Durham E-Theses Acid induced reactions of polyuoroaromatic compounds Thorpe, John Graham How to cite: Thorpe, John Graham (1969) Acid induced reactions of polyuoroaromatic compounds, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/8656/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk UNIVERSITY OF DURHAM A THESIS entitled ACID INDUCED REACTIONS OF POLYFLUOROAROMATIC COMPOUNDS Submitted by JOHN GRAHAM THORPE, B.Sc. (UNIVERSITY COLLEGE) A candidate for the degree of Doctor of Philosophy. 1969. ACKNOWLEDGEMENTS The author would like to express his gratitude to Professor W.K.R. Musgrave and Dr. R.D. Chambers for their continual help and encouragement during the supervision of this work, and to Dr. M. Hole for many helpful discussions and valuable advice. Thanks are also due to many technical and laboratory staff for their help, and to Imperial Smelting Corporation Limited for a maintenance grant. MEMORANDUM The work described in this thesis was carried out in the University of Durham between October 1966 and May 1969, This work has not been submitted for any other degree and is the original work of the author, except where acknowledged by reference* Part of this work has been presented by Professor W.K,R. Musgrave at the Symposium on Fluoro-organic Compounds, held by the Fine Chemicals Group of the Society of Chemical Industry at Birmingham, March 1968, and also at the Fifth International Fluorine Symposium, in Moscow, July 1969. SUMMARY Acid Induced Reactions of Polyfluoroaromatic Compounds This work is, in general, concerned with reactions of polyfluoro- N-heterocyclic aromatic compounds, which were previously regarded as exhibiting few basic properties, with acidic reagents. These reactions provide routes to compounds containing potentially functional groups by replacing fluorine with another halogen or hydrogen. In reactions with hydrogen halides, heptafluoroquinoline reacts readily in sulpholan, giving 2-halohexafluoroquinolines and 2,4- dihalopentafluoroquinolines, whereas, the apparently less basic pentafluoropyridine and heptafluoroisoquinoline, react with difficulty, giving low yields of halo-derivatives. Under the forcing conditions required with pentafluoropyridine polysubstitution occurs, and appreciable quantities of 2,4,6-trihalodifluoropyridines are obtained. Appreciable amounts of water in the sulpholan inhibits these reactions and leads to hydroxy substituted compounds. These observations may be interpreted in terms of halogen exchange or hydrolysis of the N-protonated heterocyclic compounds. Consequently, when more acidic reagents are used, both pentafluoropyridine and heptafluoroisoquinoline give more facile reactions. Extension, of the investigation to reactions of these poly- fluoroheteroaromatic compounds with strong Lewis acids gives a good indication that co-ordination of the ring nitrogen occurs prior to substitution* These studies have even led to the isolation of crystalline hexafluoroantimonates of some polyfluoroheteroaromatic compounds, 19 and F n.m.r. spectroscopic measurements on these salts are in accord with the reactive ring carbon atoms possessing appreciable carbonium ion characteristics. The orientation of substitution in reactions of these acidic 19 compounds has been determined by F n.m.r. spectroscopy. CONTENTS General Introduction (i) INTRODUCTION CHAPTER I. Perfluoroaromatic Compounds Containing Nitrogen 1 Introduction. A. Methods of Introducing Fluorine into Aromatic 1 Systems 1. Replacement of Functional Groups by Fluorine 1 a) Replacement of the Amino Group by fluorine 1 b) Replacement of the Hydroxyl Group by Fluorine 2 2. Direct Fluoridation Techniques 3 a) Fluorination of Perchlorobenzene 3 b) Fluorination of the Aromatic Hydrocarbon k 3. The Halogen Exchange Method 6 a) Lowly fluorinated Aromatic Compounds 6 b) Highly Fluorinated Aromatic Compounds 11 c) Lowly Fluorinated Heterocyclic Compounds 14 d) Perfluoro-N-heteroaromatic Compounds 16 B. Some General Chemistry of Perfluorohetero- aromatic Compounds Containing Nitrogen 19 1. Pentafluoropyridine and its Derivatives 19 2. Heptafluoroquinoline and Heptafluoroiso- quinoline 2h Page 3» Perfluorodiazines 24 4. Nucleophilic Substitution in Polyfluoro- aromatic Compounds 29 a) Polyfluorohomocyclic Compounds 29 b) Polyfluoroheterocyclic Nitrogen Compounds 32 CHAPTER II. Acid Induced Nucleophilic Heteroaromatic Substitution 37 Introduction A. Acid Catalysis in Nucleophilic Heteroaromatic Substitution 37 1. Mechanistic Aspects 37 2. Heterocycle Base Strength 39 a) Variations in Base Strength with the Parent Systems 39 b) Effect of Halogen 1+1 c) Reactivity and Base Strength 43 3. Base Strength of the Nucleophile 46 4. Solvent Effects 48 a) Base Strength of the Solvent 48 b) Activation by Hydrogen Bonds to Azine Nitrogen 49 5. Autocatalysis 31 Page B. Reactions Involving Quateraization of the Aza Group 55 1. Quaternary Salts and N-oxides 55 a) Preparation 55 b) Nucleophilic Substitution 56 2. Co-ordination of the Ring Nitrogen with Metals 59 DISCUSSION OF EXPERIMENTAL CHAPTER III. Reactions of Protonic Acids with Polyfluoro-N-heteroaromatic Compounds 61 Introduction 61 A. Reactions of Hydrogen Halides with Perfluoro- N-heteroaromatic Compounds 62 1. Choice of Solvent 62 2. Heptafluoroquinoline 66 a) Reactions with Hydrogen Chloride and Hydrogen Bromide 66 b) Reaction with Hydrogen Iodide 69 c) Attempted Reactions with Hydrogen Cyanide 72 d) Displacement of Bromine in Bromofluoroquinolines 72 e) Preparation of, and Tautomerism in, Halohydroxypolyfluoroquinolones 73 Page 3. Heptafluoroisoquinoline 77 a) Reactions v/ith Hydrogen Chloride 77 k, Pentafluoropyridine 79 a) With Hydrogen Chloride 79 b) With Hydrogen Bromide 79 B. Reactions of Polyfluoro-N-heteroaromatic Compounds with "Super Acids" 81 Introduction 81 1. Pentafluoropyridine 81 a) Reaction with Hydrogen Chloride and Aluminium Chloride 81 b) Reaction with Hydrogen Bromide and Aluminium Bromide 83 c) Reaction v/ith Hydrogen Iodide and Aluminium Iodide 83 d) Attempted Reactions with Hydrogen Halides and Boron Halides 86 2. Reaction of 4-Aminotetrafluoropyridine with Hydrogen Bromide and Aluminium Bromide 87 3. Heptafluoroisoquinoline 89 a) Reaction with Hydrogen Chloride and Aluminium Chloride 89 b) Reaction with Hydrogen Bromide and Aluminium Bromide 89 k, Heptafluoroquinoline 90 Reaction with Hydrogen Bromide and Aluminium Bromide 90 Page 5. Attempted Extensions to Benzenoid Systems. 91 6. The Preparation and Isolation of Stable Polyfluoroheterocyclic Hexafluoroantimonate Salts. 91 7. Other Attempted Quaternisation Reactions. 100 a) Attempted N-oxidation of Heptafluoroquinoline. 100 b) N-alkylation of Pentafluoropyridine and Heptafluoroquinoline. 100 CHAPTER IV. Reactions of Perfluoroheteroaromatic Compounds with Lewis Acids. 102 Introduction A. Reactions of Perfluoroheteroaromatic Compounds with Boron Halides. 103 1. Heptafluoroquinoline. 103 2. Pentafluoropyridine and Heptafluoro- isoquinoline. 104 B. Reactions of Perfluoroheteroaromatic Compounds with Aluminium Halides. 106 1. Heptafluoroquinoline. 106 2. Pentafluoropyridine and Heptafluoro- isoquinoline. 10? CHAPTER V. Assignment of Orientation in Halopoly- fluoroheteroaromatic Compounds. 111 A. Nuclear Magnetic Resonance Spectra of 111 Halopolyfluorohe teroaromatic Compounds. 115 B. Halopolyfluoropyridines. 115 1. 2f ^-Dihalotrifluoropyridines. 117 2. 2,6-Dibromotrifluoropyridine Page 3. 2,4,6-Trihalodifluoropyridines. 117 C. Halopolyfluoroquinolines. 118 1. 2-Halohexafluoroquinolines. 118 2. 2,4-Dihalopentafluoroquinolines. 121 3. 2,8-Dihalopentafluoroquinolines. 122 h. Halomethoxypolyfluoroquinolines and Related Compounds. 123 D. 1-Halohexafluoroisoquinolines. 127 EXPERIMENTAL Reagents. 129 Instrumentation. 129 CHAPTER VI. Experimental for Chapter III. 131 A. Reactions of Polyfluoroheteroaromatic Compounds with Hydrogen Halides and Related Reactions. 131 1. An Investigation of the Effect of Various Solvents on the Reaction of Hydrogen Chloride with Heptafluoroquinoline. 131 a) In Organic Solvents. 131 b) In the Absence of a Solvent. 131 2. Reactions of Heptafluoroquinoline with Hydrogen Halides. 132 a) With Hydrogen Chloride in Sulpholan Purified only by Distillation. 132 (i) Using 2-moles of hydrogen chloride. 132 (ii) Using 10-moles of hydrogen chloride. 132 b) With Hydrogen Chloride in Dry Sulpholan. 133 (i) Using 1-mole of hydrogen chloride. 133 (ii) Using excess hydrogen chloride. 134 c) With Hydrogen Bromide in Dry Sulpholan. 134 (i) Using 1-mole of hydrogen bromide. 134 (ii) Using 2-moles of hydrogen bromide. 133 d) With Hydrogen Iodide. 135 (i) In dry sulpholan. 135 (ii) In aqueous solution. 136 e) Attempted Reactions v/ith Hydrogen Cyanide. 137 (i) At room temperature in dry sulpholan. 137 (ii) At 110°C in dry sulpholan. 137 f) Attempted Reactions with Potassium Halides. 137 (i) With potassium