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Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page i
Fluorine in Organic Chemistry
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iii
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
ß 2004 by Blackwell Publishing Ltd Editorial offices: Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Tel: þ44 (0)1865 776868 Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia Tel: þ61 (0)3 8359 1011 ISBN 1-4051-0787-1 Published in the USA and Canada (only) by CRC Press LLC, 2000 Corporate Blvd., N.W., Boca Raton, FL 33431, USA Orders from the USA and Canada (only) to CRC Press LLC USA and Canada only: ISBN 0-8493-1790-8 The right of the Author to be identified as the Author of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. First published 2004 Library of Congress Cataloging-in-Publication Data is available A catalogue record for this title is available from the British Library Set in 10/12.5 pt Times by Kolam Information Services Pvt. Ltd, Pondicherry, India Printed and bound in India by Gopsons Papers Ltd, Noida The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. For further information on Blackwell Publishing, visit our website: www.blackwellpublishing.com
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page v
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 by Professor George A. Olah Preface 1 I
GENERAL DISCUSSION OF ORGANIC FLUORINE CHEMISTRY
General introduction A Properties B Historical development II Industrial applications A Introduction B Compounds and materials of high thermal and chemical stability 1 Inert fluids 2 Polymers C Biological applications 1 Volatile anaesthetics 2 Pharmaceuticals 3 Imaging techniques 4 Plant protection agents D Biotransformations of fluorinated compounds E Applications of unique properties 1 Surfactants 2 Textile treatments 3 Dyes III Electronic effects in fluorocarbon systems A Saturated systems B Unsaturated systems C Positively charged species D Negatively charged species E Free radicals IV Nomenclature A Systems of nomenclature B Haloalkanes References
xv xvii 1 1 1 2 3 3 3 4 5 5 6 7 7 9 9 12 12 12 12 13 14 14 15 15 16 16 17 18 19
vii
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2
Contents
PREPARATION OF HIGHLY FLUORINATED COMPOUNDS
I
23
Introduction A Source of fluorine II Fluorination with metal fluorides A Swarts reaction and related processes (halogen exchange using HF) 1 Haloalkanes 2 Influence of substituent groups B Alkali metal fluorides 1 Source of fluoride ion 2 Displacements at saturated carbon 3 Displacements involving unsaturated carbon Alkene derivatives Aromatic compounds C High-valency metal fluorides 1 Cobalt trifluoride and metal tetrafluorocobaltates III Electrochemical fluorination (ECF) IV Fluorination with elemental fluorine A Fluorine generation B Reactions C Control of fluorination 1 Dilution with inert gases D Fluorinated carbon E Fluorination of compounds containing functional groups V Halogen fluorides References
23 23 23 24 25 26 27 28 29 30 30 31 31 32 33 35 35 35 36 36 39 39 40 41
3
PARTIAL OR SELECTIVE FLUORINATION
47
I II
Introduction Displacement of halogen by fluoride ion A Silver fluoride B Alkali metal fluorides C Other sources of fluoride ion D Miscellaneous reagents Replacement of hydrogen by fluorine A Elemental fluorine 1 Elemental fluorine as an electrophile B Electrophilic fluorinating agents containing O–F bonds C Electrophilic fluorinating agents containing N–F bonds D Xenon difluoride E Miscellaneous Fluorination of oxygen-containing functional groups A Replacement of hydroxyl groups by fluorine 1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent 2 Diethylaminosulphur trifluoride (DAST) and related reagents 3 Fluoroalkylamine reagents (FARs)
47 47 47 47 49 50 51 51 52 56 58 60 60 62 62 62 63 65
III
IV
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Contents
B C
Replacement of ester and related groups by fluorine Fluorination of carbonyl and related compounds 1 Sulphur tetrafluoride and derivatives D Cleavage of ethers and epoxides V Fluorination of sulphur-containing functional groups VI Fluorination of nitrogen-containing functional groups A Fluorodediazotisation B Ring opening of azirines and aziridines C Miscellaneous VII Addition to alkenes and alkynes A Addition of hydrogen fluoride B Direct addition of fluorine C Indirect addition of fluorine D Halofluorination E Addition of fluorine and oxygen groups F Other additions References 4 I II III
THE INFLUENCE OF FLUORINE OR FLUOROCARBON GROUPS ON SOME REACTION CENTRES
Introduction Steric effects Electronic effects of polyfluoroalkyl groups A Saturated systems 1 Strengths of Acids 2 Bases B Unsaturated systems 1 Apparent resonance effects 2 Inductive and field effects IV The perfluoroalkyl effect V Strengths of unsaturated fluoro-acids and -bases VI Fluorocarbocations A Effect of fluorine as a substituent in the ring on electrophilic aromatic substitution B Electrophilic additions to fluoroalkenes C Relatively stable fluorinated carbocations 1 Fluoromethyl cations D Effect of fluorine atoms not directly conjugated with the carbocation centre VII Fluorocarbanions A Fluorine atoms attached to the carbanion centre B Fluorine atoms and fluoroalkyl substituents adjacent to the carbanion centre C Stable perfluorinated carbanions
ix
66 66 66 69 71 73 73 74 75 76 76 77 79 80 82 82 83
91 91 91 92 92 92 93 94 94 97 97 98 99 99 101 102 104 105 107 108 111 112
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Contents
D Acidities of fluorobenzenes and derivatives E Acidities of fluoroalkenes VIII Fluoro radicals A Fluorine atoms and fluoroalkyl groups attached to the radical centre B Stable perfluorinated radicals C Polarity of radicals References 5
NUCLEOPHILIC DISPLACEMENT OF HALOGEN FROM FLUOROCARBON SYSTEMS
Substituent effects of fluorine or fluorocarbon groups on the SN 2 process A Electrophilic perfluoroalkylation II Fluoride ion as a leaving group A Displacement of fluorine from saturated carbon – SN 2 processes 1 Acid catalysis 2 Influence of heteroatoms on fluorine displacement B Displacement of fluorine and halogen from unsaturated carbon – addition–elimination mechanism 1 Substitution in fluoroalkenes 2 Substitution in aromatic compounds References
113 115 115 115 117 117 118
122
I
122 126 128 128 129 131 131 132 133 135
6
ELIMINATION REACTIONS
137
I
b-Elimination of hydrogen halides A Effect of the leaving halogen B Substituent effects C Regiochemistry D Conformational effects E Elimination from polyfluorinated cyclic systems b-Elimination of metal fluorides a-Eliminations: generation and reactivity of fluorocarbenes and polyfluoroalkylcarbenes A Fluorocarbenes 1 From haloforms 2 From halo-ketones and –acids 3 From organometallic compounds 4 From organophosphorous compounds 5 Pyrolysis and fragmentation reactions B Polyfluoroalkylcarbenes C Structure and reactivity of fluorocarbenes and polyfluoroalkylcarbenes
137 137 138 139 140 142 144
II III
147 147 147 149 149 151 151 154 156
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Contents
1 2 References 7 I
II
Fluorocarbenes Polyfluoroalkylcarbenes
POLYFLUOROALKANES, POLYFLUOROALKENES, POLYFLUOROALKYNES AND DERIVATIVES Perfluoroalkanes and perfluorocycloalkanes A Structure and bonding 1 Carbon–fluorine bonds 2 Carbon–carbon bonds B Physical properties C Reactions 1 Hydrolysis 2 Defluorination and functionalisation 3 Fragmentation D Fluorous biphase techniques Perfluoroalkenes A Stability, structure and bonding B Synthesis C Nucleophilic attack 1 Orientation of addition and relative reactivities 2 Reactivity and regiochemistry of nucleophilic attack 3 Products formed 4 Substitution with rearrangement – SN 20 processes 5 Cycloalkenes 6 Fluoride-ion-induced reactions 7 Addition reactions 8 Fluoride-ion-catalysed rearrangements of fluoroalkenes 9 Fluoride-ion-induced oligomerisation reactions 10 Perfluorocycloalkenes D Electrophilic attack E Free-radical additions 1 Orientation of addition and rates of reaction 2 Telomerisation 3 Polymerisation F Cycloadditions 1 Formation of four-membered rings 2 Formation of six-membered rings – Diels–Alder reactions 3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions 4 Cycloadditions involving heteroatoms G Polyfluorinated conjugated dienes 1 Synthesis 2 Reactions 3 Perfluoroallenes
xi
156 158 159
162 162 162 162 162 163 163 163 164 166 166 167 167 169 171 172 172 176 176 183 185 186 187 188 190 191 196 197 202 203 205 205 209 212 214 214 214 216 218
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Contents
III Fluoroalkynes and (fluoroalkyl)alkynes A Introduction and synthesis B Reactions 1 Perfluoro-2-butyne Formation of polymers and oligomers Reactions with nucleophiles Fluoride-ion-induced reactions Cycloadditions Free-radical additions References 8 I
FUNCTIONAL COMPOUNDS CONTAINING OXYGEN, SULPHUR OR NITROGEN AND THEIR DERIVATIVES
Oxygen derivatives A Carboxylic acids 1 Synthesis 2 Properties and derivatives 3 Trifluoroacetic acid 4 Perfluoroacetic anhydride 5 Peroxytrifluoroacetic acid B Aldehydes and ketones 1 Synthesis 2 Reactions Addition to C5O Reactions with fluoride ion C Perfluoro-alcohols 1 Monohydric alcohols 2 Dihydric alcohols 3 Alkoxides D Fluoroxy compounds E Perfluoro-oxiranes (epoxides) F Peroxides II Sulphur derivatives A Perfluoroalkanesulphonic acids B Sulphides and polysulphides C Sulphur(IV) and sulphur(VI) derivatives D Thiocarbonyl compounds III Nitrogen derivatives A Amines B N–O compounds 1 Nitrosoalkanes 2 Bistrifluoromethyl nitroxide C Aza-alkenes D Azo compounds E Diazo compounds and diazirines References
218 218 222 222 222 223 223 224 226 227
236 236 236 236 238 240 241 242 243 243 243 246 251 254 254 255 257 258 259 264 265 265 270 272 272 275 275 277 277 278 278 284 284 287
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiii
Contents
9
POLYFLUOROAROMATIC COMPOUNDS
I
xiii
296
Synthesis A General considerations B Saturation/re-aromatisation C Substitution processes 1 Replacement of H by F 2 Replacement of 2N2þ by F: the Balz–Schiemann reaction 3 Replacement of 2OH or 2SH by F 4 Replacement of Cl by F II Properties and reactions A General B Nucleophilic aromatic substitution 1 Benzenoid compounds Orientation and reactivity Mechanism 2 Heterocyclic compounds Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds Polysubstitution Acid-induced processes 3 Fluoride-ion-induced reactions Polyfluoroalkylation Other systems 4 Cyclisation reactions C Reactions with electrophilic reagents D Free-radical attack 1 Carbene and nitrene additions E Reactive intermediates 1 Organometallics Lithium and magnesium derivatives Copper compounds 2 Arynes 3 Free radicals 4 Valence isomers Nitrogen derivatives References
296 296 297 298 298 300 300 300 306 306 307 307 310 311 315 315 320 321 325 325 332 332 336 338 338 341 341 342 346 346 349 351 353 358
10
ORGANOMETALLIC COMPOUNDS
365
I
General methods and synthesis A From iodides, bromides and hydro compounds 1 Perfluoroalkyl derivatives 2 Derivatives of unsaturated systems
365 365 365 366
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Contents
B
From unsaturated fluorocarbons 1 Fluoride-ion-initiated reactions II Lithium and magnesium A From saturated compounds B From alkenes C From trifluoropropyne D From polyfluoro-aromatic compounds III Zinc and mercury A Zinc B Mercury 1 Perfluoroalkyl derivatives 2 Unsaturated derivatives 3 Cleavage by electrophiles IV Boron and aluminium A Boron 1 Perfluoroalkyl derivatives 2 Unsaturated derivatives B Aluminium V Silicon and tin A Silicon B Tin VI Transition metals A Copper B Other metals References
367 367 368 368 369 370 371 371 371 373 373 374 375 376 376 376 377 380 381 381 385 387 388 388 395
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
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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 undertaking. 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
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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 ‘specialeffect’ 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 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
1
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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 , C2 F6 , C3 F8 , C4 F10 (two isomers), cyclo-C6 F12 and C6 F14 . 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 the gaseous diffusion plant for concentrating the 235 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 CF2 Cl2CF2 Cl. 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
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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.
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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 CF2 Cl2 (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, CF3 CFH2 (HFC-134a) is an acceptable substitute for CF2 Cl2 (CFC-12) in refrigeration applications. Bromofluorocarbons possess outstanding fire-extinguishing ability: CF3 Br 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 CF3 CFHCF3 (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. Perfluorocarbons 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]
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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 F
F
n
OCF2
n
Krytox® (DuPont) Lubricants, coatings
Demnum® (Daikin)
n
OCF2CF2
m
Fomblin® (Ausimont)
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 famously 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 modulated 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].
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6
Chapter 1
Table 1.1 Applications of fluoropolymers Polymer
Monomer(s)
Applications
CF2=CF2
PTFE
FEP
CF2=CF2 + CF3CF=CF2
PFA
CF2=CF2 + RFOCF=CF2 F
Teflon AFt (DuPont)
CF2=CF2+ O CF3
F
Optically clear, used in corrosive environments where glass is unsuitable, e.g. in computer chip manufacture. Optically clear, used in corrosive environments, e.g. computer chip manufacture. Gaskets, seals, oils, coatings, transparent inert covers. Weather-resistant coatings; cable insulation; piezo-electric devices. Coatings, flexible films. Elastomers used for sealants, Orings, fuel-resistant seals for aircraft and automobiles.
O CF3
CF2=CFO(CF2)nCF=CF2
Cytopt (Asahi)
PCTFE
CF2=CFCl
PVDF
CF2=CH2 CH2=CHF
PVF VitonAt (DuPont)
CF2=CH2 + CF3CF=CF2 CF2⫽CF2 + F2C⫽C
F
CF3
2
Nafiont (DuPont)
Cookware coatings; Goretext (W.R. Gore Co.) waterproof clothing; electrical insulators; medical uses such as artificial blood vessels. Fabrication by conventional melt processing; wire and cable insulators; heat-sealable film, tubing. Injection-moulded parts for use in aggressive environments.
Membranes in chlor-alkali cells.
⫺
(OCF2CF)nO
CF2CF2X
Flemiont (Daikin)
Nafion, X ¼ CO2 H Flemion, X ¼ SO2 H
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)2CHOCH2F
CF3CHFOCHF2
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
2
7
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
O H
CF3
N
F N O N
O
O
N
HO
H OH
5-Fluorouracil (anti-cancer)
N
N
Trifluridine® (anti-viral)
N
O
N
OH
N
N
CO2H
F
F N
N
N H
F Fluconazole® (anti-fungal)
Ciprofloxacin® (antibacterial)
O
H O
OH
HO
N
CH2OH
CH3
CH3
F3C
F O Prozac® (anti-depressant)
Betamethasone® (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, 18 F-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 19 F magnetic resonance imaging (MRI); the negligible natural fluorine background and the high sensitivity of 19 F NMR spectroscopy has made possible the study of the in vivo action and metabolic pathways of fluorine-containing drugs. For instance, 19 F MRI has demonstrated that 5-fluorouracil is metabolised to NH2 CH2 CHFCOOH.
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General Discussion of Organic Fluorine Chemistry
9
F
HO
CO2H O
HO
OH HO
F
NH2
HO 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 1 H 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 herbicides, 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, CH2 FðCH2 Þ7 CH5CHðCH2 Þ7 COOH [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 NnPr2 O
NO2
O2N
O
F3C
OnBu Me
N
CF3
O Fusilade®
Trifluralin® O
CN O
F3C
O
Cl
Cyhalothrin® OH F
CF3 N
O
F
N
N
H
Flutriafol®
Flutolanil®
N
OiPr
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-trifluoro2-octanol (Figure 1.8).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 11
General Discussion of Organic Fluorine Chemistry − O
+ H3N
N Me
S
N
+
O
HO
NH2
NH2
O
N
N
−
N
F
½88
N
F
Fluorinase
11
N
N
O
HO
OH
S-adenosylmethionine
OH 5'-FDA
O
O +
NAD
OH
H
F
F Fluoroacetaldehyde
Fluoroacetate
Figure 1.6
½89
OH 58%
CH2FCOPh FH2C
Ph
R (90% ee)
Figure 1.7 OCOMe F3C
CH2CO2Et
OH
Lipase MY F3C
CH2CO2Et
OCOMe F3C
½89
CH2CO2Et
(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 19 F NMR, free from the often complex 1 H signals, can be an extremely useful probe.
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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. F3C F3C C8F17SO2NH(CH2)3NMe3
C2F5
I
Cationic
CF3 O
C2F5
SO3
Na
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. However, 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
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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 Cl
N F
Dye-NH2
Cl
NH-Dye Cl
N
N
N
Cotton-OH
F
F
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 electrondeficient 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 Electronic configuration Electronegativity (Pauling) a Ionisation energy kJmol1 1 b Electron affinity kJmol Bond energies ofC2X in CX4 kJmol1 Bond energies of X2X kJmol1 ˚) Bond lengths of C2Xc (A ˚ van der Waals radius (A) Preference as a leaving group a b c
Xþ þ e ! X X þ e ! X Covalent radii in CX4
1
F 2
Cl 5
2
Ref. 5
0
1s 2.20 1312 74.0 446.4
. . . 2s 2p 3.98 1681 332.6 546.0
434
157
242
[105]
1.091 1.20 Hþ
1.319 1.47 F
1.767 1.75 Cl
[19] [104] –
. . . 3s 3p 3d 3.16 1251 348.5 305.0
– [104] [104] [104] [19]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 14
14
Chapter 1
2Clþ 2 (as well as 2Brþ 2 or 2Iþ 2) are now well established [106], whereas the analogous fluoronium species 2Fþ 2 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
C
F
Figure 1.11
(2)
‘Double bond–no bond resonance’ (and equivalent molecular orbital descriptions) has been suggested to be involved (R) (Figure 1.12). F
C
F
F
C
F
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) (2)
Inductive (Is ) effects act as in saturated systems. Inductive and field effects result in the polarisation of p-electrons (Ip ) (Figure 1.13). F
Figure 1.13
d- d+ C C
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General Discussion of Organic Fluorine Chemistry
(3)
15
Coulombic or Pauli repulsion occurs between electron pairs on fluorine and p-electrons (þIp ) (Figure 1.14). F
δ+ δ− C C
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 ⫽C
C⫽C
F
C
F
Figure 1.15
C
Positively charged species
(1)
Inductive electron withdrawal (Is ) would tend to destabilise a carbocation (Figure 1.16). F
C 1.16A
C
F
C 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
C
+ F
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). F
C 1.18A
Figure 1.18
C
C
1.18B
F
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 16
16
(2)
Chapter 1
Repulsion between adjacent electron pairs (þIp ) would be destabilising (Figure 1.19). C
F
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 C
C
C⫽C
F
F 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+ C
dF
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). C
F
C
F
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.
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General Discussion of Organic Fluorine Chemistry
A
17
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. F
F
F
F
CF3 O CF3 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
(CF3)3C-OH
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. Cl F
1,2-dichlorohexafluorocyclobutane Cl
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 F
H F
H 1H, 2H / - perfluorocyclohexane
H 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 C2 Cl4 F2 112 Trichlorofluoromethane CCl3 F 11 Perfluorocyclobutane C4 F8 C318 Dibromodifluoromethane CBr2 F2 12B2
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General Discussion of Organic Fluorine Chemistry
19
For positional isomers, the deviation from symmetrical fluorine substitution is denoted by a letter, for example: CF2 H2CF2 H 134 CF3 2CFH2 134a
REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
D.B. Harper and D. O’Hagan, Nat. Prod. Rep., 1994, 11, 123. D.B. Harper and D. O’Hagan, J. Fluorine Chem., 2000, 100, 127. R.D. Chambers, Fluorine in Organic Chemistry, John Wiley and Sons, New York, 1973. M. Stacey, J.C. Tatlow, A.G. Sharpe, et al. (eds), Advances in Fluorine Chemistry, Vols 1–7, Butterworth, London, 1960–1973. P. Tarrant (ed.), Fluorine Chemistry Reviews, Vols 1–8, Dekker, New York, 1967–1977. M. Howe-Grant (ed.), Kirk-Othmer Encyclopedia of Chemical Technology, 4th edition, Vol. 11, Organic Fluorine Compounds, John Wiley and Sons, New York, 1994. M. Howe-Grant (ed.), Fluorine Chemistry: A Comprehensive Treatment, John Wiley and Sons, New York, 1995. A.E. Pavlath and A.L. Leffler, Aromatic Fluorine Compounds, Reinhold, New York, 1962. A.J. Rudge, The Manufacture and Use of Fluorine and its Compounds, Oxford University Press, London, 1962. W.A. Sheppard and C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969. S. Patai (ed.), The Chemistry of the Carbon–Halogen Bond, John Wiley and Sons, London, 1973. L.A. Wall, Fluoropolymers, Wiley-Interscience, New York, 1973. R. Filler, Biochemistry Involving Carbon–Fluorine Bonds, American Chemical Society, Washington DC, 1976. J.W. Root, Fluorine-containing Free Radicals, American Chemical Society, Washington DC, 1978. R.D. Chambers and S.R. James in Halo Compounds, ed. J.F. Stoddart, Pergamon, Oxford, 1979, p. 493. R. Filler and Y. Kobayashi (eds), Biomedical Aspects of Fluorine Chemistry, Elsevier Biomedical Press, Amsterdam, 1982. R. E. Banks (ed.), Preparation, Properties and Industrial Applications of Organofluorine Compounds, Ellis Horwood, Chichester, 1982. I.L. Knunyants and G.G. Yakobson, Synthesis of Fluoro-organic Compounds, Springer-Verlag, Berlin, 1985. B.E. Smart in Fluorinated Organic Molecules, ed. J.F. Liebman and A. Greenberg, VCH Publishers, Deerfield Beach, 1986, p. 141. R.E. Banks, D.W.A. Sharp and J.C. Tatlow (eds), Fluorine: The First One Hundred Years, Elsevier Sequoia, New York, 1986. J.F. Liebman, A. Greenberg and W.R. Dolbier (eds), Fluorine Containing Molecules, Structure, Reactivity, Synthesis and Applications, VCH Publishers, New York, 1988. N.F. Taylor (ed.), Fluorinated Carbohydrates: Chemical and Biochemical Aspects, American Chemical Society, Washington DC, 1988. L. German and S. Zemskov (eds), New Fluorinating Agents in Organic Synthesis, SpringerVerlag, Berlin, 1989. J.T. Welch and S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, John Wiley and Sons, New York, 1991. J.T. Welch (ed.), Selective Fluorination in Organic and Bioorganic Chemistry, American Chemical Society, Washington, DC, 1991. K.L. Kirk, Biochemistry of Halogenated Organic Compounds, Plenum, New York, 1991.
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20
Chapter 1
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 Chemistry, 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 Intermediates, 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.
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General Discussion of Organic Fluorine Chemistry
64 65 66 67 68 69 70 71 72 73 73a 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97
21
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. M. Silvester, Speciality Chemicals, 1991, 392. M.J. Molina, Angew. Chem., Int. Ed. Engl., 1996, 35, 1778. F.S. Rowland, Angew. Chem., Int. Ed. Engl., 1996, 35, 1786. C.S. Todd, The Use of Halons in the United Kingdom and the Scope for Substitution, HMSO, London, 1991. R.E. Banks, J. Fluorine Chem., 1994, 67, 193. L.C. Clark and F. Gollan, Science, 1966, 152, 1755. J.G. Riess, Chem. Rev., 2001, 101, 2797. R.M. Flynn in Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11, ed. M. HoweGrant, John Wiley and Sons, New York, 1994, p. 525. 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. G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999. D.P. Carlson and W. Schmeigel in Ullmanns Encyclopedia of Industrial Chemistry, Vol. A11, VCH Publishers, Weinheim, 1988, p. 393. R.F. Brady, Chem. Britain, 1990, 26, 427. C.A. Sperati in Properties of Fluoropolymers, ed. J. Brandrup and E.H. Immergut, Wiley, New York, 1975. A. Eisenberg and H.L. Yeager, Perfluorinated Ionomer Membranes, American Chemical Society, Washington DC, 1982. V.A. Soloshonok (ed.), Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, John Wiley and Sons, New York, 1999. M. Schlosser in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 613. D.F. Halpern in Anaesthetics Review, ed. R.E. Banks and K.C. Lowe, UMIST Chemserve, Manchester, 1994, Paper 15. B.E. Smart, J. Fluorine Chem., 2001, 109, 3. D. O’Hagan and H.S. Rzepa, J. Chem. Soc., Chem. Commun., 1997, 645. D. Seebach, Angew. Chem., Int. Ed. Engl., 1990, 29, 1320. M.R. Kilbourn in Fluorine-18 in Nuclear Medicine, ed. R.E. Banks, UMIST Chemserve, Manchester, 1994. S.B. Walker, Fluorine Compounds as Agrochemicals, Fluorochem Ltd, Glossop, 1989. S.R.A. Peters and R.J. Hall, J. Biochem. Pharmacol., 1959, 2, 25. D. O’Hagan and D.B. Harper, Nat. Prod. Rep., 1994, 11, 123. D. O’Hagan, C. Schaffrath, S.L. Cobb, J.T.G. Hamilton and C.D. Murphy, Nature, 2002, 416, 279. T. Kitazume and T. Yamazaki in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 91. 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. T.F. Herpin, W.B. Motherwell and M.J. Tozer, Tetrahedron: Asymm., 1994, 5, 2265. D.M. LeGrand and S.M. Roberts, J. Chem. Soc., Chem. Commun., 1993, 1284. D.B. Berkowitz and M. Bose, J. Fluorine Chem., 2001, 112, 13. S. Cesaro-Tadic, D. Lagos, A. Honegger, J.H. Rickard, L.J. Partridge, G.M. Blackburn and A. Pluecktun, Nat. Biotechnol., 2003, 21, 679. 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. K. Uneyama in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 391. C.R.S. Briggs, D. O’Hagan, J.A.K. Howard and D. Yufit, J. Fluorine Chem., 2003, 119, 9.
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22
Chapter 1
98 99 100 101 102
K. Shinoda, M. Hato and T. Hayaski, J. Phys. Chem., 1972, 76, 909. H. Kuneida and K. Shinoda, J. Phys. Chem., 1976, 80, 2468. W. Guo, T.A. Brown and B.M. Fung, J. Phys. Chem., 1991, 95, 1829. J.P. Badyal, Chem. Britain, 2001, 37, 45. R.D. Chambers, C. Magron, G. Sandford, J.A.K. Howard and D.S. Yufit, J. Fluorine Chem., 1999, 97, 69. P. Kirsch and M. Bremer, Angew. Chem., Int. Ed. Engl., 2000, 39, 4216. 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. N.N. Greenwood and A. Earnshaw, Chemistry of the Elements, Pergamon, Oxford, 1989. G.A. Olah, Halonium Ions, Wiley-Interscience, New York, 1975. C.G. Beguin in Enantiocontrolled Synthesis of Fluoro-organic Biomedical Targets, ed. V.A. Soloshonok, John Wiley and Sons, New York, 1999, p. 601. 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. 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.
103 104 105 106 107 108 109
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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 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
23
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 24
24
Chapter 2 H2SO4
CaF2
KF.2HF
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
PhCCl3
PhCF3
HF, rt Ph3CCl
70%
½9
62%
Ph3CF
CF3
CCl3 HF, catalyst Cl
300−500 C
N
80% 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). +
CCl4
+
HF
CF3
5hr, 100 C
½10 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). C
Figure 2.4
Cl
+
MFx
C
MFxCl
F
C
F
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 C
Cl
+
MFx
δ− MFx-1
δ+ C
F C
F
F
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 SbF3 Cl2 , 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 RF CH2 Cl 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 CCl2=CHCl
HF
HF
CF2ClCClH2
Cr(III)
CF3CH2Cl
Cr(III)
½15
HF
CF3CH2F HFC 134a
CCl3-CCl3
AlCl3
HF CF2ClCFCl2
Cr(III)
CF3CCl3 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
i, SbF3 / SbCl5, 150 C i
CCl2CClCCl3
+
PhCF2CCl3
PhCFClCCl3 6%
60%
CF3CClCCl2
+
CF2ClCClCCl2
43%
i, SbF3, 150 C i
CH3CCl2CH3
CH3CF2CH3
½17
½18
28%
+
CH3CFClCH3
½16
10%
85% i, SbF3 / SbCl5, rt i CCl3CCl2OCH3
CCl3CF2OCH3
84%
½19
i, SbF3, reflux
CCl3SCH3
i
i, SbF3 / SbCl5, 90 C
Figure 2.7
CF3−S−CH3
73%
½20
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
Cl2CCClCCl=CCl2
CCl3CClCClCCl3
CF3CClCClCF3
CF3CClCFCF3
+
SbF3, SbF3Cl2
Cl
½21
Cl
F
½22
72% Cl
Cl SbF5, 160 C
Cl
F
Cl
Cl
½23
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 Cl3C
CCl3
Chromia cat.
½20 F3C
CF3
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
C
C
C
C
F
C
C
+
Cl
Cl
Figure 2.10
1 Source of fluoride ion ˚ , respectively [27]) Fluoride ion is much smaller than chloride (ionic radii 1.47 and 1.75 A 1 and the heat of hydration of fluoride is about 134 kJmol 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]. Consequently, 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 coordinating 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 Me4 NF and other socalled ‘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). Bu4NF
+ 10H2O
+
80 C
C8H17Br
C8H17F CH3CN
+
CH2CH-C6H13
91%
½52
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
+
C
Cl
MCl
+
C
F
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 SN 2 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
Fluorinations with alkali-metal fluorides
Table 2.1 Compound
Conditions
Products
C6 H13 Cl CH2 Cl2 CHCl2 COOCH3 CH3 (CH2 )7 Br CCl3 CCl2 CCl3
KF; (CH2 OH)2 ;(HOCH2 CH2 )2 O; 175–1858 C KF, HF, 3008 C KF, 220–2308 C KF, 18-crown-6, MeCN KF, 1908 C N-Methyl-2-pyrrolidone
C6 H13 F CH2 F2 CHF2 COOCH3 CH3 (CH2 )7 F CF3 CCl2 CF3
Cl
KF, 4808 C, autoclave, no solvent
N
Yield (%) Ref. 54 82 18 92 60
[61] [62] [63] [46] [64]
Cl F
F
N
N
[32]
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 X
F
+ X
+ X
2.
F
F
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-crown6, 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).
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Preparation of Highly Fluorinated Compounds KF, NMP, 200 C
Cl NMP
31
F
= N-methyl-2-Pyrrolidone
Cl F Cl
etc.
Cl
Cl
F
½65
Cl F
F
CFCl2−CHClCCl=CCl2
CF3CH=CFCF3
KF / NMP
CCl2=CClCCl=CCl2 KF/Sulpholan, Perfluorocarbon CF3CH=CFCF3 25%
CF3C
CF3 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
C
C
+
H
2MFn
+
C
C
2MFn
+
F
C
C
F
F
HF
+
+
2MFn-1
2MFn-1
Figure 2.15
2 CoF2
C
Figure 2.16
H
+
2 CoF3 , ∆H (250 C)
F2
+
2 CoF3
C
F
= −234kJmol−1
+ HF +
½68
2 CoF2
DH is ca 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 K2 NiF6 [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 +
RH
−H +
CoF3
R
RF
½74; 75
CoF3 CoF2 + F
R'F
CoF3
R'
rearrange
R
F
RF
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,
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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 n-C5 H12
Conditions (8 C)
Product
Yield (%)
Ref.
275–325
n-C5 F12
67%
[80]
85%
[82]
C2H5
C2F5
350 F
350
F
[83]
F
350
[84] F N
N
350
Cl
C6 F12n Cln
O
III
N
CH3
70%
O
[78]
CF2CF2CF3
O
100
[85]
F
440 CF2CFHCF3
O
F
F
N
CF3
[86]
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
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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). R
H
−e
R
−H
H
R
−e
F
R
RF
½97
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 n-C8 H18 (C2 H5 )3 N
N
Product
Yield (%)
Ref.
n-C8 F18 (C2 F5 )3 N
15 þ tar 27
[89] [98]
F
37
[99]
20 þ 2 85 20 96 25
[100] [101] [102] [103] [103]
50
[104]
N
F
F
(CH3 )2 S CH3 COF C7 H15 COCl CH3 SO2 F C8 H17 SO2 Cl
CF3 SF5 þ (CF3 )2 SF4 CF3 COF C7 F15 COF CF3 SO2 F C8 F17 SO2 F F
O
CF2CFHCF3
O
CF2CF2CF3
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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
RFH
O
RFH
= -CF2CFH-CF3
O
C3F7
i
C3F7
F
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 ECB ECN 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 K2 NiF6 [108] decomposes on heating to give elemental fluorine.
IV A
FLUORINATION WITH ELEMENTAL FLUORINE [109] 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. F2 RH R
2F + +
K = 10−20
F
R
+
HF
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
temperature (F2 ¼ 2F , K ¼ 1020 ), 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). RH
+
F2
R
+
HF
+
∆H = +16.3 kJmol−1
F
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). C
C
+
F
F2
C
C
+
F
∆H
= −156.9 kJmol−1
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). CCl2=CCl2
+
Cl2
F2 (trace)
CCl3-CCl3
85%
½114
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,
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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 CH3(-OCH2CH2-)nCH3 + CF2=CFCF3
½128
RFHCH2(-OCHCH2-)nCH2RFH
F2
RFH
= CF2CFHCF3
RF
= CF2CF2CF3
RF RFCF2(-OCFCF2-)nCF2RF
i, ii RFH
RFH
O
RFH
= CF2CFHCF3
RF
F O
91% RF RF
½129, 130
= 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)
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38
Chapter 2 HOCH2CH(CH3)OC3F7
+
FC(O)CF(CF3)OC3F7
½131
C3F7OCF(CF3)C(O)OCH2CH(CH3)OC3H7 F2 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.
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Preparation of Highly Fluorinated Compounds
D
39
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 C60 F48 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 C60 F48 , carbon–carbon bond cleavage occurs, thus cracking the sphere [144, 145]. A fluoroxyfullerene, C60 F17 OF, 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
CO2
i
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).
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40
Chapter 2
Table 2.4 Fluorination using dilute fluorine Starting material
Product
Yield (%)
Ref.
89
[169]
96
[170]
26
[171]
–
[172]
91
[149]
Conditions: F2 in He or N2 , 788 C to rt (CH3 )3 CCH2 CH2 C(CH3 )3
(CF3 )3 CCF2 CF2 C(CF3 )3 F
C
C 4
4 F
F F3C H3C
F
F3C
H3C CH2CH2O
CF2CF2O
n
(CH3)3CCH2SH
n
(CF3)3CCF2SF5
Conditions: 268 C and lower CH2CH2O
CF2CF2O
20
[159] 20
Conditions: 908 C to rt O
O
F2
O
O O
F3C
O
O
F O
[160]
O
F3C
F CF3 O F3C
Conditions: Aerosol fluorination Cl
Cl
F
O
O O
F3C
CF2
60
[173]
65
[124]
CF3 F
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).
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Preparation of Highly Fluorinated Compounds BrF3
CBr4 CI4
IF5
CF3Br CF3I
41
½176
94%
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, C6 Fn (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). C6Cl6
ClF3, 240 C
C6F7Cl3 (2%) + C6F6Cl4 (10%) + C6F4Cl4 (4%)
½177
+ C6F5Cl5 (30%) + C6F4Cl6 (35%)
Figure 2.29
2I2
+
IF5
+
5CF2=CF2
2I2
+
IF5
+
5CF3CF=CF2
5CF3CF2I 150 C
5(CF3)2CFI
86%
½178, 179
99%
Figure 2.30
REFERENCES 1 2 3 4 5 6 7 8 9 10 11
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52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80
81 82 83 84 85 86 87 88 89 90 91 92 93
43
D. Albanese, D. Landini and M. Penso, J. Org Chem., 1998, 63, 9589. N. Yoneda, Tetrahedron, 1991, 47, 5329. R.D. Chambers, S.R. Korn and G. Sandford, J. Fluorine Chem., 1994, 69, 103. M. Hudlicky, Org. Reactions, 1988, 35, 513. A.S. Pilcher, H.L. Ammon and P. DeShong, J. Am. Chem. Soc., 1995, 117, 5166. W.B. Farnham and R.L. Harlow, J. Am. Chem. Soc., 1981, 103, 4608. K.O. Christe and W.W. Wilson, J. Fluorine Chem., 1990, 47, 117. A.G. Sharpe, Quart. Rev., 1957, 11, 49. G. Rotenberg, M. Royz, O. Arrad and Y. Sasson, J. Chem. Soc., Perkin Trans. 1, 1999, 1491. F.W. Hoffmann, J. Am. Chem. Soc., 1948, 70, 2596. W. Verbeck and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1966, 5, 314. E. Gryszkiewicz-Trochimowski, A. Sporzynski and J. Wnuk, Rec. Trav. Chim., 1947, 66, 413. J.T. Maynard, J. Org. Chem., 1963, 28, 112. R.D. Chambers and A.R. Edwards, J. Chem. Soc., Perkin Trans 1, 1997, 3623. M. Stacey and J.C. Tatlow, Adv. Fluorine Chem., 1960, 1, 166. J. Burdon in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 655. R.S. Jessup, F.G. Brickwedde and M.T. Wechsler, J. Res. Nat. Bur. Stand., 1950, 44, 457. P.L. Coe, R.G. Plevey and J.C. Tatlow, J. Chem. Soc. C, 1969, 1060. J. Bailey, R.G. Plevey and J.C. Tatlow, J. Fluorine Chem., 1988, 39, 23. J. Bailey, R.G. Plevey and J.C. Tatlow, J. Fluorine Chem., 1987, 37, 1. R.G. Plevey, M.P. Steward and J.C. Tatlow, J. Fluorine Chem., 1973, 3, 259. R.G. Plevey, R.W. Rendell and M.P. Steward, J. Fluorine Chem., 1973, 3, 267. R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Ritchie, J. Chem. Soc., Perkin Trans 1, 1974, 114. J. Burdon, J.C. Creasey, L.D. Proctor, R.G. Plevey and J.R.N. Yeoman, J. Chem. Soc., Perkin Trans 2, 1991, 445. J. Burdon and I.W. Parsons, Tetrahedron, 1975, 31, 2401. J. Burdon and I.W. Parsons, Tetrahedron, 1980, 36, 1423. R.D. Chambers, B. Grievson, F.G. Drakesmith and R.L. Powell, J. Fluorine Chem., 1985, 29, 323. R.W. Rendell and B. Wright, Tetrahedron, 1979, 35, 2405. R.D. Fowler, W.B. Burford, J.M. Hamilton, R.G. Sweet, C.E. Weber, J.S. Kasper and I. Litant in Preparation, Properties and Technology of Fluorine and Organic Fluoro-campounds, ed. C. Slesser and S.R. Schram, McGraw-Hill, New York, 1951, p. 349. B.D. Joyner, J. Fluorine Chem., 1986, 33, 337. R.N. Haszeldine and F. Smith, J. Chem. Soc., 1950, 3617. A.K. Barbour, G.B. Barlow and J.C. Tatlow, J. Appl. Chem., 1952, 2, 127. R.G. Plevey, R.W. Rendell and J.C. Tatlow, J. Fluorine Chem., 1982, 21, 413. P. Johncock, R.H. Mobbs and W.K.R. Musgrave, Ind. Eng. Chem., Proc. Res. Dev., 1962, 1, 267. R.W. Rendell and B. Wright, Tetrahedron, 1978, 34, 197. F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 197. J.H. Simons in Fluorine Chemistry, Vol. 1, ed. J.H. Simons, Academic Press, New York, 1950, p. 401. J. Burdon and J.C. Tatlow, Adv. Fluorine Chem., 1960, 1, 129. S. Nagase, Fluorine Chem. Rev., 1967, 1, 77. N. Watanabe, J. Fluorine Chem., 1983, 22, 205. P. Sartori, Bull. Electrochem., 1990, 6, 471. T. Abe and S. Nagase in Organofluorine Chemistry. Preparation, Properties and Industrial Applications, ed. R.E. Banks, Ellis Horwood, Chichester, 1982, p. 19.
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Chapter 2
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.
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Preparation of Highly Fluorinated Compounds
129 130 131 132 133 134
135 136 137 138 139 140 141 142 143 144 145
146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166
45
R.D. Chambers and R.C.H. Spink, J. Chem Soc., Chem. Commun., 1999, 883. R.D. Chambers, D. Holling, R.C.H. Spink and G. Sandford, Lab on a Chip, 2001, 1, 132. T. Okazoe, K. Watanabe, M. Itoh, D. Shirakawa, H. Morofushi, H. Okamoto and S. Tatematsu, Adv. Sci. Synth., 2001, 343, 215. K. Jahnisch, M. Baerns, V. Hessel, W. Erhfeld, V. Haverkamp, H. Lowe, C. Wille and A. Gruber, J. Fluorine Chem., 2000, 105, 117. N. deMas, A. Gunther, M.A. Schmit and K.F. Jensen, Ind. Eng. Chem. Res., 2003, 42, 698. M. Anand, J.P. Hobbs and I.J. Brass in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 469. F.J. du Toit and R.D. Sanderson, J. Fluorine Chem., 1999, 98, 107. A.P. Kharitonov, Pop. Plastics Packaging, 1997, 75. Various authors, Ind. Res. Dev., 1978, 12, 102. J.P. Hobbs, P.B. Henderson and M.R. Pascolini, J. Fluorine Chem., 2000, 104, 87. 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. N. Watanabe, T. Nakajima and H. Touhara, Graphite Fluorides, Elsevier, New York, 1988. G.A. Shia and G. Mani in Organofluorine Chemistry. Principles and Commercial Applications., ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 483. K. Kniaz, J.E. Fischer, H. Selig, G.B.M. Vaughan, W.J. Romanow, D.M. Cox, S.K. Chowdhury, J.P. McCauley, R.M. Strongin and A.B. Smith, J. Am. Chem. Soc., 1993, 115, 6060. A.A. Gakh, A.A. Tuinman, J.L. Adcock, R.A. Sachleben and R.N. Compton, J. Am. Chem. Soc., 1994, 116, 819. A.A. Tuinman, A.A. Gakh, J.L. Adcock and R.N. Compton, J. Am. Chem. Soc., 1993, 115, 5885. 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. A.D. Darwish, A.K. Abdul-Sada, A.G. Avent, S.M. Street and R. Taylor, J. Fluorine Chem., 2003, 121, 185. H. Fujimoto, M. Yoshikawa, A. Mabuchi and T. Maeda, J. Fluorine Chem., 1992, 57, 65. H. Fujimoto, A. Mabuchi, T. Maeda, Y. Matsumara, N. Watanabe and H. Touhara, Carbon, 1992, 30, 851. H.N. Huang, H. Roesky and R.J. Lagow, Inorg. Chem., 1991, 30, 789. K.B. Kellog and G.H. Cady, J. Am. Chem. Soc., 1948, 70, 3986. J.H. Prager, J. Org. Chem., 1966, 31, 392. P.G. Thompson, J. Am. Chem. Soc., 1967, 89, 1811. R.L. Cauble and G. Cady, J. Am. Chem. Soc., 1967, 89, 1962. F.A. Hohorst and J.M. Shreeve, J. Am. Chem. Soc., 1967, 89, 1809. D.F. Persico, H.N. Huang, R.J. Lagow and L.C. Clark, J. Org. Chem., 1985, 50, 5156. W.D. Clark, T-Y. Lin, S.D. Maleknia and R.J. Lagow, J. Org. Chem., 1990, 55, 5933. K.S. Sung and R.J. Lagow, J. Am. Chem. Soc., 1995, 117, 4276. M. Biollaz and J. Kalvoda, Helv. Chim. Acta, 1977, 60, 2703. H-C. Wei and R.J. Lagow, J. Chem. Soc., Chem. Commun., 2000, 2139. T.-Y. Lin, H-C. Chang and R.J. Lagow, J. Org. Chem., 1999, 64, 8127. W-H. Lin, W.D. Clark and R.J. Lagow, J. Org. Chem., 1989, 54, 1990. J.L. Adcock, M.L. Robin and S. Zuberi, J. Fluorine Chem., 1987, 37, 327. J.L. Adcock and M.L. Robin, J. Org. Chem., 1983, 48, 2437. J.L. Adcock and H. Luo, J. Org. Chem., 1992, 57, 4297. J.L. Adcock and R.J. Lagow, J. Am. Chem. Soc., 1974, 96, 7588. J.J. Kampa, J.W. Nail and R.J. Lagow, Angew. Chem., Int. Ed. Engl., 1995, 34, 1241.
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46
Chapter 2
167 168 169 170 171 172 173 174 175
J.L. Adcock, W.D. Evans and L. Heller-Grossman, J. Org. Chem., 1983, 48, 4953. J.L. Adcock and W.D. Evans, J. Org. Chem., 1984, 49, 2719. E.K.S. Liu and R.J. Lagow, J. Fluorine Chem., 1979, 14, 71. R.E. Aikman and R.J. Lagow, J. Org. Chem., 1982, 47, 2789. G. Robertson, E.K.S. Liu and R.J. Lagow, J. Org. Chem., 1978, 43, 4981. G.E. Gerhardt and R.J. Lagow, J. Org. Chem., 1978, 43, 4505. J.L. Adcock, H. Luo and S.S. Zuberi, J. Org. Chem., 1992, 57, 4749. W.K.R. Musgrave, Adv. Fluorine Chem., 1960, 1, 1. 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. A.A. Banks, H.J. Emele´us, R.N. Haszeldine and V. Kerrigan, J. Chem. Soc., 1948, 2188. R.D. Chambers, J. Heyes and W.K.R. Musgrave, Tetrahedron, 1963, 19, 891. R.D. Chambers, W.K.R. Musgrave and J. Savory, J. Chem. Soc., 1961, 3779. M. Hauptschein and M. Braid, J. Am. Chem. Soc., 1961, 83, 2383.
176 177 178 179
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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
CH3(CH2)15
CO2Me
CH3(CH2)15
CO2Me
84%
½24
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 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
47
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 48
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 i,
½29
76%
CH3COF
KF, CH3COOH, 100 C i
C6H5CHCHSO2Cl
C6H5CHCHSO2F
½30
51%
i, KF, xylene, reflux i or ii
MF + n-C8H17Br
i, MF = KF plus small amounts water, 85 C ii, MF = Bu4NF.3H2O, 60 C 71% i
MF + BrCH2COOEt i, MF
= CsF
½25
n-C8H17F + MBr 60%
70%
½25
O(CH2)3F
½27
FCH2COOEt + MBr
+ 10% Bu4NF, 40 C
O(CH2)3OMs i
Me i, KF,
92%
Bu N
N
BF4 , H2O (5 equiv), 100 C
i FCH2CH2OH
BrCH2CH2OH
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, tetramethylammonium 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
CH2 ¼ CHCH2 Br
Bu4 NF, 258 C
CH2 ¼ CHCH2 F
O Cl
Ref.
85
[33]
O
THF=HMPTa , 958 C, Bu4 Nþ HF 2
Ph
Yield (%)
[39] F
Ph
RX (R ¼ alkyl, X ¼ Cl, Br)
2Bu4 NFnH2 O CH3 CN
RF
PhCH2 Br
Ph4 PHF2 CH3 CN, 508 C
PhCH2 F
100
[41]
PhCH2 Cl
Cp2 CoFb THF, rt
PhCH2 F
95
[37]
C2 H5 I
TAS-Fc CH3 CN, rt
C2 H5 F
85
[12]
[40]
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
CH3 ðCH2 Þ7 Br
Bu4 Nþ Ph3 SiF 2 CH3 CN, 808 C
CH3 ðCH2 Þ7 F
O
O Ph a
85
[42]
76
[38]
F
Ph O
Pyridine9HF 08 C
Cl
Ref.
O
PS=HFd CH3 CN, rt
Cl
Ph
Yield (%)
[43] Ph
F
HMPT, hexamethylphosphoric triamide. b
c
Cp2CoF
d
TAS-F
+ − [(Me2N)3S] [(CH3)3SiF2]
Co
Me2N
PS / HF NMe2
F
. HF
Hydrogen fluoride under vigorous conditions may be used in favourable circumstances, for example to make fluoromethyl ethers [44] (Figure 3.3a). OH
+
Cl
OCCl3
OCF3
Cl
Cl
½44
i CCl4
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
R
R
Cl
F
½45
i Cl
SO2Cl R i, ii, iii,
51
Cl
SO2F ii, iii
= H, Me KF, Ph4PBr NaOH H2SO4, heat
R
F
Cl
Figure 3.3b
CH3CH2CH2Br
+
ClF
0 C
CH3CH2CH2F
70%
30% rt CH2ClCH2Br
+
CH2ClCH2F
BrF3
½47
+ CH3CHFCH3
½48, 49
80%
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
RCH2I R
= p-TsO
RCH2
IF2
F
RCH2F
½51
74%
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
Ar O
I
O
PhS
PhS
PhS N
F O
ArIF2
N
N
ArIF2
½52
F
O
O PhS
PhS N
F
N 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]. Fluorination 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 lowtemperature 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
F i
½62, 63
+
OR
OR
OR
F
F
60%
10%
R = −CO-C6H4NO2 i, F2, N2, −70 C, CHCl3, CFCl3 (1:1) OAc
OAc
i F
H AcO
AcO 50%
i, F2 in N2(10% v/v), C6H5-NO2, −78 C, CFCl3, CHCl3
Figure 3.6
H
F i
½11, 64, 65
54%, 68% conversion
H
H
i, F2 in N2 (10% v/v), CH3CN, 0 C
Figure 3.7
Nu:
+
F
F
Nuc
H
COOH
COOH
F i
F
F i, F2/N2, 98% H2SO4, room temp.
Figure 3.8
H
+
HF
½66
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54
Chapter 3 H H
F F
F
½11, 65
HCCl3
OCOC6H4NO2
OCOC6H4NO2 i 60% Me
Me
F
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
OSiMe3
Product
OEt
Ref.
78
[71]
57
[79]
84
[74]
O
F2 , N2 788 C, CFCl3
OSiMe3
Yield (%)
F
O
F2 , N2 788 C, CFCl3
OEt F
NO2 OH O2N
H
i) OH ii) F2 , N2 , 58 C, H2 O
NO2 OH O2N
F
Contd
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Partial or Selective Fluorination
55
Table 3.2 Contd Substrate O
Conditions
Product
O
O OEt
F2 , N2 108 C, HCOOH
Yield (%)
Ref.
90
[76]
71
[80]
O OEt F
O
OH
O
OHC O
O
F2 , N2 408 C, CH3 CN
F O
O
O
R
COOMe
H
F2
O
COOMe F NHCOPh
RCHF
NHCOPh
COOH F NHCOPh
RCHF
½78
COOH F NH2
R = Alkyl or aryl RCHF
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
H
Stereochemistry Retained
i, F2, CH3CN, 0 C ii, BF3.Et2O iii, CH3CN, H2O
ii
H
H iii O H N
H
Figure 3.11
Me
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Chapter 3
B Electrophilic fluorinating agents containing O–F bonds [81, 82] Several organic hypofluorites, including trifluoromethyl (CF3 OF) [83–85], perfluoroethyl (C2 F5 OF) [86], trifluoroacetyl (CF3 COOF) [87] and acetyl hypofluorite (CH3 COOF) [88, 89], are now known which have found applications as fluorinating agents [90–94] (Figure 3.12).
Nu:
+
F
Nu
OCF3
R' COOR''
R
R'
i, ii
OCF3
R'
OSiMe3
iii
COOR''
R
OR''
R
H
+
F
½89
F
i, LDA ii, Me3SiCl iii, MeCOOF
R = R' = n-Pr, R'' = Me, 90% R = Ph, R' = Et, R'' = Me, 80%
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
R1
R2
60-70%
i R1
R2
i, MeOF, CH3CN, −40 C
C6H5-CH=CH2
i
Room Temp
δ+ C6H5-C F
i,
δ−
δ− CH δ+ Ot-Bu
t-BuOF, CH3CN
C6H5-CHFCH2Ot-Bu
Figure 3.13
½95
½96
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Partial or Selective Fluorination
57
However, single-electron transfers promoted by photolysis, are the most likely processes when CF3 OF is used as the fluorinating reagent [93]. Examples of the use of hypofluorites for conversion of C2H to C2F bonds are given in Table 3.3. Table 3.3 Fluorinations using O–F reagents Substrate
Reagent/Conditions
NO2
Product F
i) MeONa, MeOH
Yield (%)
Ref.
85
[97]
86
[98]
72
[99]
NO2
ii) AcOF, CFCl3 , 08 C
O
O
F
i) LDA, THF ii) AcOF, 788 C O
O OEt
O
AcOF, CFCl3 , CHCl3 , 758 C
O OEt F
Caesium fluoroxysulphate (CsSO4 F) [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).
Cs2SO4
+
F2
H2O
CsSO3OF
½100
Figure 3.14
C6H5R
i
½102104
FC6H4R
i, CsSO3OF, BF3, CH3CN
p-XC6H4SnMe3
i
p-XC6H4F
i, CsSO3OF, CH3CN, −4 to 0 C X = H, 69%; = Cl, 87%; = Me 86%
Figure 3.15
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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
+
+
(CF3SO2)2NF
F2
HF
½108
CH2Cl
CH2Cl
N
N i
2BF4
BF4
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 Me
O
Product
Me
Ref.
O
Ph
Ph OMe
N
CH3
F
OMe CH3
S O
[122]
F
O
LDA, THF, 788 C to rt O
O n-Pr
P
OEt OEt
PhSO2 Þ2 NF LDA, THF
n-Pr
P F
OEt OEt
[123]
F
Contd
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Partial or Selective Fluorination
59
Table 3.4 Contd Substrate
Reagent/Conditions O
O
Product O
CF3 SO2 Þ2 NF CH2 Cl2 , rt
Ref.
O
[124]
F O
CH2Cl
O
Ph
NMe2
O
N
O
Ph
NMe2
−
2BF4
[125]
F
N F
CH3 CN, rt OSiMe3
O −
F
OTf
[115]
N F
CH2 Cl2 , reflux AcO
O
U
CH2Cl
AcO
O
U
N F −
[126]
2BF4 AcO
S-Ar
AcO
N
S-Ar
F
Et3 N, CH3 CN, rt O
O F
CO2Et
CO2Et
[127]
N S
F O
O
NaH, Et2 O, 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
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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
X = O, CH2
½139
F
i, XeF2, BF3.OEt2
OSiMe3
i) Aprotic conditions ii) Protic conditions
XeF2
XeF2 i O
ii O
O F
½138
O
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].
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Partial or Selective Fluorination
R3CH
R3C
H
i
R3CF
R3C NO
−
61
½143
R3CNO
i, NO+BF4, Py.HF
Figure 3.18 OH
O i
½144
30% F
F
i, PbO2, Py.HF
Figure 3.19
Oxidative fluorination of toluene derivatives to the corresponding fluoromethylbenzenes 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). Consequently, it seems unlikely that the ECF process (Chapter 2, Section III) could proceed to perfluorination by an analogous mechanism. ArCH3
Pb(OAc)4
−H+
(ArCH3)
HF, −e
ArCH2
½146
−e
etc
ArCF2H
ArCH2F Ar
ArCH2
= 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 Et3 N3HF as the electrolytic medium [149, 150]. A Pummerer-type mechanism has been proposed (Figure 3.21a). F
F S R
−H
S CH3
R
CH3
S R
H C
S H
R
CH2F
Figure 3.21a
Similarly, a-fluoro sulphoxides are prepared by fluorination using DAST [151].
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Chapter 3
Remarkably, iodine pentafluoride in Et3 N3HF acts, in some cases, like an electrophilic fluorinating agent, replacing C2H in preference to oxygen functions [152] (Figure 3.21b). COCH2SEt
COCF2SEt i, ii
+ IF5 F
½152
F
F
F 82%
i, iii CH3COCH2COOEt + IF5
CH3COCHFCOOEt 71%
i, ii, iii,
Et3N.3HF heptane 74 C 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% i, Pyridine.(HF)n, 20 C, 2 hr
F
OH
i
i, Pyridine.(HF)n, 20 C, 1 hr
Figure 3.22
95%
½43
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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). ½154
i OH
F
O
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. H Me2N
NMe2
½38
Proton Sponge. HF (PS.HF) F
PS.HF
i
CF2CFCF3
+
(CF3)2CF
C3F6
C2F3
F3C
F 72%
i, CH3CN, rt
H
F3C
H N Cl
i
N
N F
+
PS.HCl
N 79% i, PS.HF, CH3CN, rt
Figure 3.24
A combination of IF5 with Et3 N3HF 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 diethylaminotrimethylsilane [160] (Figure 3.26), can be used in normal laboratory glassware at
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64
Chapter 3 p-CH3-C6H4-CH2OH i, ii,
i, ii
+ IF5
p-CH3-C6H4-CH2F
½152
83%
Et3N.3HF CH2Cl2
Figure 3.25 Et2NSF3 + Me3SiF
SF4 + Et2NSiMe3
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 derivatives have been used and a methoxyethyl derivative has become commercially available, MeOCH2 CH2 Þ2 NSF3 (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). ROH
+
Et2NSF3
ROSF2NEt2
F
RF
+
FSONEt2
½165, 166
Figure 3.27
For most substrates SN 2 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 isomeric allyl fluorides by either an SN i or SN 20 process [12] (Figure 3.28). F F S
NEt2
½12
O R
SNi
F F NEt2 F S O R F
Figure 3.28
SN2'
R
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Partial or Selective Fluorination
65
Table 3.5 Replacement of hydroxyl groups by fluorine Substrate
Reagents/Conditions
n-C8 H17 OH
DAST CH2 Cl2 , 708 C to rt
PhCH2 CH2 OH
Deoxo-Fluort CH2 Cl2 , rt, 16 h
Yield (%)
Ref.
n-C8 H17 -F
90
[159]
PhCH2 CH2 F
85
[163]
71
[167]
53
[168]
F
HO
DAST CH2 Cl2 , 408 C to rt
O
F HO HO
O
O
SPh
O
F HO HO
OMe
Et2 OÞ2 POCHðOHÞPh H3C
Product
DAST CH2 Cl2 , rt DAST CH2 Cl2 , 08 C
OMe
Et2 OÞ2 POCHFPh H3C
OH O
O
F
[169] O
SPh 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], Et2 NCF2 CFClH, and Ishikawa’s reagent [172], Et2 NCF2 CFHCF3 , 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, Me2 NCF2 CF2 H, 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 PhCF2 2NMe2 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
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Chapter 3
O
O
½173175
i
HO
F
57%
i, Et2NCF2CFClH, CH2Cl2
O
O i HO
F
OMe
45%
OMe
i, Et2NCF2CFHCF3, CH2Cl2, 18 hr
Figure 3.29 F
Et N Et
C
CFHCF3
−F
F
Et N
C
CFHCF3
N
Et
F
F
Et Et
CFHCF3
O R
O R
C
H
H −H
Et
Et N Et
C
N
CFHCF3 Et
O
C
CFHCF3
−F
F
Et N Et
O R
+
R
F
C
CFHCF3
O R
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
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Partial or Selective Fluorination
N
COCl2
N
N
Me
Me
KF
N Me
Me
O
N
N
F
F
½181 Me
Me
Cl
67
Cl DFI
i, ii
n-C8H17OH
i, iii p-HOC6H4-NO2 O
n-C8H17F
87%
p-FC6H4-NO2
62%
F
F
F
i, iv
i, DFI ii, CH3CN, 25 C iii, CH3CN, 85 C iv, Glyme, 85 C
21%
72%
Figure 3.31 O
AcO i
O
O
½182
AcO
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
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Chapter 3 i n-C8H17OSO2C6H4CH3
½183
59%
n-C8H17F
i, KF, PEG 400, 27hr, 50 C
F
OSO2CH3
i
OCH3
OCH3
83%: 96% e.e.
½184
O
O i, KF, HCONH2, 60 C, 20 torr O
O F
i
65%
OSO2CF3
Cl
½185
Cl
i, Bu4NF, THF, 4 hr
Figure 3.33 3 SCl2 3SCl2 +
+ 4 NaF
CH3CN, 70 C
SF4
4Py.(HF)n
SF4
+ +
S2Cl2
+
4 NaCl
90%
½186 ½187
S2Cl2
Figure 3.34 C6H5CHO HOOCC
SF4, 150 C
CCOOH
C6H5CHF2
SF4, 170 C
CF3C
81%
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
C
C
δ C
XFn
O
δ O
C
F
O
F
F + SOF2 + XFn
F
δ C
SF4
XFn
δ O
½190
XFn
F
SF3
SF2
C
O
F
F
XFn−1
69
+
SF3
XFn
XFn = Lewis Acid
Figure 3.36 COOH
CF3
CF3
Li etc HOOC
COOH
F3C
CF3
F3C
½192
CF3
Figure 3.37 O
O i
i, SF4, HF, CH2Cl2
82%
F
½193
F
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, Et3 N3HF [203] and i-Pr2 NH3HF [204] efficiently cleave epoxides to give excellent yields of fluorohydrins (Figure 3.39). F
O
H H
i-Pr2NH.HF
½204
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
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70
Chapter 3
Table 3.6 Fluorination of carbonyl and related groups Substrate
Reagent, conditions
C6 H5 CHO C6 H5 CHO
SF4 , 1508 C, 6 h Deoxo-Fluort, rt
O
Yield (%)
Ref.
C6 H5 CF2 H C6 H5 CF2 H
81 95
[194] [163]
O
F
O
SF4 , 1308 C O
Product
O
F
[195]
F
F
O
CO2H
CF3
SF4 , 1008 C N
25
[196]
76
[197]
18
[198]
45
[199]
82
[200]
N
CO2H
CF3
F
CO2H
SF4 , HF, 2008 C
F O
CO2H CF3
CO2H HO2C
F3C
CO2H
F
F
CF3
SF4 , HF, 1408 C HO2C O H
CF3
F3C
CO2H
HF2C O
O
OMe
OMe
DAST, CH2 Cl2 , rt O O
C6 H5 COCH2 F
O
O
DAST, benzene, 508 C
C6 H5 CF2 CH2 F
positive charge is most readily stabilised. Conversely, i-Pr2 NH3HF is not sufficiently acidic to protonate the ring oxygen significantly and so ring opening occurs by fluorideion attack at the least hindered carbon atom in an SN 2 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 Bu4 NF=CH3 SO2 F [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 OH
O
F
71
½205
+ OBu
OBu
OBu
F Reagent : i-Pr2N.3HF Pyridine.HF
OH
Ratio : 6 1
1 4
Yield,
81% 68%
Figure 3.40 F
F CF3
HF, 95 C
½206
O F
COF
F
Figure 3.41 F
O
CF3
F
i
(CF3)3COH
56%
½209
CF3 i, HF, SbF5, 100 C
Figure 3.42 OCOF
F
½212, 213
i
i, AlF3, HF, 200−300 C
Me
OCOF Me
F Me
Me
i
i, HF, 130 C
½214 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 C2S or C5S 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).
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72
Chapter 3
Table 3.7 Fluorodesulphurisation reactions Substrate
Reagents/Conditions
Product
Yield (%)
Ref.
BnO
BnO
p-MeC6 H4 -IF2 O
BnO BnO
CH2 Cl2 , 788 C to rt BnO
S
F BnO
S-Ar
S
[217]
O
BnO BnO
CF2CF3
PyridineðHFÞn , NBSa
CF3 78 C to rt
[218] n-Pr
n-Pr CF2Ph S
S Ph
F2 , I2 , CH3 CN, rt
[219]
Br
Br CF2H S
S
C6H11
H
BrF3
70
S
S Me
F
O
O
DASTb , CH2 Cl2 , rt
C(SEt)3
PyridineðHFÞn , NBS
S SEt
[223]
PhCH2 SMe
a b
S
CF3
BrF3 , 08 C
PhCH2 N
[222]
S Br
Br
[221]
CF3
788 C to rt
S
MeO
[220]
Bu4 N þ H2 F 3
N CF3
NBS, rt
NBS, N-bromosuccinimide. DAST, diethylaminosulphur trifluoride.
MeO
[224]
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Partial or Selective Fluorination
73
I C
S
I
R
C
S
C
R
F
F
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
R
RCF2N3
CF3SO3 S
½225
89% 3.45A
i, Me3SiN3, CH2Cl2, 0 C ii, Bu4NF, THF, 0 C iii, Et3N.3HF iv, DBH
Figure 3.45
VI A
FLUORINATION OF NITROGEN-CONTAINING FUNCTIONAL GROUPS 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]. ArNH2
i, ii
i, HCl, NaNO2 ii, HBF4
Figure 3.46
ArN2
BF4
heat
ArF
½227, 228
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74
Chapter 3 HO R
COOH
R O
R
O
H
R
COOH
F
H
½234
H H2N
H
N2
H 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 SN 1 or SN 2, 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, phenylsubstituted aziridines can be considered to react via the most stable carbocation in an SN 1 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
Me NH2
Product
Yield (%)
Ref.
Me
i, NaNO2 , HCl ii, HBF4 iii, Heat
F
Me
[235]
Me
H2N
CO2Et
N
i, NaNO2 , HBF4 ii, hn, HBF4 , 508 C
F
CO2Et
N
NH
39
[236]
93
[237]
76
[238]
NH F
NH2
NaNO2 , pyridineHF N
N H3C
COOH
H2N
H
NaNO2 , pyridineHF
R
COOH
F
H
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 75
Partial or Selective Fluorination
H
H N
H
H
Ph
H
H2 N
Ph
Me
H
H
Me
Ph
NH2
75
½239
Me
F
NH2
F Ph H
NH2
F +
Me
H Ph
Me 8%
69%
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
NO2
59%
½242, 243
70%
½242, 243
NO2 i NO2
F
i, Me4NF, DMSO, 100 C, 4 hr 18F
N(CH3)3 i
91%
ClO4
½244
NO2
NO2 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).
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Chapter 3
O
O
EtO
O
i OEt
O 70%
EtO F
N2
½248
OEt F
i, F2, CFCl3, −70 C
i
CH3
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). CH3CHCH2
HF, −45 C
CH3CHFCH3
62%
i F
65%
½250
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 fluorohaloalkanes [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 CHClCCl2
HF, TaF5
CF2CHCl
BF3, 25 C
CH2ClCCl2F
CF3CH2Cl
HF
77
½251, 252
89%
90%
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 C4H9C
C4H9CF2CH3
CH
70%
½43
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 O
C6H5
C6H5
O
OR
OR
71%
½254
R = methyl
i, Bu4NF, THF, 0 C, MeC6H4SO3H
F
i MeOOCC
CO2Me
CCOOMe MeO2C i, Bu4NH2F3, CH2Cl
H
90%
½255
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],
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Chapter 3 CF3CF=CFCF3
F2, −75 C
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 O
Product
F
O F
O N Boc AcO
F2 , N2 CFCl3 , CHCl3 , EtOH 788 C
O
[259]
65
[237]
41
[262]
40
[263]
F
F
O
F
N Boc
AcO
O
F
F
AcO OAc
35 F
F2 , Ar CFCl3 , 788 C AcO
Ref.
O
F2 , N2 CFCl3 , CHCl3 , EtOH 758 C
O
Yield (%)
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).
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Partial or Selective Fluorination
79
F δ F
F
F H
F
δ
F H
F
F
½235, 259
H
H 3.56A −H
F
F F
F
F2
Figure 3.56 Ph2CCH2
F2, N2
Ph2CFCH2F 14%
+
Ph2CCHF 78%
+
Ph2CFCF2H 8%
½238
Figure 3.57 O
O
½236 F2, N2
AcO
Cl
F
Cl
O F F F
O 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).
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80
Chapter 3 Ph
Ph H F
i Ph
F H Ph
syn:anti 65 : 35
½264
i, CsSO3OF, HF, CH2Cl2, 20 C
Figure 3.59 i PhC
CPh
75%
PhCF2CF2Ph
½267
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). PhCHCHPh
+
XeF2
HF, CH2Cl2
cis trans
PhCHFCHFPh
½270
90%
erythreo:threo = 53 : 47 62 : 38
+ XeF2
HF, CH2Cl2
F
+
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 Et2 O [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 PbðOCOCH3 Þ2 F2 , formed in situ by the reaction of lead tetraacetate 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).
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Partial or Selective Fluorination Hal
Hal
81
Hal
F 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
a
F
NIS , pyridineHF
Yield (%)
Ref.
65
[43]
87 (9:1)
[279]
60
[280]
85
[43]
I C4H9
DBH b, KF2H2 O H2 SO4 , CH2 Cl2
C4H9
Br F +
C4H9
F Br
Me
Me N
I
− BF4
F I
2
CH2 Cl2 , 08 C F
Br2 , AgNO3 pyridineHF Br a b
NIS, N-iodosuccinimide. DBH, 1,3-dibromo-5,5-dimethylhydantoin.
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Chapter 3
i Br
½276
53%
F
i, NBS, Et3N.3HF, CH2Cl2, 0 C 38%
Br F
5%
Br 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
i
AcO
Y
AcO
AcO i, CF3OF, CFCl3, −70 C
AcO
½281
O
O
X
X=F, Y=OCF3, 31% X=Y=F, 22%
+
AcO
Y AcO
X
X=F, Y=OCF3, 11% 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). CsSO3 OF reacts with alkenes to give fluoroalkyl sulphates [284].
F Other additions In a similar process to halofluorination, sulphur- [285], selenium- [286] and nitrogencontaining [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
½282
OMe i
40%
i, CH3OF, CH3OH, CH3CN, −40 C
OAc
OAc
½283
i AcO
AcO
F
OCF3
i, CF3OF, CFCl3, −75 C
59%
Figure 3.65 Ph
SCH3
Ph H F
i CH3
H CH3
½285
90%
−
i, (CH3)2SSCH3 BF4 , Et3N.3HF, CH2Cl2, rt
SePh
i F
MeO
MeO
½286 53%
i, PhSeCl, AgF, CH3CN F i 65%
½43
NO2 i, NO2BF4, Pyridine.HF, 0 C
Figure 3.66
REFERENCES 1 2 3 4 5 6 7 8
W.A. Sheppard, Org. Reactions, 1974, 21, 125. G.A. Boswell, W.C. Ripka, R.M. Scribner and C.W. Tullock, Org. Reactions, 1974, 21, 1. M. Schlosser, Tetrahedron, 1978, 34, 3. M.R.C. Gerstenberger and A. Haas, Angew. Chem., Int. Ed. Engl., 1981, 20, 647. S. Rozen and R. Filler, Tetrahedron, 1985, 41, 1111. A. Haas and M. Lieb, Chimia, 1985, 39, 134. C.J. Wang, Org. Reactions, 1985, 34, 319. S.T. Purrington, B.S. Kagen and T.B. Patrick, Chem. Rev., 1986, 86, 997.
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9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
Chapter 3
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H. Suga, T. Hamatani and M. Schlosser, Tetrahedron, 1990, 46, 4247. M. Muehlbacher and C.D. Poulter, J. Org. Chem., 1988, 53, 1026. W. Dmowski and R.A. Kolinski, Pol. J. Chem., 1974, 48, 1697. M. Shimizu and H. Yoshioka, Tetrahedron Lett., 1989, 30, 967. H. Seto, Z.H. Qian, H. Yoshioka, Y. Uchibori and M. Umeno, Chem. Lett., 1991, 1185. F.J. Pavlic and P.E. Toren, J. Org. Chem., 1970, 35, 2054. M. Shimizu, Y. Nakahara and H. Yoshioka, Tetrahedron Lett., 1985, 26, 4207. D.U. Robert, G.N. Flatau, A. Cambon and J.G. Reiss, Tetrahedron, 1973, 29, 1877. G.A. Olah and S.J. Kuhn, J. Org. Chem., 1956, 21, 1319. H. Garcia, M.C. Perrod, L. Gilbert, S. Ratton and C. Rochin, J. Fluorine Chem., 1991, 54, 117. N. Lui, A. Marhold and D. Bielefeldt, Germ. Pat. 422 576 (1994); Chem. Abstr., 1994, 120, 216933a. J. Kollonitsch, S. Marburg and L.M. Perkins, J. Org. Chem., 1976, 41, 3107. M. Kuroboshi and T. Hiyama, J. Synth. Org. Chem. Jpn., 1993, 51, 1124. S. Caddick, W.B. Motherwell and J.A. Wilkinson, J. Chem. Soc., Chem. Commun., 1991, 674. M. Kuroboshi and T. Hiyama, J. Fluorine Chem., 1994, 69, 127. R.D. Chambers, G. Sandford and M. Atherton, J. Chem. Soc., Chem. Commun., 1995, 177. R. Sasson, A. Hagooly and S. Rozen, Org. Lett., 2003, 5, 769. W.H. Bunnelle, B.R. McKinnis and B.A. Narayanan, J. Org. Chem., 1990, 55, 768. D.P. Matthews, J.P. Whitten and J.R. McCarthy, Tetrahedron Lett., 1986, 27, 4861. S. Rozen and E. Mishani, J. Chem. Soc., Chem. Commun., 1994, 2081. M. Kuroboshi and T. Hiyama, Tetrahedron Lett., 1992, 33, 4177. P. Kirsch and A. Taugerbeck, Eur. J. Org. Chem., 2002, 3923. B. Langlois in Houben-Weyl: Methods of Organic Chemistry, Vol. E10a, Organo-fluorine Compounds, ed. B. Bassner, H. Hagemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 686. A. Roe, Org. Reactions, 1949, 5, 193. H. Suschitsky, Adv. Fluorine Chem., 1965, 4, 1. H. Diehl, H. Pelster and H. Habetz, Germ. Pat. 3 141 659 A1 (1983); Chem. Abstr., 1983, 99, 70360k. K.G. Rutherford, W. Redmond and J. Rigamonti, J. Org. Chem., 1961, 26, 5149. C. Sellers and H. Suschitzky, J. Chem. Soc. (C), 1968, 2317. K. Takahashi, K.L. Kirk and L.A. Cohen, J. Org. Chem., 1984, 49, 1951. K.K. Laali and V.J. Gettwert, J. Fluorine Chem., 2001, 107, 31. G.A. Olah, G.K.S. Prakash, and Y.L. Chao, Helv. Chim. Acta, 1981, 64, 2528. T. Iwaoka, C. Kaneko, A. Shigihara and H. Ichikawa, J. Phys. Org. Chem., 1993, 6, 195. D.H.R. Barton, J.L. James, R.H. Hesse, M.M. Pechet and S. Rozen, J. Chem. Soc., Perkin Trans. 1, 1982, 1105. R.F. Merritt and T.E. Stevens, J. Am. Chem. Soc., 1966, 88, 1822. R.F. Merritt, J. Org. Chem., 1966, 31, 3871. T.N. Wade, J. Org. Chem., 1980, 45, 5328. G.M. Alvernhe, C.M. Ennakoua, S.M. Lacombe and A.J. Laurent, J. Org. Chem., 1981, 46, 4938. T.N. Wade and R. Kheribet, J. Org. Chem., 1980, 45, 5333. M. Kamlet and H.G. Adolph, J. Org. Chem., 1968, 33, 3073. M. Boechat and J.H. Clark, J. Chem. Soc., Chem. Commun., 1993, 921. G. Angelini, M. Speranza, A.P. Wolf and C.-Y. Shiue, J. Fluorine Chem., 1985, 27, 177. T.B. Patrick and P.A. Flory, J. Fluorine Chem., 1984, 25, 157. G.K.S. Prakash, V.P. Reddy, X.Y. Li and G.A. Olah, Synlett, 1990, 594. S. Rozen and D. Zamir, J. Org. Chem., 1991, 56, 4695. T.B. Patrick, J.J. Schiebel and G.L. Cantrell, J. Org. Chem., 1981, 46, 3917.
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249 P. Wolfram in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b/Part 1, Organofluorine 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.
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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 ˚ , rv ðFÞ 1.47 A ˚ and are isosteric. A comparison of the van der Waals radii, rv ðHÞ 1.20 A ˚ 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 ˚ ) is slightly longer than C–H (1.09 A ˚ ); in very crowded [2]. The C–F bond length (1.38 A 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 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
91
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½3
X
Figure 4.1
are more demanding than isopropyl groups. Indeed, van der Waals volumes, ˚ 3 compared to CF3 ¼ 42:6 A ˚ 3 , further illustrate this point [5] (Figure 4.2). CH3 ¼ 16:8 A ½5 H H
F H
F
16.8A3
F
42.6A3
Figure 4.2 Table 4.1
III
Steric parameters [4]
Substituent
Taft Es
Charton n
H F OH CH3 CH2 CH3 CHðCH3 Þ2 CðCH3 Þ3 CH2 F CHF2 CF3
þ1.24 þ0.78 þ0.69 0 0.07 0.47 1.54 0.24 0.67 1.16
0 — — 0.52 0.56 0.76 1.24 0.62 0.68 0.91
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
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Table 4.2
93
pKa values of some organic acids and alcohols [7]
Carboxylic acid
pKa
Alcohol
pKa
CH3 COOH CH2 FCOOH CH2 ClCOOH CHF2 COOH CHCl2 COOH CF3 COOH CCl3 COOH CF3 CH2 CH2 COOH CF3 CH5CHCOOH
4.76 2.59 2.86 1.34 1.35 0.52 0.56 4.15 3.48
CH3 CH2 OH CF3 CH2 OH CCl3 CH2 OH ðCF3 Þ2 CHOH ðCH3 Þ3 COH ðCF3 Þ3 COH ðCHF2 Þ2 CðOHÞ2 ðCF3 Þ2 CðOHÞ2 ðCF3 Þ2 CðOHÞCF2 NO2
15.9 12.4 12.2 9.3 19.2 5.1 8.9 6.5 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 CH2 FCOOH and CH2 ClCOOH). 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 CF3 COOH 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 compared with the corresponding alkyl derivatives. Bis(trifluoromethyl)phosphinic acid, CF3 Þ2 POOH, is as strong as perchloric acid and is the strongest phosphorus acid known [12], while trifluoromethanesulphonic (triflic) acid, CF3 SO3 H, is the strongest readily available monobasic organic acid (H0 13:8) (compare conc. H2 SO4 , 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.
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Table 4.3 pKb values of some amines Amine CH3 CH2 NH2 CF3 CH2 NH2 CCl3 CH2 NH2 C6 H5 NH2 C6 F5 NH2
pKb 10.6 5.7 5.4 4.6 0:36
The observations that secondary amines, RF Þ2 NH, 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
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Table 4.4 Substituent constants for some fluorinated groups Substituent
sm
sp
sI
sR
CH2 F CHF2 CF3 CF2 CF3 CF2 Þ2 CF3 CFðCF3 Þ2 SF5 NðCF3 Þ2 OCF3
0.12 0.29 0.43 0.47 0.47 0.37 0.63 0.47 0.47
0.11 0.32 0.54 0.52 0.52 0.53 0.86 0.53 0.27
0.12 0.32 0.42 0.41 0.39 0.48 0.56 0.44 0.50
0.02 0.06 0.10 0.11 0.11 0.04 0.27 0.06 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
C
F F
C
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 C
C
C
C
Figure 4.4 CF3 −
CF3O
+
TAS
F
½22
− +
½23
TAS
F3C 4.5A
4.5B +
TAS
Figure 4.5
+
= (Me2N)3S
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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 doublebond character [25]. F F C F
− F
− O
F C
O
½22
F
Figure 4.6
Stabilities of perfluorinated carbanions have also been described using FNHC; a reexamination [26, 27] of the acidity of CF3 Þ3 CH compared with the bicyclic compound (Figure 4.7), in which FNHC in the carbanion would result in the formation of an internal alkene contrary to Bredt’s rule, found that the unconstrained CF3 Þ3 CH 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 CF2 2CF3 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
− C
C
CF3
C
C
− CF3
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-CF3 Þ ¼ þ0:54 and sðm-CF3 Þ ¼ þ0:43, the ratio sð p-CF3 Þ=sðm-CF3 Þ being 1.25, and this is essentially
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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 δδ+
CF3
δ+ δδ+
δ+
δ+
N
δ+
δ+
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
X
X H 4.9bA
H
Y
Y X
H
4.9bB
H Y 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
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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
CH2 5CHCOOH CF2 5CFCOOH CCl2 5CClCOOH C6 H5 OH C6 F5 OH C6 Cl5 OH C6 H5 COOH C6 F5 COOH
4.25 1.8 1.21 10.0 5.5 5.26 4.21 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
F4
F
F
Figure 4.10
½38, 39
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It has been concluded from pKa measurements and fluorine NMR data on pentafluorobiphenyl derivatives, for example C6 F5 C6 H4 CO2 H, C6 F5 C6 H4 F 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 F2Cþ 2, either directly or by conjugation, but we will also make reference to the effect of a fluorine atom in the situation F2C2Cþ 2. 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 C
F
C
F
Stabilising
C
C
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
H
E
E +
X
Figure 4.12
X
X
H
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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 C6 H5 X
1
6.3
0.4
0.25
1a
4.62
0.145
0.062
Relative rates of bromination of X Me
Me
Me a
Me
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) sþ p value (Table 4.7). E
H
E
H
+ 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 principles may be drawn from the data [43]. The sm and sþ m 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]
F Cl Br
so
sm
sþ m
sp
sþ p
0.93 1.28 1.35
0.335 0.375 0.39
0.35 0.40 0.405
0.06 0.225 0.23
0:075 0.115 0.15
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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
H3C
+ C
CH3
H3C
F
C
CH3
½46
F + CF3COO−
CH3 H3C
C
OCOCF3
F
Figure 4.14 Table 4.8 First-order rate constants for reaction of trifluoroacetic acid with CH2 5CXCH3 at 258 C [46] X
105 kðs1 Þ
kX =kH
H F Cl Br
4.81 340 1.70 0.395
1 71 0.35 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 4.15A
Figure 4.15
+ CF3CH2CH2 4.15B
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102
Chapter 4 H FSO3H
F3CCHCH2
F
H F
CF3CH=CH2 H
−
FSO3 HF
H
−
½49
(H shift)
CF3
−
F3C
FSO3 HF
F CH3 F
+
+
H CF3
H
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. SbF5
CF3CFCF2
F3C
F
½50 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 H3C
C F
CH3
H3C i, SbF5, −60 C, SO2
C
CH3
SbF6
½56
F
Figure 4.18
The 19 F 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
Figure 4.19
F
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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.
CH3 CF2
[61]
Carbocation F
Ref.
F
[62]
F
F F
H3C
C
CH3
F
[56]
F
F
Ar
[50] F
F
CF2
[57]
(CF3)2CFCH2CF CH CFCH2CF3
[63]
F
[64]
C
[59]
CH3
F7
F
Ph
[57]
C Ar
F
F
Ph
ðC6 F5 Þ3 Cþ
[65]
2+
Ar
[66]
[67] C6F5
The difluorobenzyl cation (Figure 4.20) is stable under conditions in which the benzyl cation undergoes rapid polymerisation [57] and 13 C and 19 F 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 CF2Cl
i, SbF5, −75 C, SO2
C
F
½57 R
R
Figure 4.20
CF2
i
R
SbF5Cl
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Chapter 4
Other Lewis acids, such as BF3 Et2 O, have been used to induce ionisation [59, 60] whilst protonation of suitably fluorinated unsaturated substrates may also lead to carbocationic species (Figure 4.21). F
F BF3.Et2O
F
½59
CH3CN
F7
F
F FSO3H, SbF5
½60
−78 C H
H
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). H
H
H
F
H
F
F
F
½52 4.22A F
F
4.22B
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 fluoromethyl cations is CHþ 3 < CF3 < CH2 F < CHF2 , indicating that the introduction of fluorine increases the stability of the cations relative to hydrogen [54]. The trifluoromethyl cation CFþ 3 has been generated and observed by IR spectroscopy upon photolysis of CF3 I in an argon matrix at very low temperatures [69]. However, attempts to observe CFþ 3 in solution by ionisation of trifluorohalomethanes [32] only resulted in the
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres H
F
105
F
(CF3)2CFCH2 CH2CF(CF3)2 F
F
½68
H
4.23A H (CF3)2CFCH2
CH2CF3 F
F
n
n = 1−3
4.23B
Figure 4.23
production of CF4 , even though CFþ 3 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 SN 1 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, 13 C 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).
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106
Chapter 4 OTos H
OTos
H
H
OTos
CF3
F3C
CF3
½70
OMe
OMe
4.24A Relative rates of Solvolysis
4000 H
OMe
4.24B
4.24C
5.2 - 2.4
1
H
CF3
CF3
OMe
OMe 4.24B
Figure 4.24
AnO2SO
F3CH2CO R1 CF3CH2OH
R1
R1
R2
½71
R2
R2 Relative Rate
4.25A
R1 = R2 = H
1012
4.25B
R1 = CF3, R2 = H
106
4.25C
R1 = R2 = CF3
1
Figure 4.25
CF3
CF3
C
C
H
CH3
Figure 4.26
H O
½73
C F3C
4.26A
H O
4.26B
H
CH3
4.26C
F3C
CH3 4.26D
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres H3C
CH3
H3C
X
Y
H3C
i
CH3
½74
CH3
H3C
X = Cl, Y = F, Cl X = Br, Y = F, Br X = I, Y = F
107
CH3
X
i, SbF5, SO2, −60 C
Figure 4.27 H3C H3C F
CH3 CH3
i
CH3 CH3
H3C H3C
F
H3C H3C
CH3 F
H3C
F
½75
i, SbF5, SO2, −90 C
Figure 4.28
However, mass-spectral breakdown patterns of PhOCH2 CH2 F suggest that a cyclic fluoronium ion can be observed as an ion-neutral complex in the gas phase [76], whilst calculations indicate that the fluoronium ion is more stable than the isomeric þ CH2 CH2 F 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). CF3COO
H F
F
OCOCF3 F
½46
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
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Chapter 4
−
Ar-N2
BF4
N2
CF3
δ
−N2
δ
Ar----F----BF3
ArF
+ BF3
½77
CF3 40 C
F
COOEt
F
F
CF2
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. C
H
4.31A
δ− δ+ C H Base
C
4.31B
4.31C
+ H-Base
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
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109
Table 4.10 Base-catalysed deuterium exchange in haloforms [80] Haloform
Rate of exchangea (105 k) (l:mol1 s1 )
CHF3 CHCl3 CHBr3 CHI3 CHCl2 F CHBr2 F CHI2 F
Too slow to measure in this medium 820 101 000 105 000 16 3600 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 CF3 H 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). Iσ H2C
F
Stabilising
−Iπ
H2C
F
Destabilising
Figure 4.32
Table 4.11 Apparent ionisation constants of substituted nitromethanes (in water, at 258 C) [83] XYCHNO2 Y ¼ COOC2 H5 X ¼ Cl X¼H X¼F Y ¼ Cl X ¼ Cl X¼H X¼F
pKa
XYCHNO2
pKa
4.16 5.75 6.28
Y ¼ NO2 X ¼ Cl X¼H X¼F
3.80 3.57 7.70
5.99 7.20 10.14
½84
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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 nonbonding electron pairs on carbon are closer in space to electron pairs on fluorine [79] (Figure 4.33). 90
109
C
109
F
Tetrahedral (sp3) C
½79 C
F
109
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). C
Br
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 the CH2 F carbanion a pyramidal structure is 55 kJmol1 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 ).
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B
111
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 monohydrofluorocarbons, 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 ðCF3 Þ3 CH, 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]! D
C
C
D2O
Hal
C
C
Hal
−Hal
C
½88
C
Figure 4.35
RFH
+
CH3OD
kH
RFD
+
CH3OH
½89
kD (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] CF3 ðCF2 Þ5 CF2 H
ðCF3 Þ2 CFH
ðCF3 Þ3 CH
CF3
CF3 ðCF2 Þ5 CF 2
ðCF3 Þ2 CF
ðCF3 Þ3 C
Relative reactivity
1
6
2 105
109
Approx. pKa
31
30
20
11
Compound
CF3 H
Derived ion
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112
Chapter 4
C
C
F
F F F
C
F
C F
Figure 4.37
bridgehead compound 4.38B in which negative hyperconjugation in the derived carbanion is unfavourable. Elongated b-C2F bonds and shortened Ca 2Cb bonds in 4.38C, as measured by X-ray crystallography, provides direct experimental evidence [23] (Figure 4.38). CF3 (CF3)3C
H
(Me2N)3S+
CF3
H 4.38A
F
F
½27
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 carbanionstabilising 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-striazine 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 Bu4 NI via a single-electron transfer pathway [104] (Figure 4.43).
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres F3C
F3C
i C
CF2
C
F3C
½97
Cs+
CF3
113
F3C i, CsF, tetraglyme F
i F
+
F
F
F
F
F
Cs+
½95
i, CsF, tetraglyme
F CF3
F3C F3C
F3C
i
•
CF3
CF3
CF3
(Me2N)3S+
½98
CF3
i, (Me2N)3S+Me3SiF2− (TAS-F), THF F
F
Cs+
F
½100
4.39A
Figure 4.39 F
F
CF3 THF
F
CF3
F
TAS-F
F3C
½23
F
F F3C
F
F
(Me2N)3S+
Figure 4.40 F N
N
F
N
N
F N
Cs+ F
N
½101
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].
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Chapter 4
CF3 CF3
CF3
H CF3
CF3
CF3
H2O CF3
½103, 104
H3O
CF3
CF3
CF3
Figure 4.42
CF3 CF3
CF3
CF3 CF3
CF3
CF3
Bu4NI CF3
CF3
Bu4N CF3
CF3I
½104
CF3
Figure 4.43 Table 4.13
Relative rates of base-catalysed deuterium exchange [107] Rate, relative to
Compound
Benzene 6:3 10 107 11.2 580 —
[2-D] Fluorobenzene [3-D] Fluorobenzene [4-D] Fluorobenzene [3-D] Benzotrifluoridea 2,5-Difluoro[Me-D1 ]toluene a
Toluene
5
— — — — 350
Trifluoromethyl [3-D] benzene.
Also, the order of acidity of the dihalobenzenes, m-C6 H4 F2 > m-C6 H4 ClF > m-C6 H4 Cl2 , 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] 104 k ðl:mol1 s1 Þ Polyfluorobenzene Pentafluorobenzene 1,2,3,4-Tetrafluorobenzene 1,2,4,5-Tetrafluorobenzene 1,2,3,5-Tetrafluorobenzene 1,3-Difluorobenzene
Exchange at 408 C 1360 0.0053 58 5.6 0.0061
Displacement at 508 C 1.05 0.018 < 104 0.049
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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 to toluene is shown in Table 4.13. Indeed, a comparison of the equilibrium acidities of C6 F5 Þ2 CH2 and ðC6 F5 Þ3 CH 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]
VIII A
Carbon acid
pKa
CCl2 5CHBr CCl2 5CHCl CF2 5CHCl CCl2 5CHF CF2 5CHF
24.6 25.0 25.3 26.3 27.2
FLUORO RADICALS [112, 113] 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
O
O
CH2
CH2
Figure 4.44
Stabilities of methyl and fluoromethyl radicals have been calculated [114] to be in the order CF3 < CH3 < CF2 H < 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]. l
l
l
l
O + CH3 R
C
O
∆
CO2
CH3
k1
CH3 R
C
CH3
½115
O k2
CH3
2
R
CH3
O H3C
+
R
CH3
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 increasingly pyramidal structures upon further fluorination, with CF3 l measured to be 49.18 from planarity. The barriers to inversion of fluoromethyl radicals increase in the order CFH2 < CF2 H < 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]. l
l
l
F
½117 H3C
CH3
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).
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres
H
117
H C
F
H
C
F
C
F
H
Figure 4.47 H
H C
F
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 CH3 CH2 > FCH2 CH2 > F2 CHCH > CH3 > CF3 CH2 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. l
l
F F3C
l
l
l
CF3 CF3
F2
F F3C
CF3 C2F5
F3C F
F
F3C F
CF3
½120
CF3
Figure 4.49
Likewise, the radical shown in Figure 4.50 is a stable perfluorovinyl system [121].
(CF3)3CFC CCF(CF3)3
CF(CF3)3
F2 C (CF3)3CF
C
½121 F
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.
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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] R
rel kadd
OCH3 CH3 H Cl CF3
1.41 1.33 1.0 0.77 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 X
X
X F2C
CF2
X
CX2H
CF2
+ F
X
H F
X
CF2
½124 4.52A
4.52B
X = F, kA 4.9 x 105 s−1, Only 3-4% 4.52A formed X = H, kA 1.06 x 107 s−1, kB 3.5 x 106 s−1
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.
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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. R.D. Chambers, R.S. Matthews, G. Taylor and R.L. Powell, J. Chem. Soc., Perkin 1, 1980, 435. W.B. Farnham, D.A. Dixon and J.C. Calabrese, J. Am. Chem. Soc., 1988, 110, 2607. A.E. Bayliff and R.D. Chambers, J. Chem. Soc., Perkin 1, 1988, 201. W.B. Farnham, W.J. Middleton, W.C. Fultz and B. E. Smart, J. Am. Chem. Soc., 1986, 108, 3125. B.E. Smart, W.J. Middleton and W.B. Farnham, J. Am. Chem. Soc., 1986, 108, 4905. R.D. Chambers and T. Nakamura, J. Chem. Soc., Perkin Trans. 1, 2001, 398. R.D. Chambers, P.D. Philpot and P.L. Russell, J. Chem. Soc., Perkin 1, 1977, 1605. R.D. Chambers and M.P. Greenhall, J. Chem. Soc., Chem. Commun., 1990, 1128. E.D. Laganis and D.M. Lemal, J. Am. Chem. Soc., 1980, 102, 6633. R.D. Chambers, S.J. Mullins, A.J. Roche and J.F.S. Vaughan, J. Chem. Soc., Chem. Commun., 1995, 841. R.D. Chambers, M.P. Greenhall and M.J. Seabury, J. Chem. Soc., Perkin 1, 1991, 2061. A. Streitwieser and J.H. Hammons, Prog. Phys. Org. Chem., 1965, 3, 41. A. Streitwieser and F. Mares, J. Am. Chem. Soc., 1968, 90, 644. R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385. A. Streitwieser, J.A. Hudson and F. Mares, J. Am. Chem. Soc., 1968, 90, 648. R. Filler and C.-S. Wang, J. Chem. Soc., Chem. Commun., 1968, 287. P.v.R. Schleyer and A.J. Kos, Tetrahedron, 1983, 39, 1141. W.R. Dolbier, Chem. Rev., 1996, 96, 1557. W.R. Dolbier in Organofluorine Chemistry. Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 97. D.J. Pasto, R. Krasnansky and C. Zercher, J. Org. Chem., 1987, 52, 3062. X.K. Xiang, X.Y. Li and K.Y. Wang, J. Org. Chem., 1989, 54, 5648. R.W. Fessenden and R.H. Schuler, J. Chem. Phys., 1965, 43, 2704. T. Kawamura, M. Tsumara, Y. Yokomichi and T. Yonezawa, J. Am. Chem. Soc., 1977, 99, 8251. S.F. Wnuk, D.R. Companioni, V. Neschadimenko and M.J. Robins, J. Org. Chem., 2002, 67, 8794. A. Pross and L. Radom, Tetrahedron, 1980, 36, 1999. K.V. Scherer, T. Ono, K. Yamanouchi, R. Fernandez, P. Henderson and H. Goldwhite, J. Am. Chem. Soc., 1985, 107, 718. 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. W.B. Motherwell and D. Crich, Free Radical Chain Reactions in Organic Synthesis, Academic Press, London, 1992. D.V. Avila, K.U. Ingold, J. Lusztyk, W.R. Dolbier, H.Q. Pan and M. Muir, J. Am. Chem. Soc., 1994, 116, 99. X.X. Rong, H.Q. Pan and W.R. Dolbier, J. Am. Chem. Soc., 1994, 116, 4521. W.R. Dolbier and X.X. Rong, Tetrahedron Lett., 1994, 35, 6225.
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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 SN 1 process were considered earlier, in a more general discussion of carbocations (see Chapter 4, Section VI); effects on the SN 2 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 SN 2 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 SN 2 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:mol1 s1 104 )
CH3 CH2 CH3 CH2 CH2 FCH2 CH2 ClCH2 CH2 BrCH2 CH2
122
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
39.1 25.6 4.95 5.61 4.99
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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- or g- to the reaction centre in solvolysis reactions can be very substantial, especially inhibiting SN 1 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 CF3 CH2 I, 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 SN 1 and SN 2 processes. Nucleophilic substitution of halogen in RF CF2 Hal 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 SN 2 process involving these substrates. For example, RCF2 Br compounds are quite inert to halide exchange under conditions where CH3 CH2 Br is reactive [4]. However, in principle there are other ways in which RF Hal 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 CF2 Br2 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). Nuc
+ ICF3
H
NucI + CF3
Solvent
CF3H
Figure 5.2
R3P
+
CF2Br2
R3PBr
CF2
CF2Br
+
+
CF2Br
Br
½11 R3P
+
R3PCF2
Figure 5.3
CF2
+
R3P-CF2
R3PBr
Br
(R3PCF2Br)
Br
R3P
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Chapter 5
+
PhS
PhSBr
CF2CF2Br
Br
CF2CF2Br
+
½12 PhSCF2CF2Br
PhSBr
PhS
PhSCF2CF2
CF2CF2
Figure 5.4
(2)
Single-electron transfer (SET) [13, 14] (Figure 5.5). RFI
Nuc
RFI
Nuc
RFI
RF
e.g.
I
RF i NR2
etc
RF I
+
NR2 NR2
½13, 14 I
−H+ RF
RF O
i , RFI (RF
= C8F17 ), Pentane,
H3O
+ HI
NR2 uv
Figure 5.5
(3)
A radical chain process (SRN 1) (Figure 5.6).
Nuc
RF
+
+ Nuc
RF-I
Nuc
Nuc-RF
+ RFI
RF-I
Nuc-RF
RF
+
+ I
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.
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Nucleophilic Displacement of Halogen from Fluorocarbon Systems
125
(CF3)2CFSPh PhS (CF3)2CF
(CF3)2CFI
Norbornene
½15 CF(CF3)2 (CF3)2CFI
I
(CF3)2CF
CF(CF3)2
Figure 5.7a Table 5.2 Substitution of halogen in RCF2 Hal systems Substrate
Nucleophile, conditions
Product
Yield (%)
Ref.
53
[16]
50
[17]
94
[18]
CH3
C5 F11 CF2 I
NO2 ðCH3 Þ2 C Li DMF, 3 h
O
C6F13
NO2
C CH3 H
O OEt
−
ClCF2 CF2 I
þ
CO2Et
+
Na
ClCF2 CO2Et O2N
O2N
N
N +
Bu4N
C5 F11 CF2 I N −
Electrochemistry, CH3 CN
C6F13
N H
CF2 BrCF2 Br
PhO Kþ HMPAa, rt
PhOCF2 CF2 Br
C6 F13 Br
PhS Kþ DMF, rt
C6 F13 SPh
62
[20]
C6 F13 I
PhS Bu4 Nþ Benzene, H2 O, rt
C6 F13 SPh
76
[15]
CF2 Br2
Ph3 P Diglyme, rt
ðPh3 PCF2 BrÞþ Br
100
[11]
a
HMPA, hexamethylphosphoric triamide.
[19]
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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
H(CF2)4Cl
+
C6H5OCH3
i
(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]. C3F7C(CF3)2I
i
−I
[C3F7C(CF3)2I]
C3F7C(CF3)2
i, Zn, CH2CHR, AcOEt, 80 C
½23
−F
CF3CF2CFC(CF3)2
CF3CF2CF2C(CF3)CF2 5
1 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 2CF2 I 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 perfluoroalkylphenyliodonium 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
+1e
−F
F
F
F
F
F
F
127
½26
+1e +1e etc. F
F
F
F
−F
F
F
PhS SPh PhS
SPh
PhS
SPh
i
F
F
SPh
SPh
SPh
i, PhS Na, DMEU, 70 C, 10 days
Figure 5.9 i
RFI
RFI(OCOCF3)2
ii
O-Tf
RF I Ph
i,
½27
80% H2O2, (CF3CO)2O
ii, Benzene, CF3SO2OH (TfOH)
Figure 5.10
PhCH2MgCl
C3F7IPh
OTf
−110 C
PhCH2C3F7
82%
O
OTMS +
C8F17
I Ph
OTf
MeCN, 45 C
C8F17 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
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Chapter 5
DMF, 80 C
+ O-Tf
N
S
H
CF3
N
CF3
H
90%
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, SN 1 and SN 2, we can envisage a spectrum of transition states for the SN 2 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+ Nuc
δ− C 5.13A
F
δ+ Nuc
C 5.13B
δ− F
δ+ Nuc
C
δ− F
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-
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129
Table 5.3 Relative reactivities of isoamyl halides ðCH3 Þ2 CHðCH2 Þ2 X with piperidine and sodium methoxide at 188 C [29] Reagent
X¼F
C5 H11 N CH3 ONa=CH3 OH
1 1
X ¼ Cl
X ¼ Br
X¼I
68.5 71
17 800 3500
50 500 4500
Table 5.4 Fluorine : chlorine rate ratios for reactions of alkyl halides [28] Halide
Reagent
Solvent
Temp. (8 C)
Ph3 CX Ph2 CHX PhCH2 X CH3 X
H2 O H2 O/EtOH H2 O H2 O
85% aq. Me2 CO 80% aq. EtOH 10% aq. Me2 CO H2 O
25 25 50 100
kF =kCl 1:0 106 1:6 104 3:2 103 2:9 102
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 SN 1 to SN 2.
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
F
H
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 1,2diethoxytetrafluorocyclobutene 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).
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130
Chapter 5 RCHCHCHF2 H
RCHFCHCFH
+F
aq. HCOOH R −F
5.15A
H H
H2O
F
½35 RCHCHCHO
F RCHFCFCH2
R
H H
5.15B
H
Figure 5.15
2 O
OEt
O
OH
H2SO4
F
½36
2+ O
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
Benzene
½37
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). F
Figure 5.18
+
AlCl3
0 C
Cl
½38
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Nucleophilic Displacement of Halogen from Fluorocarbon Systems
2
131
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). CHF2CF2OC2H5
H2SO4
CHF2COOC2H5
½39
CHClFC(OC2H5)3
½40
Figure 5.19
CHClFCF2OC2H5
EtOH KOH
Figure 5.20
The exceptional ease of nucleophilic displacement of fluorine from ðC2 H5 Þ2 NCF2 CFClH 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 SN 1 process with internal assistance to ionisation coming from the adjacent nitrogen [41] (Figure 5.21). F
Me N Me
C F
−F
−
F
Me
CF2H
N
C
CF2H
Me
etc
½41
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
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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 δ
Nuc
X
Nuc
F
Nuc
X
Addition
F
X
+
X
F
Elimination
Nuc
F
Figure 5.22 Table 5.5 Isopropanolysis of acid halides at 258 C [43] k2
Halogen mobility ratio Cl ¼ 1
8:4 1010 5:1 106 2:7 103
1:6 104 1 5200
1:6 103 3:5 102
4:6 102 1
Compound C3 H7 CO2X X¼F X ¼ Cl X ¼ Br C4 F9 CO2X X¼F X ¼ Cl
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-NO2C6H4
H
H
X
X¼F X ¼ Cl X ¼ Br
1
104 kðl:mol1 s Þ 7.21 0.025 0.016
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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). C6H5 F3C
Cl
MeONa
F
C6H5
O-Me
C6H5
F
F3C
O-Me
+ F
F3C 96%
½45, 46
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 CF2 5CF2 , CF2 ¼ CFCF3 CF2 5CðCF3 Þ2 , the last of these being extremely susceptible to nucleophilic attack (Figure 5.24). Nuc
CF2C(CF3)2
NucCF2CF(CF3)2
−F
NucCFCF(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 ðk1 Þ and a fast second step ðk2 Þ, 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
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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 X δ
_ Nuc
Nuc
Nuc
X
NO2
NO2
NO2
k1
k2
½49, 50
k−1 NO2
NO2 X = F, Cl, Br, I
NO2
5.25A
Figure 5.25 X
H2RN NO2
NHR
X
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). H3C
F Cr(CO)3
LiCMe2CN CF3SO3H
H3C
CN
½56
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.
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Nucleophilic Displacement of Halogen from Fluorocarbon Systems
ArF ArF
+
−e
135
ArF [NucArF]
Nuc
½57 [NucArF] ArNuc
+
ArNuc ArF
+
ArNuc
F
+
ArF
Figure 5.28
REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
C.A. Bunton, Nucleophilic Substitution at a Saturated Carbon Atom, Elsevier, Amsterdam, 1963. J. Hine and W.H. Brader, J. Am. Chem. Soc., 1953, 75, 3964. J. Hine and R.G. Ghirardelli, J. Org. Chem., 1958, 23, 1550. F.G. Bordwell and W. Brannen, J. Am. Chem. Soc., 1964, 84, 4645. T. Nakai, K. Tanaka and N. Ishikawa, J. Fluorine Chem., 1977, 9, 89. G.V.D. Tiers, J. Am. Chem. Soc., 1953, 75, 5978. X. Creary, Chem. Rev., 1991, 91, 1625. A.D. Allen and T.T. Tidwell in Advances in Carbocation Chemistry, ed. X. Creary, JAI Press, Greenwich, CT, 1989. F.G. Bordwell and C.A. Wilson, J. Am. Chem. Soc., 1987, 109, 5470. G. Kohnstam, D. Routledge and D.L.H. Williams, J. Chem. Soc., Chem. Commun., 1966, 113. D.J. Burton, J. Fluorine Chem., 1983, 23, 339. X.Y. Li, X. Jiang, H.Q. Pan, J.S. Hu and W.M. Fu, Pure Appl. Chem., 1987, 59, 1015. C. Wakselman, J. Fluorine Chem., 1992, 59, 367. V.I. Popov, V.N. Boiko and L.M. Yagupolskii, J. Fluorine Chem., 1982, 21, 365. A.E. Feiring, J. Fluorine Chem., 1984, 24, 191. A.E. Feiring, J. Org. Chem., 1983, 48, 347. Q.Y. Chen and Z.M. Qiu, J. Fluorine Chem., 1987, 35, 343. M. Medebielle, J. Pinson and J.M. Saveant, J. Am. Chem. Soc., 1991, 113, 6872. X.Y. Li, H. Pan and X. Jiang, Tetrahedron Lett., 1984, 25, 4937. C. Wakselman and M. Tordeux, J. Org. Chem., 1985, 50, 4047. C.-M. Hu and W.M. Huang in Fluorine Chemistry at The Millenium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 261. X.-T. Huang, Z.-Y. Long, and Q.-Y. Chen, J. Fluorine Chem., 2001, 111, 107. S.M. Igumnov, I.N. Rozhkov, S.I. Pletnev, Y.A. Borisov and G.D. Rempel, Bull. Acad. Sci. USSR, 1989, 38, 2122. A. Hasegawa, M. Shiotani and F. Williams, J. Chem. Soc., Faraday Discuss., 1978, 157. 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. D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59. A.T. Umemoto, Chem. Rev., 1996, 96, 1757. R.E. Parker, Adv. Fluorine Chem., 1963, 3, 63. B.V. Tronov and E.A. Kruger, J. Russ. Phys. Chem. Soc., 1926, 58, 1270. J.A. Revetllat, A. Oliva, and J. Bertran, J. Chem. Soc., Perkin Trans. II, 1984, 815. A.K. Coverdale and G. Kohnstam, J. Chem. Soc., 1960, 3806.
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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.
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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 A
b-ELIMINATION OF HYDROGEN HALIDES 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 C
α C
H
X
B
C
C
+
+
BH
+
X
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 PhCH2 CH2 X [1, 2] Substrate
Reaction conditions
X¼F
X ¼ Cl
X ¼ Br
PhCH2 CH2 2X PhCHBrCF2 2X
EtONa, EtOH, 308 C EtONa, EtOH, 258 C
1 1
68 4 105
4100 3 107
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
137
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138
Chapter 6 δ− F
δ+ C
C
H
F
C
+
C
−
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 + F
F
F
½4
(9:1)
6.3A
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
HO2C
CO2H
Figure 6.4 B
B Br HO2C
H δ+ δ−
δ+H
F
Br
CO2H
HO2C
6.5A
δ− 6.5B
F CO2H 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
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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]. C
C
X
C
δ−
C
X
H
Hδ+
6.6A Concerted
6.6B E1cB - like
½9
Figure 6.6 Base (−H+) C
C
X
Solvent (+D+) C
C
C
X
Solvent (+H+)
H
C
X
½9
D
Internal Return
C
C
X
C
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 PhCHClCF2 Cl has been measured to be 1:65 102 l:mol1 s1 [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 C3H7CH2
C F
CH3
NaOMe
C4H9
MeOH
H
C3H7
H
H
½13
+ H 69%
H
CH3 21% C3H7
CH3
+ H
H 9%
Figure 6.8
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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
EtOH
CHCl2CCl2CHF2 CCl3CH2CF2Cl
Aq. KOH
CF3CHCHCH3
½14
CCl2CClCHF2
½15
CCl2CHCF2Cl
½16
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. CF3CFCHF
CF3CHFCHF2
+
70%
CF3CHCF2
½17
30%
Figure 6.10 RFH
RF KOtert-Bu
½18
−10 C RFH RFH
= CF2CFHCF3
RF RF
=
CFCFCF3
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).
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141
F C5H11
C5H11
H
C5H11
H
t-BuOK THF
F
(only alkene formed) C5H11
½19
F
H F C5H11 F
C5H11
H
H
t-BuOK
C5H11
(only alkene formed)
THF
F
C5H11
H
Figure 6.12
X Y H
X Y F
B
X
X
Y
Y
+
M M
B
BH
+
B
= Base
MF
½19
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).
RCF2CFHCF3
i
F
R
F
F
R
CF3
6.14C F3C
6.14A
F
F
½18
6.14B ii
R = Adamantyl
i,
R
F
F
CF3
KOtert-BuOH, tert-BuOH, 0 C
ii, CsF, Tetraglyme, 200 C
6.14D
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.
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142
Chapter 6 F
F CO2Et
H H
CO2Et
H H
CO2Et
Br
EtO2C
H
CO2Et
i syn
½22 EtO2C
Br
Br
6.15A i, NaOH, H2O
anti
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 H
H
F
aq. KOH
F
F F
F
H
F
F
F F
F 6.16A
F
½25
F
H
H
F
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
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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]. H F
H >
H
F
F
H
H
>>
F
H
H H H H
½26
Figure 6.17
F
F H H H
H aq. KOH
F
½26 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
H
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.
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144
Chapter 6 H
H H
F
−HF
H −HF
F
H
F
H
H
H
6.20A
6.20B
Figure 6.20 H
H
H F
F
aq. KOH
F
+
F
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- or b-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]. Pentafluoroethyllithium 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. Consequently, perfluoroadamantyl-lithium is stable at 08 C for several days [31] (Figure 6.22).
Figure 6.22
H
Li
F
F
½31
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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
CH3Li
F
F
furan 25−30 C
H
½24, 32, 33
O
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.
F Li
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]. −
CF3CF2CF2CO2
Na
+
∆, −CO2
F 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.
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146
Chapter 6 O F
C
CF(CF3)OCF2CF(CF3)OCF2CF2SO2F
½35
Heat, Na2CO3 CF2CFOCF2CF(CF3)OCF2CF2SO2F
Figure 6.26
− CF3CHOTs
i CF3CH2OTs
CF2CHOTs
i, LDA, THF, −78 C ii, n-BuLi, R3B
Electrophiles
½36, 37
ii CF2CLiOTs OTs
R
CF2C
CF2 C BR2
Electrophiles B R
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 R
−F
−
i F3C
( +1e)
F3C
− O
−
R
F2C
( +1e)
½38, 39 R
R = Alkyl or Aryl
i, Mg (2 equiv.), TMS-Cl (4 equiv.), 0 C, 30 min. ii, R1R2CO ii Product
OTMS 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).
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III
147
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). X
C
−
C
X
Figure 6.29
(2)
Elimination of metal and non-metal fluorides (Figure 6.30). F C
+ MF
C
M
Figure 6.30
(3)
Fragmentation reactions (Figure 6.31). C X
C
C
X
Y
C
C
+
Y
C
Figure 6.31
(4)
Decomposition of diazo compounds (Figure 6.32). N C
N2
or
N2
C
+
C
N
Figure 6.32
Examples of each of these types follow.
A 1
Fluorocarbenes 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).
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148
Chapter 6
CHXYZ
−
+
OH
CXYZ
X
CXYZ
C
+
H2O
Y +
½42, 43 −
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].
F CH2Br2
+
CF2Br2
H3C
CH3
H3C
CH3
i
+
CH3
H3C
CH3
i, Bu4N HSO4, 60% KOH
F H3C
CH3
H3C
CH3
i + CHFCl2
Cl
H3C
CH3
H3C
CH3
Br
½46
+
−
i, 50% NaOH, CH2Cl2, Et3N CH2Ph Cl
Figure 6.34
F
i
CFHBr2
½45
43%
i, NaOH, tetraglyme, 95 C
+
½48
+ 2KBr + CBr4 + 2H2O
−
+
F
H3C
90%
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Elimination Reactions
2
149
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
ClCF2C
ClCF2 + CO2
O
ClCF2
FCF + Cl
Figure 6.35
It is found that decarboxylation of dichlorofluoroacetate [49] gives about 70% of CCl2 FH via competitive abstraction of a proton from solvent by the intermediate CCl2 F anion, whereas chlorodifluoroacetate [50] gives very little CClF2 H, 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]. F Ph H
H
i
F
Ph CH3
CH3
88%
½51
H
OAc
OAc
i, ClF2CCOO− Na+, diglyme, reflux
C8H17
i OAc
F C8H17 H
F
½52 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).
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150
Chapter 6 O
O
i H3C
CFCl2
C
H3C
CFCl2
CFCl2
½53
H −Cl
i, NaH, MeOH F Cl
CFCl
60%
Figure 6.37 i CF3I
CF3Li
−LiF
CF2
F2C
CF2
½54
i, CH3Li, −45 C
Figure 6.38
CF2Br2
n-BuLi
CF2BrLi
−LiBr
F CF2
½55
F
Figure 6.39
Perfluoroalkyl anions, which form carbenes upon subsequent elimination of afluorine, 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 I
−
Me3Sn
CF3
−
CF3 +
−
Me3Sn-I
−F
½56
CF2
F F 89%
F
i + PhHgCF3
F
+ −
i, NaI, Bu4N I , 18-crown-6, 80 C
Figure 6.40
56%
½57
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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 CF2 Br2 can be used to add difluorocarbene to relatively reactive alkenes [58] (Figure 6.41a). F Ph
i
Ph
H3C
F 71%
½58
H3C i, CF2Br2, Zn, I2 (cat), rt
Figure 6.41a
Remarkably, ðCF3 Þ3 Bi generates difluorocarbene at low temperatures in the presence of aluminium trichloride [59] (Figure 6.41b). i (CF3)3Bi
ii
F
[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].
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152
Chapter 6 F +
Br
[Ph3PCF2Br]
−
+ CsF +
H3C
CH3
H3C
CH3
i
CH3
H3C
CH3
i, diglyme, rt
+
+
[Ph3PCF2Br]
F
i
−
Br
F
H3C
½60
79%
F
F
F
+
½61
i, CsF, triglyme, rt 38%
+
+
[Ph3PCF2Br]
Br
22%
F
i
−
½62
F i, KF, triglyme, rt
92%
Figure 6.42
F H3C +
Ph3P + CsF + CF2Br2
F
H3C
i
H3C
½60
H3C i, diglyme, rt
66%
Figure 6.43
PhC
CH
+
+
[Ph3PCF2Br]
Br
−
F
i Ph
F
H
½63
i, KF, 18-crown-6, glyme, rt 79%
Figure 6.44
CHClF2
Figure 6.45
> 650 C 0.5 atm.
CF2
F2C
CF2
½64
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Elimination Reactions i
CHFCl2
C6F6
+ CFCl3 + CFClCFCl + CFCl2CFCl2
153
½65
i, Pt, 700−750 C i
CFBr3
C6F6
½66
35%
i, Pt, 640 C
Figure 6.46
O
F F3C
F
O
165−185 C
+ F3C
F
½68
CF2
F
Figure 6.47
F F
F
H
F
F
i H F
½69
65%
F F
i, HFPO, 185 C, 6 h
F
H
F F
F
i
F
F
F
½70
63%
F
H
H
H
F
F
i, HFPO, 175 C
F
CF3
•
i
F3C
CF3 F
½71
52% CF3
F
F
i, HFPO, 175 C
F F
Cl i
F
F Cl
Cl
+
Cl 50%, 1:1
i, HFPO, CaCO3, 185 C
Figure 6.48
F
Cl Cl
½72
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154
Chapter 6
Pyrolysis of various phosphorane, e.g. ðCF3 Þ2 PF2 [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
F
N
135 C 85%
½75
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. Cl F
CF3
CF2
Cl
½76
i
F
F
+
F
F
F
F
CF3
i, CF2CF2, 640 C F3C
CF3
i
F
F
+
N
½77
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
F
C
CF3
CF2
+
CF
N
F
F
F +
N
½78
CF2
½79
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
F3C N2 F3C
250 C Low pressure
CF3CF=CF2
(CF3)2C=C(CF3)2
+
155
½80
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. F3C
N2
H
F3C
N2 +
F
hν
+
H3C
CH3
H3C
CH3
F3C N2
+
F
CF3CH2
76%
F3C 170 C
150 C
½81
F
H3C
CH3
H3C
CH3
CF3
F
F3C
30%
20%
½82
½83
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).
N2 F3C
CH3
H3C
F3C + CH3C
CCH3
CF3
N N
½80
CF3 400C −N2
F3C
H3C
CF3
CH3
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 HSiCl3 + C2F4
hν
SbF3
CHF2CF2SiCl3
CHF2CF2SiF3
½84
150 C
(CH)3CCHFCHF2
(CH3)3CH
F2HC
61%
C
F
+ SiF4
6.55A
Figure 6.55
The mercurial C6 H5 HgCFBrCF3 serves as a useful transfer agent for CF3 CF [85] (Figure 6.56). + C6H5HgCFBrCF3
F
160 C
87%
C6H6
½85
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. F
δ+ C 6.57A
δ− F
F
C
F
F
C
F
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
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Elimination Reactions
157
Table 6.2 Calculated energy difference between singlet and triplet states of carbenes, DEST [89, 90] Carbene
DEST ðkJmol1 Þ
CH2 CHF CF2 CðCF3 Þ2
246 142 808 313
(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). R1
R2
R3
R4
F
F
singlet CF2 R2
R1 R3
R4
triplet CF2
R1 R3
R2 R4
F
Spin Inversion
CF2
R1 R3
F
F +
R2
R1 R3
R4
F R4 R2
Figure 6.58 F
C2H5
F
Me3Sn-CF3 C2H5
NaI
H
C2H5 H
74%
½91
C2H5
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 temperaturedependent [93, 94].
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 158
158
Chapter 6
Cl CCl2 CCl2H
O
O
Cl
½91
+ O (1 : 1)
CF2 F
F
O
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− RF
δ+ C
RF
δ− RF
6.61A
δ+ C
F
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
CF3
i
+
+
½80
CF3 47%
44%
9%
i, (CF3)2CN2, hν
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). i H3C
CH3 i, (CF3)2CN2, hν
F3C
CH3
F3C
CH3
F3C +
49%
CF3
H
H
H3C
CH3
cis 39%
½80
trans 8%
Figure 6.63
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Chapter 6
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72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96
161
W.P. Dailey, P. Ralli, D. Wasserman and D.M. Lemal, J. Org. Chem., 1989, 54, 5516. R.G. Cavell, R.C. Dobbie and W.J.R. Tyerman, Canad. J. Chem., 1967, 45, 2849. J.M. Birchall, R.N. Haszeldine and D.W. Roberts, J. Chem. Soc., Chem. Commun., 1967, 287. R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 758. V.M. Karpov, V.E. Platonov, I.P. Chuikov and G.G. Yakobson, J. Fluorine Chem., 1983, 22, 459. R.D. Chambers, R.P. Corbally, T.F. Holmes, and W.K.R. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1974, 108. 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. R. Sztyrbicka, M. Rhaman and M.E. D’Aunoy, J. Am. Chem. Soc., 1990, 112, 6712. D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617. J.H. Atherton and R. Fields, J. Chem. Soc. C, 1968, 2276. W.P. Dailey, Tetrahedron Lett., 1987, 28, 5801. D.M. Gale, J. Org. Chem., 1968, 33, 2536. R.N. Haszeldine and J.G. Speight, J. Chem. Soc., Chem. Commun., 1967, 995. D. Seyferth and G. J. Murphy, J. Organometal. Chem., 1973, 52, C1. J.P. Simons, J. Chem. Soc., 1965, 5406. R.A. Moss, Acc. Chem. Res., 1980, 13, 58. R.A. Seburg and R.J. McMahon, J. Org. Chem., 1993, 58, 979. D.A. Dixon, J. Phys. Chem., 1986, 90, 54. K.K. Irikura, W.A. Goddard and J.L. Beauchamp, J. Am. Chem. Soc., 1992, 114, 48. D. Seyferth and S.P. Hopper, J. Org. Chem., 1971, 26, 620. N.G. Rondan, K.N. Houk and R.A. Moss, J. Am. Chem. Soc., 1980, 102, 1770. B. Giese, W.B. Lee and J. Meister, Ann. Chem., 1980, 725. K.N. Houk, N.G. Rondan and J. Mareda, J. Am. Chem. Soc., 1984, 106, 4291. J.H. Atherton and R. Fields, J. Chem. Soc. C, 1967, 1450. R.N. Haszeldine, R. Rowland, J.G. Speight and A.E. Tipping, J. Chem. Soc., Perkin Trans. 1, 1980, 314.
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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] X¼F
CXH3 CX2 H2 CX3 H CX4
X ¼ Cl
˚) r(C2F) (A
B(C2F) (kJmol1 )
˚) r(C2Cl) (A
B(C2Cl) (kJmol1 )
1.385 1.357 1.332 1.319
459.8 500.0 533.5 546.0
1.781 1.772 1.758 1.767
354.0 335.1 324.7 305.8
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 162
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 163
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives F F
C
F F
F
F
C
163
F F
F
F
C
F
etc.
½6
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 CH3 2CH3 CH3 2CH2 F CH3 2CHF2 CH3 2CF3 CF3 2CH2 F CF3 2CF3
˚) r(C2F) (A
BDE(C2C) (kJmol1 )
1.532 1.502 1.498 1.494 1.501 1.545
378.2 381.6 400.0 423.4 395.8 413.0
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 1
Reactions 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.
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164
Chapter 7 150
100
Boiling point ( C)
50
0 4
2
6
8
Number of carbon atoms −50
−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]. Perfluorocycloalkanes 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
CF2CF2
CF2CF2
n
−F n
CF2CF2
CF2CF
n-1
−
+e −
etc.
Figure 7.3
+e
−
CF2CF2
n-1
CF=CF
−F
CF2CF2
n-1
CF2CF
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
165
Table 7.3 Defluorination of perfluorocarbons Substrate
Reagents/Conditions
Product
F
F
Cp2 TiF2 Al, HgCl2 , THF, rt
F
F
F
F
Cp2 Co LiðO3 SCF3 Þ, Et2 O, rt
F
F
F
F
Ph2 C5O, Na THF, rt
F
F
Yield (%)
Ref.
40
[15]
53
[16]
62
[17]
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
PhS
SPh
i F
F
½18 −
SPh
+
i, PhS Na , DMEU, 70 C, 10 days
SPh
Figure 7.4
F3C CF F3C
NC
i
CF2 CF2CF3
NC
½19
CF2CF3
CN
CF3 HN
NH2
i F
F i, Hg/hν, NH3
Figure 7.5
NH2
½19
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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). F
725 C
CF2
C(CF3)2
+
70%
CF2
CFCF3
½20
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/H2
CO/H2
1-octene 25 C, C7F14 [Rh] P(4-C6H4C6F13)3
Heat
1-octene 70 C, C7F14 [Rh] P(4-C6H4C6F13)3
CO/H2 n-nonanal 81% 25 C, C7F14
½26
[Rh] 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 RF1
A1
A1
RF1
A6
6
B1
RF1
B6
RF6
167
½27, 28
i RF6
A6
RF
Separate Components
Mixture
Mixture
i, various chemical transformations Chromatography 1
RF
etc. = Fluorinated tag 1
6
B1
RF1
B6
RF6
Recovery of B -B and RF tags
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,
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168
Chapter 7
Table 7.4 Substrate
Ring opening of cyclobutenes [34] Product
F2C
CF3
F2C
F
F2C
CF3
F CF3 T7.4B
F2C
Eað kJmol1 Þ
Keq at 3158 C
33.5
136.0
9000
48.9
197.0
5:6 103
1.7
192.5
8.4
F
F T7.4A
DHðkJmol1 Þ
CF3
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 [36] of CF2 5CF2 , which is 29 kJmol1 less than that for ethene. However, the situation is less clear for partly fluorinated systems such as CF2 5CH2 , 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
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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
F
109
109 90 F
F
C
109 C
Figure 7.9
F
C
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 F
KOH/H2O
F
[43, 44]
Reflux/30 min.
Contd
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170
Chapter 7
Table 7.5 Contd Reaction
Ref.
CF2CFHCF3
CF CFCF3
[45]
NaOH 85 C
F Cl
F
F KOH
[46]
F
H F
F
Dehalogenation Cl 200 C
CF2 CFCl
Zn, EtOH
F
F
[47]
100%
Cl
Pyrolysis i
CF2 CF2
CF2 CFCF3
[48]
i, 750-800 C, Atmos Press. i
(CF2 CF2)n
CF2 CFCF3
32%
CF2 C(CF3)2
+
CF2 CFC2F5
+
9%
[49]
53%
i, 700 C, Atmos Press. CF3CF2CF2CO2−Na+
∆
CF2 CFCF3
−CO2
[50]
Halogen exchange F3C
i
CCl2 CClCCl CCl2
H 59%
F
[51, 52]
CF3
i, KF, 200 C, NMP
Cl
i
F
72%
[51]
i, KF, NMP, 200 C
CCl2 CCl CCl CCl2
i
i, KF, 18-Crown-6, Perfluorocarbon
CF3C CCF3
[53]
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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 catalyst
CHCl3
700 C
CHClF2
CF2
CF2
½54
Pt 860 C Vacuum CF2
CH3
HF
CCl3
catalyst
CH3
∆
CClF2
− HCl
CFCF3
CH2
CF2
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.
n-C3H7COF
−
+
n-C3F7COO Na
∆ −CO2
H2O
n-C3F7COF
C3F7
−F
n-C3F7COOH
½50
−
CF2=CFCF3
+
NaF
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
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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). −
Nuc
F +
C C F
E
Nuc F
H +
H
H E
H
C
F C
C H
H+
Nuc
F
F
H C C
+
F
F
H
−
F
F
C
C
F
F
H
H
C
C
H
H
H
Nuc
E
C H
Nuc
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 CF2 5 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 F3C
CF2CF3
tetraglyme +
F3C
F3C
rt
F
½58
+
Cs
CF2CF2CF3
CsF
173
F3C 7.14A, Observable by NMR
I
CF3 CF2CF2CF3 CF3 −
CH3O
+
CF2
−
CF2
½59
CH3OCF2CF2
(CH3O)2C=O CH3OCF2CF2CO2CH3
74%
O Nuc
CF2 CF2
NucCF 2CF2 i,
eg
−
−
−
−
RFCOOR
i
NucCF2CF2 C RF
½60, 61
OR
−
Nuc = N3 , PhO, CH3O, CH3S.
Figure 7.14 −
CH3O
CF2
CFCF3
CH3OCF2CFCF3
CH3OH
CH3OCF(CF3)CF2
CH3OCF2CFHCF3
−
CH3O
Figure 7.15
(2)
(3)
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 . When fluorine is directly attached to the carbanionic site, e.g. X or Y ¼ F in 7.16A, 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).
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174
Chapter 7 δ C
F
Nuc
C δ
F δ
δ
δ F
>>
CXY
δ Cl
C
Nuc
etc.
CXY
CF2 7.16A
Figure 7.16
CF2
CF2
<
CF2
7.17A
<
CFCF3
CF2
7.17B
−
NucCF2CF2
7.17C
NucCF2CFCF3
<
<
NucCF2C(CF3)2
7.17E
7.17D
C(CF3)2
7.17F
Figure 7.17
Furthermore, the rates of nucleophilic addition of diethylamine have been found to increase in the series CF2 5CF2 < CF2 5CFCl < CF2 5CFBr [70] (Figure 7.18), again in the order of increasing stability of the supposed intermediate carbanion. (C2H5)2NH
CF2
CFBr
−H
+
+
+H
−
(C2H5)2NCF2CFBr
(C2H5)2NCF2CFBrH
Figure 7.18
The order of reactivity CF2 5CðRF Þ2 > CFRF 5CðRF Þ2 > ðRF Þ2 C5CðRF Þ2 (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 7.19A
CF3CF2(CF3)C
C(CF3)CF2CF3
½68
7.19B −
F
RF = CF3CFCF2CF3 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 −
CF2
CH3O
CFBr
½71
CH3OCF2CFBr
CF2
175
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 marginally 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 marginal (Figure 7.22). −
Nuc
CF3CF
CFCF3
NucCF(CF3)CF(CF3)
7.21A
Products
7.21B
Figure 7.21 RFCF C(RF)2 7.22A NucCF(RF)C(RF)2 7.22C
>
(RF)2C C(RF)2 7.22B
RF = Perfluoroalkyl
NucC(RF)2C(RF)2 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 CF2 5CF2 < CF2 5CFCF3 > CF3 CF5CFCF3 is observed.
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176
Chapter 7 F3C
F3C C
C
CF3 C
C
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 F
F Y
X, Y = F (7.24A) X = F, Y = OMe
F
F
CF3 CF3
F3C F3C
Y
Y X, Y = F (7.24B) X = F, Y = OMe X = Y = OMe
X, Y = F (7.24C) X = F, 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 opportunity is available, an SN 20 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).
4 Substitution with rearrangement – SN20 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
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
Nuc
C
C
F
R
Nuc-H Nuc
−
C
C
H + Nuc
F
R
(Base catalysed addition)
7.25A
7.25B
177
−
−F
SN2' R = −CFR'2 Nuc
Nuc
R' F
R
R' 7.25D
7.25C
Figure 7.25 C4H9O− Na+ n-C4H9OH
+
CF2
CF2
0-40 C
n-C4H9OCF2CF2H
81%
½74
CH3OCF2CH(CF3)2
65%
½75
Room CH3OH
CF2
C(CF3)2
Temp.
CH3OCF
C(CF3)2
8%
Figure 7.26 i CF2
CH3OCF2CFHCF2C4F9
(45%, addition)
+ CH3OCF
(15%, substitution)
CFCF2C4F9
CFCF2C4F9
+ CH3OCF2CF
CFC4F9
½76
(40%, SN2')
i, CH3O− Na+, CH3OH, 50 C
Figure 7.27
4C6H5Li + CF2 CF2
Room Temp
(C6H5)2C C(C6H5)2
½77
Figure 7.28
reactions are concerted, they will be referred to as SN 20 processes here [81] (Figure 7.30). That substitution occurs by attack at the CF2 5 group, rather than direct displacement of chloride from 2CF2 Cl, has been deduced from the fact that, under equivalent conditions, C6 H5 CClF2 , CClF5CF2CClF2 and CCl2 5CCl2CClF2 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
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178
Chapter 7 XHFC CF2
NH3
CFX
CFHX
N C
C
N
N
½78
C CFHX
CF3CF
(CF3)2C
CF2
CF2
Vap.
NH3
Et2O
NH3
½79
CF3CHFCN
Phase
(CF3)2CHFCN
−60 C
½80
21%
(CF3)2CHCONH2
13%
Figure 7.29 CH3O−
CF2
CFCF2Cl
CH3OCF2CF
CF2
Cl−
½81
Figure 7.30
C6H5
CF2 + C2H5O−
k1
C6H5 CCF2OC2H5
R
products
½84
R
R
k1 x 103s−1 (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 CF2 Cl, 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).
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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
i
CF2 CF2
NCCF2CF2CO2CH3
95%
[93]
[60]
72%
i, NaCN, CO2, (CH3O)2SO2 i
XYCCF2
Ph2CCN
Ph2C(CN)CF2CXY
[94]
i, Phase Transfer Conditions Ph2C(CN)CF=CXY
Ph2C(CN)CF2CHXY 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] +
F
F
CH3CN, rt 73% F
CH3MgX
CF2 CCl2
CH3CF2CCl2H
F
[97]
CH3CF CCl2
Contd
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180
Chapter 7
Table 7.6 Contd Reaction
Ref.
Nitrogen nucleophiles F F N
rt
+ CH3NH2
CF CF2
F
F
[98]
N N
H
CH3
78%
F
CF3
C2F5
F
C2F5
C2F5
NH3, Et2O 0 C
F
CH2CN
F3C
[99]
94%
C2F5
C2F5
F3C
Oxygen nucleophiles F3C
CF3
O
F3C
CF3
CF3
+ C2F5
C2F5
C2F5
O
F3C
i
C2F5
[100] H
C2F5 28%
62% i, NaOCl, H2O, CH3CN F3C
xylene
CF2 + Bu3SnOMe
F
OMe
[101]
H
i O
Ph F
F3C H
OH
H
F 62%
0 C
F3C
F3C
78%
[102]
68%
[103]
Ph
F i, Montmorillonite (cat), KIO3, Hexane, Reflux O i
(CH2OH)2
C(CF3)2
CF2 C(CF3)2 i, CH3CN, −5 to 0 C
O
Phosphorous nucleophiles C3F7CF CF2 + Bu3P
C3F7CF CFP(F) Bu3
[104]
(100%, Z)
Contd
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
181
Table 7.6 Contd Reaction
Bu3P
Ref. i
CF2 CFCF3
Bu3P CF CFCF3
[105]
F
i, Et2O, −70 C to rt
BF3.Et2O CF3
F I
ii
Bu3P CF CFCF3
−
BF4
F ii, I2, DMF, NaCO3
F
+ Ph3P
F
[106] PPh3
Sulphur nucleophiles F3C
F
F3C
S
F3C
K2S, DMF
F3C
F i
CF3
[107]
CF3
S
29%
CF3CFHCF2SC( S)NMe2
CF2 CFCF3
62%
+ CF3CF CFSC( S)NMe2
63%
[108]
i, Me2N CS2− Na+, DMA, 20 C
Halide ions I NaI, DMF
F
[109]
F
Transition metal nucleophiles F
F
−
+ Re(CO)5
[110] Re(CO)5
Reduction PhCF CFCF3
i
F
CF3 9%
Ph
H
[111]
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 C2F5
HO +
CF3
F3C
i
C2F5
F3C C2F5
CF3
OH i, Na2CO3, tetraglyme
58%
i CF3CF CFCF3 +
77%
I
N
[113]
N
NH2
CF3
N i, K2CO3, CH2Cl2, rt
CF3
OH +
O i, ii F
[114]
F
NH2
N
i, K2CO3, CH3CN ii, NEt3
59%
i Li
[112]
O
O
CF CF
Li
n i, CF2 CF2, Et2O, −110 C SH
[115]
n = 10−20
S i
CF2 CFCF3
CH(CF3)2
NH2
[116]
N i, THF, i-Pr2NEt i
Me3SiOCH2(CF2)3CH2OSiMe3
F
[117]
OCH2(CF2)3CH2O
i, CsF, Glyme, Stepwise F
F OCH2(CF2)3CH2O
Contd
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
183
Table 7.6 Contd Reaction
Ref. N
i D.B.U. + CF3CH CFCF3
[118]
N F3C
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, vinylic substitution is usually preferred over SN 20 processes. Cl F F
C2H5O−
Cl
½85
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
F F
Cl
F
C2H5OH
Cl
KOH
Cl
OEt Cl
Cl OEt
Cl
Cl
Cl
Cl
Cl
F
7.33B, 10% F
7.33A
OEt
F
Cl
Cl Cl
Cl
F
Cl
F
OEt +
OEt
Cl
Cl
Cl
Cl
Cl
F F
7.33C, 61%
7.33D, 23%
Figure 7.33
F
F
F
F
−
F
F
F
C2H5O
F
F OEt
F
OEt
F
7.34A
7.34B
Figure 7.34 F R
R MeO−
F
R F
F
F
F
7.35B
F OMe
7.35C
7.35D
R
%
%
H
49
51
CH3
54
46
OCH3
38
62
Figure 7.35
½119
F
OMe
OMe
7.35A
R +
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 185
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives F
F
F F
F
F
F
R
F
F MeO F
F
F
F F
185
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
−
F +
+
C
C
F3C
C
C
C
H3C
C
E
F3C
C
E
F3C
C
Nuc
F Compare
H
+
H +
−
Nuc
H
Substitution with Rearrangement F F −
F
F
F
F F F
−
+
F
F
Compare H +
H
H
H
Figure 7.37
H H H
+
+
H
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Chapter 7
7 Addition reactions Addition of an alkali-metal fluoride, frequently KF, CsF, ðMe2 NÞ3 Sþ Me3 SiF 2 (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.
F3C
CF2-CF3
F3C
F
CF3 CsF
+ CH3I
C3F7
C
DMF
CH3
79%
[122]
CF3 O
KF, DMF
CF2 CFCF3 + PhCOCl
CF3
Ph CF3 −
KF CF2 CF2
CH3CN
i, ii
CF3CF2
66%
[123]
F
CF3CF2CO2H
75%
[124]
i, CO2, 150 C, ii, H2SO4
−
+
CF2 CFCF3 + C6H5N2 Cl
F3C F F3C
CsF CH3CN
N N C6H5
[125]
41% CF3 CF2 C(CF3)2
+ C6H5SCl
CsF
F3C
glyme
C
SC6H5
82%
[126]
CF3
CF2 CFCF3 + S
KF, 120 C
F3C F3C
CF3
S
70%
[127]
CF3
S Br
F
F
CsF, Br2
CF2 CFCF3 + IF5 + I2
F
150 C
[128]
F
(CF3)2CFI
99%
[129] Contd
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
187
Table 7.7 Contd Reaction
Ref. CF3
CF3
F3C
+ KF F3C
+
I2
200 C
IF5
+
CF3CF2
F
C
I
79%
[130]
CF3 i
Hg(CF(CF3)2)2
2CF2 CFCF3 + HgCl2
[131]
i, KF, (CH2OMe)2, 50 C i
(CF3)2CFSO2F
CF2 CFCF3 + SO2F2
[132]
i, KF, CH3CN, 150 C, Autoclave F i
E C C E +
F
E = CO2CH3
F
E
E
[133]
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
F N +
CF2
CFCF3
(CF3)2CF
F
½134
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 rather than concerted SN 20 processes is supported by the isolation, in some cases, of
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188
Chapter 7 C3F7CF2CF
CsF
CF2
CF3 F
C3F7CF
diglyme
F3C
KF, MeCN CF
CFCF3
18-crown-6
½136
CF2CF3
F3C
CF3
½135
95%
CFCF3
96%
F
Figure 7.39
CF2 F
F
F2C
F
½137
F
F2C F
F
−
−
F
F
F
CF2 F2C
F
F2C CF2 F F F CF2 F
i, ii
F
F2C
F
F2C CF2 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 −
F
CF
F2C +
CF2
CFCF2CF
189
CF2
CF2
½138
CF CF3
F
F
F3C
F3C
Figure 7.41 CF2 hν F
F
F
F
F
F
½139
7.42A hν F
(Photoequilibrium)
95%
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). n −
F
F
+
½56, 57, 92
F 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
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Chapter 7 −
CF2
F CF2
CF2
CF2 CF3CF2CF2CF2
CF3CF2 A
−
−F
CF3CF2CF
½91, 92, 14042
CF2 −
+F CF3CF2 CF3
−
C
CF3 CF3
C
−
F
SN2'
CF3 A
C
CFCF3 B
CF2 −
F
CF3
CF3
C2F5 F C2F5
−
A
B
CF3
CF3CF
C2F5
F
F, Dimerisation
CF3
C2F5
C2F5
CF3 Tetramer
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 −
(CF3)2C
CF2
−
+F
CF2
(CF3)3C
CF2
− (CF3)3CCF2C F2
½146
(CF3)2C
−
(CF3)3CCF2CF2CF
−F
C(CF3)2
191
CF2
−
(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
F
A
F
F
A
F
½151
−
−F −
−
F
F
F
F
F
F
F
F
A
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 strainfree 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 F
F
F
F
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 Xþ F . 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). AgF
CF2
CFCF3
HF
½156
AgCF(CF3)2
125 C HF
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 Hn F nþ1 , 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 −
+
HgF2
nHF
HgF2
2CF2 CFCF3
HnF
HgF
HF 85C
Hg[CF(CF3)2]2
n+1
etc
193
½156
60%
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 , 2OCH2 2, CH2 NH2 , CH2 OH 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
[157]
CF3CHCl2 + polymer H AlCl3
C10H21CH CF2 + C2H5COCl
C10H21
CO.C2H5
C
[158]
CF2Cl C6H5 CF3
CF3
C6H5
+ Br2 F
Br
F
C
C
F
F
Br
86%
[159]
anti : syn 1:1
CF2 CH2
+ HI
−20 C
HNO3
CF2 CF2
CH3-F2I + polymer
i
CF3CF2NO2
[160]
93%
[161]
i, HF, 20 C
CF2 CFCF3
HNO3
i
(CF3)2CFNO2
76%
[154]
i, HF, 60 C
FClC CFCl
HNO3
i
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 CF2 CF2 + IF5/I2 CF2 CXCF3 + BF3/ICl/HF
(CF3)2CFI
99%
[129]
CF3CF2I
86%
[129]
60-80%
(CF3)2CXI
[164]
X = H, F
i
CF2 CFCl + (CF3)2CO
F3C
[165, 166]
F
i, AlClXFY, 100 C
98%
O
F3C Cl
F
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, Cþ 2F, is stabilising whereas fluorine that is b- to the carbocation centre is destabilising (Chapter 4, Section VI).
+
F
Cl
F
Cl
E-CCl2CF2
Stabilising
E-CF2CCl2
Destabilising
E
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 F
F CF2
F
SbF5
CFCF3
F
CF3 F
F
C3F6
F
½168
+
F
CF2
F
195
F
F
−
shift
F F CF3-CF
F
CFCF(CF3)2
−
CF(CF3)2
F F
F
Figure 7.51
CF2
CFCF3
CF2
i
CF2
F(CF2)2CF
CF3
47 %
½170
i, AlCl3, 25 C
F
+ CF2
SbF5
CF2
½171
F CF2CF3
HCF2CF2CF
SbF5
CF2
FCH
½172
CFCF2CF3
Figure 7.52
F
F
F CF2
CF2
SO3
O
F CF2
CFCl
SO3
i
½173
F SO2
F
F
F Cl
O
SO2
½174
F
Cl
F O
SO2
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
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Chapter 7
CF2
CFCF3 i,
F C
SO3
F2C
i or ii CF2
CF2
CFCF2OSO2F
½152
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 CF2
C
CF3CH
CF2
99%
CF2
½175, 176
i, anhyd. HF, −72 to 20 C
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. A
B
Initiator
A• + B
A
Initiation
A
A• +
A
In
Addition
Propagation
A
+
+
A
B
A
B
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). A
B +
In
A
B
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
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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 CH2 5CH2 CH2 5CHF CH2 5CF2 CHF5CF2 CF2 5CF2 CF2 5CFCF3
CF:3 132 30 9 6 8
C2 F:5 340 108 13 9 7 0.33
C3 F:7 290 40 — — <0.3
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 CF2 5 site in a fluorinated alkene exclusively and, in parallel with these observations, nucleophilic radicals, such as CH3 S 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. l
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Chapter 7
A
CF2
1
ACF2CFCF3
2
CF2CFACF3
AB
ACF2CFBCF3
A
BCF2CFACF3
A
CFCF3 AB
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 CH2 5CHF CH2 5CF2 CHF5CHF CH2 5CHCH3 CH2 5CðCH3 Þ2 CH2 5CHCH5CH2 CH2 5CHCF3 CHF5CHCF3 CF2 5CHCH3 CF2 5CHCF3 CF2 5CFCF3
A:B 1:0.09 1:0.05 1:0.05 1:0.1 1:0.08 1:0.01 1:0.01 1:0.33 1:50 1:1.5 1:0.25
A decreasing order of reactivity (towards free-radical addition of methanol) has been observed [188] in the order CF2 5CCl2 > CF2 5CFCl > CFCl5CFCl > CF2 5CHCl, 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 CF2 5CCl2 > 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 electrondonating 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
Table 7.11
199
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
75%
(CH3)2CHCF2CFHCF3
[45] 3%
CH3CH2CH2CF2CFHCF3
i, (t-BuO)2, 140 C
RFH
+ CF2 CFCF3
i
RFH
RFH RFH RFH
i, (t-BuO)2, 140 C
RFH
[45]
RFH
36%
59%
RFH = CF2CFHCF3
CH3OH + CF2 CFCF3
i
93%
CF3CFHCF2CH2OH
[190, 191]
i, (t-BuO)2, 140 C OH + CF2 CFCF3
OH
i
[191] CF2CFHCF3
i, (t-BuO)2, 180 C OH
HO + CF2 CFCF3
OH
i, (t-BuO)2, 140 C
87%
CF2CFHCF3
i
[192] 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.
O + CF2 CFCF3
CF2CFHCF3
O
i
[193–195]
70%
i, γ rays, or hν i
CH3(OCH2CH2)nOCH3 + CF2 CFCF3
[196, 197]
RFHCH2[OCH(RFH)CH2]nOCHRFH
i, (t-BuO)2, 140 C
RFH = CF2CFHCF3 F
F
F
RF
F
i
(CH3CH2)2O + [(CF3)2C CHCF2]2
RF H3C
i, γ-rays, rt
O
[198]
CH3
RF = CH(CF3)2 H F
O F
O
γ ray
[194] 83%
O C3H7
C
O H
i
+ CF2 CFCF3
C3H7
[190]
O
O i C
CF2CFHCF3
70%
i, (C6H5CO2)2, 80 C, 16 h.
Ph
C
H
+ CF2 CFCF3
i, (t-BuO)2, 140 C
Ph
CF2CFHCF3 F CF3
+
[199]
F F O CHCl3 + CF2 CFCF3
CCl3CF2CFHCF3
[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
Contd
Table 7.11 Reaction
Ref. Hg/hν
SiH4 + CF2 CFCF3
CF3CHFCF2–SiH3
51%
[201]
F +
F2HC
SiH3
34%
CF3 H F
SiCl3
hν
+ HSiCl3
20 C
+ HSn(CH3)3
F i
(C2H5)2P(O)H + CF2 CF2
[201]
Sn(CH3)3
H F
80%
F
[202]
94%
(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). FH
Me
FH
H
i
F H
H OH
H
F OH
F
OH CF3
F
CF3
7.59A i i, CF2
CFCF3 Me
Figure 7.59
CH2CF2CFHCF3
OH
OH
CF2CFHCF3
CF2CFHCF3
½205
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 202
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Chapter 7
2 Telomerisation [178, 206] Telomerisations [207, 208] are regarded as reactions in which a telogen (A2B) and several molecules of a monomer ðR2 C5CR2 Þ 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 CF3 I and CF2 5CF2 , a broad range of telomers is produced unless a considerable excess of the iodide is employed [215]; but with ðCF3 Þ2 CFI as telogen, where the C2I bond is more easily broken [216] (Figure 7.60), the chain length is more easily controlled. (CF3)2CFI
+
CF2=CF2
(4.6 : 1)
175 C
(CF3)2CF(CF2CF2)nI
½216
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 CH2 5CF2 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 fourcentre 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
Table 7.12
Telomerisation reactions of 1,1-difluoroethene [216]
Fluoroalkyl iodide Molar ratio RF I RF I: CH2 CF2
CF3 I C2 F5 I n-C3 F7 I i-C3 F7 I
203
1 1 1 1 1 1
: : : : : :
1 1 1 1 1 4
Temp. (8 C)
200–210 190 200 185 220 220
CH2
(CF3)2CFI
Composition of RF ðCH2 CF2 Þn I (mol%)
Time Conversion (h) of iodide (%)
41 45 36 36 36 36
35 55 88 88 90 100
n51
2
3
4
5
6
46 92 70 90 87 2
33 6 25 10 13 21
14 2 5 Trace Trace 29
5 — — — — 26
1 — — — — 18
— — — — — 4
180 C
CF2
(CF3)2CF(CH2CF2)nI
½217
SbF5 / 0 C CsF (CF3)2C
CHCF2(CH2CF2)n-1F
(CF3)2CF(CH2CF2)nF
130 C
Figure 7.61
CF2=CFCF3
194 C CF3I
CF3
CF2CFCF3
n
I
½218, 219
n = 1 (47%); n = 2 (23%) n = 3 (19%); n = 4 (8%) n = 5 (4%).
Figure 7.62 RF 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 CF2 5CF2 , CF2 5CFH, CF2 5CH2 , CF2 5CFCl and CF2 5CFBr 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 CF2 5CFCF3 with CF2 5CF2 (i.e. FEP) and with CF2 5CH2 (Vitont rubber) have been developed. Polytetrafluoroethene (PTFE), 2ðCF2 CF2 Þn 2 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 CF2 5CF2 and CF2 5CFCF3 (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
(CF2CF2)x
(CF2CF)
(CF2CF) OC3F7
CF3 FEP
PFA
Figure 7.64
Recently, amorphous fluoropolymers have been developed in order to obtain highperformance 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 CF2 5CF2 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
O
O
F3C
CF3 PDD
CF CF2
CF2
In
CF2
CF
O
O
F3C
CF3
x
CF2 y
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 R CF2
CF
O(CF2)2CF
CF2
RCF2
Monomer
Route B
½222
O
Route A
R
F
205
etc.
CF2 F2CR
etc.
F
Polymer
Monomer
O
Figure 7.66
Polychlorotrifluoroethene (PCTFE), 2ðCF2 2CFClÞn 2 This material melts at 2138 C and is therefore melt-processable giving clear films. Polyvinyl fluoride (PVF), 2ðCH2 2CHFÞn 2 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), 2ðCH2 CF2 Þn 2 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). 2 CF2
Figure 7.67
= CF2
200 C Autoclave
F
½226
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
CF2 CFCl
Ref. Cl
130−250 C
[228]
(E/Z = 1:1)
F Cl CF3
(E + Z)
F CF3
[229]
CF3CF CF2 CF3 F
(E + Z)
F3C CF2 CF2 C CF2
[175]
F CF2 F
H
F CF2 CF2
CH2 CH2
H
150 C
40% F
H F
H F
H
F CF2 CF2
[230]
H
(CH2 CH )2
[230] F
H CH CH2
F F H
F CF2 CF2
225 C
35%
HC CH F F
[231]
H
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 207
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
Table 7.13
207
Contd
Reaction
Ref. F
H
F CF2 CFCl
H
100 C
CH2 CHC6H5
[232] F Cl
H C6H5
(CF3)2CF
(CF3)2CF
<0 C
(CF3)2CFC CF
[233] F
F 72%
18% F
CF2
110 C, 7 days
+
F 47%
[234]
A particular driving force appears to be the presence of CF2 5 in the alkene; 1,2difluoroalkenes, 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 CF2 5CF2 than in ethene [36, 237]. In forming a cyclobutane ring, not only are these repulsive forces removed but, if a CF2 5 was originally present, then stronger carbon–fluorine bonds are formed in 2CF2 2. 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
(1) (2) (3)
Chapter 7
Ip repulsion is relieved. F atoms are mutually bond strengthening in the product. 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. Pathway A 2 CF2
CCl2
CCl2
CF2
CF2
CCl2
7.69A Pathway B
CF2—CCl2
F2
CF2—CCl2
F2
Cl2 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 2 CF2
CFH
7.70C H
CF2—CFH F CFH—CF2 7.70D
Figure 7.70
H
(E + Z isomers)
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).
CF2
CClSPh
C(CN)t-Bu
i
7.71B i, 120 C,
½241
> Cl
<
7.71A
CH2
<
SPh F2
> CN
t-Bu 10hr. SPh F2
Cl CN
88%
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 CF3
F3C
Br F F3C
CF3
F3C
F3C
CF3
F3C
CF3
Li, −20 C
CF3 CF3
CF3
½243
CF3 CF3
F3C
CF3 F
F3C
CF3 CF3
CF3
F3C
CF2
CF3 CF3
300 C
300 C hν
hν
(CF3)8
(CF3)8
300 C
(CF3)8
Figure 7.72 (CF3)2C
C(CN)2
CH2
CHOC2H5
(CF3)2C H2C
C(CN)2
½244
CH.OC2H5
F3C
CN
F3C H
CN H OC2H5
H 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 CF2CCl2 80 C
+
+
+
½248
Cl2
CF2 — CCl2
CF2 — CCl2 7.74 B
1.6%
7.74 A
F2
F2
211
F2
Cl2
Cl2 83%
15%
Figure 7.74
+ CF2
F2
F2
475 C
CF2
+ F2
½246, 249
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 unrelated. 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
CF2
i + CF2
CFCF3
F F
i, 120 C, 16 h., Et2O
35%
½251
F
F + CF3CF
CFCF3
260 C 30 h
CF3 CF3
Figure 7.76
F
42%
½252
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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%
80 C
[253]
F
H2
F
F
O
F
O
F
H2
O
O
[254]
100%
F2 F10 Me
Cl F F
F
Cl
Me
F2
Me
89%
170 C, 48 h Me
F F
100 C
CF2 +
[255]
F2
[256]
F F F
F
100 C
F
+
F
30%
[257]
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 ðRF Þ2 C5CðRF Þ2 > ðRF Þ2 C5CFRF > ðRF Þ2 C5CF2 , RF CF5CFRF ðRF 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
1,3-Dipolar cycloaddition reactions involving fluoroalkenes
Table 7.15 Reaction
Ref.
CF3
C2F5
CF3
F
+
CH2—N N
C2F5
C2F5
CF3
H
N CF3
+ CH2—N N
N
H
i
C2F5
CF3 F
H
N
93%
CF3 C2F5 CF3
i, Et2O, rt
C2F5
N
H H
N CF3 CF3
CF3 +
CF3
CF3
H N
H CF3
N
H CF3 CF3
CH2Ph
N
N
i
CF2 + PhCH2N3
H
N
i, Et2O, rt
87% CF3
F
CF3
[198]
H CF3
i
CH2—N N
CF3
[72, 258]
94%
i, Et2O, rt
CF3
N
H i
F
i, 190 C, 16 h
[259]
CF3
F N
i + CH2—N N
F
i, Et2O, rt, 14 days
N
55%
[72]
F
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 N
CH2
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 N F
20 C CF2
CF2
O
F
CF3NO −45 to 20 C
N
F
O
CF2
n
O
O CF2
+ SO3
0 C R
R = CH2ClCHClCH2-
CF2
CF2
SO2
i
S
O
C
C
F
F
F
F
F
F
½262
44%
F S
i, CF2Cl2, N2, hν, −32 to 90 C
64%
CF2
CF3
RCF
½261
62%
F
FCOCF2SOF 80%
O
CF3 F
CF3CN
½263
O
F
F N
N
40%
½264
CF3
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.
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
Table 7.16
215
Synthesis of fluorodienes and polymers
Reaction
Ref.
Dehydrohalogenation H
CF3
H CF 3
CF2
CF3
CF3 i, t-BuOK/t-BuOH
CF2
i
CF3
CF3
i
(CF3)2CFCH2CF2
[266]
(CF3)2C CHCF2
2
70%
2
[267]
i, CsF, 150 C, Sealed Tube
Dehalogenation Zn
BrCF2CClFCClFCF2Br CF3
CF2 CFCF CF2 CF3
F Cl CF2Cl
CF3
F F
i CF3 F
F
40%
[269]
F
i, Zn, 120 C, diglyme CF3
CF3
C2F5
C2F5
CF3
CF3
i F
F CF3
Me2N i, Me N 2
F
F
NMe2 NMe2
90%
[270]
CF3
, CH2Cl2, rt
F
i
79%
F
F
[268]
78%
[270]
F i, Na, Hg (0.5% w/w), water cooling
O
Cl
O
O
i
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
25−37%
CF2 CFCF CF2 +
NaO2C(CF2)4CO2Na
[272]
CF2 CF(CF2)2CO2Na
i, 450 C, 0.01 mm
Reductive coupling Cl
I i
F
75%
F
F
[273]
Cl Cl i, Cu powder, DMF, 135 C
F
F
i F
F
I
+
F I
[273] F
F
F
i, Cu powder, DMF, 135 C 34%
50%
hν F
F F
F
[274] Anti : Syn = 20 : 1
CF3
F
CF3
F
Cu
Ph
F
CF3
F
Ph
+
[265, 275]
F
I
F
CF3
CF3
CF3 i F
F
F
75%
[276]
CF3 i, PPh3, CH3CN, 25C
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
Reactions of polyfluorinated dienes
Table 7.17 Reaction
Ref.
Nucleophilic attack OPh i
F
F
F
+ PhOH
F PhO
i, KF, CH3CN, rt CF3
CF3
F
CF3
+ K2S
DMF rt
72%
[73] S (CF ) 3 4
CF3
F
H
F
CF3
[73]
58%
F F
F
CF3
MeOH rt
CF3
CF3
[269, 279] F
F
CF2OMe
MeO F
F
MeOH rt
F
[73]
MeO F
CF3 CF3
CF3
CF2
CF2
O
F CO2Et
O
i
CF2
+
[280] Na +
OEt
F
O
Me
F
i, Tetraglyme, rt, 17 h
CF3
CF3 CF3
CF3 i
F CF3
70%
O
+ t-BuOOH
F
O F
CF3
CF3
F
CF3
[281]
i, BuLi, THF, −78 C to rt
Rearrangements CF3
F
F F
0 to 5C
CF3 F
F
CF3
SbF5
CF3 F F
[269]
F
Contd
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Chapter 7
Table 7.17
Contd
Reaction
Ref.
F
F CF2
CF2 F
hν 85 C, 5 h
F F
+
F
F
[282]
CF2
F
64%
36%
Cycloadditions F F
CF2 HC CCPh
F2C
F
Dioxane 60 C
F
F
+ H
CF2
Ph
Ph
F
[283]
H 38%
4%
1,4-cycloadditions of fluorinated dienes may occur involved perfluorocyclo-1,3-hexadiene, as shown in Figure 7.79. CO.CH3 Heat F
+
CH2
½277
F
CHCO.CH3
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). +
F
F
+ [C5Me5]2Fe
F
F
[C5Me5]2Fe
½278
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).
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Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
219
Reactions of perfluoroallenes
Table 7.18 Reaction
Ref. CF3
CF3
F
CsF
CCCF2
F3C
F
(CF3)2CF
F
F3C
CF3
CF3
F
F3C
F
72%
[284]
F 18%
CF2
CF2=C=CF2 + PhCHN2
F
Ph
i
[285]
F N
i, benzene, rt
N
78%
H
CF2=C=CF2 +
N
F
O
Ph + N
N
i O
N
Ph
[286]
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). F
O F O
650 C 1-2mm
HC
CF
½287
+ CO + CO2 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
CF2Br2 + CH2=CF2
ii
CF2BrCH2CF2Br
CF2BrCH=CF2 86%
½288
i, Bz2O2, 110 C; ii, C, 300C; iii, hν, Br2 iii
CF3C
CF
Zn dioxane
CF3CBr=CFBr
AlBr3
CF2BrCHBrCF2Br
Figure 7.82
i
CCl2=CClCCl=CCl2
CF3CCl=CClCF3
½292
85% i, SbF3, SbF3Cl2, 115 C ii
ii, Zn, (CH3CO)2O, reflux CF3C
63%
CCF3
Figure 7.83
i
CCl2=CClCCl=CCl2
CF3CH=CFCF3
ii CF3C
i, Fluorocarbon, sulpholan (25% v:v), KF ii, Molecular Sieve
F
CCF3
½53
56%
CF2 i
F
CF3C F
CF2
F
CCF3
½293
80%−90%
i, CsF or KF, 510−590 C, Flow system in N2
Figure 7.84
A recent direct route from CF3 CH2 CF2 H (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 i, ii CF3CH2CF2H
221
i, ii
CF3CH=CHF
CF3C
CH
½294 i
CF3C
PhCHO
CCH(OH)Ph
CF3C
CLi
60% Ph3SnCl CF3C
i, n−BuLi ii, −LiF
CSnPh3
84%
Figure 7.85 Synthesis of fluoroalkynes
Table 7.19 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 C3F7C CZnCl
C3F7CCl2CCl3
HCl
CF3C CH
[297]
77% i, Zn, DMF, 90−100 C RF RF
RF N
hν rt
N
RFC CRF
[298]
+ RFC N
N RF = CF(CF3)2
CH3(CH2)5C CSnMe3
+ C6F13I
70 C 6h
C6H13C CC6H13
[299]
55%
C3F7I +
HC CH
220 C
C3F7CH=CHI
KOH
i
i, C3F7I, 220 C C3F7C CC3F7
C3H7C CH
[300] KOH
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
p-ClC6H4
Cl Cl
CF3
H
i p-ClC6H4
ii
p-C6H4C CCF3
[301]
Cl 81%
i, Ac2O, Et3N, Zn, DMF; ii, NaNH2, t-BuOH, benzene, rt i PhC CLi
PhC CC8F17
+ C8F17IPhOTf
[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, RF C;CM, had been prepared previously (e.g. M ¼ Cu, Ag, Hg; RF ¼ CF3 , C2 F5 , CF3 CH2 ) [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 CF3
F3C CF3C
CCF3
375 C
hν F3C
Stable valence isomers
½303306
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 hν CF3C
-C(CF3)=C(CF3)-
CCF3
223
½307, 308
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). F3C
NaOBu n–C4H9OH + CF3C
CCF3
H 89%
20 C
n-BuO
CF3
F3C CF3C
CCF3
+
OH
½309
½310
O
NaOH 50 C F3C
O
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.
CF3C
CCF3
i
i, CsF, Sulpholan
CF3CFCCF3
½311313
C4F6
CF3CFC(CF3)C(CF3)CCF3 C4F6
F
Figure 7.89
CF3CC(CF3)
etc.
n
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224
Chapter 7 F CF3
F3C
½315
7.90A F N F CF3C
i
CF3F=CCF3
CCF3
C(CF3)=C(CF3)nF F
i =
F
N
7.90B
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). F
CF2=CF
i
i CF3C
2
C(CF3)=C(CF3)
CCF3
n
½315, 316
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).
Cycloaddition reactions with perfluoro-2-butyne
Table 7.20 Reaction
Ref. COPh
COCH3
N
N +
i
CF3C CCF3
100%
[317]
CF3 CF3
i, THF, 100 C
CF3C CCF3 + PhN3
50 C
N N
CF3
Ph N
80%
[318]
CF3
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 225
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives
Table 7.20
225
Contd
Reaction
Ref. CF3 F3C 200 C
CH3
H3C
CF3C CCF3
[319]
10 h H3C
CH3
O CF3
100 C CF3C CCF3
O 6h H3C
CH3
CF3
OH CF3
CF3
[320]
i
ii
F3C
CH3
CH2=CH2
O F3C CH3
i, BF3.Et2O ii, H2, Pt/C, 400 C CF3
CF3C CCF3
∆
F3C
[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
CF3CH=CFCF3
F3C
−HF
½322
CF3 91% CF3
Figure 7.92
F CF3C
CCF3
[CF2]
F3C
CF3
100 C
[CF2]
F
F3C
CF3
100 C F
F
F
½323
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). S
(CF3)4 CF3C
CCF3
S
S
½326
I2 S
CF3
F3C
7.94A 11% F3C
F3C
7.94B 26% S
S
CF3
S
S
CF3
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 CH3CHO
+ CF3C
O
CF3 CF3
H
C3F7I
+
CF3C
CCF3
220 C 7 days
½327
30%
CCF3
CF3CIC(CF3)C3F7 Z:E
68%
½328
3:4
Figure 7.95
REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
G. Sandford, Tetrahedron, 2003, 59, 437. 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. 603. B.E. Smart in Fluorinated Organic Molecules, ed. J.F. Liebman and A. Greenberg, VCH, Deerfield Beach, 1986, p. 141. D.F. McMillen and D.M. Golden, Ann. Rev. Phys. Chem., 1982, 33, 493. L. Pauling, The Nature of the Chemical Bond, Cornell Univ. Press, Ithaca, NY, 1960. N.C. Baird, Can. J. Chem., 1983, 61, 1567. E.T. McBee, Ind. Eng. Chem., 1947, 19, 237. M. Hudlicky, Chemistry of Organic Fluorine Compounds, Pergamon, Oxford, 1961. T.J. Brice in Fluorine Chemistry, ed. J.H. Simons, Academic Press, New York, 1950, p. 436. J.G. Riess, Chem. Rev., 2001, 101, 2797. R. Taylor, Chemistry – A European Journal, 2001, 7, 4074. W.A. Sheppard and C.M. Sharts, Organic Fluorine Chemistry, Benjamin, New York, 1969. A.M.G. MacDonald in Comprehensive Analytical Chemistry, Vol. 1B, ed. C.L. Wilson and D.W. Wilson, Elsevier, London, 1960, p. 547. S. Tasker, R.D. Chambers and J.P.S. Badyal, J. Phys. Chem., 1994, 98, 124421. J.L. Kiplinger and T.G. Richmond, J. Am. Chem. Soc., 1996, 118, 1805. B.K. Bennett, R.G. Harrison and T.G. Richmond, J. Am. Chem. Soc., 1994, 116, 11165. J.A. Marsella, A.G. Gilicinski, A.M. Coughlin and G.P. Pez, J. Org. Chem., 1992, 57, 2856. D.D. MacNicol and C.D. Robertson, Nature, 1988, 332, 59. J. Burdeniuc, W. Chupka and R.H. Crabtree, J. Am. Chem. Soc., 1995, 117, 10119. W.H. Pearlson and L.J. Hals, US Pat. 2 617 836 (1952); Chem. Abstr., 1952, 47, 8770. E.E. Lewis and M.A. Naylor, J. Am. Chem. Soc., 1947, 69, 1968. M. Hudlicky, Chemistry of Organic Fluorine Compounds 2nd (revised) edition, Ellis Horwood, Chichester, 1992. J. Rabai, S. Zoltan and I.T. Horva´th in Handbook of Green Chemistry, ed. J. Clark and D. Macquarrie, Blackwell Science, Oxford, 2002, p. 502. D.P. Curran, S. Hadida, A. Studer, M. He, S.-Y. Kim, Z. Luo, M. Larhed, A. Hallberg and B. Linclau, Comb. Chem., 2000, 327. I.T. Horva´th, Acc. Chem. Res., 1998, 31, 641. D.F. Foster, D. Gudmunsen, D.J. Adams, A.M. Stuart, E.G. Hope, D.J. Cole-Hamilton, G.P. Schwarz and P. Pogorzelec, Tetrahedron, 2002, 58, 3901.
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27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
63 64
Chapter 7
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N.S. Rao and B.E. Baker in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 321. R.N. Haszeldine, J. Fluorine Chem., 1953, 3761. R.D. Chambers, J. Hutchinson, R.H. Mobbs and W.K.R. Musgrave, Tetrahedron, 1964, 20, 497. R.D. Chambers, G.C. Apsey, P. Odello, G. Moggi and W. Navarrini, IUPAC Macromolecular Symposia 82, Fluorinated Polymers, Prague, 1994, ed. J. Kahovec. H. Hauptschein, M. Braid and F.E. Lawlor, J. Am. Chem. Soc., 1957, 79, 2549. J. Balague, B. Ameduri, B. Boutevin and G. Caporiccio, J. Fluorine Chem., 1995, 74, 49. G. Hougham (ed.) Fluoropolymers, Academic/Plenum Publishers, New York, 1999. A.E. Feiring in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 339. H.S. Eleuterio, US Pat 2 958 685 (1960); Chem. Abstr., 1961, 55, 6041. M. Nakamura, N. Sugiyama, Y. Etoh, K. Aosaka and J. Endo, J. Chem. Soc. Jpn, Chem. Ind. Chem., 2001, 659. A.L. Logothetis in Organofluorine Chemistry. Principles and Commercial Applications, ed. R.E. Banks, B.E. Smart and J.C. Tatlow, Plenum, New York, 1994, p. 373. B.E. Smart in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath, ACS Monograph 187, Washington DC, 1995, p. 767. M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd (revised) edition, Ellis Horwood, Chichester, 1992. J. Harmon, US Pat. 2 404 374 (1946); Chem. Abstr., 1946, 40, 7234. A.B. Shtarov, P.J. Krusic, B. Smart and W.R. Dolbier, J. Am. Chem. Soc., 2001, 123, 9956. J.D. Park, K.V. Holler and J.R. Lacher, J. Org. Chem., 1960, 25, 990. M. Hauptschein, A.H. Fainberg and M. Braid, J. Am. Chem. Soc., 1958, 80, 842. D.C. Coffman, P.L. Barrick, R.D. Cramer and M.S. Raasch, J. Am. Chem. Soc., 1949, 71, 490. J.L. Anderson, R.E. Putnam and W.H. Sharkey, J. Am. Chem. Soc., 1961, 83, 382. P. Tarrant, R.W. Johnson and W.S. Brey, J. Org. Chem., 1962, 27, 602. R.D. Chambers, T. Sheppard, M. Tamura and M.R. Bryce, J. Chem. Soc., Chem. Commun., 1989, 1657. W.R. Dolbier, M. Seabury, D. Daly and B.E. Smart, J. Org. Chem., 1986, 51, 974. P.D. Bartlett and J.J.B. Mallet, J. Am. Chem. Soc., 1976, 98, 143. B. Atkinson and A.B. Trenwith, J. Chem. Soc., 1953, 2082. S.J. Getty and W.T. Borden, J. Am. Chem. Soc., 1991, 113, 4334. D.W. Roberts, Tetrahedron, 1985, 41, 5529. P.D. Bartlett, G.M. Cohen, S.P. Elliot, K. Hummel, R.A. Minns, C.M. Sharts and J.Y. Fukunaga, J. Am. Chem. Soc., 1972, 94, 2899. P.D. Bartlett, K. Hummel, S.P. Elliot and R.A. Minns, J. Am. Chem. Soc., 1972, 94, 2898. C. DeCock, S. Piettre, F. Lahousse, Z. Janousek, R. Merenyi and H.G. Viehe, Tetrahedron, 1985, 41, 4183. W.T. Miller, R.J. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850. W.T. Miller and L.F. Pelosi, J. Am. Chem. Soc., 1976, 98, 4311. R. Huisgen and R. Bruckner, Tetrahedron Lett., 1990, 31, 2553. W.R. Dolbier in Chemistry of Organic Fluorine Compounds II, ed. M. Hudlicky and A.E. Pavlath, ACS Monograph 187, Washington DC, 1995, p. 797. D.R.A. Perry, Fluorine Chem. Rev., 1967, 1, 253. W.H. Sharkey, Fluorine Chem. Rev., 1968, 2, 1. P.D. Bartlett, G.E.H. Wallbillich, A.S. Wingrove, J.S. Swenton, L.K. Montgomery and B.D. Kramer, J. Am. Chem. Soc., 1968, 90, 2049. J.J. Drysdale, W.W. Gilbert, H.K. Sinclair and W.H. Sharkey, J. Am. Chem. Soc., 1958, 80, 245.
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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. Drakesmith, 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.
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288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328
235
R.E. Banks, M.G. Barlow, W.D. Davies, R.N. Haszeldine and D.R. Taylor, J. Chem. Soc. (C), 1969, 1104. M.I. Bruce and W.R. Cullen, Fluorine Chem. Rev., 1969, 4, 79. H. Muramatsu and K. Inukai, J. Synth. Org. Chem. Jpn., 1973, 31, 466. E.S. Turbanova and A.A. Petrov, Russ. Chem. Rev., 1991, 60, 501. A.L. Henne and W.G. Finnegan, J. Am. Chem. Soc., 1949, 71, 298. R.D. Chambers, C.G.P. Jones, G. Taylor and R.L. Powell, J. Chem. Soc., Chem. Commun., 1979, 964. A.K. Brisdon and I.R. Crossley, J. Chem. Soc., Chem. Commun., 2002, 2420. R. Sauvetre and J.F. Normant, Tetrahedron Lett., 1982, 23, 4325. J.J. Mielcarek, J.G. Morse and K.W. Morse, J. Fluorine Chem., 1978, 12, 321. D.J. Burton and T.D. Spawn, J. Fluorine Chem., 1988, 38, 119. R.D. Chambers, T. Shepherd, M. Tamura and P. Hoare, J. Chem. Soc., Perkin Trans. 1, 1990, 983. S. Matsubara, M. Mitani and K. Utimoto, Tetrahedron Lett., 1987, 28, 5857. M. Hudlicky, J. Fluorine Chem., 1981, 18, 385. G. Meazza, L. Capuzzi and P. Piccardi, Synthesis, 1989, 331. T. Umemoto and Y. Gotoh, Bull. Chem. Soc. Jpn., 1986, 59, 439. H.C. Brown, H.L. Gewanter, D.M. White and W.G. Woods, J. Org. Chem., 1960, 25, 634. H.C. Brown, J. Org. Chem., 1957, 22, 1256. J.F. Harris, R.J. Harder and G.N. Sausen, J. Org. Chem., 1960, 25, 633. J.L. Boston, D.W.A. Sharp and G. Wilkinson, J. Chem. Soc., 1962, 3488. J.F. Harris, US Pat. 2 923 746 (1960); Chem. Abstr., 1962, 54, 9799a. H.C. Brown and H.L. Gewanter, J. Org. Chem., 1960, 25, 2071. R.D. Chambers, C.G.P. Jones, M.J. Silvester and D.B. Speight, J. Fluorine Chem., 1984, 25, 47. C.G. Krespan, Tetrahedron, 1967, 23, 4243. R.D. Chambers, W.K.R. Musgrave and S. Partington, Chem. Commun., 1970, 1050. W.T. Flowers, R.N. Haszeldine and P.G. Marshall, Chem. Commun., 1970, 371. R.D. Chambers and C.G.P. Jones, J. Fluorine Chem., 1981, 17, 581. W.T. Miller, R. Hummel and L.F. Pelosi, J. Am. Chem. Soc., 1973, 95, 6850. R.D. Chambers, S. Partington and D.B. Speight, J. Chem. Soc., Perkin Trans. 1, 1974, 2673. R.D. Chambers, S. Nishimura and G. Sandford, J. Fluorine Chem., 1998, 91, 63. R.W. Kaesler and E. LeGoff, J. Org. Chem., 1982, 47, 4779. N.P. Stepanova, N.A. Orlova, V.A. Galishov, E.S. Turbanova and A.A. Petrov, Zh. Org. Khim., 1985, 51, 979. C.G. Krespan, B.C. McKusick and T.L. Cairns, J. Am. Chem. Soc., 1961, 83, 3428. R.D. Chambers, A.J. Roche and M.H. Rock, J. Chem. Soc., Perkin Trans. 1, 1996, 1095. W.J. Feast in Fluorine Chemistry at the Millennium, ed. R.E. Banks, Elsevier, Amsterdam, 2000, p. 142. R.D. Chambers and A.R. Edwards, Tetrahedron, 1998, 54, 4949. W. Mahler, J. Am. Chem. Soc., 1962, 84, 4600. W.R. Cullen and M.C. Waldman, Inorg. Nucl. Chem. Lett., 1968, 4, 205. B. Verkoczy, A.G. Sherwood, I. Safarik and O. Strausz, Can. J. Chem., 1983, 61, 2268. C.G. Krespan, J. Am. Chem. Soc., 1961, 83, 3434. R.D. Chambers, C.G.P. Jones and M.J. Silvester, J. Fluorine Chem., 1986, 32, 309. R. Fields, R.N. Haszeldine and I. Kumadaki, J. Chem. Soc., Perkin Trans. 1, 1982, 2221.
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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 CF3 SO2 group is one of the most electron-withdrawing groups known [3] and consequently the carbon acid ðCF3 SO2 Þ2 CH2 is more acidic than trifluoroacetic acid. Also, the sulphonamide ðCF3 SO2 Þ2 NH 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 (pKb ¼ 3:3) is ca. 105 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]
236
Acid
pKa
CH3 COOH CF3 COOH ðCH3 Þ2 CHOH ðCF3 Þ2 CHOH ðCF3 Þ3 COH ðCF3 SO2 Þ2 CH2 ðCF3 SO2 Þ2 NH
4.76 0.52 16.1 9.3 5.4 1.0 1.7
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
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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. ECF
RCOCl
RFCOF
H2O
RFCOOH
[13]
e.g. RF = CF3, C4F9 i
CF3CCl3
[14]
CF3COOH
i, SO3, BF3 i
C8F17I
C7F15COF 83%
[15]
i, Fuming H2SO4, PCl5 i, ii
CF2=CF2
i, K2S2O8, FeSO4, H2O ii, Esterification i
CF3(CF2)6I(Br)
[16]
(CF2)n(COOMe)2 n = 1−11
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
[19]
i, HNO3, FeCl2.nH2O
CHF2COF
hν
+ Br2
i
CF2ClCFClCCl3
65%
BrCF2COF
[20]
CF2ClCFClCOOCl ii
[21] CF2ClCFClCOOCD3
iii
CF2=CFCOOCD3
i, Oleum ii, CD3OD iii, Zn
Contd
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238
Chapter 8
Table 8.2 Contd Reaction
Ref. X SbF5
Cl
i
F
(CF2)4(COOH)2 X
i, Alk. KMnO4
X = Cl, F Cl
Cl
i Cl
ii
F O
O
[22, 23]
i, SbF3.SbCl5.
O(CF2COOH)2
[24]
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
CF3
O O
OH
[28]
i
O
O
i, CF3COOH
Contd
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239
Table 8.3 Contd Reaction
Ref.
CF3COOH + C6H5COX
CF3COX + C6H5COOH
[29]
X = Cl, F
CF3COONa + POCl3
i
[30]
90%
CF3COCl
i, 100 C, 24 h CF3COOH + P2O5
[27]
(CF3CO)2O i
CF3COOC2H5 + NH3
[31]
99%
CF3CONH2 i, (C2H5)2O, 0 C
i
C2F5CONH2
C2F5Br
[32] i, Br2, NaOH i CF3COOC2H5 + NH3
99%
CF3CONH2
[33]
i, (C2H5)2O, 0 C i CF3COOC4H9 + LiAlH4
76%
CF3CH2OH
[34]
i, (C2H5)2O, Reflux i CF3COCl
CF3COCHN2
ii
CF3CH2COOC2H5
62%
40%
[35]
i, CH2N2, 0−20 C; ii, Ag2O, C2H5OH i CF3CONH2
CF3CN
74%
[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).
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240
Chapter 8
CF2=CF2
SO3
F2C
CF2
O
SO2
F FCOCF2SO2F
½37
F OCF2CF(CF3)OCF2CF2SO2F
HFPO
OCF2CF2SO2F
HFPO Na2CO3
FCO[CF(CF3)OCF2]2CF2SO2F
Heat CF2=CFOCF2CF(CF3)OCF2CF2SO2F
HFPO =
CF2
CF3CF
CF2=CF2
O
Co-polymer
Figure 8.1
(CF2)4(COONa)2
i
CF2=CF(CF2)2COONa
i, 460 C, 10
−2mm
ii
(CF2=CF-)2
ii, 160−450 C, 10−2mm
½38
61%
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]. CF3CO2Na
AgNO3
CF3CO2Ag
I2 Heat
CF3I
91%
½40
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
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives IF5/I2
CF2=CF2
CF2=CFCF3
IF5/I2
½45, 46
86%
½45, 46
99%
(CF3)2CFI i
CF2=CFCF3
F
C2F5I
241
(CF3)2CFI
61%
½47
(CF3)3CFI
61%
½48
i, KF, I2, CH3CN, 100 C CF2=C(CF3)2
F
i
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 CF3 COO 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 SN 1 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). RX
+
NaNHCOCF3
RNHCOCF3
e.g. RX = n-C8H17I,
NaBH4
RNH2
½51
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'
Figure 8.6
+
2 CF3COOH
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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].
(CF3CO)2O
+
H2O2
CF3COOH
CF3
C
δ− O
δ+ OH
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 electronwithdrawing 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 CF3CO2OH
C6F5NH2
F
C6F5NO2
i
F
243
½63
F
½64
S
S O
i, CF3COOH, H2O2
O
OH H3C
½66
CH3
H3C
CH3 CF3CO2OH
CH3
CH3
O
(CH3)6
CF3CO2OH/BF3
½66 (CH3)6
90%
Figure 8.9
B 1
Aldehydes and ketones 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. Hexafluoroacetone [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, CF3 CHO, has also been made on a commercial scale by analogous catalytic processes, starting with chloral, CCl3 CHO [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 FSO3 H=SbF5 mixture [8].
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244
Chapter 8
Table 8.4 Syntheses of perfluorinated aldehydes and ketones Reaction
Ref. i
CF3CHBrCl
CF3CHO
[73]
ii, H2O
i, Oleum, HgO, reflux; i, ii
CF3Br
ii
(CF3CHSO3)
ca. quant.
CF3CH(OCOCH3)2
[74] i, Electrochem. Red'n, DMF, Bu4NBr, Al anode, Lewis acid or Me3SiCl (trace). ii, (CH3CO)2O, HCl, Pyridine i, ii
iii
RF(CF2)nCH(OH)2
RF(CF2)nCOOH
i, LiAlH4; ii, H2SO4; iii, P2O5
[75]
n = 0, 1, 2 F
i
RF(CH2)nCH2OH
CF3(CF2)nCHO
CHO
RF(CH2)nCHO R'F
H
[76]
i, Swern Oxidation or Pyridinium Chlorochromate RF = C4F9, R'F = C3F7, n = 1−4 i
CF2=CFCF3
FCO(CF2)3COF
(CF3)2CFCO(CF2)3COCF(CF3)2 75% Conversion
i, CH3CN, KHF2, 120−125 C SbF5
CF3CF2CF=C(OMe)CF3
[77]
CF3CF=CFCOCF3
[78]
i, ii FCO(CF2)nCOF
CF3CO(CF2)nCOCF3
Me3SiCF3
n = 2,3
[79]
(ca. 90%)
i, KF; ii, Heat, Vacuum
(C2H5O)2CO
(n-C3F7)2C(OH)2
P2O5
(n-C3F7)2CO
[80]
88% CF3CCl=CClCF3
i
CF3COCOCF3 31%
[81]
i, CrO3, fum. H2SO4, 60−70C, 1.5 h
Contd
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
245
Table 8.4 Contd Reaction
Ref.
F3C
F
F
F
Cr2O3 or Al2O3
[82, 83]
(CF3)2CO
O i
O
F
F
O
[84] i, CsF, Pt, 150−300 C, 1.5h, 300 C, 2h OCH3 CF2=CF2
CF2=CFOCH3
175 C
F
H2SO4
[85]
OH
O
P2O5
OH
F
F
Heat F
OCH3
F OCH3
(CF2)n
CoF3
(CF2)n
OCH3 (CF2)n F
F
F
F
[86, 87]
H2SO4 O
OH P2O5
OH (CF2)n
(CF2)n
F
F F
F
CF2=C(CF3)2
P2O5
H2O
(CF3)2CHCOOH
THF
(CF3)2C=C=O
[88]
77% OH RF
C
OH CF=CF2
Br2
RF
H
C
CFBrCF2Br
H Na2Cr2O7.2H2O H2SO4 Zn/Dioxane
RFCOCFBrCF2Br
[89]
RFCOCF=CF2 RF = CF3; C2F5
Contd
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246
Chapter 8
Table 8.4 Contd Reaction F F
C
Ref. O C
F C F3C OH
O
CF2
i
Na
CF2HCOCF3
C OH
F3C
[90]
45%
i, Nitrobenzene, 200 C i, ii
C6F13(CH2)2I
RFCO(CH2)2C6F13
i, t-BuLi, −78 C ii, RFCO2Et, −78 C
RFCOCl + (i-Pr)3SiH
[91]
RF = CF3 (89%) RF = C7F15 (68%) i
RFCHO + (i-Pr)3SiCl
i, Pd/C, 25 to 30 C
RF = C7F15 RF = n-C3F7
[92]
90% 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 CH3
i X
CO
CH2CH3
ii X
X Et2BO
Re
i, Et2BOTf, i-Pr2NEt, −5 C, 30min. ii, (CF3)2CO, −78 to 5 C
CF3 OH
O
½101
CF3
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]
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
247
C(CF3)2 Y
X = O, S, NR2
½95, 96
Y = N, CH R1
X 8.11A C(CF3)2
C(CF3)2OH NH2
HN
i
e.g. (CF3)2CO R1
NR2
R1
N R1
NR2
NR2 80−90%
i, POCl3, Pyridine F3C CN
i
N
(CF3)2CO R1
CF3
NH
O
R1
NH 75−84%
i, Et2O, −30C - room temp.
R1 = 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
C(CF3)2 N C R1
NR2
½95, 96
NR2
N
i
NR3
CF3
NR3
R1 77−93%
i, Toluene, 50−70 C, 24−36 hr.
Figure 8.12 F3C N
N
R
F 1
X
R
½95
N
−F
SnCl2 1
F3C
C=CF2
C(CF3)2
X
R1
X SnCl2F2
X = O, S, NR2
Figure 8.13
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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 F3C
O 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 (CF3)2C=NPh + H2NNHCONH2
(CF3)2C
½103, 104
NHPh
∆ 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). OH
RF MOH
+
(RF)2CO
C RF OM
RFCOOM
+
RFH
½105
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 CF3 OOH [93, 107]. Reaction of CF3 COCH3 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 K2 SO4 ) with CF3 COC6 H13 , in aqueous ðCF3 Þ2 CHOH as solvent, has been developed [91]. Oxonet
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
249
in combination with ðCF3 Þ2 CO 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.
CF3COCH3
+
H2O2
F3C
CH3
O
O
O
O
½108
CH3
F3C
Figure 8.17
O
F3C CF3COCF3
C F3C
Oxidation reactions
½110
O
Figure 8.18
CF3COCF3
CF3COCF3
H2O
H2O2
(CF3)2C(OH)2
(CF3)2C(OH)OOH
½112
½106, 107
∆ CF3COOH
CF3COCF3
H2S
(CF3)2C(OH)SH
½113
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].
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250
Chapter 8 OH i
CF3COCF3
C(CF3)2
HO
OH
½93
i, BF3, or HF
Figure 8.20 (CF3)2C=CHCOCH3
CF3COCF3 + (C6H5)3P=CHCOCH3
½114
Figure 8.21
Some unusual reactions can occur between fluorinated ketones and trialkylphosphines [117] or trialkylphosphites [118] (Figure 8.22). C6H5 C6H5COCF3
+
(n-C4H9)3P
H C
F3C
(C2F5)2CO
+
½117
C (CH2)2CH3
C2F5C(OC2H5)=CFCF3
P(OC2H5)3
+
½118
FPO(C2H5)2
Figure 8.22
Uncatalysed reactions with alkenes or alkynes will occur and cycloaddition products may be obtained (Figure 8.23). (C2F5)2CO + CH2=C(CH3)C(CH3)=CH2
100−200 C
C2F5
H3C O
C2F5
½119
H3C
CH2
O F
CH2=CH
CH=CH2
F
CH=CH2
½85
OH
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]. Remarkably, 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.
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives hν (CF3)2CO
+
½120
(CF3)2CHOSiCl3
CCl3SiH
251
C(CF3)2OH
OC(CF3)2H
½121
hν
(CF3)2CO
C(CF3)2OH C(CF3)2OH
(CF3)2CO
+
(CH3)2CHOH
hν
(CF3)2COH
(CF3)2CHOH
½93 2
Figure 8.24
2 CF2=C(OH)CF3
Base CF2
8.25A
C
½122
CF3
O 8.25C
Slow
8.25B
8.25C CF2HCOCF3
CF3COCF2C(CF3)(CF2H)OH
Fast
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 F
F
OH F
½123
Stable in THF
Figure 8.26
Reactions with fluoride ion: With the exception of CF3 OH (see the next section), fluorinated alcohols of the type RF CF2 OH are not known [124] but complexes of K, Rb, Cs, Ag or ðC2 H5 Þ4 Nþ 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].
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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 CF3 O 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). COF2
+
−
+
(Me2N)3S Me3SiF2
THF −75 C
−
CF3O
(Me2N)3S
+
½129
8.28A
'TAS' fluoride
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).
−
(CF3)2C=O
(CF3)2CF
F
N
½130
−
O
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]. (CF3)2CO
+
CH2=CHCH2Br
i
CH2=CHCH2OCF(CF3)2
½131, 132
i, CsF, Diglyme, 55 C, 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 consequently undergo competing side-reactions. Perfluoro-esters RF CO2 R1F have been made [133] in reactions using ðRF Þ2 CFOM 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 RF O will be quite a good leaving group in a nucleophilic displacement process (Figure 8.32).
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives (CF3)2CO + MF
RFCOF
−
RFCO2CF(CF3)2 + F
253
½133
−78 C
Figure 8.32
Likewise, perfluoroalkoxytriazines may be isolated at low temperatures [134] (Figure 8.33). RF
N (CF3)2CO
N
RF
N
½134
KF
Cl
N
N
N RF
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 ðCF3 Þ2 COCsF 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, RF OI (Figure 8.35). −
CF2=CF2 + F
+ (CF3)2CO
−
½135
(CF3)2CFO
CF3CF2
(CF3)2CO
−
CF3CF2C(CF3)2O 8.34A
CF2=CF2
(CF3)2CFOCF2CF2
etc
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 ðCF3 Þ3 COH 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).
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Chapter 8
CO
i, ii
iii
CF3OF
i, ii
CF3CF2CF2OF
CF3OCFClCF2Cl
∆
CF3CF2CF=O
½137
CF3OCF=CF2
iii C3F7OCF=CF2
C3F7OCFClCF2Cl
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 CF3CF
CF2
F
F2
CF3CF2CF2OF
F
½137
Figure 8.38
The chemistry of fluorinated 1,3-diketones has been reviewed [138].
C Perfluoro-alcohols 1 Monohydric alcohols The 2CF2 OH system is thermodynamically unstable, by an estimated 80160 kJmol1 , 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). CF3OCl + HCl
Figure 8.39
−120 C
CF3OH + Cl2
½139
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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 RF CH2 OH are, however, quite stable and are extremely useful solvents [141] because of their high polarity [142]. OH
O HX
½140
X X = F, Cl, Br, I
Figure 8.40
Perfluoro-t-alcohols are quite stable and are very strongly acidic; for example, compare ðCF3 Þ3 OH and ðCH3 Þ3 OH 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 (CF3)2CO
ii
CF3COF + (CF3)3COCs
(CF3)3COH 34%
i, CsF, 150 C, Diglyme.
½145
ii, H2SO4
Figure 8.41
(CF3)2CO
CsF CF3
δ+ δ − Cs O
O
CF
C
CF3
δ+ Cs CF3
CF3
O
δ− O
CF
C(CF3)3
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, ðRF Þ2 CðOHÞ2 , 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].
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256
Chapter 8
i, ii
CCl3Li + (CF3)2CO
iii
(CF3)2C(CCl3)OH
(CF3)3OH
50%
60%
½146
i, THF, −100C ii, H2SO4 iii, SbF5
i
CF3CH2Cl + H2O
CF3CH2OH
½147
i, 400−500C, Catalyst
hν
CH3OH + CF2=CF2
HCF2CH2OH
½148
O (CF3)2C
CH2
HX
XCH2C(CF3)2OH
½149
X = FSO2O, CF3SO2O, Cl, I
Figure 8.43a i
CF3CH2OTs
OTs
OTs
ii
CF2=C
CF2=C
Li i, n-BuLi ii, R3B iii, CuI, HMPA
½150
Li BR3 1,2 shift
OTs CF2=C
R
iii
CF2=C BR2
Cu
i, ii
F
OMEM
CF3CH2OMEM F
iii
F
OMEM
F OH
O
MEM = CH2OCH2CH2OCH3
F F O
OMEM
OMEM F O
i, LDA, THF, −78 C; ii, EtCHO; iii, Hg(OAc)2, Ethyl vinyl ether, reflux
Figure 8.43b
½151
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives (CH3)2CO + (CF3)2C(OH)C(OH)CF3)2
i (CF3)2CO
257
½112 iv
ii CF3
F3C CF3
CF3 O
CF3
F3C iii
CF3
O
O
P
i, ii, iii, iv,
CF3
½153
P
OEt OEt
EtO
O
OH
HO OH
8.44A
(CH3)2CHOH/hν P(OC2H5)3 H2SO4 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 CF3CF=CF2 i, γ rays, rt
OH
i 83% RFH
HO 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. F
+
RFR1FCO
F
+
RFCOF
F
+ RFFC
RFR1FCFO RFCF2O
O
O CFR1F
RFCF2CFR1F
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
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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 F2C CF2
F
CF3COF
[CF3CF2O ]
C2F5O(CF2CF2O)nCF2COF
½155
(R4NF)
CF2CF2
F
[CF3CF2]
(CF3)2CO
CF3 CF3CF2C
½155, 156 O
CF3 HFPO
CF3CF2C(CF3)2OCF(CF3)COF
O
[CF3CF2C(CF3)2OCF(CF3)CF2O]
i
F3CFC CF2 HFPO
(CF3CF2CF2O)
i, MF, Tetraglyme
−F
½158
CF3CF2COF
HFPO
CF3CF2CF2O[CF(CF3)CF2O]nCF(CF3)COF n = 1−4
Figure 8.47
D Fluoroxy compounds [137] An interesting series of compounds RF OF [160, 161] has been synthesised and found to be reasonably stable; for example, the O2F bond energy in CF3 OF 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 CF3 OF 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 i
CO + F2
F2
(COF2)
259
½165, 166
CF3COF
i, Cu Tube, 350 C
CsF
(CF3)2CO + F2
CsF
CO2 + F2
(CF3)3OH
CH3OH
CF2(OF)2
−78 C
+
+
(CF3)2CFOF
−78 C
−20 C
F2
F2
½167
98%
99%
½168
½169
(CF3)3COF
i
ii [CH3OF]
½170
CF3CFClOCH3
i, CH3CH2CN, −40 C, 1hr ii, CF2=CFCl, −75 C to rt
Figure 8.48
CF2(OF)2
−184 C
CF4
+
O2
∆H0 = −360 kJ mol−1
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 RF OF 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 CF3 OF 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
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260
Chapter 8 i FSO2CF2COF
i, ii
−
FSO2CF2CF2O
FSO2CF2CF2OF
½137
iii FSO2CF2CF2OCF=CF2 i, CsF;
FSO2CF2CF2OCFClCF2Cl
ii, F2; iii, CFCl=CFCl
Figure 8.51
CF3OF + SO3
CF3OF + CO
½165
CF3OOSO2F + SO2FOOSO2F hν
CF3OCOF
½174
86%
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]. CF3CF=CF2
i
F
O F
CF3
½178
25%
F
i, KOH, H2O/CH3OH, 30%H2O2, −78 C
Figure 8.53
CF2=CF2 + O2 (containing O3)
F
O
F F
F 46%
+
CF2CF2O
n
½181
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-chloroperbenzoic acid (mCPBA) or iodobenzene has been reported and is effective with alkenes having perfluoroalkyl groups attached to the double bond [187] (Figure 8.57).
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
261
Cl CF3CF2
CF3
F3C
O
CF3CF2
OCl
CF2CF3
½158, 182184
CF3
F3C
CF2CF3
Z+E
O
CF3CF2
CF3
F3C
74%
CF2CF3 Z : E = 1:1
F3C
CF3
F3C F
O
F3C i
O
F
F
CF3
F3C
CF3
F3C
CF3 O
O
F3C
CF3
F
O
F
F3C
O
CF3
F
F
F
i, t-BuOOLi, THF, −78 C to rt
½186
CF3
O
F3C
CF3
Figure 8.55 CF3
F
CF3
F3C
O
F
CF3 CF3
i
8.56A
F3C F3C
F
F3C
½186
F
O ii
CF3
F3C i, t-BuOOLi, THF, −78 C to rt ii, Sealed tube, 220 C, 19 days
O F3C
O
F F
8.56B
CF3 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 2CF2 O
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262
Chapter 8 CF3
F
½187
O m-ClC6H4CO3H
Me3N
RF
RF
CF3
F
m-ClC6H4CO2H
Me3N-O
RF
RF RF
= CF(CF3)2
Figure 8.57 O
F3C
O
Nuc
F
F −F
½156, 158
RFCFCF2O
RFCFCF2Nuc F
−
−
−F
RFCFCOF
RFCOCF2Nuc
Nuc
8.58A
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 > 2CF2 2 > 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-molecularweight 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 i
CF2=CF2 + (CH2O)n
F
F
½188
F H H
O
ii
F
CF2CF2CF2O
n
i, HF ii, e.g. CsF iii, F2, 100−120 C
Figure 8.59
F
iii
F
CH2CF2CF2O
n-1
CH2CF2COF
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
263
Examples of other ring-opening reactions are illustrated in Figure 8.60. O
F
F
F
i
−
+
F
−
−
CF3COF + F
[CF3CF2O]
½179
F i, KF, 80 C, 4hr
F3C
O
F
F
i
½189
97%
(CF3)2CFCOF
F i, (CH3)3N, 100 C, 30hr (CH3)3N
−
F −
(CF3)2CCOF
CF3CFCF2O
+ N(CH3)3
+ N(CH3)3
CH3OH
+
O
F3C
F
½178
[CF3CF(OCH3)COF]
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). F3C F
O
F +
C4H9Li
[CF3C(O)CF2C4H9]
½156
F i, BuLi, ii, H+
i, ii 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
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264
Chapter 8 H F3C
+ (CF3)2CCF2OH
O
+ F
F3C
+ (CF3)2C(OH)CF2
½190
F
8.63B
8.62A
H F3C
O
+ F
250 C +
F3C
(CF3)3COH
HF 64hr
F
Figure 8.62
O
i F
F
O
½191
i, Al2O3, 150−300 C
O
C5F11
F
i C5F11CO.CF3
F
½192
F i, SbF5, 150 C, 18hr
Figure 8.63
Acid
Acid
O
O C
F
C 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 AgF2
2 CO + 3 F2 2 (CF3)3COH
+
C3F7COCl
t-BuOOH
+
½194
CF3OOCF3
ClF3
+
(CF3)2C(OLi)2
CsF
½194
(CF3)3COOC(CF3)3
½194
C3F7C(O)OOt-Bu O
FC(O)OF
CF2
O
F
O
F
O
F
F3C
O
F3C
O
+ F2
265
½195
½196
Figure 8.65
13COF 2
F
O
13
CF3O
O
F
13CF OOC(O)F 3
½197
F A −F
13CF OOCF O 3 2
nA
13CF O(OCF O) OC(O)F 3 2 n
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
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266
Chapter 8
CH3SO2Cl
Eletrochemical Fluorination
CF3SO2OH
CF3SO2F
87%
½203
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 ðH0 Þ: CF3 SO2 OH (13.8); FSO3 H (15.1); FSO3 H=20%SbF5 , ‘Magic Acid’ (20); and H2 SO4 (11.1). Furthermore, the extreme electron-withdrawing capacity of the CF3 SO2 group [5, 209] is such that ðCF3 SO2 Þ2 NH is the most acidic amide known [4] and it leads to systems with remarkable C2H acidity, e.g. ðCF3 SO2 Þ2 2CH2 ðpKa ¼ 1Þ is more acidic than CF3 CO2 HðpKa ¼ 0:52Þ. Consequently, perfluoroalkanesulphonic acids are outstanding Friedel–Crafts catalysts [208, 210]. Moreover, 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 X
OCH2CF3 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-C4 F9 SO2 F [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
C4F9SO2F
45%
S O
O
Ph(CH2)3OH
i,
HF, E.C.F. ii
Ph(CH2)3F ii, n-C4F9SO2F
Figure 8.70
½213
79%
½212
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
i
Me3SiCH2Li
ii
CH2(SO2CF3)2
[(CF3SO2)3CLi]
267
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 (CF3SO2)2O
i
Nuc-CF3
CF3SO2OCF3
½216
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). (C2H5)2OH(CF3SO3)
CF3SO2OH + (C2H5)2O 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
∆
CF3
(CH3)3CN=O
RFSO2Cl +
O (CH3)3C
i
CF3
Cl SO2
i, hν, or peroxides
Figure 8.75
RF
N
½220
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268
Chapter 8
Trifluoromethyl radicals may also be generated by electrolysis of salts of trifluoromethanesulphinic acid [222] (Figure 8.76). −1e CF3SO2
K
CF3SO2
½222
+ SO2
CF3
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 illfamed 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 CF2=CF2
F
F
+ SO3
F
F
½223
CO2H
½223
F
F
F O
SO2
F
F
F
1, NaOH
F2C
F i
i, F , (C2H5)3N
F
F
F
SO2
Figure 8.77
SO2OH
2, Ion Exchange
F O
61%
SO2
O
O F
CO.FCF2SO2F
SO2 N(C2H5)3
F
(C2H5)3N
½37, 223, 224
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives FCOCF2SO2F + F
½37
OCF2CF2SO2F
CF3 O F
269
i
i,
F F ii, ∆, Na2CO3
FCOCF(CF3)OCF2CF(CF3)OCF2CF2SO2F
iii, CF2=CF2 iv, Hydrolysis
ii
CF2=CFOCF2CF(CF3)OCF2CF2SO2F iii Co-polymer
iv
Membrane
Figure 8.78 R
R
+
i n-BuONO2
15-98% NO2
i, Nafion H
C6H6
+
CH2=CH2
½225
½226
i C6H5C2H5
i, Nafion H
i RSO3H
½227
RSO2Ar
+ ArH
30-82%
R = alkyl or aryl 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). CF2=CF2
+
NaHSO3
120 C
CF3CF=CF2 + NaHSO3 i, (C6H5COO)2, 120 C
Figure 8.80
i
CHF2CF2SO3Na
CF3CFHCF2SO3Na
½228
64%
½229
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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. 243 C Sx + (CF3)2CFI
[(CF3)2CF]2S
11%
+ [(CF3)2CF]2S3
+
[(CF3)2CF]2S2
34%
½231
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). CF3SSH
+
CF3SCl
120 C
½232
CF3SSSCF3
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 Sx +
CF2=CF2
N2 445 C
S
S F
F S
S
S
S
10%
44% 300 C
½234
10hr S 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 Sx
+
CF2=CF2
+ I2
F
F
S
S
½236
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
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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). CS2
IF5
(CF3)2S2
195 C
(CF3)2S3
76% i
(CF3)2S2
CSCl2
½239
7%
+
½240
CS2
37% i, NaF, Sulpholan, 245 C
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
CH3SCH3
SbF5
CCl3SCH3
½242
CF3SCH3
Figure 8.86
Base-induced [243] addition of thiols to fluoroalkenes yields polyfluoroalkyl sulphides, which have also been further fluorinated (Figure 8.87). CH3SH + CF2=CFCl
i
ii
CH3SCF2CFClH
CH3SCF=CFCl
½243
90% i, NaOCH3, 5−70 C ii, (CH3)2SO, KOH
Cl2
iii, SbF3/SbF5
iii
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 Sulpholan
CCl3SCl
PhMgBr
+
PhN(CH3)2
Figure 8.88
CF3SCl
CF3SCl
CF3SCl
Et2O
½240 PhSCF3
½244
52%
p-CF3SC6H4N(CH3)2
58%
½245
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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 (CH3)2S
Fluorination
CoF3
CH3SH
250−275C F2/N2
CS2
48C
CF3SF5 + (CF3)2SF4
½247
CF3SF5
CF3SF5
½246
CF3SF3
etc.
½248
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 perfluoroalkanesulphonyl fluorides [250] (Figure 8.91). CF3CF=CF2
+ SF4
CsF 100C
(CF3)2CFSF3 + [(CF3)2CF]2SF2
½249
Figure 8.90
CF2=CF2 + SO2F2
CsF
(C2F5)2SO2
83%
½250
100C
CF3CF=CF2
+ SO2F2
CsF Diglyme, 100C
(CF3)2CFSO2F etc
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 SF5 Br 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
CF3SRF
+
−78 C
ClF
CF3SF2RF
+
273
½251
Cl2
RF = CF3, C2F5, n-C3F7
F2, −196 C
(CF3)2S
C2F6
½255
(CF3)2SO
(CF3)2SF2
i, ii, iii
Ar2S2
ArSF5 i, F2/N2(1:9 v/v), MeCN, −5 C
Ar =
½252254
ii, F2, CH3CN, Micro-reactor
NO2 F
iii, AgF2, CF2ClCFCl2, 60−130 C, Cu
Ar = NO2
Figure 8.92
SF5Br
+
CF2=CFPh
hν SF5CF2CFBrPh
AgBF4
SF5CF2CF2Ph
½256
Figure 8.93
Cl
S
Cl
Cl
S
Cl
i
F
S
F
F
S
F
8.94A
ii
2 CF2=S
½233
8.94B i, SbF3/90 C ii, 457−500 C
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). (CF3)2CFHgCF(CF3)2 + S
445 C
(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
½258
(C2F5)CF3C=S
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). 2(CF3)2CS
Base
F3C
S
CF3
600 C
F3C
S
CF3
½258
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). CF3CF=CF2
F3C F3C
SO2
−
+
−
F
(CF3)2CF
CF3
i
S
CF3
F3C
S
CF3
−
½259, 260
(CF3)2CFS
(CF3)2C=S
CF3
S
F3C
Sx
i, Quinuclidine
(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
S
i (CF3)2C
EtOOC
COOEt
C(CF3)2
70%
½261
S 750 C/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 F3C
S
CF3
S
F3C
S
CF3
CF3
S
S
CH2=CH2
Ni S
F3C
275
½262
Ni S
F3C
S
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, CF3 NH2 has been characterised when generated at low temperatures [139] (Figure 8.101). CF3NCl2 + HCl
Base
CF3NH2.HCl
½139
CF3NH2
Figure 8.101
Ammonia reacts readily with fluoroalkenes (see Chapter 7) but amines are not isolated from these reactions [230] (Figure 8.102) CF2=CF2
+
−2HF
HCF2CF2NH2
NH3
½230
HCF2CN
R
R
N N
N
R = CF2H R
Figure 8.102
Addition of hydrogen fluoride [263, 264] to the imine CF3 N5CF2 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
i
(CF3)2NH
(CF3)2N NO2
i, HNO3, (CF3CO)2O
Figure 8.103
½263, 264 ½264
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, perfluorot-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)3CNHOH
(CF3)3CNO
(CF3)3CNH2
½269
i, H2/Pd black; ii, HI, Red P
Figure 8.104
i
(CF3)3COH
(CF3)3CNH2
+
(CF3)3CNO
½270
i, HNO2, 0 C
Figure 8.105
Fluoroalkylbenzylamines are obtained by the Lewis-acid-catalysed reactions of fluoroalkylimines with aromatic compounds [270], and reactions also occur with alkenes [270, 271] (Figure 8.106). (CF3)2C=NH
+
i
CH3OC6H5
C(CF3)2NH2
CH3O
½270
i, AlCl3, 150C (CF3)2C=NH
+
i
CH2=CHCH3
CH2=CHCH2C(CF3)2NH2
½270
i, AlCl3, 100 C H (CF3)2C=NH
+
CH2=CHCH=CH2
i, ii
N
CF3
½271
CF3
i, 100C, 13hr; ii, 150 C, 6hr
Figure 8.106
The fluoroalkylbenzylamines are characterised by their particular inertness [270], being devoid of the tendency towards oxidative decomposition that is generally characteristic of amines. In fact, oxidation of methyl will occur in preference to that of an amino group in these systems (Figure 8.107). H3C
i C(CF3)2NH2 i, Na2Cr2O7, H2SO4
Figure 8.107
HOOC
C(CF3)2NH2
½270
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
277
Perfluoro tertiary amines ðRF Þ3 N 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 ðCF3 CF2 Þ3 N have suggested susceptibility to attack at the CF2 positions by electrophiles [274].
B 1
N–O compounds 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
+
(CF3CO)2O
NO
+
CF3NO
N2O3
½276
80%
CF3COONO
½277, 278
92%
190 C 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 CF3
CF3NO CF3
CF3NO
(CF3)2NO
½276
NO
(CF3)2NO (CF3)2NONO
CF3NO
+ 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 CF3NO + CF2=CF2
Figure 8.110
N
O F
CF2CF2N(CF3)O
n
½280
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 278
278
Chapter 8
2 Bistrifluoromethyl nitroxide Bistrifluoromethyl nitroxide, ðCF3 Þ2 NO, 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]. hν
CF3NO
(CF3)2NONO
HCl, H2O
(CF3)2NOH
AgO
(CF3)2NO
½284
Quantitative
Figure 8.111
A range of products containing ðCF3 Þ2 NO groups may be obtained by addition to unsaturated compounds [286–289] (Figure 8.112). (CF3)2NO
i
CF2=CFCF3
+
(CF3)2NOCF2CF(CF3)ON(CF3)2
½287
i, 15 min., rt i (CF3)2NO
+
F
C6F6-n[ON(CF3)2]n
i, Sealed tube, 150 C, 1−4hr
½288
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.
F 3C N O
i
F
CF3N=CF2
[280]
i, Si tube, 550 C, 5mm i
(CF3)2NCOF
CF3N=CF2
96%
[290]
i, Ni tube, 576 C
(C2H5)2NH
i
(C2F5)2NF
ii
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
i, AlCl3, 65−100C; ii, KF, Sulpholan
82%
ii
[292]
(CF3)2C=NCF3 + (CF3)2CFN=CF2 70 : 30 92% total i
F
F N
F
N
N
i
[293]
CF3
i, Mild Steel, 400−600C
CF3CHFCF2N3
CF3CF2CF2CF=NCF3
F
CF3CHFN=CF2
CF3CH=NCF3
[294, 295]
i, Pt, 270−280 C i
CBr2=NN=CBr2
CF3N=NCF3
92%
i, AgF2, 100 C 70 C
AgF
[296] i
CF2=NN=CFBr
CF2=NN=CF2
33% overall
i, AgF, 125C CCl2N=CCl2
HF
CF2NHCF3
2
NaF, 50C 2
CF=NCF3
[297] 2
N
N i
F
F
[298]
N
N i, CoF3.CaF2, 80C
F
N
i
F
N
N
+F
F
N
N
N
i, CoF3.CaF2, 175 C
F N
N
N
[298] + F2
F
F
N
N
RF
N
F N
RF
RF F
N
N
N
i
N
i, CoF3.CaF2, 172 C
F RF
83%
N RF = CF(CF3)2
[299] Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 280
280
Chapter 8
Table 8.5 Contd Reaction
Ref. [300]
i
CF3CCl=NN=CClCF3
CF3CONHNHCOCF3
i, PhNMe2.HCl, POCl3 CF2=CFCF3 +
[301]
CF3CHFCF2N3 + CF3CF=CFN3 25%
−
Distil
i, Et4N N3 , −5 C F3C
F3C
F
F
F
N <5%
F N 25%
Polyfluoroaza-alkenes are even more susceptible to nucleophilic attack than polyfluoroalkenes. Hydrolysis of CF2 5NCF3 occurs readily giving the isocyanate [302, 303], and a variety of reactions with nucleophiles have been recorded (Figure 8.113). i
CF3N=CF2
CF3NCO
½302
50%
i, H2O, 20 C, 24hr CF3N=CF2
+
CH2=CHCH2OH
i
CF3NHCO2CH2CH=CH2
52%
½304
i, aq KF, Et2O CF3N=CF2
+
CH2=CHCH2OH
Et3N
CF3N=C(OCH2CH=CH2)2
½304
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. ½124, 305 (CF3)2NCF=NCF3 i F
CF3N=CF2
(CF3)2N ii
CF3N=CF2
(CF3)2COF
i, ii,
CF3N=CF2; CsF, COF2, 100−150 C, 2hr
+
HgF2
100 C, 15hr
[(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 F3C CF3N=CF2
F
i
F3C N
N
F
ii
F
2
CF3N
281
F
F
½306
N
CF3N
F
CF=NCF3
CF3
F
−F
i, CsF, Sulpholan, −23 C ii, CF3N=CFCF=NCF3
CF3 F
CF=NCF3 94% F
N
F N
CF3
CF3N
RF
RF
RF
i
i
F
F
N
N
N
Cs
8.114B
8.114A ii
iii
½307
F
RF = (CF3)2CF
RF 8.114A F N
+ 8.114B
Ratio 4:1
i, CsF, Sulpholan; ii, CH3I; 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 ðCF3 Þ2 N 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
F
F
N
N
N
N
N
½308
F N
N
F
F
N
8.115A
2 F
1
2
F
N F N N
N F N
F
N N
N
i
F
F
i,
1
CsF, 150 C, 16hr
F
F3C
F
N F
N
N CF3
F
N N
F
N
N
N F 8.115 B
F
Figure 8.115
CF3N=CF2
+
CF3OOH
O
CF3NHCF2OOCF3 N
F3C
F
½310
F
+ COF2 BrCF2CF2N=CFCF3
O
i BrCF2CF2
O
CF3
N
CF3CF2
F 55
:
CF3
N
½310
F 45
i, m-CPBA, Sulpholan, 22 C O N RF
F RF RF = n-C4F9
Figure 8.116
R1SR2
R1SOR2
+
RFN=CFRF
½310
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 283
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
F3C CF3N=CF2
CF3 N
2hr, 20 C
+ SbF5
283
N
(CF3)2NCF=NCF3
F
½311
N
8.117A
CF3 (CF3)2NCF2N=CFN(CF3)2
F3C
F
CF3 N
N
CF3 N
i
F
F
F3C N
−
8.117B
− CF4, −F
N
F
CF3
N
i, SbF5
CF3
F3C N
N
N
i
F
CFN(CF3)2
(CF3)2NCF
−2CF4
N
i, SbF5, SO2 CF3
CF3 N
N
CF2
F2C
C F2
F2C
N
CF3
CF3N=CF2 CF3
CF3 N
N C F2
N C F
CF3N=CF2
N
½312
8.117C
CF3
F2C
½312
F
F2C
CF2
N C
CF3
F CF3 N F2C
N C
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 CF3CN i,
C2F5N=NC2F5
90%
AgF2, Ambient Temp. i
205 C
C2F5CF2NCl2
C2F5CN
i, ClF, −78 to −0 C
CF2(CN)2
½313
ClF
C3F7N=NC3F7
½314
85%
Cl2NCF2CF2CF2NCl2
200−250 C
½314
F N
N
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). CF3N=NCF3 2CF3
hν
2CF3
+ N2
½315
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 F2Cðsp3 Þ bonds, rather than F2Cðsp2 Þ, thus making the diazirine structure thermodynamically preferred, although calculations have suggested that the diazomethane structure is slightly preferred for CF2 N2 [317]. X
X C
N
N
C
Y
Y Diazoalkane
Figure 8.120
N
X
N
Y
N
N
Diazirine
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). (CF3)2CO
+
i
NH3
(CF3)2C=NH
½103
70%
i, Pyridine, −25 to −30C (CF3)2C=NH
+
NH2NH2
i
(CF3)2C=NNH2
68%
½103
i, P2O5, 0 C i
(CF3)2C=NNH2
(CF3)2CN2
½318
77%
i, Pb(OAc)4, C6H5CN, 0 C
Figure 8.121
Diazotisation of hexafluoroisopropylamine has also been achieved [319] (Figure 8.122). CF3CF=CF2
ii
i
(CF3)2CHNH2
(CF3)2CFNO2
75%
½319
i, HF/HNO3; ii, H2, Pd, 70 C, 100atm (CF3)2CN2
(CF3)2CHNH2.HCl
½319
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 of the subsequent reactions have been formulated as reactions of the carbenes F2 C : and CF3 Þ2 C : , 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 (CF3)2CN2 + CH2=CHCN
60 C
F3C
½318
N
F 3C
N
CN F3C
N
F3C
N H
(Quant.) CH3
H3C (CF3)2CN2 + CH3C
150 C
CCH3
F3C
½318
N
F3C
N
H3C
CH3
400 C F3C
CF3 56%
Figure 8.124
i
F
N
F
N
CF2(NF2)2
½321
i, (C5H5)2Fe, (C2H5)4NCl (or I)
i
F2NCN
H2NCN(H2O)
20%
½322
i, F2, He, Buffered, 5−9 C
CsF/24 C
F
N
F
N
F2NCN F
½322 F
N
N
F N F
Figure 8.125
F F
N F
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 287
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives i
F
N
F
N
(CF3)2C(NH2)2
287
78%
½323
i, NaOCl, NaOH, 40−60 C
Figure 8.126
REFERENCES 1 2 3 4 5 6 7 8 9 10
11 12 13 14 15 16 17 18 19 20 21 22 23
24 25 26 27 28 29
Houben-Weyl: Methods of Organic Chemistry, Vol. E10, Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999. M. Hudlicky, Chemistry of Organic Fluorine Compounds, 2nd revised edition, Ellis Horwood, Chichester, 1992. L.M. Yagupol’skii, A.Y. Il’chenko and N.V. Kondratenko, Russ. Chem. Rev., 1974, 43, 32. J. Foropoulous and D.D. DesMarteau, Inorg. Chem., 1984, 23, 3720. L.M. Yagupol’skii, J. Fluorine Chem., 1987, 36, 1. S.L. Bell, R.D. Chambers, W.K.R. Musgrave and J.G. Thorpe, J. Fluorine Chem., 1971/72, 1, 51. R.E. Banks and R.N. Haszeldine in The Chemistry of Organic Sulphur Compounds, ed. N. Karasch, Pergamon, Oxford, 1966, p. 137. G.A. Olah and C.U. Pittman, J. Am. Chem. Soc., 1966, 88, 3310. J.F. Liebman in Fluorine-containing Molecules, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH, Weinheim, 1988. 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. L.O. Brockway, J. Phys. Chem., 1937, 41, 185. S.K. Kim, J. Org. Chem., 1967, 32, 3673. H.M. Scholberg and H.G. Brice, US Pat. 2 717 871 (1955). W. Hirsch, Ger. Offen. 2 947 376 (1981); Chem. Abstr., 1981, 95, 42398c. Jap. Pat. 58 152 839 (1983); Chem. Abstr., 1984, 100, 51105d. I.M. Robinson, Eu., Pat. Appl. 112 714 (1984); Chem. Abstr., 1985, 102, 5704s. B.N. Hang, A. Haas and M. Lieb, J. Fluorine Chem., 1987, 36, 49. T. Takakura, M. Yamabe and M. Kato, Nippon Kagaku Kaishi, 1985, 2208; Chem. Abstr., 1987, 105, 171822k. K. Ichihara and H. Aoyama, Int. Pat. WO 99 62 859 (1999); Chem. Abstr., 2000, 132, 22694a. K. Ooharu and S. Kumai, Jap. Pat. 08 27 058 (1996); Chem. Abstr., 1996, 124, 316530t. B. Boutevin, Y. Pietrasanta, A. Rousseau and D. Bosc, J. Fluorine Chem., 1987, 37, 151. J. Burdon and J.C. Tatlow, J. Appl. Chem. (London), 1958, 8, 293. N. Lui and J. Fischer-Lui in Houben-Weyl: Methods of Organic Chemistry, Vol. E10b, Pt. 1, Organo-fluorine Compounds, ed. B. Baasner, H. Hegemann and J.C. Tatlow, Georg Thieme, Stuttgart, 1999, p. 691. N. Reeves, W.J. Feast and W.K.R. Musgrave, J. Chem. Soc., Chem. Commun., 1970, 67. A.M. Lovelace, W. Postelnek and D.A. Rausch, Aliphatic Fluorine Compounds, Reinhold, New York, 1958. R.E. Banks, Fluorocarbons and their Derivatives, Macdonald, London, 1970. F. Swarts, Bull. Acad. Roy. Belg., 1922, 8, 343. E. Pop, F. Soti and M.E. Brewster, Synth. Commun., 1995, 4099. G.A. Olah and A. Pavlath, Acta Chim. Acad. Sci. Hung., 1953, 3, 191.
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W.R. Brasen, H.N. Cripps, C.G. Bottomley, M.W. Farlow and C.K. Krespan, J. Org. Chem., 1965, 30, 4188. G.V.D. Tiers, J. Fluorine Chem., 1998, 90, 97. R.N. Haszeldine and J.M. Kidd, J. Chem. Soc., 1953, 3219. C.W. Tullock and D.D. Coffman, J. Org. Chem., 1960, 25, 2016. 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. W.E. Truce, G.H. Birum and E.T. McBee, J. Am. Chem. Soc., 1952, 74, 3594. R.D. Chambers and R.H. Mobbs, Adv. Fluorine Chem., 1965, 4, 50. W.A. Sheppard, J. Org. Chem., 1964, 29, 895. S. Andreades, J.F. Harris and W.A. Sheppard, J. Org. Chem., 1964, 29, 898. A.L. Clifford, H.K. El-Shamy, H.J. Emele´us and R.N. Haszeldine, J. Chem. Soc., 1953, 2372. G.A. Silvey and G.H. Cady, J. Am. Chem. Soc., 1950, 72, 3624. E.A. Tyczkowski and L.A. Bigelow, J. Am. Chem. Soc., 1953, 75, 3523. R.M. Rosenberg and E.L. Muetterties, Inorg. Chem., 1962, 1, 756. S. Temple, J. Org. Chem., 1968, 33, 34. D.T. Sauer and J.M. Shreeve, J. Chem. Soc., Chem. Commun., 1970, 1679. R.D. Bowden, P.J. Comina, M.P. Greenhall, A. Loveday and D. Philip, Tetrahedron, 2000, 56, 3399. R.D. Chambers and R.C.H. Spink, J. Chem. Soc,. Chem. Commun., 1999, 883. A.M. Sipyagin, C.P. Bateman, Y.-T. Tan and J.S. Thrasher, J. Fluorine Chem., 2001, 112, 287. E.W. Lawless, Inorg. Chem., 1970, 9, 2796. R.W. Winter, R. Dodean, J.A. Smith, R. Anilkumar, D.J. Burton and G.L. Gard, J. Fluorine Chem., 2003, 122, 251. W. Sundermeyer and W. Meize, Z. Anorg. Allg. Chem., 1962, 317, 334. W.J. Middleton, E.G. Howard and W.H. Sharkey, J. Org. Chem., 1965, 30, 1375. D.C. England, J. Org. Chem., 1981, 46, 153. U. Hartwig, H. Pritzkow, K. Rall and W. Sundermeyer, Angew. Chem., Int. Ed. Engl., 1989, 28, 221. M.S. Raasch, J. Org. Chem., 1970, 35, 3470. K. Wang and E.I. Stiefel, Science, 291, 106. D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 2532. J.A. Young, S.N. Tsoukalas and R.D. Dresdner, J. Am. Chem. Soc., 1958, 80, 3604. F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Chem. Eng. Data, 1965, 10, 398. R.E. Banks and G.J. Moore, J. Chem. Soc. (C), 1966, 2304. R.E. Banks, R.N. Haszeldine and R. Hatton, J. Chem. Soc. (C), 1967, 427. R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1964, 2485. I.L. Knunyants, B.L. Dyatkin and E.P. Mochalina, Bull. Acad. Sci. USSR, 1965, 1056. D.M. Gale and C.G. Krespan, J. Org. Chem., 1968, 33, 1002. Y.V. Zeifman, N.P. Gambaryan and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 1431. S. Nagasi, Fluorine Chem. Rev., 1967, 1, 77. F.G. Drakesmith in Organofluorine Chemistry. Techniques and Synthons, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 197. M. Gaensslen, U. Gross, H. Oberhammer and S. Rudiger, Angew. Chem., Int. Ed. Engl., 1992, 31, 1467. R.N. Haszeldine, J. Chem. Soc., 1953, 2075. A.H. Dinwoodie and R.N. Haszeldine, J. Chem. Soc., 1965, 1675. C.W. Taylor, T.J. Brice and R.L. Wear, J. Org. Chem., 1962, 27, 1064. R.E. Banks, M.G. Barlow, R.N. Haszeldine and M.K. McGrath, J. Chem. Soc. (C), 1966, 1350.
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294
279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319
Chapter 8
M.C. Henry, C.B. Griffis and E.C. Stump, Fluorine Chem. Rev., 1967, 1, 1. D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1955, 1881. J.M. Birchall, A.J. Bloom, R.N. Haszeldine and C.J. Willis, J. Chem. Soc., 1962, 3021. 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. R.N. Haszeldine and B.J.H. Mattinson, J. Chem. Soc., 1957, 1741. W.D. Blackley and R.R. Reinhard, J. Am. Chem. Soc., 1965, 87, 802. 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. 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. R.E. Banks, R.N. Haszeldine and M.J. Stevenson, J. Chem. Soc. (C), 1966, 901. M.A. Englin and A.V. Mel’nikova, Zh. Vses. Khim. Obshchest., 1968, 13, 594; Chem. Abstr., 1969, 70, 28503. R.E. Banks, R.N. Haszeldine and T. Myerscough, J. Chem. Soc. (C), 1971, 1951. J.A. Young, T.C. Simmons and F.W. Hoffman, J. Am. Chem. Soc., 1956, 78, 5637. R.A. Mitsch, J. Am. Chem. Soc., 1965, 87, 328. V.A. Petrov, J. Fluorine Chem., 2001, 109, 123. R.E. Banks, W.M. Cheng and R.N. Haszeldine, J. Chem. Soc., 1962, 3407. I.L. Knunyants, E.G. Bykhovskaya and V.N. Frosin, Dokl. Akad. Nauk. SSSR, 1960, 132, 357; Chem. Abstr., 1960, 54, 20841. R.E. Banks, D. Berry, M.J. McGlinchey and G.J. Moore, J. Chem. Soc. (C), 1970, 1017. R.A. Mitsch and P.M. Ogden, J. Org. Chem., 1966, 31, 3833. H.J. Scholl, E. Klauke and D. Lauerer, J. Fluorine Chem., 1972/73, 2, 205. R.D. Chambers, D.T. Clark, T.F. Holmes, W.K.R. Musgrave and I. Richie, J. Chem. Soc., Perkin Trans. 1, 1974, 114. R.N. Barnes, R.D. Chambers, R.D. Hercliffe and W.K.R. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1981, 2059. M. Barlow, D. Bell, N.J. O’Reilly and A.E. Tipping, J. Fluorine Chem., 1983, 23, 293. C.S. Cleaver and C.G. Krespan, J. Am. Chem. Soc., 1965, 87, 3716. D.A. Barr and R.N. Haszeldine, J. Chem. Soc., 1956, 3428. J.A. Young, W.S. Durrell and R.D. Dresdner, J. Am. Chem. Soc., 1959, 81, 1587. V.G. Andreev, A.F. Kolomiets and G.A. Sokolskii, Izv. Akad. Nauk. SSSR, Ser. Khim., 1990, 1643; Chem. Abstr., 1990, 113, 1643. F.S. Fawcett, C.W. Tullock and D.D. Coffman, J. Am. Chem. Soc., 1962, 84, 4275. R.N. Barnes, R.D. Chambers, M.J. Silvester, C.D. Hewitt and E. Klauke, J. Fluorine Chem., 1984, 24, 211. R.N. Barnes, R.D. Chambers and R.S. Mathews, J. Fluorine Chem., 1982, 20, 307. R.N. Barnes, R.D. Chambers and C.D. Hewitt, J. Fluorine Chem., 1986, 34, 59. U. Heider, M. Schmidt, P. Sartori, N. Ignatyev and A. Kucheryna, Eur. Pat. 1 081 129 (2001); Chem. Abstr., 2001, 134, 207547. V.A. Petrov and G. Resnati, Chem. Rev., 1996, 96, 1809. I.L. Knunyants, A.F. Goutar and A.S. Vinogradov, Izv. Akad. Nauk. SSSR, Ser. Khim., 1983, 476; Chem. Abstr., 1983, 99, 53706k. G. Pawelke and H. Burger, J. Fluorine Chem., 1984, 26, 321. J.K. Ruff, J. Org. Chem., 1967, 32, 1675. J.B. Hynes and T.E. Austin, Inorg. Chem., 1966, 5, 488. M.E. Jacox, Chem. Phys., 1984, 83, 171. C.G. Krespan and W.J. Middleton, Fluorine Chem. Rev., 1971, 5, 57. C. Glidewell, D. Higgins and C. Thompson, J. Comput. Chem., 1987, 8, 1170. D.M. Gale, W.J. Middleton and C.G. Krespan, J. Am. Chem. Soc., 1966, 88, 3617. E.P. Mochalina and B.L. Dyatkin, Bull Acad. Sci. USSR, 1965, 899.
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Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives
320 321 322 323
295
R.A. Mitsch, J. Heterocycl. Chem., 1966, 3, 245. R.A. Mitsch, J. Org. Chem., 1968, 33, 1847. M.D. Meyers and S. Frank, Inorg. Chem., 1966, 5, 1455. R.B. Minasyan, E.M. Rokhlin, N.P. Gambaryan, Y.V. Zeifman and I.L. Knunyants, Bull. Acad. Sci. USSR, 1965, 746.
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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
2HF
Electrolysis
2ArF + HF
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], a reaction that was referred to in Chapter 7, Section IIIB, Subsection 1. 6 CFBr3
3 CF3C
Pt 630−640⬚ C CCF3
9 Br2
C6(CF3)6
Figure 9.3
296
+
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
C6F6
55%
½4 ½6, 7
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Polyfluoroaromatic Compounds
B
297
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
C6Cl6
ii
C6ClxF12-x
C6F6 C6F5Cl C6F4Cl2 C6F3Cl3
x = mainly 5, 6, and 7 i, F2, CF2ClCFCl2 ii, Fe, 330 C
C6H6
C6H3F9 etc
KOH C6F6
C6H3F7
CH3
½17
C6F5H
CF3
CF3 CoF3
½16
Fe
F
½18
F
460 C CF3
CF3
CH3
H
H i
F
−
F
2F
½13
H
H i,
Hg Cathode
F CoF3
F Fe
F
½19
F
410 C F
i N
N F i, ii,
Figure 9.4
F
Electrochemical Fluorination Fe/600 C/,1mm
F
ii
F N
½15 25%
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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 S
½20
F S
KOH F O
H
H
H
H
H
H KOH
F O
F H
½21
F O
½21
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
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Polyfluoroaromatic Compounds
299
indicated, and others, the orientation of substitution is quite consistent with an electrophilic aromatic substitution process. F H
F "F"
H
9.6A F
H H
F F
9.6C
9.6B
Figure 9.6
½25
COOH
COOH
Solvent
F2 Solvent
98% H2SO4 CH3CN CF2ClCFCl2
F
F
F
NO2
NO2
Yield, % 84 53 0
½26
NO2
i F X
i, F2, HCOOH, 10⬚ C X = OH X = F
NO2
F
F
X
X
70% 53%
8% Trace
NO2
NO2
½26
i F Me i, F2, H2SO4, 10⬚ C
F
F
Me
Me
81%
2%
Figure 9.7
Substitution in pyridine is more consistent with an addition–elimination process (Figure 9.8).
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300
Chapter 9
½27
−HF
i H N
N i, F2, CFCl3, −78 C
N
F
F
F
−HI
i
70%
F Cl
N
Cl i, IF5/2I2
N
Cl
H
N
½28
F
I a
b 14% Cl b
N I
N
F
a
F
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 fluorodesilylation using this reagent has also been reported [32] (Figure 9.10).
2 Replacement of 2N2þ 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
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Polyfluoroaromatic Compounds
F
F
F
n = 0, 20% n = 1, 40%
F n
F
F
5%
i
N
N
F
F
8%
7%
301
½29
½30
N
F
F
F
N
N
N
i, CoF3, CaF2, 183⬚ C Coupling etc
N
N
+F
F
F
N
N
Figure 9.9
CF3C6H5
XeF2
SiMe3
meta-CF3C6H4F
SiMe3
FXe
para-CF3C6H4F
71%
XeF
F
R
R
XeF2
R
R
Figure 9.10 HNO3 ArH
ArN2 BF4
Figure 9.11
ArNO2
∆ −N2
ArNH2
Ar
BF4
ArF
+
BF3
3%
½31
½32
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302
Chapter 9
N2
NH2 COOH
F
F
COOH
COOH
i
ii
½2
OH i, NaNO2, HF/H2O ii, 58⬚ C
COOH
Figure 9.12 i COCl2
COClF i, AsF3, SbF3, or SiF4 COClF
ArXH
∆
ArXCOF
ArF
+
COX
F (X = O, S) or ArXCOCl
i
C6H5OCOF
C6H5OH i, COClF, Bu3N;
α-naphth.-OCOF
ii
C6H5F
70%
½36
99% ii, Pt Gauze, 800⬚ C ∆
680⬚ C
α -naphth.-F
25%
½37
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).
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Polyfluoroaromatic Compounds
ArCl + KF
303
½2
ArF + KCl
Figure 9.14
C6Cl6(g)
+
6KF(s)
C6F6(g)
+
6KCl(s)
C6F6(g)
+
6NaCl(s)
½40
∆H298 = −126 kJmol−1
C6Cl6(g)
+
6NaF(s)
∆H298 = +63 kJmol−1
Figure 9.15
NO2
NO2 Cl
½2
F
i
71%
Cl
F i, KF, DMSO, phase transfer agent, heat
NO2
NO2
½2
i 82% Cl
Cl F
Cl i, KF, DMF, heat
Figure 9.16
Cl i
F
Cl Cl i, KF, 195⬚ C, NMP
+
C6F4Cl2 + C6F5Cl
½42, 43
Cl 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).
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Chapter 9
i Cl
F
Cl
52%
F
½44
i, KF, 235⬚ 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
N
Cl
N
F
N
½45
74% N
i, NaF, 245⬚ C, Sulpholan Cl N
N
HF
Cl N
N
N
N
Cl
N Cl
N
F
N
Cl
H
½46
F
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 Cl
F
F
N
N
N
i, KF, 200⬚ C, Sulpholan
Figure 9.20
10
:
1
½47
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Polyfluoroaromatic Compounds
i
C6F3Cl3
C6F6 11% + C6F5Cl 34% + C6F4Cl2 28%
305
½40
i, KF/KCl Melt, 780⬚ C + C6F3Cl3 18% + C6F2Cl4
i
C6Cl6
0.4%
C6F6 21% + C6F5Cl 20% + C6F4Cl2 14%
½48
i, KF, Autoclave, 450−500⬚ C + C6F3Cl3 12%
Cl
i Cl
F
F
N
N
N
68%
7%
i, KF, Autoclave, 480⬚ C
½47
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 Cl2, AlCl3 N
PCl5
Cl
Cl N 78%
Figure 9.22a
87%
140−160⬚ C
KF 480˚C
N
315⬚ C
F
F N
71%
½52
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Chapter 9
F
F
F
N
F
F N
N N N
N
F N
F
F
N
N
N F
N
N
F
F
F
F
F
N N
N
N
N
N F N
F
F 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 perfluoroazabenzenoid 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 Compound Benzene Toluene p-Xylene Pyridine Quinoline Isoquinoline Pyridazine (1,2-diazine) Pyrimidine (1,3-diazine)
Boiling point (8C) [54]
Boiling point of perfluorinated derivative (8C)
Ref.
80.1 110.6 138 115.5 237.1 243.2 208 123.5
80.2 102–103 117–118 83.3 205 212 117 89
[55] [11] [11] [55] [52] [52] [56] [55]
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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 k2
k1 F
Nuc
Nuc
F
F
F5
k−1 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.
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308
Chapter 9
Table 9.2 Reactions of perfluorobenzenoid compounds with nucleophilic reagents and some simple interconversions Reaction
Ref.
Reactions starting from hexafluorobenzene i C6F5OCH3
ii
C6F5OH
72% i, NaOCH3, MeOH; i
[63]
58% ii, AlCl3, 120⬚ C
C6F5OH
[5]
i, KOH, t-BuOH 71% i
C6F5SH
i, NaSH, Pyridine;
ii
C6F5H
[64]
ii, Raney Ni, n-BuOH ii
C6F5SO2Cl
[65]
ii, Cl2, H2O2 ii
iii
C6F5SCH3
C6F5SO2Me
[65]
ii, Me-nitrosourea, KOH, Et2O; iii, H2O2, CH3COOH i
C6F5NH2
i, aq. NH3, EtOH, 167⬚ C;
ii
C6F5NO2
85%
[66, 67]
ii, CF3CO3H, CH2Cl2 ii
C6F5NH2HCl
[68]
ii, HCl, Et2O NaOCl
ii
C6F5N=NC6F5
C6F5NO2
[69]
48%
[70]
ii, HCO3H, CH2Cl2 ii
C6F5N2
iii F
C6F5Br
[68] ii, NaNO2, 80% HF;
iii, Cu2Br2, HBr
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 309
Polyfluoroaromatic Compounds
309
Table 9.2 Contd i
ii
C6F5NHNH2
C6F5C6H5 74%
71%
[71]
i, NH2NH2.H2O, EtOH; ii, Ca(OCl)2, C6H6 H NaOH
[72]
90%
F
H NO2Cl
LiAlH4
C6F5N3
[71]
52%
[73] C6F5H OCH2CH2OH
i
O
ii F
[74]
F O
i, (CH2OH)2, NaOH;
ii, K2CO3, DMF, Reflux
Reactions of other perfluorobenzenoid compounds NHNH2 i
F
F
F
F
[75]
iii
ii
H F
F
i, NH2NH2, aq. EtOH; ii, LiAlH4, Et2O; iii, Fehlings soln. H F
i
F
F
F
[76]
H i, LiAlH4, THF i F
F
i, C6F5O , DMAC
F
F
OC6F5
[77]
90 %
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 310
310
Chapter 9
Table 9.2 Contd i F
H2NHN
F
F
F
NHNH2 18%
i, NH2NH2, aq. EtOH H2NHN
a
F
[78, 79]
F 72%
DMAC, dimethylacetamide. Table 9.3
Nucleophilic substitution in C6 F5 X compounds Orientation of product(%)
Substituent, X H Me
CF3
NH2
NO2
NH2
OH
Nucleophile LiAlH4 NaOMe/MeOH MeLi MeO NH3 LiAlH4 NH3 EtO NH3 NH3 MeNH2 NH3 (ether) NH3 (liq.) MeNH2 (benzene) MeOH ðEt2 OÞ MeOH ðEt2 OÞ NH3 NH3 MeNH2 KOH
Ortho
Meta
Para
Reference
7 3 — — — — — — — — — 70 33 77 8 50 — — — —
1 — — — — — — — 100 87 88 — — — — — 100 87 88 100
92 97 100 100 100 100 100 100 — 13 12 30 67 23 92 50 — 13 12 —
[80] [81] [82] [83] [83] [84] [84] [84] [66, 73] [85, 86] [86] [67] [87] [88] [89] [88] [66, 73] [85, 86] [86] [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 C6 F5 X 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 , NðCH3 Þ2 , SO2 CH3 , NO2 , C6 F5 , OC6 F5 , etc.). In a few cases ðX ¼ NH2 , O Þ 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 electronwithdrawing groups activate; for example, C6 F5 NH2 and C6 F5 O are strongly deactivated. The magnitude of these effects, such as the relative reactivities of NaOCH3 ðCH3 OH 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
X
F X
+
F e.g. X = H, CH3, CF3
Nuc Nuc
F Nuc
X +
F
F
Nuc
e.g. X = NH2, O
Figure 9.24 Table 9.4 Relative rates of reaction of C6 F5 X towards NaOC6 F5 , DMAC [93] X CF3 CO2 C2 H5 C6 F5 Br Cl H F
Relative reaction rate 2.4 104 2.9 103 7.3 102 39 32 1 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 Fδ δ
Nuc
Nuc ortho
F
meta
para
ortho F
meta
+ F
para
Figure 9.25
Table 9.5 Ratios of measured rate constants (CH3 O =CH3 OH, 588 C) [91, 94] kF =kH
Benzene derivatives compared H
F
F
F
vs
para-F / para-H
0.43
(Position of nucleophilic attack) a
(ie k/6)
H
H F
vs
F
meta- F / meta- H
106
H
H
H
F
a
57
H
F
F
ortho-F / ortho- H
vs
F
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
MeO =MeOH, 588 C Benzene derivatives Pyridine derivatives NH3 /dioxane, 258C Pyridine derivatives C
C
Ortho
Meta
Para
57 79
106 30
0.43 0.33
31
23
0.26
C
F
Strongly Stabilising
Nuc
Slightly de-stabilising for a planar system
Nuc
F
δ−
F
F
Nuc
δ−
δ−
δ− F δ+
F
F
meta-F
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 C6 F5 X 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 o m
X o
F
m
p m
o F o
4- activating F
Figure 9.27
3- activating F
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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 pm
δ−
δ− δ−
F
δ−
pm
F
F
δ−
pm
ortho
meta
δ−
pp
meta
pm
δ−
F δ− pp
Nuc
δ − ortho F
δ− ortho
F Nuc
5- activating F
4- 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
F F
F
F F
Figure 9.29
Ortho attack [1] can occur, however. Although nucleophilic substitution at sites para to X in C6 F5 X 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
F
Figure 9.30
½96
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 315
Polyfluoroaromatic Compounds O
BrMgO C
C6F5COOH
O
BrMgO MgBr
C
MgBr F
NHPh
2PhNHMgBr
315
F
F
½97
NH Ph H O
HO C
NHPh F
Figure 9.31
2
Heterocyclic compounds
Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds: Polyfluoroaromatic 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 F
F
N
N
N 1
Figure 9.32
37.4
N
N
F
F
N
N >105
2000
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
i
OCH3
OCH3
F
F
N
N
OCH3 i
[98, 99]
F OCH3
CH3O
N
OCH3
i, CH3ONa, CH3OH
Contd
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316
Chapter 9
Table 9.7 Contd N2
NH2 aq. NH3
i
F
F
F
Br CuBr
F
N i, aq. HF, NaNO2, −20 to −25 C
N
N
[98, 100, 101] Cu, 230 C
CF3COOOH NO2
N
F
F
N
F N OH
OCH3
i
ii F
F
N
N
10
1
OH
F
F
N
N
[102] OCH3
i, KOH, t-BuOH; ii, KOH, CH3I, 100⬚ C I i
[103]
F N
i, NaI, DMF, 150⬚ C π−C5H5Fe(CO)2 i
F
[104]
N i, [π−C5H5Fe(CO)2 ]
Perfluoroisoquinoline LiAlH4
F
F N
[105]
H
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 317
Polyfluoroaromatic Compounds
317
Table 9.7 Contd CH3O CH3ONa
F
F
F
N
OCH3
OCH3
CH3OH
aq. NaOH
[105]
F
N
F
F
F
F
[106]
NH
N OH
O
Perfluoroquinoline OCH3 i
F
F N
i, CH3ONa, CH3OH
F
F N
OCH3
AlCl3, 120⬚ C
AlCl3, 120⬚ C
OH i, H2SO4
F
ii, H2O
F N
F
F
[52, 105, 106]
N
OH
F N H
F
F O
F N
O
CH3
CH2N2, Et2O
F
F N
OCH3
Contd
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318
Chapter 9
Table 9.7 Contd Miscellaneous Perfluoro-3,3’-bipyridyl OCH3 i
F
88%
F
N
[107]
N
i, CNH3ONa, CH3OH
Perfluoropyridazine CH3O
CH3O
i
N
F
N
F N
also tri- and tetra-methoxy derivatives
N CH3O
[108]
i, CH3ONa, CH3OH
N
C6H5SNa
N
H+, H2O
(SC6H5)4
N
F
[108]
85%
F N
N
Polymer
N
[109]
H OH
O
NH2
NH2
Perfluoropyrimidine
aq NH3
N
N
or
F N
F H2N
[110]
N
OCH3 N
i
F H3CO
[110]
N
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 NH3/Dioxane
F
H
H
H
F
F N
N
½76
N
H2N
1
3.7
Figure 9.33
F
δ− F
δ+ o
o
Nuc
F
m
Figure 9.34
o
o
m
m
N
Nuc
Nuc
F
F
m
N
F
N
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
N
F
F
N F
F
N
N
N
N
N
N F
F
F
F
N
N
F
F
cf N
N
F
F
N
F
N
F
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
F N
Figure 9.36
Br aq NH3
½100 F N
NH2
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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 i
F N
X
X
X
F
F
N
N
X = F,
90
10
X = Cl,
30
70
i, KOH, t-BuOH
½102 OH
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. NH2
NO2
NO 2
NO2 NH2
i F N i, NH3, Et2O
F
F
F
N
N
N
27%
48%
25%
½101 NH2
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 CF2 CF3 , 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
R
R F
F
F
F
F
Nuc
N
321
R
F
Nuc
F
F
N
R
9.39B
9.39A
Figure 9.39 1
F 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, CFðCF3 Þ2 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 H
Br i
ii F
F N
N
Br i, HBr/AlBr3, 150⬚ C;
H
ii, Pd/C/H2(4Bar), Et3N, CH2Cl2, rt
Br X2
X1 Nuc
F N
½112
Br
N
Br
X1 = X2 = OMe
Nuc = NH3
X1 = F, X2 = NH2
Br i
F N
Br
Nuc = NaOMe
Br
Br
N
H
Br
Br
Br
½112
F
½112
F RC
Br
N
C
i, CuI/(Ph3P)3PdCl2, Et3N, RC CH
C
CR
(R = C3H7 or Ph)
Y1
Br Nuc
F
F Br
N
Br
Br
Nuc = Et2NH;
Nuc = PhSH;
½112
N
Y
2
Y1 = Et2N, Y2 = Br
3:
Y1 = Br,
2
Y1
= PhS,
Y2 = Et2N 2
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
F
F
323
½114
N
Nuc
X
X F
F
F
N
F
F
N
F
X
N
X
9.42A
9.42B
9.42C
Nucleophile 100%
HS , DMF/(CH2OH)2 PhS
(X = SH)
99%
, EtOH
MeO , MeOH
93%
4-NO2C6H4O , EtOH
100%
1%
7%
(X = SPh)
(X = MeO) (X = 4-NO2C6H4O)
Figure 9.42 Nuc F
F Nuc
F
etc
N
F
F
N
R
etc
F R
9.43B
9.43A
Figure 9.43 OCH3
OCH3 i F
F
F N
OCH3
N
CH3O
½116
F OCH3
9.44A
i, CH3O , CH3OH
CF(CF3)2
CF(CF3)2 CH3O i F
F N
F CF(CF3)2
i, CH3O , CH3OH
Figure 9.44
F N 9.44B
CF(CF3)2
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 324
324
Chapter 9
Acc
F N
Nuc
F N
F
F
Nuc
N
F
F
Acc.
Acc. −F
Acc. = Electron Acceptor
F N
Nuc
Acc.
Figure 9.45 OMe i
F
F
F
F
N
N
F
F
N
OMe
ii
iii F
F
F
F
N
N
OMe
H i, = MeONa/MeOH
ii, = c. H2SO4
iii, = MeOH/Slow dilution OMe
H F
N
MeOH
F
N
35%
N
N
OMe
H2SO4
O Et N
F
Et3OBF4
F
Et H2O
N
N
MeOH
N
MeO N N MeO
Figure 9.46
F N
MeO
F
N
70%
½108, 109
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 325
Polyfluoroaromatic Compounds H
δ−
F N
C
Nuc
F δ+ C
325
F C
Nuc
9.47B
9.47A
Figure 9.47 Cl
F
½117
i
F
F
N
F N
F
F N
Cl
Cl
57%
23% i, HCl, 100⬚ C, Sulpholan
Br
Cl F
F xs BBr3
F N
F
150⬚ C Br
88%
F
xs BCl3
½118
F
140⬚ C N
N
Cl
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
N
Br i
F N
CC3H7
C
N F
½112
ii
N
Br
C
CC3H7
i, CuI, (Ph3P)3PdCl2, Et3N ii, C3H7C CH
Figure 9.49 CF2=C
F
CF3
ArF
C
cf
CF3
C
CF3CF=CF2
F
C
CF
C
C
ArH
i
F N
F N i, KF, Sulpholan
F
Ar
H
RF
RF
F
F
N
N
i, KF, Sulpholan
CF2=CF2
Ar
½120 RF
RF = CF(CF3)2
i
RF
RF
F
F
N
N
½121 RF
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
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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 19 F 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. RF RF F N
½116, 122, 123
RF = CF(CF3)2
RF
9.51A −
−
F F
F
RF
RF
RF
F N
F
RF
F N
RF
RF 9.51B
RF RF CF(CF3)2
F N
RF
N
9.51C
RF F
−
−F
F N
RF
9.51D
RF
RF
CF(CF3)2
F
F RF
RF
9.51E
F N
RF
9.51F
−
CF3CF=CF2
−F
(CF3)2CF CF3CF=CF2 Dimers and Trimers
Figure 9.51 Contd
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328
Chapter 9
CF3
F C
F
F3C F3C
CF3
F
F
N F3C
F CF3
N
F
F3C
CF3
9.51D2
9.51D1
Figure 9.51
½125, 126, 129
C
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 ðCF3 Þ3 C > ðCF3 Þ2 CF > CF3 CF 2 and therefore reversibility and crowding also follow this series (Figure 9.52). RF RF
½121, 124
i CF2=CF2
F
F
N
N
N (RF)n
RF
i, CsF, Tetraglyme, 80 C
RF = CF2CF3 RF
CF2=C(CF3)2
F N i, CsF, Tetraglyme
i
½124
F RF
N
RF
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-dimethylbutadiene with 9.53B, giving the unusual spiro system 9.53D [131] (Figure 9.53), but without the loss of fluorine. F3C RF
N
Cl
CF3
RF
F RF
C
RF
RF
½130
RF
RF
RF N
N
N
N
N
N
N
N
N
N N RF
RF = C(CF3)3 9.53A
9.53B
RF RF
RF RF
RF
9.53C
RF
RF
RF
RF i N
N
N
N
N
N
½131
N N
N H3C
CH3
9.53B
H3C
CH3 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.
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330
Chapter 9 F
CF2=CFX
CF3CFX
½134
X = Cl, Br
F
ArFCF2CF3 9.54B
9.54A
ArFF
CF3CFX
F
ArFCFXCF3
+
CF2=CFX CF3CFX2
+
CF2CF
9.54C
ArFF F
(ArF)2CFCF3
ArFCF=CF2
ArFCFCF3 9.54E
9.54D
9.54F
Figure 9.54
Table 9.8 Polyfluoroalkylations and related reactions Reaction
Ref. N
N F N
C3F6
N
CsF N
200−300 C
N
[135]
[CF(CF3)2]nF3−n
n = 1, 39%; n = 2, 51%; n = 3, 5% RF
RF
RF RF
N
i
F N
N
F
5 C3F6 RF
N 6%
+
F
RF
N
N
N
[136]
+ RF RF
N
RF
3%
81% RF = CF(CF3)2
i, CsF, Sulpholan, 70⬚ C
RF
F
CF3CF=CFCF3
i
F N
N
[137] RF
i, CsF, Sulpholan, 100⬚ C RF = CF(CF3)CF2CF3
Contd
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Polyfluoroaromatic Compounds
331
Table 9.8 Contd CF3CF2 F
N
CF2=CFCl
CF3CF2 N
i
F
F
N
N
CF2=CFBr
F
i N
F
19%
+
CFCF3
N
[134]
N
CF3CF2
57%
i, CsF, Sulpholan, 90 C
N
CF3CFBr2
[134]
2
i, CsF, Sulpholan, 90⬚ C CF3CF2 F
N N
CF2=CFBr
CF3CF2
i
N
F
F
N
N
[134]
N CF3CF2
i, CsF, Sulpholan, 90 C F
CF3
C F3C
F
CF3C CCF3
CF3
C
C F3C
C
F n
[138]
i
N
F
F
N
N
i, CsF, Sulpholan, 110⬚ C
n = 2 and 3 F CO2Et
EtCO2C F
[138, 139]
i
EtO2CC CCO2Et
F
N
N i, CsF, Sulpholan CF3 C F3C
F
CF3C CCF3
i
C
F
CN
CN i, CsF, DMF, 125⬚ C
F n
[140]
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332
Chapter 9
The mechanism of displacement of chlorine and bromine by fluoride from the side chain of these systems is of interest. It has been suggested that an SN 20 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
CF3
H CF2
i N
OEt
½141
N i, NaOEt/EtOH/Reflux
CF=OEt
CF2OEt −F N
N
EtO
etc
CO2Et
C(OEt)3 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). CF3
NMe2 RF
RF N F
i
N
ii
N
N
N
N
Me2N
Me2N
RF (Yellow)
RF RF = CF(CF3)2
F
RF
CF3
NMe2
iii
H3C CH3 CF3 N F3C
NMe2
C
F3C
C
F3C
C
N
N BF4
N
H2C
N N
Me2N
H3C
RF
RF
iv
(Purple)
CF3
F3C i, ii, iii, iv,
NM e
H
Me2NH/DMF/Room Temp. Standing or on addition of water BF3.Et2O Moist Acetone
H
N N
N CH3
RF
(Colourless)
Figure 9.56
CF3C CCF3 + F ArFF
CF3CF=CCF3 CF3C CCF3 CF3CF=C(CF3)C(CF3)=CCF3
ArFF CF3C CCF3
C(CF3)=CF(CF3) Polymer
Figure 9.57
n
½142
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334
Chapter 9 RFO
+
ArX
ArORF
N N
Cl
+
X
(X + Cl or F)
N
Diglyme (CF3)2CO.KF
N
−10⬚ C
½146
N
N
[OCF(CF3)2]3
86% conversion
Figure 9.58 COOEt C
i, ii
F
F
C
SH
S
i, n-BuLi ii, EtOOCC
½148
COOEt iii, −F iv, H2SO4
CCOOEt
COOEt F
CH
Cu
CH
Quinoline
C F
S
C S
COOEt
H CH3COCHCOOEt
F
Na
C
NaH
F
COOEt
C
THF O
CH3
COOEt
COOEt
C F
C
Base
C
F
CH3
O
C HO
H C F
H CH3
C F
C O
i, NaH.1THF, 2DMF reflux
Figure 9.59
CH3
H i
C O
½149
½146, 150 CH3
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 335
Polyfluoroaromatic Compounds
H C F
H
F
C O
½148
H C
i
H
C SH CH3
HS
CH3
335
i, H2S, EtOH, O⬚ C ii, Pyridine, NaOH, Reflux
ii H C F
C S
CH3
Figure 9.60
F
F
i
+ SCl2 or S2Cl2
Li Li
F
½151
F S
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
N
O
X
O i
O
N
O
F
O ii
O
O
O
N O
F
N
N
O
F X X X = CF(CF3)2, 94% X = OMe, 80%
Figure 9.62
X = CF(CF3)2, 64% X = OMe, 85%
i,
Me3SiOCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days
ii,
Me3SiOCH2CH2OCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days
½152
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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 NO2 BF4 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 F
F
½1, 154
F
F
F
F
i, CH3F, SbF5, SO2ClF, 20⬚ C
Figure 9.63
Ring fission to the phthalic acid derivative has been observed [155] (Figure 9.64). NO2 F
F i F
F
F F
F
NO2
F
½153, 155
F F
F F
F
F
61% c. HNO3
H2O
F
O
O
COOH
F
F
F
F
COOH 71%
O
F
O
F
+ 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 O
F SF4
F
½156, 157
F
SbF5
F
337
F5 SbF6
O
H2O O
O
F
F
O
Figure 9.65
F
C6F6
+
½158
SO3.SbF5
F
F
Oleum
O2AsF6
SO3.SbF5
F
C6F6 AsF6
+
O2
½159, 160
NO
C6F6
+ NO AsF6
Figure 9.66 COOH
CF3 i
½18
F
F CF3
COOH i, H2SO4, SO3, 150⬚ C, 12hr
CF3 F
CF2 i
½161
F
i, SbF5, HF, 50-60⬚ C
CF3CF=CF2
CF2CF(CF3)2 F
Figure 9.67
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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 C6 F5 . 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 ðC6 F5 COOÞ2 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 C6 H5 CðOÞO [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
H i
F
F
½162
CH 3
i, CHCl3, AlCl3, 150⬚ C H
Br i
F
½163
F i, Br2 (or I2), Oleum, 60−65⬚ C
H
NO2 i
F
½164, 165
F i, HNO3, Sulpholan, BF3, 60−70⬚ C CH(CH3)2
H i
F
½166
F 90-94%
i, C3H6, CBr4, AlBr3, 0⬚ C C6F5
H
3
F
SbF5,
F
½1, 154
F C6F5
C6F5
Br i
½167
F
F
i, FeBr2.CCl4, Reflux NO2 i F
F
i, HNO3, Oleum, 70⬚ C
Figure 9.68
½167
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340
Chapter 9 H
E
F5
Figure 9.69 C6Cl5Hg
H Cl
i C6F5HgC6Cl5
− C6Cl5HgCl
+
+
C6F5H
½168
F5
i, HCl, 100⬚ C, 65hr, Sealed tube
Figure 9.70 F
Cl
F
48hr
F Cl F Cl
Cl2, hn F
Cl
F Cl F Cl
Cl2, hn
35hr
N
½170
F Cl F F
Cl
Cl
F Cl F N
½171
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
F
Ar
F
Ar
ArCOO
Ar
341
F5
ArCOOF
F
½172, 174, 175
Coupling
F
Ar F
F
F
Ar
Figure 9.73
−e
C6F5NH2
C6F5NH2
−H
½177
C6F5NH C6F5NH2 H N
N
−e
F
F
F
etc
N
F H2N
O
O
C
C
F
F
F H2N
F
F
½178
N 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 1
Reactive intermediates 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.
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342
Chapter 9 X
X
X
½179
i
F N
N
F4
N
ii
H
H
X
F4
F N X = Cl, F
N
F4
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
i, Zn (Cu), DMF, H2O, 1-Hexene, 65⬚ C COOH
COOH
½181
i F
F
F
F
H i, Zn, aq.NH3, rt, 2hr
Figure 9.76
C6F6 +
C6F6
hν N2
+ (CF3)2CN2
30%
F
CF3
hν
20%
F
½182
½183
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 C6F6 +
550⬚ C
CF2CF2
C6F6
n
343
½185
+ C6F6-n(CF3)n n = 1,2,3
CF2 C6F5X
C6F5CF2
CF2=CF2
½186
C6F5CF2CF2CF2 −F (?)
F
F
Figure 9.78
F
F
F
C6F6
CF2
(KF)
F5 9.79A
(b) Addition
(a) Insertion
C6F6
C6F6 F C6F5CF3
F
F
F F F
F F
Figure 9.79
CF3 F3C F
550⬚ C CF2CF2
n
N
CF3
F
F
N
N
60%
6%
CF3 F
i
N i, KF, 8hr, 550−560⬚ C
Figure 9.80
F N
85−90% +2- and 4- isomers
½193
½189
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344
Chapter 9 F3C
½194
H3C N
C
R F3C
Figure 9.81
C6F6
+
C6F5N3
N3CN
i
45⬚ C
F
[C6F5N:]
½195
NC
N
½196
F N
i,
Flash Vac. Pyrolysis/300⬚ C N F
F N
Figure 9.82 CN
F
CN
hν
N3
F
CN c-C6H12
½197
F
N
N H
C6H11
75−80%
Figure 9.83 i C6F5Br
C6F5MgBr
CO2
C6F5COOH
½200
67%
i, Mg, Et2O, or THF
½201
O 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-
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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). C6F5Br
+
Et2O
n-BuLi
−78⬚ C
C6F5Li
H
F
+
n-BuBr
½204
Li Et2O
+ n -BuLi
F
½205, 208
−78⬚ 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
C6F5Li
Ref. i
C6F5OH
39%
[209]
i, B(OMe)3, H2O2 i, ii C6F5Li i, S8;
C6F5SH
46%
C6F5COOH
99%
[210]
ii, H2O i
C6F5Li
[205]
+
i, CO2; ii, H, Et2O, <55⬚ C
C6F5Li
HCO(NMe2)
C6F5CHO
61%
[211] Contd
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346
Chapter 9
Table 9.9 Contd (MeO)2CO
C6F5Li
(C6F5)2CO
OH
70%
OH
OLi
i, CO2
n-BuLi
F
F
F
+
ii, H
H
84%
Br
Br
Br H
F
F
H
H
ii
i Li
Br
H
Br
[207, 213]
HOMe2C
F
F
[209]
COOH
Li
F
[212]
+ (C6F5)3COH
Br F
i, LDA, THF, −78⬚ C; ii, Me2CO, −78⬚ C Li
H Cl
Cl
F
F
i N
H
COOH F
ii, iii H
F
Cl
N
F
[214] H
F F
+
i, LDA, THF, −78 C; ii, Me2CO, −78 C; iii, H
F
F
Li Li
SCl2
F
F
66%
[212]
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 Monoglym e C6F5I
+
2Cu
C6F5MgBr
+
C6F5Cu
rt CuI
+
½221224
CuI
Dioxane
Et2O
½216, 219, 220
C6F5Cu.Dioxane
[C6F5Cu]
−Dioxane
130⬚ C PhI
C6F5C6H5
347
[C6F5Cu]4
87% MeI 200⬚ C C6F5Me 39% Cu(I)Cl, Mg
C6F5Cl
[C6F5Cu]
C6F5C6F5
MeCOCl
C6F5COMe
−5⬚ C
THF
72%
½225
CBr2=CHBr C6F5C i
C6F5Cl
C6F5Li
Cu(I)I
[C6F5Cu]
CC6F5
CF2=CFI
43%
½217
C6F5CF=CF2 55%
n-BuLi, THF, −70⬚ C
i,
C6F5Cu
+
CH2I2
½226
CH2(C6F5)2
Figure 9.86 C6F5Cu
+
−30⬚ C
CF3Cu
½227
C6F5CF2CF2Cu
DMF
Figure 9.87 X Li F
X
X S F
F
S X X
X = H, Cl −S
F
Figure 9.88
X
½228
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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 C6F5Li
F
F
H
F
½204
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 C6F5MgBr
C6F5MgBr
F
½230, 231 F
F
C6F5MgBr MgBr F
MgBr F
C6F5
F
F
C6F5
n
Figure 9.90
This type of process appears to occur even more easily with trifluoropyridyne [232] (Figure 9.91). Br
Li Furan
i F
F
F
N
N
N
i, n-BuLi, Et2O, −78⬚ C
½232
n-BuL i
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
F
F
i F
F
Br
SH
349
½233
S
i, n-BuLi, Et2O, C6H8, 0⬚ C
F
F
F
F
S
S
70%
Figure 9.92 Ph
H Li F
F
PhCH=N(Ph)O
N Ph
F
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 kðC6 H5 Cl=C6 H6 Þ ¼ 0:72 in comparison with a value for phenyl radicals kðC6 H5 Cl=C6 H6 Þ ¼ 1:06. 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.
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Chapter 9
F
O Hg O F
Hg
300⬚ C F
O
83%
Hg
½155
Hg O
F
F Hg Ag F
Hg
F
F
~255⬚ C
39%
½155
Hg F
O 750⬚ C
O
F
F
F
24%
½235
0.6mmHg O I i F
F
½236
9.94A I
i, hν, Ne matrix, 3K
Figure 9.94
C6F5NH2
+
C5H11ONO
C6F5
C6F5
+
C6H5CH3
C6F5 C6H4CH3
½237
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 C6 F5 O radicals [244, 245] (Figure 9.99).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 351
Polyfluoroaromatic Compounds
i
½198
C6F5C6H5
C 6F5NHNH2
351
i, Bleaching Powder, C6H6
i
C6F5COCl
(C6F5COO)2
i, NaOH, H2O2;
ii
½238, 239
C6F5COOH + C6F5C6F5 + C6F5COOC6F5
ii, C6H6, 80⬚ C
Figure 9.96 S, 230⬚ C C6F5I
(C6F5)2S I
S S, 250⬚ C
F
½241
70%
I
½241
60%
F
F S
C6F5
½242
hν
C6F5I
70% Me
N
CH3CN Me
Me
N
H
Me
H
Figure 9.97
hν
(C6F5)2CO
HO (C6F5)2OH
Me2CHOH
F
C
etc
½243
C6F5
9.98A
Me2CHOH
(C6F5)2CHOH
cf
(C6H5)2C=O
(C6H5)2COH 9.98B
+ Ph Ph HO
Me2CO Ph Ph OH
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
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352
Chapter 9 O
½244
O F
i
C6F5OH
i, ii, iii,
C6F5O
ii F F
Pb(OAc)4 Dimerisation C6F5O etc.
F
OC6F5
OC6F5 iii
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). X6 +
X6
9.100A
X6
9.100B
+ X6 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 [C6 F6 ], 117 [C6 ðCF3 Þ6 ] and 35 kJmol1 ½C6 ðC2 F5 Þ6 . It appears that the thermal stability of valence isomers increases with the number of perfluoroalkyl substituents. Not the least advantage of fluorocarbon
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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 (CH3)3CC
CF
F
+
F
F
½250
+ 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, C6 F5 XðX ¼ H, CH3 , CF3 , OCH3 Þ [255], and trifluorobenzenes, C6 H3 F3 [256], all form para-bonded species on irradiation. hn F
F6
½254
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,
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354
Chapter 9 F6
F5
F4
MeO
OMe
OMe
NaOMe
½254
+
9.103A F6
F6
Br2
½254
Br Br
9.103A F6
COOH
O3
F
H2O
9.103A
O P2O5
F
O
COOH
½248
O i, ii
i
i, hν ii, hν, furan
F
O F
Figure 9.103
170⬚ C t1/2 9hr (CF3)6
<270nm
½258, 259
>200nm
(F3C)6
>200nm 170⬚ C t1/2 135hr (CF3)6 >200nm
(CF3)6 170⬚ C t1/2 129hr
Figure 9.104
F3C CF3C
CCF3
+
C Cl
Figure 9.105
N N
(CF3)3
(CF3)3
½261
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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 promotors, leading to the conclusion that these processes involve free-radical-promoted formation of diazabenzvalene derivatives [263] (Figure 9.106). RF
RF N F
RF N
R
F RF
RF
N F
N
N
R
½263
N
RF
R −R
RF
RF
N
N
F N
F RF
RF
N
F
N
N
RF
RF
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. RF
F F
RF
N
254nm gas phase N RF
F
N
N
RF
F
i
RF
i
RF N
+
N
N
RF
RF
F
F
F
F
½264, 265
i = hν or heat RF
F RF
F N N
F
254nm gas phase
RF i
F N
F N
+
N
N
RF
RF F
RF
i = hν or heat RF = F , CF(CF3)2 , CF2CF3 , CF(CF3)(C2F5)
Figure 9.107
½264, 265
N
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356
Chapter 9 3
4
4
N
2
5
N
1
N
1
3
N
6
2
5
6
3
3
4
4
N
2
4
N
2
5
N
1
5
N
1
1
N
6
3
N
5
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
>200nm N
(CF3CF2)5
270nm
N
>200nm
½266
(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 b
b
hν
c
c
N
b c
x c b
b +
N
xN y
c
c
y
x a b a
b +
x N
c
½267
b c
heat heat cleavage, y
heat cleavage, x b b c
N
heat cleavage, x
b c
b
a
c N
b a
b
c
a
c N
c
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).
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Polyfluoroaromatic Compounds
357
Adduct ii F RF N
RF
F
RF
RF
RF
F
½268, 269
N
i N
N
N
RF
N
F
RF
RF iii
RF RF F
RF
N F F
−RFCN N
RF
F
RF
RF
RF
F N
RF
N
RF
RF
N
F RF
i = hv; ii = furan; iii = 350⬚ 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
½270
CY
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 S
(CF3)4
(CF3)4
ii
S
(CF3)3 O
ii,
S
heat or Pd Catalyst
hν
X
(CF3)3 X O
X = F or CF3
Figure 9.113
½246
F3C
9.113A i, hν;
(CF3)3
½271
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Chapter 9
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R.D. Chambers, R.P. Corbally, T.F. Holmes and W.R.K. Musgrave, J. Chem. Soc., Perkin Trans. 1, 1974, 108. S. Sole, H. Gornitzka, W.W. Schoeller, D. Bournisson and G. Bernard, Science, 2001, 292, 1901. F.D. Marsh and H.E. Simmons, J. Am. Chem. Soc., 1965, 87, 3529. R.E. Banks, N. Venayak and T.A. Hamor, J. Chem. Soc., Chem. Commun., 1980, 900. R.S. Pandurangi, K.V. Katti, C.L. Barnes, W.A. Volkert and R.R. Kunrz, J. Chem. Soc., Chem. Commun., 1994, 1841. R.D. Chambers and T. Chivers, Organometal. Chem. Rev., 1966, 1, 279. S.C. Cohen and A.G. Massey, Advan. Fluorine Chem., 1970, 6, 83. R.J. Harper and C. Tamborski, Chem. Ind., 1962, 1824. G. Fuller and D.A. Warwick, Chem. Ind., 1965, 651. J. Jappy, Specialty Chemicals, 1995, 15, 58. E. Kinseella and A.G. Massey, Chem. Ind., 1971, 1017. D.E. Fenton, A.J. Park, D. Shaw and A.G. Massey, J. Organometal. Chem., 1964, 2, 437. R.J. Harper, E.J. Soloski and C. Tamborski, J. Org. Chem., 1964, 29, 2385. A.J. Bridges, W.C. Patt and T.M. Stickney, J. Org. Chem., 1990, 55, 773. P.L. Coe, A.J. Waring and T.D. Yarwood, J. Chem. Soc., Perkin Trans. 1, 1995. C. Tamborski and E.J. Soloski, J. Org. Chem., 1966, 31, 743. G.M. Brooke and B.S. Furniss, J. Chem. Soc. (C), 1967, 869. G.M. Brooke, B.S. Furniss, W.K.R. Musgrave and M.A. Quasem, Tetrahedron Lett., 1965, 2991. P.L. Coe, R. Stephens and J.C. Tatlow, J. Chem. Soc., 1962, 3227. R.D. Chambers and D.J. Spring, J. Chem. Soc. (C), 1968, 2394. T.D. Yarwood, A.J. Waring and P.L. Coe, J. Fluorine Chem., 1996, 78, 113. C. Bobbio and M. Schlosser, Eur. J. Org. Chem., 2001, 4533. D.J. Burton and L. Lu in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer Verlag, Berlin, 1997, p. 45. A. Cairncross and W.A. Sheppard, J. Am. Chem. Soc., 1968, 90, 2186. C. Tamborski, E.J. Soloski and R.J. de Pasquale, J. Organometal. Chem., 1968, 15, 494. S.S. Dua, A.E. Jukes and H. Gilman, J. Organometal. Chem., 1968, 12, 24. A. Cairncross, H. Omura and W.A. Sheppard, J. Am. Chem. Soc., 1971, 93, 248. A. Cairncross, W.A. Sheppard and E. Wonchoba, Org. Synth., 1980, 122. R.D. Rieke and L.D. Rhyne, J. Org. Chem., 1979, 44, 3445. G.W. Ebert and R.D. Rieke, J. Org. Chem., 1984, 49, 5280. G.W. Ebert and R.D. Rieke, J. Org. Chem., 1988, 53, 4482. D.J. Burton, Z.Y. Yang and K.J. MacNiel, J. Fluorine Chem., 1991, 52, 251. A.F. Webb and H. Gilman, J. Organometal. Chem., 1969, 20, 281. D.J. Burton and L. Lu in Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates, ed. R.D. Chambers, Springer-Verlag, Berlin, 1997, p. 75. Z.Y. Yang, D.M. Wiemers and D.J. Burton, J. Am. Chem. Soc., 1992, 114, 4402. D.D. Callender, P.L. Coe, J.C. Tatlow and A.J. Uff, Tetrahedron, 1969, 25, 25. D.D. Callender, P.L. Coe and J.C. Tatlow, Tetrahedron, 1966, 22, 419. J. Thrower and M.A. White, Abstracts., 148th Meeting, American Chemical Society, Washington DC, 1964, p. 19K. C. Tamborski, E.J. Soloski and J.P. Ward, J. Org. Chem., 1966, 31, 4230. R.D. Chambers, F.G. Drakesmith, J. Hutchinson and W.K.R. Musgrave, Tetrahedron Lett., 1967, 1705. R.D. Chambers and D.J. Spring, Tetrahedron Lett., 1969, 2481. M.A. Bigneli and A.E. Tipping, J. Fluorine Chem., 1992, 58, 101. D.V. Gardner, J.F.W. McOmie, P. Albriktsen and R.K. Harris, J. Chem. Soc. (C), 1969, 1994.
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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.
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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 dimethyland 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 1
From iodides, bromides and hydro compounds 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 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
365
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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). n-C4H9Li
+
i
i-C3F7I
i-C3F7Li
+
½22
n-C4H9I −LiF
CF3CF=CF2 i CH3Li + C2F5I
ii
[C2F5Li]
C2F5C(OH)PhCH3 +
i, Et2O, −78 C
ii, PhCOCH3, H
88%
½23
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 perfluoroethyllithium 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
∆
½20
CF3HgI 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 CF3 Li, which may have little more than a fleeting existence when generated, to RF LiðRF 5C2 F5 , n- and i-C3 F7 ), CF5CFLi and C6 F5 Li 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 i
CF3CH2CF2H
[CF3CH=CFH]
(−LiF) i, n-BuLi;
i
[CF3C
CH]
367
½27
(−LiF) i
ii, Ph3SnCl Ph3SnC
ii
CCF3
CF3C
CLi
84% i
CF3CFH2
i
[CF2=CFH]
CF2=CFLi
½30
(−LiF) +
i, n-BuLi;
ii
etc.
ii, PhCHO, H
PhCH(OH)CF=CF2 n-BuLi
C6F5H
i
C6F5I
HgCl2
C6F5Li
(C6F5)2Hg
(C6F5)2M
M = Zn or Cd
½11 ½11
i, Zn (200 C) or Cd (230 C)
Figure 10.3 −LiF
CF3Li
CF2=CFLi
−LiF
[ CF2]
[CF
etc
CF]
or
[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
+
[Re(CO)5]
−
½6
F Re(CO)5
N
[πC5H5Fe(CO)2]
N
½6
N
−
+
F
F
N Fe(CO)2πC5H5
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). −
F
i
−
+ CF2=CFCF3
(CF3)2CF
Hg[CF(CF3)2]2
½31
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
i, H2SO4, Et2O i
i-C3F7Li
N.B.
Little or no i-C3F7H formed
½22
66%
EtCH(i-C3F7)OH
½22
53%
i, EtCHO, H2SO4 ICF2CF2I
+
i, ii
[n-C4F9Li + MeCHO] i, −80 C to −85 C
[MeCH(OH)CF2-]2
½32
+
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].
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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
F
D2O
F
Et2O, −40 C Li
H
D
Furan I2
½37
F
i, MeCHO
MeI
+
ii, H
F 10.8A
F I
F Me
F CH(OH)Me
F O
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).
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370
Chapter 10 i
CF2=CFBr
CF2=CFMg
H2SO4
CF2=CFH
43%
½40
i, Mg + I2, THF, ~ −22 C i Me2SnCl2
+
65%
½42
CF2=CFLi + C4H10
½28
Me2Sn(CF=CF2)2
Mg
i, CF2=CFBr, THF, 0 C CF2=CFH + n-BuLi
i
i, Et2O or THF, −78 C ii, CO2
ii iii
iii, H+
CF2=CFCOOH H F
65%
½26
Li + MeLi
(CF2)n
Et2O −70 C
F
CH4 + (CF2)n
i, MeCHO ii, H+
n = 1, 23% n = 2, 42% n = 3, 63%
CH(OH)Me F (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 CF3 CH2 CF2 H [27] (Section IA, Subsection 2) is more direct. i CF3C
CH
+
n-BuLi
C4H10
+
CF3C
i, C5H10, Et2O, −78 C
CLi
½43
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
D
371
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
C6F5MgBr
(C6F5)4Si
½44
i, SiCl4, Et2O i
C6F5MgBr
(C6F5)2Hg
½45
73%
i, HgCl2, Et2O
½46 C6F5Li
i
(C6F5)3B
50%
i, BCl3, Pentane/Hexane, −78 C to rt CF3
CF3 F3C
n-BuLi
F3C
CF3
CF3 Li
MX2
F3C
M
CF3 M = Zn, Cd, Hg.
½47, 48
CF3
2
10.11A
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).
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372
Chapter 10
i
n-C3F7I
~155 C
n-C3F7ZnI
i, Zn, Dioxane, 100 C, ii, Removal of Solvent
CF3CF=CF2
½51
ii
n-C3F7ZnI/dioxane
n-C3F7COCl
(n-C3F7)2CO 15%
i
n-C3F7I
ii
n-C3F7ZnI
½50
n-C3F7ZnI/dioxane
i, Zn, Dioxane, 100 C, ii, Removal of Solvent
H2O
100 C
n-C3F7H
96%
Figure 10.12 Ph C3F7I
Ph
i
+
½53
66%
Br
C3F7 i, Pd(Ph3P)4, Zn, THF
Ph C3F7I
Ph
i
+
71%
Br
½53
C3F7 i, Pd(Ac)2, Zn, THF CF3I
+
HOCH2C
i
CH
CF3CH=CHCH2OH
½53
61%
i, CuI, Zn, THF C2F5I
i
+
½53
51% C2F5
i, Cp2TiCl2, Zn, THF CF3I
+
PhCHO
Zn DMF
PhCH.OHCF3
72%
½53
OH CF3CCl3 +
PhCO
Zn DMF
½54
86% Ph
CCl2CF3
Figure 10.13
CF2=CFBr
Figure 10.14
Zn DMF
[CF2=CFZnBr]
Me3SiCl
CF2=CFSiMe3
65%
½55
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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
ZnCl
Cl F
F
N
N
½56 25%
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). CF3
CF3
F
i
F
ZnCl
CF3 Br2
½57
F
Br
i, Zn, SnCl2, DMF, Ultrasound
Figure 10.16
B 1
Mercury 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. Perfluoroalkyl 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).
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374
Chapter 10
CF3I
+
80% (i)
i or ii
Hg
CF3HgI
½20
22% (ii) i, hν (150 C), or ii, ~275 C i
½61
(CF3)2Hg
(CF3COO)2Hg i, K2CO3, 120 to180 C
Figure 10.17
CF3CF=CF2
+
HgF2
i
[(CF3)2CF]2Hg
60%
½62
[(CF3)2CF]2Hg
65%
½31
[(CF3)3C]2Hg
66%
½31
i, Anhyd HF, 110 C CF3CF=CF2
+
HgCl2
i
i, KF, DMF, 40 C (CF3)2C=CF2
+
HgF2
i
i, KF, DMF, −78 C
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). CF2=CFLi
+
HgCl2
C6F5MgBr
+
HgCl2
COO
Et2O
(CF2=CF)2Hg
52%
½41
(C6F5)2Hg
73%
½45
Hg
Hg ∆
F N
Et2O
2
½64
F 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 C6F5H + Hg(OCOCF3)2
150 C
C6F5HgOCOCF3
85%
½65
i
i, EtOH, NaI, rt
(C6F5)2Hg 2−
375
72% −
−
(C6F5)2Hg + 4Br
C6F5H + HgBr4 + 2 OH
+ 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(diphenylphosphino)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). (C6F5)2Hg + KOH
t-BuOH 100C
(4-HOC6F4)2Hg
½67
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). (C6F5)2Hg
(C6F5)2Hg
S 250 C Sn 260 C
(C6F5)2S
82%
½68
(C6F5)4Sn
60%
½68
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 fourcentre process [45] (Figure 10.23). An order of susceptibility to electrophilic attack may be formulated as C6 H5 > C6 F5 > C6 Cl5 > CH3 , which correlates with similar cleavage reactions of tin derivatives. These reactions have applications in the synthesis of boron and aluminium compounds.
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Chapter 10
F (C6F5)2Hg
+
2 C6F5HgCl
HgCl2 C6F5Hg Cl
δ+ HgCl δ−
HCl (g) C6F5HgCH3
½45
C6F5H + CH3HgCl HCl (g)
C6F5HgC6H5
C6H6
½45
½45, 70
+ 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 CF3 BF2 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 CF3BF2
F
C F
10.24A
BF2
or
F
C
BF2
F 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 Markovnikov or anti-Markovnikov additions may be obtained, depending on the hydroborating system; dicyclohexylborane, Chx Þ2 BH, 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
iii, ii
OH
i,ii
½73, 74
RFCHOH.CH3
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,
377
HBCl2, Hexane; ii, H2O2, alkaline; iii, (Chx)2BH, THF
Figure 10.25
X B
X B
RF X
10.26A
RF
B
RF
X
10.26B X = O- or N<
Figure 10.26
Several salts containing the anion ½RF BF3 ðe:g: RF ¼ CF3 , C2 F5 Þ 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-C3 F7 H 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 CF3 BF2 CF2 5CFBF2 < C6 F5 BF2 [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 C6 F5 BF2 rather than ½C6 F5 BF3 indicates that C6 F5 BF2 is a weaker Lewis acid than BF3 , i.e. CF3 BF2 > BF3 > C6 F5 BF2 . A complex salt 10.29A can, however, be obtained by addition of C6 F5 BF2 to an aqueous solution of potassium fluoride; the salt undergoes a novel elimination process on pyrolysis, giving polyphenylenes 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).
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Chapter 10
i Me3SnCF3
aq. KF
Me3Sn(CF3BF3)
K(CF3BF3) + Me3SnF ∆
i, BF3, CCl4, −196 to −20C CF2=CF2
F
+
F
+
[ CF2] + KBF4
Unchanged O
O
i B
½75
Cl
120C, 3hr B
O
½76
C3F7 172C,12hr
O 30%
n-C3F7H
i, n-C3F7Li, −50C, Et2O
n-C3F7Li
(Me2N)2BX
10.27A
25%
½76
(Me2N)2BC3F7 10.27B
Figure 10.27
i
Me2Sn(CF=CF2)2
CF2=CFBCl2 + Me2SnCl2
½77
93% i, BCl3, rt SbF3 CF2=CFBF2 i
Me3SnC6F5
Me3SnBF2
+
59%
C6F5BF2
½78
i, BF3 CCl4 Me3SnC6F5
BCl3
C6F5BCl2
C6F5BF2
½78
Figure 10.28
C6F5BF2
+
KF
H2O
K(C6F5BF3) 10.29A
Figure 10.29
300 C
KBF4
+
-(C6F4)-n 10.29B
½79
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 379
Organometallic Compounds 194 C
C6F5BF2
BF3
+
379
½78
(C6F5)2BF
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
C6F5BCl2
C6F5B(OH)2
H2O
C6F5B(OH)2.OH2
½78
89%
i, H2O, Acetone, −78 C
Base
H2O
C6F5H + H3BO3
C6F5B(OH)3
Figure 10.31
Tris(pentafluorophenyl)boron forms etherates but it can also be obtained uncoordinated in a hydrocarbon solvent (Figure 10.32). i
(C6F5)3B
3 C6F5Li + BCl3
½46
50%
i, Pentane/Hexane, −78 C to rt 3 C6F5MgBr + BF3.OEt2
i
(C6F5)3B
80%
½81
i, Toluene, Reflux
i (C6F5)3B
(C6F5)4BLi
½46
ii
i, C6F5Li, Et2O, Hexane, −78 C ii, Pyridine
(C6F5)3B.NC5H5
Figure 10.32
The contrast in thermal stability between ðC6 F5 Þ3 B and CF3 BF2 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
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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-C3 F7 Þ2 AlI2 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). Attempts to remove the ether from the etherate, 10.34A, inevitably led to explosions. 3C6F5MgBr + AlBr3
Et2O −20 to 0 C
(C6F5)3Al.OEt2
½81, 85
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. C6F5HgMe + AlBr3
i
i, Petroleum, 70 C, 5days
C6F5AlBr2 + MeHgBr 10.35A C6F5HgMe (C6F5)2AlBr + MeHgBr 10.35B
Figure 10.35
½85
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 381
Organometallic Compounds C6F5 Al Br
Br Br Al Br C6F5
C6F5 Al C6F5
381
Br Br Al 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). C6F5AlBr2 + MeCH=CH2
C6F5Al(C3H6)Br2 +
CHMe
½86
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 polysiloxanes, manufactured by Dow Corning Co. (Figure 10.39). The siloxane 10.39A chars at 150–2008 C and 10.39B decomposes above 2008 C to 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]
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Chapter 10
(Figure 10.41), or simply heating bromotrifluoromethane with ðCH3 Þ3 SiCl and aluminium powder, is particularly effective [97] (Figure 10.42). Et2SiCl2 + n-C3F7Li
hν
MeSiHCl2 MeCl2Si
~ −50 C
Et2Si(n-C3F7)2
10%
+ Et2Si(n-C3F7)Cl
17%
+
MeCl2Si
+ CF2=CF2
½34
H
½90
MeCl2SiCF2CF2 MeSiHCl2 H2O
[MeSi(CF2CF2H)O]n hν
SiHCl3 + CF2=CF2
MeCl2SiCF2CF2H + MeCl2Si H2O
HCF2CF2SiCl3
etc
[HCF2CF2SiO1.5]n
½91
10.39A hν
SiHCl3 + CF2=CH2
H2O
HCF2CH2SiCl3
[HCF2CH2SiO1.5]n
½91
10.39B hν
SiHCl3 + CF3CH=CH2
H2O
CF3CH2CH2SiCl3
[CF3CH2CH2SiO1.5]n
½91
10.39C
Figure 10.39
Si
∆
C
Si
F +
C
F
C
∆
C
Si
Si
F +
F
Figure 10.40 i
CF3Br
Me3SiCF3
½93
i, Me3SiCl, anisole - HMPA (5 : 1) Sacrificial Al anode, Bu4NPF6 ( electrolyte) CF3Br + 2e −
CF3
+
+
−
Br
−
Me3SiCF3 + Cl
Me3SiCl
Anode: 2/3 Al0
Figure 10.41
−
CF3
2e
2/3 Al3+
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 383
Organometallic Compounds CF3Br
+
i
Me3SiCl i,
62%
Me3SiCF3
383
½97
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 R1
+
½94
CF3SiMe3
2
R
−
F3C
NBu4 F
R1
FSiMe3
OH R2
H+
CF3SiMe3
F3C
O
R1
R2
NBu4 F3C
TMS
R1
R2 O
F3C Me
Si
F3C
O
R1
R2
C R1
Me
R2
Me NBu4
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 Me3 SiCF3 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, ðCF2 5CFÞ4 Si, Et2 SiðCF5CF2 Þ2 and Et3 SiCF5CF2 , 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).
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384
Chapter 10 i, ii
RCOOCH3
½94
RCOCF3
i, Me3SiCF3, THF, TBAF, −78 C
R = Ph = C6H11
ii, H+ R1
Ph
R1
Ph
i 2
R
78% 72%
R2
F3C
½94
41 − 86%
N
N
SiMe3 i, Me3SiCF3, THF, TBAF O
O
H i
R1
S N
t-Bu
CF3
t-Bu
½94, 98 R1
S N H
i, Me3SiCF3, THF, TBAF, −55 C
Yield
R1 = p-ClC6H4
(RS1S)/(RS1R)
95%
>99
= Ph
80%
97 : 3
= t-Bu
75%
99 : 1
Figure 10.44 i
Ph2CO + CF3H
Ph2C(OH)CF3 i, (Me3Si)3N / Me4NF,
72%
DMF
N(SiMe3)3 O
Me2N
Me3SiF
H
R1 R
F3C
N(SiMe3)2 CF3H
N(SiMe3)3 N
O F3C
O
NMe2 H 10.45A
M
O
CF3 R
O
F3C R1
R1 R + Me2N
O R
Figure 10.45
½96
OSiMe3
F
R1
O H
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 385
Organometallic Compounds
385
RFSiMe3
½99
+1e i RFI
+
TDAE
ii
[RFI]
RF
Transfer
55−81%
i, (Me2N)2C=C(NMe2)2 ii, Me3SiCl RF = C2F5, n-C3F7, n-C4F9
Figure 10.46
CF2=CFMgI
SiCl4
15%KOH
(CF2=CF)4Si
−15 C
−110C
CF2=CFH
½100
Figure 10.47
Et2O
Et3SiCF=CF2 + RLi
Et3SiCF=CFR + LiF
10.48A
R = Ph
½102
76%
= C4H9
79%
Figure 10.48
B
Tin [15]
Some syntheses of perfluoroalkyl and polyfluoroalkyl derivatives are shown in Figure 10.49. hν Me3SnSnMe3
+ RFI
Me3SnRF
or ∆
½25, 105
+ Me3SnI
RF = CF3, C2F5, etc 90 C
n-Bu2SnH2 + 2CF2=CF2
Me3SnSnMe3
4hr
+ CF2=CF2
Me2SnCl2 + Mg
i
hν
n-Bu2Sn(CF2CF2H)2
Me3SnCF2CF2SnMe3 Me2Sn(C2F5)2
34%
28%
½106
½107 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 fiveco-ordinate species, such as 10.50A, rather than an SN 2-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
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Chapter 10 HO
+
Me3SnCF3
[(Me3Sn(OH)CF3] 10.50A CF3H
+
Me3SnOH
+ OH
Figure 10.50
i I
Me3SnI +
+ Me3SnCF3
½109
CF3
i, NaI, DME, 80 C −F F
F 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 ðCH3 Þ3 SnCF3 , difluorocarbene is probably formed (Figure 10.52); see Chapter 6, Section IIIA, Subsection 3. CF2=CF2 Me3SnCF3
150 C
Me3SnF +
CF2 F
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 ðCH3 Þ3 SnC6 F5 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). −
[Me3(C6F5)SnX]
−
Me3SnOH + C6F5H + X
Figure 10.53
½111
−
Me3SnC6F5 + X
−
[Me3(C6F5)SnX (H2O)]
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). CF=CF2
I
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 CF2 5CF C6 H5 > CH2 5CH > alkyl > perfluoroalkyl [42], and p-MeC6 H4 > C6 H5 > C6 F5 > Me [111], illustrating the effect of electron withdrawal by fluorine; nevertheless, quantitative work on the acid cleavage of Me3 SnC6 F5 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(C6F5)4Sn + SnCl4
3(C6F5)3SnCl
7days
(C6F5)4Sn + 3 SnCl4
140C 11 weeks
4 C6F5SnCl3
½114
½114
Figure 10.55
The trichloride is more effectively made by cleavage of methylpentafluorophenylmercury [111] (Figure 10.56). C6F5HgMe + 3 SnCl4
20C 20 hours
C6F5SnCl3 + MeHgCl
½111
Figure 10.56
Cleavage of tetrakis(pentafluorophenyl)tin does not occur with boron halides, but pentafluorophenylboron halides can be obtained from ðCH3 Þ3 SnC6 F5 [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
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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 ½CF3 CuI 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
i
CF3I + Cu
PhI
[CF3Cu]
389
½118
PhCF3
i = DMF, ~135 C i
½119
n-C6F13I N
Br
Br
N
n-C6F13
n-C6F13
i = Cu, DMSO, 125−130 C i
I(CF2)3I + 2 ICHCHCl
ClHCCH(CF2)3CHCHCl
½120
i = Cu, Pyridine, 100 C CHF2Cu + CH
i
CCMe2Cl
HCF2CHCCMe2
½121
78%
i = DMF, −55 C i CF3Cu
+
I
½14
S
S
CF3
i = DMF, HMPA, 70 C NH2
NH2 N CF3Cu
+
N
N
i
I
½122
N
F3C N
N
N
AcO
N
AcO O
OAc
O
OAc
OAc
OAc
i = HMPA
Figure 10.57 i CF3CF2CO2Na + p-ClC6H4I
p-ClC6H4CF2CF3
i = DMF, HMPA, 170 C, Cu2I2
½125
54%
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 CF3
Cl
NO2
NO2
½126
i
CF3SO2Cl + Cu +
NO2
NO2 i = DMAC, Heat
Figure 10.59 CF2XY + M (Zn, Cd, Cu) [ CF2]
CF3
½14
Me2NCHF F
+ [ CF2] +
[ CF2]
Me2NCHF2 + CO
Me2NCHO
Me2NCHF2 F
MXY +
CF3
MXY
CF3MX + (CF3)2M
Figure 10.60 i
FSO2CF2I + PhI
½127
PhCCF3 80%
i = Cu, DMF, 60−80 C. ~6Hr. i FSO2CF2COOMe
ii [CuCF3]
i, CuI, DMF/HMPA, Pd(PPh3)4 ii, PhCHCBr2
PhCHC(CF3)2
½128
55 %
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 F3C
F
F3C
F
F3C
Cu
Ph
I
F
F Ph
F
391
F
½15
CF3 54%
F
½15
F Cu
CF2=CFCu
CF3C
CCF3
F CF3
F3C I2 F
F I
F CF3
F3C 63%
½129
(CF2)n (CF2)n (CF2)n I
Cu
(CF2)n
(CF2)n
I (CF2)n n = 2, 3
Figure 10.62 C6F5I
½15
Activated Cu C6F5M + CuX M = Li, MgBr, CdX X = Cl, Br, I
C6F5Cu
C6F5H + LiCuMe2
60 C C6F5COOCu
C6F5Cu + CF2CFI
C6F5Cu + CH2I2
Figure 10.63
C6F5CFCF2
(C6F5)2CH2
88%
½15
70%
½15
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 392
392
Chapter 10
CF3CF=CF2
THF
π-C5H5Fe(CO)2Na
½130
CF3CF=CFFe(CO)2πC5H5 + NaF (CO)5MnCF2CF=CF2
CF2=CFCF2Cl
(CO)5Mn M
½131; 132
M = Li, Na (CO)5MnCF=CFCF3 C6F6 +
C6F5Ru(CO)2π-C5H5
[π-C5H5Ru(CO)2]
½133
Figure 10.64
π-C5H5Co(CO)2 + CF3I
Benzene
π-C5H5Co(CO)(CF3)I + CO
½134
MeCF2CF2Re(CO)5
½135
(Ph3P)2Pt(CF=CFCl)2
½136
hν
MeRe(CO)5 + CF2=CF2
Benzene
(Ph3P)4Pt + CF2=CFCl
Figure 10.65
X F
X F
F
½138, 139
F
i N
Br
Br
RC
C
N
C
CR
R = Ph, C3H7
X = Br, CF(CF3)2 i = RC
CH, CuI, (Ph3P)3PdCl2 , Et3N CF=CF2 i
CF3CFH2 + ZnCl2 i = LDA, THF, 15−20 C ii = RC6H4I, Pd(PPh3)4, Heat
[CF2=CFZnCl]
½140
ii
R 61−86%
Figure 10.66 Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 393
Organometallic Compounds Ar
F
H
Br
i
Ar
F
H
Br
Ar
ii
½141
Ph
H
100% Z isolated, 73%
High E/Z ratio
E/Z ~1:1
F
393
Ar = p-FC6H4i, −20 C, 7 days ii, PhSnBr3, Pd[(PPh3)]4, CuI, DMF, rt
F
F Bu3Sn
CF2CF
SiMe3 i,
½142
F
F
i
+ CF2=CFI
SiMe3
Pd[(PPh)3]4, CuI, DMF, rt
Ph
F
H
Br
Ph
i, ii
Br
Ph
F
H
H
½143
+ H
E/Z 1:1
F 100% Z
i, iii
i, Cl2Pd(PPh3)2 ii, HCOOH, n-Bu3N, DMF, 35 C iii, CO, 160psi, n-BuOH, n-Bu3N, 70 C
Ph
COO n-Bu
H
F
I
4
½144
i R
4
RF
R i, PdCl2[PPh3]2 , Et3N, CuI
RF
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 F
F
F
F
½139
L2Pd(0) N
N
Br
Br
Br
R
X
X
F
L2Pd(II) N
F
F
Br
L2Pd(II)
F
N
Br
Br R X
Et3NHBr
R
H
F
F
Et3N L2Pd(II) N
H
X = Br, CF(CF3)2
R
Br
Br
L = Ph3P
Figure 10.67
i
F N
½145
HCl
F
F
PEt3
N
N
Ni
Et3P
H
F
i, Ni(COD)(PEt3)2 F
Et3P Ni i F
F
i, Ni(COD)(PEt3)2
Figure 10.68
Heat [Complex]
F
F
PEt3
½146
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).
[Ni(COD)2]
F
PEt3
F
½147
N
Cl
N
Et3P
Ni
PEt3
Cl I2 I
MeLi −[Ni] N F
F N Et3P
Ni
PEt3
Me O
CO −[Ni] Me
F N
PEt3
H
O Me
F N
Figure 10.69
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Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 399
Index
acid fluorides elimination of COF2 , 146 acid strengths, 93, 98 aerosol fluorination, 37 alcohols, 254–7 acidity, 93 diols, 255–6 aldehydes reactions, 243 synthesis, 243 alkali metal fluorides use in synthesis, 27–31, 47–9 alkenes acidities, 115 addition of 1,3-dipoles, 212–13 addition of fluorine, 77–9 addition of HF, 76–7 addition of radicals, 196 cycloadditions, 205 electrophilic addition, 101, 191–6 nucleophilic attack, 174 oxidation, 200–201 polymerisation, 203–5 rearrangement, 176 alkoxides, 251–4, 257–8, 269 alkynes synthesis, 218–22 allenes, 218 allylic cations, 102–3 aluminium, see organometallics amides, 241 amine hydrofluorides, 62 reactions with epoxides, 69 amino-acids diazotisation, 74 reaction with hexafluoroacetone, 248 amorphous polymers, 204–5 anaesthetics, 6 anhydrides, 241–2 aromatic compounds, 296 carbene additions, 338 free radical attack, 338
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
introduction of fluorine, 297–300 nitrene additions, 338 arynes, 346–9 aza-alkenes, 278–84 azabenzenoid compounds, 304–6, 315–32 azo compounds, 284 photolysis, 284 Balz-Schiemann reaction, 73, 108, 300–301 base strengths, 94 biological applications, 5 biotransformations, 9 bis(perfluoroalkyl)alkynes, 218 bistrifluoromethyl nitroxide, 278 bistrifluoromethylcarbene reactions of, 155–6 structure, 158 bistrifluoromethylthioketene, 274 bond energies, 13 boron derivatives, see organometallics bromine trifluoride, 51 bromofluoroalkanes reaction with phosphines, 123 synthesis, 41 bromopentafluorobenzene, 339 Burton, 123 caesium fluoroxysulphate, 57, 79, 82 capto-dative substituents, 209 carbanions, 15, 96, 107–10 effects of F, 109 formation by addition of fluoride ion, 186, 241 H/D exchange, 107, 109, 111, 114 internal return, 108 pentakis(trifluoromethyl)cyclopentadienyl, 111, 114 perfluorocyclopentadienyl, 110, 114 pKa values for methane derivatives, 109 s-complexes, 112 stable salts, 112, 113, 173 stereochemistry, 110
399
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 400
400
Index
carbanions, (cont’d) synthesis of iodo derivatives, 241, 253 trapping of intermediates, 173, 186–7, 241 see polyfluoroalkylation carbenes fluorocarbenes, 147–59 from haloforms, 147 from halo-ketones and -acids, 149 from organometallic compounds, 149, 157, 386 from organophosphorus compounds, 151 (perfluoroalkyl)carbenes, 154–6, 158 push-pull stabilisation, 344 structure, 156 via pyrolysis and fragmentation reactions, 151 carbocations, 15, 99 long-lived, 102–5 polyconjugated systems, 105 polyfluorobenzenium, 104 trifluoromethyl, 104–5 carbonyl compounds reactions with SF4 and derivatives, 66 fluorination, 58–60, 66 carboxylic acids, 236 pKa values, 93, 98, 236 strengths, 92, 98, 236 synthesis, 237–40 CFCs, 4 Charlton n valves, 91–2 chlorine-fluorine exchange, 24–7 catalysts, 24, 25 chlorine monofluoride, 51 chlorofluorocarbons, 4 synthesis, 24–7 chlorotrifluoroethene polymer, 6 ciprofloxacin, 7 cobalt trifluoride, 32, 297–8, 301 copper compounds, 346 coupling reactions, 216, 389–91 organometallics, 387–91 cubane derivatives, 210 cuneane derivative, 209–10 cycloadditions, 205–12 cyclobutadiene intermediates, 210, 354 cyclo-octatetraene derivatives, 210, 216, 354, 391 cyclopolymerisation, 205 Cytopt, 6
DAST, 63–5, 70 decarboxylation, 145–6, 171 defluorination electrochemical, 297 of perfluoroalkanes and cycloalkenes, 164–5 of trifluoroethanol derivatives, 146 using phosphorus compounds, 250 using SnCl2 , 247 using tetrakis(dimethylamino)ethene, 215 Demnumt fluids, 5, 262 Desflurane, 6 DFI, 65, 67 diazirines, 147, 284, diazo compounds, 147, 284, diazonium salts, 73, 108, 301 dications, 104–5 Diels-Alder reactions, 209–12, 214, 218 dienes, 214–18, 391 charge transfer salts, 218 electrophilic attack, 339 epoxidation, 217 heterodienes, 247 nucleophilic attack, 176, 217 photolysis, 218 strain, 176 diethylaminosulphur trifluoride, see DAST difluorocarbene, 148–51, 156–8 2,2-difluoro-1,3-dimethylimidazoline, see DFI diols, 255–6 dioxirane formation, 249 1,3-dipoles, 213 displacement of fluorine from aromatic compounds, 307–36 from fluorinated alkenes, 132–3 dithionylium salts, 73, 300 DOPA, 9 dyes, 12 ECF, 33–5, 61, 171 electrochemical fluorination, 33–5, 61, 266 electronegativity, 13 electronic effects, 13, 16, 169 electron pair repulsion, 109, 110 electron transfer processes formation of cyclopentadienylides, 114 oxidative fluorination, 61 see also single electron transfer electrophilic aromatic substitution, 94, 99, 100, 299 in pentafluorobenzene, 339 electrophilic fluorinating agents
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 401
Index
containing N–F bonds, 58 containing O–F bonds, 56 FITS reagents, 126 fluorine, 52, 299 electrophilic perfluoroalkylation, 126–9 elimination reactions, 137 a-eliminations, 147 b-eliminations, 137–47 conformational effects, 140–41, 143 effect of leaving halogen, 137 ElcB processes elimination of hydrogen halide, 137 elimination of metal fluorides, 144 formation of alkenes, 169–71 formation of aromatics, 297–8 formation of carbenes, 147 formation of di-enes, 215–8 norbornyl systems, 145 polyfluorinated cyclic systems, 142 regiochemistry, 139 syn-/anti-elimination, 140 from trifluoroethanol, 146 enols, 251 epoxides, see oxiranes ethers iodoethers, 253 synthesis, 253 FAR reagents, see fluoroalkylamine reagents FEP, 6 FITS reagents, 126, 222 Flemiont, 5, 6 fluoride ion acid catalysis, 129–30 addition to alkenes, 77, 173 addition to alkynes, 77, 185 catalysts, 47–9 F/Cl rate constant ratios, 129 induced reactions, 185–91 as a leaving group, 128–31 oligomerisation of F-alkenes, 188–91 reactions with fluoroalkenes, 174, 253, 367 reactions with ketones, 251–4, 257–8 reactions with oxiranes, 257–8 rearrangements induced, 174, 187–8 solvents, 28, 48 source, 28, 49 synthesis of iodoperfluoroalkanes, 241 use in synthesis, 28–31, 47–50 see HALEX reactions see polyfluoroalkylation reactions with alkynes, 331–3
401
fluorinase, 10, 11 fluorinated alkenes LUMOs, 175 reactions with nucleophiles, 132, 171–85 reactions with transition metal anions, 368 reactivity order, with nucleophiles, 174 rearrangement by fluorine, 174 synthesis, 166 fluorinated alkynes stability, 169, 218 synthesis, 218–22 fluorinated allenes reactions, 219 synthesis, 218–19 fluorination alcohols, 62–6 alkenes, 56, 77–80 amino-acids, 54, 55 aromatic systems, 53, 57, 63 carbanions, 58 carbohydrates, 65 carbonyl compounds, 66–9 decalin, 53, 55 dicarbonyl comounds, 55, 57, 59, 62 esters, 58, 127 nitro compounds, 57 nitrogen-containing functional groups, 275 nucleosides, 59 oxidative, 61 phosphonates, 58 selective, 47 steroids, 53, 63, 66, 78, 79 thioethers, 72 fluorine aerosol fluorination, 37 bond energy, 35 control of reactivity, 36 as an electrophile, 52–4, 299 fluorine-18, 2 mechanism of fluorination, 35, 53–4 reaction with hydrazones, 75–6 replacement of hydrogen by fluorine, 51–5 selective fluorination, 51–5 stereochemistry of substitution, 53–5 use in synthesis of highly fluorinated compounds, 35–40 use of microreactors, 38 fluorine displacement addition-elimination mechanism, 131 F/Cl reactivity ratios at unsaturated sites, 131–2 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) from unsaturated sites, 131–5 see nucleophilic aromatic substitution fluoroalkylamine reagents, 65–6 enantioselectivity, 65 mechanism, 66 use in supercritical CO2 , 65 fluoroalkynes, 218 fluoroaromatics aryne generation, 346–9 free radicals, 349–51 lithium derivatives, 345 synthesis, 296 valence isomers, 351–7 see nucleophilic aromatic substitution fluorodediazotisation, see Balz-Schiemann reaction 2-fluorodeoxyglucose, 7, 9 fluorodesulphurisation, 71–3 fluoroformates decarboxylation, 70, 71, 300, 302 fluoromethyl cations, 104 5-fluorouracil, 6, 7, 8 fluorous biphase techniques, 166 fluoroxy compounds, 258 synthesis, 259 fluorspar, 23, 24 Fluothanet (halothane), 6 Fomblint fluids, 5 frontier orbitals, 98 graphite fluoride, 39 HALEX process, 300, 303–6 halofluorination, 80–82 halogen exchange, 300, 303–6 halogen fluorides, 40, 80, 77, 72, 64, 62, 80–82 halonium ions, 105–7 halophilic processes, 123 halothane, 6 Hammett s values, 94–5, 100 heteroaromatic compounds boiling points, 306 polyfluoroalkylation, 327 synthesis, 298, 300–306 via cyclisation reactions, 332–5 heterodienes synthesis, 247, 355–7 hexachlorobenzene reaction with KF, 297 hexachlorobutadiene, 27 hexafluoro-2-butyne, 31, 220, 222
cycloadditions, 222, 224–6 formation of poly-enes, 331–3 free-radical additions, 226–7 polymerisation, 223–4 reaction with carbenes, 354 reactions with sulphur, 226 trimerisation, 296 hexafluoroacetone, 27–8, 243 cleavage, 248 formation of a dioxirane, 249 formation of heterodienes, 247 formation of peroxides, 248–9 reaction with water, 248 Wittig reaction, 250 hexafluorobenzene, 296–7 reaction with carbenes, 342–3 hexafluoropropene cycloadditions, 206, 211 formation of oligomers, 188 in polyfluoroalkylation, 327–8 radical additions, 197–204 reaction with SbF5 , 102 reaction with SO2 F2 , 272 reactions with electrophiles, 193–6 reactions with nucleophiles, 174, 177 sodium sulphite addition, 269 synthesis, 170–71 hexafluorothioacetone, 274 hexakis(trifluoromethyl)benzene, 296 HFCs, 4 high valency metal fluorides, 31 Hunsdiecker reaction, 240 hydrogen-deuterium exchange, 138–9 hydrogen fluoride, 23 additions to alkenes and alkynes 76–7, 193 amine hydrofluorides, 62, 68–70 cleavage of ethers and epoxides, 69, 71 diazonium salts, 73–4 electrochemical fluorination, 33–5 hazards, 23 reactions with azirenes and aziridines, 74–5 use in synthesis, 24 use with lead tetra-acetate, 61 hypofluorites, 56, 82 formation, 254 Ip effect, 98 imaging techniques, 7 imines, 275–6, 278–83 inductive effects, 94, 97, 169 industrial applications, 3 inert fluids, 4
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 403
Index
iodine pentafluoride, 271 fluorination of dicarbonyl compounds, 62 see iodoperfluoroalkanes iodoperfluoroalkanes formation of copper compounds, 389–91 formation of organometallics, 365–6, 368, 372–3 reactions with nucleophiles, 123–6, 194 synthesis, 41, 202–3, 241, 253 synthesis of alkynes, 221 2-iodoperfluorobutane, 125 2-iodoperfluoropropane, 241 Ishikawa reagent, 65, 66 Isofluranet, 6 ketones addition of fluoride ion, 251 enantioselective reduction, 10, 11 formation of heterodienes, 247 free-radical reactions, 250–51 protonation, 105 reactions, 243–54 synthesis, 243–5 kinetic acidities, 96, 111, 109, 113, 115 Krytoxt fluids, 5, 262 LaMar process, 36 lead tetra-acetate-hydrogen fluoride, 61 lithium derivatives, 345, 366–9 from alkenes, 369 from trifluoropropyne, 370 norbornyl derivatives, 145, 369 vinyl compounds, 370 lubricants, 5 Lumiflont, 5 macrocycles, 335 magnesium derivatives, 368 Meisenheimer s-complexes, 113 mercurials, 366, 373–6 generation of carbenes, 150 metal fluorides eliminations, 145 as fluorinating agents, 23–32, 47–9 microreactors, 38 Moissan, 2 monofluoroacetate, 9 Nafiont, 5, 6, 268 naturally occurring compounds containing C–F, 1 negative hyperconjugation, 16, 94–7
in perfluoroalkanes, 163 nickel insertion reactions, 394–5 nitrenes, 344 nitro groups displacement by fluoride ion, 75 nitrogen derivatives, 236, 275 nitrosoalkanes, 277 nitroxides, 278 nomenclature, 16–19 nonaflates, 265 norbornyl cation, 106 nucleophilic aromatic substitution from alkenes and cycloalkenes, 171–85 attack on nitrogen, 329 benzenoid compounds, 307–15 effect of acid, 324–5 effect of ring N, 315 fluoride-ion-induced reactions, 325–31 HOMO-LUMO interaction, 175 mechanism, 134, 307 orientation of substitution, 312–14, 319, 321–5 pyridine derivatives, 315–25 substituent effects of F, 312–14 nucleophilic displacement of halogen from fluorocarbon systems, 122 from alkanes, 132, 171–85 from arenes, 133, 307 from cycloalkenes, 171–85 effect of F substituents, 123 HOMO-LUMO interaction, 175 mechanisms, 123, 124 SN 1 SN 2 processes, 122 nucleosides fluorination, 59 Olah generation of stable carbocations, 102 Olah’s reagent, 62 oligomerisation of fluorinated alkenes, 188–91 organometallic compounds aluminium, 380–81 boron, 376–80 cleavage reactions, 366, 375–6, 380–81 copper, see copper from cyclo-alkanes, 369 mercury, 373–6 nickel insertion reactions, 394–5 norbornyl derivatives, 369 palladium coupling, 392–4 polyfluoroaryl, 367, 371
403
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 404
404
Index
organometallic compounds (cont’d) from polyfluoroiodoalkanes, 365–7, 368 tin, 366, 370, 375, 378, 385 transition metals, 387 via fluoride addition, 367 vinyl derivatives, 370 zinc, 371–3 oxetanes, 262 oxidation of F-alkenes, 260–61 using bis(trifluoromethyl)dioxirane, 249 using fluoroketones, 248–9 using peroxytrifluoroacetic acid, 242 oxiranes reactions with hydrogen fluoride, 69, 71, 180, 217, 254, 255 ring opening, 257, 263–4 synthesis, 259–61 oxygen derivatives, 236 ozone depletion, 4 palladium coupling, 392–4 PCTFE, 6 pentafluorophenyl compounds from hexafluorobenzene, 307 pentafluorophenyl group acidifying effect, 115 pentafluorophenyl lithium, 366 pentafluoropyridine carbene addition, 343 electrochemical reduction, 342 free radical attack, 340–41 polyfluoroalkylation, 327 synthesis, 297, 304 perchloryl fluoride, 60 perfluoro-2-butyne, 31 perfluoroacetic anhydride, 241 perfluoroacetone, see hexafluoroacetone perfluoroalcohols, 254–7 perfluoroalkanes, 162 by addition of fluorine to F-alkenes, 78 defluorination, 164–5 by direct fluorination, 35 fragmentation, 166 hydrolysis, 163 physical properties, 163 reaction with thiols, 127 structure and bonding, 162–3 using cobalt trifluoride, 32 perfluoroalkenes electrophilic attack, 191–6 epoxidation, 180
nucleophilic attack, 171–85 oligomerisation, 189 oxidation, 260 polymerisation, 203–5 radical addition, 196–205 structure and bonding, 167 synthesis, 164, 169–71 perfluoroalkyl effect, 97 perfluoroalkylation electrophilic, 126, 222 nucleophilic, 325 perfluoroallene, 219 Perfluorocycloalkenes cycloadditions, 210–14 formation of oligomers, 191 photochemistry, 189 radical additions, 200–201, 204 reactions with nucleophiles, 183–5 ring-opening, 168 perfluorocyclobutene, 168, 170, 201 perfluorocyclopentene, 31, 170, 200 perfluorodecalin defluorination, 165 reaction with thiols, 127, 165 perfluoroisobutene addition of diazamethane, 213 reactions with nucleophiles, 180 synthesis, 166, 170 perfluorooctyl bromide, 9 perfluorophenol, 98 perfluoropolyethers, 4, 5, 258, 269 perfluoroquinoline, see quinoline derivatives perfluoro-t-butanol, 71, 255 peroxides, 242, 264 peroxytrifluoroacetic acid, 242 PET scanning, 7, 9 PFA, 6 pharmaceuticals, 7 effects of F substitution, 7 phosphate mimics, 11 phosphonates, 11 phosphorus acids, 93 photochemistry formation of valence isomers, 351–7 photoelectron spectroscopy of fluorinated alkenes, 98 phthalocyanine complexes, 329 physical properties, 3 pi-inductive effect, 98 plant protecting agents, 9, 10 polyfluoroalkylation, 325 polyfluoroalkylcarbenes, 154–6
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 405
Index
polyfluorobenzenium cations, 104 polymers, 5, 203–5 polysulphides, 270 polytetrafluoroethene, 5, 6, 204, 260, 262 positron emission tomography, 7, 9 potassium fluoride, see HALEX process proton sponge, 49–50, 63 Prozact, 7, 8 PTFE defluorination, 164 see polytetrafluoroethene Pummerer-type processes, 51, 61 PVF, 6 pyridinium poly(hydrogen fluoride), 62, 68–9 pyrimidines, 13 pyrolysis of CHClF2 , 151 formation of carbenes, 151–4, 343 quinoline derivates perfluoroquinoline, 305–6 radical additions to fluorinated alkenes, 196–205 examples, 199 orientation, 197 rearrangement, 201 radical clock experiments, 54, 59–60 radicals addition to F-alkenes, 196–205 polarity effects, 117 relative stabilities, 116 Scherer radical, 117 stereochemistry, 116 substituents effects, 115–7 rearrangements Claisen, 256 of di-enes using SbF5 , 217 induced by fluoride, 185, 187–8 radicals, 201 see SN 20 processes thermal, 355 via valence isomers, 351–7 resonance effects, 94, 100 Ruppert’s reagent, 382–4 safety toxicity of fluorinated alkenes, 172 use of hydrogen fluoride, 23 use of perchloryl fluoride, 60 Scherer radical, 117 Scotchgardt, 12 Selectfluort, 58–60
Sevofluranet, 6 sigma, s, sþ values, 95, 100 silicon derivatives, 381–5 silver fluoride, 47 silver fluorine, 23 Simons, 2, 23 single electron transfer processes, 124, 125–6 SN 2 processes effect of substituents, 122 F/Cl rate constant ratios, 129 fluoride as a leaving group, 128 transition-states, 128 SN 20 processes, 176, 185 solvolysis reactions, 106 source of fluorine, 23 squaric acid, 130 stable radicals, 117 stereoselectivity addition of fluorine to alkenes, 56, 78–9 addition to enolates, 246 in direct fluorination, 53–4 in H/D exchange, 112 using DAST, 64–5 steric effects, 91, 246, 328, 371 in b-eliminations, 141 in SN 2 processes, 123 sulphides, 270–71 sulphonic acids, 265 by ECF, 266 polymerisable monomers, 260 sulphur derivatives, 265, 272 use in ethene recovery, 275 sulphur pentafluoride derivatives, 273 sulphur tetrafluoride, 63, 64, 66, 69–70 sulphur trioxide, cycloaddition, 214 surfactants, 12 Swarts, 2, 24 Taft Es values, 91–2 TAS-F, see tris(dimethylamino)sulphonium difluorotrimethylsiliconate tautomers, 251 Teflont, see PTFE Teflont AF, 6 telomerisation, 202–3 tetrabutylammonium fluoride, 49 tetrafluoroethene addition of electrophiles, 193–5 addition of sulphur trioxide, 268 cycloaddition, 205–12, 268, 277 formation of oligomers, 190
405
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 406
406
Index
tetrafluoroethene (cont’d) in polyfluoroalkylation, 328 radical additions, 198, 202–4 reactions with nucleophiles, 173–4, 177 reaction with SO2 F2 , 272 reaction with sulphur, 270 sodium sulphite addition, 269 synthesis, 170 in triazine synthesis, 275 tetrakis(dimethylamino)ethene, 215 textile treatment, 12, 13 thiete formation, 226 thiocarbonyl compounds, 272 thiols fluorination, 272 tin, see organometallics toxicity, see safety transition metal derivatives, 368 triazines, 13, 275, 304, 329–30 1,2,3-triazines photolysis, 221 triflates, 265 triflic acid, 265–6 strength, 92 trifluoroacetic acid, 240 trifluoroethanol formation of CF2 derivatives, 146, 250 trifluoroiodomethane nucleophilic attack, 123 trifluoromethanesulphonic acid, see triflic acid trifluoromethanesulphonyl chloride, 267 trifluoromethanesulphonyl group, 267 trifluoromethoxide salts, 96
trifluoromethyl formation, 24 hydrolysis, 332 s values, 94–6 size, 92 transfer from CF3 H, 384 transfer from silicon, see Ruppert’s reagent trifluoromethylation transfer from CF3 H, 384 using Ruppert’s reagent, 382–4 trifluoromethylcarbene, 158 trifluoropropene electrophilic addition, 102 trifluoropropyne, 221 trioxide, 265 tris(dimethylamino)sulphonium difluorotrimethylsiliconate, 49–50 valence isomers, 222, 351–7 van der Waals radii, 91 volumes, 92 vinyl radicals, 117 vinyllithium derivatives, 366 Vitont, 6 wartime developments, 2 Wittig reaction, 250 xenon difluoride, 60, 80, 301 Yaravenko reagent, 65 ylides, 123