effects, trifluoroacetic acid provides a useful medium for solvolytic reactions of pronounced SN1 character because this allows inductive and anchimeric assistance effects to play a more important part in carbocation generation than is observed using more nucleophilic solvents [50]. The acid may be used as a solvent for promoting the formation of strong electrophiles, e.g. for nitration. Trifluoroacetamide has been used in an alternative procedure to the Gabriel synthesis for amines [51] (Figure 8.5).

NaBH4 RX + NaNHCOCF3 RNHCOCF3 RNH2 ½51

e.g. RX = n-C8H17I, Yield = 79%

Figure 8.5

The field of fluorinated amino acids and peptides is already established and recent developments are important to both chemistry and biology. The reader is directed to an excellent entry volume [52] and reviews [53].

4 Perfluoroacetic anhydride The utility of perfluoroacetic anhydride as a medium for promoting esterifications is well known [54] and, again, is based on the stability of the trifluoroacetate ion (Figure 8.6).

RCOOH + R'OH + (CF3CO)2O ½54

RCOOR' + 2 CF3COOH

Figure 8.6 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 242

242 Chapter 8

It is probable that on addition of a carboxylic acid to the alcohol/anhydride mixture trifluoroacetic acid is formed, together with a mixed anhydride that is either highly polar or actually ionised to give an acylium ion in solution (Figure 8.7).

RCOOH + (CF3CO)2O CF3COOH + CF3CO.OCOR

− + CF3COO + RCO

Figure 8.7

Esterification of a wide range of compounds has been achieved, often under very mild conditions. Trifluoroacetates are also formed readily using perfluoroacetic anhydride and are subsequently easily hydrolysed; consequently the trifluoroacetate group finds common usage in carbohydrate and peptide chemistry [54] for blocking OH and NH2 groups. The anhydride has been used to form N-(trifluoroacetyl)succinimide, which is claimed to be a convenient trifluoromethylating agent [55].

5 Peroxytrifluoroacetic acid The uses of this reagent were developed by Emmons. It is prepared by mixing the anhydride with 90–95% hydrogen peroxide [56] (Figure 8.8); although a mixture of hydrogen peroxide and trifluoroacetic acid is sometimes used, it is less effective. It is claimed that the use of sodium percarbonate and the anhydride is also an effective methodology [57].

δ− δ+ (CF3CO)2O + H2O2 CF3COOH CF3 C OOH ½56 O

Figure 8.8

Peroxytrifluoroacetic acid is a powerful peroxy-acid and only the expense of the reagent inhibits its more widespread use. It will efficiently bring about the oxidations for which peracids are normally used, such as the Baeyer–Villiger oxidation of ketones to esters [58] and the conversion of alkenes to glycols [59] or, when a buffer is present, to epoxides [60] and nitrosamines to nitramines [56, 61]. However, the reagent will also convert aromatic amines to nitro compounds [62], even with amines containing electron- withdrawing substituents [63]. Similarly, oxidation of perfluorodibenzothiophene to the dioxide occurred [64] where other reagents had failed. Peroxytrifluoroacetic acid reacts with aromatic systems by effecting electrophilic hydroxylation [65] leading to phenols, quinones or cyclohexadienone derivatives [65, 66], and the efficiency of the reagent is significantly increased by the addition of boron trifluoride [66] (Figure 8.9). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 243

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 243

CF3CO2OH C6F5NH2 C6F5NO2 ½63

i FF F ½64 S S O O i, CF3COOH, H2O2

OH CH H3C CH3 H3C 3 ½66

CF3CO2OH

CH3 CH3

O ½66 CF3CO2OH/BF3 (CH3)6 (CH3)6 90%

Figure 8.9

B Aldehydes and ketones 1 Synthesis Selective fluorination of aldehydes and ketones has been carried out by a variety of electrophilic procedures [67–70] and enantiomerically enriched forms have been achieved in a number of cases. A range of polyfluoroalkyl ketones has been synthesised but, generally, by methods quite distinct from those that would be used to synthesise corresponding hydrocarbon derivatives. Some examples are given in Table 8.4. Hexa- fluoroacetone [67] and chlorofluoroacetones are commercially available and are made by exchange of chlorine in hexachloroacetone by fluorine, using a Cr(V) or Cr(III) catalyst, and fluoral, CF3CHO, has also been made on a commercial scale by analogous catalytic processes, starting with chloral, CCl3CHO [71]. Preparations of trifluoromethyl ketones have been reviewed [72].

2 Reactions [93–96] The carbonyl group in a perfluorinated ketone is clearly very electron-deficient and this feature dominates the chemistry of these compounds. It is reflected in, for example, the rise in vibrational frequency of the carbonyl group in polyfluoro-ketones [97, 98] from normal values and by the fact that hexafluoroacetone is not protonated in the superacidic FSO3H=SbF5 mixture [8]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 244

244 Chapter 8

Table 8.4 Syntheses of perfluorinated aldehydes and ketones

Reaction Ref.

i ii CF3CHBrCl (CF3CHSO3) CF3CHO [73]

i, Oleum, HgO, reflux; ii, H2O

i, ii CF3Br CF3CH(OCOCH3)2 ca. quant. [74] i, Electrochem. Red'n, DMF, Bu4NBr, Al anode, Lewis acid or Me3SiCl (trace). ii, (CH3CO)2O, HCl, Pyridine

i, ii iii [75] RF(CF2)nCOOH RF(CF2)nCH(OH)2 CF3(CF2)nCHO

i, LiAlH4; ii, H2SO4; iii, P2O5 n = 0, 1, 2

i F CHO RF(CH2)nCH2OH RF(CH2)nCHO

R'F H [76] i, Swern Oxidation or Pyridinium Chlorochromate

− RF = C4F9, R'F = C3F7, n = 1 4

i (CF ) CFCO(CF ) COCF(CF ) FCO(CF2)3COF CF2=CFCF3 3 2 2 3 3 2 [77] − 75% Conversion i, CH3CN, KHF2, 120 125 C

SbF5 [78] CF3CF2CF=C(OMe)CF3 CF3CF=CFCOCF3

i, ii FCO(CF2)nCOF Me3SiCF3 CF3CO(CF2)nCOCF3 [79] n = 2,3 (ca. 90%) i, KF; ii, Heat, Vacuum

P2O5 (C H O) CO (n-C3F7)2C(OH)2 (n-C3F7)2CO 2 5 2 [80] 88%

i CF3CCl=CClCF3 CF3COCOCF3 [81] 31% − i, CrO3, fum. H2SO4, 60 70 C, 1.5 h

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 245

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 245

Table 8.4 Contd

Reaction Ref.

F3C F Cr2O3 or Al2O3 (CF3)2CO [82, 83] F F O

i O F F O [84]

i, CsF, Pt, 150−300C, 1.5h, 300C, 2h

OCH3 175C F CF2=CF2 CF2=CFOCH3

H2SO4 [85]

OH O P2O5 F OH F Heat

F OCH3 F OCH OCH CoF 3 3 3 (CF ) (CF2)n (CF2)n 2 n F

F F F

[86, 87] H2SO4

OH O

OH P2O5 (CF ) (CF2)n F 2 n F

F F

H2O P2O5 CF2=C(CF3)2 (CF ) CHCOOH (CF3)2C=C=O THF 3 2 [88] 77%

OH OH Br2 RF C CF=CF2 RF C CFBrCF2Br H H

Na2Cr2O7.2H2O [89] H2SO4

Zn/Dioxane RFCOCFBrCF2Br RFCOCF=CF2

R = CF ; C F F 3 2 5 Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 246

246 Chapter 8

Table 8.4 Contd

Reaction Ref.

F O CF F C C i 2 O Na F C C CF2HCOCF3 F C OH [90] F3C OH 3 45%

i, Nitrobenzene, 200C

i, ii C6F13(CH2)2I RFCO(CH2)2C6F13

− [91] i, t-BuLi, 78 C RF = CF3 (89%) − ii, RFCO2Et, 78 C RF = C7F15 (68%)

i RFCOCl + (i-Pr)3SiH RFCHO + (i-Pr)3SiCl

[92] i, Pd/C, 25 to 30 CRF = C7F15 90% RF = n-C3F7 60%

Addition to C5O: Synthesis of homochiral systems is an important aim [99, 100] and the steric requirements of hexafluoroacetone may lead to quite different stereochemical outcomes from other carbonyl systems [101] (Figure 8.10).

H CH i 3 ii ½101 X CO CH2CH3 X X CF3

Et2BO CF3 Re O OH

− i, Et2BOTf, i-Pr2NEt, 5 C, 30min. − ii, (CF3)2CO, 78 to 5 C X = N SO2

Figure 8.10

Because of the ready reaction of fluorinated ketones with nucleophiles there is a considerable literature on this subject, although it is dominated by that of hexafluoroacetone. Burger and co-workers have prepared a variety of heterodienes, 8.11A (Figure 8.11), from hexafluoroacetone and developed an extensive chemistry of these derivatives, especially the formation of heterocycles [95, 96]. A significant feature in this chemistry is the presence of low-lying HOMOs in the heterodienes; this has made possible a range of cycloaddition reactions [95, 96] Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 247

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 247

C(CF3)2 Y X = O, S, NR2 Y = N, CH ½95, 96 R1 X 8.11A

C(CF3)2OH C(CF3)2 N NH2 HN i e.g. (CF3)2CO 1 R1 NR2 R1 NR2 R NR2 80−90%

i, POCl3, Pyridine

F3C CF3 CN i N O (CF3)2CO R1 NH R1 NH 75−84%

− 1 i, Et2O, 30 C - room temp. R = CH3, CH(CH3)2

Figure 8.11

(Figure 8.12). The heterodienes are useful traps for a variety of reactive intermediates and they are good one-electron acceptors. For example, reaction with SnCl2 leads to defluorination and cyclisation [95] (Figure 8.13).

F3C CF3 C(CF3)2 N NR2 ½95, 96 i N C NR3 1 2 R NR R1 NR3

77−93% i, Toluene, 50−70C, 24−36 hr.

Figure 8.12

F3C F3C C(CF3)2 C=CF2 N ½95 N N − F SnCl 2 1 F X R R1 X R1 X

SnCl2F2 X = O, S, NR2

Figure 8.13 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 248

248 Chapter 8

Hexafluoroacetone reacts with amino acids to give heterocyclic systems (Figure 8.14) which are highly volatile and may be used for GLC analysis. They also show potential for synthesis of natural and unnatural amino acids [96, 102]. O ½96, 102 HOOC

HN O

F3C CF3

Figure 8.14

Addition of amino compounds to hexafluoroacetone occurs very readily indeed, but subsequent dehydration to form, for example, oximes or semicarbazones from the corresponding adducts does not normally occur. Special procedures usually have to be employed, the most effective being elimination of amines from adducts to form imines that are derived from the ketone, as illustrated in Figure 8.15.

NHNHCONH2 (CF ) C (CF3)2C=NPh + H2NNHCONH2 3 2 103, 104 NHPh ½

∆ or HCl − ( PhNH2)

(CF3)2C=NNHCONH2

Figure 8.15

Haloform-type cleavage of fluoro-ketones occurs in the presence of excess base but intermediate metal salts of the gem-diols can be isolated in some cases [105] (Figure 8.16).

RF OH MOH + (RF)2CO C RFCOOM + RFH ½105 RF OM

Figure 8.16

Reaction of hexafluoroacetone with water occurs exothermically to give a stable solid gem-diol that is acidic (pKa ¼ 6:58) [94], or a liquid sesquihydrate; an adduct is formed with hydrogen peroxide that functions as a peroxy-acid [106] and, on thermal decomposition, gives the interesting peroxide CF3OOH [93, 107]. Reaction of CF3COCH3 with 30% hydrogen peroxide gave a stable tetroxane [108] (Figure 8.17). In recent developments, the hydrogen peroxide is generated in situ, in a catalytic process using N-hydroxyphthalimide and oxygen, in the presence of hexafluoroacetone or its hydrate. The system is useful for epoxidation of alkenes, which occurs in a regio- and stereoselective manner [109]. Also, the use of Oxonet (KHSO5 KHSO4 K2SO4) with CF3COC6H13, in aqueous ðCF3Þ2CHOH as solvent, has been developed [91]. Oxonet Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 249

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 249 in combination with ðCF3Þ2CO is a very powerful oxidant, proceeding by the intermediate formation of the corresponding dioxirane [110] (Figure 8.18). Catalytic diastereoselective epoxidation of chiral allylic alcohols, using hexafluoroacetone hydrates, has also been reported [111]. Some additions are shown in Figure 8.19.

F C 3 CH3 ½108 O O CF3COCH3 + H2O2 O O

F3C CH3

Figure 8.17

O F3C CF3COCF3 C Oxidation reactions ½110

F3C O

Figure 8.18

H2O CF3COCF3 (CF3)2C(OH)2 ½112

H2O2 CF3COCF3 (CF3)2C(OH)OOH ½106, 107

∆

CF3COOH

H2S 113 CF3COCF3 (CF3)2C(OH)SH ½

Figure 8.19

Even though protonation of hexafluoroacetone has not been observed, reaction with aromatic compounds may be achieved in the presence of Lewis acids, suggesting at least some degree of co-ordination of the Lewis acid [93]. The orientation of substitution depends on the catalyst but, using weaker systems, e.g. boron trifluoride or hydrogen fluoride, the cross-linking agent bisphenol AF is obtained (Figure 8.20). Wittig reagents, including apparently even the normally unreactive derivatives, give the corresponding alkene derivative on reaction with hexafluoroacetone [114], as for example in Figure 8.21. Unusually, intermediates may be isolated; these may then be converted to the alkene by gentle heating [115, 116]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 250

250 Chapter 8

i CF3COCF3 HO C(CF3)2 OH ½93

i, BF3, or HF

Figure 8.20

CF3COCF3 + (C6H5)3P=CHCOCH3 (CF3)2C=CHCOCH3 ½114

Figure 8.21

Some unusual reactions can occur between fluorinated ketones and trialkylphosphines [117] or trialkylphosphites [118] (Figure 8.22). C H H 6 5 ½117 C6H5COCF3 + (n-C4H9)3P C C

F3C (CH2)2CH3

½118 (C2F5)2CO + P(OC2H5)3 C2F5C(OC2H5)=CFCF3

+ FPO(C2H5)2

Figure 8.22

Uncatalysed reactions with alkenes or alkynes will occur and cycloaddition products may be obtained (Figure 8.23). C F H3C 2 5 100−200C ½119 (C F ) CO + CH C(CH )C(CH ) CH 2 5 2 2= 3 3 = 2 C2F5 O H3C

O CH2 CH=CH2 ½85 OH F CH2=CH CH=CH2 F

Figure 8.23

Carbonyl groups are normally resistant to radical attack but fluorinated ketones appear to be exceptional in that an extensive free-radical chemistry is possible [93] (Figure 8.24). Copolymers are obtained by free-radical copolymerisation of hexafluoroacetone with, for example, alkenes, tetrafluoroethene and epoxides. Highly fluorinated ketones show some unusual keto–enol phenomena [122]. Remark- ably, the pair 8.25A and 8.25B in Figure 8.25 cannot be equilibrated by acid or base; the enol 8.25A, for example, can be distilled from concentrated sulphuric acid. In the presence of base, aldol condensation occurs faster than equilibration. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 251

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 251

hν (CF3)2CO + CCl3SiH (CF3)2CHOSiCl3 ½120

OC(CF3)2H C(CF3)2OH ½121 hν (CF3)2CO

C(CF3)2OH

hν ½93 (CF3)2CO + (CH3)2CHOH (CF3)2COH (CF3)2CHOH 2

Figure 8.24

Base 2 CF2=C(OH)CF3 CF2 C CF3 ½122 8.25A O 8.25C 8.25B Slow

8.25C CF HCOCF CF COCF C(CF )(CF H)OH 2 3 Fast 3 2 3 2 8.25B

Figure 8.25

Clearly, the tautomerism is inhibited by a kinetic barrier and this could be the relative instability of the anion 8.25C, where electron-pair repulsion involving non-bonding pairs on fluorine could be significant. Enols of cyclic systems are also unusually stable [123] and the equilibrium constant depends on the solvent (Figure 8.26).

OCH2Ph OH ½123 F F F

Stable in THF

Figure 8.26

Reactions with fluoride ion: With the exception of CF3OH (see the next section), fluorinated alcohols of the type RFCF2OH are not known [124] but complexes of þ K, Rb, Cs, Ag or ðC2H5Þ4N fluorides with hexafluoroacetone have been isolated [125, 126], following from the earlier isolation of some similar complexes with carbonyl fluoride [127]. These complexes have been reasonably formulated as fluorinated alkoxides (Figure 8.27), but the use of these salts in synthesis is often difficult because the complexes may also act as fluoride-ion donors [128]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 252

252 Chapter 8

MF + (CF3)2CO (CF3)2CFOM

Figure 8.27

More stable complexes have been obtained by using ‘TAS’ fluoride [129], and X-ray data on the salt (8.28A) are quite revealing (Figure 8.28). Carbon–fluorine bonds are exceptionally long in CF3O while the C–O distance is quite short; these observations have been advanced as evidence for negative hyperconjugation (Chapter 4, Section IIIB) (Figure 8.29).

+ − THF − + COF2 + (Me2N)3S Me3SiF2 CF3O (Me2N)3S −75C ½129 'TAS' fluoride 8.28A

Figure 8.28

− − CF3 O F CF2=O

Figure 8.29

Other stable alkoxide salts have been prepared [130] using hexamethylpiperidinium fluoride, and X-ray structural data for these systems are also consistent with negative hyperconjugation (Figure 8.30).

− ½130 (CF3)2C O (CF3)2CF O − = N F N

Figure 8.30

Reaction of a mixture containing hexafluoroacetone and caesium fluoride with allyl bromide or chloride occurs readily [131, 132] (Figure 8.31) but the mixture does not react with trimethylchlorosilane [131]. i (CF3)2CO + CH2=CHCH2Br CH2=CHCH2OCF(CF3)2 ½131, 132 i, CsF, Diglyme, 55C, 12hr

Figure 8.31

Difficulties undoubtedly arise because perfluorinated alkoxides are very weak nucleophiles but they are also potentially fluoride-ion donors and therefore, at the temperatures necessary for reaction, the alkoxides are probably significantly dissociated and conse- 1 quently undergo competing side-reactions. Perfluoro-esters RFCO2RF have been made [133] in reactions using ðRFÞ2CFOM carried out at low temperatures, with the products being isolated before they are allowed to warm up. Otherwise, fluoride ion attacks the ester itself, giving the reverse reactions, because (it must be remembered) the corresponding alkoxide ion RFO will be quite a good leaving group in a nucleophilic displacement process (Figure 8.32). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 253

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 253

RFCOF − (CF3)2CO + MF RFCO2CF(CF3)2 + F ½133 −78C

Figure 8.32

Likewise, perfluoroalkoxytriazines may be isolated at low temperatures [134] (Figure 8.33). R R N F N F 134 KF ½ (CF3)2CO Cl NN NN

RF = OCF(CF3)2

Figure 8.33

Perfluoroalkoxyanions are also generated by reaction of fluoride ion with acid fluorides and with epoxides (see Section IIIB, below). Reaction of the ðCF3Þ2COCsF complex with tetrafluoroethene [135] gives alkoxide 8.34A, not a carbanion 8.34B (Figure 8.34). In the presence of iodine, however, ethers are formed [126], indicating the formation of intermediate hypoiodites, RFOI (Figure 8.35).

− CF2=CF2 + F + (CF3)2CO ½135

− CF3CF2 (CF3)2CFO

(CF3)2CO CF2=CF2

− CF CF C(CF ) O 3 2 3 2 (CF3)2CFOCF2CF2 etc

8.34A 8.34B

Figure 8.34

CF2=CF2 + (CF3)2CO + KF + I2 (CF3)2CFOCF2CF2I ½126

ca. 98% yield 17% conversion

Figure 8.35

A hypochlorite has been obtained by reaction of ðCF3Þ3COH with ClF at low temperature [136]. In an analogous way, hypofluorites may be formed by reactions of intermediate perfluoroalkoxide ions with elemental fluorine; this chemistry is being exploited in industry for the manufacture of important monomers [137] (Figure 8.36). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 254

254 Chapter 8

i, ii iii CO CF3OF CF3OCFClCF2Cl ½137

i, ii ∆ CF OCF CF CF3CF2CF2OF CF3CF2CF=O 3 = 2

iii

C3F7OCFClCF2Cl C3F7OCF=CF2

i, F2 ii, MF (M = K, Rb, Cs), −78C iii, CFCl=CFCl

Figure 8.36

It appears that hypofluorite formation occurs by nucleophilic attack via the very weakly nucleophilic perfluoroalkoxide ions on elemental fluorine, regenerating fluoride ion, because the process is catalytic in alkali-metal fluoride (Figure 8.37).

F + RFCF=O RFCF2O + F F RFCF2OF + F

Figure 8.37

Hypofluorites are also formed by similar catalytic formation of perfluoroalkoxide ions from the corresponding oxiranes (Figure 8.38).

O F2 ½137 CF3CF CF2 F CF3CF2CF2OF F

Figure 8.38

The chemistry of fluorinated 1,3-diketones has been reviewed [138].

C Perfluoro-alcohols 1 Monohydric alcohols

1 The 2CF2OH system is thermodynamically unstable, by an estimated 80160 kJmol , with respect to formation of C5O and hydrogen fluoride. Nevertheless, a remarkable low-temperature synthesis of trifluoromethanol [139] led to a system that is sufficiently kinetically stable at low temperatures to be characterised, and a gas-phase IR spectrum has been obtained (Figure 8.39).

−120C 139 CF3OCl + HCl CF3OH + Cl2 ½

Figure 8.39 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 255

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 255

The driving force for forming C5O via elimination of hydrogen fluoride is much reduced in strained systems, and therefore the alcohols in Figure 8.40 are more stable [140]. Systems of the form RFCH2OH are, however, quite stable and are extremely useful solvents [141] because of their high polarity [142]. OH O ½140 HX X

X = F, Cl, Br, I

Figure 8.40

Perfluoro-t-alcohols are quite stable and are very strongly acidic; for example, compare

ðCF3Þ3OH and ðCH3Þ3OH which have pKa values of 5.4 and 19.0 respectively [143, 144]); see Chapter 4, Section IIA. Perfluoro-t-butanol is obtained most easily from hexafluoroacetone when it is heated with caesium fluoride in diglyme containing traces of moisture [145] (Figure 8.41). The first stage involves a carbanion transfer and can be formulated in a manner similar to the benzil–benzilic acid rearrangement although it occurs, in this case, by an intermolecular process (Figure 8.42).

i ii (CF3)2CO CF3COF + (CF3)3COCs (CF3)3COH ½145 34% i, CsF, 150 C, Diglyme. ii, H2SO4

Figure 8.41

δ+ δ+ Cs δ− Cs δ− CsF O O O O (CF3)2CO CF CF C CF3 3 CF C(CF3)3

CF3 CF3 CF3

Figure 8.42

Some other routes to fluorinated alcohols are shown in Figure 8.43a. Trifluoroethanol has become a much-used ‘building-block’ [150] for a wide range of synthetic procedures (see also Chapter 6, Section II) (Figure 8.43b), and sigmatropic rearrangements have been exploited to move the fluorine labels to ‘internal’ sites [151].

2 Dihydric alcohols

Perfluorinated ketones form stable hydrates, ðRFÞ2CðOHÞ2, and these diols are very acidic. Hexafluoroacetone hydrate is known to be a very good solvent and is particularly useful for certain polymers [112, 152]. Perfluoropinacol may be obtained from hexafluoroacetone by photolytic reduction (Figure 8.44), whilst classical reduction with magnesium amalgam gives only low yields [112]. The same pinacol is also obtained by heating 8.44A, which is produced as shown in Figure 8.44 [153]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 256

256 Chapter 8

i, ii iii CCl3Li + (CF3)2CO (CF3)2C(CCl3)OH (CF3)3OH ½146 50% 60% i, THF, −100C ii, H2SO4 iii, SbF5

i CF CH OH CF3CH2Cl + H2O 3 2 ½147

i, 400−500C, Catalyst

hν CH3OH + CF2=CF2 HCF CH OH 2 2 ½148

(CF3)2C CH2 HX XCH2C(CF3)2OH ½149

X = FSO2O, CF3SO2O, Cl, I

Figure 8.43a

OTs OTs i ii ½150 CF3CH2OTs CF2=C CF2=C Li

Li BR3

i, n-BuLi 1,2 shift ii, R3B iii, CuI, HMPA OTs R iii CF2=C CF2=C

Cu BR2

151 OMEM ½ i, ii F iii F OMEM CF3CH2OMEM F F

OH O

MEM = CH2OCH2CH2OCH3

F OMEM F OMEM O F O

− i, LDA, THF, 78 C; ii, EtCHO; iii, Hg(OAc)2, Ethyl vinyl ether, reflux

Figure 8.43b Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 257

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 257

(CH ) CO + (CF ) C(OH)C(OH)CF ) i 3 2 3 2 3 2 ½112

(CF3)2CO iv ii CF 3 CF3 F3C F3C

CF3 iii CF3 CF3 CF3 O O O O ½153 P P EtO OEt HO OH OEt OH

ν 8.44A i, (CH3)2CHOH/h ii, P(OC2H5)3 iii, H2SO4 iv, H2O, Boil

Figure 8.44

Diols may also be used in free-radical additions to fluorinated alkenes [154] (Figure 8.45). OH HO RFH ½154 i CF3CF=CF2 83%

HO RFH OH i, γ rays, rt

RFH = CF3CFHCF2

Figure 8.45

3 Alkoxides The formation of polyfluoroalkoxyanions from perfluoroketones was discussed, along with other addition reactions of perfluoroketones, in Section IB, Subsection 2; similar anions can also be generated from acid fluorides and epoxides (oxiranes), as represented in Figure 8.46.

1 1 F + RFR FCO RFR FCFO

F + RFCOF RFCF2O

O O 1 1 F + RFFC CFR F RFCF2CFR F

Figure 8.46

Examples of fluoride-ion-initiated reactions involving perfluorinated epoxides are shown in Figure 8.47 [155–158]. Hexafluoropropene oxide (HFPO) and tetrafluoroethene oxide will polymerise under certain conditions in the presence of fluoride ion. The process involves an extending alkoxide and it is terminated by elimination of fluoride ion to give Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 258

258 Chapter 8 an acid fluoride. This reactive end-group may be converted by a variety of procedures [156] into the well-known stable fluids Krytoxt and Fomblint [159].

O F CCF F 2 2 CF3COF [CF3CF2O ] C2F5O(CF2CF2O)nCF2COF ½155 (R4NF)

CF (CF ) CO 3 ½155, 156 F 3 2 CF2CF2 [CF3CF2] CF3CF2C O

CF3

HFPO

CF3CF2C(CF3)2OCF(CF3)COF [CF3CF2C(CF3)2OCF(CF3)CF2O] ½158

O i −F F3CFC CF2 (CF3CF2CF2O) CF3CF2COF HFPO i, MF, Tetraglyme HFPO

− CF3CF2CF2O[CF(CF3)CF2O]nCF(CF3)COF n = 1 4

Figure 8.47

D Fluoroxy compounds [137]

An interesting series of compounds RFOF [160, 161] has been synthesised and found to be reasonably stable; for example, the O2F bond energy in CF3OF has been calculated to be 183 kJmol1 [162]. Compounds containing more than one fluoroxy group may be obtained but these can be very unstable [163, 164]; indeed, all fluoroxy compounds should be treated with caution. Fluoroxy derivatives of hydrocarbons are less stable, probably due to easy elimination of hydrogen fluoride from these systems. Some syntheses of fluoroxy derivatives are given in Figure 8.48. Fluoroxy compounds are very strong oxidising agents [169]; this may be attributed to the ‘positive halogen’ character of fluorine in an O2F group. Such an approach [170–172] led to the application of CF3OF as a selective electrophilic fluorinating agent, but the hazards associated with this system have precluded its development as a laboratory reagent. For example, the system is prone to explosive reaction with organic reagents. In fact, a complex interplay of radical and polar intermediates has been indicated for reactions of hypofluorites with electron-rich alkenes [137]. Some hypofluorites may be susceptible to spontaneous exothermic decomposition (Figure 8.49) but, in spite of this, industry has mastered the application of intermediate Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 259

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 259

i F 2 ½165, 166 CO + F2 (COF2) CF3COF

i, Cu Tube, 350C

CsF (CF3)2CO + F2 (CF3)2CFOF 98% ½167 −78C

CsF CF (OF) 99% CO2 + F2 2 2 ½168 −78C

−20C (CF3)3OH + F2 (CF3)3COF ½169

iii ½170 CH3OH + F2 [CH3OF] CF3CFClOCH3

− i, CH3CH2CN, 40 C, 1hr − ii, CF2=CFCl, 75 C to rt

Figure 8.48

−184C ∆ 0 − −1 CF2(OF)2 CF4 + O2 H = 360 kJ mol N2

Figure 8.49 hypofluorites to make new perfluorinated ethers and industrially significant monomers. Indeed, this chemistry illustrates well the view that an essential part of the skill of science is to be able to operate potentially hazardous procedures while ensuring the complete safety of the operators. For example, addition of RFOF to fluorinated alkenes (Figure 8.50) has been exploited for the synthesis of important monomers (Figure 8.51) for copolymerisation (See Figure 8.78, page 269).

− 2 CF2=CF2 + CF2(OF)2 CF2(OCF2CF3)2 80 90% ½173

Figure 8.50

Additions of CF3OF to sulphur dioxide and trioxide [165], at high temperatures, and to carbon monoxide [174], on photolysis, have been described (Figure 8.52).

E Perfluoro-oxiranes (epoxides) [156, 158, 175] Some reactions of epoxides with fluoride and perfluoroalkoxide ions were referred to in Section IB, Subsection 2 (above), and the importance of polymers of these systems was stressed. There are numerous publications or patents concerning the synthesis of these Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 260

260 Chapter 8

i − i, ii FSO2CF2COF FSO2CF2CF2O FSO2CF2CF2OF ½137

iii

FSO2CF2CF2OCF=CF2 FSO2CF2CF2OCFClCF2Cl

i, CsF; ii, F2; iii, CFCl=CFCl

Figure 8.51

CF3OF + SO3 CF3OOSO2F + SO2FOOSO2F ½165

ν h 174 CF3OF + CO CF3OCOF 86% ½

Figure 8.52 compounds [156, 158]. The most general process involves reaction of a fluoroalkene with alkaline hydrogen peroxide at low temperatures [176–178]. This method may be used for oxidising hexafluoropropene and higher fluoroalkenes, as well as for cyclic systems (Figure 8.53), but not for tetrafluoroethene, in which case various procedures involving direct reaction with oxygen have been employed [156, 179, 180] (Figure 8.54). It is useful to note that some of the products of these reactions, especially those involving tetrafluoroethene, may be extremely hazardous [179].

O i F F ½178 CF3CF=CF2 25% CF3 F − i, KOH, H2O/CH3OH, 30%H2O2, 78 C

Figure 8.53

O F F CF CF + O (containing O ) + 2= 2 2 3 CF2CF2O 181 F F n ½ 46% 18%

Figure 8.54

Bleaching powder has proved to be a very effective reagent for various epoxidations [158, 182–184], and lithium t-butyl peroxide has been used as an epoxidising agent [185] with electron-deficient alkenes (Figure 8.55). A very unusual, but efficient, rearrangement of the dioxirane 8.56A to a diether 8.56B occurs on heating, but the mechanism of the process is uncertain [186] (Figure 8.56). An interesting use of trimethylamine as catalyst in combination with m-chloroperben- zoic acid (mCPBA) or iodobenzene has been reported and is effective with alkenes having perfluoroalkyl groups attached to the double bond [187] (Figure 8.57). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 261

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 261

Cl O ½158, 182184 CF3CF2 CF CF3CF2 CF 3 OCl 3

F3C CF2CF3 F3C CF2CF3

Z + E

CF CF O 3 2 CF3 74%

F3C CF2CF3 Z : E = 1:1

F C 3 CF3 F3C O O CF3 F3C CF3 i ½186 F3C F FCF3 F3C CF3

F O CF3 O F3C F F O F

O F3C CF3 F F i, t-BuOOLi, THF, −78C to rt O F3C CF3

Figure 8.55

F CF3 F O CF3 CF CF 3 i 3 F3C ½186 F3C 8.56A F3C F F3C O F

F3C CF3

i, t-BuOOLi, THF, −78C to rt O O ii, Sealed tube, 220 C, 19 days 8.56B

F C CF3 3 F F 96%

Figure 8.56

Fluorinated oxiranes undergo a variety of ring-opening reactions with nucleophiles, the most simple of which is formation of an acid fluoride. In most cases, terminal oxiranes open to give an acid fluoride 8.58B rather than a ketone [156, 158] (Figure 8.58) and this specificity of a ring opening is a puzzling feature; it may well be that, in forming an acid fluoride, the strongest set of carbon–fluorine bonds is produced because the 2CF2O Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 262

262 Chapter 8

F CF3 ½187 O

m-ClC6H4CO3H Me3N RF RF

F CF3 m-ClC6H4CO2H Me3N-O

RF RF

RF = CF(CF3)2

Figure 8.57

O O Nuc ½156, 158 F3C F R CFCF O RFCFCF2Nuc F 2 F F − − − −F F

R CFCOF RFCOCF2Nuc F 8.58A Nuc 8.58B

Figure 8.58 group is isoelectronic with 2CF3. This would then be consistent with the well-known order of decreasing carbon–fluorine bond strengths in the series 2CF3 > 2CF22 >CF2; see Chapter 7, Section IB. Ring-opening oligomerisation of the oxirane derived from hexafluoropropene (see Figure 8.47) forms the basis of the production of Krytoxt fluids (DuPont Co.), with end-group stabilisation by direct fluorination etc. Clearly, achieving high-molecular- weight material by this process is not easy. For comparison, oxetanes are oligomerised in an analogous way to give intermediate polyfluoro-polyethers that are then further fluorinated to give perfluoro-polyethers in the process for the production of Demnumt fluids (Daikin Co.) [188] (Figure 8.59). F F ½188 i CF2=CF2 + (CH2O)n F F O H H

iii FCFCF CF O 2 2 2 F FCH2CF2CF2OCH2CF2COF n n-1

i, HF ii, e.g. CsF − iii, F2, 100 120 C

Figure 8.59 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 263

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 263

Examples of other ring-opening reactions are illustrated in Figure 8.60.

F O F − i − − + F [CF3CF2O] CF3COF + F ½179 FF i, KF, 80C, 4hr

O F3C F i ½189 (CF3)2CFCOF 97% F F i, (CH3)3N, 100 C, 30hr (CH3)3N − F

− CF3CFCF2O (CF3)2CCOF + + N(CH ) N(CH3)3 3 3

O F3C F CH3OH + [CF3CF(OCH3)COF] ½178 F F

CH3OH

CF3CF(OCH3)COOCH3 96%

Figure 8.60

So far, the only case where attack occurs at the CF2 position in hexafluoropropene oxide involves reaction with butyl lithium [156] (Figure 8.61). O F3C F + ½156 C4H9Li [CF3C(O)CF2C4H9] F F i, ii i, BuLi, ii, H+

CF3C(C4H9)(OH).CF2C4H9

Figure 8.61

Ring opening with a strong protonic acid gives the corresponding alcohol [190] and this is consistent with the idea that an intermediate carbocation, 8.62A, would be more stable than 8.62B, where CF3 groups would certainly raise the energy of an adjacent carbocation centre (Figure 8.62). Conversely, cleavage with a Lewis acid catalyst gives a ketone [191, 192] (Figure 8.63). These are interesting reactions because they involve a 1,2-fluorine shift to a positive centre (Figure 8.64), a process that is, of course, very well known for hydride shifts. The conversion of hexafluoropropene oxide to hexafluoroacetone is probably the Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 264

264 Chapter 8

H + O + F3C F + (CF3)2CCF2OH (CF3)2C(OH)CF2 ½190 F3C F 8.63B 8.62A

H + O F3C F 250C +HF (CF3)3COH 64hr F3C F

Figure 8.62

i O F F ½191 O

− i, Al2O3, 150 300 C

O i C5F11 F C5F11CO.CF3 ½192 F F

i, SbF5, 150 C, 18hr

Figure 8.63

Acid Acid O O CC

F F

Figure 8.64 preferred industrial route to this compound (N.B. The ketone is much more toxic than the epoxide [67].) Carbene formation on pyrolysis of epoxides was discussed earlier: see Chapter 6, Section IIIA.

F Peroxides [193, 194] Some examples of formation of fluorinated peroxides are given in Figure 8.65. It has been demonstrated by labelling studies that, in reactions with caesium trifluoromethoxide, ring-opening occurs by attack at the peroxide bond [197] (Figure 8.66). A direct, but mechanistically obscure, synthesis of trifluoromethyl hydroperoxide has been developed, involving the decomposition of the adduct formed between hexafluoroacetone and hydrogen peroxide [107] (Figure 8.67). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 265

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 265

AgF2 2 CO + 3 F2 CF3OOCF3 ½194

2 (CF3)3COH + ClF3 (CF3)3COOC(CF3)3 ½194

½194 C3F7COCl + t-BuOOH C3F7C(O)OOt-Bu

O F O FC(O)OF + CsF CF2 OF ½195 F O

F3C O (CF3)2C(OLi)2 + F2 O ½196 F3C

Figure 8.65

13 F 13 O O 13 COF2 CF3O CF3OOC(O)F ½197 FF A −F

nA 13 13 CF3OOCF2O CF3O(OCF2O)nOC(O)F

n = 1-3

Figure 8.66

(CF3)2C(OH)OOH CF3OOH + CO2 + O2 ½107

Figure 8.67

Also, intermediate peroxides are formed in the oxidation of perfluorinated alkenes, e.g. in the photo-oxidation of perfluoroethene and perfluoropropene for the formation of Fomblint (Ausimont Co.) perfluoro-polyether fluids [198, 199].

II SULPHUR DERIVATIVES [5, 7, 200, 201] A Perfluoroalkanesulphonic acids Trifluoromethanesulphonic acid is commercially available and is the most readily obtained member of this series by electrochemical fluorination [202–205] (Figure 8.68), since the yields of perfluoroalkanesulphonic acids decrease as the size of the alkyl group increases. The acids are very thermally stable; longer straight-chain derivatives are surface-active [206]. This combination of properties appears to be responsible for the application of Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 266

266 Chapter 8

Eletrochemical CH SO Cl CF SO F CF SO OH 87% ½203 3 2 Fluorination 3 2 3 2

Figure 8.68 these systems as the basis for textile treatment leading to grease resistance. However, the discovery of traces of perfluoro-octane sulphonic acid in the blood of workers in the industry has caused the removal of these products from the market. Clearly, the long-term stability of sulphonamides derived from perfluorinated sulphonic acids is not as complete as had previously been believed. Of course, the most outstanding property of perfluoroalkanesulphonic acids is that they are extremely useful strong acids, in the ‘super acid’ range [207, 208]; compare the Hammett acidity functions ðH0Þ: CF3SO2OH (13.8); FSO3H(15.1); FSO3H=20%SbF5, ‘Magic Acid’ (20); and H2SO4 (11.1). Furthermore, the extreme electron-withdrawing capacity of the CF3SO2 group [5, 209] is such that ðCF3SO2Þ2NH is the most acidic amide known [4] and it leads to systems with remarkable C2H acidity, e.g.

ðCF3SO2Þ22CH2ðpKa ¼1Þ is more acidic than CF3CO2HðpKa ¼ 0:52Þ. Consequently, perfluoroalkanesulphonic acids are outstanding Friedel–Crafts catalysts [208, 210]. More- over, esters of trifluoromethanesulphonic acid, i.e. ‘triflates’, are super leaving groups in nucleophilic displacement reactions and, as such, are extremely important in both mechanistic and synthetic organic chemistry [208]. Significantly, the first example of generating an aryl cation utilised both a triflate leaving group and the ionising ability of trifluoroethanol as solvent [211] (Figure 8.69).

OSO2CF3 OCH2CF3 X X X X X X ½211 i

i, 120 C, K2CO3, CF3CH2OH X = SiMe3

Figure 8.69 Moreover, the outstanding leaving-group ability of the nonofluorobutylsulphonyl group, ‘nonaflate’, allows the conversion of hydroxyl to fluorine in some cases using n-C4F9SO2F [212], which itself is obtained by electrochemical fluorination (Figure 8.70). Triflate salts are important catalysts because the anions are poorly co-ordinating [214, 215] (Figure 8.71).

i 45% C4F9SO2F ½213 S O O i, HF, E.C.F.

ii ½212 Ph(CH2)3OH Ph(CH2)3F 79%

ii, n-C4F9SO2F

Figure 8.70 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 267

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 267

i ii Me SiCH Li [(CF SO ) CLi] 3 2 CH2(SO2CF3)2 3 2 3 ½214

M2O3 i, (CF3SO2)2O, pentane, 0 C − ii, t-BuLi (2 equiv), (CF3SO2)2O, 78 C [(CF3SO2)3C]3 M

M = Y, Sc

Figure 8.71

Trifluoromethyltriflate can be made easily but nucleophilic attack does not occur on carbon and therefore the system does not act as a source of ‘electrophilic CF3’ [216, 217] (Figure 8.72). Nuc i Nuc-CF ½216 (CF3SO2)2OCF3SO2OCF3 3 90% i, Cat. SbF4(OSO2CF3)

Figure 8.72

Trifluoromethanesulphonic acid forms a very stable crystalline hydrate [205, 218] and reacts vigorously with alcohols, ethers and ketones. Oxonium salts are formed and further reaction may occur on heating (Figure 8.73).

CF3SO2OH + (C2H5)2O (C2H5)2OH(CF3SO3)

Figure 8.73

Perfluoralkanesulphonyl chlorides may be obtained from the corresponding iodides [219] (Figure 8.74), and they will act as a source of perfluoroalkyl radicals under pyrolysis or photolysis, by losing sulphur dioxide [220] (Figure 8.75). i n-C4F9I n-C4F9SO2Cl 80% ½219

i, SO2,Cl2,DMF,Ni

Figure 8.74

∆ CF3SO2Cl CF3Cl + SO2 ½221

∆

O (CH3)3CN=O (CH ) C N CF CF3 3 3 3

R Cl i F ½220 RFSO2Cl + SO2

i, hν, or peroxides

Figure 8.75 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 268

268 Chapter 8

Trifluoromethyl radicals may also be generated by electrolysis of salts of trifluoro- methanesulphinic acid [222] (Figure 8.76).

−1e CF3SO2 K CF3SO2 CF3 + SO2 ½222 E = 1.05V +1e E = −0.8v

SO2

OMe OMe OMe

CF3

OMe OMe OMe

CF3 Total yield = ca.47%

Figure 8.76

Sulphur-containing compounds are also obtained from reactions involving fluoroalkenes. Polyfluoro-b-sultones are produced in reactions of fluoroalkenes with freshly distilled sulphur trioxide [223, 224]; these sultones have a varied chemistry, including nucleophilic ring opening to give sulphonic acid derivatives (Figure 8.77) (see also Chapter 7, Section IID). This ring-opening reaction is important in the synthesis of co-monomers for the production of Nafiont-type (DuPont) membranes [37] (Figure 8.78). Resins of this type have allowed membrane cells to displace the ill- famed mercury cells for chlor-alkali production. Also, Nafiont resin is a useful strong acid and has been developed for solid-phase catalytic processes [225–227] (Figure 8.79).

F F F F CF2=CF2 + SO3 61% ½223 O SO2

F F CO H F F 1, NaOH 2 ½223 F2C O SO 2 2, Ion Exchange SO2OH

F F F F

F F i F F CO.FCF2SO2F ½37, 223, 224

OSO2 O SO2

N(C H ) F (C2H5)3N F 2 5 3 i, F , (C2H5)3N

Figure 8.77 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 269

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 269

FCOCF2SO2F + F OCF2CF2SO2F ½37

CF3 O F i i, F F ∆, Na CO ii, 2 3 FCOCF(CF3)OCF2CF(CF3)OCF2CF2SO2F iii, CF2=CF2 iv, Hydrolysis ii

CF2=CFOCF2CF(CF3)OCF2CF2SO2F iii

iv Co-polymer Membrane

Figure 8.78

R R

i + n-BuONO2 15-98% ½225

NO i, Nafion H 2

i ½226 C6H6 + CH2=CH2 C6H5C2H5

i, Nafion H

i ½227 RSO3H + ArH RSO2Ar R = alkyl or aryl 30-82%

i, Nafion H, Reflux

Figure 8.79

Salts of polyfluoroalkanesulphonic acids may be obtained directly from fluoroalkenes simply by reaction of aqueous sodium sulphite in an autoclave, in some cases in the presence of benzoyl peroxide [228–230] (Figure 8.80).

120C CF CF + NaHSO 2= 2 3 CHF2CF2SO3Na ½228

i CF3CF=CF2 + NaHSO3 CF3CFHCF2SO3Na 64% ½229 i, (C6H5COO)2, 120 C

Figure 8.80 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 270

270 Chapter 8

B Sulphides and polysulphides A general method for making perfluoroalkyl sulphides and perfluoroalkyl polysulphides involves heating a perfluoroalkyl iodide with sulphur in a sealed vessel, as illustrated in Figure 8.81. 243C Sx + (CF3)2CFI [(CF3)2CF]2S 11% + [(CF3)2CF]2S2 34% ½231

+ [(CF3)2CF]2S3 18%

Figure 8.81

Many interesting sulphides have been formed [7, 200, 201] by reactions of sulphur with other iodides or certain di-iodides, or by other procedures [232, 233] (Figure 8.82).

120C CF3SSH + CF3SCl CF3SSSCF3 ½232

Figure 8.82

A series of cyclic sulphides is produced in reactions of fluoroalkenes and fluoroalkynes with sulphur or sulphur halides [234–238]; some examples have been discussed in Chapter 7 (Figure 8.83). S S N2 S Sx + CF2=CF2 ½234 445C F F S S S S 44% 10%

300C 10hr

F 56% S

Figure 8.83

The reaction between tetrafluoroethene and sulphur is activated by iodine, presumably via the intermediate formation of a di-iodide [236] (Figure 8.84).

S S + CF CF + I x 2= 2 2 F F ½236

S S

39%

Figure 8.84

Direct syntheses of fluorocarbon–sulphur compounds from non-fluorinated starting materials are limited, but bis(trifluoromethyl) disulphide may be obtained from carbon Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 271

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 271 disulphide using iodine pentafluoride [239], or from thiophosgene using sodium fluoride [240] (Figure 8.85).

IF5 (CF ) S (CF ) S CS2 3 2 2 3 2 3 ½239 195C 76% 7%

i CSCl2 (CF3)2S2 + CS2 ½240 37% i, NaF, Sulpholan, 245C

Figure 8.85

Fluorination of thiophene and derivatives and of 1,4-dithiane [241] with KCoF4 gives a series of fluorinated derivatives. Chlorine–fluorine exchange in sulphides is also possible in some cases [242] (Figure 8.86).

PCl5 SbF5 ½242 CH3SCH3 CCl3SCH3 CF3SCH3

Figure 8.86

Base-induced [243] addition of thiols to fluoroalkenes yields polyfluoroalkyl sulphides, which have also been further fluorinated (Figure 8.87).

i ii 243 CH3SH + CF2=CFCl CH3SCF2CFClH CH3SCF=CFCl ½ 90% − i, NaOCH3, 5 70 C Cl2 ii, (CH3)2SO, KOH iii iii, SbF3/SbF5 CH3SCF2CF3 CH3SCFClCFCl2

Figure 8.87

Reaction of arylmagnesium halides with trifluoromethanesulphenyl chloride, or simply condensation of the latter with aromatic systems, has been exploited successfully [244, 245] (Figure 8.88).

NaF CCl3SCl CF3SCl Sulpholan ½240

Et2O ½244 PhMgBr + CF3SCl PhSCF3 52%

PhN(CH3)2 CF3SCl p-CF3SC6H4N(CH3)2 58% ½245

Figure 8.88 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 272

272 Chapter 8

C Sulphur(IV) and sulphur(VI) derivatives Electrochemical fluorination of dialkyl sulphides leads to sulphur(VI) derivatives (see Chapter 2, Section III), and oxidation of sulphur also occurs [246] in cobalt fluoride or direct fluorination reactions (Figure 8.89).

Electrochemical (CH ) S CF3SF5 + (CF3)2SF4 ½246 3 2 Fluorination

CoF3 ½247 CH3SH CF3SF5 250−275C

F2/N2 CS CF3SF5 CF3SF3 etc. ½248 2 48C

Figure 8.89

An effective route to some sulphur(IV) compounds involves fluoride-ion-initiated reactions of a fluoroalkene with sulphur(IV) fluoride [249] (Figure 8.90). Alternatively, similar reactions with sulphuryl fluoride give perfluorodialkylsulphones or perfluoroalk- anesulphonyl fluorides [250] (Figure 8.91).

CsF CF3CF=CF2 + SF4 (CF3)2CFSF3 + [(CF3)2CF]2SF2 ½249 100C

Figure 8.90

CsF CF2=CF2 + SO2F2 (C2F5)2SO2 83% ½250 100C

CsF CF3CF=CF2 + SO2F2 (CF3)2CFSO2F etc Diglyme, 100C

Figure 8.91

It has been shown that perfluoroalkylsulphur(II) compounds can be oxidised to corresponding sulphur(IV) and sulphur(VI) compounds [251–254] (Figure 8.92). Free-radical reactions of SF5Br provide a useful approach to sulphur(VI) compounds [256] (Figure 8.93).

D Thiocarbonyl compounds The most simple member of this class of compounds is thiocarbonyl fluoride [257, 258], which is obtained from the thiophosgene dimer 8.94A, and then pyrolysis of 8.94B, to the corresponding fluoro monomer [233] (Figure 8.94). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 273

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 273

−78C CF3SRF + ClF CF3SF2RF + Cl2 ½251

RF = CF3, C2F5, n-C3F7

F , −196C 2 (CF ) SO ½255 (CF3)2S (CF3)2SF2 3 2 C2F6

i, ii, iii Ar2S2 ArSF5

− ½252254 Ar = i, F2/N2(1:9 v/v), MeCN, 5 C

ii, F2, CH3CN, Micro-reactor NO2 F

− Ar = iii, AgF2, CF2ClCFCl2, 60 130 C, Cu

NO2

Figure 8.92

ν h AgBF4 SF5Br + CF2=CFPh SF5CF2CFBrPh SF5CF2CF2Ph ½256

Figure 8.93

F S F Cl S Cl i ii 233 2 CF2=S ½ Cl S Cl F S F 8.94A 8.94B i, SbF3/90 C ii, 457−500C

Figure 8.94

A general route to perfluorothioketones has been developed [258] involving reaction of appropriate bis-organomercurials with sulphur vapour (contact at lower temperatures gives polysulphides) (Figure 8.95). 445C (CF3)2CFHgCF(CF3)2 + S (CF3)2C=S + HgF2 ½258 60%

Figure 8.95

Thioketones may also be obtained by heating perfluoroalkyl iodides with phosphorus pentasulphide [258] (Figure 8.96). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 274

274 Chapter 8

i C2F5CFICF3 (C2F5)CF3C=S ½258

i, P2S5, 550 C

Figure 8.96

Hexafluorothioacetone does not readily form a hydrate, but dimerises readily, particularly in the presence of base; high temperatures are then required to reverse the process [258] (Figure 8.97).

Base F3C S CF3 2(CF3)2CS ½258 600 C F3C S CF3

Figure 8.97

The dimer of hexafluorothioacetone may also be obtained from hexafluoropropene [259] and the former has now been used in a route to a sulphene [260] (Figure 8.98).

− − Sx − CF3CF=CF2 + F (CF3)2CF (CF3)2CFS ½259, 260

SO F3C S CF3 F3C 2 CF3 (CF3)2C=S F3C S CF3 F3C S CF3

i, Quinuclidine i

(CF3)2C=SO2

Figure 8.98

Bistrifluoromethylthioketene has been obtained as a monomer; that is very unusual, since thioketenes generally dimerise [261] (Figure 8.99).

EtOOC COOEt i S (CF3)2C C(CF3)2 70% ½261 EtOOC COOEt S

750C/1mm − i, SF4, HF, 125 200 C

(CF3)2C=C=S 70%

Figure 8.99

The nickel–dithiolene complex (Figure 8.100) is considered as a potential means of recovering ethene, because it is capable of binding ethene reversibly by a redox-switch process [262]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 275

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 275

F3CFCF3 3C CF3 ½262 SS S S Ni CH2=CH2 Ni S S S S F3C CF3 F3C CF3

Figure 8.100

III NITROGEN DERIVATIVES A Amines Primary and secondary perfluoroalkylamines are relatively unstable systems with respect to the elimination of hydrogen fluoride, although the situation is not as extreme as that obtained with the corresponding alcohols. Consequently, CF3NH2 has been characterised when generated at low temperatures [139] (Figure 8.101).

Base ½139 CF3NCl2 + HCl CF3NH2.HCl CF3NH2

Figure 8.101

Ammonia reacts readily with fluoroalkenes (see Chapter 7) but amines are not isolated from these reactions [230] (Figure 8.102) −2HF CF2=CF2 + NH3 HCF2CF2NH2 HCF2CN ½230

R N R

R = CF2H R

Figure 8.102

Addition of hydrogen fluoride [263, 264] to the imine CF3N5CF2 occurs and this secondary system is reasonably stable, allowing some further reactions to be carried out [263–265] (Figure 8.103). Other perfluorinated secondary amines have also been isolated [266–268].

CF3N=CF2 + HF (CF3)2NH ½263, 264

i ½264 (CF3)2NH (CF3)2N NO2

i, HNO3, (CF3CO)2O

Figure 8.103 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 276

276 Chapter 8

Systems in which the nitrogen is attached to carbon bearing only perfluoroalkyl groups, rather than fluorine, are particularly stable but weak bases; for example, perfluoro- t-butylamine is practically devoid of basic properties [269] (Figure 8.104). Diazotisation of the amine gives a mixture of the alcohol and the nitroso derivative [270] (Figure 8.105).

i ii (CF3)3CNO (CF3)3CNHOH (CF3)3CNH2 ½269

i, H2/Pd black; ii, HI, Red P

Figure 8.104

i (CF3)3CNH2 (CF3)3COH + (CF3)3CNO ½270

i, HNO2, 0 C

Figure 8.105

Fluoroalkylbenzylamines are obtained by the Lewis-acid-catalysed reactions of fluoro- alkylimines with aromatic compounds [270], and reactions also occur with alkenes [270, 271] (Figure 8.106).

i (CF3)2C=NH + CH3OC6H5 CH3O C(CF3)2NH2 ½270

i, AlCl3, 150 C

i (CF3)2C=NH + CH2=CHCH3 CH2=CHCH2C(CF3)2NH2 ½270 i, AlCl3, 100 C H i, ii N (CF3)2C=NH + CH2=CHCH=CH2 CF3 ½271

i, 100C, 13hr; ii, 150C, 6hr CF3

Figure 8.106

The fluoroalkylbenzylamines are characterised by their particular inertness [270], being devoid of the tendency towards oxidative decomposition that is generally charac- teristic of amines. In fact, oxidation of methyl will occur in preference to that of an amino group in these systems (Figure 8.107).

i H3C C(CF3)2NH2 HOOC C(CF3)2NH2 ½270

i, Na2Cr2O7, H2SO4

Figure 8.107 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 277

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 277

Perfluoro tertiary amines ðRFÞ3N are very inert systems and are more akin to perfluoroalkanes than amines. They are most directly obtained by electrochemical fluorination [272, 273] (see Chapter 2, Section III) and, as inert volatile fluids, they are used commercially as evaporation coolants for electronic apparatus.

Electron-diffraction studies on ðCF3CF2Þ3N have suggested susceptibility to attack at the CF2 positions by electrophiles [274].

B N–O compounds 1 Nitrosoalkanes Trifluoronitrosomethane may be obtained from photolysis of a mixture of trifluoroiodomethane and nitric oxide [275, 276] or from pyrolysis of trifluoroacetyl nitrite [277, 278] (Figure 8.108). hν, Hg CF3I + NO CF3NO 80% ½276

(CF3CO)2O + N2O3 CF3COONO 92% ½277, 278

190C

CF3NO + CO2 56%

Figure 8.108 Trifluoronitrosomethane is unusual among nitroso compounds in that it exists as a monomer that is deep blue and is therefore one of the few highly coloured simple polyfluoro compounds. On photolysis, a species derived from radical coupling is formed [276] (Figure 8.109). hν CF3NO CF3 NO ½276

CF3 CF3NO (CF3)2NO

(CF3)2NO CF3NO (CF3)2NONO + CF3

Figure 8.109

A series of nitroso rubbers has been formed by reaction of trifluoronitrosomethane with fluoroalkenes [279]; with tetrafluoroethene an oxazetidine and a 1:1 copolymer are obtained (Figure 8.110), the polymer being formed in preference at lower temperatures [279–281]. It is claimed that the mechanism involves electron transfer [282].

F3C NO CF3NO + CF2=CF2 F CF CF N(CF )O ½280 2 2 3 n

Figure 8.110 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 278

278 Chapter 8

2 Bistrifluoromethyl nitroxide

Bistrifluoromethyl nitroxide, ðCF3Þ2NO, is a stable purple gas and is of particular interest because, of course, nitroxides are stable free radicals. The nitroxide is prepared from bistrifluoromethylhydroxylamine [283] by reaction with, for example, silver oxide [284] (Figure 8.111) or potassium permanganate [285]. ν h HCl, H2O AgO CF3NO (CF3)2NONO (CF3)2NOH (CF3)2NO ½284 Quantitative

Figure 8.111

A range of products containing ðCF3Þ2NO groups may be obtained by addition to unsaturated compounds [286–289] (Figure 8.112). i (CF3)2NO + CF2=CFCF3 (CF3)2NOCF2CF(CF3)ON(CF3)2 ½287 i, 15 min., rt

i C F [ON(CF ) ] 288 F + (CF3)2NO 6 6-n 3 2 n ½

i, Sealed tube, 150C, 1−4hr n = 2,4,6

Figure 8.112

C Aza-alkenes In contrast to the limited chemistry of fluorinated amines, a large number of aza-alkenes and -dienes have been synthesised and these have an extensive chemistry. Some routes to aza-alkenes and -dienes [96] are illustrated in Table 8.5; some were included earlier (Section IB) in the variety of heterodienes that are obtained from hexafluoroacetone.

Table 8.5 Preparation of aza-alkenes and -dienes

Reaction Ref.

F3C NO i F CF3N=CF2 [280]

i, Si tube, 550C, 5mm

i (CF3)2NCOF CF3N=CF2 96% [290] i, Ni tube, 576C

i ii (C2H5)2NH (C2F5)2NF C2F5N=CFCF3 [291] i, Electrochem. fluorination; ii, (C5H5)2Fe

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 279

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 279

Table 8.5 Contd

Reaction Ref.

i (CF3)2C=NH + CCl4 (CF3)2CClN=CCl2 82% − i, AlCl3, 65 100 C; ii [292] ii, KF, Sulpholan

(CF3)2C=NCF3 + (CF3)2CFN=CF2 70 : 30 92% total

i F F F CF3CF2CF2CF=NCF3 [293] N N N i, Mild Steel, 400−600C CF3

i F CF CHFCF N CF CHFN CF CF CH NCF 3 2 3 3 = 2 3 = 3 [294, 295] i, Pt, 270−280C

i CBr2=NN=CBr2 CF3N=NCF3 92% i, AgF2, 100 C AgF 70 C [296] i CF2=NN=CFBr CF2=NN=CF2 33% overall i, AgF, 125C

HF NaF, 50C CCl2N=CCl2 CF2NHCF3 CF NCF [297] 2 2 = 3 2

N N i F F N N [298] i, CoF3.CaF2, 80C

N i N +F N F F F N N N i, CoF .CaF , 175C 3 2 [298]

N N + F2 N N F F F F N N N N

RF RF N N F i F 83% N N [299] RF RF i, CoF3.CaF2, 172 C RF = CF(CF3)2 Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 280

280 Chapter 8

Table 8.5 Contd

Reaction Ref.

i [300] CF3CONHNHCOCF3 CF3CCl=NN=CClCF3

i, PhNMe2.HCl, POCl3

[301] CF2=CFCF3 CF3CHFCF2N3 + CF3CF=CFN3 25% − Distil + − i, Et4N N3, 5 C F C F C 3 F 3 F

F N F N <5% 25%

Polyfluoroaza-alkenes are even more susceptible to nucleophilic attack than polyfluoroalkenes. Hydrolysis of CF25NCF3 occurs readily giving the isocyanate [302, 303], and a variety of reactions with nucleophiles have been recorded (Figure 8.113). i CF3N=CF2 CF3NCO 50% ½302

i, H2O, 20 C, 24hr i CF3N=CF2 + CH2=CHCH2OH CF3NHCO2CH2CH=CH2 52% ½304

i, aq KF, Et2O ½304 Et3N CF3N=CF2 + CH2=CHCH2OH CF3N=C(OCH2CH=CH2)2

Figure 8.113 Anions may be generated by reaction of fluoride ion with polyfluorinated aza-alkenes in a manner similar to that described earlier for fluoroalkenes (see Chapter 7, Section IIC, Subsection b) but, not being as readily available as fluoroalkenes, the chemistry is less well developed. Some examples of reactions induced by formation of aza-anions from aza-alkenes are shown in Figure 8.114. (CF ) NCF NCF 124, 305 i 3 2 = 3 ½ F CF3N=CF2 (CF3)2N ii (CF3)2COF

i, CF3N=CF2; − ii, CsF, COF2, 100 150 C, 2hr

100C, 15hr CF3N=CF2 + HgF2 [(CF3)2N]2Hg ½264

Figure 8.114 Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 281

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 281

F3CF3C N N i F ii F CF=NCF3 CF3N=CF2 ½306 2 F F F N CF CF3NCFF 3N F 3

−F i, CsF, Sulpholan, −23C

ii, CF3N=CFCF=NCF3 CF3

F N CF=NCF3 94% F F N

CF3N CF3

RF RF RF

i i F F F ½307 N N N

8.114ACs 8.114B

ii iii RF = (CF3)2CF

RF 8.114A + 8.114B Ratio 4:1

F i, CsF, Sulpholan; ii, CH3I; N iii, BF3.Et2O

CH3

Figure 8.114 Continued.

A remarkable rearrangement occurs in the conversion of 8.115A to 8.115B and a mechanism has been advanced for the formation of a trifluoromethyl group [308] (Figure 8.115). Stable salts of the ðCF3Þ2N anion have been described [309]. Oxaziridines have been obtained from perfluorinated aza-alkenes using a variety of approaches, and they have been used in oxygen transfer and other reactions [310] (Figure 8.116). Remarkably, perfluoroazapropene (8.117A) reacts with SbF5 to produce oligomers [311, 312] (Figure 8.117). Further reaction of the cyclic trimer with SbF5 leads to the loss of CF4 to give the stable cation 8.117B whereas, if the reaction is carried out in Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 282

282 Chapter 8

F F ½308 F F F NNNN NNNN

8.115A

2 F F F 1

F 2 F NNF NN F N N N N i F F

1 i, CsF, 150C, 16hr

F F3C F F

N F N N F CF3 N N N NN F F 8.115 B

Figure 8.115

O CF3N=CF2 + CF3OOH CF3NHCF2OOCF3 F N ½310 F3C F

+ COF2

O O i CF CF BrCF CF N CFCF 3 3 2 2 = 3 N N BrCF CF ½310 2 2 F CF3CF2 F 55: 45 i, m-CPBA, Sulpholan, 22C

O F 1 2 R1SOR2 + R N CFR N R SR F = F ½310 RF RF

RF = n-C4F9

Figure 8.116 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 283

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 283

F3C CF3 2hr, 20C N N (CF ) NCF NCF CF3N=CF2 + SbF5 F 3 2 = 3 ½311 8.117A N

CF3

(CF3)2NCF2N=CFN(CF3)2

FF F3C CF3 F3C CF3 N N i N N F − − − 8.117B CF4, F ½312 N F N F

CF3 i, SbF5

F3C CF3 N N i N F ½312 − (CF3)2NCF CFN(CF3)2 N 2CF4 8.117C CF 3 i, SbF5, SO2

CF CF3 3 N N F C CF N 2 2 CF F2C C C 3 N F2 F

CF N CF 3 = 2 CF3N=CF2

CF3 CF3 N N N N C CF F C C CF F2C 2 2 3 F2 F

CF3 N N C F2C CF3 F

Figure 8.117 sulphur dioxide as solvent, then the major product is the cation 8.117C. The reactions probably proceed via the aza-allyl cation, following reaction paths similar to those described for the oligomerisation of hexafluoropropene, via the perfluoroallyl cation outlined in Chapter 7, Section IID. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 284

284 Chapter 8

D Azo compounds A synthesis of hexafluoroazomethane from tetrabromoazomethane has already been referred to [296], and some other routes to polyfluoroazoalkanes are illustrated in Figure 8.118. i C F N NC F 90% CF3CN 2 5 = 2 5 ½313

i, AgF2, Ambient Temp.

i 205C C2F5CN C2F5CF2NCl2 C3F7N=NC3F7 ½314

i, ClF, −78 to −0C 85%

ClF 200−250C ½314 CF2(CN)2 Cl2NCF2CF2CF2NCl2 F NN

95%

Figure 8.118

Like the hydrocarbon analogues, highly fluorinated azo compounds break down on photolysis and pyrolysis to give nitrogen and corresponding organic radicals [315] (Figure 8.119). hν CF3N=NCF3 2CF3 + N2 ½315

2CF3 C2F6

Figure 8.119

E Diazo compounds and diazirines [316] Stable diazoalkanes and diazirines (Figure 8.120, where X and Y are fluoroalkyl groups) have been isolated, but no authenticated report is available of a diazoalkane where X or Y is a fluorine atom, although difluorodiazirine is now well documented [316]. It has been suggested that this is probably yet another result of the propensity of fluorine to favour the formation of F2Cðsp3Þ bonds, rather than F2Cðsp2Þ, thus making the diazirine structure thermodynamically preferred, although calculations have suggested that the diazomethane structure is slightly preferred for CF2N2 [317].

X X X N C NN C NN N Y Y Y

Diazoalkane Diazirine

Figure 8.120 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 285

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 285

Oxidation of fluorinated hydrazones with lead tetra-acetate forms a useful method for the synthesis of bis(perfluoroalkyl)diazomethanes [318] (Figure 8.121). i (CF3)2CO + NH3 (CF3)2C=NH 70% ½103

i, Pyridine, −25 to −30C i (CF3)2C=NH + NH2NH2 (CF3)2C=NNH2 68% ½103 i, P2O5, 0 C i (CF3)2C=NNH2 (CF3)2CN2 77% ½318 i, Pb(OAc)4, C6H5CN, 0 C

Figure 8.121

Diazotisation of hexafluoroisopropylamine has also been achieved [319] (Figure 8.122).

i ii CF3CF=CF2 (CF3)2CFNO2 (CF3)2CHNH2 75% ½319 i, HF/HNO3; ii, H2, Pd, 70 C, 100atm ½319 (CF3)2CHNH2.HCl (CF3)2CN2 48%

Figure 8.122

Bis(perfluoroalkyl)diazoalkanes are surprisingly stable; for example, deliberate attempts to detonate 2-diazoperfluoropropane failed [318]. It has been emphasised [316, 319] that this compound is less readily attacked by electrophilic reagents than diazoalkanes but is unusually susceptible to nucleophilic attack, which is a consequence of electron withdrawal by trifluoromethyl (Figure 8.123).

(CF3)2CN2 + N (CF3)2CHN=N N ½318

Figure 8.123

Additions to some unsaturated compounds occur [318] (Figure 8.124). In the case of diazirines, both difluorodiazirine and bis(trifluoromethyl)diazirine have been obtained. Difluorodiazirine was originally prepared by reductive defluorination of bis(difluoroamino)difluoromethane [320, 321], but it can also be obtained by an interesting fluoride-ion-induced rearrangement of difluorocyanamide [322] (Figure 8.125). Bis(trifluoromethyl)diazirine [318, 323] is best obtained by the oxidation of 2,2-diaminohexafluoropropane, prepared from hexafluoroacetone, with sodium hypochlorite (Figure 8.126). Loss of nitrogen from these aziridines occurs on photolysis and pyrolysis, and a number ofÀ the subsequent reactions have been formulated as reactions of the carbenes F2C: and CF3Þ2C:, which have also been discussed earlier; see Chapter 6, Section IIIA. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 286

286 Chapter 8

CN ½318 60C (CF ) CN + CH CHCN F3C 3 2 2 2= N F3C N CN

F3C N F3C N H (Quant.)

H3C CH3 150C (CF ) CN + CH C CCH F3C ½318 3 2 2 3 3 N F3C N H3C CH3 400C

F3C CF3 56%

Figure 8.124

i F N 321 CF2(NF2)2 ½ F N

i, (C5H5)2Fe, (C2H5)4NCl (or I)

i F NCN 20% ½322 H2NCN(H2O) 2 − i, F2, He, Buffered, 5 9 C

CsF/24C F N F2NCN F N

F ½322

N F F N N F F N F F

Figure 8.125 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 287

Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 287

i F N 78% (CF3)2C(NH2)2 F N ½323 i, NaOCl, NaOH, 40−60C

Figure 8.126

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237 W.R. Brasen, H.N. Cripps, C.G. Bottomley, M.W. Farlow and C.K. Krespan, J. Org. Chem., 1965, 30, 4188. 238 G.V.D. Tiers, J. Fluorine Chem., 1998, 90, 97. 239 R.N. Haszeldine and J.M. Kidd, J. Chem. Soc., 1953, 3219. 240 C.W. Tullock and D.D. Coffman, J. Org. Chem., 1960, 25, 2016. 241 J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 655. 242 W.E. Truce, G.H. Birum and E.T. McBee, J. Am. Chem. Soc., 1952, 74, 3594. 243 R.D. Chambers and R.H. Mobbs, Adv. Fluorine Chem., 1965, 4, 50. 244 W.A. Sheppard, J. Org. Chem., 1964, 29, 895. 245 S. Andreades, J.F. Harris and W.A. Sheppard, J. Org. Chem., 1964, 29, 898. 246 A.L. Clifford, H.K. El-Shamy, H.J. Emele´us and R.N. Haszeldine, J. Chem. Soc., 1953, 2372. 247 G.A. Silvey and G.H. Cady, J. Am. Chem. Soc., 1950, 72, 3624. 248 E.A. Tyczkowski and L.A. Bigelow, J. Am. Chem. Soc., 1953, 75, 3523. 249 R.M. Rosenberg and E.L. Muetterties, Inorg. Chem., 1962, 1, 756. 250 S. Temple, J. Org. Chem., 1968, 33, 34. 251 D.T. Sauer and J.M. Shreeve, J. Chem. Soc., Chem. Commun., 1970, 1679. 252 R.D. Bowden, P.J. Comina, M.P. Greenhall, A. Loveday and D. Philip, Tetrahedron, 2000, 56, 3399. 253 R.D. Chambers and R.C.H. Spink, J. Chem. Soc,. Chem. Commun., 1999, 883. 254 A.M. Sipyagin, C.P. Bateman, Y.-T. Tan and J.S. Thrasher, J. Fluorine Chem., 2001, 112, 287. 255 E.W. Lawless, Inorg. Chem., 1970, 9, 2796. 256 R.W. Winter, R. Dodean, J.A. Smith, R. Anilkumar, D.J. Burton and G.L. Gard, J. Fluorine Chem., 2003, 122, 251. 257 W. Sundermeyer and W. Meize, Z. Anorg. Allg. Chem., 1962, 317, 334. 258 W.J. Middleton, E.G. Howard and W.H. Sharkey, J. Org. Chem., 1965, 30, 1375. 259 D.C. England, J. Org. Chem., 1981, 46, 153. 260 U. Hartwig, H. Pritzkow, K. Rall and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1989, 28, 221. 261 M.S. Raasch, J. Org. Chem., 1970, 35, 3470. 262 K. Wang and E.I. Stiefel, Science, 291, 106. 263 D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532. 264 J.A. Young, S.N. Tsoukalas and R.D. Dresdner, J. Am. Chem. Soc., 1958, 80, 3604. 265 F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Chem. Eng. Data, 1965, 10, 398. 266 R.E. Banks and G.J. Moore, J. Chem. Soc. (C), 1966, 2304. 267 R.E. Banks, R.N. Haszeldine and R. Hatton, J. Chem. Soc. (C), 1967, 427. 268 R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1964, 2485. 269 I.L. Knunyants, B.L. Dyatkin and E.P. Mochalina, Bull. Acad. Sci. USSR, 1965, 1056. 270 D.M. Gale and C.G. Krespan, J. Org. Chem., 1968, 33, 1002. 271 Y.V. Zeifman, N.P. Gambaryan and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 1431. 272 S. Nagasi, Fluorine Chem. Rev., 1967, 1, 77. 273 F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 197. 274 M. Gaensslen, U. Gross, H. Oberhammer and S. Rudiger, Angew. Chem., Int. Ed. Engl., 1992, 31, 1467. 275 R.N. Haszeldine, J. Chem. Soc., 1953, 2075. 276 A.H. Dinwoodie and R.N. Haszeldine, J. Chem. Soc., 1965, 1675. 277 C.W. Taylor, T.J. Brice and R.L. Wear, J. Org. Chem., 1962, 27, 1064. 278 R.E. Banks, M.G. Barlow, R.N. Haszeldine and M.K. McGrath, J. Chem. Soc. (C), 1966, 1350. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 294

294 Chapter 8

279 M.C. Henry, C.B. Griffis and E.C. Stump, Fluorine Chem. Rev., 1967, 1,1. 280 D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 1881. 281 J.M. Birchall, A.J. Bloom, R.N. Haszeldine and C.J. Willis, J. Chem. Soc., 1962, 3021. 282 V.A. Tinsburg, A.N. Medvedev, S.S. Dubov, P.O. Gitelv, V. Smolyanitskaya and G.E. Nikolaneko, J. Gen. Chem. USSR, 1969, 39, 262. 283 R.N. Haszeldine and B.J.H. Mattinson, J. Chem. Soc., 1957, 1741. 284 W.D. Blackley and R.R. Reinhard, J. Am. Chem. Soc., 1965, 87, 802. 285 S.P. Makarov, A.Y. Yakubovich, S.S. Dubov and A.N. Medvedev, Zh. Vses. Khim. Obshchestva im. D.I. Mendeleeva, 1965, 10, 106; Chem. Abstr., 1965, 62, 16034. 286 S.P. Makarov, M.A. Englin, A.F. Videiko, V.A. Tobolin and S.S. Dubov, Dokl. Akad. Nauk. SSSR, 1966, 168, 344; Chem. Abstr., 1966, 65, 8742. 287 R.E. Banks, R.N. Haszeldine and M.J. Stevenson, J. Chem. Soc. (C), 1966, 901. 288 M.A. Englin and A.V. Mel’nikova, Zh. Vses. Khim. Obshchest., 1968, 13, 594; Chem. Abstr., 1969, 70, 28503. 289 R.E. Banks, R.N. Haszeldine and T. Myerscough, J. Chem. Soc. (C), 1971, 1951. 290 J.A. Young, T.C. Simmons and F.W. Hoffman, J. Am. Chem. Soc., 1956, 78, 5637. 291 R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 328. 292 V.A. Petrov, J. Fluorine Chem., 2001, 109, 123. 293 R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1962, 3407. 294 I.L. Knunyants, E.G. Bykhovskaya and V.N. Frosin, Dokl. Akad. Nauk. SSSR, 1960, 132, 357; Chem. Abstr., 1960, 54, 20841. 295 R.E. Banks, D. Berry, M.J. McGlinchey and G.J. Moore, J. Chem. Soc. (C), 1970, 1017. 296 R.A. Mitsch and P.M. Ogden, J. Org. Chem., 1966, 31, 3833. 297 H.J. Scholl, E. Klauke and D. Lauerer, J. Fluorine Chem., 1972/73, 2, 205. 298 R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Richie, J. Chem. Soc., Perkin Trans. 1, 1974, 114. 299 R.N. Barnes, R.D. Chambers, R.D. Hercliffe and W.K.R. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1981, 2059. 300 M. Barlow, D. Bell, N.J. O’Reilly and A.E. Tipping, J. Fluorine Chem., 1983, 23, 293. 301 C.S. Cleaver and C.G. Krespan, J. Am. Chem. Soc., 1965, 87, 3716. 302 D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1956, 3428. 303 J.A. Young, W.S. Durrell and R.D. Dresdner, J. Am. Chem. Soc., 1959, 81, 1587. 304 V.G. Andreev, A.F. Kolomiets and G.A. Sokolskii, Izv. Akad. Nauk. SSSR, Ser. Khim., 1990, 1643; Chem. Abstr., 1990, 113, 1643. 305 F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Am. Chem. Soc., 1962, 84, 4275. 306 R.N. Barnes, R.D. Chambers, M.J. Silvester, C.D. Hewitt and E. Klauke, J. Fluorine Chem., 1984, 24, 211. 307 R.N. Barnes, R.D. Chambers and R.S. Mathews, J. Fluorine Chem., 1982, 20, 307. 308 R.N. Barnes, R.D. Chambers and C.D. Hewitt, J. Fluorine Chem., 1986, 34, 59. 309 U. Heider, M. Schmidt, P. Sartori, N. Ignatyev and A. Kucheryna, Eur. Pat. 1 081 129 (2001); Chem. Abstr., 2001, 134, 207547. 310 V.A. Petrov and G. Resnati, Chem. Rev., 1996, 96, 1809. 311 I.L. Knunyants, A.F. Goutar and A.S. Vinogradov, Izv. Akad. Nauk. SSSR, Ser. Khim., 1983, 476; Chem. Abstr., 1983, 99, 53706k. 312 G. Pawelke and H. Burger, J. Fluorine Chem., 1984, 26, 321. 313 J.K. Ruff, J. Org. Chem., 1967, 32, 1675. 314 J.B. Hynes and T.E. Austin, Inorg. Chem., 1966, 5, 488. 315 M.E. Jacox, Chem. Phys., 1984, 83, 171. 316 C.G. Krespan and W.J. Middleton, Fluorine Chem. Rev., 1971, 5, 57. 317 C. Glidewell, D. Higgins and C. Thompson, J. Comput. Chem., 1987, 8, 1170. 318 D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617. 319 E.P. Mochalina and B.L. Dyatkin, Bull Acad. Sci. USSR, 1965, 899. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 295

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320 R.A. Mitsch, J. Heterocycl. Chem., 1966, 3, 245. 321 R.A. Mitsch, J. Org. Chem., 1968, 33, 1847. 322 M.D. Meyers and S. Frank, Inorg. Chem., 1966, 5, 1455. 323 R.B. Minasyan, E.M. Rokhlin, N.P. Gambaryan, Y.V. Zeifman and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 746. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 296

Chapter 9 Polyfluoroaromatic Compounds

This chapter will deal mainly with the chemistry of highly fluorinated compounds, although this will be prefaced by a more general summary of synthetic methods for the introduction of fluorine into an aromatic system. A review of this topic by Brooke [1] covers the area in considerable detail and we can only be selective in our discussion here.

I SYNTHESIS [1, 2] A General considerations An ideal process would, in principle, be one where elemental fluorine could be used as indicated in Figure 9.1. Recent work with elemental fluorine has demonstrated that this is a reasonable approach in some circumstances, e.g. when the opportunity for forming isomers is limited. However, nucleophilic displacement of other halogens, or mobile groups such as nitro, by fluoride ion, when the aromatic compound is susceptible to nucleophilic attack, is a more versatile approach at the present time (Figure 9.2).

2ArH + F2 2ArF + HF

Electrolysis 2HF F2 + H2

Figure 9.1

Ar L + F Ar F + L

Figure 9.2

We are mainly concerned here with general processes but two specific reactions are of some interest. Fragmentation occurs in the pyrolysis of CFBr3, giving perfluorobenzene (Figure 9.3) [3–5]; this was probably the first synthesis of this compound, although it was not reported for some time. Trimerisation of hexafluoro-2-butyne leads to hexakis(trifluoromethyl)benzene[6,7],areaction that wasreferred toinChapter7,Section IIIB,Subsection1. Pt 6 CFBr3 9 Br2 + C6F6 55% ½4 630−640Њ C

3 CF3C CCF3 C6(CF3)6 ½6, 7

Figure 9.3

Polyfluoroaromatic Compounds 297

B Saturation/re-aromatisation Examples of saturation and then re-aromatisation by dehydrohalogenation and dehalogenation are given in Figure 9.4. Use of cobalt trifluoride [8] to form perfluorinated i ii C Cl C Cl F 6 6 6 x 12-x C6F6 ½16 x = mainly 5, 6, and 7 C6F5Cl C6F4Cl2 i, F2, CF2ClCFCl2 C6F3Cl3 ii, Fe, 330 C

KOH C H C H F etc C F 6 6 6 3 9 6 6 ½17 C6H3F7 C6F5H

CH3 CF3 CF3

CoF3 Fe F F ½18

460 C

CH3 CF3 CF3

H H i − F F 2F ½13

H H

i, Hg Cathode

F F

CoF3 Fe ½19 F F

410 C F F

i ii F F ½15 NN N 25% F i, Electrochemical Fluorination ii, Fe/600C/,1mm

Figure 9.4 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 298

298 Chapter 9 saturated systems as inert liquids is an industrial process operated by F2 Chemicals Ltd.; a variety of benzenoid derivatives have been fluorinated in this way. Re-aromatisation may be achieved by essentially two procedures: either elimination of hydrogen fluoride [9, 10] using base, or defluorination over heated iron or nickel [11, 12]. The latter is a very effective process for defluorination and is frequently overlooked in more recent literature on processes for ‘activating’ carbon–fluorine bonds. An electrochemical process has also been used to defluorinate fluorocyclohexadienes [13]. Several condensed ring benzenoids have been prepared by the fluorination/defluorination procedure [1] but less success has been achieved using heterocyclic systems, although pentafluoropyridine has been made in a low-yield sequence [14, 15]. Re-aromatisation by elimination of hydrogen fluoride has been used as a route to thiophene and furan derivatives [20, 21] (Figure 9.5).

H H

KOH F F ½20 S S

KOH F F ½21 HHO O

H H H H KOH F F ½21 O H O

Figure 9.5

C Substitution processes [22] 1 Replacement of H by F Reactions that lead to replacement of hydrogen by fluorine could, in principle, proceed by any of the processes outlined in Figure 9.6, and it is frequently difficult to make any meaningful distinction between the possibilities. Various electrophilic fluorinating reagents, including fluorine itself, are capable of transferring ‘Fþ’ to an appropriate nucleophilic centre to give a s-complex 9.6A, but these electrophilic fluorinating agents are also strong oxidising agents. Consequently, the sequence could begin with a single-electron transfer [23], giving a radical cation 9.6B which, in turn, could receive a fluorine atom from the reagent, thus reaching 9.6A by two steps. Alternatively, the radical cation 9.6B could receive fluoride ion and then give a radical s-complex 9.6C. All of these processes are feasible and probably arise in different circumstances [24], albeit difficult to establish. Some examples of what might be reasonably regarded as electrophilic fluorinations are given in Figure 9.7. In the examples Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 299

Polyfluoroaromatic Compounds 299 indicated, and others, the orientation of substitution is quite consistent with an electrophilic aromatic substitution process. F F H

"F" H

9.6A

F H

9.6B 9.6C

Figure 9.6

COOH COOH ½25 Solvent Yield, % F2 Solvent 98% H2SO4 84 F CH3CN 53 F F CF2ClCFCl2 0

NO2 NO2 NO2 ½26

F F F X X X Њ i, F2, HCOOH, 10 C

X = OH 70% 8% X = F 53% Trace

NO2 NO2 NO2 ½26

F F F Me Me Me

i, F , H SO , 10Њ C 2 2 4 81% 2%

Figure 9.7

Substitution in pyridine is more consistent with an addition–elimination process (Figure 9.8). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 300

300 Chapter 9

½27 i −HF H N N F N F − i, F2, CFCl3, 78 C F

i −HI 70% ½28 F N N N Cl Cl H Cl F i, IF5/2I2 I

b 14%

Cl N N F

b I a

Figure 9.8

The occurrence of radical intermediates is evident from the product of the fluorination of benzene [29] and of tetrafluoropyrimidine [30] (Figure 9.9). Xenon difluoride is reactive towards aromatic compounds [31], and selective fluoro- desilylation using this reagent has also been reported [32] (Figure 9.10).

þ 2 Replacement of 2N2 by F: the Balz–Schiemann reaction [33, 34] In this classical reaction the leaving group, molecular nitrogen, is lost on pyrolysis and the mechanism appears to involve formation of an aryl cation which then abstracts fluoride ion [35] (Figure 9.11). This reaction has been carried out on an industrial scale in spite of the fact that the decomposition stage is potentially hazardous. Consequently, techniques have been developed that avoid isolating a solid diazonium salt [2] (Figure 9.12).

3 Replacement of 2OH or 2SH by F Another alternative to the Balz–Schiemann reaction is now available through the thermal decomposition of aryl fluoroformates or aryl thiofluoroformates [36–38], as indicated in Figure 9.13. Fluoroformates are obtained in high yields but the pyrolysis step is quite variable.

4 Replacement of Cl by F [39] The most practicable and versatile laboratory and industrial route to polyfluoroaromatic compounds involves the use of potassium fluoride in nucleophilic displacement of Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 301

Polyfluoroaromatic Compounds 301

½29 F FFFn = 0, 20% n = 1, 40% n

FF F F

5% 8% 7%

½30 N i N N F F F N N N Њ i, CoF3, CaF2, 183 C

Coupling etc

N +F N F F N N

Figure 9.9

XeF2 CF3C6H5 meta-CF3C6H4F 71% para-CF3C6H4F 3% ½31

SiMe3 FXe SiMe3 XeF F ½32

XeF2

R R R R

Figure 9.10

HNO3 ArH ArNO2 ArNH2

∆ ArN BF ArF + BF 2 4 − Ar BF4 3 N2

Figure 9.11 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 302

302 Chapter 9

F NH2 N2 F COOH COOH COOH i ii ½2

OH i, NaNO2, HF/H2O COOH ii, 58Њ C

Figure 9.12

i COCl2 COClF

i, AsF3, SbF3, or SiF4

COClF ∆ ArXH ArXCOF ArF + COX

F (X = O, S) or ArXCOCl

i ii C6H5OH C6H5OCOF C6H5F 70% ½36 99% Њ i, COClF, Bu3N; ii, Pt Gauze, 800 C

∆ α-naphth.-OCOF α -naphth.-F 25% ½37 680Њ C

Figure 9.13 chloride by fluoride from systems activated towards nucleophilic attack. This is often referred to as the ‘Halex’ (halogen exchange) process [2, 39] (Figure 9.14). Thermodynamic data for hexafluorobenzene with potassium and sodium fluorides (Figure 9.15) [40] illustrate the feasibility of the reaction in the case of potassium fluoride. The process was pioneered by Finger and co-workers, who appreciated at an early stage the advantages of using a dipolar aprotic solvent [41–43] (see Chapter 2, Section IIB, Subsection 1, for a fuller discussion of ionic fluorides in aprotic solvents). Examples of halogen exchange using a dipolar, aprotic solvent are shown in Figure 9.16. Hexachlorobenzene gave 1,3,5-trifluorotrichlorobenzene when DMF or DMSO2 [41] was used as solvent, although the use of N-methyl-2-pyrrolidone (NMP) [42, 43] gave some tetrafluorodichlorobenzene that could not be fluorinated further in this mixture (Figure 9.17). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 303

Polyfluoroaromatic Compounds 303

ArCl + KF ArF + KCl ½2

Figure 9.14

C6Cl6(g) + 6KF(s) C6F6(g) + 6KCl(s) ½40

∆ − −1 H298 = 126 kJmol

C6Cl6(g) + 6NaF(s) C6F6(g) + 6NaCl(s)

∆ −1 H298 = +63 kJmol

Figure 9.15

NO2 NO2 ½2 Cl F i 71%

Cl F

i, KF, DMSO, phase transfer agent, heat

NO2 NO2 ½2 i 82%

Cl Cl Cl F i, KF, DMF, heat

Figure 9.16

i Cl F + C6F4Cl2 + C6F5Cl ½42, 43 Cl Cl

i, KF, 195Њ C, NMP 23% 34% trace

Figure 9.17

The significance of obtaining only the 1,3,5-trifluorotrichlorobenzene will become clear in later discussion of orientation of nucleophilic aromatic substitution. However, a higher temperature, permitted by the use of Sulpholan as solvent [44], gave perfluoronaphthalene from the perchloro compound (Figure 9.18). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 304

304 Chapter 9

i Cl Cl FF 52% ½44

i, KF, 235Њ C, Sulpholan

Figure 9.18

In contrast, with Sulpholan as solvent the very reactive cyanuric chloride is converted to the fluoride, even with sodium fluoride [45]. Indeed, if the system is sufficiently activated, then hydrogen fluoride may be used for the conversion [46], and the halogen exchange step probably occurs on the protonated system (Figure 9.19). N N i Cl F 74% ½45 NN NN

i, NaF, 245Њ C, Sulpholan

N N HF N N N N Cl Cl Cl ½46 N N N F Cl F H H

−HCl Cl

N N HF etc N N F Cl N F N

Figure 9.19

Nevertheless, reaction of perchloropyridine with potassium fluoride in Sulpholan leads mainly to 2,4,6-trifluorodichloropyridine [47] (Figure 9.20). The feature limiting the extent of fluorination is, essentially, the thermal stability of the solvent. This has been circumvented by two techniques: (a) using a melt of potassium fluoride–potassium chloride at temperatures in the region of 7508C [40]; and, more successfully, (b) employing autoclaves at high temperatures for reactions in the absence of a solvent, a technique used first to fluorinate perchlorobenzene [48, 49] and perchloropyridine [47, 50, 51] (Figure 9.21).

Cl Cl Cl i ½47 Cl F F N N N

10 : 1 i, KF, 200Њ C, Sulpholan

Figure 9.20 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 305

Polyfluoroaromatic Compounds 305

i C6F3Cl3 C6F6 11% + C6F5Cl 34% + C6F4Cl2 28% ½40

i, KF/KCl Melt, 780Њ C

+ C6F3Cl3 18% + C6F2Cl4 0.4%

i C6Cl6 C6F6 21% + C6F5Cl 20% + C6F4Cl2 14% ½48

i, KF, Autoclave, 450−500Њ C + C6F3Cl3 12%

Cl i Cl F F ½47 N N N Њ i, KF, Autoclave, 480 C 68% 7%

Figure 9.21

A general process has now evolved for the synthesis of highly fluorinated azabenzenoid compounds, involving (a) synthesis of the perchloro compound by further chlorination of partly chlorinated compounds with phosphorus pentachloride, and (b) subsequent reaction of the perchloro compound with potassium fluoride. The method is illustrated for perfluoroquinoline [52] (Figure 9.22), but the technique has also been applied to other systems (Figure 9.22b). Thus, a novel field of heterocyclic chemistry is available that is still relatively unexplored.

Cl4

Cl , AlCl 2 3 87% ½52

140−160Њ C N N Њ PCl5 315 C

KF Cl Cl FF 71% 480˚C N N 78%

Figure 9.22a Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 306

306 Chapter 9

F FF FF N N N

N N N F F F N N N

N N N FF FF FF N N N

N N N F F F N N N N N N

Figure 9.22b Perfluorinated heterocyclic systems obtained by Halex procedures [53]

II PROPERTIES AND REACTIONS A General Perfluorobenzene and perfluorobenzenoid compounds have boiling points that parallel those of the corresponding hydrocarbons but, for perfluoropyridine and other perfluoro- azabenzenoid compounds, the values are significantly lower than for their hydrocarbon counterparts (Table 9.1). The base strength of nitrogen in these perfluorinated systems is very considerably reduced compared with their hydrocarbon counterparts so that, in the nitrogen systems, it is clear that substitution of hydrogen for fluorine usually produces an overwhelming reduction of intermolecular forces, which more than offsets the increase in molecular weight.

Table 9.1 Boiling points of perfluoroaromatic compounds in comparison with hydrocarbon counterparts

Boiling point of Compound Boiling point (8C) [54] perfluorinated derivative (8C) Ref.

Benzene 80.1 80.2 [55] Toluene 110.6 102–103 [11] p-Xylene 138 117–118 [11] Pyridine 115.5 83.3 [55] Quinoline 237.1 205 [52] Isoquinoline 243.2 212 [52] Pyridazine (1,2-diazine) 208 117 [56] Pyrimidine (1,3-diazine) 123.5 89 [55] Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 307

Polyfluoroaromatic Compounds 307

The effect of fluorocarbon groups on the strengths of various acids and bases was discussed in Chapter 4, Section IIIA, where it was pointed out that pentafluorophenyl and pentachlorophenyl are similar in electron-withdrawing properties but are much less effective than trifluoromethyl [57]. Complexes are formed between hexafluorobenzene and aromatic hydrocarbons [58] or amines [59], and the 1:1 complex formed between hexafluorobenzene and mesitylene is stable enough to allow recrystallisation [58]. Much has been written about the nature of these complexes, e.g. dispensing with the idea that they may involve charge transfer; a recent study concludes that the complexes are formed principally through van der Waals forces [60]. X-ray crystal structures of complexes of hexafluorobenzene with various cyclic aromatic hydrocarbons reveal 1:1 alternating stacks [61]. Electron affinities for perfluoroaromatic compounds indicate that they are good electron acceptors [62].

B Nucleophilic aromatic substitution A considerable number of highly fluorinated aromatic compounds have now been prepared that undergo various nucleophilic aromatic substitution reactions. Taking perfluorobenzene as an example, we have the two basic requirements for nucleophilic substitution to occur readily: (a) electron-withdrawing substitutents to lower the energy of a transition state leading to the intermediate 9.23A (Figure 9.23); and (b) an atom that can leave with the bonding electron pair, which in this case is F. Indeed, just as hydrocarbon aromatic compounds provide the framework for studying electrophilic aromatic substitution, it is obvious that polyfluoroaromatic compounds are particularly appropriate systems for studying nucleophilic aromatic substitution. As we will see, problems of orientation arise that are just as fundamental to nucleophilic aromatic substitution as the classical orientation problems are to electrophilic aromatic substitution, and it should be particularly evident in this area how the chemistry of fluorocarbon systems helps to extend the mechanistic framework of organic chemistry.

F Nuc Nuc

k1 k2 F Nuc F F

k−1 F5 9.23A

Figure 9.23

1 Benzenoid compounds [1] Hexafluorobenzene will react with a wide range of nucleophilic reagents, leading to pentafluorophenyl compounds; some of these are given in Table 9.2, together with some similar chemistry of other benzenoid systems. From these direct substitution products, which are generally obtained in high yield, routes have been developed to other important functional derivatives (Table 9.3). Some of these are included but other important reactions, e.g. formation of organometallic compounds, will be covered in later discussion and are not illustrated in this table. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 308

308 Chapter 9

Table 9.2 Reactions of perfluorobenzenoid compounds with nucleophilic reagents and some simple interconversions

Reaction Ref.

Reactions starting from hexafluorobenzene

i ii C6F5OCH3 C6F5OH 72% 58% [63] Њ i, NaOCH3, MeOH; ii, AlCl3, 120 C

i C F OH 6 5 [5] i, KOH, t-BuOH 71%

i ii C6F5SH C6F5H [64] i, NaSH, Pyridine; ii, Raney Ni, n-BuOH

ii C6F5SO2Cl [65]

ii, Cl2, H2O2

ii iii C F SCH C F SO Me 6 5 3 6 5 2 [65]

ii, Me-nitrosourea, KOH, Et2O; iii, H2O2, CH3COOH

i ii C6F5NH2 C6F5NO2 85% [66, 67] Њ i, aq. NH3, EtOH, 167 C; ii, CF3CO3H, CH2Cl2

ii C6F5NH2HCl [68] ii, HCl, Et2O

NaOCl [69] C6F5N=NC6F5

ii C F NO 48% 6 5 2 [70] ii, HCO3H, CH2Cl2

ii iii C6F5N2 F C6F5Br [68]

ii, NaNO2, 80% HF; iii, Cu2Br2, HBr

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Polyfluoroaromatic Compounds 309

Table 9.2 Contd

iii C6F5NHNH2 C6F5C6H5 71% 74% [71]

i, NH2NH2.H2O, EtOH; ii, Ca(OCl)2, C6H6

NaOH F 90% [72]

NO2Cl C6F5N3 52% [71]

[73] LiAlH4 C6F5H

OCH2CH2OH O i ii [74] F F O

i, (CH2OH)2, NaOH; ii, K2CO3, DMF, Reflux

Reactions of other perfluorobenzenoid compounds

NHNH2 i F F FF

iii [75] ii

H FF

i, NH2NH2, aq. EtOH; ii, LiAlH4, Et2O; iii, Fehling s soln.

H i F F F F [76] H i, LiAlH4, THF

i FF FFOC6F5 [77]

90 % i, C6F5O , DMAC

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310 Chapter 9

Table 9.2 Contd

i FF H2NHN FFNHNH2

18% [78, 79] i, NH2NH2, aq. EtOH

H2NHN FF 72% a DMAC, dimethylacetamide.

Table 9.3 Nucleophilic substitution in C6F5X compounds

Orientation of product(%)

Substituent, X Nucleophile Ortho Meta Para Reference

H LiAlH4 7 1 92 [80] NaOMe/MeOH 3 — 97 [81] Me MeLi — — 100 [82] MeO — — 100 [83] NH3 — — 100 [83] CF3 LiAlH4 — — 100 [84] NH3 — — 100 [84] EtO — — 100 [84] NH2 NH3 — 100 — [66, 73] NH3 — 87 13 [85, 86] MeNH2 — 88 12 [86] NO2 NH3 (ether) 70 — 30 [67] NH3 (liq.) 33 — 67 [87] MeNH2 (benzene) 77 — 23 [88] MeOH ðEt2OÞ 8 — 92 [89] MeOH ðEt2OÞ 50 — 50 [88] NH2 NH3 — 100 — [66, 73] NH3 — 87 13 [85, 86] MeNH2 — 88 12 [86] OH KOH — 100 — [73, 83, 90]

Orientation and reactivity: [1, 91]: Reactions of pentafluorophenyl derivatives are particularly interesting because of the unusual orientation of substitution observed. This area was pioneered by workers at the University of Birmingham (UK) [1, 17] and, in most cases, for substitution in C6F5X derivatives the main (>90%) product arises from displacement of a fluorine atom that is para to the substituent group X (for example, where X ¼ H, CH3, SCH3,CF3,NðCH3Þ2,SO2CH3,NO2,C6F5,OC6F5, etc.). In a few cases ðX ¼ NH2,OÞ meta replacement predominates, whilst (for X ¼ OCH3 and NHCH3) comparable amounts of meta and para replacement occur (Figure 9.24). The effects of substituents on rate constants are, however, in the direction expected for nucleophilic aromatic substitution; electron-donating groups deactivate while electron- withdrawing groups activate; for example, C6F5NH2 and C6F5O are strongly deactivated. The magnitude of these effects, such as the relative reactivities of NaOCH3ðCH3OH at 608C), have been recorded [92] and some relative rates towards sodium pentafluorophenoxide (dimethylacetamide, 1068C) are shown in Table 9.4 [93]. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 311

Polyfluoroaromatic Compounds 311

F + F e.g. X = H, CH , CF X Nuc 3 3 Nuc F

Nuc X

F + F e.g. X = NH2, O Nuc

Figure 9.24

Table 9.4 Relative rates of reaction of C6F5X towards NaOC6F5, DMAC [93]

X Relative reaction rate

4 CF3 2.4 10 3 CO2C2H5 2.9 10 2 C6F5 7.3 10 Br 39 Cl 32 H1 F 0.91

Clearly, therefore, there is a very wide spread in reactivity, as in electrophilic substitution in benzene derivatives, but here we have the contrasting feature that the orientation pattern is relatively insensitive to the substituent. Consequently, it is important to establish the nature of this unusual orientating influence arising from the five fluorine atoms.

Mechanism [91, 94]: It is reasonable to assume the normal two-step mechanism (Figure 9.23) of nucleophilic attack in these systems, with the first stage k1 being rate-limiting. The type of evidence that allows this assumption to be made is that perfluorobenzene is much more reactive than perchlorobenzene, and this is only consistent with there being little or no bond breaking in the rate-determining stage. The reason for this greater reactivity of C2F over C2Cl lies in the fact that the C2F bond is more polarised and hence ion–dipole interactions with the incoming nucleophile are greater for C2F and lead to a corresponding lowering of the activation energy. Of course, a similar argument is necessary to account for the often greater reactivity of acid fluorides RCOX (X ¼ F) over acid chlorides (X ¼ Cl) towards nucleophiles, although this is rarely emphasised. We are then left with the influence of the remaining ring fluorine atoms on the substitution process. In reality, halogen atoms that are at positions ortho, meta and para to the site of nucleophilic attack (Figure 9.25) have different effects; these separate activating influences have been derived from the data contained in Table 9.5 [91, 94]. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 312

312 Chapter 9

δ F Nuc δ Nuc ortho ortho F F + F meta meta

para para

Figure 9.25

Table 9.5 Ratios of measured rate constants (CH3O =CH3OH, 588 C) [91, 94]

Benzene derivatives compared kF=kH

F H

F vs F para-F / para-H 0.43

(Position of nucleophilic attack)

(ie k/6)a

H H

F vs F ortho-F / ortho- H 57

F H

H H F H

F vs F meta- F / meta- H 106

a Statistically corrected.

In the benzenoid system, therefore, the activating effects of fluorine vary in the order meta-F > ortho-F para-F, although this can also vary with the system (see Table 9.6). Clearly, the para-F is slightly deactivating but is not very different from H at the same position. Our problem then is to rationalise these data on the basis of the known effects of F on carbanion stabilities, which we have described earlier (see Chapter 4, Section VII) (Figure 9.26). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 313

Polyfluoroaromatic Compounds 313

Table 9.6 Comparison of kF=kH

Ortho Meta Para

MeO=MeOH,588 C Benzene derivatives 57 106 0.43 Pyridine derivatives 79 30 0.33 NH3/dioxane, 258C Pyridine derivatives 31 23 0.26

CC FC F

Strongly Stabilising Slightly de-stabilising for a planar system

δ − F Nuc F Nuc F Nuc δ + F

δ − δ −

F δ − F meta-F para-F ortho-F 9.26A 9.26B 9.26C

Figure 9.26 Taking the Meisenheimer complex as a model for the transition state associated with step k1 (Figure 9.23), we can easily see why meta-F, which is adjacent to centres of high charge density, is strongly activating. Likewise, the slightly deactivating influence of fluorine at the para position (9.26B) is entirely consistent with the effect of fluorine directly attached to a planar carbanion centre. However, we would have expected ortho- and para-F to have similar effects, whereas this is clearly not the case. Consequently, it has been argued that the effect of ortho-F (9.26C) is predominantly a polar influence, enhancing the electrophilic character or ‘hardness’ of the carbon atom under attack. We might expect that the influence of this ortho-F effect would diminish as the reactivity or ‘hardness’ of the nucleophile is reduced, and the data contained in Table 9.6 support this case. We can see, therefore, that nucleophilic attack para to the substituent in C6F5X compounds (Table 9.3) stems from maximising the number of activating fluorine atoms [95] (Figure 9.27), where attack para to X involves all of the ring fluorine substituents in the positions that maximise their activating influence.

X X

o o p o F F mm m

4- activating F 3- activating F

Figure 9.27 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 314

314 Chapter 9

These simple arguments may be extended [76] to account for the orientation of substitution in perfluoronaphthalene, where pm indicates ‘pseudo-meta’ (activating), and pp ‘pseudo-para’ (slightly deactivating) (Figure 9.28).

pp para

δ − δ − pm meta

pm meta pp δ − δ − ortho δ − F F F F δ − δ − δ − ortho pm F

δ − Nuc pm δ − F Nuc pp ortho 4- activating F 5- activating F

Figure 9.28

Clearly, attack at the b-position maximises the influence of fluorine substituents. These same approaches can be used to account for the orientation of substitution in other systems (Figure 9.29). F F F F F

F F F

FF F F

Figure 9.29

Ortho attack [1] can occur, however. Although nucleophilic substitution at sites para to XinC6F5X compounds generally predominates, there are cases where specific binding interactions between the incoming reagent and the substituent X are sufficient to direct the reagent to the ortho position. Hydrogen bonding [96] (Figure 9.30) and co-ordination of X to organometallic reagents are particularly significant [97] (Figure 9.31).

O O N H

NH2 ½96 F

Figure 9.30 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 315

Polyfluoroaromatic Compounds 315

BrMgO O BrMgO O C MgBr C MgBr NHPh F 2PhNHMgBr ½97 C6F5COOH F F NH Ph

HO O C NHPh

Figure 9.31

2 Heterocyclic compounds Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds: Polyfluoroaro- matic nitrogen heterocyclic systems are all activated, relative to the corresponding benzenoid compounds, towards nucleophilic aromatic substitution. The magnitude of this activation is illustrated by the effects of a ring nitrogen, relative to C2F at the same position, for attack by ammonia [91] (Figure 9.32).

N NNN FFF F N N N N

1 37.4 2000 >105

Figure 9.32 Ratio of rate constants for attack by NH3 / aq. dioxane, 258 C It is clear from these data that ring N is a major factor affecting reactivity and orientation of attack in these systems. Nevertheless, pentafluoropyridine reacts with various nucleophiles to give products arising from exclusive attack at the 4-position (Table 9.7), whereas 3H-tetrafluoropyridine gives a mixture of both 4- and 6-attack

Table 9.7 Nucleophilic attack on pentafluoropyridine and related heterocyclic compounds, and some interconversion reactions

Reaction Ref.

Pentafluoropyridine

OCH3 OCH3 OCH3

i i F F F [98, 99]

N N OCH3 CH3O N OCH3

i, CH3ONa, CH3OH

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316 Chapter 9

Table 9.7 Contd

N F NH2 2 Br aq. NH i CuBr 3 F F F

N N N − − i, aq. HF, NaNO2, 20 to 25 C [98, 100, 101] Cu, 230 C CF3COOOH

NO2 NNF F F

OH OCH3

iii F F F F [102]

N N N N OH OCH3 10 1 Њ i, KOH, t-BuOH; ii, KOH, CH3I, 100 C

i F [103]

N i, NaI, DMF, 150Њ C

π− C5H5Fe(CO)2

[104] i F

N , [π− i C5H5Fe(CO)2]

Perfluoroisoquinoline

LiAlH 4 FF [105] N

Contd Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 317

Polyfluoroaromatic Compounds 317

Table 9.7 Contd

CH3O CH ONa 3 FF FF [105] N N CH3OH

OCH 3 OCH3

aq. NaOH FF FF [106] N NH

OH O

Perfluoroquinoline

OCH3

i FF FF

N N OCH3 i, CH3ONa, CH3OH

Њ Њ AlCl3, 120 C AlCl3, 120 C

OH i, H2SO4 FF FF [52, 105, 106] ii, H2O N OH N

FF F F

N O N O H CH2N2, Et2O CH3

N OCH3

Contd Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 318

318 Chapter 9

Table 9.7 Contd

Miscellaneous Perfluoro-3,3’-bipyridyl

OCH3

i F F 88% [107] NN i, CNH3ONa, CH3OH

Perfluoropyridazine

CH3O CH3O i N N F F also tri- and N N tetra-methoxy [108] CH3O derivatives i, CH3ONa, CH3OH

N C6H5SNa 85% [108] (SC6H5)4 N

H+, H O N N 2 Polymer F F [109] N N H OH O

Perfluoropyrimidine

NH2 NH2 aq NH3 N N F or F [110] N N H2N

OCH3

N i F [110] N H3CO

i, CH3OH, Na2CO3

(Figure 9.33). Since 4-attack (one ortho-F, two meta-F) and 6-attack (one ortho-F, two meta-F) have approximately the same activation by F substituents, it is clear that the ring N only discriminates by a factor of ca. 3.7 in favour of the 4-position. Therefore, it is clear that the F substituents determine the generally specific attack at the 4-position on pentafluoropyridine (Figure 9.34). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 319

Polyfluoroaromatic Compounds 319

NH2 H H H

NH3/Dioxane F F F ½76 N N N H2N 3.7 1

Figure 9.33

δ− F F Nuc Nuc δ+ Nuc o o o o F F F F m m m m N N N

Figure 9.34 The activating influence of the F-substituent is maximised

The positions of the most favourable monosubstitution in attack by nucleophiles are shown in Figure 9.35 for various systems; it is clear that directing effects by F have a major influence on the orientation of attack.

F F F F F cf F F N N N

N N N F F F N N N

N N N F F F F F F F N N N

Figure 9.35

Of course, when bromine or chlorine is at the 4-position in the pyridine system, then attack at the 2-position is favoured (Figure 9.36). Br Br

½100 aq NH3 F F N N NH2

Figure 9.36 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 320

320 Chapter 9

A rare case of preferential 2-attack occurs with potassium hydroxide in t-butanol. Here, this result has been attributed to the large steric requirement of the solvated nucleophile, and the fact that the 4-position is the most crowded site. Consequently, it is observed that 3,5-dichlorotrifluoropyridine gives preferential 2-attack with this reagent [102] (Figure 9.37). OH X X X X X X i F F F ½102

N N N OH i, KOH, t-BuOH

X = F, 90 10

X = Cl, 30 70

Figure 9.37

In the case of 4-nitrotetrafluoropyridine, a 4-nitro group is in competition with ring nitrogen as an orientating influence [101]. As in the benzene series, however, the effect of the nitro group is very dependent on the nucleophile and is also affected by solvent. Much more attack adjacent to the nitro group occurs with ammonia (Figure 9.38) and, again, this can be attributed to hydrogen bonding. Displacement of the nitro group itself also occurs readily.

NO2 NH2 NO2 NO 2 NH2 i F F F F ½101 N N N N NH2 i, NH , Et O 3 2 27% 48% 25%

Figure 9.38

There are other cases [102, 107] where the subtle interplay of solvent and steric effects has a profound effect on orientation of substitution.

Polysubstitution: Most groups introduced by nucleophilic substitution are subsequently electron-donating and therefore deactivating towards further attack; for example, attack on perfluoropyridine by methoxide becomes progressively more difficult but eventually leads to 2,4,6-trisubstitution [98, 99] (Table 9.7). In this case R in 9.39A and 9.39B (Figure 9.39) is electron-donating and so 9.39A is preferred. Examples will be discussed later where the substituent is electron-withdrawing, for example, R ¼ CF2CF3, and then 2,4,5-trisubstitution occurs, indicating that in this case 9.39B is preferred to 9.39A. The fact that the order of nucleophilic substitution is as indicated in Figure 9.40 allows the use of polyhalopyridines for synthesis of heterocyclic systems with unusual substitution patterns [111]. Moreover, when this methodology is applied in combination with palladium chemistry, the possibilities are extensive [112, 113] (Figure 9.41). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 321

Polyfluoroaromatic Compounds 321

R R F F F F

Nuc F F F N Nuc N R F R

9.39A 9.39B

Figure 9.39

3 N 2

Figure 9.40

Remarkably, we note that orientation of substitution in 2,4,6-tribromodifluoropyridine depends critically on the nature of the nucleophile. So-called ‘hard’ nucleophiles, e.g. OCH3 and NH3, give exclusive attack at the ‘hard’ electrophilic centres, i.e. C2F, whereas ‘soft’ nucleophiles displace bromine. This is further evidence for the importance of ion–dipole interactions, regarding attack at C2F bonds. Reactions of perfluoro-quinoline and -isoquinoline with hard and soft nucleophiles have also revealed a sensitivity towards a change in orientation of attack with the nature of the nucleophile [114] (Figure 9.42). To account for these results, it has been suggested that the 1-position, i.e. the position adjacent to the ring N, is the harder electrophilic site [114]. In the quinoline system the nature of the substituent groups also can govern the position of entry of a nucleophile. When R in 9.43A (Figure 9.43) is electron-donating, methoxyl for example, then a 2,4,7-trisubstituted compound 9.44A is obtained (Figure 9.44), because 9.43A is preferred to 9.43B; but when R is electron-withdrawing, CFðCF3Þ2 for example, then a 2,4,6-trisubstituted compound 9.44B is obtained [115] because perfluoroalkyl groups stabilise 9.43B relative to 9.43A.

Acid-induced processes: Although perfluoroaromatic nitrogen heterocyclic compounds are only weak bases, nucleophilic substitution can be induced by protonic or Lewis acids, as outlined in Figure 9.45, and interesting contrasts in orientation can sometimes be achieved because attack ortho to nitrogen is often preferred under these conditions. It is clear from the striking tendency for the protonated systems, as shown in Figure 9.46, to give attack ortho to nitrogen that, again, polar influences are extremely important in governing the reactivity of a C2F bond, at least with hard nucleophiles. In both of the examples contained in Figure 9.46, the orientation of entry of the nucleophile is changed in comparison with reaction with the neutral system. We may conclude, here, that in systems containing structure 9.47A (Figure 9.47) the positive pole involving nitrogen has significantly enhanced the reactivity of adjacent C2F bonds. It will be clear, therefore, that this is similar to the argument advanced for the activating influence of an ortho-C2F for nucleophilic attack on an adjacent 5C2F bond (9.47B). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 322

322 Chapter 9

Br H

i ii F F F ½112 N Br N Br H N H

Њ i, HBr/AlBr3, 150 C; ii, Pd/C/H2(4Bar), Et3N, CH2Cl2, rt

Br Br X1 X2 Nuc F ½112

Br N Br Br N Br

Nuc = NaOMe X1 = X2 = OMe

1 2 Nuc = NH3 X = F, X = NH2

Br Br

i F F ½112

Br N Br RC C N C CR

i, CuI/(Ph3P)3PdCl2, Et3N, RC CH (R = C3H7 or Ph)

Br Y1

Nuc F F ½112 Br N Br Br N Y2

1 2 Nuc = Et2NH; Y = Et2N, Y = Br 3 : 1 2 Y = Br, Y = Et2N 2

1 2 Nuc = PhSH; Y = PhS, Y = Br

Figure 9.41

Hydrogen halides give products where substitution para to nitrogen occurs almost as readily as at the ortho position [117], whilst Lewis acids usually give polysubstitution [118] (Figure 9.48). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 323

Polyfluoroaromatic Compounds 323

F F N ½114

Nuc

X X

F F F F F F N N N

X X 9.42A 9.42B 9.42C

Nucleophile

HS , DMF/(CH2OH)2 100% (X = SH)

PhS , EtOH 99% 1% (X = SPh)

MeO , MeOH 93% 7% (X = MeO)

4-NO2C6H4O , EtOH 100% (X = 4-NO2C6H4O)

Figure 9.42

Nuc

FF etc F F F etc F Nuc N R N R

9.43A 9.43B

Figure 9.43

OCH3 OCH3

i F F F F ½116 N OCH N OCH 3 CH3O 3

i, CH3O , CH3OH 9.44A

CF(CF3)2 CF(CF3)2 CH3O i F F F F N CF(CF ) N 3 2 CF(CF3)2

i, CH3O , CH3OH 9.44B

Figure 9.44 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 324

324 Chapter 9

FFFAcc Nuc Nuc

N F N F N F Acc. Acc.

−F Acc. = Electron Acceptor

N Nuc Acc.

Figure 9.45

OMe

i F F F F F F

N N OMe N

iii F F F F

N N OMe H

i, = MeONa/MeOH ii, = c. H2SO4 iii, = MeOH/Slow dilution

OMe H N MeOH N F F 35% ½108, 109 N N

H2SO4 OMe

O Et Et N N N Et OBF F 3 4 F H2O F N N N

MeOH MeO MeO N F 70% N MeO Figure 9.46 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 325

Polyfluoroaromatic Compounds 325

δ − H F F F N C δ+ C C Nuc Nuc

9.47A 9.47B

Figure 9.47

½117 i FFFFFF

N NNCl Cl 23% 57%

i, HCl, 100Њ C, Sulpholan

Br Cl F F ½118 xs BBr xs BCl3 F 3 FF F 140Њ C 150Њ C N Br N N Cl

88% 91%

Figure 9.48

As explained above, these are potentially important processes because introduction of bromine by these simple procedures allows access to the powerful range of palladium chemistry that is now available [112] (Figure 9.49).

3 Fluoride-ion-induced reactions Polyfluoroalkylation: Some of the chemistry of polyfluoroalkyl anions, generated by reaction of fluoroalkenes with fluoride ion, was discussed in Chapter 7, where the analogy between the role of fluoride ion in fluorocarbon chemistry and the role of the proton in hydrocarbon chemistry was emphasised. This analogy has been extended to include reactions of polyfluorinated anions, generated in the same way, with activated polyfluoro-aromatic systems in what may be regarded as the nucleophilic counterpart of Friedel–Crafts reactions [119] (Figure 9.50). Polysubstitution raises some complications for three reasons: (a) when two polyfluoroalkyl groups are already present these can, in some cases, control the position of further substitution; (b) some of the reactions are reversible; and (c) substitution at the position most activated to attack sometimes results in crowding and therefore not the most thermodynamically stable system. This can lead to a competition between kinetic and thermodynamic control of reaction products [116, 122–128]. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 326

326 Chapter 9

C CC H N Br N 3 7 i F F ½112 ii N N Br C CC3H7

i, CuI, (Ph3P)3PdCl2, Et3N ii, C3H7C CH

Figure 9.49

F CF2=C CF3 C

Ar CF3 C ArF F CF C F

cf C ArH CArH

RF RF

i F F F ½120 CF3CF=CF2

N N N RF

i, KF, Sulpholan RF = CF(CF3)2

RF RF

i F F F CF2=CF2 ½121

N N N RF i, KF, Sulpholan RF = CF2CF3

Figure 9.50

The rather complicated system that results in the pyridine system, after the trisubstitution stage has been reached using perfluoroisopropyl anions [116, 122–124, 128], is shown in Figure 9.51. At lower temperatures, after disubstitution, further attack on 9.51D is kinetically preferred at the 5-position through 9.51B, with the perfluoroalkyl groups now controlling the orientation, as explained earlier. However, at higher temperatures, the process becomes reversible with attack by fluoride ion occurring at the 5-position in 9.51A, leading to displacement of a perfluoroisopropyl group that can then re-enter, at higher temperatures, at the 6-position via 9.51F. Attack by fluoride ion can also occur at the 4-position in 9.51A, giving the 2,5-derivative 9.51C. Finally, the situation is further Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 327

Polyfluoroaromatic Compounds 327 complicated by the fact that the perfluoroisopropyl anion is in equilibrium with the perfluoroalkene and this produces oligomers (see Chapter 7). The crowding that arises from a perfluoroisopropyl group is reflected by the 19F NMR spectra where, for example, for the compound 9.51D at 408 C two geometric isomers 9.51D1 and 9.51D2 may be detected [125, 126, 129], with the 4-substituent being essentially in two conformations.

F RF = CF(CF3)2 ½116, 122, 123 N RF

9.51A − − F F

F R RF F R RF F

F F F

N RF N RF

9.51B

RF RF

F CF(CF3)2 F CF(CF3)2 N R F N RF 9.51C 9.51D

R RF F

− F −F F F F N N R RF RF RF F 9.51E 9.51F

− −F CF3CF=CF2 (CF3)2CF

CF3CF=CF2

Dimers and Trimers

Figure 9.51 Contd Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 328

328 Chapter 9

CF F 3 F3C F ½125, 126, 129 C C F C CF3 3

F F

N F N F CF3 CF F3C F3C 3 9.51D1 9.51D2

Figure 9.51 Continued.

The 2-substituent is aligned preferentially with the CF3 groups towards nitrogen and it is understandable, therefore, that the trisubstituted isomer 9.51E is more stable than 9.51A. Tetrafluoroethene leads only to the 2,4,5-trisubstituted compound [124], which does not rearrange, whilst perfluoroisobutene gives only the 2,4,6-trisubstituted compound; the 2,4,5-isomer, in this case, is probably very crowded. This variation in the orientation of trisubstitution products obtained with the alkene used is related to the reversibility of the process and to the crowding occurring in the 2,4,5-isomer. Carbanion stabilities decrease in the series ðCF3Þ3C > ðCF3Þ2CF > CF3CF2 and therefore reversibility and crowding also follow this series (Figure 9.52).

RF RF i ½121, 124 F F CF2=CF2 N N N RF (RF)n i, CsF, Tetraglyme, 80C RF = CF2CF3

i CF2=C(CF3)2 F F ½124 N N RF RF i, CsF, Tetraglyme

RF = C(CF3)3

Figure 9.52

Fluoride-ion-induced rearrangements of perfluoro(alkyl-aromatic) compounds may be regarded as a further stage in the analogy between fluoride-ion- and proton-induced reactions [124, 127]. Those that have been established so far occur by intermolecular processes, as indicated by, for example, crossover experiments [116, 122, 123], whereas proton-induced rearrangements of alkylbenzenes may be intermolecular or intramolecular, depending on the system. However, intramolecular anionic migrations of polyfluoroalkyl groups remain to be found but are very unlikely. Only in the case of triazines have perfluoroalkyl groups been introduced directly from the perchloro compounds [130]. The 1,2,3triazine system gave an unusual product, Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 329

Polyfluoroaromatic Compounds 329 arising from nucleophilic attack at N in 9.53B, accompanied by loss of fluorine from a tertiary site (Figure 9.53). A similar process occurs in the reaction of 2,3-dimethylbuta- diene with 9.53B, giving the unusual spiro system 9.53D [131] (Figure 9.53), but without the loss of fluorine.

F3C CF3 F RF C ½130 R RF F R RF RF F RF RF Cl N N N N N N N N N N N N

RF RF = C(CF3)3 9.53A 9.53B 9.53C

RF RF R R RF F F RF RF RF RF ½131 i N N N N N N N N N

H3C CH3 H3C CH3 9.53B 9.53D

i, CH2=CH(CH3)CH(CH3)=CH2

Figure 9.53

Recent methodology, using amines as initiators to provide the active fluoride ion, in the absence of a solvent, has made access to these sytems on a large scale quite feasible [115]. A recent exciting development [132, 133] of this chemistry involves conversion of perfluoro(4,5-di-isopropyl)phthalonitrile to corresponding metal perfluorophthalocyanine complexes; for example, when perfluoro(4,5-di-isopropyl)phthalonitrile was melted with zinc acetate at 1808C, a blue-green solid was obtained which was established as the phthalocyanine derivative. These perfluoroalkyl derivatives are much more soluble than other halogenated phthalocyanines and, moreover, they appear to be excellent sensitisers for the production of singlet oxygen. Reactions involving chlorotrifluoroethene and bromotrifluoroethene introduce further complexities which are summarised in Figure 9.54 [134]. Direct substitution may occur giving 9.54A, but this is frequently accompanied by loss of Cl or Br from the side chain to give a pentafluoroethyl derivative 9.54B. Exchange is also possible (when X ¼ Br) to give 9.54C, together with a vinyl anion that may then react to give 9.54F, which is also able to form an anion 9.54E, and this anion can finally give a diaryl derivative 9.54D. Results relating to this scheme are shown in Table 9.8. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 330

330 Chapter 9

F CF2=CFX CF3CFX ½134 X = Cl, Br

F F + ArFCFXCF3 ArFCF2CF3 9.54A 9.54B ArFF CF3CFX

CF2=CFX

CF3CFX2 + CF2CF

9.54C ArFF

F (ArF)2CFCF3 ArFCFCF3 ArFCF=CF2

9.54D 9.54E 9.54F

Figure 9.54

Table 9.8 Polyfluoroalkylations and related reactions

Reaction Ref.

N N CsF F C3F6 [CF(CF3)2]nF3−n [135] NN 200−300C NN

n = 1, 39%; n = 2, 51%; n = 3, 5%

RF RF RF

RF N i N N N [136] F F F 5 C3F6 + + N R N N N F RF RF RF RF 6% 81% 3% Њ i, CsF, Sulpholan, 70 C RF = CF(CF3)2

i F F CF3CF=CFCF3 [137] N N RF

i, CsF, Sulpholan, 100Њ C RF = CF(CF3)CF2CF3

Contd Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 331

Polyfluoroaromatic Compounds 331

Table 9.8 Contd

CF3CF2 CF3CF2 N i N N F [134] CF2=CFCl F F N N N CF3CF2 i, CsF, Sulpholan, 90C 57% 19%

i F CF2=CFBr NF CFCF3 + CF3CFBr2 [134]

N 2

i, CsF, Sulpholan, 90Њ C

CF3CF2 CF3CF2 N i N N [134] F CF2=CFBr F F N N N CF3CF2

i, CsF, Sulpholan, 90 C

F CF3

C CF3 C F F3C C F3C C n

[138] i F CF3C CCF3 F F N N N

i, CsF, Sulpholan, 110Њ C n = 2 and 3

CO2Et EtCO2C

i [138, 139] F F EtO2CC CCO2Et N N i, CsF, Sulpholan

CF3 C F F3C C n

i F F CF3C CCF3 [140]

CN CN

i, CsF, DMF, 125Њ C Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 332

332 Chapter 9

The mechanism of displacement of chlorine and bromine by fluoride from the side 0 chain of these systems is of interest. It has been suggested that an SN2 type of displacement of fluorine from 3-trifluoromethylquinoline occurs in reactions with sodium ethoxide [141] (Figure 9.55), and a similar process could account for the displacements of chloride or bromide by fluoride from 9.54A that were indicated in Figure 9.54.

EtO H CF 3 CF2 OEt i ½141

N N

i, NaOEt/EtOH/Reflux

CF=OEt CF2OEt −F

N N

EtO etc

C(OEt)3 CO2Et

H2O

N N

Figure 9.55

A striking example of an intramolecular nucleophilic displacement of tertiary F is shown in Figure 9.56 [142]. Further examples of polyfluoroalkylation are given in Table 9.8.

Other systems: Additions of perfluoro-2-butyne [143] and acetylene dicarboxylic ester [139] to perfluoro-aromatics will also occur (see Table 9.9 and Chapter 7, Section IIIB). The extending anion may be trapped, and the more reactive the aromatic compound used, the more effective the competition with polymer formation (Figure 9.57) [144]. Cyanuric chloride, rather than the fluoride, is used for the formation of polyfluoroalkoxy derivatives [145]: the probable advantage of using the perchloro compound lies in reducing the possibility of a back-reaction when X ¼ Cl in the sequence shown in Figure 9.58.

4 Cyclisation reactions Many procedures are now available for forming cyclic systems [147] and several will be dealt with later; this section is concerned with procedures that, at some stage, involve nucleophilic aromatic substitution. In the examples shown in Figure 9.59 the addition and cyclisation occur in a single process, whereas, in other cases (Figure 9.60), an intermedi- Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 333

Polyfluoroaromatic Compounds 333 ate is isolated before cyclisation. Polycyclic systems may be obtained from ortho-difunctional compounds (Figure 9.61).

NMe CF3 2 NMe2 R R F F F3C C N i N ii N F ½142 N N N Me N 2 Me2N R R F F F RF (Yellow) RF = CF(CF3)2 iii

H3C CH3 CF3 NMe CF3 N 2 F C C F C C 3 3 N N BF H C N N 4 2 N Me N 2 H C 3 RF RF iv (Purple)

NMe CF F3C 3 H N i, Me2NH/DMF/Room Temp. ii, Standing or on addition of water N H N iii, BF3.Et2O iv, Moist Acetone CH3 RF (Colourless)

Figure 9.56

CF3C CCF3 + F CF3CF=CCF3

ArFF CF3C CCF3

CF3CF=C(CF3)C(CF3)=CCF3

ArFF CF3C CCF3

C(CF3)=CF(CF3) n

Polymer

Figure 9.57 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 334

334 Chapter 9

RFO + ArX ArORF + X (X + Cl or F) ½146

N N Diglyme Cl (CF ) CO.KF [OCF(CF ) ] 3 2 − Њ 3 2 3 NN 10 C NN

86% conversion

Figure 9.58

COOEt i, ii C F F C SH S COOEt ½148

i, n-BuLi iii, −F ii, EtOOCC CCOOEt iv, H2SO4 COOEt CH Cu C F F CH Quinoline C S S COOEt

H C NaH COOEt F CH3COCHCOOEt Na F THF C ½149

OCH3

COOEt C COOEt F Base C C F C O CH3 HO CH3

H H C i C F H F C C ½146, 150 OCH3 OCH3

i, NaH.1THF, 2DMF reflux

Figure 9.59 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 335

Polyfluoroaromatic Compounds 335

H H ½148 C i C F H F H C C SH O CH3 HS CH3

Њ i, H2S, EtOH, O C ii ii, Pyridine, NaOH, Reflux

H C F C

S CH3

Figure 9.60

i F F + SCl2 FF½151 or S2Cl2 Li Li S − Њ i, Et2O, hexane, 78 C

Figure 9.61

More recently, it has been demonstrated [152] that polyhalopyridines may be used to synthesise a series of macrocycles, making use of the fact that, if the 4-position is blocked, then the remaining 2,6-sites are available to react with difunctional derivatives (Figure 9.62). X X

F F X N O N O O O

i ii F O O ½152 N O N O O N O F F

X X

X = CF(CF3)2, 94% X = CF(CF3)2, 64% X = OMe, 80% X = OMe, 85%

i, Me3SiOCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days

ii, Me3SiOCH2CH2OCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days

Figure 9.62 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 336

336 Chapter 9

C Reactions with electrophilic reagents Displacement of Fþ from an aromatic system by electrophiles is obviously not a very favourable process; indeed, fluorine might be considered as the worst possible leaving group in a non-concerted process. Nevertheless, reactions of concentrated nitric acid with perfluoro-aromatic compounds, for example perfluoronaphthalene, give quinones, or addition products may be obtained using HNO3 in HF or NO2BF4 in Sulpholan [153]. Thus, perfluorinated systems will undergo reactions with some strong electrophiles to give products that formally arise from electrophilic displacement of fluorine, whatever the detailed mechanism may be (Figure 9.63).

CH3 CH3 i ½1, 154 F F F F F F

Њ i, CH3F, SbF5, SO2ClF, 20 C

Figure 9.63

Ring fission to the phthalic acid derivative has been observed [155] (Figure 9.64).

F NO2 F NO2 F F ½153, 155 i F FF F F F F F F F 61% c. HNO 3 H2O

O O COOH F O

F F F

COOH F F O F 71% + i, NO2 (NO2BF4 or HNO3.HF)

Figure 9.64

Sigma-complexes have been generated, and their NMR spectra observed, by reaction of various dienes with antimony pentafluoride [156, 157] (Figure 9.65). Under certain conditions, radical cations have been observed [158] using ESR, and stable radical-cation salts have been fully characterised [159, 160] (Figure 9.66). Fluorine in the side chain can, of course, be hydrolysed under acidic conditions [18], whilst the polyfluorobenzyl cation may be obtained by removal of fluorine from perfluorotoluene [161] (Figure 9.67). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 337

Polyfluoroaromatic Compounds 337

O FF ½156, 157

SF4 SbF5 F F F5

SbF O 6

H2O O O

F F

Figure 9.65

½158 SO3.SbF5 FF SO .SbF Oleum FF 3 5

C6F6 + O2AsF6 C6F6 AsF6 + O2 ½159, 160

C6F6 + NO AsF6

Figure 9.66

CF3 COOH i F F ½18

CF3 COOH

Њ i, H2SO4, SO3, 150 C, 12hr

CF3 CF2 i F F ½161

Њ i, SbF5, HF, 50-60 C CF3CF=CF2

CF2CF(CF3)2

Figure 9.67 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 338

338 Chapter 9

Hydrogen in a highly fluorinated system can often be displaced surprisingly readily using electrophilic reagents (Figure 9.68); this reflects the fact that a transition state resembling that in Figure 9.69 is stabilised by fluorine atoms at the ortho and para sites by donation of electron density from the non-bonding p-orbitals on fluorine. Indeed, a perfluorinated arenium salt has been generated from perfluorocyclohexa-1,4-diene (Figure 9.65). Electrophilic cleavage of pentachlorophenylpentafluorophenylmercury provides a useful direct competition between pentafluorophenyl and pentachlorophenyl, for electrophilic attack. Exclusive attack at pentafluorophenyl occurs, showing that the cumulative activating effect of the ortho- and the para-fluorine substituents is dominant [168] (Figure 9.70).

D Free-radical attack [169] Photochemical chlorination of perfluorobenzene [170] and perfluoropyridine [171], and reactions with bistrifluoromethyl nitroxide [171], give addition products, although the C5N bond is very resistant to radical attack (Figure 9.71). It is well known that free-radical aromatic substitution occurs readily when aryl radicals are used, and extensive studies have been made using diaryl peroxides as the source of these radicals. The effect of fluorine on the process may be considered in two parts: first, most substituents may be expected to encourage the formation of radical intermediate 9.72A in Figure 9.72; second, in reactions with hydrocarbon radicals, polar effects should also increase reactivity, since the ring would be made more electrophilic. The converse would be expected to apply with electrophilic radicals, e.g. CF3 or C6F5. By contrast, it is not easy to predict the fate of radical 9.72A, once formed; fluorine atoms are unlikely to be generated, but transfer of a fluorine atom to another species is possible. Arylation of perfluorobenzene does indeed occur when dibenzoyl peroxide is used, but

ðC6F5COOÞ2 gives only tar: the scheme shown in Figure 9.73 has been proposed [172–174]. In contrast, perfluoronaphthalene gives a mixture of products with benzoyl peroxide, but they mainly arise from attack by C6H5CðOÞO [173]. Cyclisation may be achieved in some electrochemical oxidations. These have been formulated as radical substitutions [176, 177] (Figure 9.74). Electrochemical reduction of polyhalopyridines has been observed; the position of H-transfer corresponds with calculated spin and charge densities [179] (Figure 9.75). Reductive defluorination will also occur under relatively mild conditions, in some circumstances by electron transfer from metals, e.g. zinc [180, 181] (Figure 9.76).

1 Carbene and nitrene additions Additions of carbenes to perfluorobenzene have been reported [182, 183] and tropylidene structures for the products have been proposed (Figure 9.77). Addition of difluorocarbene to perfluorobenzene has been proposed to account for the formation of perfluorotoluene and other perfluoromethylbenzenes in the pyrolysis of perfluorobenzene with potassium fluoride, or with polytetrafluoroethene as a difluorocarbene source [184, 185]. Indeed, Russian workers have studied the pyrolysis and Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 339

Polyfluoroaromatic Compounds 339

i F F CH ½162 3 Њ i, CHCl3, AlCl3, 150 C

H Br

i F F ½163

− Њ i, Br2 (or I2), Oleum, 60 65 C

H NO2

i F F ½164, 165

− Њ i, HNO3, Sulpholan, BF3, 60 70 C

H CH(CH3)2

i F F ½166

90-94% Њ i, C3H6, CBr4, AlBr3, 0 C

H C6F5

SbF5, 3 F F F ½1, 154

C6F5 C6F5

i F F ½167

i, FeBr2.CCl4, Reflux

NO2

i F F ½167

Њ i, HNO3, Oleum, 70 C

Figure 9.68 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 340

340 Chapter 9

E H

Figure 9.69

C6Cl5Hg H − Cl i ½168 C6Cl5HgCl + C6F5H C6F5HgC6Cl5 +

F5 i, HCl, 100Њ C, 65hr, Sealed tube

Figure 9.70

Cl F F Cl Cl2, hn Cl F ½170 F 48hr F Cl Cl F FCl

Cl F F Cl Cl2, hn Cl F F ½171 35hr F N Cl N F

Figure 9.71

R R F

R F F F ?

F5 9.72A

Figure 9.72 co-pyrolysis of systems containing perfluoro-aromatic compounds and developed an extensive chemistry where a variety of substituents appear to be eliminated, frequently in preference to fluorine [186–188] (Figure 9.78). Elimination of difluorocarbene from a s-complex 9.79A has been proposed, although the fate of the rest of the molecule is not clear, and the addition could involve either an insertion reaction (a) or formation of a tropylidene (b) (Figure 9.79). Similar processes can be proposed to account for the formation of trifluoromethyl derivatives in the pyrolysis of heterocyclic compounds [189–193] (Figure 9.80). In contrast, a stable carbene has been synthesised having a push–pull combination of electron donation and withdrawal [194] (Figure 9.81). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 341

Polyfluoroaromatic Compounds 341

Ar F Ar

ArCOO F Ar F ArCOOF ½172, 174, 175

F5 Coupling

Ar F FF F Ar

Figure 9.73

−e −H ½177 C6F5NH2 C6F5NH2 C6F5NH

C6F5NH2

N N −e FF FFF etc N H2N

O O C C FF FF ½178 N H2N H

Figure 9.74

Insertion of nitrenes occurs readily and may lead to ring expansion and a variety of rearrangements [195, 196] (Figure 9.82). Cyanotetrafluorophenylnitrene gives very high yields of C2H insertion compounds [197] (Figure 9.83).

E Reactive intermediates 1 Organometallics Fluorocarbon organometallic compounds [198, 199] are discussed more generally in Chapter 10, but polyfluoroaryl-lithium, -magnesium and -copper compounds are particularly important in organic synthesis, as outlined below. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 342

342 Chapter 9

X X X ½179

i F

N N F4 N F4

ii H X H

F N N F4 X = Cl, F − i, Hg Cathode, DMF, Et4NBF4, 1.8V (SCE) ii, Hydroquinone

Figure 9.75

CF3 CF2(CH2)5CH3 CH3 CF3 ½180 H i F F F F

CF3 CF3 CF3 CF3 Њ i, Zn (Cu), DMF, H2O, 1-Hexene, 65 C

COOH COOH ½181 i FF FF

i, Zn, aq.NH3, rt, 2hr

Figure 9.76

hν ½182 C6F6 + N2 F 30%

hν CF3 ½183 C6F6 + (CF3)2CN2 F 20% CF3

Figure 9.77

Lithium and magnesium derivatives: Bromopentafluorobenzene forms a Grignard reagent readily [163] which can be used in conventional ways in syntheses [200, 201] (Figure 9.84). The tetrafluoropyridyl compound can be obtained in a similar way [98, 100, 103]. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 343

Polyfluoroaromatic Compounds 343

550ЊC C F + C F (CF ) C6F6 + CF2CF2 n 6 6 6 6-n 3 n ½185

n = 1,2,3

CF 2 CF2=CF2 ½186 C6F5X C6F5CF2 C6F5CF2CF2CF2

−F (?)

F F

Figure 9.78

F F

F C6F6 CF2 (KF) F5 9.79A (b) Addition (a) Insertion C6F6

C6F6 F F C6F5CF3 F F

F F F F

Figure 9.79

CF F C CF 3 3 3 ½193 550Њ C F CF CF F F 2 2 n N N N

60% 6%

CF3 ½189 i F F N N 85−90% +2- and 4- isomers

i, KF, 8hr, 550−560Њ C

Figure 9.80 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 344

344 Chapter 9

F3C ½194 H3C N C R

F3C

Figure 9.81

Њ 45 C F N NC ½195 C6F6 + N3CN

i C F N 6 5 3 [C6F5N:] F ½196 N

i, Flash Vac. Pyrolysis/300Њ C

N FF N

Figure 9.82

CN CN CN

hν c-C6H12 F F F ½197

N3 N N

H C6H11 75−80%

Figure 9.83

i CO2 ½200 C6F5Br C6F5MgBr C6F5COOH 67% i, Mg, Et2O, or THF

O ½201

C6F5CH2CH2OH

Figure 9.84

Lithium derivatives [202] are more versatile and more convenient to use than the Grignard reagents, although the report of serious explosions occurring with pentafluoro- Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 345

Polyfluoroaromatic Compounds 345 phenyl-lithium [203] emphasises the extreme care that must be taken. Although many and varied reactions using pentafluorophenyl-lithium and other polyfluoroaryl-lithiums have been carried out in the author’s laboratory, without incident, it is clear that all polyfluoroaryl-lithium or polyfluoroarylmagnesium derivatives should be treated as potentially hazardous, particularly when hydrocarbon solvents are used at low temperatures, at which the lithium derivative may be precipitated. In general, polyfluoroaryl-lithiums are best obtained by metal–halogen exchange [204] using, for example, commercially available butyl-lithium, or by metallation of hydro compounds [205–207], the hydrogen being especially acidic when flanked by two fluorine atoms. The latter method has the advantage of not generating alkyl bromides that can be difficult to separate from some products (Figure 9.85).

Et2O ½204 C6F5Br + n-BuLi C6F5Li + n-BuBr

−78Њ C

H Li

Et O ½205, 208 F + n-BuLi 2 F

−78Њ C

X X X = H or F

Figure 9.85

The use of some polyfluoroaryl-lithiums in organic synthesis is illustrated in Table 9.9; these reagents have, of course, been used to make many corresponding derivatives of other elements, but this will be illustrated in the next chapter.

Table 9.9 Some organic syntheses using polyfluoroaryl-lithiums

Reaction Ref.

i C6F5Li C6F5OH 39% [209] i, B(OMe)3, H2O2

i, ii [210] C6F5Li C6F5SH 46%

i, S8; ii, H2O

i C6F5Li C6F5COOH 99% [205] + Њ i, CO2; ii, H, Et2O, <55 C

HCO(NMe2) C6F5Li C6F5CHO 61% [211]

Contd Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 346

346 Chapter 9

Table 9.9 Contd

(MeO)2CO C6F5Li (C6F5)2CO 70% + (C6F5)3COH [212]

OH OLi OH n-BuLi i, CO2 [209] F F + F 84% ii, H H Li COOH

Br Br Br F H F H F H i ii [207, 213]

H Br Li Br HOMe2C Br F F F − Њ − Њ i, LDA, THF, 78 C; ii, Me2CO, 78 C

H Li COOH Cl F Cl F Cl F i ii, iii [214]

H N F H N F H F F − − + i, LDA, THF, 78 C; ii, Me2CO, 78 C; iii, H

SCl2 FF FF66% [212]

Li Li S

Copper compounds [215]: An interesting contrast occurs between phenyl- and pentafluorophenyl-copper compounds, in that the fluorinated derivatives are considerably more stable [216–220] and are useful reagents in organic synthesis (Figure 9.86). A remarkable double insertion of difluorocarbene, derived from trifluoromethyl copper, has been reported [227] (Figure 9.87).

2 Arynes Polyfluoroaryl-lithiums and, to a lesser extent, the Grignard reagents will decompose by a b-elimination of metal fluoride, leaving an aryne whose properties are considerably affected by the remaining fluorine atoms. The highly electrophilic nature of these species leads to some reactions, e.g. with benzene derivatives, that are not shown by benzyne itself [228] (Figure 9.88). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 347

Polyfluoroaromatic Compounds 347

Monoglym e C F I + 2Cu C F Cu + CuI ½221224 6 5 rt 6 5

Dioxane Et2O C6F5MgBr + CuI [C6F5Cu] C6F5Cu.Dioxane ½216, 219, 220

− 130Њ C Dioxane

PhI C6F5C6H5 [C6F5Cu]4 87% MeI 200ЊC

C6F5Me

39% C6F5C6F5

Cu(I)Cl, Mg MeCOCl C6F5Cl [C6F5Cu] C6F5COMe 72% − Њ ½225 THF 5 C

CBr2=CHBr

C6F5C CC6F5 43%

CF2=CFI i Cu(I)I ½217 C6F5Cl C6F5Li [C6F5Cu] C6F5CF=CF2 55%

i, n-BuLi, THF, −70Њ C

C6F5Cu + CH2I2 CH2(C6F5)2 ½226

Figure 9.86

−30Њ C C6F5Cu + CF3Cu C6F5CF2CF2Cu ½227 DMF

Figure 9.87

X Li X X ½228 S F FFS

X X X = H, Cl −S

F X

Figure 9.88 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 348

348 Chapter 9

In addition to these cycloaddition reactions with nucleophilic p-donors, tetrafluorobenzyne is very susceptible to more general nucleophilic attack. Biphenyl derivatives often occur as by-products in reactions of pentafluorophenyl-lithium, formed by addition to the benzyne [204, 229] (Figure 9.89). Li H Li ½204 C F Li F F 6 5 F H F

C6F5 C6F5

Figure 9.89

A similar process, but involving further attack on the biphenyl and polyphenyls initially produced, may account for the high-molecular-weight materials formed in the decomposition of pentafluorophenylmagnesium bromide at elevated temperatures in THF solution [230, 231] (Figure 9.90). MgBr ½230, 231 C6F5MgBr C6F5MgBr F FF

C6F5MgBr

MgBr MgBr

FFC6F5 FFC6F5

Figure 9.90

This type of process appears to occur even more easily with trifluoropyridyne [232] (Figure 9.91). Br Li

i Furan ½232 F F F N N N

− Њ n-BuLi i, n-BuLi, Et2O, 78 C

Polymer

Figure 9.91

The addition of lithium pentafluorothiophenate to tetrafluorobenzyne leads to perfluorodibenzothiophene by a novel cyclisation [233] (Figure 9.92). Trapping with a 1,3-dipole has also been described [234] (Figure 9.93). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 349

Polyfluoroaromatic Compounds 349

i F F F F ½233

SH Br S

Њ i, n-BuLi, Et2O, C6H8, 0 C

F F F F S 70% S

Figure 9.92

H Ph Li PhCH=N(Ph)O F F F N Ph ½234 O

Figure 9.93

Tetrafluorobenzyne may be involved in a number of other reactions, as outlined in Figure 9.94. The p-benzyne (9.94A) has been observed using matrix isolation techniques [236].

3 Free radicals Free-radical aromatic substitutions were described earlier in this chapter (Section IID); the generation of polyfluoroaryl radicals may be achieved by conventional procedures and the effect of fluorine is mainly in making the radical more electrophilic in comparison with the hydrocarbon counterparts. This has been illustrated for pentafluorophenyl radicals in a quantitative fashion by competition for the radicals between chlorobenzene and benzene [237], giving kðC6H5Cl=C6H6Þ¼0:72 in comparison with a value for phenyl radicals kðC6H5Cl=C6H6Þ¼1:06. This lower relative rate for pentafluorophenylation, coupled with a greater tendency towards ortho, para substitution than with phenyl, is a quite clear indication of the electrophilic character of the fluorocarbon radical. This is also clear from other substituent effects, e.g. the greater proportion of meta substitution with nitrobenzene shown in Figure 9.95. Other reactions involving polyfluoroaryl radicals are shown in Figure 9.96. Thermal reactions of iodo compounds provide some useful direct syntheses of various sulphur and selenium compounds [240, 241], presumably involving radicals, and radicals are also produced from iodo derivatives by photolysis [242] (Figure 9.97). The photo-reduction of perfluorobenzophenone in isopropanol [243] provides an interesting contrast with the classical reduction of benzophenone to benzopinacol under the same conditions (Figure 9.98). This difference between the two systems has been attributed to the greater resonance stabilisation of the radical 9.98A in comparison with 9.98B and to electron-pair repulsions inhibiting the dimerisation of 9.98A. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 350

350 Chapter 9

F O Hg

O 300Њ C 83% F Hg F Hg ½155 O Hg O F

Hg Ag F Hg F F 39% ½155 ~255Њ C Hg

750Њ C F O F F 24% ½235 0.6mmHg O

i F F 9.94A ½236 I i, hν, Ne matrix, 3K

Figure 9.94

C6F5NH2 + C5H11ONO C6F5 ½237

C6F5 + C6H5CH3 C6F5 C6H4CH3

o-(62.1), m-(21.5), p-(16.4)%

C6F5 + C6H5NO2 C6F5 C6H4NO2 o-(20.8), m-(53.4), p-(25.8)%

Figure 9.95

Pentafluorophenol is oxidised by lead tetra-acetate, giving products arising from intermediate C6F5O radicals [244, 245] (Figure 9.99). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 351

Polyfluoroaromatic Compounds 351

i C 6F5NHNH2 C6F5C6H5 ½198

i, Bleaching Powder, C6H6

i ii C6F5COCl (C6F5COO)2 C6F5COOH ½238, 239 + C6F5C6F5 i, NaOH, H O ; ii, C H , 80Њ C 2 2 6 6 + C6F5COOC6F5

Figure 9.96

S, 230Њ C 241 C6F5I (C6F5)2S 70% ½

I S

S, 250Њ C F F F 60% ½241 I S

C6F5 hν ½242 C6F5I 70% Me N Me CH3CN Me N Me H H

Figure 9.97

HO hν ½243 (C6F5)2CO (C6F5)2OH C F etc Me CHOH C6F5 2 9.98A

Me2CHOH

(C6F5)2CHOH + Me2CO

Ph Ph

cf (C6H5)2C=O (C6H5)2COH Ph Ph HO OH 9.98B

Figure 9.98

4 Valence isomers [246–248] Photochemistry of fluorinated aromatic systems has made an important contribution to the study of valence isomers because it has been possible to isolate and characterise some species on which there had previously only been speculation. Some of these, as might be expected, are very unstable (sometimes, treacherously so) towards reverting to Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 352

352 Chapter 9

O O ½244 F i ii C6F5OH C6F5O F F OC6F5

F OC6F5 i, Pb(OAc)4 ii, Dimerisation iii iii, C6F5O etc. O F

F OC6F5

C6F5O

Figure 9.99 the corresponding aromatic form. This is the case with perfluorobenzene but, when perfluoroalkyl groups are present, valence isomers have been isolated that are remarkably stable and thus present some fascinating systems to organic chemistry. Let us consider the possible effects of fluorine or fluorocarbon groups as substituents on the transformation of a benzene derivative to a para-bonded species 9.100A,a benzvalene 9.100B or a prismane 9.100C (Figure 9.100).

X + + 6 X 6 X6

9.100A 9.100B 9.100C

X = F or perfluoroalkyl

Figure 9.100

We established in Chapter 7, Section IIA, that fluorine prefers to be attached to saturated carbon and it is useful to recall the greater heat of polymerisation of tetrafluoroethene than ethene (by about 73 kJmol1). In the same way, fluorine in a benzenoid system may encourage the formation of 9.100A–C, where unsaturation is progressively decreasing. The most obvious effect of a perfluoroalkyl group is to increase the crowding. This is not necessarily relieved in the valence isomers and indeed it could be increased, since C–C–C bond angles are reduced from 1208, in the aromatic form, when the valence isomer is formed. However, crowding could have a profound effect on the the resonance energy of the aromatic isomer by reducing planarity, whereas no such consideration applies to the valence isomers 9.100A–C. Activation energies of reversion to the aromatic isomer vary in the range 96 128 kJmol1 [249] but the enthalpy changes DH for photoisomerisation are much more varied, e.g. 214 [C6F6], 117 [C6ðCF3Þ6] and 1 35 kJmol ½C6ðC2F5Þ6. It appears that the thermal stability of valence isomers increases with the number of perfluoroalkyl substituents. Not the least advantage of fluorocarbon Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 353

Polyfluoroaromatic Compounds 353 systems is the stability of carbon–fluorine bonds. In this sense fluorine or fluorocarbon groups are useful as ‘passive’ substituents [192], where skeletal rearrangements are being observed, in order to obtain a minimum of side-reactions. t-Butylfluoroacetylene is an extremely reactive compound that undergoes thermal oligomerisation, giving a benzene derivative and valence isomers [250] (Figure 9.101).

F F F ½250 (CH3)3CC CF F + +

F F F

∆ ∆

Figure 9.101

The para-bonded isomer of perfluorobenzene may be formed by irradiation, in the vapour phase, using 254 nm radiation [251–254] (Figure 9.102). Substituted benzenes, C6F5XðX ¼ H, CH3,CF3, OCH3Þ [255], and trifluorobenzenes, C6H3F3 [256], all form para-bonded species on irradiation.

F6 hn 254 F ½

Figure 9.102

Valence isomer 9.103A undergoes various reactions as a strained fluoroalkene (Figure 9.103). Very stable valence isomers have been isolated by irradiation of hexakis(trifluoromethyl)benzene and hexakis(pentafluoroethyl)benzene [257–259] in the gas phase or in solution. The sequence of formation of the isomers is shown in Figure 9.104. Kinetic and thermodynamic data for valence isomers have been compared [249, 260]. The bicyclopropenyl isomer (Figure 9.105) has been prepared by a carbene addition process; therefore, this system is quite unique in that all of the valence isomers are known and fully characterised.

Nitrogen derivatives: A remarkable series of transformations has been discovered with fluorinated pyridazines, giving pyrimidines and small amounts of pyrazines on pyrolysis [262, 263] and pyrazines on photolysis [264]. Highly specific substituent labelling occurs on pyrolysis and diazabenzvalenes, or vibrationally excited species approaching these, Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 354

354 Chapter 9

F6 F4 F5 MeO OMe OMe ½254 NaOMe + 9.103A

F6 F6 Br2 Br ½254 Br 9.103A

F6 O COOH O3 P2O5 F F O H O ½248 2 COOH 9.103A O

i i, ii

O ν F i, h ii, hν, furan F

Figure 9.103

170Њ C t1/2 9hr

(CF3)6 <270nm ½258, 259 >200nm

(F C) 3 6 >200nm

170Њ C

t1/2 135hr (CF3)6 >200nm (CF3)6

170Њ C

t1/2 129hr

Figure 9.104

(CF3)3 (CF3)3 F3C N ½261 CF3C CCF3 + C Cl N

Figure 9.105 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 355

Polyfluoroaromatic Compounds 355 have been suggested [192] in order to account for the results, although no valence isomers have actually been isolated. Cycloaddition processes have been ruled out by N-15 labelling experiments. Furthermore, rearrangement is encouraged by free-radical promo- tors, leading to the conclusion that these processes involve free-radical-promoted formation of diazabenzvalene derivatives [263] (Figure 9.106).

RF RF RF N R N N F F F ½263 N N N R RF F R RF R

−R

RF RF RF N N N F F N F N R N F R RF F

Figure 9.106

The situation is quite different in the photolysis reactions, where valence isomers of an aromatic diazine have been isolated, together with the pyrazines (Figure 9.107). From the structures of the isolated and characterised valence isomers, and the highly specific substituent labelling, a very unusual mechanistic pathway may be drawn as indicated in Figure 9.108. This appears to be the first case where substituent labelling has allowed each stage in a photochemical aromatic rearrangement to be identified through various intermediate valence isomers. R F F F R i F R F N F RF F N ½264,265 N 254nm N i N + N N gas phase N R RF R F F F F RF F F i = hν or heat ½264,265

F RF RF R F F F i F N 254nm N N gas phase + N N N R F RF F

RF F i = hν or heat

RF = F , CF(CF3)2 , CF2CF3 , CF(CF3)(C2F5)

Figure 9.107 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 356

356 Chapter 9

3 4

4 N 2 1 N 3

5 N 1 6 N 2

6 5

3 3 4

4 N 2 4 N 2 1 N 3

5 N 1 5 N 1 5 N 6 2 6 6 9.108A

Figure 9.108 Some of the valence isomers (e.g. 9.108A) have a half-life of a few minutes at 1008C. In contrast, valence isomers of some polyfluorinated pyridine derivatives have substantial stability [266] (Figure 9.109).

N N >200nm >200nm ½266 N 270nm (CF CF ) 3 2 5 (CF3CF2)5 (CF3CF2)5

Figure 9.109 Again, substituent labelling studies have enabled photochemical rearrangement mechanisms to be clearly associated with the intermediate valence isomers, in this case involving azaprismane derivatives (Figure 9.110).

Rearrangement a a x c y x a b b hν b b bbb ½267 x y b N + N + x N c c c cc N c c a heat heat heat heat cleavage, x cleavage, y cleavage, x

b b b b c bab c c a c c a c N NN

a = CF3CF2-; b = CF3-; c = (CF3)2CF

Figure 9.110 In some cases, photochemically induced eliminations occur; in the case of fluorinated 1,2,3-triazines, this has generated azetes [268, 269] which have been trapped and even observed by low-temperature isolation techniques [269] (Figure 9.111). Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 357

Polyfluoroaromatic Compounds 357

Adduct ii F RF R F RF RF F F RF ½268, 269 i N

N N N N R N F F RF RF

iii

RF RF N RF F F F N RF − F RF RFCN RF F

RF N R N F RF N F RF RF

i = hv; ii = furan; iii = 350Њ C

RF = CF(CF3)2

Figure 9.111 Thermal elimination of nitrogen presents a route to fluorinated alkyne derivatives [270] (Figure 9.112). Y X N ∆ XC CY ½270 N X Y X = Y = C6F5 (90%); X = CF3CF2; Y = C6F5 88%

Figure 9.112 Dewar thiophene (9.113A) and, from this, Dewar pyrrole derivatives have been isolated [246]. In contrast, photolysis of furan derivatives only promoted cyclopropenyl ketone rearrangements [271] (Figure 9.113). i (CF3)4 246 (CF3)3 ½ ii S (CF3)4 S S F C 9.113A 3

i, hν; ii, heat or Pd Catalyst

(CF3)3 ½271 ν (CF3)3 h X O X O

X = F or CF3

Figure 9.113 Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 358

358 Chapter 9

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193 R.D. Chambers, R.P. Corbally, T.F. Holmes and W.R.K. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1974, 108. 194 S. Sole, H. Gornitzka, W.W. Schoeller, D. Bournisson and G. Bernard, Science, 2001, 292, 1901. 195 F.D. Marsh and H.E. Simmons, J. Am. Chem. Soc., 1965, 87, 3529. 196 R.E. Banks, N. Venayak and T.A. Hamor, J. Chem. Soc., Chem. Commun., 1980, 900. 197 R.S. Pandurangi, K.V. Katti, C.L. Barnes, W.A. Volkert and R.R. Kunrz, J. Chem. Soc., Chem. Commun., 1994, 1841. 198 R.D. Chambers and T. Chivers, Organometal. Chem. Rev., 1966, 1, 279. 199 S.C. Cohen and A.G. Massey, Advan. Fluorine Chem., 1970, 6, 83. 200 R.J. Harper and C. Tamborski, Chem. Ind., 1962, 1824. 201 G. Fuller and D.A. Warwick, Chem. Ind., 1965, 651. 202 J. Jappy, Specialty Chemicals, 1995, 15, 58. 203 E. Kinseella and A.G. Massey, Chem. Ind., 1971, 1017. 204 D.E. Fenton, A.J. Park, D. Shaw and A.G. Massey, J. Organometal. Chem., 1964, 2, 437. 205 R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385. 206 A.J. Bridges, W.C. Patt and T.M. Stickney, J. Org. Chem., 1990, 55, 773. 207 P.L. Coe, A.J. Waring and T.D. Yarwood, J. Chem. Soc., Perkin Trans. 1, 1995. 208 C. Tamborski and E.J. Soloski, J. Org. Chem., 1966, 31, 743. 209 G.M. Brooke and B.S. Furniss, J. Chem. Soc. (C), 1967, 869. 210 G.M. Brooke, B.S. Furniss, W.K.R. Musgrave and M.A. Quasem, Tetrahedron Lett., 1965, 2991. 211 P.L. Coe, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1962, 3227. 212 R.D. Chambers and D.J. Spring, J. Chem. Soc. (C), 1968, 2394. 213 T.D. Yarwood, A.J. Waring and P.L. Coe, J. Fluorine Chem., 1996, 78, 113. 214 C. Bobbio and M. Schlosser, Eur. J. Org. Chem., 2001, 4533. 215 D.J. Burton and L. Lu in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer Verlag, Berlin, 1997, p. 45. 216 A. Cairncross and W.A. Sheppard, J. Am. Chem. Soc., 1968, 90, 2186. 217 C. Tamborski, E.J. Soloski and R.J. de Pasquale, J. Organometal. Chem., 1968, 15, 494. 218 S.S. Dua, A.E. Jukes and H. Gilman, J. Organometal. Chem., 1968, 12, 24. 219 A. Cairncross, H. Omura and W.A. Sheppard, J. Am. Chem. Soc., 1971, 93, 248. 220 A. Cairncross, W.A. Sheppard and E. Wonchoba, Org. Synth., 1980, 122. 221 R.D. Rieke and L.D. Rhyne, J. Org. Chem., 1979, 44, 3445. 222 G.W. Ebert and R.D. Rieke, J. Org. Chem., 1984, 49, 5280. 223 G.W. Ebert and R.D. Rieke, J. Org. Chem., 1988, 53, 4482. 224 D.J. Burton, Z.Y. Yang and K.J. MacNiel, J. Fluorine Chem., 1991, 52, 251. 225 A.F. Webb and H. Gilman, J. Organometal. Chem., 1969, 20, 281. 226 D.J. Burton and L. Lu in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 75. 227 Z.Y. Yang, D.M. Wiemers and D.J. Burton, J. Am. Chem. Soc., 1992, 114, 4402. 228 D.D. Callender, P.L. Coe, J.C. Tatlow and A.J. Uff, Tetrahedron, 1969, 25, 25. 229 D.D. Callender, P.L. Coe and J.C. Tatlow, Tetrahedron, 1966, 22, 419. 230 J. Thrower and M.A. White, Abstracts., 148th Meeting, American Chemical Society, Wash- ington DC, 1964, p. 19K. 231 C. Tamborski, E.J. Soloski and J.P. Ward, J. Org. Chem., 1966, 31, 4230. 232 R.D. Chambers, F.G. Drakesmith, J. Hutchinson and W.K.R. Musgrave, Tetrahedron Lett., 1967, 1705. 233 R.D. Chambers and D.J. Spring, Tetrahedron Lett., 1969, 2481. 234 M.A. Bigneli and A.E. Tipping, J. Fluorine Chem., 1992, 58, 101. 235 D.V. Gardner, J.F.W. McOmie, P. Albriktsen and R.K. Harris, J. Chem. Soc. (C), 1969, 1994. Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 364

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236 H.H. Wenk, A. Balster, W. Sander, D. Hrovat, W.T. Borden and T. Weston, Angew. Chem., Int. Ed., 2001, 40, 2295. 237 P.H. Oldham, G.H. Williams and B.A. Wilson, J. Chem. Soc. (B), 1971, 1094. 238 J. Burdon, J.B. Campbell and J.C. Tatlow, J. Chem. Soc. (C), 1969, 822. 239 P.H. Oldham and G.H. Williams, J. Chem. Soc. (C), 1970, 1260. 240 S.C. Cohen, M.L.N. Reddy and A.G. Massey, J. Chem. Soc., Chem. Commun., 1967, 451. 241 S.C. Cohen, M.L.N. Reddy and A.G. Massey, J. Organometal. Chem., 1968, 11, 563. 242 Q.-Y. Chen and Z.-T. Li, J. Chem. Soc., Perkin 1, 1993, 1705. 243 N. Filipescu, J.P. Pinion and F.L. Minn, J. Chem. Soc., Chem. Commun., 1970, 1413. 244 L.S. Kobrina, V.N. Kovtonyuk and G.G. Yakobson, Zh. Org. Khim., 1977, 13, 1447; Chem. Abstr., 1977, 87, 151814r. 245 V.N. Kovtonyuk, L.S. Kobrina and G.G. Yakobson, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 1984, 2, 119. 246 Y. Kobayashi and I. Kumadaki, Acc. Chem. Res., 1981, 14, 76. 247 D. Lemal in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 297. 248 D. Lemal, Acc. Chem. Res., 2001, 34, 662. 249 B. Sztuba and E. Ratajzak, J. Chem. Soc., Perkin Trans. 2, 1982, 823. 250 H.G. Viehe, Angew. Chem., Int. Ed. Engl., 1965, 4, 746. 251 G. Camaggi, F. Gozzo and G. Cevidalli, J. Chem. Soc., Chem. Commun., 1966, 313. 252 I. Haller, J. Am. Chem. Soc., 1966, 88, 2070. 253 I. Haller, J. Chem. Phys., 1967, 47, 1117. 254 G. Camaggi and F. Gozzo, J. Chem. Soc. (C), 1969, 489. 255 P. Cadman, E. Ratajczak and A.F. Trotman-Dickenson, J. Chem. Soc. (A), 1970, 2109. 256 G.P. Semeluk and R.D.S. Stevens, J. Chem. Soc., Chem. Commun., 1970, 1720. 257 M.G. Barlow, R.N. Haszeldine and R. Hubbard, J. Chem. Soc., Chem. Commun., 1969, 202. 258 D.M. Lemal, J.V. Staros and V. Austel, J. Am. Chem. Soc., 1969, 91, 3374. 259 M.G. Barlow, R.N. Haszeldine and R. Hubbard, J. Chem. Soc. (C), 1970, 1232. 260 D.M. Lemal and L.H. Dunlap, J. Am. Chem. Soc., 1972, 94, 6562. 261 M.W. Grayston and D.M. Lemal, J. Am. Chem. Soc., 1976, 98, 1278. 262 R.D. Chambers, M. Clark, J.R. Maslakiewicz, W.R.K. Musgrave and P.G. Urben, J. Chem. Soc., Perkin Trans. 1, 1976, 1513. 263 R.D. Chambers, W.K.R. Musgrave and C.R. Sergent, J. Chem. Soc., Perkin Trans. 1, 1981, 1071. 264 R.D. Chambers, J.A.H. MacBride, J.R. Maslakiewicz and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1975, 396. 265 R.D. Chambers, J.R. Maslakiewicz and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1975, 1130. 266 M.G. Barlow, J.G. Dingwall and R.N. Haszeldine, J. Chem. Soc., Chem. Commun., 1970, 1580. 267 R.D. Chambers and R. Middleton, J. Chem. Soc., Perkin Trans. 1, 1977, 1500. 268 R.D. Chambers, T. Shepherd and M. Tamura, J. Chem. Soc., Perkin Trans. 1, 1990, 975. 269 R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans., 1, 1990, 983. 270 R.D. Chambers, M. Clark, J.A.H. MacBride, W.K.R. Musgrave and K.C. Srivastava, J. Chem. Soc., Perkin Trans. 1, 1974, 125. 271 R.D. Chambers, A.A. Lindley and H.C. Fielding, J. Fluorine Chem., 1978, 12, 337. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 365

Chapter 10 Organometallic Compounds

Organometallic compounds have been referred to at various points in this book and their role as reactive intermediates, where significant, has been outlined. Frequent comparisons have been made between the chemistry of functional-hydrocarbon and corresponding functional-fluorocarbon systems with the aim of building up a picture of the effect of fluorine as a substituent on the chemistry of various functional groups, reactive centres and the like. Needless to say, a similar consideration of the effect of fluorine on the properties of carbon–metal bonds is fascinating in itself and, over the years, striking developments in this novel field of organometallic chemistry have been made. This book is about organic chemistry and it cannot cover this field of inorganic chemistry as a whole. What follows, therefore, is a discussion of systems that are largely of interest to, or useful to, the organic chemist. There are a number of reviews available [1–19], and other key references will be given in the text. The earliest and still one of the most dramatic contrasts between hydrocarbon and the corresponding fluorocarbon organometallic systems is that between dimethyl- and bistrifluoromethyl-mercury [20]. The latter is a white crystalline solid (melting point 1638 C) that is slightly soluble in water, whereas dimethylmercury is a covalent liquid (boiling point 928 C). In a less dramatic but more useful way, transition-metal compounds [21] are generally more thermally stable with fluorocarbon groups attached. Attached fluorocarbon groups often enhance the acceptor properties of a metal and the metal generally becomes more susceptible to nucleophilic attack. The converse also applies: that is, electrophilic attack becomes more difficult, especially in cases where a metal is attached only to perfluoroalkyl or perfluoroaryl groups, although the situation is more complicated with mixed derivatives.

I GENERAL METHODS OF SYNTHESIS It will become clear that, in some cases, the classical routes to organometallics are not available but, compensating for this, the different chemistry of, for example, unsaturated fluorocarbons has often been exploited to provide quite new synthetic approaches.

A From iodides, bromides and hydro compounds 1 Perfluoroalkyl derivatives Fluorocarbon organometallic chemistry began with the first syntheses of perfluoroalkyl iodides (see Chapter 7, Sections IIC, Subsection 7, and IIE, Subsection 2, for current methods). On the basis of classical methods, this might have been expected to lead logically to the corresponding lithio derivatives and these, in turn, to a considerable

366 Chapter 10 array of perfluoroalkyl derivatives of other elements. However, perfluoroalkyl-lithiums, as well as the corresponding magnesium compounds, too readily undergo elimination of metal fluoride; although the route has been used in some cases, the method is inevitably seriously restricted (Figure 10.1). i n-C4H9Li + i-C3F7I i-C3F7Li + n-C4H9I ½22

−LiF

CF3CF=CF2

i ii CH3Li + C2F5I [C2F5Li] C2F5C(OH)PhCH3 88% ½23

− + i, Et2O, 78 C ii, PhCOCH3, H etc.

Figure 10.1

A warning has been given [24] about carrying out exchange reactions to form pentafluoroethyl-lithium at very low temperatures, where violent decomposition has been observed. The most likely explanation for these events is that solid perfluoroethyl- lithium is precipitated at the low temperature and, of course, this is extremely unstable with respect to formation of the metal fluoride. The same cautionary note may be made for all fluorinated alkyl- or aryl-lithium compounds (see Chapter 9, Section IIE, Subsection 1) The carbon–iodine bond in perfluoroalkyl iodides is usually susceptible to homolytic fission; this was exploited in early work on the synthesis of mercurials and in later work relating to group IVB and transition-metal derivatives (Figure 10.2).

∆ CF3I + Hg CF3HgI ½20

hν (CH3)3SnSn(CH3)3 + CF3I (CH3)3SnI + (CH3)3SnCF3 ½25

Figure 10.2

2 Derivatives of unsaturated systems Perfluoropropynyl [15, 26, 27] and perfluorovinyl [16, 28–30]-lithium and -magnesium are considerably more stable than perfluoroalkyl derivatives, whilst the corresponding perfluoroaryl derivatives may be used as effectively as in the hydrocarbon series, and direct syntheses involving iodo compounds are also possible (Figure 10.3). This quite definite trend towards increasing stability in a series from CF3Li, which may have little more than a fleeting existence when generated, to RFLiðRF5C2F5, n- and i-C3F7), CF5CFLi and C6F5Li is probably a reflection of the ease of elimination of metal fluoride decreasing in this series; see also Chapter 6, Sections II and IIIA, Subsection 3 (Figure 10.4). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 367

Organometallic Compounds 367

i i CF3CH2CF2H [CF3CH=CFH] [CF3C CH] ½27 (−LiF) (−LiF)

i i, n-BuLi; ii, Ph3SnCl

ii Ph3SnC CCF3 CF3C CLi 84%

i i CF3CFH2 [CF2=CFH] CF2=CFLi ½30 (−LiF)

+ ii i, n-BuLi; ii, PhCHO, H etc.

PhCH(OH)CF=CF2

n-BuLi HgCl2 C6F5H C6F5Li (C6F5)2Hg ½11

i C6F5I (C6F5)2M M = Zn or Cd ½11

i, Zn (200C) or Cd (230C)

Figure 10.3

−LiF etc CF3Li [ CF2]

− LiF or CF2=CFLi [CF CF] [CF2=C ]

Li − F LiF F

Figure 10.4

B From unsaturated fluorocarbons The most obvious feature of the chemistry of highly fluorinated aromatic compounds and alkenes which can be exploited is their susceptibility to nucleophilic attack. Therefore, reactions with anionic species containing metals can be useful and the most significant examples of this type involve transition-metal carbonyl anions [6, 10] (Figure 10.5).

1 Fluoride-ion-initiated reactions Reactions which partly compensate for the unsuitability of the perfluoroalkyl-lithium route involve addition of fluoride ion to an unsaturated site giving corresponding carbanions (Cs or K derivatives) that may be used in synthesis (see Chapter 7, Section IIC, Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 368

368 Chapter 10

− F F ½6 + [Re(CO)5]

Re(CO)5

½6 N − N π F + [ C5H5Fe(CO)2] F N N π Fe(CO)2 C5H5

Figure 10.5

Subsection 6). Mercurials have been obtained by fluoride-ion-initiated reactions of perfluoroalkenes with mercury(II) chloride [31], and it is probable that the process could be extended considerably (Figure 10.6).

− − i ½31 F + CF2=CFCF3 (CF3)2CF Hg[CF(CF3)2]2

i, HgCl2

Figure 10.6

II LITHIUM AND MAGNESIUM A From saturated compounds Some polyfluoroalkyl-lithium and polyfluoroalkyl-Grignard reagents have been described [14] but, as already mentioned, elimination of metal fluoride seriously restricts the use of these compounds in synthesis. Perfluoroalkylmagnesium reagents are prepared either directly from perfluoroalkyl iodides and magnesium, or by exchange between perfluoroalkyl iodides and a Grignard reagent, but perfluoroalkyl-lithiums can only be made by an exchange process. Typical reactions of these reagents are given in Figure 10.7. i i-C3F7Li CF3CF=CF2 N.B. Little or no i-C3F7H formed ½22 66% i, H2SO4, Et2O

i EtCH(i-C3F7)OH 53% ½22 i-C3F7Li

i, EtCHO, H2SO4

i, ii ICF2CF2I + [n-C4F9Li + MeCHO] [MeCH(OH)CF2-]2 ½32 + i, −80 C to −85 C ii, H

Figure 10.7

The fact that exchange occurs to produce, in each case, the fluorocarbon derivative is quite consistent with the general observation that exchange generally proceeds to give a product where the metal is bonded preferentially to the most electronegative group [33]. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 369

Organometallic Compounds 369

The perfluoro-n- and -i-propyl and -n-heptyl derivatives [22, 34–36] are the most stable of the simple alkyl series. Outstandingly different in character from the perfluoroalkyl derivatives described above are the lithium and magnesium compounds derived from highly fluorinated bicyclo- [2.2.1]heptanes [37, 38]. Some reactions of the lithio derivative are shown in Figure 10.8, illustrating that it can be utilised in the normal synthetic procedures with much less competition from elimination.

MeLi D O ½37 F F 2 F − Et2O, 40 C H Li D

Furan i, MeCHO I2 MeI + ii, H F

10.8A F F F

I Me CH(OH)Me

Figure 10.8

This difference is obviously due to the difficulty in producing a double bond at a bridgehead position. Nevertheless, elimination of lithium fluoride does occur, especially at reflux temperatures; the bridgehead alkene 10.8A, which probably has only a transitory existence or may even be more appropriately described as a diradical, may be trapped with furan.

B From alkenes Several perfluoroalkene derivatives have been made and used successfully in synthesis. Trifluorovinylmagnesium bromide and the lithium derivative may be obtained [39–41] from bromotrifluoroethene but preparation from HFC 134a, which involves metallation of trifluoroethene generated in situ, is now the more accessible route (see Section IA). However, direct metallation of fluorinated alkenes and fluorinated cycloalkenes has also been reported [26, 28] (Figure 10.9). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 370

370 Chapter 10

i H2SO4 CF2=CFBr CF2=CFMg CF2=CFH 43% ½40

− i, Mg + I2, THF, ~ 22 C

i Me2SnCl2 + Mg Me2Sn(CF=CF2)2 65% ½42 i, CF2=CFBr, THF, 0 C

i ½28 CF2=CFH + n-BuLi CF2=CFLi + C4H10

i, Et O or THF, −78C 2 ii ii, CO 2 iii iii, H+

CF2=CFCOOH 65%

H Li ½26 Et O F 2 + MeLi CH4 + F −70C (CF2)n (CF2)n

i, MeCHO n = 1, 23% + n = 2, 42% ii, H n = 3, 63% CH(OH)Me

(CF2)n

Figure 10.9

C From trifluoropropyne [15] The C2H bond in trifluoropropyne is sufficiently acidic to allow ready metallation via Grignard or lithium reagents (Figure 10.10). However, the route from CF3CH2CF2H [27] (Section IA, Subsection 2) is more direct.

i ½43 CF3C CH + n-BuLi C4H10 + CF3C CLi

− i, C5H10, Et2O, 78 C Et3SiCl

Et3SiC CCF3

Figure 10.10

A number of derivatives of metals have been synthesised [15]; the lithium and magnesium derivatives, especially, are capable of quite wide application. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 371

Organometallic Compounds 371

D From polyfluoro-aromatic compounds [7, 17, 18, 21] The generation of Grignard reagents and lithium derivatives was discussed in Chapter 9, Section IIE, Subsection 1, and these reagents have already provided an impressive number of derivatives, which are discussed in detail in reviews [7, 17, 18, 21]. Some examples are shown in Figure 10.11 but more will be found in the following text. The steric requirements of the ligands in 10.11A are considerable and this feature has allowed a number of unusual systems to be synthesised [48]. i C F MgBr (C F ) Si 6 5 6 5 4 ½44 i, SiCl4, Et2O

i C6F5MgBr (C6F5)2Hg 73% ½45

i, HgCl2, Et2O ½46 i C6F5Li (C6F5)3B 50%

− i, BCl3, Pentane/Hexane, 78 C to rt

CF CF CF 3 3 3 ½47, 48 n-BuLi MX2 F3C F3C Li F3C M

CF3 CF CF 3 3 2 10.11A M = Zn, Cd, Hg.

Figure 10.11

Metallation of less highly fluorinated systems has been reviewed [49].

III ZINC AND MERCURY A Zinc Less work had been done with zinc compounds, but enough to indicate a contrast with lithium and magnesium derivatives. For example, perfluoro-n-propyl zinc iodides [50, 51] and perfluoroisopropyl zinc iodides [22] can be obtained, and the n-propyl derivative is even stable in dioxane at reflux. It should be noted that these compounds are stable largely because they are solvated and it has not been possible to remove the solvent completely. Zinc under these circumstances appears to be a very strong acceptor and therefore the compounds decompose much more readily when formed in the free state [52] (Figure 10.12). Ultrasonic radiation of perfluoroalkyl iodides may be used to form zinc reagents which undergo standard reactions (Figure 10.13). Fluorovinylzinc reagents are especially useful [14] (Figure 10.14). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 372

372 Chapter 10

i ~155C n-C3F7I n-C3F7ZnI CF3CF=CF2 ½51

i, Zn, Dioxane, 100C, ii ii, Removal of Solvent

n-C3F7COCl n-C3F7ZnI/dioxane (n-C3F7)2CO 15%

i ii n-C3F7I n-C3F7ZnI n-C3F7ZnI/dioxane ½50

i, Zn, Dioxane, 100C, ii, Removal of Solvent H2O 100 C

n-C3F7H 96%

Figure 10.12

Ph i Ph C3F7I + 66% ½53

Br C3F7

i, Pd(Ph3P)4, Zn, THF

Ph Ph i ½53 C3F7I + Br 71% C3F7

i, Pd(Ac)2, Zn, THF

i CF3I + HOCH2C CH CF3CH=CHCH2OH 61% ½53

i, CuI, Zn, THF

i ½53 C2F5I + 51% C2F5

i, Cp2TiCl2, Zn, THF

Zn CF I + PhCHO PhCH.OHCF 72% 3 DMF 3 ½53

OH Zn CF CCl + PhCO 86% ½54 3 3 DMF Ph CCl2CF3

Figure 10.13

Zn Me3SiCl CF CFBr [CF CFZnBr] CF2=CFSiMe3 65% ½55 2= DMF 2=

Figure 10.14 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 373

Organometallic Compounds 373

Perfluoroarylzinc derivatives may be obtained directly from the corresponding iodide and, sometimes, the chloride; they are also sufficiently stable to be produced by decarboxylation procedures (Figure 10.15).

C6F5I + Zn ½14

C6F5Li + ZnCl2 (C6F5)2Zn

(C6F5CO2)2Zn

Cl ZnCl ½56 F F 25%

N N

Figure 10.15

Surprisingly, zinc has been inserted directly into C2F bonds using ultrasound techniques, and in the presence of metal salts, e.g. SnCl2. The reactivity of the system appears to depend at least partly on the electron affinity of the aromatic system, because hexafluorobenzene is relatively unreactive in the process [57] (Figure 10.16).

CF CF 3 3 CF3 ½57

i Br F F 2 F

ZnCl Br

i, Zn, SnCl2, DMF, Ultrasound

Figure 10.16

B Mercury 1 Perfluoroalkyl derivatives Perfluoroalkyl derivatives of mercury were the first fluorocarbon–organometallic compounds to be reported. Alkylmercurials are valuable in that they are able to alkylate other metals, but the toxicity of mercurials greatly inhibits the use of these systems. Perfluoro- alkyl iodides react with mercury on heating or irradiation with ultraviolet light to give perfluoroalkylmercury(II) iodides [58–60] (Figure 10.17). An effective route to a number of bis(perfluoroalkyl)- and bis(perfluorocycloalkyl)- mercurials involves fluoride-ion-induced reactions of fluoroalkenes [31]; this follows an earlier method involving addition of mercury(II) fluoride to fluoroalkenes, e.g. using anhydrous hydrogen fluoride as solvent [62] (Figure 10.18). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 374

374 Chapter 10

i or ii 80% (i) ½20 CF3I + Hg CF3HgI 22% (ii) i, hν (150C), or ii, ~275C

i (CF3COO)2Hg (CF3)2Hg ½61 i, K2CO3, 120 to180 C

Figure 10.17

i CF3CF=CF2 + HgF2 [(CF3)2CF]2Hg 60% ½62

i, Anhyd HF, 110C

i CF3CF=CF2 + HgCl2 [(CF3)2CF]2Hg 65% ½31

i, KF, DMF, 40C

i (CF3)2C=CF2 + HgF2 [(CF3)3C]2Hg 66% ½31

i, KF, DMF, −78C

Figure 10.18

2 Unsaturated derivatives Alkenyl [63], alkynyl [26], and aryl [7, 8, 11] derivatives can be obtained by standard procedures (Figure 10.19).

Et2O CF2=CFLi + HgCl2 (CF2=CF)2Hg 52% ½41

Et2O 45 C6F5MgBr + HgCl2 (C6F5)2Hg 73% ½

COO Hg Hg ½64 ∆ F F

N 2 N 2

Figure 10.19

Pentafluorophenylmercurials can also be made by interesting direct mercuration procedures, e.g. with mercury(II) trifluoroacetate [65] and by a base-catalysed process [66] (Figure 10.20). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 375

Organometallic Compounds 375

150C C6F5H + Hg(OCOCF3)2 C6F5HgOCOCF3 85% ½65

i, EtOH, NaI, rt i

(C6F5)2Hg 72%

2− − − C6F5H + HgBr4 + 2 OH (C6F5)2Hg + 4Br + 2H2O ½66

Figure 10.20

These polyfluoroaryl groups enhance the acceptor properties of mercury and neutral 1:1 coordination complexes can be isolated with bipyridyl, 1,2-bis(diphenylphosphi- no)ethane, 1,10-phenanthroline, and so on [45, 63]. Whereas bis(perfluoroalkyl)mercurials are cleaved by alkali, nucleophilic aromatic substitution occurs with bis(pentafluorophenyl)mercury [67] (Figure 10.21). t-BuOH (C F ) Hg + KOH (4-HOC F ) Hg ½67 6 5 2 100C 6 4 2

Figure 10.21

Also, unlike bis(perfluoroalkyl)mercurials, bis(pentafluorophenyl)mercury may be used in a number of transformations at high temperature [68] (Figure 10.22). S (C6F5)2Hg (C6F5)2S 82% ½68 250C

Sn (C6F5)2Hg (C6F5)4Sn 60% ½68 260C

Figure 10.22

3 Cleavage by electrophiles Generally, polyfluoro-aromatic compounds and polyfluoroalkenes are not particularly susceptible to electrophilic attack and, consequently, electrophilic cleavage of these groups from metals, which in some cases occurs very rapidly, is of considerable interest. Unsymmetrical phenylpentafluorophenyl and methylpentafluorophenyl compounds are obtained from the appropriate mercury(II) halide [45], or by decarboxylation procedures [69], and these mixed derivatives are particularly susceptible to attack. Nevertheless, bis(pentafluorophenyl)mercury is very resistant to acid cleavage; for example, it can be recrystallised from concentrated sulphuric acid, but the well-known ligand-exchange process, e.g. with mercury(II) chloride, occurs very rapidly and presumably by a four- centre process [45] (Figure 10.23). An order of susceptibility to electrophilic attack may be formulated as C6H5 > C6F5 > C6Cl5 > CH3, which correlates with similar cleavage reactions of tin derivatives. These reactions have applications in the synthesis of boron and aluminium compounds. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 376

376 Chapter 10

(C6F5)2Hg + HgCl2 2 C6F5HgCl ½45 δ+ C6F5Hg HgCl δ− Cl

HCl (g) ½45 C6F5HgCH3 C6F5H + CH3HgCl

HCl (g) ½45, 70 C6F5HgC6H5 C6H6 + C6H5H (trace) + C6F5HgCl

Figure 10.23

IV BORON AND ALUMINIUM A Boron 1 Perfluoroalkyl derivatives A considerable effort was expended in attempting to prepare a compound with a perfluoroalkyl group attached to boron before success was achieved. Difficulty arises from the propensity of a fluorine atom for migration from carbon to boron; for example, the compound CF3BF2 has been isolated in low yields [71, 72] and delightfully described as ‘enduringly metastable’, with respect to formation of BF3. It is not clear, however, whether this decomposition is intermolecular (10.24A), intramolecular (10.24B) or both (Figure 10.24). F F or CF3BF2 F C BF2 F C BF2 F F

10.24A 10.24B

Figure 10.24

This ease of migration of fluorine from carbon to boron has inhibited the development of hydroboration techniques in fluorinated systems. However, when the carbon–fluorine bond is sufficiently remote from the boron, then hydroboration works well and Markov- nikov or anti-Markovnikov additionsÀ may be obtained, depending on the hydroborating system; dicyclohexylborane, ChxÞ2BH, is less electrophilic but sterically more demanding than dihaloboranes (Figure 10.25). At the root of the instability of fluoroalkylboron compounds is the availability of a vacant orbital on boron; it will be seen that when boron is co-ordinately saturated, as in four-covalent boron derivatives (10.26A), or partially saturated by p bonding with attached oxygen- or nitrogen-containing groups (10.26B), then the stability of perfluoroalkylboron compounds increases (Figure 10.26). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 377

Organometallic Compounds 377

OH iii, ii i,ii RFCHOH.CH3 ½73, 74 RF RF

86% yield (RF = C6F13) 90% yield (RF = C6F13) 95% Regioselective 99% Regioselective

80% yield (RF = CF3) 82% yield (RF = CF3) 94% Regioselective 99% Regioselective

i, HBCl2, Hexane; ii, H2O2, alkaline; iii, (Chx)2BH, THF

Figure 10.25

X X

BRF B RF B RF X X

10.26A 10.26B X = O- or N<

Figure 10.26

Several salts containing the anion ½RFBF3 ðe:g: RF ¼ CF3,C2F5Þ have been isolated [75a], as indicated below, while the tri-covalent derivatives 10.27A and 10.27B are not readily decomposed; for example, 10.27A is recovered unchanged after heating to 1208 C. Furthermore, thermal decomposition of 10.27A or 10.27B gives n-C3F7H and not perfluoropropene, which would be formed if migration of fluorine to boron was still important [76] (Figure 10.27).

2 Unsaturated derivatives There is a marked increase in stability, with respect to formation of boron trifluoride, along the series CF3BF2 CF25CFBF2 < C6F5BF2 [71, 77, 78] and this can be related to partial co-ordinative saturation of boron. Trifluorovinylboron and pentafluorophenylboron halides are synthesised by electrophilic cleavage from unsymmetrical tin compounds or mercurials [7, 17, 18] (Figure 10.28). The formation of C6F5BF2 rather than ½C6F5BF3 indicates that C6F5BF2 is a weaker Lewis acid than BF3, i.e. CF3BF2 > BF3 > C6F5BF2. A complex salt 10.29A can, however, be obtained by addition of C6F5BF2 to an aqueous solution of potassium fluoride; the salt undergoes a novel elimination process on pyrolysis, giving polyphenyl- enes 10.29B [79] (Figure 10.29). Trifluorovinylboron derivatives are only stable for short periods when heated at 1008 C, and their partial decomposition to boron trifluoride occurs even on standing at room temperature [77, 80]. Heating pentafluorophenylboron difluoride leads to disproportionation and not aryne formation [78] (Figure 10.30). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 378

378 Chapter 10

i aq. KF K(CF BF ) + Me SnF Me3SnCF3 Me3Sn(CF3BF3) 3 3 3 ½75

− − ∆ i, BF3, CCl4, 196 to 20 C

CF =CF F + F 2 2 + [ CF2] + KBF4

Unchanged ½76 O i O 120C, 3hr B Cl B C3F7 O O 172C,12hr 30% n-C F H − 3 7 i, n-C3F7Li, 50 C, Et2O 10.27A 25%

n-C3F7Li (Me2N)2BX (Me2N)2BC3F7 ½76

10.27B

Figure 10.27

i Me2Sn(CF=CF2)2 CF2=CFBCl2 + Me2SnCl2 ½77 93% i, BCl3, rt

SbF3

CF2=CFBF2 59%

i Me SnC F 3 6 5 Me3SnBF2 + C6F5BF2 ½78

i, BF3 CCl4

BCl3 ½78 Me3SnC6F5 C6F5BCl2 C6F5BF2

Figure 10.28

H O 300C C F BF + KF 2 K(C F BF ) KBF + -(C F )- 6 5 2 6 5 3 4 6 4 n ½79 10.29A 10.29B

Figure 10.29 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 379

Organometallic Compounds 379

194C C6F5BF2 BF3 + (C6F5)2BF ½78 18hr

H2O

(C6F5)2BOH F 71%

Figure 10.30

The increased susceptibility to hydrolysis of the fluorocarbon derivatives over their hydrocarbon analogues is illustrated by pentafluorophenylboronic acid which is stable in acid solution, whilst pentafluorophenyl is rapidly lost in neutral or basic solution [78] (Figure 10.31).

i H2O C6F5BCl2 C6F5B(OH)2 C6F5B(OH)2.OH2 ½78 89% − i, H2O, Acetone, 78 C

H2O Base

C6F5H + H3BO3 C6F5B(OH)3

Figure 10.31

Tris(pentafluorophenyl)boron forms etherates but it can also be obtained unco- ordinated in a hydrocarbon solvent (Figure 10.32). i 3 C6F5Li + BCl3 (C6F5)3B 50% ½46 i, Pentane/Hexane, −78C to rt

i 3 C6F5MgBr + BF3.OEt2 (C6F5)3B 80% ½81 i, Toluene, Reflux

(C F ) BLi i 6 5 4 ½46

(C6F5)3B ii

− i, C6F5Li, Et2O, Hexane, 78 C (C6F5)3B.NC5H5 ii, Pyridine

Figure 10.32

The contrast in thermal stability between ðC6F5Þ3B and CF3BF2 is significant; for example, the pentafluorophenyl compound was recovered largely unchanged after heating at 2708 C for 168 h [82]. Tris(pentafluorophenyl)boron is, in effect, a novel Lewis acid and it is a curious fact that this compound, which was first made over 40 years ago, has Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 380

380 Chapter 10 only in the last few years become important as a co-catalyst for polymerisation [18]. Similarly, pentafluorophenylaluminium compounds have been developed for the same purpose (see below), a salutary lesson to those who feel confident in predicting which basic research areas will yield great practical returns on the sums invested.

B Aluminium Factors analogous to those which limit the stability of perfluoroalkylboron compounds are even more dominant in the case of aluminium. Indeed, no perfluoroalkyl derivatives of tri-covalent aluminium have been obtained, although salts of the type Li½ðn-C3F7Þ2AlI2 are produced [83] in reactions of perfluoroalkyl iodides with LiAlH4. Tris(trifluorovinyl)aluminium may be obtained as the trimethylamine complex, as indicated in Figure 10.33.

Et2O 3(CF2=CF)2Hg + 2Me3N.AlH3 ½84

(CF2=CF)3Al.NMe3 + 3H2 + 3Hg

Figure 10.33

Tris(pentafluorophenyl)aluminium is obtained as the etherate from either the Grignard reagent in ether or the lithium derivative in ether/hexane [81, 85], whereas only complex materials are obtained from pentafluorophenyl-lithium in hexane (Figure 10.34). At- tempts to remove the ether from the etherate, 10.34A, inevitably led to explosions.

Et2O 3C6F5MgBr + AlBr3 (C6F5)3Al.OEt2 ½81, 85 −20 to 0C 10.34A

Figure 10.34

However, two pentafluorophenylaluminium derivatives, 10.35A and 10.35B, have been isolated [85] by cleavage of the mercurial (Figure 10.35). Both 10.35A and 10.35B eventually explode violently on heating and this occurs with 10.35A at about 1958 C. Nevertheless, the relative stability of these uncomplexed fluorocarbon derivatives may be attributed to bromine bridging, which saturates the covalency of aluminium and inhibits migration of fluorine from carbon to aluminium. Evidence from NMR spectra indicates either structure shown in Figure 10.36 for compound 10.35A. i ½85 C6F5HgMe + AlBr3 C6F5AlBr2 + MeHgBr

10.35A i, Petroleum, 70C, 5days

C6F5HgMe

(C6F5)2AlBr + MeHgBr

10.35B

Figure 10.35 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 381

Organometallic Compounds 381

C6F5 Br Br C6F5 Br Br Al Al Al Al

Br Br C6F5 C6F5 Br Br

Figure 10.36

Pentafluorophenylaluminium dibromide reacts with acid halides to form ketones [85], but more significant are its reactions with propene; an insertion reaction occurs, giving a polymer containing fluorine, after hydrolysis. Additionally, there is evidence to suggest the intermediacy of a p-bonded species 10.37A, since addition of toluene displaces some propene [86] (Figure 10.37).

CHMe ½86 C6F5AlBr2 + MeCH=CH2 C6F5Al(C3H6)Br2 + Al CH2 10.37A Hydrolysis Toluene

C6F5(C3H6)nH + C3H6 + C6F5H MeCH=CH2

Figure 10.37

Tris(pentafluorophenyl)aluminium has been prepared by metathesis, [87] (Figure 10.38), and the toluene complex is used as a co-catalyst for alkene polymerisation.

Me3Al + B(C6F5)3 Me3B + (C6F5)3Al ½87

Figure 10.38

V SILICON AND TIN A Silicon The Grignard or lithium route is of limited value for the preparation of perfluoroalkyl derivatives. Much of the early work was concerned with the addition of silanes to fluorinated alkenes [88, 89], leading to the preparation of important fluorinated poly- siloxanes, manufactured by Dow Corning Co. (Figure 10.39). The siloxane 10.39A chars at 150–2008 C and 10.39B decomposes above 2008 Cto give vinyl fluoride, while 10.39C only decomposes at temperatures in excess of 4008 C. Trapping experiments (see Chapter 6, Section IIIA) have shown that a-elimination occurs to give carbenes, and therefore both of the elimination processes shown in Figure 10.40 must be factors which limit the thermal stability of siloxanes 10.39A and 10.39B. Trimethyltrifluoromethylsilane, which is now generally referred to as ‘Ruppert’s reagent’ [92], has been widely investigated [93–96] as an intermediate for transferring the trifluoromethyl group as a nucleophile, thus compensating for the deficiencies of polyfluoroalkyl Grignard or lithium derivatives. This approach also complements other methods for transfer of trifluoromethide ion. A variety of procedures have now been developed for the synthesis of this compound but the electrochemical procedure [93] Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 382

382 Chapter 10

(Figure 10.41), or simply heating bromotrifluoromethane with ðCH3Þ3SiCl and aluminium powder, is particularly effective [97] (Figure 10.42). Et SiCl + n-C F Li Et Si(n-C F ) 10% 2 2 3 7 ~−50C 2 3 7 2 ½34 +

Et2Si(n-C3F7)Cl 17%

hν MeSiHCl2 MeCl2Si + H ½90

MeCl2Si + CF2=CF2 MeCl2SiCF2CF2

MeSiHCl2

H2O [MeSi(CF2CF2H)O]n MeCl2SiCF2CF2H + MeCl2Si etc

hν H2O SiHCl3 + CF2=CF2 HCF2CF2SiCl3 [HCF2CF2SiO1.5]n ½91

10.39A

hν H2O SiHCl3 + CF2=CH2 HCF2CH2SiCl3 [HCF2CH2SiO1.5]n ½91

10.39B ν h H2O SiHCl3 + CF3CH=CH2 CF3CH2CH2SiCl3 [CF3CH2CH2SiO1.5]n ½91

10.39C

Figure 10.39

∆ Si C Si F + C F

C ∆ Si C Si F +

Figure 10.40

i CF3Br Me3SiCF3 ½93

i, Me3SiCl, anisole - HMPA (5 : 1) Sacrificial Al anode, Bu4NPF6 ( electrolyte) − − + CF3Br + 2e CF3 Br − − CF3 + Me3SiCl Me3SiCF3 + Cl Anode: 2/3 Al0 2e 2/3 Al3+

Figure 10.41 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 383

Organometallic Compounds 383

i CF3Br + Me3SiCl Me3SiCF3 62% ½97 i, Al powder, NMP, Heat

Figure 10.42

Displacement of perfluoroalkyl from silicon occurs, initiated by catalytic amounts of added fluoride ion, and reaction is especially effective with carbonyl sites as electrophiles. The process that has been established is outlined in Figure 10.43 [94].

O C ½94 + CF3SiMe3 R1 R2 − F3C OH NBu4 F

R1 R2 FSiMe3 H+ F3C O NBu4

1 2 F C TMS CF3SiMe3 R R 3

R1 R2

O C F3C Me R1 R2 Me Si Me F3C O NBu4 R1 R2

Figure 10.43

Examples of the application of Ruppert’s reagent are shown in Figure 10.44, including the especially interesting diastereoselective procedures. The process and mechanism for nucleophilic transfer from Me3SiCF3 to electrophilic sites are analogous to the clever use of DMF as a reservoir for trifluoromethide (10.45A), formed by reaction of fluoroform with a base [96], in a process outlined in Figure 10.45; they are also analogous to the use of iodoperfluoroalkanes with tetrakis(dimethylamino)ethene [99] (Figure 10.46). Not surprisingly, trifluorovinyl groups are cleaved by aqueous potassium hydroxide from, for example, ðCF25CFÞ4Si, Et2SiðCF5CF2Þ2 and Et3SiCF5CF2, which may be obtained by the Grignard or lithium routes [100–104] (Figure 10.47). However, with other nucleophiles attack also occurs at carbon in 10.48A, leading to displacement of fluorine [102] (Figure 10.48). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 384

384 Chapter 10

i, ii ½94 RCOOCH3 RCOCF3 i, Me SiCF , THF, TBAF, −78C 3 3 R = Ph 78% ii, H+ = C6H11 72%

1 R1 Ph R i Ph R2 R2 − 94 F3C 41 86% ½ N N

SiMe3

i, Me3SiCF3, THF, TBAF

O H O CF3 ½94, 98 i S R1 S R1 t-Bu N t-Bu N H − i, Me3SiCF3, THF, TBAF, 55 C Yield (RS1S)/(RS1R) 1 R = p-ClC6H4 95% >99 = Ph 80% 97 : 3 = t-Bu 75% 99 : 1

Figure 10.44 i Ph2CO + CF3H Ph2C(OH)CF3 72%

i, (Me3Si)3N / Me4NF, DMF

N(SiMe3)3 O ½96 F OSiMe3

H Me SiF 1 Me2N 3 F C R 3 R N(SiMe3)2

CF3H N(SiMe3)3

O N O O CF3 O NMe2 M R 1 F3C R H F3C 1 R O 10.45A R +

H Me2N

R R1

Figure 10.45 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 385

Organometallic Compounds 385

+1e

i ii RFI + TDAE [RFI] RFSiMe3 ½99 RF Transfer 55−81% i, (Me2N)2C=C(NMe2)2 ii, Me3SiCl

RF = C2F5, n-C3F7, n-C4F9

Figure 10.46

SiCl 15%KOH CF CFMgI 4 (CF CF) Si CF CFH ½100 2= − 2= 4 2= 15 C −110C

Figure 10.47

Et2O Et3SiCF=CF2 + RLi Et3SiCF=CFR + LiF ½102 10.48A R = Ph 76%

= C4H9 79%

Figure 10.48

B Tin [15] Some syntheses of perfluoroalkyl and polyfluoroalkyl derivatives are shown in Figure 10.49. hν Me SnSnMe + R I Me3SnRF + Me3SnI ½25, 105 3 3 F or ∆

RF = CF3, C2F5, etc

90C n-Bu SnH + 2CF CF n-Bu Sn(CF CF H) 28% ½106 2 2 2= 2 4hr 2 2 2 2

hν Me3SnSnMe3 + CF2=CF2 Me3SnCF2CF2SnMe3 ½107

i Me2SnCl2 + Mg Me2Sn(C2F5)2 34% ½108

i, C2F5I, THF, rt

Figure 10.49

A few general trends can be traced from reactions of these compounds. Hydrolytic cleavage occurs readily and this may well involve a two-step process, that is, via a five- co-ordinate species, such as 10.50A, rather than an SN2-type process (Figure 10.50). Nucleophilic displacement of trifluoromethyl also occurs with iodide ion and this is a useful method for generating difluorocarbene [109] (Figure 10.51) (see Chapter 6, Section Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 386

386 Chapter 10

HO + Me3SnCF3 [(Me3Sn(OH)CF3] 10.50A

CF3H + Me3SnOH + OH

Figure 10.50

i Me SnI + CF ½109 I + Me3SnCF3 3 3

i, NaI, DME, 80C −F FF ii CF2 Me Me Me Me

ii, Me2C=CMe2

Figure 10.51

IIIA), although other perfluoroalkyltin compounds are not sources of the corresponding carbenes [110].

Thermal decomposition, again, occurs readily and, in the case of ðCH3Þ3SnCF3, difluorocarbene is probably formed (Figure 10.52); see Chapter 6, Section IIIA, Subsection 3.

CF2=CF2 150C Me3SnCF3 Me3SnF + CF2

Figure 10.52

Trifluorovinyl and pentafluorophenyl derivatives of tin [11, 15] can be obtained readily via magnesium or lithium derivatives. It is interesting that the stability of ðCH3Þ3SnC6F5 to hydrolysis is very dependent on purity; in the presence of fluoride ion, rapid hydrolysis occurs and a process involving initial co-ordination of fluoride ion, and other halide ions, to tin has been suggested [111] (Figure 10.53).

− − ½111 Me3SnC6F5 + X [Me3(C6F5)SnX]

− − Me3SnOH + C6F5H + X [Me3(C6F5)SnX (H2O)]

Figure 10.53 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 387

Organometallic Compounds 387

Perfluorovinyl [112] and perfluoromethyl derivatives apparently undergo similar cleavage with aqueous alcoholic potassium fluoride. Fluorocarbon tin compounds may be used effectively in Stille coupling processes [15] (Figure 10.54).

I CF=CF2 ½15

i Bu3SnCF=CF2 +

Y Y 15−87% i = Pd catalyst

Figure 10.54

Electrophilic cleavage of perfluorovinyl [42] and perfluorophenyl [111] from mixed compounds occurs quite readily, although electrophilic attack is much more difficult in the tetrakis derivatives such as tetrakis(pentafluorophenyl)tin. The order of ease of electrophilic cleavage from tin has been established as CF25CF C6H5 > CH25CH > alkyl > perfluoroalkyl [42], and p-MeC6H4 > C6H5 > C6F5 > Me [111], illustrating the effect of electron withdrawal by fluorine; nevertheless, quantitative work on the acid cleavage of Me3SnC6F5 indicates a rate greater than might be expected from the combined effects of the atoms on an additive basis [113]. The well-known exchange reaction between tetra-alkyl- or tetra-aryl-tin compounds and tin(IV) is much more difficult with tetrakis(pentafluorophenyl)tin [114] (Figure 10.55).

160C 3(C F ) Sn + SnCl 3(C6F5)3SnCl ½114 6 5 4 4 7days

140C (C F ) Sn + 3 SnCl 4 C F SnCl ½114 6 5 4 4 11 weeks 6 5 3

Figure 10.55

The trichloride is more effectively made by cleavage of methylpentafluorophenylmer- cury [111] (Figure 10.56).

20C C F HgMe + 3 SnCl C F SnCl + MeHgCl ½111 6 5 4 20 hours 6 5 3

Figure 10.56

Cleavage of tetrakis(pentafluorophenyl)tin does not occur with boron halides, but pentafluorophenylboron halides can be obtained from ðCH3Þ3SnC6F5 [79].

VI TRANSITION METALS Factors affecting the stability of transition-metal bonds to carbon are of continued interest and fluorocarbon transition-metal derivatives are especially interesting [115–117] because of their generally enhanced stability, relative to hydrocarbon analogues. Factors Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 388

388 Chapter 10 that could enhance stability include the electronegativity of fluorocarbon groups, which will tend to increase the energy gap between s and s orbitals in the bonds to transition metals. Also, a factor which may limit stability in some hydrocarbon systems is the ease of migration of hydrogen to the metal, e.g. in platinum or palladium derivatives, whereas migration of fluorine may be more difficult if the strength of the carbon–fluorine bond is the rate-limiting step. Alkenyl and aryl derivatives of transition metals are generally more stable than the corresponding alkyl derivatives. This has been attributed to the unsaturated groups being able to accept charge from the metal via p orbitals. This process should be enhanced by the introduction of fluorine or fluorocarbon groups into the alkene or aromatic compound. For a wider discussion of fluorocarbon–transition-metal derivatives, and aspects such as their bonding, the reader is referred to other sources [115–117].

A Copper [14, 15] Fluorocarbon derivatives of copper have been studied quite widely, probably because there is little evidence for the elimination of metal fluoride being a limitation in these systems. Early work [118] showed that when perfluoroiodoalkanes are heated with copper in DMSO or DMF, then the copper compounds are formed in solution and these have been successfully applied in a variety of coupling reactions. High-dielectric media are essential to the success of these processes (Figure 10.57). Alternative procedures involve intermediate formation of copper derivatives via decarboxylation of salts of carboxylic acids [123–125] (Figure 10.58). It was concluded, from the establishment of a crude r-value of þ0.46 for the reaction, that the process may involve ½CF3CuI as an intermediate. A similar process may be involved in the reaction of trifluoromethanesulphonyl chloride with copper (Figure 10.59). Burton and co-workers, as part of a series of ground-breaking studies on fluorinated organometallic systems [14], have established that trifluoromethyl derivatives may be obtained by reaction of halofluoromethanes with copper and other metals. The process involves electron transfer from the metal, with subsequent loss of halogen to form difluorocarbene which, in turn, generates very active fluoride ion by reaction with the solvent. The full process is indicated in Figure 10.60. In an analogous manner trifluoromethylcopper has been generated from sulphonyl fluorides (Figure 10.61). Trifluorovinylcopper reagents are also stable and have been used in various useful coupling reactions [15], especially in the synthesis of polyenes, where stereospecific systems may be obtained (Figure 10.62). Several procedures have been used to obtain pentafluorophenylcopper and this reagent (again, much more stable than phenylcopper) may be used in coupling procedures (Figure 10.63).

B Other metals Various approaches to other transition-metal derivatives have been applied which are not covered here, but some involve reactions that exploit the properties of the fluorocarbon Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 389

Organometallic Compounds 389

i PhI CF3I + Cu [CF3Cu] PhCF3 ½118

i = DMF, ~135 C

i ½119 n-C6F13I BrN Br N n-C6F13 n-C6F13

i = Cu, DMSO, 125−130C

i I(CF2)3I + 2 ICHCHCl ClHCCH(CF2)3CHCHCl ½120

i = Cu, Pyridine, 100 C

i CHF2Cu + CH CCMe2Cl HCF2CHCCMe2 ½121 78% i = DMF, −55 C

i CF3Cu + I ½14

S S CF3

i = DMF, HMPA, 70 C

NH NH2 2 ½122 N N N i N CF3Cu + I F3C N N N N AcO AcO O O

OAc OAc OAc OAc

i = HMPA

Figure 10.57

i ½125 CF3CF2CO2Na + p-ClC6H4I p-ClC6H4CF2CF3

54% i = DMF, HMPA, 170 C, Cu2I2

Figure 10.58 systems, particularly the propensity of unsaturated fluorocarbons to undergo nucleophilic attack as illustrated in Figure 10.64. Oxidative additions to iodoperfluoroalkanes proceed readily, whilst the additions to fluorinated alkenes shown in Figure 10.65 may well be radical processes. The important range of palladium-induced coupling processes [137] is not lost to fluorine chemistry: some illustrations are given in Figure 10.66. Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 390

390 Chapter 10

Cl CF3 ½126 NO2 NO2 i CF3SO2Cl + Cu +

NO2 NO2

i = DMAC, Heat

Figure 10.59

CF2XY + M (Zn, Cd, Cu) MXY + [ CF2] ½14

Me2NCHF2 + CO [ CF2] Me2NCHO

Me2NCHF2 Me2NCHF F

F + [ CF2] CF3

CF3 + MXY CF3MX + (CF3)2M

Figure 10.60

i ½127 FSO2CF2I + PhI PhCCF3 80%

i = Cu, DMF, 60−80 C. ~6Hr.

i ii ½128 FSO2CF2COOMe [CuCF3] PhCHC(CF3)2 55 % i, CuI, DMF/HMPA, Pd(PPh3)4 ii, PhCHCBr2

Figure 10.61

The effect of fluorinated systems on the reaction process shown in Figure 10.67 is of interest [139]; it is to be noted that insertion of the palladium catalyst into the carbon– halogen bond may be considered as a nucleophilic attack by the palladium centre, albeit a soft nucleophile, which prefers to attack C2Br over C2F [138]. This process is, of course, aided by the presence of electron-withdrawing groups (EWG) in the organic system. It is likely, however, that co-ordination of the other reactant, e.g. alkyne, to the palladium is the rate-determining step [137], but this will be aided by EWGs attached to the metal. It also appears that the metal can act as a nucleophile in reactions of certain nickel complexes with polyfluoro-aromatic compounds [145–147]. Surprisingly, with pentafluoropyridine, insertion occurs at the 2-position [145], which is in direct contrast with reactions of most other nucleophiles with this system (see Chapter 9), where Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 391

Organometallic Compounds 391

F3C F F3CFF 3C F Ph ½15 F Cu Ph I F F CF3 54%

F F ½15 Cu

CF2=CFCu CF3C CCF3 F F3C CF3

F F I F

F3C CF3 63%

(CF2)n ½129

(CF2)n (CF2)n Cu (CF2)n (CF2)n

(CF2)n n = 2, 3

Figure 10.62

C6F5I ½15

Activated Cu

C6F5M + CuX C6F5Cu C6F5H + LiCuMe2

M = Li, MgBr, CdX 60 C X = Cl, Br, I

C6F5COOCu

C6F5Cu + CF2CFI C6F5CFCF2 88% ½15

C6F5Cu + CH2I2 (C6F5)2CH2 70% ½15

Figure 10.63 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 392

392 Chapter 10

THF π CF3CF=CF2 -C5H5Fe(CO)2Na ½130 π CF3CF=CFFe(CO)2 C5H5 + NaF

(CO)5Mn M CF2=CFCF2Cl (CO)5MnCF2CF=CF2 ½131; 132

M = Li, Na

(CO)5MnCF=CFCF3

C F + [π-C H Ru(CO) ] π 6 6 5 5 2 C6F5Ru(CO)2 -C5H5 ½133

Figure 10.64

Benzene π π -C5H5Co(CO)2 + CF3I -C5H5Co(CO)(CF3)I + CO ½134

hν MeRe(CO)5 + CF2=CF2 MeCF2CF2Re(CO)5 ½135

Benzene (Ph3P)4Pt + CF2=CFCl (Ph3P)2Pt(CF=CFCl)2 ½136

Figure 10.65

X X F F F F ½138, 139 i

Br N Br RC C N C CR

X = Br, CF(CF3)2 R = Ph, C3H7

i = RC CH, CuI, (Ph3P)3PdCl2 , Et3N

CF=CF2 ½140

i ii CF3CFH2 + ZnCl2 [CF2=CFZnCl]

i = LDA, THF, 15−20 C R ii = RC6H4I, Pd(PPh3)4, Heat 61−86%

Figure 10.66

Contd Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 393

Organometallic Compounds 393

Ar F i Ar Ar F F ii ½141 H Br H Br H Ph

E/Z ~1:1 High E/Z ratio 100% Z isolated, 73%

Ar = p-FC6H4-

i, −20 C, 7 days ii, PhSnBr3, Pd[(PPh3)]4, CuI, DMF, rt

F F i F F ½142 + CF2=CFI Bu3Sn SiMe3 CF2 CF SiMe3

i, Pd[(PPh)3]4, CuI, DMF, rt

½143 Ph F i, ii Ph Br Ph F + H Br H F H H E/Z 1:1 100% Z

i, iii i, Cl2Pd(PPh3)2 ii, HCOOH, n-Bu3N, DMF, 35 C Ph COO n-Bu iii, CO, 160psi, n-BuOH, n-Bu3N, 70 C

H F

½144 I 4 i R 4

RF R R i, PdCl2[PPh3]2 , Et3N, CuI F

Figure 10.66 Contd selective 4-attack occurs. It is tempting to invoke interaction with the ring nitrogen as a directing influence in these processes, even though the nitrogen is essentially non-basic in the ground state, although this will change as the reaction proceeds and charge develops on the nitrogen atom. Consequently, these processes may be used to approach aromatic substitution patterns that would be difficult to obtain with other systems, and the potential would be considerable if these processes could be achieved in a catalytic way (Figure 10.68). Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 394

394 Chapter 10

X X ½139 F F F F

L2Pd(0) N N Br Br Br R

X X F F F F

L Pd(II) N Br N 2 L2Pd(II) Br Br R

X H R Et NHBr 3 F F

Et3N L Pd(II) N Br 2 R

Br H X = Br, CF(CF3)2

L = Ph3P

Figure 10.67

145 i HCl ½ F F F PEt3 N N Ni N H

Et3P F

i, Ni(COD)(PEt3)2

Et3P F ½146 Ni

i Heat PEt3 FF [Complex] FF

i, Ni(COD)(PEt3)2

Figure 10.68 Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 395

Organometallic Compounds 395

Selective insertion into C2Cl occurs in competition with C2F, leading to further useful processes (Figure 10.69).

Cl N ½147 F PEt3 [Ni(COD)2] F N Et3P Ni PEt3 Cl I2 MeLi − I [Ni] N F F N

Et3P Ni PEt3 Me CO O −[Ni]

Me F N PEt3 H O

Me F N

Figure 10.69

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Index

acid fluorides introduction of fluorine, 297–300 elimination of COF2, 146 nitrene additions, 338 acid strengths, 93, 98 arynes, 346–9 aerosol fluorination, 37 aza-alkenes, 278–84 alcohols, 254–7 azabenzenoid compounds, 304–6, 315–32 acidity, 93 azo compounds, 284 diols, 255–6 photolysis, 284 aldehydes reactions, 243 Balz-Schiemann reaction, 73, 108, 300–301 synthesis, 243 base strengths, 94 alkali metal fluorides biological applications, 5 use in synthesis, 27–31, 47–9 biotransformations, 9 alkenes bis(perfluoroalkyl)alkynes, 218 acidities, 115 bistrifluoromethyl nitroxide, 278 addition of 1,3-dipoles, 212–13 bistrifluoromethylcarbene addition of fluorine, 77–9 reactions of, 155–6 addition of HF, 76–7 structure, 158 addition of radicals, 196 bistrifluoromethylthioketene, 274 cycloadditions, 205 bond energies, 13 electrophilic addition, 101, 191–6 boron derivatives, see organometallics nucleophilic attack, 174 bromine trifluoride, 51 oxidation, 200–201 bromofluoroalkanes polymerisation, 203–5 reaction with phosphines, 123 rearrangement, 176 synthesis, 41 alkoxides, 251–4, 257–8, 269 bromopentafluorobenzene, 339 alkynes Burton, 123 synthesis, 218–22 allenes, 218 caesium fluoroxysulphate, 57, 79, 82 allylic cations, 102–3 capto-dative substituents, 209 aluminium, see organometallics carbanions, 15, 96, 107–10 amides, 241 effects of F, 109 amine hydrofluorides, 62 formation by addition of fluoride ion, 186, reactions with epoxides, 69 241 amino-acids H/D exchange, 107, 109, 111, 114 diazotisation, 74 internal return, 108 reaction with hexafluoroacetone, 248 pentakis(trifluoromethyl)cyclopentadienyl, amorphous polymers, 204–5 111, 114 anaesthetics, 6 perfluorocyclopentadienyl, 110, 114 anhydrides, 241–2 pKa values for methane derivatives, 109 aromatic compounds, 296 s-complexes, 112 carbene additions, 338 stable salts, 112, 113, 173 free radical attack, 338 stereochemistry, 110

400 Index carbanions, (cont’d) DAST, 63–5, 70 synthesis of iodo derivatives, 241, 253 decarboxylation, 145–6, 171 trapping of intermediates, 173, 186–7, 241 defluorination see polyfluoroalkylation electrochemical, 297 carbenes of perfluoroalkanes and cycloalkenes, 164–5 fluorocarbenes, 147–59 of trifluoroethanol derivatives, 146 from haloforms, 147 using phosphorus compounds, 250 from halo-ketones and -acids, 149 using SnCl2, 247 from organometallic compounds, 149, 157, using tetrakis(dimethylamino)ethene, 215 386 Demnumt fluids, 5, 262 from organophosphorus compounds, 151 Desflurane, 6 (perfluoroalkyl)carbenes, 154–6, 158 DFI, 65, 67 push-pull stabilisation, 344 diazirines, 147, 284, structure, 156 diazo compounds, 147, 284, via pyrolysis and fragmentation reactions, diazonium salts, 73, 108, 301 151 dications, 104–5 carbocations, 15, 99 Diels-Alder reactions, 209–12, 214, 218 long-lived, 102–5 dienes, 214–18, 391 polyconjugated systems, 105 charge transfer salts, 218 polyfluorobenzenium, 104 electrophilic attack, 339 trifluoromethyl, 104–5 epoxidation, 217 carbonyl compounds heterodienes, 247 reactions with SF4 and derivatives, 66 nucleophilic attack, 176, 217 fluorination, 58–60, 66 photolysis, 218 carboxylic acids, 236 strain, 176 pKa values, 93, 98, 236 diethylaminosulphur trifluoride, see DAST strengths, 92, 98, 236 difluorocarbene, 148–51, 156–8 synthesis, 237–40 2,2-difluoro-1,3-dimethylimidazoline, see DFI CFCs, 4 diols, 255–6 Charlton n valves, 91–2 dioxirane formation, 249 chlorine-fluorine exchange, 24–7 1,3-dipoles, 213 catalysts, 24, 25 displacement of fluorine chlorine monofluoride, 51 from aromatic compounds, 307–36 chlorofluorocarbons, 4 from fluorinated alkenes, 132–3 synthesis, 24–7 dithionylium salts, 73, 300 chlorotrifluoroethene DOPA, 9 polymer, 6 dyes, 12 ciprofloxacin, 7 cobalt trifluoride, 32, 297–8, 301 ECF, 33–5, 61, 171 copper electrochemical fluorination, 33–5, 61, 266 compounds, 346 electronegativity, 13 coupling reactions, 216, 389–91 electronic effects, 13, 16, 169 organometallics, 387–91 electron pair repulsion, 109, 110 cubane derivatives, 210 electron transfer processes cuneane derivative, 209–10 formation of cyclopentadienylides, 114 cycloadditions, 205–12 oxidative fluorination, 61 cyclobutadiene intermediates, 210, 354 see also single electron transfer cyclo-octatetraene derivatives, 210, 216, 354, electrophilic aromatic substitution, 94, 99, 100, 391 299 cyclopolymerisation, 205 in pentafluorobenzene, 339 Cytopt,6 electrophilic fluorinating agents Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 401

Index 401

containing N–F bonds, 58 fluorinase, 10, 11 containing O–F bonds, 56 fluorinated alkenes FITS reagents, 126 LUMOs, 175 fluorine, 52, 299 reactions with nucleophiles, 132, 171–85 electrophilic perfluoroalkylation, 126–9 reactions with transition metal anions, 368 elimination reactions, 137 reactivity order, with nucleophiles, 174 a-eliminations, 147 rearrangement by fluorine, 174 b-eliminations, 137–47 synthesis, 166 conformational effects, 140–41, 143 fluorinated alkynes effect of leaving halogen, 137 stability, 169, 218 ElcB processes synthesis, 218–22 elimination of hydrogen halide, 137 fluorinated allenes elimination of metal fluorides, 144 reactions, 219 formation of alkenes, 169–71 synthesis, 218–19 formation of aromatics, 297–8 fluorination formation of carbenes, 147 alcohols, 62–6 formation of di-enes, 215–8 alkenes, 56, 77–80 norbornyl systems, 145 amino-acids, 54, 55 polyfluorinated cyclic systems, 142 aromatic systems, 53, 57, 63 regiochemistry, 139 carbanions, 58 syn-/anti-elimination, 140 carbohydrates, 65 from trifluoroethanol, 146 carbonyl compounds, 66–9 enols, 251 decalin, 53, 55 epoxides, see oxiranes dicarbonyl comounds, 55, 57, 59, 62 ethers esters, 58, 127 iodoethers, 253 nitro compounds, 57 synthesis, 253 nitrogen-containing functional groups, 275 nucleosides, 59 FAR reagents, see fluoroalkylamine reagents oxidative, 61 FEP, 6 phosphonates, 58 FITS reagents, 126, 222 selective, 47 Flemiont,5,6 steroids, 53, 63, 66, 78, 79 fluoride ion thioethers, 72 acid catalysis, 129–30 fluorine addition to alkenes, 77, 173 aerosol fluorination, 37 addition to alkynes, 77, 185 bond energy, 35 catalysts, 47–9 control of reactivity, 36 F/Cl rate constant ratios, 129 as an electrophile, 52–4, 299 induced reactions, 185–91 fluorine-18, 2 as a leaving group, 128–31 mechanism of fluorination, 35, 53–4 oligomerisation of F-alkenes, 188–91 reaction with hydrazones, 75–6 reactions with fluoroalkenes, 174, 253, 367 replacement of hydrogen by fluorine, 51–5 reactions with ketones, 251–4, 257–8 selective fluorination, 51–5 reactions with oxiranes, 257–8 stereochemistry of substitution, 53–5 rearrangements induced, 174, 187–8 use in synthesis of highly fluorinated solvents, 28, 48 compounds, 35–40 source, 28, 49 use of microreactors, 38 synthesis of iodoperfluoroalkanes, 241 fluorine displacement use in synthesis, 28–31, 47–50 addition-elimination mechanism, 131 see HALEX reactions F/Cl reactivity ratios at unsaturated sites, see polyfluoroalkylation reactions with 131–2 alkynes, 331–3 influence of O and N substituents, 131 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 402

402 Index fluorine displacement (cont’d) cycloadditions, 222, 224–6 from unsaturated sites, 131–5 formation of poly-enes, 331–3 see nucleophilic aromatic substitution free-radical additions, 226–7 fluoroalkylamine reagents, 65–6 polymerisation, 223–4 enantioselectivity, 65 reaction with carbenes, 354 mechanism, 66 reactions with sulphur, 226 use in supercritical CO2,65 trimerisation, 296 fluoroalkynes, 218 hexafluoroacetone, 27–8, 243 fluoroaromatics cleavage, 248 aryne generation, 346–9 formation of a dioxirane, 249 free radicals, 349–51 formation of heterodienes, 247 lithium derivatives, 345 formation of peroxides, 248–9 synthesis, 296 reaction with water, 248 valence isomers, 351–7 Wittig reaction, 250 see nucleophilic aromatic substitution hexafluorobenzene, 296–7 fluorodediazotisation, see Balz-Schiemann reaction with carbenes, 342–3 reaction hexafluoropropene 2-fluorodeoxyglucose, 7, 9 cycloadditions, 206, 211 fluorodesulphurisation, 71–3 formation of oligomers, 188 fluoroformates in polyfluoroalkylation, 327–8 decarboxylation, 70, 71, 300, 302 radical additions, 197–204 fluoromethyl cations, 104 reaction with SbF5, 102 5-fluorouracil, 6, 7, 8 reaction with SO2F2, 272 fluorous biphase techniques, 166 reactions with electrophiles, 193–6 fluoroxy compounds, 258 reactions with nucleophiles, 174, 177 synthesis, 259 sodium sulphite addition, 269 fluorspar, 23, 24 synthesis, 170–71 Fluothanet (halothane), 6 hexafluorothioacetone, 274 Fomblint fluids, 5 hexakis(trifluoromethyl)benzene, 296 frontier orbitals, 98 HFCs, 4 high valency metal fluorides, 31 graphite fluoride, 39 Hunsdiecker reaction, 240 hydrogen-deuterium exchange, 138–9 HALEX process, 300, 303–6 hydrogen fluoride, 23 halofluorination, 80–82 additions to alkenes and alkynes 76–7, 193 halogen exchange, 300, 303–6 amine hydrofluorides, 62, 68–70 halogen fluorides, 40, 80, 77, 72, 64, 62, 80–82 cleavage of ethers and epoxides, 69, 71 halonium ions, 105–7 diazonium salts, 73–4 halophilic processes, 123 electrochemical fluorination, 33–5 halothane, 6 hazards, 23 Hammett s values, 94–5, 100 reactions with azirenes and aziridines, 74–5 heteroaromatic compounds use in synthesis, 24 boiling points, 306 use with lead tetra-acetate, 61 polyfluoroalkylation, 327 hypofluorites, 56, 82 synthesis, 298, 300–306 formation, 254 via cyclisation reactions, 332–5 heterodienes Ip effect, 98 synthesis, 247, 355–7 imaging techniques, 7 hexachlorobenzene imines, 275–6, 278–83 reaction with KF, 297 inductive effects, 94, 97, 169 hexachlorobutadiene, 27 industrial applications, 3 hexafluoro-2-butyne, 31, 220, 222 inert fluids, 4 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 403

Index 403 iodine pentafluoride, 271 in perfluoroalkanes, 163 fluorination of dicarbonyl compounds, 62 nickel insertion reactions, 394–5 see iodoperfluoroalkanes nitrenes, 344 iodoperfluoroalkanes nitro groups formation of copper compounds, 389–91 displacement by fluoride ion, 75 formation of organometallics, 365–6, 368, nitrogen derivatives, 236, 275 372–3 nitrosoalkanes, 277 reactions with nucleophiles, 123–6, 194 nitroxides, 278 synthesis, 41, 202–3, 241, 253 nomenclature, 16–19 synthesis of alkynes, 221 nonaflates, 265 2-iodoperfluorobutane, 125 norbornyl cation, 106 2-iodoperfluoropropane, 241 nucleophilic aromatic substitution Ishikawa reagent, 65, 66 from alkenes and cycloalkenes, 171–85 Isofluranet,6 attack on nitrogen, 329 benzenoid compounds, 307–15 ketones effect of acid, 324–5 addition of fluoride ion, 251 effect of ring N, 315 enantioselective reduction, 10, 11 fluoride-ion-induced reactions, 325–31 formation of heterodienes, 247 HOMO-LUMO interaction, 175 free-radical reactions, 250–51 mechanism, 134, 307 protonation, 105 orientation of substitution, 312–14, 319, reactions, 243–54 321–5 synthesis, 243–5 pyridine derivatives, 315–25 kinetic acidities, 96, 111, 109, 113, 115 substituent effects of F, 312–14 Krytoxt fluids, 5, 262 nucleophilic displacement of halogen from fluorocarbon systems, 122 LaMar process, 36 from alkanes, 132, 171–85 lead tetra-acetate-hydrogen fluoride, 61 from arenes, 133, 307 lithium derivatives, 345, 366–9 from cycloalkenes, 171–85 from alkenes, 369 effect of F substituents, 123 from trifluoropropyne, 370 HOMO-LUMO interaction, 175 norbornyl derivatives, 145, 369 mechanisms, 123, 124 vinyl compounds, 370 SN1SN2 processes, 122 lubricants, 5 nucleosides Lumiflont,5 fluorination, 59 macrocycles, 335 Olah magnesium derivatives, 368 generation of stable carbocations, 102 Meisenheimer s-complexes, 113 Olah’s reagent, 62 mercurials, 366, 373–6 oligomerisation generation of carbenes, 150 of fluorinated alkenes, 188–91 metal fluorides organometallic compounds eliminations, 145 aluminium, 380–81 as fluorinating agents, 23–32, 47–9 boron, 376–80 microreactors, 38 cleavage reactions, 366, 375–6, 380–81 Moissan, 2 copper, see copper monofluoroacetate, 9 from cyclo-alkanes, 369 mercury, 373–6 Nafiont,5,6,268 nickel insertion reactions, 394–5 naturally occurring compounds containing norbornyl derivatives, 369 C–F, 1 palladium coupling, 392–4 negative hyperconjugation, 16, 94–7 polyfluoroaryl, 367, 371 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 404

404 Index organometallic compounds (cont’d) nucleophilic attack, 171–85 from polyfluoroiodoalkanes, 365–7, 368 oligomerisation, 189 tin, 366, 370, 375, 378, 385 oxidation, 260 transition metals, 387 polymerisation, 203–5 via fluoride addition, 367 radical addition, 196–205 vinyl derivatives, 370 structure and bonding, 167 zinc, 371–3 synthesis, 164, 169–71 oxetanes, 262 perfluoroalkyl effect, 97 oxidation perfluoroalkylation of F-alkenes, 260–61 electrophilic, 126, 222 using bis(trifluoromethyl)dioxirane, 249 nucleophilic, 325 using fluoroketones, 248–9 perfluoroallene, 219 using peroxytrifluoroacetic acid, 242 Perfluorocycloalkenes oxiranes cycloadditions, 210–14 reactions with hydrogen fluoride, 69, 71, 180, formation of oligomers, 191 217, 254, 255 photochemistry, 189 ring opening, 257, 263–4 radical additions, 200–201, 204 synthesis, 259–61 reactions with nucleophiles, 183–5 oxygen derivatives, 236 ring-opening, 168 ozone depletion, 4 perfluorocyclobutene, 168, 170, 201 perfluorocyclopentene, 31, 170, 200 palladium coupling, 392–4 perfluorodecalin PCTFE, 6 defluorination, 165 pentafluorophenyl compounds from reaction with thiols, 127, 165 hexafluorobenzene, 307 perfluoroisobutene pentafluorophenyl group addition of diazamethane, 213 acidifying effect, 115 reactions with nucleophiles, 180 pentafluorophenyl lithium, 366 synthesis, 166, 170 pentafluoropyridine perfluorooctyl bromide, 9 carbene addition, 343 perfluorophenol, 98 electrochemical reduction, 342 perfluoropolyethers, 4, 5, 258, 269 free radical attack, 340–41 perfluoroquinoline, see quinoline derivatives polyfluoroalkylation, 327 perfluoro-t-butanol, 71, 255 synthesis, 297, 304 peroxides, 242, 264 perchloryl fluoride, 60 peroxytrifluoroacetic acid, 242 perfluoro-2-butyne, 31 PET scanning, 7, 9 perfluoroacetic anhydride, 241 PFA, 6 perfluoroacetone, see hexafluoroacetone pharmaceuticals, 7 perfluoroalcohols, 254–7 effects of F substitution, 7 perfluoroalkanes, 162 phosphate mimics, 11 by addition of fluorine to F-alkenes, 78 phosphonates, 11 defluorination, 164–5 phosphorus acids, 93 by direct fluorination, 35 photochemistry fragmentation, 166 formation of valence isomers, 351–7 hydrolysis, 163 photoelectron spectroscopy of fluorinated physical properties, 163 alkenes, 98 reaction with thiols, 127 phthalocyanine complexes, 329 structure and bonding, 162–3 physical properties, 3 using cobalt trifluoride, 32 pi-inductive effect, 98 perfluoroalkenes plant protecting agents, 9, 10 electrophilic attack, 191–6 polyfluoroalkylation, 325 epoxidation, 180 polyfluoroalkylcarbenes, 154–6 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 405

Index 405 polyfluorobenzenium cations, 104 Sevofluranet,6 polymers, 5, 203–5 sigma, s, sþ values, 95, 100 polysulphides, 270 silicon derivatives, 381–5 polytetrafluoroethene, 5, 6, 204, 260, 262 silver fluoride, 47 positron emission tomography, 7, 9 silver fluorine, 23 potassium fluoride, see HALEX process Simons, 2, 23 proton sponge, 49–50, 63 single electron transfer processes, 124, Prozact,7,8 125–6 PTFE defluorination, 164 SN2 processes see polytetrafluoroethene effect of substituents, 122 Pummerer-type processes, 51, 61 F/Cl rate constant ratios, 129 PVF, 6 fluoride as a leaving group, 128 pyridinium poly(hydrogen fluoride), 62, 68–9 transition-states, 128 0 pyrimidines, 13 SN2 processes, 176, 185 pyrolysis solvolysis reactions, 106 of CHClF2, 151 source of fluorine, 23 formation of carbenes, 151–4, 343 squaric acid, 130 stable radicals, 117 quinoline derivates stereoselectivity perfluoroquinoline, 305–6 addition of fluorine to alkenes, 56, 78–9 addition to enolates, 246 radical additions to fluorinated alkenes, in direct fluorination, 53–4 196–205 in H/D exchange, 112 examples, 199 using DAST, 64–5 orientation, 197 steric effects, 91, 246, 328, 371 rearrangement, 201 in b-eliminations, 141 radical clock experiments, 54, 59–60 in SN2 processes, 123 radicals sulphides, 270–71 addition to F-alkenes, 196–205 sulphonic acids, 265 polarity effects, 117 by ECF, 266 relative stabilities, 116 polymerisable monomers, 260 Scherer radical, 117 sulphur derivatives, 265, 272 stereochemistry, 116 use in ethene recovery, 275 substituents effects, 115–7 sulphur pentafluoride derivatives, 273 rearrangements sulphur tetrafluoride, 63, 64, 66, 69–70 Claisen, 256 sulphur trioxide, cycloaddition, 214 of di-enes using SbF5, 217 surfactants, 12 induced by fluoride, 185, 187–8 Swarts, 2, 24 radicals, 201 0 see SN2 processes Taft Es values, 91–2 thermal, 355 TAS-F, see tris(dimethylamino)sulphonium via valence isomers, 351–7 difluorotrimethylsiliconate resonance effects, 94, 100 tautomers, 251 Ruppert’s reagent, 382–4 Teflont, see PTFE Teflont AF, 6 safety telomerisation, 202–3 toxicity of fluorinated alkenes, 172 tetrabutylammonium fluoride, 49 use of hydrogen fluoride, 23 tetrafluoroethene use of perchloryl fluoride, 60 addition of electrophiles, 193–5 Scherer radical, 117 addition of sulphur trioxide, 268 Scotchgardt,12 cycloaddition, 205–12, 268, 277 Selectfluort, 58–60 formation of oligomers, 190 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 406

406 Index tetrafluoroethene (cont’d) trifluoromethyl in polyfluoroalkylation, 328 formation, 24 radical additions, 198, 202–4 hydrolysis, 332 reactions with nucleophiles, 173–4, 177 s values, 94–6 reaction with SO2F2, 272 size, 92 reaction with sulphur, 270 transfer from CF3H, 384 sodium sulphite addition, 269 transfer from silicon, see Ruppert’s reagent synthesis, 170 trifluoromethylation in triazine synthesis, 275 transfer from CF3H, 384 tetrakis(dimethylamino)ethene, 215 using Ruppert’s reagent, 382–4 textile treatment, 12, 13 trifluoromethylcarbene, 158 thiete formation, 226 trifluoropropene thiocarbonyl compounds, 272 electrophilic addition, 102 thiols trifluoropropyne, 221 fluorination, 272 trioxide, 265 tin, see organometallics tris(dimethylamino)sulphonium toxicity, see safety difluorotrimethylsiliconate, 49–50 transition metal derivatives, 368 triazines, 13, 275, 304, 329–30 valence isomers, 222, 351–7 1,2,3-triazines van der Waals radii, 91 photolysis, 221 volumes, 92 triflates, 265 vinyl radicals, 117 triflic acid, 265–6 vinyllithium derivatives, 366 strength, 92 Vitont,6 trifluoroacetic acid, 240 trifluoroethanol wartime developments, 2 formation of CF2 derivatives, 146, 250 Wittig reaction, 250 trifluoroiodomethane nucleophilic attack, 123 xenon difluoride, 60, 80, 301 trifluoromethanesulphonic acid, see triflic acid trifluoromethanesulphonyl chloride, 267 Yaravenko reagent, 65 trifluoromethanesulphonyl group, 267 ylides, 123 trifluoromethoxide salts, 96