Durham E-Theses Part I; the synthesis and reactions of polyhalogenated heterocyclic compounds containing nitrogen part II: polyhaloalkylation Storey, Robert Anthony How to cite: Storey, Robert Anthony (1967) Part I; the synthesis and reactions of polyhalogenated heterocyclic compounds containing nitrogen part II: polyhaloalkylation, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/9086/ 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 2 UNIVERSITY OF DURHAM A THESIS entitled PART I: The Synthesis and Reactions of Polyhalogenated Heterocyclic Compounds Containing Nitrogen PART II: Polyhaloallcylation Submitted by ROBERT ANTHONY STOREY, GRAD.R.I.C. (Grey College) A candidate for the degree of Doctor of Philosophy 1?67» Si"- s»-i 1 7 MVWj ACKMOViLEDG-EMEMTS The work in this thesis was carried out under the supervision of Professor W.K.R. Musgrave and I wish to record my appreciation of his help and encouragement throughout. I should like to thank Dr. R.D. Chambers, Dr. D.T. Clark, Dr. J.W. Emsley and Dr. B. Iddon for much advice and many interesting and helpful discussions and Dr. J. Feeney of Varian Associates for the recording of some spectra. Thanks are also due to the Imperial Smelting Corporation, Avonmouth, Bristol, for the av/ard of a Research Studentship. I should finally like to express my appreciation to Dr. E.E. G-lover who initially stimulated the interest in "organic chemistry research. — MEMORANDUM The work described in this thesis was carried out in the University of Durham between October 196li. and May 1967« 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 provided material for four publications: J. Chem. Soc. , (c), 19665 2328 (with Dr. R.D. Chambers, Dr. M. Hole, Dr. B. Iddon and Professor W.K.R. Musgrave), J. Chem. Soc., (c), 1966, 2331 (with Dr. R.D. Chambers, Dr. M. Hole, Professor W.IC.R. Musgrave and (in part) Dr. B. Iddon), J. Chem. Soc., (C), 1967, 53 (with Dr. R.D. Chambers, Dr. M. Hole and Professor W.K.R. Musgrave) and Chemical Communications, 1966, 38L (with Dr. R.D. Chambers and Professor W.K.R. Musgrave). Summary Part I; Synthesis and Chemistry of Poiyhalogenoisoquinolines. Heptachloroisoquinoline has been prepared by initial direct chlorination of isoquinoline and subsequent reaction of the product with phosphorus pentachloride at elevated temperatures. Reaction of the perchloro compound with potassium fluoride at elevated temperatures gave heptafluoroisoquinoline and chlorofluoroiso- quinolines in good yield. The perhalogenoisoquinolines show no basic properties at all apart from their solubility in concentrated sulphuric acid. Nucleophilic substitution in heptafluoroisoquinoline by various nucleophiles, e.g. sodium methoxide, ammonia, hydrazine, and lithium aluminium hydride etc. is described. Attack occurs first in almost all cases at the 1-position and then at the 6- posit.ion. Oxidation of heptafluoroisoquinoline and the methoxy- derivatives gives tiri- and "di-fluoropyridine dicarboxyi-ic acids which 19 aid the analysis of the F n.m.r. spectra of the methoxy-derivatives and establish their structures. Some of the derivatives have been inter-related, structurally, by means of interconversion reactions. Heptafluoroisoquinoline reacts with aqueous sodium hydroxide or with potassium hydroxide in t-butyl alcohol to give the 1-hydroxy derivative. 1-Hydroxyhexafluoroisoquinoline exists as a tautomer and reaction with diazomethane produces a mixture of 0- and N-raethyl derivatives. The factors affecting tautomerism are outlined. A plausible rationalisation of the orientation of nucleophilic attack on heptafluoroisoquinoline is given in terms of localisation energies as calculated by Htlckel Molecular Orbital techniques. The drawbacks in this idea and a possible modification of this procedure to give a method which would be more general} is outlined. Part II: Polyhaloalkylation. Highly fluorinated aromatic compounds such as pentafluoro- pyridine, hexafluorobenzene, and their derivatives will react with carbanions produced from fluorinated olefins, such as hexafluoro- propene and tetrafluoroethylene, and fluoride ion with the formation of polyfluoroalkylated derivatives. The process is equivalent to the Friedel and Crafts reaction in hydrocarbon chemistry and, if it is carried out at pressures high enough to keep a reasonable concentration at the seat reaction, several fluoroalkyl groups can be introduced into the aromatic ring. Hexafluorobenzene is less reactive in the early stages of the polyalkylation than is pentafluoropyridine but when activating groups such as -NOgj -COOMe, and particularly -CN are introduced into the hexafluorobenzene, reaction occurs much more readily. Potassium fluoride or caesium fluoride can be used as sources of fluoride ion and sulpholane is a better solvent than dimethyl- formamide, diglyme, or triglyme. C Of ITEM'S Page PARI I. The Synthesis and Reactions of Polyhalogeno Heterocyclic Compounds Containing Nitrogen Chapter I. Introduction Replacement of Functional G-roups by Fluorine 3 Cyclisation Methods 7 Conversion of Aromatic Compounds to Highly Fluorinated Aromatic Compounds by the Method of Halogen Exchange 9 The Preparation of Bromo- and Chloro- Isoquinolines 26 Nucleophilic Substitution in Polyfluoro- aromatic and Heterocyclic Compounds 34 Chapter II* Discussion of Experimental Work Section 1. The Synthesis of Heptachloro- and Heptafluoro-Isoquinoline 46 Section 2. The Chemistry of Heptafluoroisoquinoline and some of its Derivatives 77 Chapter III. Experimental Work Pyridine-1-oxide - - 144 Hexachloroisoquinoline 145 Heptachloroisoquinoline 146 Heptafluoroisoquinoline 146 4-Chlorohexafluoroisoquinoline 146 Reaction of Heptafluoroisoquinoline with c.HCl and c.HgSO^ 147 1-Methoxyhexafluoroisoquinoline 148 Page Pentafluoro-1,6-dimethoxyisoquinoline 149 1-Aminohexafluoroisoquinoline 149 1-Trifluo roacetylamino-3J 4,5»6»7»8-hexafluoro- isoquinoline 150 1-Hydrazinohexafluoroisoquinoline 151 1-Hydrohexafluoroisoquinoline 152 2,5>6-Trifluoropyridine-3»4-dicarboxylic acid 152 5»6-Difluoro-2-methoxypyridine-3t4-dicarboxylic acid 153 Reaction between Aqueous Copper Sulphate and 1-Hydrazinohexafluoroisoquinoline 154 Benzaldehyde-3 »4» 5 »6»7 >8-hexafluoroi soquinolyl- hydrazone 155 Reduction of Benzaldehyde-3»4s5»6»7>8-hexafluoro- isoquinolylhydrazone with zinc dust and glacial acetic acid 155 Diazotisation of 1-Aminohexafluoroisoquinoiine 156 1-Amino-6-methoxypentafluoroisoquinoline 157 6-Methoxyhexafluoroiso quinoline 157 1- and 6- n-Butylhexafluoroisoquinolines 158 Competition of Heptafluoroisoquinoline and Pentafluoropyridine for Methoxide Ion 159 1-Hydroxyhexafluoroisoquinoline 160 Methylation of 1-Hydroxyhexafluoroisoquinoline with Diazomethane 161 Demethylation of 1-Methoxyhexafluoroisoquinoline with Aluminium Trichloride 162 Reaction of 4-<3hlorohexafluoroisoquinoline with Sodium Methoxide 163 Page PART II. Polyhaloalkylation Chapter IV. Introduction The reaction of Fluoro-olefins with Fluoride ion and Related Reactions 164 Chapter V» Discussion of Experimental Work Polyhaloalkylation of Pentafluoropyridine and its Derivatives 180 Polyhaloalkylation of Hexafluorobenzene and its Derivatives 192 Chapter VI. Experimental Work Reaction of Pentafluoropyridine with Hexafluoropropene 202-204 2-4iethoxy-4-perfluoroisopropyl-3 *5- trifluoropyridine 204 Reaction of Hexafluoropropene with Octafluorotoluene 205-207 Reaction of Hexafluoropropene with Methylpentafluorobenzoate Reaction of Hexafluoropropene with Pentafluorobenzonitrile 208-210 Reaction of Hexafluoropropene with Pentafluoronitrobenzene 211 Reaction of Chlorotrifluoroetlrylene with Pentafluoropyridine 213 Reaction of 1,2-Difluoro-1,2-dichloro- ethylene with Pentafluoropyridine 214 Reaction of Hexafluoropropene with 3>5- Dichlorotrifluoropyridine 214 Reaction of Hexafluoropropene with 3- Chlorotrifluoropyridine 216 Reaction between Hexafluoropropene and Pentafluoropyridine at High Pressures Reaction of Hexafluoropropene with Perfluoro- (4—isopropylpyridine) using Acetonitrile as Solvent Appendix 1 Appendix 2 Infrared Spectra References General Introduction. Fluorine, like hydrogen, occupies a special place in chemistry, in that it gives rise to a whole system of organic compounds. First efforts were directed towards the synthesis and study of aliphatic fluorocarbons." The successful development of this field, along with the discovery of some fluorocarbons with very useful properties, led to the establishment of fluorine chemistry as a major field of organic chemistry. Aromatic fluorocarbon chemistry has been developed only recently, and has been limited to homocyclic systems because of the difficulties in extending early methods of synthesis from horaocyclic systems to heterocyclic ' systems.