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Fluorine in Organic
Chemistry
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page i
Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
Fluorine in OrganicChemistry
Richard D. Chambers FRSEmeritus Professor of Chemistry
University of Durham, UK
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iii
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Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page iv
Tomy wife Anne and our grandchildren,
Daniel, Benjamin, Alexandra, and Jack,who give us so much pleasure
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 10:34am page v
Contents
Foreword xv
by Professor George A. Olah
Preface xvii
1 GENERAL DISCUSSION OF ORGANIC FLUORINE CHEMISTRY 1
I General introduction 1
A Properties 1
B Historical development 2
II Industrial applications 3
A Introduction 3
B Compounds and materials of high thermal and chemical stability 3
1 Inert fluids 4
2 Polymers 5
C Biological applications 5
1 Volatile anaesthetics 6
2 Pharmaceuticals 7
3 Imaging techniques 7
4 Plant protection agents 9
D Biotransformations of fluorinated compounds 9
E Applications of unique properties 12
1 Surfactants 12
2 Textile treatments 12
3 Dyes 12
III Electronic effects in fluorocarbon systems 13
A Saturated systems 14
B Unsaturated systems 14
C Positively charged species 15
D Negatively charged species 15
E Free radicals 16
IV Nomenclature 16
A Systems of nomenclature 17
B Haloalkanes 18
References 19
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vii
2 PREPARATION OF HIGHLY FLUORINATED COMPOUNDS 23
I Introduction 23
A Source of fluorine 23
II Fluorination with metal fluorides 23
A Swarts reaction and related processes (halogen exchange using HF) 24
1 Haloalkanes 25
2 Influence of substituent groups 26
B Alkali metal fluorides 27
1 Source of fluoride ion 28
2 Displacements at saturated carbon 29
3 Displacements involving unsaturated carbon 30
Alkene derivatives 30
Aromatic compounds 31
C High-valency metal fluorides 31
1 Cobalt trifluoride and metal tetrafluorocobaltates 32
III Electrochemical fluorination (ECF) 33
IV Fluorination with elemental fluorine 35
A Fluorine generation 35
B Reactions 35
C Control of fluorination 36
1 Dilution with inert gases 36
D Fluorinated carbon 39
E Fluorination of compounds containing functional groups 39
V Halogen fluorides 40
References 41
3 PARTIAL OR SELECTIVE FLUORINATION 47
I Introduction 47
II Displacement of halogen by fluoride ion 47
A Silver fluoride 47
B Alkali metal fluorides 47
C Other sources of fluoride ion 49
D Miscellaneous reagents 50
III Replacement of hydrogen by fluorine 51
A Elemental fluorine 51
1 Elemental fluorine as an electrophile 52
B Electrophilic fluorinating agents containing O–F bonds 56
C Electrophilic fluorinating agents containing N–F bonds 58
D Xenon difluoride 60
E Miscellaneous 60
IV Fluorination of oxygen-containing functional groups 62
A Replacement of hydroxyl groups by fluorine 62
1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent 62
2 Diethylaminosulphur trifluoride (DAST) and related reagents 63
3 Fluoroalkylamine reagents (FARs) 65
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viii Contents
B Replacement of ester and related groups by fluorine 66
C Fluorination of carbonyl and related compounds 66
1 Sulphur tetrafluoride and derivatives 66
D Cleavage of ethers and epoxides 69
V Fluorination of sulphur-containing functional groups 71
VI Fluorination of nitrogen-containing functional groups 73
A Fluorodediazotisation 73
B Ring opening of azirines and aziridines 74
C Miscellaneous 75
VII Addition to alkenes and alkynes 76
A Addition of hydrogen fluoride 76
B Direct addition of fluorine 77
C Indirect addition of fluorine 79
D Halofluorination 80
E Addition of fluorine and oxygen groups 82
F Other additions 82
References 83
4 THE INFLUENCE OF FLUORINE OR FLUOROCARBON
GROUPS ON SOME REACTION CENTRES 91
I Introduction 91
II Steric effects 91
III Electronic effects of polyfluoroalkyl groups 92
A Saturated systems 92
1 Strengths of Acids 92
2 Bases 93
B Unsaturated systems 94
1 Apparent resonance effects 94
2 Inductive and field effects 97
IV The perfluoroalkyl effect 97
V Strengths of unsaturated fluoro-acids and -bases 98
VI Fluorocarbocations 99
A Effect of fluorine as a substituent in the ring on electrophilic
aromatic substitution 99
B Electrophilic additions to fluoroalkenes 101
C Relatively stable fluorinated carbocations 102
1 Fluoromethyl cations 104
D Effect of fluorine atoms not directly conjugated with the
carbocation centre 105
VII Fluorocarbanions 107
A Fluorine atoms attached to the carbanion centre 108
B Fluorine atoms and fluoroalkyl substituents adjacent to the
carbanion centre 111
C Stable perfluorinated carbanions 112
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Contents ix
D Acidities of fluorobenzenes and derivatives 113
E Acidities of fluoroalkenes 115
VIII Fluoro radicals 115
A Fluorine atoms and fluoroalkyl groups attached to the
radical centre 115
B Stable perfluorinated radicals 117
C Polarity of radicals 117
References 118
5 NUCLEOPHILIC DISPLACEMENT OF HALOGEN FROM
FLUOROCARBON SYSTEMS 122
I Substituent effects of fluorine or fluorocarbon groups
on the SN2 process 122
A Electrophilic perfluoroalkylation 126
II Fluoride ion as a leaving group 128
A Displacement of fluorine from saturated carbon – SN2 processes 128
1 Acid catalysis 129
2 Influence of heteroatoms on fluorine displacement 131
B Displacement of fluorine and halogen from unsaturated carbon –
addition–elimination mechanism 131
1 Substitution in fluoroalkenes 132
2 Substitution in aromatic compounds 133
References 135
6 ELIMINATION REACTIONS 137
I b-Elimination of hydrogen halides 137
A Effect of the leaving halogen 137
B Substituent effects 138
C Regiochemistry 139
D Conformational effects 140
E Elimination from polyfluorinated cyclic systems 142
II b-Elimination of metal fluorides 144
III a-Eliminations: generation and reactivity of fluorocarbenes and
polyfluoroalkylcarbenes 147
A Fluorocarbenes 147
1 From haloforms 147
2 From halo-ketones and –acids 149
3 From organometallic compounds 149
4 From organophosphorous compounds 151
5 Pyrolysis and fragmentation reactions 151
B Polyfluoroalkylcarbenes 154
C Structure and reactivity of fluorocarbenes and
polyfluoroalkylcarbenes 156
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x Contents
1 Fluorocarbenes 156
2 Polyfluoroalkylcarbenes 158
References 159
7 POLYFLUOROALKANES, POLYFLUOROALKENES,
POLYFLUOROALKYNES AND DERIVATIVES 162
I Perfluoroalkanes and perfluorocycloalkanes 162
A Structure and bonding 162
1 Carbon–fluorine bonds 162
2 Carbon–carbon bonds 162
B Physical properties 163
C Reactions 163
1 Hydrolysis 163
2 Defluorination and functionalisation 164
3 Fragmentation 166
D Fluorous biphase techniques 166
II Perfluoroalkenes 167
A Stability, structure and bonding 167
B Synthesis 169
C Nucleophilic attack 171
1 Orientation of addition and relative reactivities 172
2 Reactivity and regiochemistry of nucleophilic attack 172
3 Products formed 176
4 Substitution with rearrangement – SN20 processes 176
5 Cycloalkenes 183
6 Fluoride-ion-induced reactions 185
7 Addition reactions 186
8 Fluoride-ion-catalysed rearrangements of fluoroalkenes 187
9 Fluoride-ion-induced oligomerisation reactions 188
10 Perfluorocycloalkenes 190
D Electrophilic attack 191
E Free-radical additions 196
1 Orientation of addition and rates of reaction 197
2 Telomerisation 202
3 Polymerisation 203
F Cycloadditions 205
1 Formation of four-membered rings 205
2 Formation of six-membered rings – Diels–Alder reactions 209
3 Formation of five-membered rings – 1,3-dipolar cycloaddition
reactions 212
4 Cycloadditions involving heteroatoms 214
G Polyfluorinated conjugated dienes 214
1 Synthesis 214
2 Reactions 216
3 Perfluoroallenes 218
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Contents xi
III Fluoroalkynes and (fluoroalkyl)alkynes 218
A Introduction and synthesis 218
B Reactions 222
1 Perfluoro-2-butyne 222
Formation of polymers and oligomers 222
Reactions with nucleophiles 223
Fluoride-ion-induced reactions 223
Cycloadditions 224
Free-radical additions 226
References 227
8 FUNCTIONAL COMPOUNDS CONTAINING OXYGEN,
SULPHUR OR NITROGEN AND THEIR DERIVATIVES 236
I Oxygen derivatives 236
A Carboxylic acids 236
1 Synthesis 236
2 Properties and derivatives 238
3 Trifluoroacetic acid 240
4 Perfluoroacetic anhydride 241
5 Peroxytrifluoroacetic acid 242
B Aldehydes and ketones 243
1 Synthesis 243
2 Reactions 243
Addition to C5O 246
Reactions with fluoride ion 251
C Perfluoro-alcohols 254
1 Monohydric alcohols 254
2 Dihydric alcohols 255
3 Alkoxides 257
D Fluoroxy compounds 258
E Perfluoro-oxiranes (epoxides) 259
F Peroxides 264
II Sulphur derivatives 265
A Perfluoroalkanesulphonic acids 265
B Sulphides and polysulphides 270
C Sulphur(IV) and sulphur(VI) derivatives 272
D Thiocarbonyl compounds 272
III Nitrogen derivatives 275
A Amines 275
B N–O compounds 277
1 Nitrosoalkanes 277
2 Bistrifluoromethyl nitroxide 278
C Aza-alkenes 278
D Azo compounds 284
E Diazo compounds and diazirines 284
References 287
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xii Contents
9 POLYFLUOROAROMATIC COMPOUNDS 296
I Synthesis 296
A General considerations 296
B Saturation/re-aromatisation 297
C Substitution processes 298
1 Replacement of H by F 298
2 Replacement of 2Nþ2 by F: the Balz–Schiemann reaction 300
3 Replacement of 2OH or 2SH by F 300
4 Replacement of Cl by F 300
II Properties and reactions 306
A General 306
B Nucleophilic aromatic substitution 307
1 Benzenoid compounds 307
Orientation and reactivity 310
Mechanism 311
2 Heterocyclic compounds 315
Pyridines and related nitrogen heterocyclic(azabenzenoid) compounds 315
Polysubstitution 320
Acid-induced processes 321
3 Fluoride-ion-induced reactions 325
Polyfluoroalkylation 325
Other systems 332
4 Cyclisation reactions 332
C Reactions with electrophilic reagents 336
D Free-radical attack 338
1 Carbene and nitrene additions 338
E Reactive intermediates 341
1 Organometallics 341
Lithium and magnesium derivatives 342
Copper compounds 346
2 Arynes 346
3 Free radicals 349
4 Valence isomers 351
Nitrogen derivatives 353
References 358
10 ORGANOMETALLIC COMPOUNDS 365
I General methods and synthesis 365
A From iodides, bromides and hydro compounds 365
1 Perfluoroalkyl derivatives 365
2 Derivatives of unsaturated systems 366
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Contents xiii
B From unsaturated fluorocarbons 367
1 Fluoride-ion-initiated reactions 367
II Lithium and magnesium 368
A From saturated compounds 368
B From alkenes 369
C From trifluoropropyne 370
D From polyfluoro-aromatic compounds 371
III Zinc and mercury 371
A Zinc 371
B Mercury 373
1 Perfluoroalkyl derivatives 373
2 Unsaturated derivatives 374
3 Cleavage by electrophiles 375
IV Boron and aluminium 376
A Boron 376
1 Perfluoroalkyl derivatives 376
2 Unsaturated derivatives 377
B Aluminium 380
V Silicon and tin 381
A Silicon 381
B Tin 385
VI Transition metals 387
A Copper 388
B Other metals 388
References 395
Index 399
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiv
xiv Contents
Foreword
by Professor George A. OlahNobel 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.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:06pm page xv
xv
Preface
This book is a revision and update of one that was first published in 1973, followed by
two small reprintings. The original was prompted by Professor George Olah, during a year
that I spent as a Visiting Lecturer in Cleveland. My aim for the original edition was to
present an overview of organofluorine chemistry, in a way that corresponded with modern
organic chemistry. Of course this involved including a mechanistic basis of the subject,
which was still evolving at the time; to my knowledge, this was the first broad attempt to
do so. The original book appears to have served a useful purpose because, for a number of
years now, friends in the field have encouraged me to write an update.
In the intervening years since the first edition the subject has grown enormously, and
any idea of a single-author comprehensive volume would now be a preposterous under-
taking. Consequently, I have concentrated attention on illustrating the principles of the
subject, and especially those concerning highly fluorinated compounds, where the chem-
istry 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
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xvii
Chapter 1
General Discussion of OrganicFluorine Chemistry
I GENERAL INTRODUCTION
One of the major activities of chemists in industry and academia is the search for ‘special-
effect’ chemicals, i.e. systems with new chemistry and with novel properties that can be
exploited by industry. There are, of course, many ways of creating novel systems but the
introduction of carbon–fluorine bonds into organic compounds has led to spectacular
industrial developments, together with an exciting field of organic chemistry and bio-
chemistry.
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
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1Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
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 hydrocar-
bons 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 perfluor-
ocarbon to be isolated pure; it was reported in 1926 by Lebeau and Damiens [47] but
not properly characterised by them until 1930 [48] and, in the same year, by Ruff and
Keim [49]. Swarts made trifluoroacetic acid [50] as early as 1922 and in 1931 reported
that the electrolysis of an aqueous solution of the latter gave pure perfluoroethane [51].
Nevertheless, the first liquid perfluorocarbons were not characterised until 1937, when
Simons and Block found that mercury promotes reaction between carbon and fluorine
[52]; they were able to isolate CF4, C2F6, C3F8, C4F10 (two isomers), cyclo-C6F12 and
C6F14.
It was established that these compounds are very thermally and chemically stable and
this led to suggestions by Simons that these materials might be resistant to UF6, which
was found to be the case. There then ensued a period of very rapid development in the
synthesis of fluorocarbon materials, the goal being stable lubricants and gaskets for use in
the gaseous diffusion plant for concentrating the 235U isotope, using UF6. These wartime
developments have been published in various collected forms [53–55]. Tetrafluoroethene
was obtained by Ruff and Bretschneider in 1933, who decomposed tetrafluoromethane in
an electric arc [56] while Locke et al. [57] developed a synthesis in 1934, which involved
zinc dehalogenation of CF2Cl2CF2Cl. Then the formation of polytetrafluoroethene [58]
was discovered in 1938 and in the same period chlorotrifluoroethene was found to
polymerise to give a very stable inert transparent polymer. The wartime efforts involved
development of these and other new materials. Nevertheless, even at the end of the
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2 Chapter 1
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 increas-
ingly 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 com-
pounds 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 chemicalstability [29]
The greater strength of the carbon–fluorine over the carbon–hydrogen bond leads to
considerably enhanced thermal stability for perfluorocarbon systems over their hydrocar-
bon 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 perfluorocar-
bons is that they are both water- and hydrocarbon-repellent and the implications for fabric
treatment are obvious.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 3
General Discussion of Organic Fluorine Chemistry 3
1 Inert fluids
The chlorofluorocarbons (CFCs) were introduced over 60 years ago as refrigerants [46] to
replace gases such as ammonia and sulphur dioxide. In 1974, at the peak of production,
900 000 tonnes of CFCs, principally CF2Cl2 (CFC-12), CFCl3 (CFC-11) and CHFCl2(CFC-22), were manufactured mainly for use as refrigerants, aerosols and foam blowing
agents. However, it was eventually recognised that the inertness of volatile CFCs is itself
a problem because they survive unchanged up to the stratosphere, where they dissociate
under short-wavelength solar ultraviolet radiation, releasing chlorine atoms which then
catalyse the decomposition of ozone to oxygen [66, 67]. Consequently, the Montreal
Protocol, which was introduced in 1987 and revised in 1990 and 1992, caused the
complete phase-out of production and use of the CFC range of compounds. This legisla-
tion forced refrigerant manufacturers to identify alternative ranges of non-toxic, stable
chemicals which, additionally, possess low ozone depletion potentials (ODPs) and low
global warming potentials (GWPs) to meet customer needs and regulatory requirements.
Hydrofluorocarbons (HFCs), being free of chorine atoms, have ODPs of zero, making
these products ideal systems for replacing CFCs. One of the major unsung achievements
of the chemical industry has been the rapid development to large-scale production of these
substitutes for CFCs; for example, CF3CFH2 (HFC-134a) is an acceptable substitute for
CF2Cl2 (CFC-12) in refrigeration applications.
Bromofluorocarbons possess outstanding fire-extinguishing ability: CF3Br has been
used for automatic systems where the use of water is as potentially damaging as a fire, for
instance in art galleries and in libraries, or in aircraft where highly efficient non-toxic
agents are required. However, on an atom-to-atom basis bromine atoms are estimated to
be 40 times more effective at destroying ozone than chlorine atoms, and therefore the
Montreal Protocol required the complete phase-out of bromofluorocarbon use in 1994.
Alternative ‘in-kind’ replacements [68] of these halon fire extinguishers are being de-
veloped and currently CHF3 (DuPont) and CF3CFHCF3 (Great Lakes), amongst others,
are on the market [69], but at the time of writing the problem of finding replacements for
bromofluorocarbons for application as fire-fighting agents in aircraft is largely unsolved.
Perfluorocarbon fluids, such as the Flutect range (F2 Chemicals Ltd), find many uses
in the electronics industry. For instance, the complete immersion of electronic compon-
ents in a bath of perfluorocarbon fluid can efficiently cool overheated circuits and, by a
similar process, the airtight packaging around highly valuable and sensitive equipment
can be tested in complete safety for leaks.
Since perfluorocarbons are inert to microbiological attack, many potential medical uses
of these fluids have been investigated. The report by Clark in 1966 that perfluorocarbons
can dissolve significant amounts of oxygen [70] prompted the exciting suggestion that such
fluids could be used as ‘artificial blood’ [71] and the now-classic photograph of a rat
breathing under liquid perfluorocarbon has been reproduced countless times. Perfluorocar-
bons are immiscible with blood and do not dissolve the essential mineral nutrients required.
Consequently, emulsions of perfluorocarbons with an aqueous buffer solution containing
various surfactants have been formulated as potential blood substitutes. Although products
have been approved and marketed, there is no commercially successful emulsion.
The need to extend the liquid range of perfluorinated systems to very high molecular
weights was satisfied by the important introduction of perfluoropolyethers (PFPEs) [72]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 4
4 Chapter 1
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 �1008C to 3508C 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.
2 Polymers [73a]
Since the first synthesis of polychlorotrifluoroethene and the discovery of polytetrafluor-
oethene (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 proper-
ties [74–76] which ensure a wide range and continually growing number of applications
for these materials. The fabled ‘non-stick’ properties of PTFE may be attributed to the
abundance of non-bonding electron pairs and the coefficient of friction has been related to
that of wet ice on wet ice. Some examples of commercial fluoropolymers are listed in
Table 1.1 along with just some of the many applications.
The remarkable feature of this area is that materials such as Vitont (DuPont) and
related elastomers, which were once regarded as esoteric and appropriate in cost only for
‘space flight’ and related applications, have now entered widely into the automobile
industry. Lumiflont (Asahi Glass Co., Japan), a high-performance paint which is fam-
ously used on the Hikari ‘bullet trains’ in Japan, and various coatings for protection of
concrete and stone building materials have also emerged. The gradual public realisation
that the higher cost of high-performance products makes longer-term economic sense is
the driving force behind the continued growth of this industry. Perfluorinated ionomer
membranes [77], such as Nafiont (DuPont) and Flemiont (Daikin), are increasingly
being used as cell-dividing membranes for chlor-alkali cells, replacing the mercury
cells that have, understandably, led to so much public concern.
C Biological applications [29, 61, 62]
The physiological properties of many biologically significant molecules can be modu-
lated if fluorine or fluorinated groups are incorporated into their structure [24, 78]; factors
affecting the change in biological activity of a substrate upon fluorination are complex
[79].
F
F
O
F
CF3
OCF2CF2CF2 OCF2 OCF2CF2
n
Lubricants, coatings
Fomblin® (Ausimont)Krytox® (DuPont)
n m
Demnum® (Daikin)
Lubricants, vacuum pump oils
n
Figure 1.1
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 5
General Discussion of Organic Fluorine Chemistry 5
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).
Table 1.1 Applications of fluoropolymers
Polymer Monomer(s) Applications
PTFE CF2=CF2 Cookware coatings; Goretext
(W.R. Gore Co.) waterproof
clothing; electrical insulators;
medical uses such as artificial
blood vessels.
FEP CF2=CF2 + CF3CF=CF2 Fabrication by conventional melt
processing; wire and cable
insulators; heat-sealable film,
tubing.
PFA CF2=CF2 + RFOCF=CF2 Injection-moulded parts for use in
aggressive environments.
Teflon AFt (DuPont)O O
F F
CF3 CF3
CF2=CF2+Optically clear, used in corrosive
environments where glass is
unsuitable, e.g. in computer chip
manufacture.
Cytopt (Asahi) CF2=CFO(CF2)nCF=CF2 Optically clear, used in corrosive
environments, e.g. computer
chip manufacture.
PCTFE CF2=CFCl Gaskets, seals, oils, coatings,
transparent inert covers.
PVDF CF2=CH2 Weather-resistant coatings; cable
insulation; piezo-electric devices.
PVF CH2=CHF
CF2=CH2 + CF3CF=CF2
Coatings, flexible films.
VitonAt (DuPont) Elastomers used for sealants, O-
rings, fuel-resistant seals for
aircraft and automobiles.
Nafiont (DuPont)CF2�CF2 + F2C�C
(OCF2CF)nO
F
CF2CF2X
CF3
�
2
Membranes in chlor-alkali cells.
Flemiont (Daikin)
Nafion, X ¼ CO2H
Flemion, X ¼ SO2H
(CF3)2CHOCH2F CF3CHFOCHF2
Sevoflurane® Desflurane®
CF3CHClBr CF3CHClOCHF2
Fluothane® Isoflurane®
Figure 1.2
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 6
6 Chapter 1
2 Pharmaceuticals
Fluorinated corticosteroids were the first successful commercial products where useful
modification of biological activity was achieved by introduction of a carbon–fluorine
bond. Subsequently, the interest of the pharmaceutical industry in this approach has
grown substantially and many new fluorine-containing products are available or are in
advanced screening stages.
Simplistically, an orally administered drug must: (a) be absorbed through the gut into
the bloodstream, (b) then pass through a series of phospholipid membranes (transport)
before reaching the correct site of action, and (c) bind and produce the desired effect at
the appropriate enzyme site. Following this stage, the drug should be metabolised neither
too quickly, nor into toxic by-products. The incorporation of fluorine into a biologically
active molecule may modulate all of these functions as well as the more obvious effects
of enhancing the acidity or reducing the base strength of appropriate proximate functional
groups. Size is not the dominant factor, although steric requirements in biology are not so
easy to establish, and a range of factors arising from fluorine substitution are at work [81–
83] and will continue to be evaluated for some considerable time. Fluorine
or trifluoromethyl substituents generally enhance the lipophilicity of an aromatic sub-
strate 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 metab-
olism is inhibited because of the fluorine, thus effectively trapping the radiolabelled
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 7
General Discussion of Organic Fluorine Chemistry 7
molecule in a cell. Uptake of fluorine-18 gives a direct measure of the rate of glucose
metabolism in the part of the body under study. Similarly, 18F-DOPA acts as a tracer for
DOPA, which is a neurotransmitter in the brain, and the PET study of the complex
metabolism and biodistribution of DOPA is hoped to provide a quantitative measure of
the dopaminergic neurons in the brain [84] (Figure 1.4).
Non-invasive monitoring of therapeutic agents can also be performed by 19F magnetic
resonance imaging (MRI); the negligible natural fluorine background and the high
sensitivity of 19F NMR spectroscopy has made possible the study of the in vivo action
and metabolic pathways of fluorine-containing drugs. For instance, 19F MRI has demon-
strated that 5-fluorouracil is metabolised to NH2CH2CHFCOOH.
N
N
H
H
F
ON
NH CF3
HO
OH
N
OHN
N
F
F
N
CO2H
N
F
NH
O NCH3
H
5-Fluorouracil(anti-cancer)
Trifluridine®(anti-viral)
Fluconazole®(anti-fungal)
Ciprofloxacin®(antibacterial)
Prozac®(anti-depressant)
N
NN O
O
O
O
O
F3C
CH2OH
CH3
HO
F
OH
O
O
Betamethasone®(anti-inflammatory)
Figure 1.3 Examples of drugs containing fluorine
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 8
8 Chapter 1
Perfluorooctyl bromide is being used very successfully to enhance the contrast between
healthy and diseased tissue in 1H MRI procedures and as a general imaging agent for
X-ray and other forms of examination of soft tissue.
4 Plant protection agents [62]
Environmental concerns have imposed massive constraints on plant protection products,
and the impressive progress towards lower dose levels for effective control is another of
the unrecognised success stories of the chemical industry. Fluorinated molecules have
played an important role in these developments, leading to a range of successful herbi-
cides, insecticides and fungicides [85]. Trifluralin (Dow), a herbicide used principally for
the control of grassy weeds in a wide range of crops, has been in use for over 25 years and
peak sales in the mid 1980s reached US$400 million per annum. Fusiladet is another
widely successful herbicide used for the control of weeds in broad-leaf crops at low
dosage rates. The pyrethroid derivative Cyhalothrint is a successful insecticide and the
fungicide sector contains five significant products with fluorine incorporated in the
substrate. Flutriafolt is used for protecting cereal crops and Flutolanilt is used mainly
in the Far East for controlling crop diseases (Figure 1.5).
D Biotransformations of fluorinated compounds
As the occurrence of fluoride ion is so widespread, it is particularly surprising that
compounds containing carbon–fluorine bonds are rarely found in nature [1, 2]. Potassium
monofluoroacetate occurs in several tropical and sub-tropical plants located in the
southern hemisphere, such as Dichapetalum cymosum (South Africa, very toxic to
animals) and Oxylobium parviform (Australia). Some plants, such as soya bean (Glycine
max), are able to synthesise fluoroacetate when grown in fluoride-rich soil. A shrub
occurring in Sierra Leone, Dichapetalum toxicarium (ratsbane), is also poisonous, par-
ticularly the seeds, and this has been attributed to the occurrence of v-fluoro-oleic acid,
CH2FðCH2Þ7CH5CHðCH2Þ7COOH [86]. Nucleocidin, an adenine-containing antibiotic,
has been isolated from the fermentation broths of a micro-organism Streptomyces calvus [1].
The fact that only 12 compounds containing C–F bonds have been found in nature so
far [87] leads to the questions of (a) whether this is a consequence of the difficulty of
forming C–F bonds in the first place, and (b) whether subsequent enzymic transform-
ations 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
O
FHO
HO
HO
OH
F
OH
HONH2
CO2H
18F-2-Fluorodeoxyglucose(PET Scanning Agent)
18F-6-Fluoro-DOPA(NMR Scanning Agent)
Figure 1.4
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 9
General Discussion of Organic Fluorine Chemistry 9
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 reduc-
tion of carbonyl (Figure 1.7).
Likewise, various kinetic resolutions of fluorinated compounds have been achieved,
e.g. the acetate of 1,1,1-trifluoro-2-octanol has been transformed into (R)-1,1,1-trifluoro-
2-octanol (Figure 1.8).
NnPr2
NO2O2N
CF3N
F3C
O
OOnBu
Me
F3C
Cl
OO
Flutriafol® Flutolanil®
N
OH
N N
F
Trifluralin®
F
Fusilade®
N
H
CF3
OiPr
Cyhalothrin®
O
O CN
O
Figure 1.5 Examples of plant-protecting agents containing fluorine
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 10
10 Chapter 1
The use of CHF [91] and CF2 [92] groups as oxygen mimics has been explored and
fluoromethylenephosphonates, as phosphate mimics [93], have been employed as binding
agents for a promising approach to catalytic antibodies [94] although inevitably these sites
must be more sterically demanding than oxygen. Of course a fluorine atom itself is
isoelectronic with an oxygen anion and, not surprisingly, fluorinated carbohydrates
have been widely explored [22, 95], as have fluorinated amino-acids and peptides [31,
96]. Indeed, fluorine is advocated as a tool for exploring the conformations of amides and
peptides [97]. The presence of fluorine, with the opportunity of observation by 19F NMR,
free from the often complex 1H signals, can be an extremely useful probe.
N
NN
N
NH2
N
NN
N
NH2
F−
OS+Me
O
OH3N
+−
HO OH
O
HO OH
F
NAD+
F
O
OH
F
O
H
Fluorinase
5'-FDAS-adenosylmethionine
FluoroacetaldehydeFluoroacetate
½88�
Figure 1.6
CH2FCOPh
FH2C Ph
58%
R (90% ee)
OH ½89�
Figure 1.7
OCOMe
F3C CH2CO2Et
Lipase MYOH
F3C CH2CO2Et
OCOMe
F3C CH2CO2Et
(R) 96% ee
½89�
Figure 1.8
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 11
General Discussion of Organic Fluorine Chemistry 11
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 per-
fluorinated groups have been marketed; examples of each are given in Figure 1.9.
2 Textile treatments [29]
Polyacrylates bearing pendant perfluoroalkyl groups are extremely difficult to wet, due to
the very low surface energy of the partially fluorinated polymer. When surfaces of
materials are coated with such polymers, their oil and water repellencies are greatly
enhanced and this has been used to great effect in the textile-finishing area. Products such
as Zepelt (DuPont) are used for coating fabrics, as furniture sprays, and as carpet and
leather finishing agents. However, the highly successful Scotchgardt (3M) was removed
from the marketplace following concerns about the appearance of perfluoro-octyl
sulphonic acid in various blood samples, albeit in extremely low concentrations. How-
ever, the extreme stability of the acid could lead to a build-up in biological systems.
Techniques for plasma polymerisation have been progressed significantly in recent
years [101] and direct formation of fluorocarbon coatings on surfaces, including textiles,
holds much promise.
3 Dyes [29]
Fibre-reactive dyes are water-soluble dyes containing a chromophore that is attached to a
reactive group which then may be attacked by fibres containing nucleophiles to form a
F3C CF3
O
C2F5
C2F5
F3C
SO3
Anionic
Na
I
Cationic
C8F17SO2NH(CH2)3NMe3
C8F17CH2CH2O(CH2CH2O)nH
Non-ionic
Figure 1.9 Fluorinated surfactants
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 12
12 Chapter 1
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
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 de-
scribed using perfluoro(isopropyl-s-triazine)s [102].
For various reasons, the superior properties of most liquid-crystalline materials con-
tained in LCD displays depend critically on the presence of fluorinated substructures
[103]. In particular, perfluorinated groups have displaced cyano groups for their role in
inducing polarity.
III ELECTRONIC EFFECTS IN FLUOROCARBON SYSTEMS
The electronic properties and size of fluorine relative to hydrogen and chlorine are set out
in Table 1.2; at this point it is worthwhile to examine some of the possible consequences
of these differences for the chemistry of fluorocarbon systems. In this way it can be
emphasised, at the outset, how far-reaching these effects will be and, at the same time, it
sets the scene for a rational approach to the chemistry.
First, the large ionisation energy of fluorine implies that species involving electron-
deficient fluorine might be less common than those involving hydrogen or chlorine. The
ionisation energy of chlorine is, in fact, less than that of hydrogen and chloronium ions
N
NCl
N
NCl
NH-Dye
N
NCl
NH-Dye
OCotton
FDye-NH2
FCotton-OH
F
Figure 1.10
Table 1.2 Electronic properties
H F Cl Ref.
Electronic configuration 1s1 . . . 2s22p5 . . . 3s23p53d0 –
Electronegativity (Pauling) 2.20 3.98 3.16 [104]
Ionisation energy kJmol�1� �a
1312 1681 1251 [104]
Electron affinity kJmol�1� �
b 74.0 332.6 348.5 [104]
Bond energies of C2X in
CX4 kJmol�1� � 446.4 546.0 305.0 [19]
Bond energies of X2X
kJmol�1� � 434 157 242 [105]
Bond lengths of C2Xc (A) 1.091 1.319 1.767 [19]
van der Waals radius (A) 1.20 1.47 1.75 [104]
Preference as a leaving group Hþ F� Cl� –
a Xþ þ e� ! Xb Xþ e� ! X�c Covalent radii in CX4
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 13
General Discussion of Organic Fluorine Chemistry 13
2Clþ2 (as well as 2Brþ2 or 2Iþ2) are now well established [106], whereas the
analogous fluoronium species 2Fþ2 have not been observed. It is particularly interesting
that the electron affinity of fluorine is actually less than that of chlorine because, here, we
have the first indication of repulsion between unshared electron pairs raising the energy of
the system, and it is likely that this factor accounts for the lower bond strength of F2F
than Cl2Cl bonds; it will become apparent that electron-pair repulsions are very import-
ant 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).
(2) ‘Double bond–no bond resonance’ (and equivalent molecular orbital descriptions)
has been suggested to be involved (�R) (Figure 1.12).
This may be described in molecular orbital terms as interaction of s-electrons in C2F
with low-lying s�-orbitals in the other C2F bonds.
B Unsaturated systems
(1) Inductive (�Is) effects act as in saturated systems.
(2) Inductive and field effects result in the polarisation of p-electrons (�Ip)
(Figure 1.13).
C F
dd +
Figure 1.11
CF F F C F
Figure 1.12
C C
Fd - d +
Figure 1.13
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 14
14 Chapter 1
(3) Coulombic or Pauli repulsion occurs between electron pairs on fluorine and
p-electrons (þIp) (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.
C Positively charged species
(1) Inductive electron withdrawal (�Is) would tend to destabilise a carbocation (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).
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).
δ+ δ−C C
F
Figure 1.14
C C F CC
F
F
CF3C
� �
Figure 1.15
C CCF F
1.16A 1.16B
Figure 1.16
C+
F
1.17A
C F+
Figure 1.17
C C CF F
1.18A 1.18B
Figure 1.18
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 15
General Discussion of Organic Fluorine Chemistry 15
(2) Repulsion between adjacent electron pairs (þIp) would be destabilising (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).
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).
(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).
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.
C F
1.19A
Figure 1.19
C C
F
F
F CCF
FF�
Figure 1.20
C F
d -d +
Figure 1.21
C F C F
Figure 1.22
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 16
16 Chapter 1
A Systems of nomenclature
The number of fluorine atoms is indicated in the name and the positions are indicated by
numerals or Greek letters according to normal conventions, for example as in Figure 1.23.
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.
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.
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.
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.
OCF3
CF3
F F
F F
Hexafluoroacetone 1,1,4,4-Tetrafluorocyclohexane
Figure 1.23
CF3CFHCF3 2H-heptafluoropropane
CHClFCF2CF3 1H-1-chlorohexafluoropropane
Figure 1.24
N
CF3
FF
Perfluorocyclobutane
(CF3)3C-OH
Perfluoro-t-butanol Perfluoro(4-methylpyridine)
Figure 1.25
F Perfluorocyclohexane
Figure 1.26
Cl
Cl
F 1,2-dichlorohexafluorocyclobutane
Figure 1.27
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 17
General Discussion of Organic Fluorine Chemistry 17
A simple method for indicating the geometry of stereoisomers is indicated in 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).
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.
B Haloalkanes [109]
A perverse system of nomenclature exists for the CFC, HCFC and HFC groups of
compounds and, whatever objections to it may be made, it seems to be here to stay.
Therefore, to avoid much frustration it is advisable to become acquainted with the rules.
A series of three numbers are used (or two if the first is zero) that indicate, in order, the
following:
Number of carbon atoms minus one (C� 1)
Number of hydrogen atoms plus one (H þ 1)
Number of fluorine atoms (F)
Chlorine atoms are not included and, for bromine derivatives, B is added, followed by the
number of bromine atoms. Also, a cyclic system has the numbers prefixed by C, for
example:
Tetrachlorodifluoroethane C2Cl4F2 112
Trichlorofluoromethane CCl3F 11
Perfluorocyclobutane C4F8 C318
Dibromodifluoromethane CBr2F2 12B2
H
H
F
H
H
F
1H, 2H / - perfluorocyclohexane 1H, / 2H - perfluorocyclohexane
Figure 1.28
C6H5CF2CF2CF2CF2CF3 (Perfluoro-n-pentyl)benzene
C6H5CF2CF2CFHCF2CF3 (3H-decafluoro-n-pentyl)benzene
Figure 1.29
CF3CF2COOH F-propanoic acid F F-benzene
Figure 1.30
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 18
18 Chapter 1
For positional isomers, the deviation from symmetrical fluorine substitution is denoted by
a letter, for example:
CF2H2CF2H 134
CF32CFH2 134a
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General Discussion of Organic Fluorine Chemistry 21
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Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 22
22 Chapter 1
Chapter 2
Preparation of Highly FluorinatedCompounds
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. 19.58C) 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
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 23
23Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
CaF2 anhydrous HF
Metal Fluorides Transition MetalFluorides
F2KF.2HF
m.p. ca. 100� C
H2SO4
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 exchangeusing 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).
PhCCl3 PhCF3
N
CCl3
Cl
HF, 40 � C70%
N
CF3
Cl
Ph3CCl Ph3CFHF, rt
HF, catalyst
300−500 � C80%
62%
½9�
Figure 2.2
Hydrogen fluoride acts both as a Friedel–Crafts catalyst and a fluorinating agent in a
one-step preparation of trifluoromethylated aromatics [10] (Figure 2.3).
CF3
+ CCl4 + HF5hr, 100 � C
92%
½10�
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 Cl + MFx C MFxCl C FF
Figure 2.4
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 24
24 Chapter 2
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).
C Cl + MFx CF
C F
Cl
F
MFx-1
δ + δ −
Figure 2.5
Generally, reactions performed in the liquid phase utilise hydrogen fluoride in combin-
ation with antimony fluoride catalysts and their efficiency stems from the greater strength
of the bond from antimony to chlorine than to fluorine. Pentavalent antimony catalysts,
such as SbF5 and SbF3Cl2, are more efficient than trivalent species because they are
extremely strong Lewis acids. Carbocations are formed in the presence of antimony
pentahalides and, indeed, one of the now-classic techniques developed by Olah and
his co-workers for the generation of relatively stable carbocations involves the reaction
of an organic halide with antimony pentafluoride, in solvents such as sulphur dioxide, at
low temperature [11]. On the industrial scale, reactions are performed in the vapour
phase and chromium(III)-based catalysts are extensively used in the production of
hydrofluorocarbons (HFCs).
In general, in this group of fluorination reactions, reactivities of the substrates and the
nature of the products obtained can be accounted for in terms of the corresponding
carbocation intermediates.
1 Haloalkanes
For many years chlorofluorocarbons (CFCs) were manufactured in huge quantities by
Swarts-type processes but, after the introduction of the Montreal Protocol legislation,
these compounds were superseded by non-ozone depleting HFCs (see Chapter 1).
Fortunately, much of the chemistry developed for the manufacture of the CFCs can be
adapted for the production of HFCs [7, 12–15].
Generally, conversion of 2CCl3 groups to 2CFCl2 can be easily accomplished,
reflecting both the stabilisation of the intermediate carbocations by chlorine and the relief
in steric strain associated with replacement of chlorine by fluorine. Further fluorination of
the 2CFCl2 group is possible but becomes progressively more difficult [3] due to the
decrease in the donating ability of the chlorine. Fluorination of 2CFCl2 groups can also
be achieved but RFCH2Cl moieties (where RF ¼ perfluoroalkyl) are generally very
difficult to fluorinate due to the lower stability of the derived carbocation intermediates.
These effects can all be seen in the two most important industrial routes to HFC-134a,
now a leading refrigerant, in which chromium(III) catalysts are used in conjunction with
HF for the halogen exchange steps [15] (Figure 2.6).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 25
Preparation of Highly Fluorinated Compounds 25
HF HF
Cr(III) Cr(III)
HF AlCl3CF2ClCFCl2
CF3CH2F
CCl3-CCl3
Cr(III)
CF3CCl3
CF3CH2F
CF3CH2Cl
CF3CFCl2
HF
HF
CCl2=CHCl CF2ClCClH2
HFC 134a
H2 / Pd
HFC 134a
Cr(III)
½15�
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, SbF3 / SbCl5, 150� C60% 6%
+
CCl2�CClCCl3 CF3CCl�CCl2 CF2ClCCl�CCl2
43% 28%
i+
i+
85% 10%
iCCl3CF2OCH3 84%
CCl3�S�CH3 CF3−S−CH3 73%
PhCCl2CCl3 PhCF2CCl3 PhCFClCCl3
CH3CCl2CH3 CH3CF2CH3 CH3CFClCH3
CCl3CCl2OCH3
i
i, SbF3, 150� C
i, SbF3 / SbCl5, rt
i, SbF3 / SbCl5, 90� C
i
i, SbF3, reflux
½17�
½18�
½16�
½19�
½20�
Figure 2.7
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 26
26 Chapter 2
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).
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl2C�CClCCl=CCl2 CCl3CCl�CClCCl3
CF3CCl�CClCF3 + CF3CCl�CFCF3
Cl F 72%SbF3, SbF3Cl2
ClSbF5, 160 � C
F
30%
F +
20%
SbF3Cl2½21�
½22�
½23�
Figure 2.8
The fluorination of hexachloroacetone by HF over chromia catalysts at high tempera-
ture is an efficient process for the synthesis of hexafluoroacetone [20] (Figure 2.9).
O
Cl3C CCl3
O
F3C CF3Chromia cat.
HF, 350 � C ½20�
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 displace-
ment 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 27
Preparation of Highly Fluorinated Compounds 27
F C C C C C CClF
ClF + Cl
Figure 2.10
1 Source of fluoride ion
Fluoride ion is much smaller than chloride (ionic radii 1.47 and 1.75 A, respectively [27])
and the heat of hydration of fluoride is about 134 kJmol�1 greater than chloride. The order
of nucleophilic strength of halide ions in aqueous solution is I� � Br� > Cl� > F�,
which is the opposite of the order of strengths of the bonds of the halogens to carbon.
Therefore, the order of reactivity is a consequence of the greater difficulty in disturbing
the hydration sphere of the smaller ions. The same order seems to be observed in most
hydrogen-bonding solvents but, in dipolar aprotic solvents, the order follows that of
increasing halogen bond strength to carbon, that is F� > Cl� > Br� � I� [28]. Conse-
quently, in order to reduce hydrogen bonding between the fluoride ion source and the
solvent, and hence to increase the nucleophilic strength of fluoride, reactions are generally
carried out using polar, aprotic media [29, 30] such as acetonitrile, sulpholane,
N-methylpyrollidinone or glymes. These solvents dissolve sufficient metal fluoride, due
to coordination of the oxygen or nitrogen donor groups present with the metal cation, and
presumably the fluoride ion remains relatively unsolvated. These fluorinations are not
simply solution-phase processes, because some reaction undoubtedly occurs on the
surface; indeed, the surface area of the metal fluoride is extremely important to reactivity
and in some cases it has been demonstrated that the amount of solid metal fluoride is
important [31]. Also, in some circumstances the alkali metal fluorides can be used most
effectively without a solvent [32, 33], and in these cases it is likely that an MF/MCl melt
is produced as the reaction proceeds.
Fluoride ion is a relatively strong base which has been used to effect a large number of
base-catalysed reactions in general organic synthesis [34, 35] and so, if forcing conditions
are required for a particular halogen exchange reaction, the limiting feature can be proton
abstraction by fluoride ion from the solvent or the substrate. Because of the low solubility
of metal fluorides in even very polar aprotic solvents, high temperatures are generally
required; this restricts the use of alkali metal fluorides to relatively simple substrates.
Consequently, development of more reactive forms of fluoride ion, which may be useful
for introduction of fluorine into more complex molecules, is an area of continuing interest
[36, 37]. Methods of activating metal fluorides (usually potassium fluoride) fall into two
broad classes: (a) increasing the surface area of the metal fluoride by spray drying [38,
39], freeze drying [40], recrystallising from methanol [41] or absorbing onto a solid inert
support such as calcium fluoride [42], alumina [43], graphite [44] or a polymer [45]; or,
(b) increasing the solubility of the metal fluoride in aprotic solvents by the addition of co-
ordinating crown ethers [46, 47] such as 18-crown-6 or a phase-transfer catalyst such as
tetraphenylphosphonium bromide [48, 49] or a tetra-alkylammonium salt [50]. A search
for other more soluble sources of nucleophilic fluoride continues and reagents such as
tetra-alkylammonium fluorides [51, 52], various amine hydrofluorides [53, 54], diethyl-
aminosulphur trifluoride [55] (DAST), tetrabutylammonium (triphenylsilyl)difluorosili-
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 28
28 Chapter 2
cate [56] and tris(dimethylamino)sulphonium difluorotrimethylsiliconate [57] (TAS-F)
have been used for the selective introduction of fluorine into organic substrates with
varying degrees of success. However, in soluble reagents such as Me4NF and other so-
called ‘naked fluoride’ systems, the fluoride ion is so exceptionally reactive that compet-
ing 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 + C8H17Br80 � C
C8H17F + CH2�CH-C6H13
91% 9%CH3CN
½52�
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].
C Cl C FMF + MCl +
Figure 2.12
A general process that involves direct and efficient reaction of fluorspar with organic
halides would be very desirable but, so far, this has not been realised, except through
generation in situ of hydrogen fluoride [60].
2 Displacements at saturated carbon
Displacement of halide by fluoride ion from alkyl halides usually occurs by an SN2
process with inversion of configuration [37], and since it is well known that nucleophilic
displacement of chloride from polychloroalkanes becomes progressively more difficult
with increasing chlorine content, it is hardly surprising that highly fluorinated alkanes are
not generally synthesised by this method. However, in favourable cases more than one
fluorine atom can be introduced; some examples illustrating different conditions used in
‘Halex’ processes are given in Table 2.1. Other selective nucleophilic fluorinations are
discussed later (Chapter 3, Section II).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 29
Preparation of Highly Fluorinated Compounds 29
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).
X
X
F F
XF
F + + X
F+ X
1. Addition / Elimination
2. Allylic or Benzylic Substitution
3. Nucleophilic Substitution with Rearrangement, SN2'
X
F+ XF
Figure 2.13 Displacement of halide by fluoride
Only perfluorocyclopentene has been synthesised directly by this route; it can be seen that,
here, allylic rearrangements can occur to make all positions potentially vinylic and therefore
reactive [64]. An analogous situation applies to hexachlorobutadiene. These reactions may
also be carried out with potassium fluoride that has been exposed to Sulpholan or 18-crown-
6, but then suspended in a fluorocarbon. Under these conditions, a significant proportion of
hexafluoro-2-butyne is formed, presumably because the latter is extracted into the fluoro-
carbon, pre-empting further reaction with fluoride [65] (Figure 2.14).
Table 2.1 Fluorinations with alkali-metal fluorides
Compound Conditions Products Yield (%) Ref.
C6H13Cl KF; (CH2OH)2;(HOCH2CH2)2O; 175–1858C C6H13F 54 [61]
CH2Cl2 KF, HF, 3008C CH2F2 82 [62]
CHCl2COOCH3 KF, 220–2308C CHF2COOCH3 18 [63]
CH3(CH2)7Br KF, 18-crown-6, MeCN CH3(CH2)7F 92 [46]
CCl3CCl2CCl3 KF, 1908C CF3CCl2CF3 � 60 [64]
N
Cl
N-Methyl-2-pyrrolidone
KF, 4808C, autoclave, no solvent
N
F
N
F
Cl
[32]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 30
30 Chapter 2
25% 75%
Cl
Cl
F
NMP = N-methyl-2-Pyrrolidone
Cl
F
KF, NMP, 200 � CCl
ClCl
F
F
Fetc.
CCl2=CClCCl=CCl2
KF / NMP
KF/Sulpholan,Perfluorocarbon
CFCl2−CHClCCl=CCl2 CF3CH=CFCF3
CF3CH=CFCF3 CF3C CF3
½65�
Figure 2.14
Aromatic compounds: Nucleophilic displacement of halide ion from haloaromatic com-
pounds 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 aro-
matic 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 31
Preparation of Highly Fluorinated Compounds 31
C H C F
C C C
F
C
F
+ 2MFn + HF + 2MFn-1
+ 2MFn + 2MFn-1
Figure 2.15
2 CoF2 + F2
H
2 CoF3 , ∆H (250�C) = −234kJmol−1
+ F2 CoF3 + HF + 2 CoF2C C
½68�
Figure 2.16 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 K2NiF6 [73] (compare also NiF3, Section III) are milder
fluorinating agents for aromatic systems. It is also worthwhile to re-emphasise that the
classifications presented here must not be regarded as rigid because, for example, antim-
ony 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.
CoF3
CoF2 + F
R�H−H +
RCoF3
R-H
rearrange
R�F+
R' R R�FR'�FF
CoF3
½74; 75�
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 tech-
nique pioneered by Fowler and his co-workers [80] whereby cobalt trifluoride is formed,
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 32
32 Chapter 2
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 (300–4008C). 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].
III ELECTROCHEMICAL FLUORINATION (ECF) [87]
Simons and his co-workers discovered a remarkable fluorination process [88–90] which is
still being studied [87, 91–95]. Many organic compounds dissolve readily in anhydrous
Table 2.2 Fluorinations using cobalt trifluoride
Starting material Conditions (8C) Product Yield (%) Ref.
n-C5H12 275–325 n-C5F12 67% [80]
C2H5
350
C2F5
F
85% [82]
350 F F [83]
N
350
NF F
[84]
Cl 350 C6F12�nCln [85]
O CF2CFHCF3
440
O CF2CF2CF3
F 70% [78]
O N CH3 100 O N CF3F [86]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 33
Preparation of Highly Fluorinated Compounds 33
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 fluor-
ides 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 R H R R−e −e
R�F−H F 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 hydrocar-
bons and, in general, as the length of the hydrocarbon chain in functional compounds
increases, so the yields decrease. Under its present state of development the method is
only preparatively useful in limited cases, for example for carboxylic or sulphonic acids,
amines and some ethers (see Table 2.3) where the yields are particularly high, or in cases
where alternative methods are even more inefficient. The process is in commercial use for
the production of a range of perfluorocarbons and perfluoro acids.
Table 2.3 Electrochemical fluorinations
Starting material Product Yield (%) Ref.
n-C8H18 n-C8F18 15 þ tar [89]
(C2H5)3N (C2F5)3N 27 [98]
N F N
F
F 37 [99]
(CH3)2S CF3SF5 þ (CF3)2SF4 20þ 2 [100]
CH3COF CF3COF 85 [101]
C7H15COCl C7F15COF 20 [102]
CH3SO2F CF3SO2F 96 [103]
C8H17SO2Cl C8F17SO2F 25 [103]
O CF2CFHCF3 O CF2CF2CF3
F50 [104]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 34
34 Chapter 2
Work with pre-formed high-valency nickel fluorides, i.e. NiF3 and NiF4, has demon-
strated 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.
O RFHRFH O C3F7C3F7
i, NiF3, anhyd.HF, −28� C to rt, 24hr
F
RFH = -CF2CFH-CF3
i
Figure 2.19
Clearly these results support the idea of forming higher nickel fluorides at the anode
surface during ECF but there is also the possibility that these high-valency systems could
be simply regarded as fluorine atom carriers, which would account for the high level of
reactivity. For any oxidation process proceeding by the ECBECN mechanism described in
Figure 2.18, it would be expected that fluorination should become progressively more
difficult to achieve. However, presentation of a surface of, essentially, fluorine atoms to a
substrate would circumvent this difficulty of interpretation. It is worth noting that the
nickel fluoride K2NiF6 [108] decomposes on heating to give elemental fluorine.
IV FLUORINATION WITH ELEMENTAL FLUORINE [109]
A Fluorine generation
Since anhydrous hydrogen fluoride is not sufficiently conducting, fluorine is generated at
the anode by electrolysis of KF�2HF, which melts conveniently around 1008C 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 be-
cause of the high heats of formation of bonds from fluorine to carbon and hydrogen
(approximately 456 and 560 kJmol�1, respectively) [27, 111]. The value of DH for the
dissociation of fluorine is very low (ca. 157 kJmol�1), 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 2F
RH + F R + HF
R + F2 RF + F
K = 10−20
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 35
Preparation of Highly Fluorinated Compounds 35
temperature (F2 ¼ 2F � , K ¼ 10�20), the low activation energy of the hydrogen abstrac-
tion 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).
R + HF + F ∆H = +16.3 kJmol−1RH + F2 ½113�115�
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 C C+ F2 + 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 CCl3-CCl3F2 (trace)
85% ½114�
Figure 2.23
Also, it has been suggested that dimerisation of haloalkenes observed during the
interaction with fluorine at low temperatures (< �508C) 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 kJmol�1) is sufficient
to cause carbon–carbon bond cleavage (ca. 355 kJmol�1) 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 sub-
strate is now less activated towards radical substitution. Therefore, the concentration of
fluorine and the temperature of the reaction may be raised to effect perfluorination. The
‘LaMar’ process has been developed by Lagow and Margrave with their co-workers [111,
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 36
36 Chapter 2
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 fluorin-
ation 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).
CH3(-OCH2CH2-)nCH3 + CF2=CFCF3
RFCF2(-OCFCF2-)nCF2RF
RF
RFH RFRF
F 91%
RF = CF2CF2CF3RFH = CF2CFHCF3
i, ii
i, 50% v:v F2 in N2; ii, Room temperature, then 280� C
RFH O O
RFH
RFH = CF2CFHCF3
RF = CF2CF2CF3
F2
RFHCH2(-OCHCH2-)nCH2RFH
½128�
½129, 130�
Figure 2.24
Using these approaches, the successful further fluorination of partly fluorinated esters
has been cleverly developed into a process for the synthesis of the important copolymer
component perfluoro(propyl vinyl ether), PPVE [131] (Figure 2.25).
A quite different, but realistic, approach to temperature control and efficient mixing
involves the use of microreactors [129, 130, 132, 133]; a simple design is shown in Figure
2.26 [129]. These techniques are under active development but microreactor designs are
now available that could be used on an industrial scale for the efficient and safe use of
fluorine.
Polyethylene vessels may be treated with fluorine in a blow moulding process (Airopakt,
Air Products) so as to provide a fluorocarbon coating [134], but it seems highly unlikely that
this treatment can be regarded as simply providing a polytetrafluoroethene (PTFE)
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 37
Preparation of Highly Fluorinated Compounds 37
HOCH2CH(CH3)OC3F7 FC(O)CF(CF3)OC3F7
C3F7OCF(CF3)C(O)�OCH2CH(CH3)OC3H7
C3F7OCF(CF3)C(O)�OCF2CF(CF3)OC3F7
2 FC(O)CF(CF3)OC3F7
CF2=CFOC3F7 PPVE
F2
+
i) NaOHii)Heat
∆
½131�
Figure 2.25
Figure 2.26 Reprinted with the permission of the Royal Society of Chemistry
surface [135, 136]. Such containers [137] possess excellent resistance to hydrocarbon
solvent penetration [135, 138], probably because of enhanced cross-linking in the surface,
and have been used successfully as fuel tanks by the automobile industry for many years.
Other techniques of surface fluorination and oxyfluorination have been used to modify
polymer surfaces.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 38
38 Chapter 2
D Fluorinated carbon [139]
Fluorination of graphite at high temperature (300–5008C) gives a white powder which
approximates to the composition (CF)n. X-ray studies indicate that the fluorine atoms are
strongly bonded to carbon but are contained between the graphite layers [140]. Graphite
fluorides have similar properties to PTFE and have been exploited commercially as
speciality lubricants and in high-performance lithium batteries [141].
Direct fluorination of Buckminsterfullerene, C60, has been studied by several groups
[142]. It is claimed that C60F48 can be isolated as an intact sphere [143] and, moreover, as
a single isomer after fluorination at 2508C. Photoelectron spectroscopy studies suggest
that as the level of fluorination is raised above C60F48, carbon–carbon bond cleavage
occurs, thus cracking the sphere [144, 145]. A fluoroxyfullerene, C60F17OF, has been
characterised [146].
Mesophase pitch, derived from coal tar, reacts smoothly with fluorine to give pitch
fluoride [147, 148] with a composition between CF1:3 and CF1:6, as a yellowish white
solid which differs from graphite fluoride in that it is soluble in some fluorocarbon
solvents. Consequently, thin films of pitch fluoride may be deposited on materials
and the resulting surfaces have been claimed to have even lower surface energies than
PTFE.
E Fluorination of compounds containing functional groups
When functional groups are present, the products can be quite complex. Primary and
secondary amines give NF2 and NF compounds respectively and fluorination of sulphur
compounds gives products in which the sulphur has been oxidised to its maximum
valency state of six [149] (Table 2.4). Hydroxy compounds can give fluoroalkyl hypo-
fluorites (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).
CH3OH
i, F2, Cu/Ag, 160−180 � C
CO2
i, F2, CsF, −196 � C to rt
CF2(OF)2
CF3OFi
i
½150�
½153�
Figure 2.27
Perfluorinations of many ethers [155], cryptands [156], polyethers [119, 157], includ-
ing the largest perfluoro-macrocycle [158], perfluoro [60]-crown-20 [123, 159], and the
first perfluorinated sugar [160], orthocarbonates [161, 162], ketones [163, 164], esters
[124, 165], phosphanes [166] and alkyl halides [167, 168] have been successfully
accomplished by the LaMar or aerosol processes (Table 2.4).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 39
Preparation of Highly Fluorinated Compounds 39
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).
Table 2.4 Fluorination using dilute fluorine
Starting material Product Yield (%) Ref.
Conditions: F2 in He or N2, �788C to rt
(CH3)3CCH2CH2C(CH3)3 (CF3)3CCF2CF2C(CF3)3 89 [169]
C
4
C
4
F 96 [170]
F
F
H3C
H3C F3C
F3C
F 26 [171]
CH2CH2O
(CH3)3C�CH2�SH
n CF2CF2O n
(CF3)3C�CF2�SF5
–
91
[172]
[149]
Conditions: 268C and lower
CH2CH2O20
CF2CF2O20
[159]
Conditions: �908C to rt
O
O
O
O
O
O
O
OF3C
F3C
F3C
O
OCF3
F2
F
F[160]
Conditions: Aerosol fluorination
Cl Cl
F60 [173]
O
O
F3CCF2 O
O CF3
CF3
F 65 [124]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:41pm page 40
40 Chapter 2
CBr4 CF3Br 94%
CI4 CF3I 95%
BrF3
IF5
½176�
Figure 2.28
Liquid-phase halogenation of hexachlorobenzene with chlorine trifluoride appears to
proceed by a series of additions and vinylic and allylic substitutions until all of the
hexachlorobenzene is converted into chlorofluorocyclohexenes, C6Fn(Cl10�n) (n ¼mainly 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 cyclohex-
ene 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).
C6Cl6ClF3, 240�C
C6F7Cl3 (2%) + C6F6Cl4 (10%) + C6F4Cl4 (4%)
+ C6F5Cl5 (30%) + C6F4Cl6 (35%)
½177�
Figure 2.29
2I2 + IF5 + 5CF3CF=CF2150� C
5(CF3)2CFI 99%
2I2 + IF5 + 5CF2=CF2 5CF3CF2I 86% ½178, 179�
Figure 2.30
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Preparation of Highly Fluorinated Compounds 45
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46 Chapter 2
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).
CH3(CH2)15 CO2Me
Br
CH3(CH2)15 CO2Me
F
i AgF, CH3CN, H2O, 80 � C, 2hr
84%
C8H17I
i AgF, CaF2, 75 � C, 10min
C8H17F 80%
i
i
½24�
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
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 47
47Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
aprotic solvents (see Chapter 2, Section IIB). Acid fluorides, alkyl fluorides and fluoro-
aromatics 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,
CH3COCl CH3COF
i, KF, CH3COOH, 100 � C
76%
C6H5CH�CHSO2Cl C6H5CH�CHSO2F
i, KF, xylene, reflux
51%
i
i
MF + n-C8H17Bri or ii
n-C8H17F + MBr
i, MF = KF plus small amounts water, 85� C 60%ii, MF = Bu4NF.3H2O, 60 � C 71%
MF + BrCH2COOEti
FCH2COOEt + MBr 70%
i, MF = CsF + 10% Bu4NF, 40 � C
BrCH2CH2OHi
FCH2CH2OH 72%
CH3CH2CHBrCOOEti
CH3CH2CHFCOOEt 78%
i, KF, Hexadecyltributylphosphonium bromide, heat
O(CH2)3OMs
i
O(CH2)3F
92%
N NBuMe
BF4 , H2O (5 equiv), 100 � Ci, KF,
½29�
½30�
½25�
½25�
½27�
½28�
Figure 3.2
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 48
48 Chapter 3
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 hexa-
decyltributylphosphonium bromide (m.p. 56–588C) 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 mois-
ture; tetrabutylammonium fluoride (TBAF), obtained commercially as the trihydrate, can
be partially dried either by heating at 408C under high vacuum [31] or, chemically, by
reaction with hexamethyldisilazane [32], but prolonged heating of TBAF causes
decomposition to occur via a Hofmann elimination pathway [33]. However, tetramethyl-
ammonium fluoride [34] and adamantyltrimethylammonium fluoride [35] are more
stable and they can be obtained in an anhydrous state by heating under vacuum after
recrystallisation from propanol. Fluoride ion sources have been described that contain
more elaborate counter-ions including tris(dimethylamino)sulphonium difluorotrimethyl-
siliconate (TAS-F) [12], a phosphazenium fluoride [36], cobaltocenium fluoride [37] and
‘Proton Sponge’ (PS) [38] (Table 3.1).
Table 3.1 Halogen exchange by various sources of fluoride ion
Substrate Reagent/Conditions Product Yield (%) Ref.
CH2¼CHCH2Br Bu4NF, 258C CH2¼CHCH2F 85 [33]
Cl
O
Ph
THF=HMPTa, 958C, Bu4NþHF�2
F
O
Ph
[39]
RX 2Bu4NF�nH2O RF [40]
(R ¼ alkyl, X ¼ Cl, Br) CH3CN
PhCH2Br Ph4PHF2 PhCH2F 100 [41]
CH3CN, 508C
PhCH2Cl Cp2CoFb PhCH2F 95 [37]
THF, rt
C2H5I TAS-Fc C2H5F 85 [12]
CH3CN, rt
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 49
Partial or Selective Fluorination 49
Hydrogen fluoride under vigorous conditions may be used in favourable circumstances,
for example to make fluoromethyl ethers [44] (Figure 3.3a).
OH
Cl
+ CCl4
OCCl3
Cl
OCF3
Cl
70%
i
i, HF, 150 � C
½44�
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 mono-
fluoride [47] (Figure 3.4) and the less reactive bromine trifluoride [48–50]. Since tertiary
Table 3.1 Contd
Substrate Reagent/Conditions Product Yield (%) Ref.
CH3ðCH2Þ7Br Bu4NþPh3SiF�2 CH3ðCH2Þ7F 85 [42]
CH3CN, 808C
Cl
O
Ph
PS=HFd
CH3CN, rtF
O
Ph76 [38]
Ph Cl
OPyridine�9HF
08CPh F
O[43]
a HMPT, hexamethylphosphoric triamide.
b Cp2CoF
Co F
c TAS-F
[(Me2N)3S]+ [(CH3)3SiF2]− Me2N NMe2
. HF
d PS / HF
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 50
50 Chapter 3
Cl
R Cl
SO2Cli
Cl
R F
SO2F
Cl
R Fii, iii
R = H, Mei, KF, Ph4PBrii, NaOHiii, H2SO4, heat
½45�
Figure 3.3b
CH3CH2CH2Br + ClF CH3CH2CH2F + CH3CHFCH3
30% 70%
CH2Cl�CH2Br + BrF3
rtCH2Cl�CH2F 80%
0 � C½47�
½48, 49�
Figure 3.4
bromides react the most readily, and rearrangement occurs on reaction with primary
alkyl bromides, a carbocationic mechanism has been proposed.
The use of p-iodotoluene difluoride for replacement of iodine by fluorine has beeen
described as a nucleophilic displacement of IF2, as a good leaving group, in a pre-formed
iodoalkane difluoride [51]. Note that iodine is displaced in preference to p-TsO in this
system (Figure 3.5a).
RCH2Ii RCH2 IF2
F
RCH2F
i, p-MeC6H4IF2, Et3N.4HF, CH2Cl2
74%R = p-TsO
½51�
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 51
Partial or Selective Fluorination 51
NPhS
O
ArIF2 NPhS
O
ArIF2 NPhS
O
F
F
I F
Ar
NPhS
O
F
N
O
F
PhS
F
½52�
Figure 3.5b
The first indication that fluorine could be used as a selective fluorinating agent was
reported by Bockemuller in 1933 concerning reactions with butyric acid [57]. Fluorin-
ation only occurs at the b- and g- positions, demonstrating that the regioselectivity of the
process can be heavily influenced by the presence of an electron-withdrawing group in
the substrate. This demonstrates the electrophilic nature of fluorine, although low-
temperature fluorination of hydrocarbons is still much less selective than the correspond-
ing 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 52
52 Chapter 3
OR ORF
OR
F
F
AcO
OAc
H
AcO
OAc
F
i, F2, N2, −70 � C, CHCl3, CFCl3 (1:1)
+
60% 10%
R = −CO-C6H4NO2
50%
i
i, F2 in N2(10% v/v), C6H5-NO2, −78 � C, CFCl3, CHCl3
i
½62, 63�
Figure 3.6
H
H
H
F
i, F2 in N2 (10% v/v), CH3CN, 0 � C
i54%, 68% conversion ½11, 64, 65�
Figure 3.7
F H H + HF
COOH
F
COOH
F
Nu: + F
F
Nuc
i, F2/N2, 98% H2SO4, room temp.
i
½66�
Figure 3.8
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 53
Partial or Selective Fluorination 53
H FH
F F HCCl3
OCOC6H4NO2
Me
OCOC6H4NO2
Me F
i, F2, N2, −70 � C, CHCl3, CFCl3 (1:1)
60%i
½11, 65�
Figure 3.9
N–F reagents acting as electrophiles, because radical clock experiments with these
systems do not support a radical process [69, 70].
Consequently, in a given situation, the question as to whether a fluorination involves
fluorine atoms (which themselves are very electrophilic, and such processes will therefore
have polar characteristics) or nucleophilic attack on a molecule of elemental fluorine is
difficult to assess. Both processes almost certainly occur, depending on the system and
conditions.
The changing perspective on the viability of fluorine as a reagent is illustrated by the
fact that many selective fluorinations of substrates [8] containing carbon centres of high
electron density have now been described, including a variety of enolate derivatives [71,
72], stabilised carbanions [73, 74], steroids [75] and 1,3-dicarbonyl derivatives [76]
(Table 3.2) as well as some aromatic compounds [77]. Fluorinated aminoacids have
been obtained by direct fluorination [78] (Figure 3.10).
Table 3.2 Selective fluorinations with elemental fluorine
Substrate Conditions Product Yield (%) Ref.
OSiMe3 F2, N2
�788C, CFCl3
OF
78 [71]
OEt
OSiMe3 F2, N2
�788C, CFCl3 OEt
O
F
57 [79]
NO2
HO2N
OHi) OH�
ii) F2, N2, 58C, H2O
NO2
FO2N
OH84 [74]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 54
54 Chapter 3
COOMe
NHCOPh
F2COOMe
NHCOPh
R = Alkyl or aryl
H
RRCHF F
COOH
NH2
RCHF F
COOH
NHCOPhRCHF F ½78�
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
H
i
StereochemistryRetained
F
H
ii
H
N
H
HMe
O
iiii, F2, CH3CN, 0 � Cii, BF3.Et2Oiii, CH3CN, H2O
½65�
Figure 3.11
Table 3.2 Contd
Substrate Conditions Product Yield (%) Ref.
O
OEt
O
F2, N2
108C, HCOOH
O
OEt
O
F
90 [76]
O
O
OHO
O
F2, N2
�408C, CH3CNO
OOHC
O
O
F 71 [80]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 55
Partial or Selective Fluorination 55
B Electrophilic fluorinating agents containing O–F bonds [81, 82]
Several organic hypofluorites, including trifluoromethyl (CF3OF) [83–85], perfluoroethyl
(C2F5OF) [86], trifluoroacetyl (CF3COOF) [87] and acetyl hypofluorite (CH3COOF)
[88, 89], are now known which have found applications as fluorinating agents [90–94]
(Figure 3.12).
OCF3 FNu: + F Nu + OCF3
R
R'
H
COOR''i, ii R'
R
OSiMe3
OR''
iiiR
R'
F
COOR''
i, LDAii, Me3SiCliii, MeCOOF
R = R' = n-Pr, R'' = Me, 90%R = Ph, R' = Et, R'' = Me, 80%
½89�
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 electro-
philic fluorinating reagents.
R1 R2 R1 R2
F OMe
i, MeOF, CH3CN, −40 � C Room Temp
C6H5-CH=CH2
i, t-BuOF, CH3CN
CHC6H5-C
Fδ +
δ −δ +
δ −
60-70%i
i
C6H5-CHFCH2Ot-Bu
Ot-Bu
½95�
½96�
Figure 3.13
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 56
56 Chapter 3
However, single-electron transfers promoted by photolysis, are the most likely pro-
cesses when CF3OF 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.
Caesium fluoroxysulphate (CsSO4F) [94] is a solid electrophilic fluorinating agent that
is very easily prepared [100] (Figure 3.14) but, unfortunately, is very prone to rapid
uncontrolled decomposition. However, it has been used for the fluorination of hydrocar-
bons [101] and aromatics [102–104] (Figure 3.15).
Cs2SO4 + F2 CsSO3OFH2O ½100�
Figure 3.14
p-XC6H4SnMe3
i, CsSO3OF, CH3CN, −4 to 0 � C
p-XC6H4F
X = H, 69%; = Cl, 87%; = Me 86%
i, CsSO3OF, BF3, CH3CN
FC6H4RC6H5Ri
i
½102�104�
Figure 3.15
Table 3.3 Fluorinations using O–F reagents
Substrate Reagent/Conditions Product Yield (%) Ref.
NO2 i) MeONa, MeOH
ii) AcOF, CFCl3, 08C
F NO2
85 [97]
O
i) LDA, THF
ii) AcOF, �788C
OF
86 [98]
OEt
O OAcOF,
CFCl3, CHCl3, � 758C OEt
O O
F
72 [99]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 57
Partial or Selective Fluorination 57
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).
N
N
CH2Cl
(CF3SO2)2NH +
N
N
(CF3SO2)2NFF2
CH2Cl
F
HF+
2BF4BF4
i, F2, N2, NaBF4, CH3CN, −35 � C
i
Selectfluor®
½108�
½109�
Figure 3.16
Reported reagents of this class include N-fluorobis(trifluoromethanesulphonyl)imide
[110, 111], N-fluoro-N-alkyl-sulphonamides [112], dihydro-N-fluoro-2-pyridone [113],
N-fluoropyridinium salts [114–116], N-fluoroquinuclidinium [117] and related salts [118,
119], N-fluoroperfluoroalkyl sulphonamides [120, 121] and N-fluorosultams [122], some
of which are commercially available (e.g. Selectfluort, Air Products). Many fluorinations
of resonance-stabilised carbanions [119], phosphonates [123], 1,3-dicarbonyls [124, 125],
enol acetates [115], enol silyl ethers [119], enamines [119], aromatics (Chapter 9), double
bonds and compounds containing carbon–sulphur bonds [126] have been performed under
mild conditions (Table 3.4) and even enantioselective fluorinations of enolates are
possible when appropriate homochiral N-fluorosultams are used [127, 128], or other
homochiral substrates [129]. Considerable encouragement is given by reports of relatively
high enantioselectivity in some processes where N–F compounds have been used in the
presence of various chiral catalysts [130, 131], although the latter are currently used in
significant proportions.
Table 3.4 Fluorinations using electrophilic N–F fluorinating reagents
Substrate Reagent/Conditions Product Ref.
PhOMe
CH3
O
S
N
Me Me
F
O O
PhOMe
CH3
O
F
[122]
n-Pr P
O
OEtOEt
LDA, THF, �788C to rt
PhSO2Þ2NF�
LDA, THF
n-Pr P
O
OEtOEt
F F
[123]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 58
58 Chapter 3
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
Table 3.4 Contd
Substrate Reagent/Conditions Product Ref.
O OCF3SO2Þ2NF�
CH2Cl2, rt
O O
F
[124]
Ph NMe2
O O
N
N
CH2Cl
F
2BF4−
Ph NMe2
O O
F
[125]
CH3CN, rt
OSiMe3
N
F
OTf−
O
F
[115]
CH2Cl2, reflux
OAcO U
S-ArAcO
N
N
CH2Cl
F
2BF4−
OAcO U
S-ArAcO
F [126]
Et3N, CH3CN, rt
O
CO2Et
N
SF
O
O
O
F
CO2Et [127]
NaH, Et2O, rt
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 59
Partial or Selective Fluorination 59
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 supercrit-
ical 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).
+ +
i ii
i) Aprotic conditionsii) Protic conditions
OSiMe3
O
F
O
F
O
OO
X X
F
X = O, CH2
i, XeF2, BF3.OEt2
i
XeF2XeF2
½139�
½138�
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 pyridine�HF [143] (Figure 3.18).
Oxidative fluorination of phenols in amine�HF solution gives difluorodienones [144]
(Figure 3.19).
Fluorination of aromatic substrates has been reported [145].
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 60
60 Chapter 3
H
NO
R3C�H R3C
R3C
R3C�NO
R3C�F
i, NO+BF−4, Py.HF
i ½143�
Figure 3.18
OH O
F F
30%
i, PbO2, Py.HF
i½144�
Figure 3.19
Oxidative fluorination of toluene derivatives to the corresponding fluoromethylben-
zenes is possible using appropriate lead or nickel complexes in liquid hydrogen fluoride,
but fluorination becomes more difficult as the reaction progresses because fluorine
substituents increase the oxidation potential of the substrate [146] (Figure 3.20). Conse-
quently, it seems unlikely that the ECF process (Chapter 2, Section III) could proceed to
perfluorination by an analogous mechanism.
HF, −e
−e
etc
−H+Pb(OAc)4Ar�CH3 (Ar�CH3) Ar�CH2
Ar�CH2Ar�CH2FAr�CF2H
Ar = p-C6H4NO2
½146�
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 Et3N�3HF as
the electrolytic medium [149, 150]. A Pummerer-type mechanism has been proposed
(Figure 3.21a).
RS
CH3 RS
CH3
F
S CR
F
RS
CH2F
H
H
−H
Figure 3.21a
Similarly, a-fluoro sulphoxides are prepared by fluorination using DAST [151].
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 61
Partial or Selective Fluorination 61
Remarkably, iodine pentafluoride in Et3N�3HF acts, in some cases, like an
electrophilic fluorinating agent, replacing C2H in preference to oxygen functions [152]
(Figure 3.21b).
F F
COCH2SEt
i, ii
F F
COCF2SEt
82%
CH3COCH2COOEt + IF5
i, iiiCH3COCHFCOOEt
71%i, Et3N.3HFii, heptane 74� Ciii, heptane 40� C
+ IF5
½152�
Figure 3.21b
IV FLUORINATION OF OXYGEN-CONTAINING FUNCTIONALGROUPS
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(hydrogen-
fluoride) and pyridinium poly(hydrogenfluoride) (PPHF, Olah’s reagent). Secondary
and tertiary alcohols can be converted to the corresponding fluorides by reaction
with pyridine�ðHFÞn [43] (Figure 3.22). Preferential fluorination of tertiary alcohols over
OH F
OH F
i, Pyridine.(HF)n, 20 � C, 2 hr
99%
95%
i
i, Pyridine.(HF)n, 20 � C, 1 hr
i
½43�
Figure 3.22
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 62
62 Chapter 3
secondary hydroxyl groups is possible, due to the much higher reactivity of tertiary
hydroxyl groups towards pyridine�ðHFÞn [154] (Figure 3.23).
O
HO
OH O
HO
F
i, Pyridine.(HF)n, −35� C, CH2H2
i ½154�
Figure 3.23
Proton Sponge�HF (Figure 3.24) is a particularly useful system which is an effective
fluoride-ion donor for appropriate fluorinations [38, 155]; it is likely that the proton in this
system is much less involved in H-bonding to fluoride than is the proton in hydrogen
fluoride.
Me2N NMe2
H
FProton Sponge. HF (PS.HF)
PS.HF + CF2�CFCF3
i(CF3)2CF
C3F6F3C
F3C
C2F3
F
72%i, CH3CN, rt
N
NH
Cli
N
NH
F + PS.HCl
i, PS.HF, CH3CN, rt79%
½38�
Figure 3.24
A combination of IF5 with Et3N�3HF appears to be effective in replacing hydroxyl
[152] (Figure 3.25).
2 Diethylaminosulphur trifluoride (DAST) and related reagents [156–158]
DAST was first used as an alternative fluorinating agent to sulphur tetrafluoride, by
Middleton [159]. Although DAST, prepared by the reaction of SF4 with diethylamino-
trimethylsilane [160] (Figure 3.26), can be used in normal laboratory glassware at
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 63
Partial or Selective Fluorination 63
p-CH3-C6H4-CH2OH p-CH3-C6H4-CH2Fi, ii
83%i, Et3N.3HFii, CH2Cl2
+ IF5 ½152�
Figure 3.25
Et2N�SF3 + Me3SiFSF4 + Et2N�SiMe3
DAST
½159�
Figure 3.26
atmospheric pressure, care must be exercised since it may decompose violently above
508C [161]. Consequently, more stable analogues such as the morpholino [162] and
piperidino derivatives have been used and a methoxyethyl derivative has become com-
mercially available, MeOCH2CH2Þ2NSF3
�(Deoxo-Fluort, Air Products Company)
[163].
Primary, secondary, tertiary and allylic hydroxyl groups are replaced by fluorine in
excellent yields [12, 164] via a process involving an intermediate alkoxysulphur difluor-
ide, the presence of which is supported by both spectroscopic [165] and chemical
evidence [166] (Figure 3.27).
R�O�SF2NEt2R�OH + Et2N�SF3 R�F + FSONEt2F ½165, 166�
Figure 3.27
For most substrates SN2 replacement of hydroxyl by fluorine occurs with complete
inversion of configuration [12] although retention of stereochemistry is observed when
neighbouring groups containing either C5C double bonds, oxygen or nitrogen become
involved in the reaction centre [17]. Allylic alcohols may be converted to mixtures of
isomeric allyl fluorides by either an SNi or SN20 process [12] (Figure 3.28).
R
OSF
F NEt2
R
OSF
F NEt2
F
SN2'
RF
SNi
½12�
Figure 3.28
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 64
64 Chapter 3
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], Et2N�CF2CFClH,
and Ishikawa’s reagent [172], Et2N�CF2CFHCF3, 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,
Me2N�CF2CF2H, has been shown to be a viable alternative reagent [176].
Enantio-controlled processes have been developed [177]; polymer-supported [178]
FARs and other related systems such as PhCF22NMe2 have also been studied [179],
and reactions in supercritical carbon dioxide have been reported [180].
2,2-Difluoro-1,3-dimethylimidazoline (DFI) has recently been prepared and is
very useful for replacing OH in alcohols by F. Carbonyl is converted to CF2 with
accompanying elimination in some cases, whereas carboxyl is not converted to CF3
[181] (Figure 3.31).
Table 3.5 Replacement of hydroxyl groups by fluorine
Substrate Reagents/Conditions Product Yield (%) Ref.
n-C8H17OH DAST n-C8H17-F 90 [159]
CH2Cl2, �708C to rt
PhCH2CH2OH Deoxo-Fluort PhCH2CH2F 85 [163]
CH2Cl2, rt, 16 h
O
OMeHO
F
HO
HO
DAST
CH2Cl2, �408C to rt O
OMeHO
F
F
HO71 [167]
Et2OÞ2POCHðOHÞPh�
DAST Et2OÞ2POCHFPh�
53 [168]
CH2Cl2, rt
OH3C
O
O
SPh
OH
DAST
CH2Cl2, 08C
OH3C
O
O
F
SPh
[169]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 65
Partial or Selective Fluorination 65
HO
O
F
O
HO OMe
O
F OMe
O
45%
57%
i, Et2NCF2CFClH, CH2Cl2
i, Et2NCF2CFHCF3, CH2Cl2, 18 hr
i
i½173�175�
Figure 3.29
N CEt
EtCFHCF3
F
F
N CEt
EtCFHCF3
F
RO
H
N CEt
EtCFHCF3
F
O
N CEt
EtCFHCF3
F
O
N CEt
EtCFHCF3
O
R H
RR
N CEt
EtCFHCF3
O
R F
−F
+ F
−F
−H
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. �388C) with toxicity of the same order as
phosgene, has been commercially available since a practical method for its synthesis was
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 66
66 Chapter 3
NNMe Me
O
COCl2NN
Me MeCl
Cl
KFNN
Me MeF F
DFI
n-C8H17OH
i, iii
n-C8H17F 87%
p-HOC6H4-NO2
i, ii
p-FC6H4-NO2 62%
O
i, iv
F F F
21% 72%i, DFIii, CH3CN, 25 � Ciii, CH3CN, 85 � Civ, Glyme, 85� C
½181�
Figure 3.31
O
OO
O
O
OCOCH3
i, HF, CH3NO2, Ac2O, 0 � C, 3 hr
O
OO
AcO
AcO
F
i½182�
Figure 3.32
developed [186, 187] (Figure 3.34), although it is difficult to purify [188]. Its most general
function is to exchange C5O for CF2 and it is usefully applied to the conversion of
aldehydes and ketones to the corresponding difluorides, and of carboxylic acids (via the
acid fluoride) to trifluoromethyl derivatives. Many examples have been documented and
reviewed [2, 7, 156, 189] (Figure 3.35).
The observation that anhydrides are not as reactive as carboxylic acids led to the use of
acid catalysts with sulphur tetrafluoride; reactions are frequently carried out in the
presence of anhydrous hydrogen fluoride, while BF3, AsF3, PF5 and TiF4 are also potent
catalysts [190]. Conversions can be achieved in the presence of a wide range of other
functional groups, for example bromo, chloro and unsaturated functions, although under
some circumstances halogen exchange occurs [191]. Exchange of C5O for CF2 occurs in
many classes of carbonyl compounds [2, 7, 156, 189], such as amides, esters,
1,2-dicarbonyls, hydroxy ketones, lactones, acid halides, carboxylic acids, some quinones
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 67
Partial or Selective Fluorination 67
n-C8H17OSO2C6H4CH3 n-C8H17F
OCH3
O
OSO2CH3
OCH3
O
F
O
ClOSO2CF3
O
Cl
F
i, KF, PEG 400, 27hr, 50� C
59%
i, KF, HCONH2, 60 � C, 20 torr
83%: 96% e.e.
i, Bu4NF, THF, 4 hr
65%
i
i
i
½183�
½184�
½185�
Figure 3.33
3 SCl2 + 4 NaF SF4 + S2Cl2 + 4 NaCl 90%CH3CN, 70 � C
3SCl2 + 4Py.(HF)n SF4 + S2Cl2
½186�
½187�
Figure 3.34
C6H5�CHOSF4, 150 � C
81%C6H5�CHF2
80%SF4, 170 � C
CF3C CCF3HOOCC CCOOH
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 organo-
metallic 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 tri-
fluoride [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 68
68 Chapter 3
C OXFn
C O XFn
SF4C O XFn
F SF3
C
F
O SF3 + XFnC
F
O SF2
F
F XFn−1
C F
F
+ SOF2 + XFnXFn = Lewis Acid
δ δ δδ½190�
Figure 3.36
HOOC
COOH
COOH F3C
CF3
CF3 F3C
CF3
CF3
Lietc ½192�
Figure 3.37
F F
82%
i, SF4, HF, CH2Cl2
O O
i ½193�
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,
pyridine�HF, Et3N�3HF [203] and i-Pr2NH�3HF [204] efficiently cleave epoxides to
give excellent yields of fluorohydrins (Figure 3.39).
O FH
H
OHi-Pr2NH.HF ½204�
Figure 3.39
The regioselectivity of the reaction is dependent on the hydrofluorinating reagent used.
Pyridine�ðHFÞn is highly acidic and the reaction proceeds by protonation of the ring
oxygen, followed by fluoride ion attack on the carbon atom upon which the developing
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 69
Partial or Selective Fluorination 69
positive charge is most readily stabilised. Conversely, i-Pr2NH�3HF is not sufficiently
acidic to protonate the ring oxygen significantly and so ring opening occurs by fluoride-
ion attack at the least hindered carbon atom in an SN2 process [205] (Figure 3.40). Larger
oxygen-containing rings can also be cleaved [206] (Figure 3.41).
Recently, silicon tetrafluoride [207] and tetrabutylphosphonium fluoride [208] have
been used to prepare fluorohydrins from epoxides. Generation of a superacid is required
for the ring opening of a perfluorinated oxirane [209] (Figure 3.42).
Silyl ethers may be cleaved by either Bu4NF=CH3SO2F [210] or ArPF4 [211] to give
alkyl fluorides. Fluoroformates decarboxylate, on heating in the presence of an acid
catalyst, to give the corresponding fluoride [212, 213] (Figure 3.43).
Table 3.6 Fluorination of carbonyl and related groups
Substrate Reagent, conditions Product Yield (%) Ref.
C6H5CHO SF4, 1508C, 6 h C6H5CF2H 81 [194]
C6H5CHO Deoxo-Fluort, rt C6H5CF2H 95 [163]
O
O O
O
SF4, 1308C
O
O F
F
F
F [195]
N
CO2H
SF4, 1008C
N
CF3
25 [196]
CO2H
CO2H
CO2H
CO2H
SF4, HF, 2008C
CF3
CF3
O
F F
F F
76 [197]
HO2C CO2H
HO2C CO2H
SF4, HF, 1408C
F3C CF3
F3C CF3
18 [198]
OOMe
O O
O
H
DAST, CH2Cl2, rt
OOMe
O O
HF2C
45 [199]
C6H5COCH2F DAST, benzene, 508C C6H5CF2CH2F 82 [200]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:22pm page 70
70 Chapter 3
O
OBu OBu
F
OH
OBu
OH
F
+
Reagent : i-Pr2N.3HF Ratio : 6 1 Yield, 81% Pyridine.HF 1 4 68%
½205�
Figure 3.40
O
F F
F F
CF3
COF
HF, 95 � C½206�
Figure 3.41
O CF3F
F CF3
(CF3)3COH 56%
i, HF, SbF5, 100 � C
i ½209�
Figure 3.42
OCOF F
i, AlF3, HF, 200−300 � C
i
Me MeOCOF
i
Me MeF
i, HF, 130 � C 69-75%
½212, 213�
½214�
Figure 3.43
V FLUORINATION OF SULPHUR-CONTAINING FUNCTIONALGROUPS
Several methods concerning the formation of CF, CF2 and CF3 groups by fluorodesul-
phurisation [215, 216] processes have been reported (Table 3.7). Generally, these fluor-
inations 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).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 71
Partial or Selective Fluorination 71
Table 3.7 Fluorodesulphurisation reactions
Substrate Reagents/Conditions Product Yield (%) Ref.
O
BnO
BnOBnO
BnOS-Ar
p-MeC6H4-IF2
CH2Cl2, � 788C to rt
O
BnO
BnOBnO
BnO
F
[217]
n-Pr
CF3
S S Pyridine�ðHFÞn, NBSa
�78�C to rtn-Pr
CF2CF3
[218]
Ph
S S
Br
F2, I2, CH3CN, rt
CF2Ph
Br[219]
S S
C6H11 H
BrF3
CF2H
70 [220]
OMe
S
DASTb, CH2Cl2, rtO
F
S
[221]
S
C(SEt)3Pyridine�ðHFÞn, NBS
�788C to rt S
CF3 [222]
S
SEtBr
BrF3, 08C
Br CF3
[223]
MeO
N
S
SMe
PhCH2
Bu4Nþ H2F�3
NBS, rt
MeO
NCF3
PhCH2
[224]
a NBS, N-bromosuccinimide.b DAST, diethylaminosulphur trifluoride.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 72
72 Chapter 3
C S R C S R
I
C F
F
I
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
S
R CF3SO3
3.45A
RCF2N3
89%
i-iv
i, Me3SiN3, CH2Cl2, 0�Cii, Bu4NF, THF, 0�Ciii, Et3N.3HFiv, DBH
½225�
Figure 3.45
VI FLUORINATION OF NITROGEN-CONTAININGFUNCTIONAL GROUPS
A Fluorodediazotisation [226]
In the classic Balz–Schiemann reaction [227, 228], arylamines are converted to fluoro-
aromatics 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 pyridine�ðHFÞn, 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].
Ar�NH2
i, HCl, NaNO2ii, HBF4
Ar�N2 BF4heat
Ar�Fi, ii ½227, 228�
Figure 3.46
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 73
Partial or Selective Fluorination 73
R COOH
H2N H
R
N2 H
HO
O
R
HO H
O
R COOH
F H
(HF)nF
½234�
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 ob-
served 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 amine�HF mixtures to
give b-fluoroamine derivatives [239, 240]. The mechanism, either SN1 or SN2, and
consequently the stereochemical outcome of the reaction are greatly influenced by the
precise nature of both the aziridine and the fluorinating agent used. For example, phenyl-
substituted aziridines can be considered to react via the most stable carbocation in an SN1
process, which accounts for the mixture of stereoisomers obtained [239] (Figure 3.48).
1-Azirines also may be ring-opened in a similar manner [241].
Table 3.8 Fluorodediazotisation
Substrate Reagents/Conditions Product Yield (%) Ref.
Me
NH2
Me
i, NaNO2, HCl
ii, HBF4
iii, Heat
Me
F
Me
[235]
N NH
H2N CO2Eti, NaNO2, HBF4
ii, hn, HBF4, � 508CN NH
F CO2Et39 [236]
N
NH2
NaNO2, pyridine�HF
N
F
93 [237]
H3C COOH
H2N H
NaNO2, pyridine�HFR COOH
F H
76 [238]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 74
74 Chapter 3
HN
Ph Me
HH
Ph Me
HNH2
H2N
Ph Me
HH
H Me
PhNH2
Ph Me
HNH2F F
69% 8%
+
H
F
½239�
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).
NO2
NO2
NO2
F
N(CH3)3
NO2
18F
NO2
KF, sulpholan(NO2)2CF2 59%(NO2)3CF
70%
ClO4
i, Me4NF, DMSO, 100� C, 4 hr
i, Cs18F, DMSO, 120� C
91%
i
i
½242, 243�
½242, 243�
½244�
Figure 3.49
Hydrazones can be converted into gem-difluorides upon reaction with either fluorine
[245], bromine monofluoride (generated in situ) [246] or ‘iodine monofluoride’ [247],
and the reaction of diazoketones with fluorine results in similar transformations [248]
(Figure 3.50).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 75
Partial or Selective Fluorination 75
CH3
NNH2
CF2CH3
EtO OEt
O O
N2
EtO OEt
O O
i, Pyridine.(HF)n, NBS, CH2Cl2
F F
60%
70%
i, F2, CFCl3, −70 � C
CH3
NNH2
‘IF’
CF2CH3
80%
i
i
½248�
½246�
½247�
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 transaddition 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 amine�HF mixture [43] (Figure 3.51).
F
CH3�CH�CH2
HF, −45 � CCH3CHFCH3 62%
i, Pyridine.(HF)n, THF, 0 � C
65%i
½250�
½43�
Figure 3.51
Reactions with less nucleophilic, halogenated alkenes require more vigorous conditions
and a Lewis acid catalyst is generally added to prepare commercially significant fluoro-
haloalkanes [251, 252] (Figure 3.52).
Addition to acetylenes occurs under a variety of conditions; the reaction of acetylene
with hydrogen fluoride is important for the manufacture of vinyl fluoride, although the
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 76
76 Chapter 3
CF2�CHCl
CH2Cl�CCl2F 89%
BF3, 25�C
HF
CHCl�CCl2HF, TaF5
CF3CH2Cl 90%
½251, 252�
Figure 3.52
addition proceeds further to give some difluoroethane [253]. With pyridine�HF the
reaction goes via the expected intermediate fluoroalkene to give difluoroalkanes only
[43] (Figure 3.53).
70%
i, Pyridine.(HF)n, THF, 0�C
C4H9CF2CH3C4H9C CHi ½43�
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).
C6H5
FF
OR
O C6H5
OR
O
CF3
CO2Me
H
F
MeO2C
i, Bu4NF, THF, 0�C, MeC6H4SO3H
R = methyl
71%
90%
MeOOCC CCOOMe
i
i, Bu4NH2F3, CH2Cl CH2Cl, 60�C
i
½254�
½255�
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, re-
spectively. Selective fluorination of many alkanes [8, 259], such as acenaphthene [260],
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 77
Partial or Selective Fluorination 77
CF3CF=CFCF3
F2, −75 � CCF3CF2CF2CF3 + [CF3CF2CF(CF3)]2
CFCl3
½256�
Figure 3.55
1,1-diphenylethene [261] and many steroids [236], is now possible in sometimes surpris-
ingly high yield by passing fluorine diluted with an inert gas through a solution of the
unsaturated compound (Table 3.9).
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 electro-
philic 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).
Table 3.9 Direct fluorination of alkenes
Substrate Reagent, conditions Product Yield (%) Ref.
OF2, N2
CFCl3, CHCl3, EtOH
�758C
O
F F
35 [259]
O OF
F
65 [237]
N
Boc
OF2, N2
CFCl3, CHCl3, EtOH
�788CN
Boc
OF
F 41 [262]
OAcO
OAc
AcO
F2, Ar
CFCl3, �788C
OAcO
OAc
AcO
F
F
40 [263]
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 78
78 Chapter 3
H
F
F
H
FF
F FF
HH
FF FF
δδ
−H
F
F2
3.56A
½235, 259�
Figure 3.56
Ph2C�CH2 Ph2CFCH2F + Ph2C�CHF + Ph2CFCF2H14% 78% 8%
F2, N2 ½238�
Figure 3.57
O
Cl
AcOCl
F2, N2
O
F
O
F
F
F
FO
½236�
Figure 3.58
C Indirect addition of fluorine
Reaction of alkenes with an electrophilic fluorinating agent such as caesium fluoroxy-
sulphate, 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 pyridine�ðHFÞn [267] (Figure 3.60).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 79
Partial or Selective Fluorination 79
Ph
Ph
PhH
FH
F
Ph
i, CsSO3OF, HF, CH2Cl2, 20 � C
syn:anti65 : 35
i ½264�
Figure 3.59
i, NO BF4, Pyridine.(HF)n
75%iPhCF2CF2PhPhC CPh
½267�
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).
++ XeF2
1387
HF, CH2Cl2
PhCH�CHPh + XeF2
HF, CH2Cl2PhCHFCHFPh 90%
cistrans
erythreo:threo = 53 : 47
62 : 38
F
F FF
½270�
Figure 3.61
The reaction is non-stereoselective, contrary to direct fluorination, and it is found that
only slight changes in either the reaction conditions or the structure of the substrate can
give rise to differing amounts of syn or anti addition. The addition of a Lewis acid, usually
HF [270] or BF3 �Et2O [271], to the reaction mixture gives much higher yields of the
desired difluoroalkanes, and both ionic and single-electron transfer pathways have been
suggested [272, 273].
The very reactive species PbðOCOCH3Þ2F2, formed in situ by the reaction of lead tetra-
acetate with hydrogen fluoride [274], has been used very effectively for adding fluorine to
alkenes, especially in the synthesis of the biologically important 6a-fluoro steroidal
hormones [275].
D Halofluorination
The combination of a source of electrophilic halogen together with a fluoride ion reagent
permits efficient halofluorination of nucleophilic carbon–carbon double bonds; products
resulting from addition in a trans stereochemistry are usually obtained (Figure 3.62).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 80
80 Chapter 3
HalHal 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 rearrange-
ments, for instance in the halofluorination of norbornadiene [276] (Figure 3.63).
The reaction has been used extensively for the introduction of fluorine into steroids
[277], where a curious anomaly arises between BrF and IF addition. As indicated,
stereospecific anti addition occurs in most reactions but syn addition of BrF or IF to
carbohydrates has been observed [278]. Halofluorination of alkynes proceeds as expected,
although further reaction of the resulting alkene derivative can occur.
Table 3.10 Halofluorination of alkenes and alkynes
Substrate Reagent/Conditions Product Yield (%) Ref.
NIS ,a
pyridine�HF
I
F65 [43]
C4H9DBH ,b KF�2H2O
H2SO4, CH2Cl2
C4H9Br
F
C4H9F
Br
+
87 (9:1) [279]
Me
N I BF4−
2
Me
I
F 60 [280]
CH2Cl2, 08C
Br2, AgNO3
pyridine�HF
F
Br
85 [43]
a NIS, N-iodosuccinimide.b DBH, 1,3-dibromo-5,5-dimethylhydantoin.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 8:23pm page 81
Partial or Selective Fluorination 81
Br F
F
Br
Br
Br
i, NBS, Et3N.3HF, CH2Cl2, 0 � C
53%
38%
5%
i ½276�
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).
O
AcO
H3C
AcO
O
AcO
H3C
AcO
O
AcO
H3C
AcOX
Y +
X
Y
X=F, Y=OCF3, 31%X=Y=F, 22%
X=F, Y=OCF3, 11%X=Y=F, 12%
i, CF3OF, CFCl3, −70 � C
i½281�
Figure 3.64
Additions of hypofluorites to unsaturated sites have been performed [17] on a wide
variety of substrates [282, 283] (Figure 3.65).
CsSO3OF reacts with alkenes to give fluoroalkyl sulphates [284].
F Other additions
In a similar process to halofluorination, sulphur- [285], selenium- [286] and nitrogen-
containing [43] groups and fluorine may be added to hydrocarbon double bonds by
reaction of an alkene with an electrophilic reagent of the heteroatom species in conjunc-
tion 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 82
82 Chapter 3
OMeF
OAc
AcO
OAc
AcOOCF3F
59%
40%
i, CH3OF, CH3OH, CH3CN, −40 � C
i
i, CF3OF, CFCl3, −75 � C
i
½282�
½283�
Figure 3.65
CH3
Ph SCH3
FH
PhH
CH3
MeO MeOF
SePh
i, (CH3)2SSCH3 BF4−, Et3N.3HF, CH2Cl2, rt
90%
i, PhSeCl, AgF, CH3CN
NO2
F
53%
65%
i, NO2BF4, Pyridine.HF, 0� C
i
i
i ½285�
½286�
½43�
Figure 3.66
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90 Chapter 3
Chapter 4
The Influence of Fluorineor Fluorocarbon Groups on someReaction 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 corres-
ponding 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 add-
ition to effects arising from different electronegativities, the effect of the lone pairs of
electrons of fluorine that are not involved in s-bonds must be taken into consideration.
Furthermore, the relative importance of these effects seems to be very dependent on the
centre to which the fluorine is attached.
In this chapter we assess the effect of fluorine on some charged and neutral
systems largely at a qualitative level, where this effect can be relatively well defined.
Indeed, it could be argued that models of reactivity that are to be useful over a variety
of related reagents, in various concentrations and solvents, are by necessity only
qualitative.
II STERIC EFFECTS
Replacing hydrogen in an organic molecule by fluorine does not significantly alter the
geometry of many systems, but this does not necessarily mean that fluorine and hydrogen
are isosteric. A comparison of the van der Waals radii, rvðHÞ 1.20 A, rvðFÞ 1.47 A and
rv(O) 1.52 A [1], suggests that fluorine is isosteric with oxygen, and this fact has long
been recognised for the development of bioisosteric compounds in medicinal chemistry
[2]. The C–F bond length (1.38 A) is slightly longer than C–H (1.09 A); in very crowded
systems this can be significant. For example, phenyl ring rotation of the cyclophane
system (Figure 4.1) is slower when X ¼ F than when X ¼ H, because of the larger steric
requirement of fluorine over hydrogen [3].
Substituent steric effects are generally regarded in terms of Taft Es or Charlton n
parameters [4], and a number of these values for fluorinated groups, along with those for
some hydrocarbon groups, are listed in Table 4.1. These data suggest, for instance, that
CF3 groups are much more sterically demanding than methyl substituents and that they
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 91
91Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
X½3�
Figure 4.1
are more demanding than isopropyl groups. Indeed, van der Waals volumes,
CH3 ¼ 16:8 A3
compared to CF3 ¼ 42:6 A3, further illustrate this point [5] (Figure 4.2).
FF
FHH
H
42.6A316.8A3
½5�
Figure 4.2
III ELECTRONIC EFFECTS OF POLYFLUOROALKYLGROUPS [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
Table 4.1 Steric parameters [4]
Substituent Taft Es Charton n
H þ1.24 0
F þ0.78 —
OH þ0.69 —
CH3 0 0.52
CH2CH3 �0.07 0.56
CHðCH3Þ2 �0.47 0.76
CðCH3Þ3 �1.54 1.24
CH2F �0.24 0.62
CHF2 �0.67 0.68
CF3 �1.16 0.91
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 92
92 Chapter 4
as an alcohol or carboxylic acid, would increase the acidity of the system and, indeed, this
is the case. The pKa values [7] of a number of fluorine-containing acids, along with
related systems for comparison, are collated in Table 4.2; these data suggest that the effect
of introducing one fluorine atom is very close to that of a single chlorine atom (compare
CH2FCOOH and CH2ClCOOH).
A single fluorine substituent increases the acidity of acetic acid by ca. 100 times while
trifluoroacetic acid is ca. 1000 times stronger. As expected, the inductive effect of
trifluoromethyl falls off rapidly with distance, although the presence of a double bond
helps to relay the effect. Various workers have drawn attention to the fact that, in aqueous
solution, it is the entropy rather than the enthalpy that is more significant in determining
the differences between the strengths of acids. This is a consequence of ordering of
solvent which is greater as the acids become stronger. However, this is equally a
consequence of inductive/field effects of groups. It is not surprising that, in the gas
phase, acidities are determined by differences in enthalpies [8, 9]. It is still worth noting,
however, that perfluoroalkanecarboxylic acids are much weaker than the strong inorganic
acids: for example, the Hammett acidity function Ho for CF3COOH is �3:03 while Ho for
sulphuric acids is �11:1.
The strong inductive effect of fluoroalkyl groups has a corresponding additive
acidifying effect on alcohols (Table 4.2). For instance, perfluoro-t-butanol is of the
same order of acidity as acetic acid. The hydrates of fluoroketones are also remarkably
acidic [10].
Perfluoroalkyl groups attached to phosphorus and sulphur [11] lead to a considerable
increase in the strength of derived acids, as compared with the corresponding alkyl
derivatives. Bis(trifluoromethyl)phosphinic acid, CF3Þ2PO�OH�
, is as strong as per-
chloric acid and is the strongest phosphorus acid known [12], while trifluoromethanesul-
phonic (triflic) acid, CF3SO3H, is the strongest readily available monobasic organic acid
(H0 � 13:8) (compare conc. H2SO4, H0�11:1).
2 Bases
Fluoroalkyl groups correspondingly lower the strengths of bases. Table 4.3 shows the
dissociation constants of some amines, together with hydrocarbon derivatives for com-
parison.
Table 4.2 pKa values of some organic acids and alcohols [7]
Carboxylic acid pKa Alcohol pKa
CH3COOH 4.76 CH3CH2OH 15.9
CH2FCOOH 2.59 CF3CH2OH 12.4
CH2ClCOOH 2.86 CCl3CH2OH 12.2
CHF2COOH 1.34 ðCF3Þ2CHOH 9.3
CHCl2COOH 1.35 ðCH3Þ3COH 19.2
CF3COOH 0.52 ðCF3Þ3COH 5.1
CCl3COOH 0.56 ðCHF2Þ2CðOHÞ2 8.9
CF3CH2CH2COOH 4.15 ðCF3Þ2CðOHÞ2 6.5
CF3CH5CHCOOH 3.48 ðCF3Þ2CðOHÞCF2NO2 3.9
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 93
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 93
The observations that secondary amines, RFÞ2NH�
, do not react with boron trifluoride,
hydrogen chloride or trifluoroacetic acid [13] also serve to indicate a lack of basic
properties. Similarly, tertiary perfluoroalkylamines are quite without basic properties.
Moreover, the oxygen atoms in perfluoroalkyl ethers and ketones are poor donors; this is
exemplified by the fact that hexafluoroacetone cannot be protonated by superacids in
solution. Such findings parallel similar observations with unsaturated derivatives where
the base strength is considerably reduced in, for example, perfluoropyridine or perfluoro-
quinoline [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 correspond-
ingly 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 immedi-
ately tempting to draw an analogy with hydrocarbon systems and invoke ‘fluorine
Table 4.3 pKb values of some amines
Amine pKb
CH3CH2NH2 10.6
CF3CH2NH2 5.7
CCl3CH2NH2 5.4
C6H5NH2 4.6
C6F5NH2 �0:36
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 94
94 Chapter 4
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.
C C
FF
F
etc.
FF
F
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].
C CF
C C
F
Figure 4.4
CF3O−
TAS+
4.5A 4.5B
TAS+
TAS+ = (Me2N)3S
+
F3C
F
CF3
−½23�
Figure 4.5
Table 4.4 Substituent constants for some fluorinated groups
Substituent sm sp sI sR
CH2F 0.12 0.11 0.12 �0.02
CHF2 0.29 0.32 0.32 0.06
CF3 0.43 0.54 0.42 0.10
CF2CF3 0.47 0.52 0.41 0.11
CF2Þ2CF3
�0.47 0.52 0.39 0.11
�CF CF3ð Þ2 0.37 0.53 0.48 0.04
SF5 0.63 0.86 0.56 0.27
N CF3ð Þ2 0.47 0.53 0.44 0.06
OCF3 0.47 0.27 0.50 �0.23
½22�
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 95
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 95
In molecular orbital terms, the unshared p-electrons at the carbanion site are donated
into the s� orbital of the adjacent C–F bond when the orbitals are in an anti-periplanar
configuration which ensures maximum orbital overlap [19, 20].
Trends in the C–F bond lengths and strengths in the fluoromethane series, in which the
C–F bonds strengthen and shorten with increasing fluorination, have been explained in
terms of resonance effects, but theoretical work suggests that Coulombic interactions and
hybridisation changes could also explain these observations [24]. However, the unusually
long C–F bond and short C–O bond measured for the trifluoromethoxide ion [22]
(Figure 4.6) suggests that the C–O bond possesses some double-bond character and,
similarly, the high barrier to rotation of a-fluoroamines indicates some C–N double-
bond character [25].
FF F
F
FC O C O
− −
F
½22�
Figure 4.6
Stabilities of perfluorinated carbanions have also been described using FNHC; a re-
examination [26, 27] of the acidity of CF3Þ3CH�
compared with the bicyclic compound
(Figure 4.7), in which FNHC in the carbanion would result in the formation of an internal
alkene contrary to Bredt’s rule, found that the unconstrained CF3Þ3CH�
undergoes H/D
exchange much more rapidly. If FNHC is the dominant process involved, then we would
expect sR for CF3 to be greater than for CF22CF3 but this is not the case (Table 4.4).
Calculations suggest [28] that perfluoroalkyl negative hyperconjugation can also occur, as
indicated in Figure 4.8, although this seems unlikely given the destabilising effect of
fluorine directly attached to carbanion centres (Section VI).
F F
−H
−H+
Figure 4.7
C CF3
CF3C C C
−−
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-CF3Þ ¼ þ0:54 and
sðm-CF3Þ ¼ þ0:43, the ratio sð p-CF3Þ=sðm-CF3Þ being 1.25, and this is essentially
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 96
96 Chapter 4
the same as the ratio for the corresponding trifluoromethylbenzoic acids. This suggests
that the electronic effects of CF3 operating in the phenol system are the same as those
operating in the benzoic acid system and not, therefore, in accord with a resonance effect.
Also, other fluorinated groups have apparent resonance effects (Table 4.4) that would be
difficult to defend on the basis of any negative hyperconjugation scheme. For many
processes it is not really necessary to invoke the concept of fluorine hyperconjugation to
account for the observations and the most easily appreciated description of many, but by
no means all, of the results available involves polarisation of the p-electron system.
2 Inductive and field effects
It is generally recognised that the inductive effect should be subdivided into a polarisation
effect on the s-bond framework and also on the p-electrons, and it has been indicated that
a major effect of strongly electron-withdrawing groups like perfluoroalkyl is by a
through-space polarisation of the aromatic p-electrons (direct field effect).
The Ip effect of trifluoromethyl would result in polarisation of the p-system and
perhaps approach a situation similar to that which exists in pyridine (Figure 4.9a).
CF3 CF3
Nδ+
δδ+δδ+ δ+δ+
δ+
δ+
δ+
δ+
Figure 4.9a
This kind of description allows for a similar effect to be produced by other perfluor-
oalkyl 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 ‘gaucheeffect’, 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).
X
Y
X
Y
H H
HH
X
H
H H
YH
4.9bA 4.9bB 4.9bC
Figure 4.9b
IV THE PERFLUOROALKYL EFFECT
Saturated, strained, small ring systems are uniquely stabilised by the introduction of
perfluoroalkyl groups, as compared with the corresponding hydrocarbon derivatives,
and this has allowed the study, for instance, of many long-lived valence-bond isomers
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 97
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 97
of aromatic and heterocyclic systems [32] (see Chapter 9). This stabilising influence,
denoted the ‘perfluoroalkyl effect’ [33], is considered to be kinetic rather than thermo-
dynamic 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-ACIDSAND -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 compli-
cated 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.
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
F
O
F
F4 ½38, 39�
Figure 4.10
Table 4.5 Strengths of unsaturated
carboxylic acids and phenols [1, 7]
Compound pKa
CH25CHCOOH 4.25
CF25CFCOOH 1.8
CCl25CClCOOH 1.21
C6H5OH 10.0
C6F5OH 5.5
C6Cl5OH 5.26
C6H5COOH 4.21
C6F5COOH 1.75
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 98
98 Chapter 4
It has been concluded from pKa measurements and fluorine NMR data on pentafluoro-
biphenyl derivatives, for example C6F5C6H4CO2H, C6F5C6H4F etc., that the penta-
fluorophenyl group inductively withdraws electrons more strongly than phenyl but
much less strongly than trifluoromethyl, whilst pentafluorophenyl and pentachlorophenyl
have a similar capacity for electron withdrawal [40].
VI FLUOROCARBOCATIONS
In this section we will be mainly concerned with situations where fluorine atoms are
bonded to carbon, which has some formal charge F2Cþ2, either directly or by conjuga-
tion, but we will also make reference to the effect of a fluorine atom in the situation
F2C2Cþ2. As a guide we can consider boron compounds as a useful qualitative model
for carbocations, because of the isoelectronic relationship of a carbocation to boron, and
we note immediately that comparative chemistry of boron halides is most commonly
discussed in terms of 2p–p overlap being more effective with fluorine than with the other
halogens [41]. For the 2B2C2C2F situation, we note that fluoroalkyl derivatives of
tricovalent boron are extremely unstable with respect to migration of fluorine from a- or
b-carbon atoms to boron. Thus the fluorine atoms in these positions are enhancing the
electrophilic nature of boron and we might reasonably predict the same situation for a
carbocation.
This is indeed the case and, at the outset, two major effects of fluorine towards
positively charged carbon centres can be envisaged; fluorine directly bonded to a posi-
tively 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).
C F
Stabilising
C F C C
F
Destabilising
Figure 4.11
A Effect of fluorine as a substituent in the ring on electrophilicaromatic 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.
X
E H
X
E
E
X
+ H
Figure 4.12
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 99
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 99
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)
sþp value (Table 4.7).
E EH 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 fluoro-
benzene 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 sþm 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 4.6 Relative rates of para-chlorination and bromination of halobenzenes and halodurenes [42]
Substituent (X) H F Cl Br
Partial rate factor, fp, for para-chlorination of C6H5X 1 6.3 0.4 0.25
Relative rates of bromination of
X
MeMe
Me Me
1a 4.62 0.145 0.062
a After statistical correction.
Table 4.7 s Values for halogen substituents on an aromatic ring [43, 44]
so sm sþm sp sþp
F 0.93 0.335 0.35 0.06 �0:075
Cl 1.28 0.375 0.40 0.225 0.115
Br 1.35 0.39 0.405 0.23 0.15
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 100
100 Chapter 4
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 H3C
H3C OCOCF3
CH3 CH3
CH3
CF3COO−
C
F
+C
F
C
F
+
+ ½46�
Figure 4.14
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 4.15B
+CF3CH2CH2
+
Figure 4.15
Table 4.8 First-order rate constants for reaction of trifluoroacetic
acid with CH25CX�CH3 at 258C [46]
X 105kðs�1Þ kX=kH
H 4.81 1
F 340 71
Cl 1.70 0.35
Br 0.395 0.082
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 101
F3C�CH�CH2
FSO3HFSO3
− HF+
+
FSO3− HF
(H− shift)
H
H
H
F
F
H
H
H
HCF3
CF3CH=CH2
CF3CH3
CH3
F3C
F
F
½49�
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.
CF3CF�CF2
SbF5
F3C
F
F
CF(CF3)2
½50�
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 observa-
tion 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).
H3C CH3C
F
H3C CH3C
F
F
SbF6
i, SbF5, −60 � C, SO2
i
½56�
Figure 4.18
The 19F NMR spectrum of the dimethylfluorocarbocation [56] shows that the fluorine
is de-shielded by a massive 260 ppm from the covalent starting material and this observa-
tion argues quite commandingly for p(p–p) resonance stabilisation of the carbocation by
fluorine (Figure 4.19).
F F
Figure 4.19
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 102
102 Chapter 4
The difluorobenzyl cation (Figure 4.20) is stable under conditions in which the benzyl
cation undergoes rapid polymerisation [57] and 13C and 19F NMR studies [58] have shown
that, as the electron demand of the aromatic ring increases (i.e. R is electron-withdrawing),
the p( p–p) donation of fluorine to the carbocation centre also increases, leaving the
electron density at Cþ relatively constant for a variety of aromatic substituents.
CF2Cl CF2
R R
C
R
F
F
SbF5Cli, SbF5, −75�C, SO2
i½57�
Figure 4.20
Table 4.9 Stable fluorinated carbocations observed in solution by NMR spectroscopy
Carbocation Ref. Carbocation Ref.
CH3 CF2 [61]
F F
F F
F
[62]
H3C CH3C
F
[56]
Ar F
F F
F
[50]
CF2 [57](CF3)2CFCH2CF CH CFCH2CF3
[63]
CCH3
F
[64]
F7
[59]
F
CAr Ar
[57]
Ph F
FPh
2+ [65]
ðC6F5Þ3Cþ [66]
C6F5
[67]
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 103
Other Lewis acids, such as BF3 �Et2O, have been used to induce ionisation [59, 60]
whilst protonation of suitably fluorinated unsaturated substrates may also lead to carbo-
cationic species (Figure 4.21).
F F
F F
H H
−78� C
FSO3H, SbF5
F BF3.Et2O
CH3CN F7
½59�
½60�
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).
F F
F
H HF F
F
H H
F4.22A 4.22B
½52�
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
fluoromethyl cations is CHþ3 < CFþ3 < CH2Fþ < CHFþ2 , indicating that the introduction
of fluorine increases the stability of the cations relative to hydrogen [54]. The trifluoro-
methyl cation CFþ3 has been generated and observed by IR spectroscopy upon photolysis
of CF3I in an argon matrix at very low temperatures [69]. However, attempts to observe
CFþ3 in solution by ionisation of trifluorohalomethanes [32] only resulted in the
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 104
104 Chapter 4
(CF3)2CFCH2
F
H
F
F
H
F
CH2CF(CF3)2
(CF3)2CFCH2
F
H
F
CH2CF3
n
4.23A
4.23B
n = 1−3
½68�
Figure 4.23
production of CF4, even though CFþ3 is observed as a fragment ion in the mass spectra of
many organofluorine compounds.
D Effect of fluorine atoms not directly conjugated with thecarbocation centre
Even though fluoroalkyl substituents are inductively electron-withdrawing, several cat-
ionic species have been studied in which a trifluoromethyl group is attached directly to the
positively charged carbon centre [55]. The destabilising influence of a trifluoromethyl
group is manifested in a comparison of the reaction rates for the solvolysis [70], via SN1
processes, of the tosylates 4.24A and 4.24B in which the replacement of hydrogen by CF3
leads to a rate retardation of ca. 103 (Figure 4.24). Surprisingly, the introduction of a
second trifluoromethyl, as in 4.24C, leads to only a slight reduction in the rate of
solvolysis and this has been attributed to the fact that the positive charge in intermediate
4.24B is largely delocalised into the aromatic ring and so the introduction of a second
electron-withdrawing substituent, as in 4.24C, has little effect on the stability of the
resulting carbocation.
When such delocalisation is not possible, however, the effect of attaching CF3 groups
adjacent to the carbocation site on the rate of solvolysis is additive; for instance, compare
the rates of solvolysis [71] for 4.25A, 4.25B and 4.25C in Figure 4.25.
Resonance-stabilised long-lived carbocations such as 4.26A and 4.26B have
been generated from precursor alcohols in superacidic solution [72] but, if conjugative
stabilisation is absent as in 4.26C, then only protonated alcohols are observed. Similarly,
ketones with up to three a-fluorine atoms can be protonated giving, for example, 4.26D,
whilst hexafluoroacetone is not protonated in a superacidic medium [73] (Figure 4.26).
Direct observation of a number of bridged halonium ions (X ¼ Br, Cl, I) is possible
[74] when, for example, 2,3-dihalo-2,3-dimethylbutanes are ionised in SbF5=SO2 mix-
tures; however, as yet, no analogous fluoronium ions have been observed in solution
(Figure 4.27).
Indeed, 13C NMR studies suggest that ionisation of 2,3-difluoro-2,3-dimethylbutane
gives a rapidly equilibrating mixture in which methyl 1,2-shifts, rather than fluorine
shifts, occur [75] (Figure 4.28).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 105
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 105
H H
OTos
OMe
H CF3
OTos
OMe
F3C CF3
OTos
OMe
H CF3
OMe
Relative ratesof Solvolysis 4000 5.2 - 2.4 1
H CF3
OMe
4.24A 4.24B 4.24C
4.24B
½70�
Figure 4.24
AnO2SO
R1
R2
R1
R2
F3CH2CO
R1
R2
4.25A R1 = R2 = H 1012
4.25B R1 = CF3, R2 = H 106
4.25C R1 = R2 = CF3 1
Relative Rate
CF3CH2OH½71�
Figure 4.25
CCH3
CF3
C
CF3
C
O
F3C CH3H
HHO
F3C CH3
H
4.26A 4.26C 4.26D4.26B
½73�
Figure 4.26
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 106
106 Chapter 4
H3C
X
CH3
Y
i, SbF5, SO2, −60� C
H3C CH3
H3C CH3 H3C CH3X
X = Cl, Y = F, ClX = Br, Y = F, BrX = I, Y = F
i ½74�
Figure 4.27
H3CH3C
F
CH3
CH3
F
H3CH3C
CH3
CH3
F
H3CH3C
H3C
CH3
F
i, SbF5, SO2, −90� C
i
½75�
Figure 4.28
However, mass-spectral breakdown patterns of PhOCH2CH2F suggest that a cyclic
fluoronium ion can be observed as an ion-neutral complex in the gas phase [76], whilst
calculations indicate that the fluoronium ion is more stable than the isomeric þCH2CH2F
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).
F FOCOCF3
F
OCOCF3
FH3C
F3COCO
H CF3COO
CF3COOH
½46�
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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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 107
Ar-N2 BF4− −N2 Ar----F----BF3
δ δArF + BF3
N2 CF3
40 �C
CF3
CF2F
CF2FCOOEtF
Et2O
HCO3
½77�
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 C H Base C + H-Base
Product 4.31D
4.31C
δ −
4.31A 4.31B
δ +
Figure 4.31
If a substituent lowers the activation energy for production of 4.31B, then we assume
that the energy of 4.31C is also lowered. However, it must be remembered that 4.31C may
still have a very short lifetime, i.e. it is kinetically unstable with respect to initial state
4.31A or some product 4.31D, even though we may refer to the effect of a substituent as
being strongly stabilising. The effect of ‘internal return’, i.e. return from 4.31B to 4.31A,
or from 4.31C to 4.31B, is also a complicating factor which affects the interpretation of
kinetic acidities. Sometimes equilibrium data are available and, obviously, this reflects
substituent effects on the energy of 4.31A and 4.31C directly.
A Fluorine atoms attached to the carbanion centre
Superficially, we would expect the high electronegativity of fluorine to stabilise a
carbanion centre, but measurements of acid strengths and exchange rates for a variety
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 108
108 Chapter 4
of halogenated compounds, discussed below, suggest that the inductive effect (Is)
of fluorine is not the dominant factor in determining the stability of the carbanions
formed [79].
Base-catalysed H/D exchange experiments for a series of haloforms [80] (Table 4.10)
demonstrate that carbanion formation is stabilised by halogen in the order I> Br>Cl> F.
When these results are combined with acidity measurements which show that
CF3H ðpKa 31Þ is little more acidic than methane (pKa 40) [81], we can conclude that,
in these systems, fluorine attached to a carbanion centre is stabilising with respect to
hydrogen but destabilising compared with the effects of other halogens. Similar conclu-
sions 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 in-
creases 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).
StabilisingIσ H2C F Destabilising−Iπ H2C F½84�
Figure 4.32
Table 4.10 Base-catalysed deuterium exchange in haloforms [80]
Haloform Rate of exchangea (105k) (l:mol�1s�1)
CHF3 Too slow to measure in this medium
CHCl3 820
CHBr3 101 000
CHI3 105 000
CHCl2F 16
CHBr2F 3600
CHI2F 8800
a 08C in water.
Table 4.11 Apparent ionisation constants of substituted nitromethanes
(in water, at 258C) [83]
XYCHNO2 pKa XYCHNO2 pKa
Y ¼ COOC2H5 Y ¼ NO2
X ¼ Cl 4.16 X ¼ Cl 3.80
X ¼ H 5.75 X ¼ H 3.57
X ¼ F 6.28 X ¼ F 7.70
Y ¼ Cl
X ¼ Cl 5.99
X ¼ H 7.20
X ¼ F 10.14
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 109
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 109
The net stabilising or destabilising influence of fluorine attached to a carbanion centre
is, therefore, a result of these two effects. A consideration of the geometry of carbanions
formed at both planar and tetrahedral carbon, as depicted in Figure 4.33, illustrates that
�Ip repulsion is greater at a planar carbon since, in this situation, the repelling non-
bonding electron pairs on carbon are closer in space to electron pairs on fluorine [79]
(Figure 4.33).
Tetrahedral (sp3) C Planar (sp2) C
C F C F109 �
109 � 109 �
90 �½79�
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 repul-
sions are minimised is supported by calculations [86] from which it was deduced that for
the �CH2F carbanion a pyramidal structure is 55 kJmol�1 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 kJmol�1) than for the cyclopropyl anion
(73 kJmol�1).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 110
110 Chapter 4
B Fluorine atoms and fluoroalkyl substituents adjacent to thecarbanion centre
When a fluorine atom is located b- to a carbanion centre, F2C2C�, we would expect the
high electronegativity of fluorine to give rise to a very dominant stabilising effect (Is),
since, in this situation, there is no opportunity for Ip repulsion. Indeed, b-fluorine
substituents are very strongly stabilising but the basis of the effect has been a subject of
varied interpretation.
Attempts to determine the effect on carbanion formation of halogen atoms attached to
the adjacent carbon are generally complicated by a competing b-elimination process [88]
(Figure 4.35). However, Andreades [89] found that, for a series of monohydrofluorocar-
bons, the exchange process proceeds much more rapidly than elimination; the forward (kH)
and reverse (kD) reactions were studied (Figure 4.36; Table 4.12). These observed relative
reactivities and derived acidities indicate that the stabilities of perfluorocarbanions are in
the order tertiary > secondary > primary and, therefore, that b-fluorine (F2C2C�) is
much more effective at carbanion stabilisation than a-fluorine (F2C�) [79]. A further
demonstration of these effects is observed for ðCF3Þ3CH, which is 50 orders of magnitude
more acidic than methane. Furthermore, pentafluorocyclopentadiene [90] is only slightly
more acidic than cyclopentadiene (pKa 15) whereas pentakis(trifluoromethyl)cyclopenta-
diene ðpKa < �2Þ is even more acidic than conc. nitric acid [32, 32a]!
D CC Hal C C Hal C C−HalD2O ½88�
Figure 4.35
RF�H + CH3OD RF�D + CH3OHkH
kD
(NaOCH3)
½89�
Figure 4.36
The enhanced stability of b-fluoro carbanions (Figure 4.37) has been attributed to
fluorine negative hyperconjugation (FNHC; see Section IIIB). For instance, negative
hyperconjugation (see Section III) has been invoked to explain the enhanced reactivity
(100-fold) [27] and the higher gas-phase acidity (by 5.4 pKa units) [91] of 4.38A over the
Table 4.12 Deuterium exchange and acidities of monohydroperfluoroalkanes [89]
Compound CF3H CF3ðCF2Þ5CF2H ðCF3Þ2CFH ðCF3Þ3CH
Derived ion �CF3 CF3ðCF2Þ5CF�2 ðCF3Þ2CF� ðCF3Þ3C�
Relative reactivity 1 6 2� 105 109
Approx. pKa 31 30 20 11
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 111
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 111
C CFF
FC C F
F
F
Figure 4.37
bridgehead compound 4.38B in which negative hyperconjugation in the derived
carbanion is unfavourable. Elongated b-C2F bonds and shortened Ca2Cb bonds in
4.38C, as measured by X-ray crystallography, provides direct experimental evidence
[23] (Figure 4.38).
(CF3)3C H
HCF3
F
CF3
F (Me2N)3S+
4.38A 4.38B 4.38C
½27�
Figure 4.38
The stereochemical course of hydrogen–deuterium exchange in homochiral
PhEtHC�CF3 has been studied [15] and, like systems containing other carbanion-
stabilising groups, the extent of racemisation of the product varies with solvent.
C Stable perfluorinated carbanions [92–94]
Inevitably, the successful generation of long-lived carbocations by the protonation of
alkenes in superacid solution prompted attempts to generate observable perfluorocarba-
nions 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 perfluoro-
carbanions 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 inter-
mediates in hydrocarbon chemistry, is possible upon the addition of CsF to perfluoro-s-
triazine derivatives [101] (Figure 4.41) but direct observation of similar s-complexes
derived from less-activated perfluoroaromatic systems has not yet been reported.
Deprotonation of hydroperfluorocarbons provides an alternative route to perfluorocar-
banions and, for example, several perfluoropentadienide [90, 102–104] (Figure 4.42) and
benzylic [105] carbanions have been prepared by this method.
A cyclopentadienide ion can also be prepared by reaction of a diene with Bu4NI via a
single-electron transfer pathway [104] (Figure 4.43).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 112
112 Chapter 4
C CF2
F3C
F3CC CF3
F3C
F3C
F
CF3
•
CF3 CF3
CF3
CF3
F
F3C
Cs+
F F FF +i
F F Cs+
(Me2N)3S+
F F
F
i, CsF, tetraglyme
i
i, CsF, tetraglyme
i, (Me2N)3S+Me3SiF2
− (TAS-F), THF
i
4.39A
Cs+
F3C
F3C
½97�
½95�
½98�
½100�
Figure 4.39
F
F
F3C
CF3
F
FTAS-F
THF
F
F
F3C
CF3
F
F(Me2N)3S
+
½23�
Figure 4.40
N
N
N N
N
N
F
F F
F
F Cs+½101�
Figure 4.41
D Acidities of fluorobenzenes and derivatives
Inductive effects of ortho substituents are important in governing the acidity of a C–H
bond in substituted benzenes [106], and a variety of data indicate that the acidifying
influence of fluorine falls off in the order ortho � meta > para; this is illustrated by
Table 4.13 [107].
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 113
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 113
CF3
CF3 CF3
CF3
CF3 HCF3
CF3 CF3
CF3
CF3
H2O H3O½103, 104�
Figure 4.42
CF3
CF3 CF3
CF3
CF3 CF3
Bu4NICF3
CF3 CF3
CF3
CF3
Bu4N CF3I½104�
Figure 4.43
Also, the order of acidity of the dihalobenzenes, m-C6H4F2 > m-C6H4ClF >
m-C6H4Cl2, obtained from exchange data on the monodeutero derivatives [88], indicates
the greater acidifying influence of ortho-fluorine than of ortho-chlorine and is a further
illustration of the significance of inductive effects. Polyfluorobenzenes are very acidic, as
evidenced by the fact that pentafluorobenzene and 1,2,4,5-tetrafluorobenzene, for
example, are metallated with butyl lithium rather than undergoing nucleophilic substitu-
tion [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 4.13 Relative rates of base-catalysed deuterium exchange [107]
Rate, relative to
Compound Benzene Toluene
[2-D] Fluorobenzene 6:3� 105 —
[3-D] Fluorobenzene 107 —
[4-D] Fluorobenzene 11.2 —
[3-D] Benzotrifluoridea 580 —
2,5-Difluoro[Me-D1]toluene — 350
a Trifluoromethyl [3-D] benzene.
Table 4.14 Rates of tritium exchange and of nucleophilic substitution by sodium
methoxide [109]
104k l:mol�1s�1ð Þ
Polyfluorobenzene Exchange at 408C
Displacement at
508C
Pentafluorobenzene 1360 1.05
1,2,3,4-Tetrafluorobenzene 0.0053 0.018
1,2,4,5-Tetrafluorobenzene 58 < 10�4
1,2,3,5-Tetrafluorobenzene 5.6 0.049
1,3-Difluorobenzene 0.0061
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 114
114 Chapter 4
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 C6F5Þ2CH2
�
and C6F5ð Þ3CH 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) demon-
strate 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].
VIII FLUORO RADICALS [112, 113]
A Fluorine atoms and fluoroalkyl groups attached to the radicalcentre
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.
Table 4.15 Acidities of halogenated
alkenes [26]
Carbon acid pKa
CCl25CHBr 24.6
CCl25CHCl 25.0
CF25CHCl 25.3
CCl25CHF 26.3
CF25CHF 27.2
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 115
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 115
O CH2 O CH2
Figure 4.44
Stabilities of methyl and fluoromethyl radicals have been calculated [114] to be in the
order CFl
3 < CHl
3 < CF2Hl
< CFHl
2 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].
R C
CH3
CH3
O CO2 R C
CH3
CH3
O
O
R CH3
O
H3C CH3
+ CH3
∆
2 k2
+ R
k1
½115�
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 CF3l measured to be
49.18 from planarity. The barriers to inversion of fluoromethyl radicals increase in the
order CFHl
2 < CF2Hl
< CFl
3 while fluorocyclopropyl radicals (Figure 4.46) adopt a fixed
pyramidal conformation at the radical centre [117], as determined by ESR at �1088C.
The tendency for fluorine to induce pyrimidalisation of radical centres has also been used
to account for the stereochemistry of products [118].
F
H3C CH3
½117�
Figure 4.46
Electronegative groups lower orbital energies and therefore, in principle, the high
electronegativity of fluorine should lower the orbital energy of an attached carbon radical
centre. Additionally, conjugative interactions between the singly occupied orbital of the
carbon and the lone pairs on fluorine would be a stabilising interaction, which would
simultaneously render the carbon atom more nucleophilic (Figure 4.47). The fact that
further stabilisation by fluorine substitution is negligible, after the first substituent,
suggests that Ip repulsion becomes more important as we increase the charge on carbon
and this also accounts for the tetrahedral nature of the trifluoromethyl radical. This is
exactly analogous to the effect of fluorine substituents on carbanions, where electron-pair
repulsions are minimised in a pyramidal conformation (Figure 4.48).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 116
116 Chapter 4
C FH
HC F
H
H
Figure 4.47
C FH
FC F
H
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
CH3CHl
2 > FCH2CHl
2 > F2CHCHl
> CHl
3 > CF3CHl
2 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.
CF3
CF3
F3CF
CF3
F3CF
F
CF3
F3CF
CF3
F3CF
C2F5
F2½120�
Figure 4.49
Likewise, the radical shown in Figure 4.50 is a stable perfluorovinyl system [121].
F2
(CF3)3CF
C C
CF(CF3)3
F
(CF3)3CFC CCF(CF3)3 ½121�
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, perfluoro-
alkyl radicals reacted 40 000 times faster with 1-hexene than the corresponding alkyl
radicals.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 117
The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 117
R R
C8F17
+ C8F17½123�
Figure 4.51
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.
F2CCF2
CF2
CF2
X
X X X CX2H
F
X XH
X F+
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
4.52A 4.52B½124�
Figure 4.52
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The Influence of Fluorine or Fluorocarbon Groups on some Reaction Centres 121
Chapter 5
Nucleophilic Displacement ofHalogen from FluorocarbonSystems
It is the aim of this chapter to develop a model for the very broad spectrum of reactivity of
fluorine-containing systems towards nucleophiles. Substituent effects of fluorine and
fluorocarbon groups on the SN1 process were considered earlier, in a more general
discussion of carbocations (see Chapter 4, Section VI); effects on the SN2 process will
now be examined. Then the broader principles of displacement of fluorine, as fluoride ion,
from carbon in different environments will be discussed to emphasise why, for example,
nucleophilic displacement of fluoride ion from perfluoroalkenes occurs extremely rapidly
while, in contrast, perfluoroalkanes are characterised by extreme inertness.
I SUBSTITUENT EFFECTS OF FLUORINE ORFLUOROCARBON GROUPS ON THE SN2 PROCESS
In general, substituent effects on the SN2 process are not easy to predict [1] because, in
principle, electron-withdrawing or -donating groups can either accelerate or retard the
process, depending on whether bond making, between carbon and nucleophile, or bond
breaking, between carbon and the leaving group, is emphasised. The situation is further
complicated by substituent effects either resulting in mechanistic change or creating very
significant steric effects. Nevertheless, halogen substituents not directly attached to the
reaction centre usually reduce SN2 reactivity in alkyl halides [2], as illustrated by the data
in Table 5.1. Clearly, the effects are not large and are not very different for the individual
halogens.
Similarly, nucleophilic displacements from centres substituted with CF3 groups are
retarded [3–5] in comparison with corresponding alkyl derivatives, due to steric hindrance
and fluorine lone-pair repulsion of the incoming nucleophile, but preparatively useful
Table 5.1 Reactivities of RBr towards NaOPh (in MeOH
at 208C) [2]
R k (l:mol�1s�1 � 104)
CH3CH2 39.1
CH3CH2CH2 25.6
FCH2CH2 4.95
ClCH2CH2 5.61
BrCH2CH2 4.99
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 122
122 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
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 SN1 processes [7, 8].
CF3CH2X + I− CF3CH2I + X− ½6�
Figure 5.1
A single-electron transfer process may be a competing mechanism in reactions between
sterically demanding nucleophiles and CF3CH2I, since side products arising from radical
coupling reactions are observed [9].
In contrast, fluorine or fluorocarbon groups directly attached to the reaction centre have
a much more pronounced effect [4]; for example, the hydrolytic displacement of chloride
from PhCHFCl appears to be activated with respect to benzyl chloride [10], although the
situation is complicated by concomitant SN1 and SN2 processes.
Nucleophilic substitution of halogen in RFCF2Hal systems is very difficult, due to
a combination of steric effects and shielding of the carbon skeleton by surrounding
non-bonding pairs on fluorine, and there are no examples of halogen substitution by an
SN2 process involving these substrates. For example, RCF2Br compounds are quite
inert to halide exchange under conditions where CH3CH2Br is reactive [4]. However, in
principle there are other ways in which RFHal systems could react with nucleophiles,
namely:
(1) Nucleophilic attack on halogen (Figure 5.2). However, this process is often very
difficult to distinguish from the single-electron process, (2), shown below. Burton
and co-workers have demonstrated that phosphorous nucleophiles react with CF2Br2
to give synthetically useful ylids and they suggested carbene intermediates to
explain their findings [11] (Figure 5.3). Halophilic attack on polyfluorinated
systems, followed by b-elimination to give intermediate polyfluorinated alkenes
that are susceptible to nucleophilic attack, has also been suggested [12] (Figure 5.4).
Nuc + Nuc�I + CF3Solvent
HCF3HI�CF3
Figure 5.2
R3P + CF2Br2 R3PBr + CF2Br
CF2Br CF2 + Br
R3P + CF2 R3P-CF2
R3P�CF2 R3PBr+ (R3PCF2Br) Br R3PBr
½11�
Figure 5.3
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 123
Nucleophilic Displacement of Halogen from Fluorocarbon Systems 123
CF2�CF2
+ PhSBr + CF2CF2Br
PhSBrPhSCF2CF2PhSCF2CF2Br
PhS
PhS
CF2CF2BrBr
½12�
Figure 5.4
(2) Single-electron transfer (SET) [13, 14] (Figure 5.5).
e.g.
NR2 +NR2
I
RF
NR2
RF
I
i
NR2
RF
−H+
H3OO
RF
i , RFI (RF = C8F17 ), Pentane, uv
Nuc RF�I Nuc
RF I etc
RF�I
RF�I
+ HI
½13, 14�
Figure 5.5
(3) A radical chain process (SRN1) (Figure 5.6).
Nuc + Nuc +
+ Nuc Nuc-RF + etcNuc-RF
RF-I
RF
RFI
RF-I
RF-I
RF+ I
Figure 5.6
An essential feature of this process is the reaction of a nucleophile with a fluoro-
carbon radical. It is important to emphasise that radicals, being electron-deficient,
are electrophilic and therefore that fluorocarbon radicals are even more electro-
philic. These processes are, of course, aided by ultraviolet irradiation and inhibited
by radical traps, or the radicals may be intercepted, e.g. by norbornene as in the
example shown in Figure 5.7a [15]. Further examples are given in Table 5.2.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 124
124 Chapter 5
(CF3)2CFI (CF3)2CF
PhS
Norbornene
(CF3)2CFSPh
CF(CF3)2
CF(CF3)2
(CF3)2CFI
(CF3)2CFI
½15�
Figure 5.7a
Table 5.2 Substitution of halogen in RCF2Hal systems
Substrate Nucleophile, conditions Product Yield (%) Ref.
C5F11CF2I NO2ðCH3Þ2C�
Liþ
DMF, 3 h
C6F13 C
CH3
CH3
NO2 53 [16]
ClCF2CF2I OEt−
O O
Na+ CO2Et
H
ClCF2
CO2Et
50 [17]
C5F11CF2I
N
N−
O2N
Bu4N+
Electrochemistry, CH3CN
N
N
O2N
H
C6F13
94 [18]
CF2BrCF2Br PhO� Kþ PhOCF2CF2Br [19]
HMPA ,a rt
C6F13Br PhS� Kþ
DMF, rt
C6F13SPh 62 [20]
C6F13I PhS� Bu4Nþ
Benzene, H2O, rt
C6F13SPh 76 [15]
CF2Br2 Ph3P ðPh3PCF2BrÞþ Br� 100 [11]
Diglyme, rt
a HMPA, hexamethylphosphoric triamide.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 125
Nucleophilic Displacement of Halogen from Fluorocarbon Systems 125
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).
H(CF2)4Cl + C6H5OCH3i
OMe
(CF2)4H
i, Na2S2O4, NaHCO3, DMSOortho : meta : para = 50 : 35 : 15
½21, 22�
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, Zn, CH2�CHR, AcOEt, 80� C
[C3F7C(CF3)2I]−I
C3F7C(CF3)2
−F
CF3CF2CF�C(CF3)2 CF3CF2CF2C(CF3)�CF2
1 590%
i½23�
Figure 5.8
Remarkably, electron transfer from phenylthiolate anions to perfluorodecalin occurs, to
give naphthalene derivatives [26]. It is not clear why this has not proved to be a general
process but it may be considered to involve a series of electron transfer steps (Figure 5.9).
A Electrophilic perfluoroalkylation
The 2CF2I group may be activated towards nucleophilic attack by enhancing the leaving
group ability of iodine through expansion of its valence shell to an iodonium species, and
this has culminated in the development of a range of electrophilic perfluoroalkylphenyl-
iodonium triflate (FITS) reagents [27] (Figure 5.10).
These remarkable electrophilic reagents have been used to carry out perfluoroalkyla-
tion 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 126
126 Chapter 5
F F F F F
SPh SPh
SPh
SPh
SPhSPh
PhS
PhS
FFF FF F
F
F F
i, PhS Na, DMEU, 70�C, 10 days
+1e −F
+1e
−F
i
PhS
+1e etc.
½26�
Figure 5.9
RF I
Ph
RFIi
RFI(OCOCF3)2 O-Tfii
i, 80% H2O2, (CF3CO)2O
ii, Benzene, CF3SO2OH (TfOH)
½27�
Figure 5.10
OTMS
C8F17 I
Ph
O
C8F17+
MeCN, 45� C
76%
O�Tf
PhCH2MgCl C3F7IPh O�Tf−110� C
PhCH2C3F7 82%
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 127
Nucleophilic Displacement of Halogen from Fluorocarbon Systems 127
N
HS
CF3
N
H
CF3
90%
+O-Tf
DMF, 80�C
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 – SN2processes
In addition to the two overall nucleophilic displacement processes, SN1 and SN2, we can
envisage a spectrum of transition states for the SN2 process. Various stages can be
represented by 5.13A, in which there is little or no carbon–fluorine bond breaking;
5.13B, which is concerted; and 5.13C, where carbon–fluorine bond breaking is in advance
of the new bond being formed (Figure 5.13).
C FNuc
δ +Nuc C F
δ − δ −Nuc C F
δ −δ +δ +
5.13B5.13A 5.131C
Figure 5.13
Of course, the extreme of 5.13A would be complete bond formation with the nucleo-
phile in an addition–elimination process, such as can occur when fluorine is bound to
unsaturated carbon. Since a fluorine atom attached to carbon leads to a very polar, yet
very strong, Cdþ � Fd� bond, we have two conflicting effects: (a) the attached carbon is
electron-deficient and therefore susceptible to nucleophilic attack; (b) if the transition
state involves much carbon–fluorine bond breaking, it may be of relatively high energy
depending on the degree of solvation of the developing fluoride ion. Also, fluorine is not a
polarisable atom and this contributes to the high energy of the process. Consequently,
because carbon–chlorine bonds are weaker and more polarisable, the ratio kF=kCl, for
displacement from the corresponding fluorides and chlorides, is regarded as a useful
probe for indicating the amount of carbon–halogen bond breaking in the transition state.
Factor (b) is the more important with alkyl fluorides since they are, for example, much
less readily hydrolysed than other alkyl halides (Table 5.3), but it is also evident that the
reactivity ratios are influenced considerably by the reagent.
Fluoride ions (or incipient fluoride ions) form very strong hydrogen bonds, much
stronger than corresponding bonds to chloride, and so a change to a more hydrogen-
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 128
128 Chapter 5
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 SN1 to SN2.
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 1,2-
diethoxytetrafluorocyclobutene leads to the well-known, very stable, ‘squarate anion’
[36] (Figure 5.16a).
Hydrogen iodide is very effective in replacing fluorine by iodine in fluoroalkanes [33]
(Figure 5.16b).
Cleavage of a carbon–fluorine bond can be induced by reaction with a Lewis acid (see
Chapter 4, Section VIC). In Friedel–Crafts alkylations, alkyl fluorides are more reactive
than the chlorides [37] with, for example, aluminium halides or boron halides as catalysts
(Figure 5.17).
Table 5.3 Relative reactivities of isoamyl halides ðCH3Þ2CHðCH2Þ2X with
piperidine and sodium methoxide at 188C [29]
Reagent X ¼ F X ¼ Cl X ¼ Br X ¼ I
C5H11N 1 68.5 17 800 50 500
CH3ONa=CH3OH 1 71 3500 4500
Table 5.4 Fluorine : chlorine rate ratios for reactions of alkyl halides [28]
Halide Reagent Solvent Temp. (8C) kF=kCl
Ph3CX H2O 85% aq. Me2CO 25 1:0� 10�6
Ph2CHX H2O/EtOH 80% aq. EtOH 25 1:6� 10�4
PhCH2X H2O 10% aq. Me2CO 50 3:2� 10�3
CH3X H2O H2O 100 2:9� 10�2
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 129
Nucleophilic Displacement of Halogen from Fluorocarbon Systems 129
RCHF�CH�CFH R
H
H
FH
R
F
H
HH
R�CH�CH�CHO
aq. HCOOH
−F
+F
R�CH�CH�CHF2
R�CHF�CF�CH2
5.15A
5.15B
H2O ½35�
Figure 5.15
OEt
F
OEt
OH
OH
O
O
O O
O O
2+
2
H2SO4 ½36�
Figure 5.16a
RF + HIi
RI + HF
i, R = 1-heptyl, 105� C, 10hr. (85%) R = cyclohexyl, 105� C, 1hr. (90%)
½33�
Figure 5.16b
BBr3
BenzeneFCH2CH2Cl C6H5CH2CH2Cl 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 kJmol�1;
D(A1–Cl) ¼ 494 kJmol�1]. 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).
+ AlCl30� CF Cl ½38�
Figure 5.18
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 130
130 Chapter 5
2 Influence of heteroatoms on fluorine displacement
Oxygen or, particularly, nitrogen adjacent to a carbon–fluorine bond greatly increases
reactivity towards nucleophiles. Hydrolysis of a, a–difluoro ethers occurs under acid
conditions [39] (Figure 5.19). Orthoesters are produced by reaction with alkoxides;
such reactions may, however, occur via initial elimination of hydrogen fluoride, rather
than by direct nucleophilic displacement of fluoride [40] (Figure 5.20).
H2SO4CHF2CF2OC2H5 CHF2COOC2H5
½39�
Figure 5.19
KOHCHClFCF2OC2H5 CHClFC(OC2H5)3
EtOH ½40�
Figure 5.20
The exceptional ease of nucleophilic displacement of fluorine from ðC2H5Þ2-
NCF2CFClH and similar systems has been utilised as a general method for replacement
of hydroxyl by fluorine (see Chapter 3, Section IVA, Subsection 3), and probably
involves an SN1 process with internal assistance to ionisation coming from the adjacent
nitrogen [41] (Figure 5.21).
N CMe
MeCF2H
F
F
N CMe
MeCF2H
F
RCH2
OH
−F−etc
½41�
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 approach-
ing nucleophile, has been under-appreciated.
If the addition stage is rate-limiting, which is usually the case, polarity of the bond to
carbon is probably the most important factor governing the activation energy required,
since fluorine is sometimes displaced more easily than chlorine or the other halogens. For
example, benzoyl fluoride reacts more readily with hydroxide than the corresponding
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 131
Nucleophilic Displacement of Halogen from Fluorocarbon Systems 131
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.
X
FNuc X
F
Nuc X
F
X
Nuc
Nuc Addition
Elimination+ F
δδ
Figure 5.22
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 5.5 Isopropanolysis of acid halides at 258C [43]
Compound k2 Halogen mobility ratio Cl ¼ 1
C3H7CO2X
X ¼ F 8:4� 10�10 1:6� 10�4
X ¼ Cl 5:1� 10�6 1
X ¼ Br 2:7� 10�3 5200
C4F9CO2X
X ¼ F 1:6� 10�3 4:6� 10�2
X ¼ Cl 3:5� 10�2 1
Table 5.6 Nucleophilic substitution of p-nitrohalostyrenes using
NaOMe at 258C [44]
H
X
p-NO2�C6H4
H 104kðl:mol�1s�1Þ
X ¼ F 7.21
X ¼ Cl 0.025
X ¼ Br 0.016
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 132
132 Chapter 5
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).
Cl
F
C6H5
F3C
O-Me
F
C6H5
F3C
96%
F
O-Me
C6H5
F3C
4%
+MeONa
½45, 46�
Figure 5.23
Displacement of vinylic chlorine is predominantly stereoselective whereas, in some
cases, substitution of fluorine can give a mixture of isomeric products. It has been argued
that the fluorine-containing carbanionic intermediates are more stable and longer-lived
than the corresponding chlorinated derivatives, thus allowing rotation to occur in the
carbanionic intermediate before elimination of the halide, and enabling the formation of
geometric isomers [47, 48]. The importance of the addition step, leading to a developing
carbanion in the transition state, is made evident by the very wide range of reactivity in
the series CF25CF2, CF2¼CFCF3 � CF25CðCF3Þ2, the last of these being extremely
susceptible to nucleophilic attack (Figure 5.24).
Nuc CF2�C(CF3)2 Nuc�CF2CF(CF3)2−F
Nuc�CF�CF(CF3)2
Figure 5.24
Reactions of polyfluoroalkenes are discussed in Chapter 7.
2 Substitution in aromatic compounds
Nucleophilic substitution in highly fluorinated aromatic compounds will be dealt with in
detail in Chapter 9, but it is worth noting here that, in common with most other
nucleophilic aromatic substitutions [49], the processes are likely to involve two steps,
with very little bond breaking in the rate-limiting transition state. In the classic work on
2,4-dinitrohalobenzenes with many nucleophiles, the ease of replacement of aromatic
halogen is in the order F� Cl > Br > I [49, 50], arising from a slow first step ðk1Þ and a
fast second step ðk2Þ, consistent with the scheme outlined in Figure 5.25. Of course, the
nitro groups are extremely important in lowering the energy of the developing carbanionic
transition state, leading to the intermediate complex 5.25A.
Both oxygen and nitrogen nucleophiles react more rapidly with fluoroaromatics than
corresponding sulphur and carbon nucleophiles, in accordance with Hard–Soft Acid–Base
principles [51]. It should be remembered, however, that the situation can become more
complex with, for example, base catalysis, where the rate of the second stage becomes
important; under these rather unusual conditions, an order of replacement Br > Cl > F has
been observed [52].
The second step may be rate-limiting in reactions of fluoroaryl systems with neutral
amines [53]. Loss of halide ion from the intermediate complex is catalysed by base and is
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 133
Nucleophilic Displacement of Halogen from Fluorocarbon Systems 133
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].
X
NO2
NO2
NO2
NO2
Nuc
NO2
NO2
Nuc X
k1
X = F, Cl, Br, I
Nuc
δ
δk2
k−1
5.25A
_
½49, 50�
Figure 5.25
X
NO2
NO2
NO2
NO2
NHR
NO2
NO2
H2RN X
Base
X = F, Cl, Br, I
RNH2
½54�
Figure 5.26
Fluoroaromatics with electron-releasing substituents may be activated towards nucleo-
philic attack by complexation with chromium species [56] (Figure 5.27).
H3C F
Cr(CO)3
H3C
Cr(CO)3
CNCF3SO3H
LiCMe2CN
½56�
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 perfluorocar-
bons like polytetrafluoroethene are relatively inert to nucleophiles, at the other extreme
are perfluoroisobutene, which reacts with neutral methanol, and perfluoro-1,3,5-triazine,
which is hydrolysed in moist air. As a note of caution, great care should be taken with
the systems that are very reactive to nucleophiles and correspondingly potentially
very toxic, although there is no good correlation between toxicity levels and reactivity
towards nucleophiles. More will be said about some of these systems in later chapters.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 134
134 Chapter 5
ArF ArF−e
+ Nuc [Nuc�Ar�F]
[Nuc�Ar�F] Ar�Nuc + F
Ar�Nuc + Ar�FAr�Nuc + Ar�F
ArF
½57�
Figure 5.28
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Nucleophilic Displacement of Halogen from Fluorocarbon Systems 135
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, Synthesisand Applications, ed. J.F. Liebman, A. Greenberg and W.R. Dolbier, VCH Publishers, New
York, 1988, p. 99.
47 Y. Apeloig and Z. Rappoport, J. Am. Chem. Soc., 1979, 101, 5095.
48 B.E. Smart in The Chemistry of Functional Goups, Supplement D, ed. S. Patai and
Z. Rappoport, John Wiley and Sons, New York, 1983, p. 603.
49 J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam, 1968.
50 V.M. Vlasov, J. Fluorine Chem., 1993, 61, 193.
51 F.G. Bordwell and D.L. Hughes, J. Am. Chem. Soc., 1986, 108, 5991.
52 T.J. Broxton, D.M. Muir and A.J. Parker, J. Org. Chem., 1975, 40, 3230.
53 N.S. Nudelman, J. Phys. Org. Chem., 1989, 2, 1.
54 E.T. Akinyela, I. Onyido and J. Hirst, J. Chem. Soc., Perkin Trans. II, 1988, 1859.
55 T.O. Bamkole, J. Hirst and E.J. Udoessien, J. Chem. Soc., Perkin Trans. II, 1973, 110.
56 F. Rose-Munch, L. Mignon and J.P. Sanchez, Tetrahedron Lett., 1991, 32, 6323.
57 L. Eberson, L. Jonsson and L.G. Wistrand, Tetrahedron, 1982, 38, 1087.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:41pm page 136
136 Chapter 5
Chapter 6
Elimination Reactions
Since eliminations cover a very wide spectrum of chemical reactions, this chapter is a
selective discussion of the subject. The mechanistic basis of b-eliminations is discussed,
largely with reference to dehydrohalogenation, and a variety of a-eliminations are
included here. Other eliminations, such as dehalogenation, are described throughout
later chapters with reference to specific syntheses.
I b-ELIMINATION OF HYDROGEN HALIDES
A Effect of the leaving halogen
Effects arising from the halogen atom that is eliminated during b-elimination of hydrogen
halide may be summed up (Figure 6.1) as: (a) b-halogen has an acidifying influence on
the adjacent hydrogen; and (b) ease of elimination will vary with the strength of the
carbon–halogen bond and the ability of halogen to accommodate a negative charge. The
combination of these effects is likely to be in the order F < Cl < Br. Of course, elimin-
ation 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).
C C
H X
C C + BH+ + X
X = HalogenB
αβ
Figure 6.1
Eliminations from fluorides are often autocatalytic [3], due to assistance in ionisation
by hydrogen bonding between the leaving fluoride ion and hydrogen fluoride produced in
the reaction (Figure 6.2). As a consequence, fluorides can sometimes be more stable
in even slightly alkaline solution than in the pure state [3].
Table 6.1 Relative rates of elimination of HX from PhCH2CH2X [1, 2]
Substrate Reaction conditions X ¼ F X ¼ Cl X ¼ Br
PhCH2CH22X EtONa, EtOH, 308C 1 68 4100
PhCHBrCF22X EtONa, EtOH, 258C 1 4� 105 3� 107
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 137
137Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
C C CF H Fδ −
+ HF2−δ+
C
H
½3�
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).
F
Br
F F
(9:1)
+
6.3A
½4�
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
HO2C
F
CO2H
Br
HO2C CO2H½5, 6�
Figure 6.4
Br
HO2C CO2H
F
H
HO2C
F
CO2HBr
δ+
δ−
δ+H
δ−
B B
6.5A 6.5B more stable
Figure 6.5
B Substituent effects
A spectrum of transition states is possible for eliminations [8], varying from transition
states with considerable double-bond character, 6.6A, through those with increasing
amounts of charge developed on the b-carbon atom, 6.6B, until an E1cB mechanism is
observed [9] when the b-hydrogen has been made sufficiently acidic to be removed,
leaving a carbanion (Figure 6.6).
Base-catalysed hydrogen/deuterium exchange is still probably the only definitive probe
for the ElcB process in which H/D exchange occurs in the starting material at a rate faster
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 138
138 Chapter 6
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 C C XX
HHδ+
δ−
6.6AConcerted
6.6BE1cB - like
½9�
Figure 6.6
C C X
H
C C X C C X
D
C C X CC
Base (−H+)
Solvent (+H+)
+ X−
Solvent (+D+)
Internal Return
½9�
Figure 6.7
Highly halogenated alkanes often undergo base-catalysed H/D exchange at rates faster
than elimination [11]; for example, H/D exchange for PhCHClCF2Cl has been measured
to be 1:65� 102 l:mol�1s�1 [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 con-
trolled 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).
C3H7CH2 C
H
F
CH3
C4H9
H
H
H
C3H7
H
H
CH3
C3H7
H
CH3
H
MeOH
NaOMe+
+
69% 21%
9%
½13�
Figure 6.8
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 139
Elimination Reactions 139
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].
CF3CH2CHBrCH3 CF3CH�CHCH3
CHCl2CCl2CHF2 CCl2�CClCHF2
CCl3CH2CF2Cl CCl2�CHCF2Cl
KOH
EtOH
Aq. KOH
½14�
½15�
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.
CF3CHFCHF2 CF3CF�CHF CF3CH�CF2+
70% 30%½17�
Figure 6.10
RFH
RFH
RF
RF
KOtert-Bu
−10�C
RFH = CF2CFHCF3 RF = CF�CFCF3
½18�
Figure 6.11
D Conformational effects
In many cases, elimination of hydrogen halide via an anti-coplanar transition state is
observed [19] (Figure 6.12) in what is commonly regarded as the most favourable process
[20, 21].
However, overall syn elimination is more common than was once thought; a variety of
factors may be responsible. The ratio of products arising from syn/anti elimination can
depend on the reaction medium, e.g. syn elimination appears to be enhanced by a less
polar medium, and this has led to the suggestion that a concerted cyclic process involving
the base may be involved [19] (Figure 6.13).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 140
140 Chapter 6
F
FC5H11
H
C5H11 H C5H11 H
C5H11 F
F
C5H11F
H
C5H11 H C5H11 H
F C5H11
THF(only alkene formed)
(only alkene formed)THF
t-BuOK
t-BuOK
½19�
Figure 6.12
HYX
FY
X
B
M B
M
X
Y
X
Y
+ BH + MF
B = Base
M = Metal
½19�
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
6.14B
F3C F
F F
R
F
CF3
R
F
F
CF3
i
i, KOtert-BuOH, tert-BuOH, 0� C
ii, CsF, Tetraglyme, 200� C
ii
6.14A
6.14C
6.14D
R = Adamantyl
R
F
½18�
Figure 6.14
The preferential syn elimination of hydrogen fluoride, in preference to elimination of
hydrogen bromide, from 6.15A is particularly surprising [22] (Figure 6.15).
It is not clear how much the true preference for a gauche relationship between
a fluorine substituent and an adjacent electron-withdrawing centre [23] will have on
the ease of elimination of hydrogen fluoride, but it is clearly an area of interest.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 141
Elimination Reactions 141
F
CO2EtBr
H
H CO2Et
Br
H CO2Et
F
EtO2C
H
H CO2Et
EtO2C Br
anti
syn
i
i, NaOH, H2O
6.15A
½22�
Figure 6.15
E Elimination from polyfluorinated cyclic systems
Tatlow and his co-workers conducted an extremely comprehensive programme of
syntheses and structure derivations of a series of fluorinated cycloalkanes [24], and
concluded that the reactivity of the system, as well as the orientation of the cycloalkene
produced, are similarly influenced by electronic factors which have been outlined in
the preceding sections of this chapter. Anti elimination is generally the more favourable
process but conformational effects may make the syn/anti rates nearly comparable.
Elimination from the cyclohexanes 6.16A and 6.16B illustrates the balance between
electronic and conformational effects [25]. Anti elimination is possible from 6.16A,
involving removal of fluoride from >CHF rather than >CF2 since in this case electronic
(the carbon–fluorine bond in CFH is weaker than in CF2) and conformational effects
(H and F are anti-periplanar) are in concert (Figure 6.16). In contrast, anti elimination
from 6.16B can only occur with elimination of fluoride from the more stable >CF2
position and therefore anti and syn eliminations occur together.
F
F
F
F
H
F
F
F
FF
F
H
aq. KOHH
F
F
F
F
F
F
H
H
F
F
FF
F
F
aq. KOHH
F
F + F
6.16B
6.16A½25�
Figure 6.16
Electronic factors dominate reactivity in the series shown in Figure 6.17; in this
series, qualitatively, the order of reactivity indicated has been established [26]. There
is probably a relationship between reactivity and the number of acidifying b-fluorine
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 142
142 Chapter 6
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 H
H
H
H
H
H
HH
H
F F F F> >> ½26�
Figure 6.17
F
HH
H
H
H
Faq. KOH
F ½26�
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 transi-
tion state is energetically favourable; this can, of course, be accommodated in anti
elimination from cyclohexane systems, but only in syn elimination from highly fluorin-
ated 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.
F
H
Base
F
H
F FBase
Cyclohexane Cyclopentane
Repulsion
Figure 6.19
The reactions of cyclopentanes 6.20A and 6.20B with aqueous alkali both give the same
cylopentene by anti and syn elimination respectively, with only traces of by-products
arising from syn elimination from 6.20A or anti elimination from 6.20B (Figure 6.20).
Inward syn elimination occurs from 6.20B, giving the cyclopentene in 86% yield, and this
is a further indication that removal of fluoride from >CHF is easier than from >CF2
(Figure 6.20)
In the cyclobutane series [28] (Figure 6.21) syn and anti eliminations from 6.21A and
6.21B proceed again at much more nearly comparable rates than from corresponding
cyclohexane systems.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 143
Elimination Reactions 143
H
H
H
H
H H
H
F FF
6.20A 6.20B
H
−HF −HF
Figure 6.20
H
F
F
H
H
F
H
Faq. KOH+
6.21A cis6.21B trans
F F F ½28�
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 organo-
metallic reagents will be discussed separately in Chapter 10, where these points will be
illustrated; only examples of some eliminations from organolithium derivatives of poly-
fluoroalkanes and polyfluorocycloalkanes will be referred to here.
Perfluoroalkyl-lithium derivatives are thermally unstable and their use in organic syn-
thesis has been limited by competing b-elimination processes [29]. Pentafluoroethyl-
lithium has a half-life of around 8 h at �788C [30]. In complete contrast, perfluorinated
bridgehead lithio derivatives are much more stable since, in these cases, elimination of LiF
would contravene Bredt’s rule and would, therefore, be a higher-energy process. Conse-
quently, perfluoroadamantyl-lithium is stable at 08C for several days [31] (Figure 6.22).
H Li
F F½31�
Figure 6.22
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 144
144 Chapter 6
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).
H LiO
F FF furan
25−30�C
6.23A
CH3Li
½24, 32, 33�
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.
Li
F
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−
C
F
CF2F3C
F
Na+
CF3CF�CF2 + NaF
∆, −CO2
½34�
Figure 6.25
Novel chemistry that was initiated by Nakai and co-workers [36, 37] involves elimin-
ation of hydrogen fluoride from the tosylate of trifluoroethanol, followed by reaction of
the intermediate with appropriate electrophiles (Figure 6.27). A wide range of approaches
to the synthesis of difluoromethylene derivatives has ensued.
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 145
Elimination Reactions 145
F C CF(CF3)OCF2CF(CF3)OCF2CF2SO2F
CF2�CFOCF2CF(CF3)OCF2CF2SO2F
Heat, Na2CO3
O
½35�
Figure 6.26
CF3CH2OTs CF3CHOTs CF2�CHOTs
CF2�CLiOTs
Electrophiles
Electrophiles
Various products.
i
i, LDA, THF, −78� C
CF2�C
R
BR2
CF2�C
OTs
B R
RR
ii, n-BuLi, R3Bii
−
½36, 37�
Figure 6.27
A simple alternative approach to the synthesis of difluoromethylene compounds in-
volves electron transfer from metals to carbon–oxygen or carbon–nitrogen double bonds
[38, 39] (Figure 6.28).
F3C R
−F−
( +1e)
−
−O
F3C R
R = Alkyl or Aryl
i, Mg (2 equiv.), TMS-Cl (4 equiv.), 0� C, 30 min.ii, R1R2CO
Productii
F2CR
OTMS
O
F2CR
Oi
( +1e)½38, 39�
Figure 6.28
Reactions of lithium derivatives and Grignard reagents from polyfluoroalkenes or
polyfluoroaromatic compounds are often complicated by eliminations but are generally
much more useful in synthesis than polyfluoroalkane derivatives. Generation of arynes is
discussed later (see Chapter 9).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 146
146 Chapter 6
III a-ELIMINATIONS: GENERATION AND REACTIVITYOF FLUOROCARBENES ANDPOLYFLUOROALKYLCARBENES
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).
C M
F
C + M�F
Figure 6.30
(3) Fragmentation reactions (Figure 6.31).
C
C
CX Y X CC Y + C
Figure 6.31
(4) Decomposition of diazo compounds (Figure 6.32).
C N2 or N2 + CN
N
C
Figure 6.32
Examples of each of these types follow.
A Fluorocarbenes
1 From haloforms
The classic work of Hine and co-workers [42, 43] established that carbenes could be
generated by base hydrolysis of haloforms and that the process could be divided into two
steps (Figure 6.33).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 147
Elimination Reactions 147
X C Y
CHXYZ + OH−
+ Z−
CXYZ
CXYZ + H2O½42, 43�
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 elimin-
ation 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 ap-
proach 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].
CH3
CH3
F F
H3C
H3C CH3
CH3
H3C
H3C
H3C
H3C CH3
CH3
F Cl
H3C
H3C CH3
CH3
CH2Br2 + CF2Br2 +
+ 2KBr + CBr4 + 2H2O
+ CHFCl2
i, NaOH, tetraglyme, 95� C43%
i, Bu4N+HSO
−4, 60% KOH
Br F
+ CFHBr2
i, 50% NaOH, CH2Cl2, Et3N+CH2Ph Cl
−90%
i
i
i
½48�
½45�
½46�
Figure 6.34
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 148
148 Chapter 6
2 From halo-ketones and �acids
The formation of dihalocarbenes by decomposition of trihaloacetate anions is well known
and is usually formulated as involving two steps (Figure 6.35) but, of course, the process
could be concerted.
Cl�CF2�CO
O
F�C�F
Cl�CF2 + CO2
Cl�CF2 + Cl
� �Figure 6.35
It is found that decarboxylation of dichlorofluoroacetate [49] gives about 70% of
CCl2FH via competitive abstraction of a proton from solvent by the intermediate�CCl2F anion, whereas chlorodifluoroacetate [50] gives very little CClF2H, suggesting
either that chloride ion loss in this case is faster than protonation, or that the process is
concerted. Decarboxylation procedures have been widely used, mainly for the preparation
of fluorocyclopropyl derivatives as illustrated in Figure 6.36 [51, 52].
Ph
H
H
OAc
CH3
Ph
H
F F
OAc
CH3
i, ClF2C�COO− Na+, diglyme, reflux
88%
C8H17
OAc
C8H17
H
F F
OAc
i
i, ClF2C�COO− Na+, diglyme, reflux
i
½51�
½52�
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 de-
composition probably involves generation of difluorocarbene, which dimerises [54]
(Figure 6.38).
Elimination of bromine from dibromodifluoromethane is readily achieved, and various
trapping experiments have been carried out with difluorocarbene from this source [55]
(Figure 6.39).
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 149
Elimination Reactions 149
H3C CFCl2
OO
C
H
CFCl2H3C
i, NaH, MeOH
CFCl2
F
Cl
60%
−Cl
i
CFCl
½53�
Figure 6.37
F2C CF2CF3I CF3Li−LiF
CF2
i, CH3Li, −45� C
i
½54�
Figure 6.38
F
FCF2Br2 CF2BrLi CF2
−LiBrn-BuLi ½55�
Figure 6.39
Perfluoroalkyl anions, which form carbenes upon subsequent elimination of a-
fluorine, may be generated by cleavage of the carbon–tin and carbon–mercury bonds
in, for example, (trifluoromethyl)trimethyltin [56] and phenyl(trifluoromethyl)mercury
[57] (Figure 6.40) under very mild conditions. Carbenes may be generated from
F
F
Me3Sn CF3
89%
I−
CF3−
+ Me3Sn-I−F
−
F
F+ PhHgCF3
i, NaI, Bu4N+ I
−, 18-crown-6, 80� C 56%
CF2
i
½56�
½57�
Figure 6.40
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 150
150 Chapter 6
perfluoroalkyl anions which, in turn, may be displaced from, for example, tin, mercury or
silicon by halide ions. Here the driving force is the strength of the new bond to halogen
being formed.
A combination of zinc and CF2Br2 can be used to add difluorocarbene to relatively
reactive alkenes [58] (Figure 6.41a).
Ph
H3C
i, CF2Br2, Zn, I2 (cat), rt
Ph
H3C
F F
71%i
½58�
Figure 6.41a
Remarkably, ðCF3Þ3Bi generates difluorocarbene at low temperatures in the presence
of aluminium trichloride [59] (Figure 6.41b).
(CF3)3Bi [CF2]F
F
i ii
i, AlCl3, −30� Cii, Cyclohexene
½59�
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 cyclopropana-
tion 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 tetra-
fluoroethene 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 inter-
mediate in the corresponding pyrolysis of CFBr3 [66] (Figure 6.46).
Hexafluoropropene oxide (HFPO) [67] fragments exclusively by a reversible process
at high temperature to give trifluoroacetyl fluoride and difluorocarbene only [68]
(Figure 6.47).
Cyclopropanation of electron-deficient alkenes is also possible, as shown in
Figure 6.48, but molecular rearrangements at the high temperature required for HFPO
decomposition may reduce the yield of the desired product [69–72].
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 151
Elimination Reactions 151
H3C
H3C
CH3
CH3
F F
H3C
H3C
CH3
CH3
F F F F
Br−
+ CsF +
79%
+ Br−
22%38%
+
+ Br− F
F
92%
i, diglyme, rt
i
i, KF, triglyme, rt
i
i, CsF, triglyme, rt
i
[Ph3PCF2Br]+
[Ph3PCF2Br]+
[Ph3PCF2Br]+
½60�
½61�
½62�
Figure 6.42
H3C
H3C
F F
H3C
H3C
+ Ph3P + CsF + CF2Br2
66%i, diglyme, rt
i
½60�
Figure 6.43
Ph H
F F
+ Br−
i, KF, 18-crown-6, glyme, rt79%
iPhC CH [Ph3PCF2Br]
+
½63�
Figure 6.44
CHClF2> 650� C
0.5 atm.F2C CF2CF2 ½64�
Figure 6.45
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 152
152 Chapter 6
CHFCl2
i, Pt, 700−750� C
C6F6 + CFCl3 + CFCl�CFCl + CFCl2�CFCl2
CFBr3
i, Pt, 640� C
C6F6 35%
i
i
½65�
½66�
Figure 6.46
O F
F
F
F3C F3C F
O165−185� C
+ CF2½68�
Figure 6.47
F
H
F
FF
F
H
F F
F
F
F
FF
HH
FF
HH
FF
FF
Cl
Cl
Cl
ClCl
Cl
F
•F
F
F
CF3F3C
FF
65%
i, HFPO, 185� C, 6 h
63%
F F F
50%, 1:1
52%
+
i
i, HFPO, 175� C
i
i
i, HFPO, 175� C
i, HFPO, CaCO3, 185� C
i
CF3
CF3
½69�
½70�
½71�
½72�
Figure 6.48
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 153
Elimination Reactions 153
Pyrolysis of various phosphorane, e.g. ðCF3Þ2PF2 [73], and fluoroalkylated tin com-
pounds [74] has been used to generate difluorocarbene. Diazirines decompose to give
carbenes by either photolysis or pyrolysis [75] (Figure 6.49).
N
N
F
F
F
+135� C
85%
F
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.
F F
i, CF2�CF2, 640� C
F F
CF2
+ F F
CF3
N
F
i, (CF2)n, 550� C
N N
F F
F3C CF3
CF3+
isomers
Cl Cl
i
i
½76�
½77�
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 CF2
N
+ CF
N
F
N
F
+
F
½78�
½79�
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 154
154 Chapter 6
N2
F3C
F3CCF3CF=CF2
250� C (CF3)2C=C(CF3)2+Low pressure
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
F
CH3
CH3
H3C
H3C
H3C
H3C
CH3
CH3
F3C F
+170� C
30%
N2
F3C
F3C
CF3
CF3
+ F150� C F 20%
N2
F3C
H+N2
CF3CH2 76%hν ½81�
½82�
½83�
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)dia-
zomethane with but-2-yne, which then loses nitrogen on pyrolysis [80] (Figure 6.54).
N2
F3C
F3C+
NN
CH3H3C
CF3
CF3
400�C
F3C CF3
H3C CH3
−N2
CH3C CCH3
½80�
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 155
Elimination Reactions 155
HSiCl3 + C2F4
hνCHF2CF2SiCl3 CHF2CF2SiF3
150� C
F2HC C F + SiF4(CH)3CCHFCHF2
61% 6.55A
SbF3
(CH3)3CH
½84�
Figure 6.55
The mercurial C6H5HgCFBrCF3 serves as a useful transfer agent for CF3CF [85]
(Figure 6.56).
+ C6H5HgCFBrCF3160� C
C6H6
F
CF3
87% ½85�
Figure 6.56
C Structure and reactivity of fluorocarbenesand 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 fluorocar-
bocations (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 C F F C FC FF
6.57A 6.57B
δ + δ −
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 (DES�T ¼ ET � ES) for several
different carbenes are given in Table 6.2. Electron-withdrawing substituents lower orbital
energies and we have noted the stabilising effect of perfluoroalkyl groups on radicals
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 156
156 Chapter 6
(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
R3
R2
R4 R3 R4
R1R2
F F
R1
R3
R2R4
CF2 R3 R4
R1R2
F F
R3 R2
R1R4
F F
singlet CF2
triplet CF2
+Spin
Inversion
Figure 6.58
C2H5
C2H5H C2H5
C2H5H
F FMe3Sn-CF3
NaI74% ½91�
Figure 6.59
The selectivity of carbenes has been qualitatively estimated by a series of competition
reactions between various carbenes and mixtures of different alkenes; it is found that
electrophilic carbenes react preferentially with the most electron-rich alkene present [87,
92]. Fluorocarbenes, being less reactive, give rise to fewer products from C2H insertion
reactions than CCl2 [91] (Figure 6.60). However, selectivity may be temperature-
dependent [93, 94].
Table 6.2 Calculated energy difference between singlet
and triplet states of carbenes, DES�T [89, 90]
Carbene DES�T ðkJmol�1Þ
CH2 �246
CHF 142
CF2 808
CðCF3Þ2 �313
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 157
Elimination Reactions 157
OO
O CCl2H
Cl Cl
CCl2
O
+
F F
CF2
(1 : 1)
½91�
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.
C RFRF FCRF
δ + δ − δ +δ −
6.61A 6.61B
Figure 6.61
The extremely electrophilic nature of bis(trifluoromethyl)carbene has already been
illustrated by the formation of addition products, even with hexafluorobenzene [83]
(Section IIIB), and the high reactivity results in more side-reactions, such as insertion
into C2H bonds, than with difluorocarbene (Figure 6.62).
C(CF3)2H C(CF3)2HCF3
CF3
i, (CF3)2C�N2, hν
47% 9%44%
++i ½80�
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 158
158 Chapter 6
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).
H3C CH3
F3C
F3C
CH3
CH3 H3C
HH
F3C CF3
CH3
+
cis39%
trans8%49%
i, (CF3)2C�N2, hν
i
½80�
Figure 6.63
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Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:50pm page 161
Elimination Reactions 161
Chapter 7
Polyfluoroalkanes,Polyfluoroalkenes,Polyfluoroalkynes and Derivatives
I PERFLUOROALKANESAND 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.
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 hyper-
conjugation, 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
Table 7.1 Bond lengths r and bond strengths B of various halomethanes [3, 4]
X ¼ F X ¼ Cl
r(C2F) (A) B(C2F) (kJmol�1) r(C2Cl) (A) B(C2Cl) (kJmol�1)
CXH3 1.385 459.8 1.781 354.0
CX2H2 1.357 500.0 1.772 335.1
CX3H 1.332 533.5 1.758 324.7
CX4 1.319 546.0 1.767 305.8
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 162
162 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
F C
F
F
F F C
F
F
F F C F
F
F
etc. ½6�
Figure 7.1
found that carbon–carbon bond strengths in a series of fluoroethanes increase upon
a-fluorination (Table 7.2).
Paradoxically, the carbon–carbon bond in hexafluoroethane is stronger than in ethane,
even though it is longer; as yet, such observations remain unaccounted for.
B Physical properties
Since the molecular weight of a fluorocarbon is considerably higher than that of the
corresponding hydrocarbon, we might expect boiling points to be increased.
It can be seen from Figure 7.2 [7] that this is not so, and that there is a remarkable similarity
between the boiling points of fluorocarbons and the corresponding hydrocarbons [8], the
increase in molecular weight being offset by a decrease in intermolecular bonding forces in
the fluorocarbon [9]. Perfluorocarbons have the potentially valuable property of dissolving
useful amounts of certain gases, including oxygen, carbon dioxide and even fluorine, and the
inertness of fluorocarbons to oxidation has led to a long-term study of fluorocarbon
emulsions in water for use as ‘artificial’ blood and other transport applications [10].
Although working systems have been demonstrated, drawbacks associated with reactions
of the immune system have, so far, limited their successful commercial development.
Fluorinated fullerenes have been studied intensively [11].
C Reactions
1 Hydrolysis
Perfluorocarbons are essentially inert to hydrolysis unless heated to very high tempera-
tures, although it has been calculated that the free energy of hydrolysis of carbon
tetrafluoride is exothermic by 304 kJmol�1 [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.
Table 7.2 Carbon–carbon bond strengths and lengths in
fluoroethanes [3]
Ethane r(C2F) (A) BDE(C2C) (kJmol�1)
CH32CH3 1.532 378.2
CH32CH2F 1.502 381.6
CH32CHF2 1.498 400.0
CH32CF3 1.494 423.4
CF32CH2F 1.501 395.8
CF32CF3 1.545 413.0
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 163
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 163
150
100
50
02
Boi
ling
poin
t (�
C)
4 6
Number of carbon atoms
Fluorocarbons
Hydrocarbons
8
−50
−100
−150
−200
Figure 7.2 Boiling points of alkanes
2 Defluorination and functionalisation [1]
Either fusion with alkali metals or reaction with alkali-metal complexes with aromatic
hydrocarbons will break down most fluorocarbon systems, due to the high electron
affinities of these systems. Such reactions form the basis of some methods of elemental
analysis [13], the fluorine being estimated as hydrogen fluoride after ion exchange. Surface
defluorination of PTFE occurs with alkali metals and using other techniques [14]. Per-
fluorocycloalkanes give aromatic compounds by passage over hot iron and this provides a
potential route to a variety of perfluoroaromatic systems (Chapter 9, Section IB).
Electron transfer from other, less vigorous, reducing agents (Table 7.3) can result in
selective defluorination, which arises from a single-electron transfer process, under very
mild conditions (Figure 7.3).
+e−
+e−
+e−
−F−
−F−
CF2CF2 CF2CF2n
etc.
nCF2CF2 n-1
CF2CF
CF2CF2 n-1CF2CFCF2CF2 n-1
CF=CF
Figure 7.3
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 164
164 Chapter 7
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.
F F
i, PhS−Na
+, DMEU, 70�C, 10 days
SPh
SPh SPh
SPh
SPh
SPh
PhS
PhS
i½18�
Figure 7.4
F3CCF
F3C
CF2
CF2CF3
NC
NC
NH2
CF2CF3
i, Hg/hν, NH3
CF3
Fi
HN
CN
NH2
F
i ½19�
½19�
Figure 7.5
Table 7.3 Defluorination of perfluorocarbons
Substrate Reagents/Conditions Product
Yield
(%) Ref.
F F Cp2TiF2
Al, HgCl2, THF, rtF F 40 [15]
F F Cp2Co
LiðO3SCF3Þ, Et2O, rtF F 53 [16]
F F Ph2C5O, Na
THF, rtF F 62 [17]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 165
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 165
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).
F725�C
CF2 C(CF3)2 CF2 CFCF3+
70% 20%
½20�
Figure 7.6
Vacuum pyrolysis of polytetrafluoroethene gives tetrafluoroethene as virtually the only
product [21]; this unzipping reaction is almost unique amongst depolymerisation pro-
cesses. 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 Horvath 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 perfluorocar-
bon 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.
1-octene n-nonanal 81%
CO/H2
25�C, C7F14
[Rh]
P(4-C6H4C6F13)3
CO/H2CO/H2
1-octene
70�C, C7F14
[Rh]
P(4-C6H4C6F13)3
25�C, C7F14
[Rh]
P(4-C6H4C6F13)3
Heat ½26�
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 chro-
matography. 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 166
166 Chapter 7
A1 RF1
A6 RF6
A1 RF1
A6 RF6
B1 RF1
B6 RF6
MixtureSeparateComponents
Mixture
Chromatography
B1 RF1
B6 RF6
SeparateComponents
Recovery of B1-B6
and RF tags
RF1 etc. = Fluorinated tag
i
i, various chemical transformations
½27, 28�
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 kJmol�1 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 photo-
electron spectroscopy confirms that perfluoroalkyl groups have this effect on attached
p-bonds. The same technique [32, 33] also points to the ambiguous nature of a fluorine
atom attached to a double bond (Chapter I, Section IIIB) where inductive electron
withdrawal is offset by interaction of non-bonding electron pairs on fluorine with the
p-system. Consequently, the effect of fluorine attached to a double bond on the energies
of the p-orbitals is little different from that of hydrogen, whereas perfluoroalkyl is
strongly stabilising. In contrast, a fluorine atom attached to a saturated site can only be
a stabilising influence, so we can appreciate that there is a driving force towards
decreasing the number of sites where a fluorine atom is attached to an unsaturated carbon
centre.
A consideration of the cyclobutene ring-opening reactions [34, 35] (Table 7.4) reveals
that the changes in hybridisation of carbon bonded to fluorine are the same for both
compounds T7.4A and T7.4B, and so any changes in carbon–fluorine bond energies must
also be the same. Consequently, as DH for T.7.4A is more endothermic than for T7.4B,
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 167
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 167
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 CF25CF2, which is 29 kJmol�1 less than that for ethene. However, the situation is
less clear for partly fluorinated systems such as CF25CH2, in which the p-bond is
12:5 kJmol�1 more stable than in ethene [37].
cis-1,2-Difluoroethene is more thermodynamically stable by about 4�8 kJmol�1 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 fluorocarb-
anions (see Chapter 4, Section VIIA), and that these repulsive forces appear to be
critically interdependent with stereochemistry. Similar effects on fluoroalkenes are repre-
sented 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
Table 7.4 Ring opening of cyclobutenes [34]
Substrate Product DHðkJmol�1Þ EaðkJmol�1Þ Keq at 3158C
�33.5 136.0 9000
F
T7.4A F
FF2C
F2C
48.9 197.0 5:6� 10�3
F
T7.4B
CF3
CF3
F2C
F2C
CF3
CF3
1.7 192.5 8.4
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 168
168 Chapter 7
be forgotten that the electronegativity of carbon increases in the series sp3, sp2, sp and the
carbon–fluorine bond strength decreases correspondingly.
F
7.9A, C sp2
7.9B, C sp3
F C
90�109�
F
109�
C
109�
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
F
H
FReflux/30 min.
KOH/H2O [43, 44]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 169
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 169
Table 7.5 Contd
Reaction Ref.
NaOH
CF2CFHCF3
85�C
CF CFCF3
[45]
F
F
H
Cl
F
F
F
F
KOH [46]
Dehalogenation
Cl
Cl
F F 100%CF2 CFCl200�C Zn, EtOH
[47]
Pyrolysis
iCF2 CF2 CF2 CFCF3
i, 750-800�C, Atmos Press.[48]
+
+32% 9%
53%
i(CF2 CF2)n CF2 CFCF3 CF2 CFC2F5
CF2 C(CF3)2
i, 700�C, Atmos Press.
[49]
∆CF3CF2CF2CO2
−Na+
−CO2
CF2 CFCF3 [50]
Halogen exchange
F
H59%
iCCl2 CClCCl CCl2
F3C
CF3i, KF, 200�C, NMP
[51, 52]
Cl F 72%i
i, KF, NMP, 200�C
[51]
i, KF, 18-Crown-6, Perfluorocarbon
iCCl2 CCl CCl CCl2 CF3C CCF3
[53]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 170
170 Chapter 7
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.
CHCl3 catalystCHClF2
700�CCF2 CF2
860�CVacuum
CF2 CFCF3
CH3 CCl3catalyst
CH3 CClF2 CH2 CF2∆
HF
Pt
HF
− HCl
½54�
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).
n-C3H7COFE.C.F.
n-C3F7COF n-C3F7COOH
n-C3F7COO− Na
+ ∆
−CO2
C3F7 CF2=CFCF3 + NaF− F
−
H2O ½50�
Figure 7.12
Perfluorocyclopentene is exceptional in being obtained from non-fluorinated materials
by a simple one-step procedure, i.e. displacement of chlorine in perchlorocyclopentene by
fluoride ion [51], although some polyfluorochloro- and polyfluorohydro-alkenes can be
made by analogous processes [51, 52]. If a perfluorocarbon is used as the reaction
medium with potassium fluoride/18-crown-6 complex, then a variety of products may
be obtained, including hexafluoro-2-butyne [53].
Many useful, higher-molecular-weight fluoroalkenes can be conveniently prepared
by fluoride-ion-induced oligomerisation reactions of smaller fluoroalkenes such as
tetrafluoroethene and hexafluoropropene, and these methods are discussed in Section C.
C Nucleophilic attack [55–57]
Fluoroalkenes are generally much more susceptible to attack by nucleophiles than
by electrophiles and, in this respect, the chemistry of polyfluoroalkenes and their
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 171
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 171
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).
C CF
F
F
FNuc
−+ Nuc C
F
F
CF
F
Nuc C C
F
F
H
F
F
E+
+ E C
H
H
CH
H
E C C
H
H
Nuc
H
H
Nuc−
C CH
H
H
H
H+
Figure 7.13
Nucleophilic attack on a double bond proceeds via carbanionic intermediates;
a consideration of the relative stabilities of such species as models for the corresponding
transition states accounts for most, but not all, of the observations concerning nucleophilic
addition to fluoroalkenes. The formation and direct observation by NMR of perfluoro-
alkyl 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 develop-
ments showed that various nucleophiles may be used, and that fluoro-esters may be
employed as the trapping agent [60, 61] (Figure 7.14).
1 Orientation of addition and relative reactivities
Problems of orientation of attack and reactivities of fluorinated alkenes arise in a way
that is analogous but entirely complementary to the classical problems of electrophilic
attack on alkenes. For example, typical of the results that we must be able to account for is
the reaction of methoxide in methanol which occurs specifically at the CF25 site in
perfluoropropene (Figure 7.15). Also, there is a very wide range of reactivity with
perfluoroalkenes: for example, reactions of tetrafluoroethene usually require base cataly-
sis, 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 172
172 Chapter 7
F3C
F3C
CF2CF3
F+ CsF
tetraglyme
rtCF2CF2CF3
F3C
F3CCs
+
I
CF2CF2CF3
CF3
CF3
7.14A, Observable by NMR
CH3O−
+ CF2 CF2 CH3OCF2CF2−
(CH3O)2C=O
CH3OCF2CF2CO2CH3 74%
Nuc CF2 CF2 NucCF2CF2 C
O
RF
OR
NucCF2CF2
eg Nuc− = N3
−, PhO,
− CH3O,
− CH3S.
−
i
i, RFCOOR
½58�
½59�
½60, 61�
Figure 7.14
CH3O−
CF2 CFCF3
CH3OCF2CFHCF3 CH3O−
CH3OCF2CFCF3
CH3OH
CH3OCF(CF3)CF2
Figure 7.15
(2) Fluorine attached to carbon, which is itself adjacent to the carbanionic site (7.16A),
is carbanion-stabilising and therefore strongly activating, for example when X or Y
in 7.16A is CF3.
(3) When fluorine is directly attached to the carbanionic site, e.g. X or Y ¼ 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).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 173
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 173
C Fδδ
>> Clδδ
Nuc C CXY Nuc CF2 CXY etc.F
F
7.16A
δδ
C
Figure 7.16
CF2 CF2 < CF2 CFCF3 CF2 C(CF3)2
7.17A 7.17B 7.17C
NucCF2CF2−
7.17D 7.17E 7.17F
<
< <NucCF2CFCF3 NucCF2C(CF3)2
Figure 7.17
Furthermore, the rates of nucleophilic addition of diethylamine have been found to
increase in the series CF25CF2 < CF25CFCl < CF25CFBr [70] (Figure 7.18), again in
the order of increasing stability of the supposed intermediate carbanion.
(C2H5)2NH CF2 CFBr (C2H5)2NCF2CFBrH(C2H5)2NCF2CFBr−H
++H
+−
Figure 7.18
The order of reactivity CF25CðRFÞ2 > CFRF5CðRFÞ2 > ðRFÞ2C5CðRFÞ2 (where RF ¼perfluoroalkyl) has been clearly established from the isomeric system, 7.19A–7.19C, in
competition for reactions with methanol [68] (Figure 7.19).
CF2 C(RF)CF2CF3 CF3CF2(CF3)C C(CF3)CF2CF3
CF3CF C(CF3)RF
RF = CF3CFCF2CF3
7.19A 7.19B
7.19C
F−
F−
½68�
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 174
174 Chapter 7
CH3O−
CF2 CFBr CH3OCF2CFBr
CF2 CFBr
CH3OCF2CFBr2 CF2 CF
Other products
½71�
Figure 7.20
However, the type of argument outlined above is insufficient to account for the
reactivity of perfluoropropene being greater than that of perfluoro-2-butene (7.21A)
(Figure 7.21), because the corresponding intermediate (7.21B) could only have margin-
ally different stability from the intermediate derived from perfluoropropene (7.17E).
There is also the greater reactivity of 7.22A than 7.22B to account for, where any
difference in stability of intermediate carbanions 7.22C and 7.22D would also be mar-
ginal (Figure 7.22).
Nuc−
CF3CF CFCF3 NucCF(CF3)CF(CF3) Products
7.21A 7.21B
Figure 7.21
RFCF C(RF)2 > (RF)2C C(RF)2
7.22A 7.22B RF = Perfluoroalkyl
NucCF(RF)C(RF)2 NucC(RF)2C(RF)2
7.22C 7.22D
Figure 7.22
Consequently, a frontier-orbital approach has also been used to account for reactivity
and orientation of attack [72]. This approach recognises that HOMO–LUMO interaction,
between nucleophile and fluorinated alkene respectively, will be important, and that
replacing a fluorine atom that is directly attached to unsaturated carbon in a fluorinated
alkene by trifluoromethyl reduces LUMO energy. This increased HOMO–LUMO inter-
action 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, coeffi-
cients also appear to be important, and introduction of trifluoromethyl increases the
coefficient in the LUMO at the adjacent carbon, i.e. as shown for 7.23A (Figure 7.23).
When two trifluoromethyl groups are attached to adjacent carbon atoms (7.23B), then it is
reasonable to assume that their effect on coefficients, and hence on reactivity, is opposing;
consequently the reactivity order CF25CF2 < CF25CFCF3 > CF3CF5CFCF3 is
observed.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 175
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 175
F3C
F3CC C C C
F3C CF3
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
F3C
CF3
CF3
F3C Y
F F
X
Y
X
Y
FF
X, Y = F (7.24C)X = F, Y = OMeX = Y = OMe
X, Y = F (7.24B)X = F, Y = OMeX = Y = OMe
X, Y = F (7.24A)X = F, 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 SN20 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
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 176
176 Chapter 7
Nuc C
F
C
R
Nuc-HNuc C
F
C
R
H
Nuc
R
SN2'
R = −CFR'2
R'
R'F
Nuc
−F−
(Base catalysedaddition)
7.25A 7.25B
7.25D 7.25C
+ Nuc−
Figure 7.25
n-C4H9OH + CF2 CF2 n-C4H9OCF2CF2HC4H9O
− Na+
0-40�C81%
CH3OH CF2 C(CF3)2Room
Temp.
CH3OCF C(CF3)2
CH3OCF2CH(CF3)2 65%
8%
½74�
½75�
Figure 7.26
CF2 CFCF2C4F9 CH3OCF2CFHCF2C4F9
CH3OCF CFCF2C4F9
CH3OCF2CF CFC4F9
i, CH3O− Na+, CH3OH, 50�C
(45%, addition)
+
+ (15%, substitution)
(40%, SN2')
i ½76�
Figure 7.27
4C6H5Li + CF2 CF2Room
(C6H5)2C C(C6H5)2Temp
½77�
Figure 7.28
reactions are concerted, they will be referred to as SN20 processes here [81] (Figure 7.30).
That substitution occurs by attack at the CF25 group, rather than direct displacement of
chloride from 2CF2Cl, has been deduced from the fact that, under equivalent conditions,
C6H5CClF2, CClF5CF2CClF2 and CCl25CCl2CClF2 are unreactive [82].
In non-aqueous media the relative order of reactivity of the attacking halide ions, as
nucleophiles in these processes, is F� > Cl� � I� [83]. This in itself indicates that the
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 177
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 177
NH3 CF2 CFXC
NC
N
CNXHFC CFHX
CFHX
NH3CF3CF CF2Vap.
PhaseCF3CHFCN
(CF3)2C CF2 NH3Et2O
−60�C(CF3)2CHFCN 21%
(CF3)2CHCONH2 13%
½78�
½79�
½80�
Figure 7.29
CH3O− CF2 CFCF2Cl CH3OCF2CF CF2 Cl− ½81�
Figure 7.30
CF2
C6H5
R+ C2H5O
−k1
CCF2OC2H5
C6H5
Rproducts
R k1 x 103s−1 (77�C)
CF3
CF2Cl
CF2CF3
1.9
1.8
0.67
½84�
Figure 7.31
bond-making process is most important and that the reactions involve a two-step add-
ition–elimination, rather than a concerted displacement in which the most polarisable
anion would be the most reactive. The same conclusion was drawn from a comparison of
the rates of reaction of various alkenes with ethoxide in ethanol under pseudo first-order
conditions [84] (Figure 7.31). Rearrangement products were only obtained when R was
CF2Cl, where elimination of chloride was easier, but the rate constants for the other two
examples are comparable, which indicates a rate-controlling addition step (k1).
In general it is very difficult to make any distinction between a concerted process and
the involvement of a short-lived carbanion. For clarity a number of alkene rearrangements
in the following text are written as two-step processes, but it should be emphasised that
they could involve concerted mechanisms. Products arising from substitution with re-
arrangement are frequently encountered in reactions of cyclic fluoroalkenes and in
fluoride-ion-induced rearrangements (Subsection 6, below).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 178
178 Chapter 7
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 illustra-
tive 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
+ F F 95%C8F17SiMe3
C8F17
[93]
iNCCF2CF2CO2CH3 72%CF2 CF2
i, NaCN, CO2, (CH3O)2SO2
[60]
Ph2CCN
i, Phase Transfer Conditions
Ph2C(CN)CF2CXY
Ph2C(CN)CF2CHXY Ph2C(CN)CF=CXY
iXYC�CF2
[94]
iPh-CF CFCF3 Ph2C CFCF3 PhCF C(CF3)Ph
i, PhLi, Et2OPh2C C(CF3)Ph (1 : 3.3 : 2.1)
[95]
+ F F
FF
73%
NMe2
CH3CN, rt
NMe2
[96]
CH3MgX CF2 CCl2 CH3CF2CCl2H
CH3CF CCl2
[97]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 179
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 179
Table 7.6 Contd
Reaction Ref.
Nitrogen nucleophiles
Nrt
NN
F
CH3
F
H
F
78%
F CF CF2 + CH3NH2 [98]
F
F
F
94%
CF3
C2F5
C2F5
F3C C2F5
NH3, Et2O
0�C
C2F5
F3C
C2F5
CH2CN [99]
Oxygen nucleophiles
H
O O
+
62% 28%
iF3C
C2F5
CF3
C2F5
F3C CF3
C2F5 C2F5
F3C CF3
C2F5
i, NaOCl, H2O, CH3CN
[100]
xylene F
OMe
62%
F3C
F3C
CF2 + Bu3SnOMe0�C
F3C
F3C
[101]
F
H
F
Ph
OH
O
H
F
Ph
H
78%i
i, Montmorillonite (cat), KIO3, Hexane, Reflux
[102]
i
O
O
68%(CH2OH)2 CF2 C(CF3)2C(CF3)2
i, CH3CN, −5 to 0�C
[103]
Phosphorous nucleophiles
(100%, Z)
C3F7CF CF2 + Bu3P C3F7CF CFP(F) Bu3 [104]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 180
180 Chapter 7
Table 7.6 Contd
Reaction Ref.
F
F
I F
i
ii
Bu3P CF2 CFCF3 Bu3P CF CFCF3
i, Et2O, −70�C to rt
BF3.Et2O
CF3Bu3P CF CFCF3 BF4
−
ii, I2, DMF, NaCO3
[105]
FF
+ Ph3P
PPh3
[106]
Sulphur nucleophiles
F
F S
S62%
F3C
F3C
K2S, DMF F3C
F3C
CF3
CF3
[107]
29%
63%
iCF2 CFCF3 CF3CFHCF2SC( S)NMe2
+ CF3CF CFSC( S)NMe2
i, Me2N CS2− Na+, DMA, 20�C
[108]
Halide ions
F F
INaI, DMF [109]
Transition metal nucleophiles
F +F
Re(CO)5−
Re(CO)5
[110]
Reduction
F
Ph H9%
iPhCF CFCF3
CF3
i, LiAlH4, glyme, 70�C
[111]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 181
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 181
Table 7.6 Contd
Reaction Ref.
Bifunctional nucleophiles
HO
OH+
O
58%
iC2F5
C2F5
CF3
F3C
CF3
CF3
O
F3C
C2F5
i, Na2CO3, tetraglyme
[112]
NI
N
N
77%iCF3CF CFCF3 +
NH2
CF3
CF3i, K2CO3, CH2Cl2, rt
[113]
OH
+ F
N
O
F
59%
i, ii
NH2i, K2CO3, CH3CNii, NEt3
[114]
LiLi CF CF
n = 10−20n
i
i, CF2 CF2, Et2O, −110 �C
[115]
SH
i
S
NNH2
CF2 CFCF3 CH(CF3)2
i, THF, i-Pr2NEt
[116]
Fi
F Fi, CsF, Glyme, Stepwise
Me3SiOCH2(CF2)3CH2OSiMe3
OCH2(CF2)3CH2O
OCH2(CF2)3CH2O[117]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 182
182 Chapter 7
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 SN20 processes.
F
Cl
F
OC2H5
Cl
FC2H5O
−
7.32A
½85�
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 be-
tween 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).
Table 7.6 Contd
Reaction Ref.
N
N
iD.B.U. + CF3CH CFCF3
i, Hexane, rt
F3C CF2H
[118]
D. B. U., 1, 5-diazabicyclo [3.4.D] nonene-5
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 183
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 183
7.33A
Cl
Cl
FF
Cl
Cl
C2H5OH
KOH
Cl
F
F
Cl
OEt
Cl
Cl
F
F
Cl
Cl
OEt
Cl
F
F
Cl
Cl
Cl
OEt
Cl
OEt
Cl
F
F
Cl
Cl
Cl
OEt
F
F
Cl
Cl
+
7.33C, 61% 7.33D, 23%
7.33B, 10%
Figure 7.33
F
F
FF C2H5O
−FF
F
F
OEt
FFF
OEt
7.34A 7.34B
Figure 7.34
R
F
F
R
FF
OMe
F
OMe
R
OMe
R
F
F F+
R
H
CH3
OCH3
% %
49 51
54
38
46
62
7.35A 7.35B 7.35C 7.35D
MeO− ½119�
Figure 7.35
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 184
184 Chapter 7
F
F
F
F
F
R
F
F
MeOF
F
FR
MeO
F
F
F
F
F
F F
F
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).
F−
+ C CF
F
F3C C E+
F3C C E
H+
+ C CH
HH3C C
Nuc−
F3C C Nuc
Addition
Compare
Substitution with Rearrangement
H+ + H
+
F− + F
−
Compare
F
F F
F
F F
F
F
H
H
HH
HH
Figure 7.37
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 185
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 185
7 Addition reactions
Addition of an alkali-metal fluoride, frequently KF, CsF, ðMe2NÞ3SþMe3SiF�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.
F DMFC 79%
F3C
F3C
CF2-CF3
+ CH3ICsF C3F7
CF3
CF3
CH3 [122]
KF, DMFPh
O
F66%CF2 CFCF3 + PhCOCl
CF3
CF3 [123]
KF75%
i, iiCF2 CF2 CH3CN
CF3CF2−
CF3CF2CO2H
i, CO2, 150�C, ii, H2SO4
[124]
F
41%
CF2 CFCF3 + C6H5N2+ Cl
− CsF
CH3CN
F3C
F3CN N C6H5
[125]
glyme82%CF2 C(CF3)2 + C6H5SCl
CsFF3C C
CF3
CF3
SC6H5 [126]
S70%CF2 CFCF3 + S
KF, 120�C F3C
F3C CF3
S CF3[127]
F F F F
Br
CsF, Br2 [128]
CF2 CFCF3 + IF5 + I2150�C 99%(CF3)2CFI [129]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 186
186 Chapter 7
The related reactions of polyfluorinated carbanions with fluoroarenes (Figure 7.38) will
be discussed fully in Chapter 9, Section IIB.
F−
CF2 CFCF3 (CF3)2CF+N
N
F
FCF(CF3)2
½134�
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 SN20 processes is supported by the isolation, in some cases, of
Table 7.7 Contd
Reaction Ref.
F
79%F3C
F3C
CF3
+ KF I2+ + IF5200�C
CF3CF2
CF3
CF3
C I [130]
i2CF2 CFCF3 + HgCl2 Hg(CF(CF3)2)2
i, KF, (CH2OMe)2, 50�C
[131]
iCF2 CFCF3 + SO2F2
(CF3)2CFSO2F
i, KF, CH3CN, 150�C, Autoclave
[132]
Fi
F E
FE
i, CsF, tetraglyme
E C C E +
E = CO2CH3
[133]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 187
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 187
C3F7CF2CF CF2
CsF
diglymeC3F7CF CFCF3
95%
F
CF3
CF3
CF CFCF3
KF, MeCN
18-crown-6
F3C
F3C
CF2CF3
F96%
½135�
½136�
Figure 7.39
F− F
−
FF
F
F2C
F2CF
F
CF2
F
F2C
F2C CF2
F
F
CF2
F
F
F
F2C
F2C CF2
F
F
CF2
F
F
Fi, ii
i, −F− ; ii, Rearrangement
½137�
Figure 7.40
cyclised products, resulting from internal nucleophilic attack by an intermediate carba-
nion [138] (Figure 7.41).
In many thermally induced rearrangements, it is often difficult or impossible to distin-
guish 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 188
188 Chapter 7
F− CF2 CFCF2CF CF2+
F2C CF
CF2
CFCF3
F3CF3C
F F
½138�
Figure 7.41
F Fhν
F F
CF2
F F
F F
7.42A
7.42B
95%hν (Photoequilibrium)
½139�
Figure 7.42
carbanions do indeed react further with the original fluoroalkenes but this results in only
short-chain oligomers [56, 57, 92] rather than polymers. This occurs because the
extending carbanion loses fluoride ion (Route A, Figure 7.43), rather than continuing
the propagation step (Route B, Figure 7.43).
F−
+ F etc.
n + 1
B, PropagationA, Elimination of F
−
Fluoroalkenesn + 2
F
n
F ½56, 57, 92�
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 pro-
cesses like this can be used to build up useful, synthetically more sophisticated systems
from readily available fluoroalkene precursors (Figure 7.44). The product distribution
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 189
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 189
CF2 CF2 CF3CF2CF2CF2
CF3CF2CF CF2
+F−
SN2'
CF2 CF2F−
C C
CF3
F
CF3
C2F5
CF3CF CFCF3
CF3CF2
C−
CF3
CF2CF3
Tetramer
Pentamer
CF3C2F5
CF3CF3 CF3
F
CF3
C2F5
C2F5
C2F5
CF3CF2
A−F
−
F−
F−
A
B
AB F,
− Dimerisation
½91, 92, 140�42�
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 propaga-
tion 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 carba-
nion 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 190
190 Chapter 7
(CF3)3C− CF2 CF2
60%
(CF3)3CCF2C−F2
(CF3)3CCF2CF2CF2C(CF3)2(CF3)3CCF2CF2CF C(CF3)2
+F−
−F−
(CF3)2C CF2
(CF3)2C CF2
−
½146�
Figure 7.45
dimers (see the preceding section) whilst perfluorocyclo-pentene and -hexene give dimers
only [151] (Figure 7.46).
F FF
−F F
−F−
F F F F F FF− F
−
FF
F
A
A
A½151�
Figure 7.46
For the resultant fluorocycloalkene dimers [56, 147], the number of fluorine atoms at
the double bond is not the controlling factor in determining the position of equilibrium. In
Figure 7.47, only 7.47A1 is observed from perfluorocyclohexene, preserving one strain-
free ring, whereas 7.47B2 is formed exclusively from perfluorocyclopentene, thereby
minimising eclipsing interactions. In contrast, equivalent proportions of 7.47C1 and
7.47C2 are formed from perfluorocyclobutene as a result of the reduced angle strain in
7.47C1 over 7.47C2, which compensates for eclipsing interactions.
D Electrophilic attack [152]
In general terms, highly fluorinated alkenes are relatively resistant to attack by the types
of reactant that are normally considered to be electrophilic in character [55, 153–155].
When one or more perfluoroalkyl groups are attached to the double bond, then the system
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 191
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 191
F−
F F F F
F F
F−
FF F
F F F F
(Not observed)
(Formed exclusively)
(Equimolar mixture)
7.47A1 7.47A2
7.47B1 7.47B2
7.47C1 7.47C2
½56, 147�
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 electro-
philic attack, although other possibilities often arise.
A number of reactions using anhydrous hydrogen fluoride as solvent have been
formulated as involving electrophilic addition of XþF�. Hexafluoropropene is unreactive
towards anhydrous hydrogen fluoride, even at 2008C, but silver fluoride in anhydrous
hydrogen fluoride reacts at 1258C and it has been suggested, therefore, that an initial
electrophilic addition of silver fluoride occurs [156] (Figure 7.48).
AgF CF2 CFCF3 AgCF(CF3)2HF
125�C
HF
HCF(CF3)2 AgF
½156�
Figure 7.48
Mercuric fluoride under similar conditions gives a stable mercurial and it was sug-
gested that strong solvation of fluoride ion, to give HnF�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 192
192 Chapter 7
HgF2 nHF+HgF HnF
−n+1 etc
HgF2 2CF2 CFCF3HF85�C
Hg[CF(CF3)2]2 60%
½156�
Figure 7.49
A variety of interesting electrophilic addition processes have been developed, where
additions (where the electrophile is, for example, Cl, Br, I, NO2, 2OCH22,
CH2NH2, CH2OH etc.) to fluoroalkenes are achieved by reaction with a series of
reagents (Table 7.8).
Table 7.8 Electrophilic additions to fluoroalkenes
Reaction Ref.
CF2 CCl2 + HFBF3 CF3CHCl2 + polymer [157]
C
H
C10H21CH CF2 + C2H5COClAlCl3 C10H21 CO.C2H5
CF2Cl
[158]
F FBr C C Br
FF
86%
anti : syn 1:1
C6H5 CF3
+ Br2
C6H5 CF3
[159]
+ HICF2 CH2−20�C
CH3-F2I + polymer [160]
93%i
CF2 CF2 HNO3 CF3CF2NO2
i, HF, 20� C[161]
i76%CF2 CFCF3 HNO3 (CF3)2CFNO2
i, HF, 60� C[154]
63%i
FClC CFCl HNO3 NO2CFClCOOH
i, H2SO4, rt[162]
70%i
H2C CHF + CH3COCl CH3COCH2CHFCl
i, FeCl3, CH2Cl2, 0� C[163]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 193
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 193
The orientations of addition (Table 7.8) are consistent with an electrophilic process
(Figure 7.50), bearing in mind that fluorine attached to positively charged carbon, Cþ2F,
is stabilising whereas fluorine that is b- to the carbocation centre is destabilising (Chapter
4, Section VI).
E+
E-CCl2CF2
E-CF2CCl2
F
F
Cl
Cl
Stabilising
Destabilising
Figure 7.50
Systems with perfluoroalkyl groups directly attached to the double bond are particu-
larly 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 chlorotrifluoro-
ethene (CTFE) is not regioselective [174] (Figure 7.53).
Table 7.8 Contd
Reaction Ref.
99%CF2 CFCF3 + IF5/I2 (CF3)2CFI [129]
CF2 CF2 + IF5/I2 86%CF3CF2I [129]
CF2 CXCF3 + BF3/ICl/HF
X = H, F
(CF3)2CXI 60-80%[164]
CF2 CFCl + (CF3)2CO
i, AlClXFY, 100�C
O
F3C
F3C
FCl
FF
98%i
[165, 166]
CF2 CFCF3 + CH2F2
iFCH2CF(CF3)2 90%
i, SbF5, 35−50�C[167]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 194
194 Chapter 7
CF2 CFCF3
SbF5
F
F
F
F
F
CF3-CF CFCF(CF3)2
F
F
FF
F
CF3
F
CF2+
C3F6
F−
shift
F
F
F
CF(CF3)2
F
F−
½168�
Figure 7.51
CF2 CFCF3 CF2 CF2
i, AlCl3, 25� C
F(CF2)2CF CF3 47 %
+ CF2 CF2SbF5F F
CF2CF3
HCF2CF2CF CF2 FCH CFCF2CF3
SbF5
i½170�
½171�
½172�
Figure 7.52
CF2 CF2 SO3O SO2
FF
FF
CF2 CFCl SO3O SO2
FF
FCl
O SO2
FCl
FF
i
i, CTFE bubbled through liq. SO3
½173�
½174�
Figure 7.53
However, sulphur trioxide is also a very strong Lewis acid and reaction with hexa-
fluoropropene 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 nucleo-
philic attack discussed earlier, the compound also reacts readily with anhydrous hydrogen
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 195
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 195
CF2 CFCF3 SO3 CF2 CFCF2OSO2Fi or ii
i, BF3, 50�C, 6hr, (60%);
ii, B(OMe)3, 35�C, 6hr, (52%)
F2C
FC
CF2 ½152�
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).
CF2 C CF2
i, anhyd. HF, −72 to 20 �C
CF3CH CF2 99%i
½175, 176�
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 BInitiator
A• + B In Initiation
A• +
A
Addition
+ Propagation
A B+ Chain Transfer
A
A
A A B A
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 + A BIn
Figure 7.57
Conversely, when the rate of propagation is faster than chain transfer, products arising
from telomerisation and polymerisation are formed in greater concentration. In this
section, free-radical addition to fluoroalkenes will be dealt with first, in order to establish
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 196
196 Chapter 7
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 perfluor-
oalkyl 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.
Addition of radicals to unsymmetrical perfluoroakenes could lead to two possible
products (Figure 7.58).
Earlier in this chapter we noted that nucleophiles attack the CF25 site in a fluorinated
alkene exclusively and, in parallel with these observations, nucleophilic radicals, such as
CH3Sl 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.
Table 7.9 Relative rates of addition of perfluoroalkyl radicals
to alkenes versus their rates of hydrogen-atom abstraction from
heptane at 508C [186]
Alkene CF:3 C2F:5 C3F:7CH25CH2 132 340 290
CH25CHF 30 108 40
CH25CF2 9 13 —
CHF5CF2 6 9 —
CF25CF2 8 7 <0.3
CF25CFCF3 0.33
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 197
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 197
2
1 ACF2CFBCF3
BCF2CFACF3CF2CFACF3
ACF2CFCF3
A CF2 CFCF3
AB
AB
A
A
Figure 7.58
A decreasing order of reactivity (towards free-radical addition of methanol) has been
observed [188] in the order CF25CCl2 > CF25CFCl > CFCl5CFCl > CF25CHCl,
and this is largely consistent with expected effects on the relative stabilities of intermedi-
ate radicals after attack at the CF2 sites, where there is a choice. Steric inhibition to attack
accounts for the order CF25CCl2 > CFCl5CFCl.
Frontier orbital theory can also be used to explain the observed rate and orientation
patterns [185]. As we have seen (Section IIC, Subsection 2), vinylic fluorine substituents
do not affect alkene orbital energies that much in relation to hydrogen, whereas perfluoro-
alkyl groups lower LUMO energies considerably. Energies of the SOMO (singly
occupied molecular orbital) of radicals are increased in radicals containing electron-
donating substitutents and so the SOMO (of the attacking radical)–LUMO (of the
alkene) interaction is at a maximum with alkenes containing perfluoroalkyl groups in
reactions with nucleophilic radicals. The coefficients of the LUMO of the alkene can be
used, just as in nucleophilic substitution, to explain the orientation of radical addition. As
we have seen, perfluoroalkyl groups polarise the LUMO in such a way as to increase the
coefficient at the b-carbon (i.e. the CF2 sites in Table 7.11) and so SOMO–LUMO
overlap is greatest at this position.
Many examples of free-radical addition to fluoroalkenes have been recorded; some
examples are listed in Table 7.11.
Table 7.10 Regiochemistry of trifluoromethyl
radical additions to fluoroalkenes: ratio of attack at
A:B (Figure 7.58) [182, 184, 187]
Alkene Ratio
A B A:B
CH25CHF 1:0.09
CH25CF2 1:0.05
CHF5CHF 1:0.05
CH25CHCH3 1:0.1
CH25CðCH3Þ2 1:0.08
CH25CHCH5CH2 1:0.01
CH25CHCF3 1:0.01
CHF5CHCF3 1:0.33
CF25CHCH3 1:50
CF25CHCF3 1:1.5
CF25CFCF3 1:0.25
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 198
198 Chapter 7
Table 7.11 Free-radical additions to fluoroalkenes
Reaction Ref.
CF2 CFHg rays
CF2CFH2 CFHCF2H
60% 40%
[189]
i, g rays, or peroxide
CF2CFHCF3
+ CF2 CFCF3
i[45]
(CH3)2CH2 + CF2 CFCF3 (CH3)2CHCF2CFHCF3
CH3CH2CH2CF2CFHCF3
75%
3%i, (t-BuO)2, 140� C
i
[45]
+ CF2 CFCF3
RFH = CF2CFHCF3
36% 59%
RFH
RFH
RFH
RFH
RFH
RFH
RFHi, (t-BuO)2, 140� C
i
[45]
CH3OH + CF2 CFCF3 93%CF3CFHCF2CH2OH
i, (t-BuO)2, 140� C
i[190, 191]
OH
+ CF2 CFCF3
CF2CFHCF3
OH87%
i, (t-BuO)2, 180� C
i
[191]
OH
OH
+ CF2 CFCF3i
HO CF2CFHCF3
CF2CFHCF3OHi, (t-BuO)2, 140� C
[192]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 199
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 199
Table 7.11 Contd
Reaction Ref.
O O CF2CFHCF3
70%+ CF2 CFCF3
i
i, γ rays, or hν
[193–195]
CH3(OCH2CH2)nOCH3 + CF2 CFCF3
RFHCH2[OCH(RFH)CH2]nOCHRFH
RFH = CF2CFHCF3
i, (t-BuO)2, 140 �C
i
[196, 197]
(CH3CH2)2O + [(CF3)2C CHCF2]2
O
RF
RF
F F
CH3
H3C
FF
i
i, γ-rays, rtRF = CH(CF3)2
[198]
O
Fγ ray O
H
F
83%[194]
C H
O
C
O
70%
C3H7 C3H7 CF2CFHCF3+ CF2 CFCF3
i, (C6H5CO2)2, 80� C, 16 h.
i
[190]
Ph C H
O
+ CF2 CFCF3 Ph
O
FCF3
FF
O
+i, (t-BuO)2, 140� C
iCF2CFHCF3
[199]
CHCl3 + CF2 CFCF3
i, 280� C, 116 h
CCl3CF2CFHCF3 [200]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 200
200 Chapter 7
An interesting process, reminiscent of the Barton reaction, occurs during the radical
addition of 7.59A to HFP [205] (Figure 7.59).
Me
OH
7.59A
Me
OH
CF2CFHCF3
OH
CF2CFHCF3
CH2CF2CFHCF3
F
CF3OH
H
HF
F
F
CF3OH
H
HF
F
Hi
i, CF2 CFCF3
i
H ½205�
Figure 7.59
Table 7.11 Contd
Reaction Ref.
SiH4 + CF2 CFCF3
Hg/hνCF3CHFCF2–SiH3 51%
34%+ F2HC SiH3
F
CF3
[201]
F + HSiCl3
H SiCl3
F 80%hν [201]
F + HSn(CH3)320� C
H Sn(CH3)3
F 94%[202]
+ CF2 CF2 33%(C2H5)2P(O)H (C2H5)2P(O)CF2CF2H
i, (t-BuO)2, 140�C
i
[203]
CF2 CHCl + SF5Br 73%F5SCF2CHClBri
i, 100� C[204]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 201
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 201
2 Telomerisation [178, 206]
Telomerisations [207, 208] are regarded as reactions in which a telogen (A2B) and
several molecules of a monomer ðR2C5CR2Þ react to give short-chain products with,
correspondingly, low molecular weights. In these reactions, the propagation step (Figure
7.56) competes with chain transfer, and a number of factors can influence the relative
effectiveness of these two processes.
In all telomerisations, the distribution of molecular weights increases, i.e. n increases
with (a) an increasing rate of free-radical addition to the alkene, (b) a decreasing rate of
the atom-transfer step, i.e. the A2B bond is stronger, (c) a higher concentration of alkene
relative to the telogen and (d) temperature.
As explained earlier in this chapter (Section IIA), the propagation step for the homo-
polymerisation of tetrafluoroethene is approximately 71 kJmol�1 more exothermic than
for ethene [2], in spite of adverse polar effects of fluorine substitution on the addition step.
It is therefore easy to obtain telomers with tetrafluoroethene and this is also the case with,
for example, trifluoroethene, chlorotrifluoroethene and 1,1-difluoroethene.
Many telogens (A2B in Figure 7.56) have been used in these processes, including
perfluoroalkyl iodides [209], a, v-di-iodoperfluoro- [210] and chlorofluoroalkanes
[211], iodine [211], iodine monochloride [212] and perfluoroalkyl bromides [213]. All
of the readily available fluorine-containing ethenes have been used as monomers in
telomerisation reactions for the production of many telomers, some of which have
important commercial applications, e.g. in the synthesis of high-efficiency surfactants
and for fire-fighting foams [214]. With CF3I and CF25CF2, a broad range of telomers is
produced unless a considerable excess of the iodide is employed [215]; but with
ðCF3Þ2CFI as telogen, where the C2I bond is more easily broken [216] (Figure 7.60),
the chain length is more easily controlled.
(CF3)2CFI + CF2=CF2175�C (CF3)2CF(CF2CF2)nI
(4.6 : 1) n = 1 (69%); n = 2 (18%)n = 3 (10%); n = 4 (3%)
½216�
Figure 7.60
The effect of the fluoroalkyl iodide on the telomer distribution is illustrated for
CH25CF2 in Table 7.12, as well as the effect of molar ratio of telogen to alkene and of
the reaction temperature.
Telomers may be used for further transformations and they are often useful ‘model
compounds’ for related polymers, for exploring cross-linking and other processes [217]
(Figure 7.61).
Telomerisation of hexafluoropropene may be achieved using fluoroalkyl iodides as
telogens [218, 219]; this is rather surprising, considering that it is very difficult to achieve
homopolymerisation of hexafluoropropene (Figure 7.62). It has been suggested [218] that
these reactions may not be radical-chain processes but could involve successive four-
centre additions of fluorocarbon iodides to the olefin (Figure 7.63).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 202
202 Chapter 7
(CF3)2CFI CH2 CF2180� C (CF3)2CF(CH2CF2)nI
(CF3)2CF(CH2CF2)nF(CF3)2C CHCF2(CH2CF2)n-1F
SbF5 / 0�C
CsF
130� C
½217�
Figure 7.61
CF2=CFCF3 CF3I CF3 CF2CFCF3 In
n = 1 (47%); n = 2 (23%)n = 3 (19%); n = 4 (8%)n = 5 (4%).
194� C
½218, 219�
Figure 7.62
CF2 I
CF2 CFCF3
RF
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 sta-
bility, 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
Table 7.12 Telomerisation reactions of 1,1-difluoroethene [216]
Fluoroalkyl
iodide
RFI
Molar ratio
RFI: CH2CF2
Temp.
(8C)
Time
(h)
Conversion
of iodide (%)
Composition of RFðCH2CF2ÞnI
(mol%)
n51 2 3 4 5 6
CF3I 1 : 1 200–210 41 35 46 33 14 5 1 —
C2F5I 1 : 1 190 45 55 92 6 2 — — —
n-C3F7I 1 : 1 200 36 88 70 25 5 — — —
i-C3F7I 1 : 1 185 36 88 90 10 Trace — — —
1 : 1 220 36 90 87 13 Trace — — —
1 : 4 220 36 100 2 21 29 26 18 4
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 6:59pm page 203
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 203
the relatively mundane but important everyday items, like coatings for pans, to crucial
materials for the development of supersonic flight and space travel, but the nature of this
book dictates that only a sample of the materials available can be illustrated here.
The fluorinated ethenes CF25CF2, CF25CFH, CF25CH2, CF25CFCl and CF25CFBr
each form homopolymers in conventional free-radical initiation procedures [220] and it is
notable that the heat of polymerisation for tetrafluoroethene is much greater than for
ethene [2]. Indeed, tetrafluoroethene and trifluoropropene are relatively dangerous mono-
mers to handle because of the risk of explosive polymerisation. In marked contrast, quite
drastic conditions are required in order to form a homopolymer from hexafluoropropene
(HFP) [221], although commercially successful copolymers of CF25CFCF3 with
CF25CF2 (i.e. FEP) and with CF25CH2 (Vitont rubber) have been developed.
Polytetrafluoroethene (PTFE), 2ðCF2CF2Þn2
PTFE is polymerised using conventional initiators [220] to give linear polymers whose
non-stick properties and chemical inertness are now familiar to all. A disadvantage of
PTFE is that it has a very high melt viscosity and cannot be used for melt-processing.
Consequently, copolymers of CF25CF2 and CF25CFCF3 (FEP polymers) are used for
this purpose (Figure 7.64). Also, introduction of a perfluoropropoxy group is a more
expensive solution to the problem, giving perfluoroalkoxy (PFA) resins.
(CF2CF2)x (CF2CF)
CF3
(CF2CF2)x (CF2CF)
OC3F7
FEP PFA
Figure 7.64
Recently, amorphous fluoropolymers have been developed in order to obtain high-
performance materials with optical clarity for microelectronic etching processes. It is
interesting that the monomer perfluoro(2,2-dimethyl-1,3-dioxole) (PDD) (Figure 7.65) is
sufficiently reactive to copolymerise with CF25CF2 to give copolymers with a high
proportion of PDD. This suggests that ether groups, which are isoelectronic with fluorine,
have a similar effect to fluorine on reactivity of alkenes towards radicals (Figure 7.65).
CF CF
O O
CF3F3C
CF2 CF2In
CF CF
O O
CF3F3C
xCF2 CF2
y
Teflon AF®PDD
Figure 7.65
Cytopt (Asahi Glass Co.) is a similar product and is produced by a novel cyclopoly-
merisation 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 204
204 Chapter 7
CF2 CF O(CF2)2CF CF2
R
Route A O
RCF2 F
R Route B
O
F2CR
CF2
Fetc.
etc.
Polymer
Monomer
Monomer
½222�
Figure 7.66
Polychlorotrifluoroethene (PCTFE), 2ðCF22CFClÞn2
This material melts at 2138C and is therefore melt-processable giving clear films.
Polyvinyl fluoride (PVF), 2ðCH22CHFÞn2
PVF films can be made that adhere to various surfaces and are particularly important as
protective coatings for both indoor and outdoor applications.
Polyvinylidene fluoride (PVDF), 2ðCH2CF2Þn2
This material has excellent mechanical properties and is used extensively as weather
resistant coating for aluminium and various outdoor applications. The piezoelectrical
properties of the material have been exploited in a range of electronic applications [220].
Vinylidene fluoride/HFP copolymersVitont 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, tetrafluoro-
ethene dimerises to perfluorocyclobutane, a reaction that is not observed for ethene [226]
(Figure 7.67).
2 CF2 = CF2200�C
FAutoclave
½226�
Figure 7.67
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 205
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 205
Codimerisation occurs not only between different fluoroalkenes but also between
fluoroalkenes and other unsaturated hydrocarbons. Moreover, some of these codimerisa-
tions 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 ½2pþ 2p� and ½2pþ 4p� cycloadditions involving fluorinated
alkenes, employing gas-phase NMR techniques [227].
Table 7.13 Cycloaddition reactions of fluoroalkenes
Reaction Ref.
CF2 CFCl F
Cl
Cl130−250�C (E/Z = 1:1) [228]
CF3CF CF2
CF3
CF3
F3C
F
CF3
(E + Z)
(E + Z)
F
[229]
CF2 C CF2 F
CF2
CF2
[175]
CF2 CF2 CH2 CH2
FF
FF
H
HH
H
40%150�C [230]
CF2 CF2 (CH2 CH )2
FF
FF
H
HH
CH CH2
[230]
CF2 CF2
FF
FF
H
H
35%225�CHC CH [231]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 206
206 Chapter 7
A particular driving force appears to be the presence of CF25 in the alkene; 1,2-
difluoroalkenes, 2CF5CF2, are much less reactive in this context but examples have
been recorded [235].
Dimerisation of tetrafluoroethene to perfluorocyclobutane takes place at 2008C whilst
the reverse reaction occurs at about 5008C [226]. Activation energies, measured for the
forward and back reactions, indicate that the dimerisation is exothermic by 209 kJmol�1
[236], as compared with approximately 67 kJmol�1 for the hypothetical dimerisation of
ethene, and point to factors which destabilise the fluoroalkene. Similarly, when the DH
values for cyclobutene ring opening for hydrocarbon and fluorocarbon systems were
compared earlier in this chapter (Table 7.4), it was concluded that fluorine attached to a
vinylic carbon atom raises the energy of the system, relative to that for the corresponding
hydrocarbon, leading to a lower bond strength in CF25CF2 than in ethene [36, 237]. In
forming a cyclobutane ring, not only are these repulsive forces removed but, if a CF25
was originally present, then stronger carbon–fluorine bonds are formed in 2CF22.
Therefore, the factors that probably lead to the driving force for fluoroalkenes to dimerise
as in Figure 7.68 are:
2
F
F
F
F
F
F
Figure 7.68
Table 7.13 Contd
Reaction Ref.
CF2 CFCl CH2 CHC6H5
FF
FCl
H
HH
C6H5
100�C [232]
(CF3)2CFC CF <0�C
(CF3)2CF
F
72%
(CF3)2CF
F
18%
[233]
CF2 + 110�C, 7 days
F
F47% [234]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 207
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 207
(1) Ip repulsion is relieved.
(2) F atoms are mutually bond strengthening in the product.
(3) Substituents that stabilise di-radical intermediates will activate (see later).
With few exceptions, products are formed which result from a combination of alkenes
in a head-to-head manner, or a correspondingly regiospecific manner in codimerisations
(see Table 7.13). Furthermore, the reactions are not stereospecific.
In considering the mechanism of these reactions it is important to stress that they are
[2pþ 2p] additions, which are formally forbidden as thermally induced [2psþ 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.
2 CF2 CCl2
CCl2 CF2
CF2 CCl2
7.69A
CF2—CCl2
CF2—CCl2
7.69B
F2
F2
Cl2
Cl2
Pathway A
Pathway B
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).
2 CF2 CFH
CF2—CFH
CF2—CFH
7.70C
CF2—CFH
CFH—CF2
7.70D
H
H
F
H
F
H
(E + Z isomers)
(E + Z isomers)
Figure 7.70
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 208
208 Chapter 7
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 CH2 C(CN)t-Bu
SPh
Cl
t-Bu
CN
>
>
<
<
SPh
ClCN
t-Bu
88%
i
i, 120� C, 10hr.
7.71A 7.71B
F2
F2
½241�
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 corres-
ponding 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 209
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 209
F3C
F3C
CF3
BrF
CF3
F3C
F3C
CF3
CF3
F3C
F3C
CF3 CF3
CF3 CF3
CF3
CF3
F3C
F3C
CF3 CF3
CF3 CF3
CF3
CF2
F
Li, −20� C
hνhν
(CF3)8
300� C 300� C
(CF3)8(CF3)8
300� C
½243�
Figure 7.72
(CF3)2C C(CN)2 CH2 CHOC2H5
(CF3)2C C(CN)2
H2C CH.OC2H5
F3C
F3C
H
H
CN
CNH
OC2H5
95%
½244�
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 210
210 Chapter 7
F2
CF2 — CCl2
Cl2
7.74 A
F2
Cl2
F2
CF2 — CCl2
Cl2
7.74 B
CF2�CCl280� C
+ +
1.6%
15% 83%
+ ½248�
Figure 7.74
+ CF2 CF2475�C F2
F2
+
F2
F2
2 : 1
½246, 249�
Figure 7.75
The thermal addition of trifluoroethene to cyclopentadiene at and below 1228C yields a
1,4-cycloadduct, with less than 0.1% of 1,2-cycloadduct, whereas a photosensitised
reaction between these two reactants (a di-radical process) leads to a product consisting
of 87% of the 1,2-cycloadduct and 13% of the 1,4-cycloadduct [250]. These contrasting
results led to the conclusion that the thermally induced Diels–Alder product arises from a
normal concerted process and it is probable that, in general, whilst the 1,2-cycloadditions
and 1,4-Diels–Alder additions are competing processes, they are mechanistically unre-
lated.
Fluoroalkenes possessing perfluoroalkyl substituents, which reduce the energy of the
frontier orbitals, undergo Diels–Alder reactions, as shown in Figure 7.76 [251, 252].
O
+ CF2 CFCF3
i, 120� C, 16 h., Et2O
O
F F
CF2
F 35%
+ CF3CF CFCF3260� C30 h
CF3F
F
CF342%
i ½251�
½252�
Figure 7.76
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 211
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 211
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)
3 Formation of five-membered rings – 1,3-dipolar cycloaddition reactions
A number of 1,3-dipolar cycloadditions to fluoroalkenes have been reported [245]; some
examples are listed in Table 7.15.
Addition of diazomethane to fluoroalkenes [72] follows the order of reactivity
ðRFÞ2C5CðRFÞ2 > ðRFÞ2C5CFRF > ðRFÞ2C5CF2, RFCF5CFRFðRF ¼ perfluoroalkyl).
In reactions involving unsymmetrical fluoroalkenes the additions are highly regiospecific,
with the carbon atom of the dipole becoming attached to the site most susceptible
Table 7.14 Diels–Alder additions to fluorinated alkenes
Reaction Ref.
80� CF
F
F
72%F [253]
F FO
O F
F OO
F10
H2H2
100%F2
[254]
Cl
F
FMe
Me
170� C, 48 h
Cl
F
F2
F2
89%
Me
Me
[255]
CF2 +
F
F
100�CF
F[256]
100�C+
F
F
F
F
30%F [257]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 212
212 Chapter 7
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)
NN
CH2
Figure 7.77
Table 7.15 1,3-Dipolar cycloaddition reactions involving fluoroalkenes
Reaction Ref.
CF3
CF3
C2F5
F
+ CH2—N NN
N HH
C2F5FCF3
CF3
94%
i, Et2O, rt
i[72, 258]
CF3
CF3C2F5
C2F5+ CH2—N N
NN HH
CF3C2F5
93%
CF3
i, Et2O, rt
i
C2F5
CF3
CF3
CF3
H
+ CH2—N Ni
NN H
HCF3
CF3 CF3
NN HH
HCF3
CF3 CF3
H
i, Et2O, rt
[198]
CF3
CF3
CF2
N NN CH2Ph
CF3CF3
FFi, 190� C, 16 h
87%+ PhCH2N3
i
[259]
F + CH2—N N N
N
F
F
55%
i, Et2O, rt, 14 days
i[72]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 213
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 213
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).
CF3NOCF2 CF2
20� C
−45� to 20� C
N O
F3C
F
F
F
F
62%
N
CF3
O CF2 CF2n
64%
RCF CF2 + SO30� C S
C C
O
FR
F F
O O
44%
CF2 CF2 SO2
S O
F
F F
F
O
FCOCF2SOF
80%
i
i, CF2Cl2, N2, hν, −32 to 90� C
CF3CNN
F FCF3
N
F
CF3
40%
R = CH2ClCHClCH2-
½261�
½262�
½263�
½264�
Figure 7.78
G Polyfluorinated conjugated dienes
1 Synthesis
Many of the synthetic approaches that are used for the preparation of fluoroalkenes can be
adopted for the synthesis of polyfluorodienes. Examples of other processes such as
reductive coupling methods and syntheses based on organometallic precursors [265] or
phosphorous ylids are also included in Table 7.16.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 214
214 Chapter 7
Table 7.16 Synthesis of fluorodienes and polymers
Reaction Ref.
Dehydrohalogenation
HCF3
CF3
CF3
CF3CF3
CF3
HCF2
CF2
i, t-BuOK/t-BuOH
i [266]
(CF3)2CFCH2CF2 2i
(CF3)2C CHCF2 2
i, CsF, 150� C, Sealed Tube
70%[267]
Dehalogenation
CF2 CFCF CF2 78%ZnBrCF2CClFCClFCF2Br [268]
CF3
CF3
F
CF2ClCl
F
CF3
CF3
FF
FF
40%
i, Zn, 120� C, diglyme
i[269]
CF3
CF3
CF3CF3
CF3CF3
C2F5
C2F5
FF 90%
Me2NMe2N
NMe2
NMe2
, CH2Cl2, rt
i
i,
[270]
F
F
F
F
i, Na, Hg (0.5% w/w), water cooling
F
F79%i
[270]
O
Cl i
O
(FCl)6
ii
O
F
i, F2, CF2ClCFCl2 ii, Cu Bronze
[271]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 215
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 215
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
Table 7.16 Contd
Reaction Ref.
Decarboxylation
iCF2 CFCF CF2 25−37%
i, 450� C, 0.01 mm
+
CF2 CF(CF2)2CO2Na
NaO2C(CF2)4CO2Na
[272]
Reductive coupling
I
Cl
F
i, Cu powder, DMF, 135� C
Cl
Cl
F F 75%i
[273]
I
I
F F
F
F
+
FF
F
F
50% 34%i, Cu powder, DMF, 135� C
i[273]
Fhν
F F F
Anti : Syn = 20 : 1
[274]
CF3 CF3CF3
F
F
Cu Ph
F
I
+F
F
F CF3
Ph[265, 275]
CF3CF3
CF3
F
i, PPh3, CH3CN, 25 �C
FF75%
i
[276]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 216
216 Chapter 7
Table 7.17 Reactions of polyfluorinated dienes
Reaction Ref.
Nucleophilic attack
FF58%FF
PhO
OPh
+ PhOH
i, KF, CH3CN, rt
i[73]
F
F
CF3
CF3
CF3
CF3
+ K2SDMFrt
S
72%
(CF3)4
[73]
CF3
CF3
FF
FF
MeOHrt
F
F
CF3
CF3
H
CF2OMe
[269, 279]
F
FMeOH
rt
F
FMeO
MeO
[73]
CF3 CF3
CF2CF2+
OEt
O O
Na+
CF2
F O Me
CO2Et
FCF3
F
i
i, Tetraglyme, rt, 17 h
[280]
FF
CF3
CF3 CF3
CF3
+ t-BuOOH O
F
OCF3
CF3
CF3
CF3
F70%
i, BuLi, THF, −78� C to rt
i
[281]
Rearrangements
F
F
CF3
CF3
F
CF3
CF3
F
F F
F SbF5
0 to 5�CF
[269]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 217
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 217
1,4-cycloadditions of fluorinated dienes may occur involved perfluorocyclo-1,3-hexa-
diene, as shown in Figure 7.79.
F + CH2 CHCO.CH3
HeatF
CO.CH3
HH
½277�
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).
Table 7.17 Contd
Reaction Ref.
CF2
F FCF2
CF2
FF
hν85� C, 5 h
F
F
36%
+ F F
64%
[282]
Cycloadditions
CF2
F2C
F
FF
Ph
H
F
Ph
F CF2
H
Dioxane
60� C
4%
+
38%
HC CCPhF
[283]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 218
218 Chapter 7
Indeed, monofluoroethyne, obtained by the pyrolysis of monofluoromaleic anhydride,
is dangerously explosive whilst difluoroethyne has not been isolated, although claims to
its preparation have been reported [287] (Figure 7.81).
O
O
O
F
650� C1-2mm
+ CO + CO2
F
F
F
HC CF ½287�
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).
Table 7.18 Reactions of perfluoroallenes
Reaction Ref.
CF3
C�C�CF2
(CF3)2CF
CsF F
CF3
F
F
CF3
CF3
F3C
F3C
F3C F
F
F
72% 18%
[284]
CF2=C=CF2 + PhCHN2N N
CF2
F
F
Ph
78%i, benzene, rt
i [285]
CF2=C=CF2 +N
N O
H
Ph
63%i, xylene, 120� C
O+ NF
CF3
i N Ph[286]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 219
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 219
CF2Br2 + CH2=CF2
i, Bz2O2, 110� C; ii, C, 300C; iii, hν, Br2
ii CF2BrCH=CF2
86%
Zndioxane
CF3CBr=CFBrAlBr3
CF2BrCH2CF2Br
CF2BrCHBrCF2BrCF3C C F
i
iii
½288�
Figure 7.82
CCl2=CClCCl=CCl2
i, SbF3, SbF3Cl2, 115� C
CF3CCl=CClCF3
85%
ii, Zn, (CH3CO)2O, reflux
63%
i
ii
CF3C CCF3
½292�
Figure 7.83
CCl2=CClCCl=CCl2 CF3CH=CFCF3
i ii
i, Fluorocarbon, sulpholan (25% v:v), KFii, Molecular Sieve
56%
F
F CF2
CF2F F
i
i, CsF or KF, 510−590� C, Flow system in N2
80%−90%
CF3C CCF3
CF3C CCF3
½53�
½293�
Figure 7.84
A recent direct route from CF3CH2CF2H (hydrofluorocarbon 245fa) to the lithium salt
now makes the trifluoropropyne ‘building block’ very accessible for many potential
developments [294] (Figure 7.85).
Other syntheses of a variety of fluoroalkynes are given in Table 7.19 where, in many
cases, the synthetic approaches to these compounds can be seen to be adaptations of
methods for the preparation of fluoroalkenes.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 220
220 Chapter 7
CF3CH2CF2H CF3CH=CHF
PhCHO
Ph3SnCl
i
i, ii i, ii
60%
84%
i, n−BuLi ii, −LiF
CF3C CSnPh3
CF3C CCH(OH)Ph CF3C CLi
CF3C CH
½294�
Figure 7.85
Table 7.19 Synthesis of fluoroalkynes
Reaction Ref.
CF2=CH2 90%
i, s-BuLi, −110� C to −80� C
FC CHi
[295]
CF3CH=CICH3 45%CF3C CCH3
i, KF, crown ether, dioxane
i
[296]
C3F7CCl2CCl3HCl
77%
C3F7C CZnCl CF3C CH
i, Zn, DMF, 90−100� C
i
[297]
NN
N
RF
RF RF
hνrt
+
RF = CF(CF3)2
RFC CRF RFC N[298]
+ C6F13I70� C6 h
55%
CH3(CH2)5C CSnMe3 C6H13C CC6H13 [299]
C3F7I +220� C
C3F7CH=CHI
i, C3F7I, 220� C
KOH C3F7CI=CHC3F7
KOHC3H7C CH
C3F7C CC3F7
HC CH
i[300]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 221
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 221
B Reactions
Formation of the lithium derivative of trifluoropropyne was described in the preceding
section [294] and the various acetylides, RFC;CM, had been prepared previously (e.g.
M ¼ Cu, Ag, Hg; RF ¼ CF3, C2F5, CF3CH2) [289]. However, most studies concerning
the reactions of perfluoroalkynes [291] have centred on the use of perfluoro-2-butyne, as
this is commercially available.
1 Perfluoro-2-butyne [289, 291]
Formation of polymers and oligomers: When perfluoro-2-butyne is heated, either
alone or with halogen compounds or a metal carbonyl, hexakis(trifluoromethyl)benzene
is obtained [303–306] (Figure 7.86). This is a very interesting compound that gives
stable valence isomers on irradiation with ultraviolet light (see Chapter 9, Section IIE,
Subsection 4).
F3C
F3C
CF3
CF3
CF3
CF3
hνStable valence isomers
375� CCF3C CCF3 ½303�306�
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.
Table 7.19 Contd
Reaction Ref.
HO CF3
Cl
Cl
i, Ac2O, Et3N, Zn, DMF; ii, NaNH2, t-BuOH, benzene, rt
CF3
Cl
H
81%
i iip-ClC6H4
p-ClC6H4
p-C6H4C CCF3 [301]
66%
PhC CLi PhC CC8F17
i, THF, −78� C
i+ C8F17IPhOTf
[302]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 222
222 Chapter 7
hνCF3C CCF3 -C(CF3)=C(CF3)-
n½307, 308�
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).
n–C4H9OH +20� C
89%NaOBu F3C
n-BuO
H
CF3
+ OHNaOH
50� C
OF3C
F3C
F3C
O
CF3
CF3C CCF3
CF3C CCF3
½309�
½310�
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 conjuga-
tion in the polyene system is inhibited by steric effects.
CF3C CCF3 CF3CF�CCF3
CF3CF�C(CF3)C(CF3)�CCF3
F
C4F6
CF3C�C(CF3)
i
i, CsF, Sulpholan
C4F6 etc.
n
½311�313�
Figure 7.89
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 223
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 223
FCF3F=CCF3
i
N
Fi =
N
F
F3C
F
CF3
7.90A
N
F
C(CF3)=C(CF3)nF
7.90B
CF3C CCF3
½315�
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=CF2
C(CF3)=C(CF3)n
i, CsF, Sulpholan, 100� C
iiCF3C CCF3 ½315, 316�
Figure 7.91
Cycloadditions [40]: Perfluoro-2-butyne is a highly reactive dienophile and many [4þ 2]
cycloaddition and 1,3-dipolar addition reactions involving this alkyne have been reported
(Table 7.20). Moreover, [2þ 2] additions with hydrocarbon alkenes are possible (Table
7.20).
Table 7.20 Cycloaddition reactions with perfluoro-2-butyne
Reaction Ref.
N
COCH3
+
i, THF, 100� C
N
CF3
CF3
100%
COPh
CF3C CCF3
i[317]
CF3CF3
+ PhN350� C N N
N Ph
80%CF3C CCF3 [318]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 224
224 Chapter 7
Heptafluoro-2-butene, which is readily available in a laboratory synthesis from hexa-
chlorobutadiene, 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
Table 7.20 Contd
Reaction Ref.
CF3
200� C
10 h
H3C
F3CCH3
CH3H3C
CF3C CCF3 [319]
O
CH3
100� C
6 h
OH
CF3
CF3
CH3 O
CH3
F3C
F3C
CH2=CH2
i ii
i, BF3.Et2O
ii, H2, Pt/C, 400� C
O
H3C
CF3
CF3
CF3C CCF3
[320]
∆
CF3
F3C
Polyacetylene
CF3C CCF3
[321]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 225
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 225
CF3CH=CFCF3
CF3
−HF
CF3
CF3
F3C
91%
½322�
Figure 7.92
[CF2]F3C
F3CCF3
CF3
F F
100� C
[CF2]
100� C
F F
F F
25%
CF3C CCF3 ½323�
Figure 7.93
7.94B is produced which is a rare, and probably unique, example of the dithiete system
[326] (Figure 7.94).
CF3
CF3
CF3
S
S I2
S S
F3C
F3C
F3CS
S
S
S
7.94A 11% 7.94B 26%
7.94C 29%
CF3C CCF3
(CF3)4 ½326�
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 226
226 Chapter 7
H
CF3
CF3
CF3
O30%
γ
220� C7 days
CF3CI�C(CF3)C3F7 68%
Z : E 3 : 4
+CH3CHO
+C3F7I
CF3C CCF3
CF3C CCF3
½327�
½328�
Figure 7.95
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Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:00pm page 235
Polyfluoroalkanes, Polyfluoroalkenes, Polyfluoroalkynes and Derivatives 235
Chapter 8
Functional CompoundsContaining Oxygen, Sulphuror Nitrogen and their Derivatives
This chapter contains only a brief survey of the chemistry of a range of derivatives that are
of interest to the organic chemist; further aspects have been discussed in detail and may be
referred to elsewhere [1, 2]. Because of the extreme electronegativity of fluorine and
fluorocarbon groups, the acidities of various functions are increased by introduction of
these groups. Some examples are given in Table 8.1: it is clear that fluorocarbon groups
have a dramatic effect on the acidities of alcohols and carboxylic acids. Moreover, the
CF3SO2 group is one of the most electron-withdrawing groups known [3] and conse-
quently the carbon acid ðCF3SO2Þ2CH2 is more acidic than trifluoroacetic acid. Also, the
sulphonamide ðCF3SO2Þ2NH is a strong acid [4].
Conversely, fluorine or fluorocarbon groups have a major effect in reducing the base
strength of amines, ethers and carbonyl compounds; for example, 2,2,2-trifluoroethylamine
(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]
Acid pKa
CH3COOH 4.76
CF3COOH 0.52
ðCH3Þ2CHOH 16.1
ðCF3Þ2CHOH 9.3
ðCF3Þ3COH 5.4
ðCF3SO2Þ2CH2 �1.0
ðCF3SO2Þ2NH 1.7
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 236
236 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
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.
RCOClE C F RFCOF RFCOOH
H2O
e.g. RF = CF3, C4F9
[13]
CF3CCl3i
CF3COOH
i, SO3, BF3
[14]
C8F17Ii
C7F15COF 83%
i, Fuming H2SO4, PCl5
[15]
CF2=CF2 (CF2)n(COOMe)2i, ii
i, K2S2O8, FeSO4, H2Oii, Esterification
n = 1−11
[16]
CF3(CF2)6I(Br)i
CF3(CF2)5COONa 83%
i, HOCH2SO2Na, NaHCO3, DMF, H2O, 90�C
[17]
(CF2)4(CH2CH2OH)2i
(CF2)4(CH2COOH)2 69−95%
i, CrO3−H2SO4
[18]
H(CF2)6CH2OHi
H(CF2)6COOH 65%
i, HNO3, FeCl2.nH2O[19]
CHF2COF + Br2hν
BrCF2COF [20]
CF2ClCFClCCl3i
CF2ClCFClCOOCl
ii
CF2ClCFClCOOCD3iii
CF2=CFCOOCD3
i, Oleumii, CD3ODiii, Zn
[21]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 237
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 237
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 perfluoroalk-
anoic 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 8.2 Contd
Reaction Ref.
ClSbF5
X
X
(CF2)4(COOH)2
X = Cl, F
Fi
i, Alk. KMnO4
[22, 23]
O
Cl Cl
O(CF2COOH)2
i, SbF3.SbCl5.
i ii
ii, KMnO4
Cl F
O[24]
Table 8.3 Reactions of perfluoroalkanoic acids and derivatives
Reaction Ref.
OH
O
OH
O
O
O
CF3
i
i, CF3COOH
[28]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 238
238 Chapter 8
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).
Table 8.3 Contd
Reaction Ref.
CF3COOH + C6H5COX CF3COX + C6H5COOH
X = Cl, F
[29]
CF3COONa + POCl3 CF3COCli
i, 100�C, 24 h
90% [30]
CF3COOH + P2O5 (CF3CO)2O[27]
CF3COOC2H5 + NH3 CF3CONH2 99%i
i, (C2H5)2O, 0�C
[31]
C2F5CONH2i
C2F5Br
i, Br2, NaOH[32]
CF3COOC2H5 + NH3 CF3CONH2 99%i
i, (C2H5)2O, 0�C[33]
CF3COOC4H9 + LiAlH4 CF3CH2OH 76%i
i, (C2H5)2O, Reflux
[34]
CF3COCl CF3COCHN2 CF3CH2COOC2H5
i ii
i, CH2N2, 0−20�C; ii, Ag2O, C2H5OH
62% 40%[35]
CF3CONH2 CF3CN 74%i
i, P2O5, 150−200�C
[31]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 239
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 239
FCO[CF(CF3)OCF2]2CF2SO2FNa2CO3
Heat
CF2=CFOCF2CF(CF3)OCF2CF2SO2F
CF2=CF2
CF2F2C
O
SO3 FFCOCF2SO2F
OCF2CF2SO2FOCF2CF(CF3)OCF2CF2SO2FHFPO
HFPO
HFPO =O
CF2CF3CFCF2=CF2
Co-polymer
F
SO2
½37�
Figure 8.1
(CF2)4(COONa)2 CF2=CF(CF2)2COONa (CF2=CF-)2
61%
i ii
i, 460�C, 10−2mm ii, 160−450�C, 10−2mm
½38�
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].
CF3CO2NaAgNO3
CF3CO2AgI2
HeatCF3I 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
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 240
240 Chapter 8
CF2=CF2
IF5/I2
IF5/I2
C2F5I 86%
CF2=CFCF3
CF2=CFCF3
(CF3)2CFI
(CF3)2CFI
(CF3)3CFI
99%
F
i, KF, I2, CH3CN, 100�C
61%
F CF2=C(CF3)2 61%
i
i, KF, I2, CH3CN, 130�C
i
½45, 46�
½45, 46�
½47�
½48�
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 stabil-
isation of the CF3COO� ion. Conversely, the medium is highly efficient in solvating
anions through hydrogen bonding. As a consequence of these effects, trifluoroacetic acid
provides a useful medium for solvolytic reactions of pronounced SN1 character because
this allows inductive and anchimeric assistance effects to play a more important part in
carbocation generation than is observed using more nucleophilic solvents [50]. The acid
may be used as a solvent for promoting the formation of strong electrophiles, e.g. for
nitration. Trifluoroacetamide has been used in an alternative procedure to the Gabriel
synthesis for amines [51] (Figure 8.5).
RX + NaNHCOCF3 RNHCOCF3 RNH2
NaBH4
e.g. RX = n-C8H17I, Yield = 79%
½51�
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
RCOOR' + 2 CF3COOH
½54�
Figure 8.6
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 241
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 241
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
CF3COO− + RCO
+
CF3COOH + CF3CO.OCOR
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
O
O OHδ+δ−
½56�
Figure 8.8
Peroxytrifluoroacetic acid is a powerful peroxy-acid and only the expense of the
reagent inhibits its more widespread use. It will efficiently bring about the oxidations
for which peracids are normally used, such as the Baeyer–Villiger oxidation of ketones to
esters [58] and the conversion of alkenes to glycols [59] or, when a buffer is present, to
epoxides [60] and nitrosamines to nitramines [56, 61]. However, the reagent will also
convert aromatic amines to nitro compounds [62], even with amines containing electron-
withdrawing substituents [63]. Similarly, oxidation of perfluorodibenzothiophene to the
dioxide occurred [64] where other reagents had failed. Peroxytrifluoroacetic acid reacts
with aromatic systems by effecting electrophilic hydroxylation [65] leading to phenols,
quinones or cyclohexadienone derivatives [65, 66], and the efficiency of the reagent is
significantly increased by the addition of boron trifluoride [66] (Figure 8.9).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 242
242 Chapter 8
CF3CO2OH
S
F F
i, CF3COOH, H2O2
S
F
O O
H3C CH3CH3
CH3CH3
CF3CO2OH
H3COH
CF3CO2OH/BF3
O
90%
C6F5NH2 C6F5NO2
i
(CH3)6 (CH3)6
½63�
½64�
½66�
½66�
Figure 8.9
B Aldehydes and ketones
1 Synthesis
Selective fluorination of aldehydes and ketones has been carried out by a variety of
electrophilic procedures [67–70] and enantiomerically enriched forms have been
achieved in a number of cases. A range of polyfluoroalkyl ketones has been synthesised
but, generally, by methods quite distinct from those that would be used to synthesise
corresponding hydrocarbon derivatives. Some examples are given in Table 8.4. Hexa-
fluoroacetone [67] and chlorofluoroacetones are commercially available and are made by
exchange of chlorine in hexachloroacetone by fluorine, using a Cr(V) or Cr(III) catalyst,
and fluoral, CF3CHO, has also been made on a commercial scale by analogous catalytic
processes, starting with chloral, CCl3CHO [71]. Preparations of trifluoromethyl ketones
have been reviewed [72].
2 Reactions [93–96]
The carbonyl group in a perfluorinated ketone is clearly very electron-deficient and this
feature dominates the chemistry of these compounds. It is reflected in, for example, the
rise in vibrational frequency of the carbonyl group in polyfluoro-ketones [97, 98] from
normal values and by the fact that hexafluoroacetone is not protonated in the superacidic
FSO3H=SbF5 mixture [8].
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 243
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 243
Table 8.4 Syntheses of perfluorinated aldehydes and ketones
Reaction Ref.
CF3CHBrCli
(CF3CHSO3)ii
CF3CHO
i, Oleum, HgO, reflux; ii, H2O
[73]
CF3Br
i, Electrochem. Red'n, DMF, Bu4NBr, Al anode, Lewis acid or Me3SiCl (trace).
ii, (CH3CO)2O, HCl, Pyridine
i, iiCF3CH(OCOCH3)2 ca. quant.
[74]
RF(CF2)nCOOH RF(CF2)nCH(OH)2 CF3(CF2)nCHOi, ii iii
i, LiAlH4; ii, H2SO4; iii, P2O5 n = 0, 1, 2
[75]
i, Swern Oxidation or Pyridinium Chlorochromate
RF(CH2)nCH2OHi
RF(CH2)nCHOF
R'F
CHO
H
RF = C4F9, R'F = C3F7, n = 1−4
[76]
FCO(CF2)3COF CF2=CFCF3
i, CH3CN, KHF2, 120−125 �C
(CF3)2CFCO(CF2)3COCF(CF3)2
75% Conversion
i[77]
CF3CF2CF=C(OMe)CF3SbF5 CF3CF=CFCOCF3
[78]
FCO(CF2)nCOF Me3SiCF3 CF3CO(CF2)nCOCF3
i, ii
i, KF; ii, Heat, Vacuum
n = 2,3 (ca. 90%)[79]
(C2H5O)2CO (n-C3F7)2CO
88%
(n-C3F7)2C(OH)2P2O5
[80]
CF3CCl=CClCF3
i, CrO3, fum. H2SO4, 60−70�C, 1.5 h
CF3COCOCF3
31%
i
[81]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 244
244 Chapter 8
Table 8.4 Contd
Reaction Ref.
OF
F3C F
F
Cr2O3 or Al2O3 (CF3)2CO [82, 83]
OF F
i, CsF, Pt, 150−300�C, 1.5h, 300�C, 2h
Oi
[84]
CF2=CF2 CF2=CFOCH3
OCH3175�C
F
H2SO4
OH
F OHP2O5
HeatF
O
[85]
(CF2)n
F
F
OCH3 (CF2)n
OCH3
F
CoF3 (CF2)n
F
F
OCH3
F
H2SO4
(CF2)n
OH
F
OH
F
P2O5(CF2)n
F
F
O
[86, 87]
CF2=C(CF3)2 (CF3)2CHCOOH (CF3)2C=C=OH2O
THF
P2O5
77%[88]
RF C
OH
H
CF=CF2
Br2 RF C
OH
H
CFBrCF2Br
Na2Cr2O7.2H2OH2SO4
RFCOCFBrCF2Br RFCOCF=CF2
Zn/Dioxane
RF = CF3; C2F5
[89]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 245
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 245
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).
X CO CH2CH3
iX
Et2BO
H
CH3 ii
Re
X
O OHCF3
CF3
i, Et2BOTf, i-Pr2NEt, −5�C, 30min.
ii, (CF3)2CO, −78 to 5�CX =
NSO2
½101�
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 hexafluoro-
acetone. 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]
Table 8.4 Contd
Reaction Ref.
C
F3C OH
C CF
OF
F
iC
F3C OH
CF2
i, Nitrobenzene, 200�C
CF2HCOCF3
45%
NaO
[90]
C6F13(CH2)2Ii, ii
RFCO(CH2)2C6F13
i, t-BuLi, −78�C
ii, RFCO2Et, −78�C
RF = CF3 (89%)RF = C7F15 (68%)
[91]
RFCOCl + (i-Pr)3SiH RFCHO + (i-Pr)3SiCli
i, Pd/C, 25 to 30�C RF = C7F15 90%RF = n-C3F7 60%
[92]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 246
246 Chapter 8
R1 X
YC(CF3)2
X = O, S, NR2
Y = N, CH
8.11A
e.g. (CF3)2CO
R1 NR2
NH2
R1 NR2 NR2
HNC(CF3)2OH
R1
NC(CF3)2
i
i, POCl3, Pyridine
80−90%
(CF3)2CO
R1 NH
CNON
F3C CF3
R1 NH
i
i, Et2O, −30�C - room temp.
75−84%
R1 = CH3, CH(CH3)2
½95, 96�
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 defluor-
ination and cyclisation [95] (Figure 8.13).
R1 NR2
NC(CF3)2
C NR3N
F3C CF3
R1
NR2
NR3
77−93%
i
i, Toluene, 50−70�C, 24−36 hr.
½95, 96�
Figure 8.12
SnCl2
R1 X
NC(CF3)2
X = O, S, NR2
R1 X
NC=CF2
F3CF3C
N
X R1F
− F
SnCl2F2
½95�
Figure 8.13
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 247
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 247
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].
OHN
HOOCO
F3C CF3
½96, 102�
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 corres-
ponding 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.
(CF3)2C=NPh + H2NNHCONH2 (CF3)2CNHNHCONH2
NHPh
∆ or HCl (− PhNH2)
(CF3)2C=NNHCONH2
½103, 104�
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).
MOH + (RF)2CO C
OM
RF
RF
OH
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 decom-
position, gives the interesting peroxide CF3OOH [93, 107]. Reaction of CF3COCH3
with 30% hydrogen peroxide gave a stable tetroxane [108] (Figure 8.17). In recent
developments, the hydrogen peroxide is generated in situ, in a catalytic process using
N-hydroxyphthalimide and oxygen, in the presence of hexafluoroacetone or its hydrate.
The system is useful for epoxidation of alkenes, which occurs in a regio- and stereo-
selective manner [109]. Also, the use of Oxonet (KHSO5 � KHSO4 � K2SO4) with
CF3COC6H13, in aqueous ðCF3Þ2CHOH as solvent, has been developed [91]. Oxonet
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 248
248 Chapter 8
in combination with ðCF3Þ2CO is a very powerful oxidant, proceeding by the intermediate
formation of the corresponding dioxirane [110] (Figure 8.18). Catalytic diastereoselective
epoxidation of chiral allylic alcohols, using hexafluoroacetone hydrates, has also been
reported [111]. Some additions are shown in Figure 8.19.
CF3COCH3 + H2O2O
O O
O
F3C
F3C
CH3
CH3
½108�
Figure 8.17
CF3COCF3 C
O
O
Oxidation reactions
F3C
F3C
½110�
Figure 8.18
CF3COCF3
CF3COCF3
(CF3)2C(OH)2H2O
H2O2 (CF3)2C(OH)OOH
∆
CF3COOH
CF3COCF3H2S (CF3)2C(OH)SH
½112�
½106, 107�
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].
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 249
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 249
OH
CF3COCF3 HO C(CF3)2 OHi
i, BF3, or HF
½93�
Figure 8.20
CF3COCF3 + (C6H5)3P=CHCOCH3 (CF3)2C=CHCOCH3 ½114�
Figure 8.21
Some unusual reactions can occur between fluorinated ketones and trialkylphosphines
[117] or trialkylphosphites [118] (Figure 8.22).
C6H5COCF3 + (n-C4H9)3PC6H5
CF3C
CH
(CH2)2CH3
(C2F5)2CO + P(OC2H5)3 C2F5C(OC2H5)=CFCF3
+ FPO(C2H5)2
½117�
½118�
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
O
C2F5
C2F5
H3C
H3C
100−200�C
F
O
CH2=CH CH=CH2
CH2 CH=CH2
OHF
½119�
½85�
Figure 8.23
Carbonyl groups are normally resistant to radical attack but fluorinated ketones appear
to be exceptional in that an extensive free-radical chemistry is possible [93] (Figure 8.24).
Copolymers are obtained by free-radical copolymerisation of hexafluoroacetone with,
for example, alkenes, tetrafluoroethene and epoxides.
Highly fluorinated ketones show some unusual keto–enol phenomena [122]. Remark-
ably, the pair 8.25A and 8.25B in Figure 8.25 cannot be equilibrated by acid or base;
the enol 8.25A, for example, can be distilled from concentrated sulphuric acid. In the
presence of base, aldol condensation occurs faster than equilibration.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 250
250 Chapter 8
(CF3)2CO + (CH3)2CHOH (CF3)2COH (CF3)2CHOH2
(CF3)2CO + CCl3SiH
(CF3)2CO
hν
hν
hν
(CF3)2CHOSiCl3
OC(CF3)2H C(CF3)2OH
C(CF3)2OH
C(CF3)2OH
½120�
½121�
½93�
Figure 8.24
2 CF2=C(OH)CF3
Slow
CF2HCOCF3
CF2 C
O
CF3
CF3COCF2C(CF3)(CF2H)OH
8.25A
8.25B
8.25C 8.25B
Fast
8.25C
Base½122�
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).
F F
OCH2Ph
F
OH
Stable in THF
½123�
Figure 8.26
Reactions with fluoride ion: With the exception of CF3OH (see the next section),
fluorinated alcohols of the type RFCF2OH are not known [124] but complexes of
K, Rb, Cs, Ag or ðC2H5Þ4Nþ 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 alkox-
ides (Figure 8.27), but the use of these salts in synthesis is often difficult because the
complexes may also act as fluoride-ion donors [128].
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 251
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 251
MF + (CF3)2CO (CF3)2CFOM
Figure 8.27
More stable complexes have been obtained by using ‘TAS’ fluoride [129], and X-ray
data on the salt (8.28A) are quite revealing (Figure 8.28). Carbon–fluorine bonds are
exceptionally long in CF3O� while the C–O distance is quite short; these observations
have been advanced as evidence for negative hyperconjugation (Chapter 4, Section IIIB)
(Figure 8.29).
COF2 + (Me2N)3S+Me3SiF2
− THF
−75�CCF3O
− (Me2N)3S
+
8.28A'TAS' fluoride
½129�
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).
N F−
(CF3)2C=O (CF3)2CF O−
N
½130�
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 CH2=CHCH2OCF(CF3)2
i, CsF, Diglyme, 55�C, 12hr
i
½131, 132�
Figure 8.31
Difficulties undoubtedly arise because perfluorinated alkoxides are very weak nucleo-
philes but they are also potentially fluoride-ion donors and therefore, at the temperatures
necessary for reaction, the alkoxides are probably significantly dissociated and conse-
quently undergo competing side-reactions. Perfluoro-esters RFCO2R1F have been made
[133] in reactions using ðRFÞ2CFOM carried out at low temperatures, with the products
being isolated before they are allowed to warm up. Otherwise, fluoride ion attacks the
ester itself, giving the reverse reactions, because (it must be remembered) the correspond-
ing alkoxide ion RFO� will be quite a good leaving group in a nucleophilic displacement
process (Figure 8.32).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 252
252 Chapter 8
(CF3)2CO + MF RFCO2CF(CF3)2 + F−RFCOF
−78�C½133�
Figure 8.32
Likewise, perfluoroalkoxytriazines may be isolated at low temperatures [134] (Figure
8.33).
(CF3)2CON N
N
ClN N
NRF RF
RF
RF = OCF(CF3)2
KF½134�
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 ðCF3Þ2CO�CsF complex
with tetrafluoroethene [135] gives alkoxide 8.34A, not a carbanion 8.34B (Figure 8.34).
In the presence of iodine, however, ethers are formed [126], indicating the formation of
intermediate hypoiodites, RFOI (Figure 8.35).
CF2=CF2 + F− + (CF3)2CO
CF3CF2−
(CF3)2CO
(CF3)2CFO
CF2=CF2
CF3CF2C(CF3)2O−
(CF3)2CFOCF2CF2 etc
8.34A 8.34B
½135�
Figure 8.34
CF2=CF2 + (CF3)2CO + KF + I2 (CF3)2CFOCF2CF2I
ca. 98% yield17% conversion
½126�
Figure 8.35
A hypochlorite has been obtained by reaction of ðCF3Þ3COH with ClF at low tempera-
ture [136]. In an analogous way, hypofluorites may be formed by reactions of intermedi-
ate perfluoroalkoxide ions with elemental fluorine; this chemistry is being exploited in
industry for the manufacture of important monomers [137] (Figure 8.36).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 253
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 253
CO CF3OF CF3OCFClCF2Cl
CF3OCF=CF2CF3CF2CF2OF
C3F7OCFClCF2Cl C3F7OCF=CF2
i, ii iii
∆i, iiCF3CF2CF=O
iii
i, F2ii, MF (M = K, Rb, Cs), −78�Ciii, CFCl=CFCl
½137�
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 RFCF2OF + FF
Figure 8.37
Hypofluorites are also formed by similar catalytic formation of perfluoroalkoxide ions
from the corresponding oxiranes (Figure 8.38).
CF3CF CF2
OCF3CF2CF2OFF
F2F ½137�
Figure 8.38
The chemistry of fluorinated 1,3-diketones has been reviewed [138].
C Perfluoro-alcohols
1 Monohydric alcohols
The 2CF2OH system is thermodynamically unstable, by an estimated 80�160 kJmol�1,
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 CF3OH + Cl2−120�C ½139�
Figure 8.39
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 254
254 Chapter 8
The driving force for forming C5O via elimination of hydrogen fluoride is much
reduced in strained systems, and therefore the alcohols in Figure 8.40 are more stable
[140]. Systems of the form RFCH2OH are, however, quite stable and are extremely useful
solvents [141] because of their high polarity [142].
O
HX
OH
X
X = F, Cl, Br, I
½140�
Figure 8.40
Perfluoro-t-alcohols are quite stable and are very strongly acidic; for example, compare
ðCF3Þ3OH and ðCH3Þ3OH which have pKa values of 5.4 and 19.0 respectively [143,
144]); see Chapter 4, Section IIA. Perfluoro-t-butanol is obtained most easily from
hexafluoroacetone when it is heated with caesium fluoride in diglyme containing traces
of moisture [145] (Figure 8.41). The first stage involves a carbanion transfer and can be
formulated in a manner similar to the benzil–benzilic acid rearrangement although it
occurs, in this case, by an intermolecular process (Figure 8.42).
(CF3)2CO CF3COF + (CF3)3COCs (CF3)3COH
34%i, CsF, 150�C, Diglyme. ii, H2SO4
iii
½145�
Figure 8.41
(CF3)2COCsF
CF3
CF3 CF3 CF3
CF3CF
O
Cs
O
CF
O O
C(CF3)3
Cs δ−δ−δ+ δ+
C
Figure 8.42
Some other routes to fluorinated alcohols are shown in Figure 8.43a.
Trifluoroethanol has become a much-used ‘building-block’ [150] for a wide range of
synthetic procedures (see also Chapter 6, Section II) (Figure 8.43b), and sigmatropic
rearrangements have been exploited to move the fluorine labels to ‘internal’ sites [151].
2 Dihydric alcohols
Perfluorinated ketones form stable hydrates, ðRFÞ2CðOHÞ2, and these diols are very
acidic. Hexafluoroacetone hydrate is known to be a very good solvent and is particularly
useful for certain polymers [112, 152]. Perfluoropinacol may be obtained from
hexafluoroacetone by photolytic reduction (Figure 8.44), whilst classical reduction with
magnesium amalgam gives only low yields [112]. The same pinacol is also obtained by
heating 8.44A, which is produced as shown in Figure 8.44 [153].
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 255
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 255
CCl3Li + (CF3)2CO (CF3)2C(CCl3)OH (CF3)3OHi, ii iii
50% 60%i, THF, −100�Cii, H2SO4iii, SbF5
CF3CH2Cl + H2O CF3CH2OHi
i, 400−500�C, Catalyst
CH3OH + CF2=CF2
hνHCF2CH2OH
(CF3)2CO
CH2 HX XCH2C(CF3)2OH
X = FSO2O, CF3SO2O, Cl, I
½146�
½147�
½148�
½149�
Figure 8.43a
CF3CH2OTs CF2=C
CF2=C
CF2=C
CF2=C
i
1,2 shift
ii
i, n-BuLi ii, R3Biii, CuI, HMPA
Li
iii
CF3CH2OMEM
MEM = CH2OCH2CH2OCH3
F
F
OMEM
OH
i, ii F
F
OMEM
O
F
F
OMEM
O
F OMEMO
iii
i, LDA, THF, −78�C; ii, EtCHO; iii, Hg(OAc)2, Ethyl vinyl ether, reflux
OTs
Li
OTs
BR3
BR2
ROTs
Cu
½150�
½151�
Figure 8.43b
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 256
256 Chapter 8
(CF3)2CO
(CH3)2CO + (CF3)2C(OH)C(OH)CF3)2
POO
F3C F3C
CF3
CF3
CF3
CF3
CF3CF3
OEtOEtEtO
POO
OHOHHO
i
ii
iii
iv
i, (CH3)2CHOH/hνii, P(OC2H5)3iii, H2SO4iv, H2O, Boil
8.44A
½112�
½153�
Figure 8.44
Diols may also be used in free-radical additions to fluorinated alkenes [154] (Figure
8.45).
OH
OH
CF3CF=CF2
HO RFH
RFHHO
i
RFH = CF3CFHCF2
i, γ rays, rt
83%
½154�
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 RFR1
FCFO
F + RFCOF RFCF2O
F + RFFC CFR1F RFCF2CFR1
F
OO
Figure 8.46
Examples of fluoride-ion-initiated reactions involving perfluorinated epoxides are
shown in Figure 8.47 [155–158]. Hexafluoropropene oxide (HFPO) and tetrafluoroethene
oxide will polymerise under certain conditions in the presence of fluoride ion. The process
involves an extending alkoxide and it is terminated by elimination of fluoride ion to give
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 257
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 257
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].
CF3COF [CF3CF2O ]FF2C CF2
O
C2F5O(CF2CF2O)nCF2COF
F [CF3CF2](CF3)2CO
CF3CF2C
CF3
CF3
O
[CF3CF2C(CF3)2OCF(CF3)CF2O]CF3CF2C(CF3)2OCF(CF3)COF
F3CFC CF2
O
(CF3CF2CF2O)
i, MF, Tetraglyme
CF3CF2COF
CF3CF2CF2O[CF(CF3)CF2O]nCF(CF3)COF n = 1−4
i −F
HFPO
HFPO
(R4NF)
CF2�CF2
HFPO
½155�
½155, 156�
½158�
Figure 8.47
D Fluoroxy compounds [137]
An interesting series of compounds RFOF [160, 161] has been synthesised and found to
be reasonably stable; for example, the O2F bond energy in CF3OF has been calculated
to be 183 kJmol�1 [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 synthe-
ses of fluoroxy derivatives are given in Figure 8.48.
Fluoroxy compounds are very strong oxidising agents [169]; this may be attributed to
the ‘positive halogen’ character of fluorine in an O2F group. Such an approach
[170–172] led to the application of CF3OF as a selective electrophilic fluorinating
agent, but the hazards associated with this system have precluded its development as a
laboratory reagent. For example, the system is prone to explosive reaction with organic
reagents. In fact, a complex interplay of radical and polar intermediates has been
indicated for reactions of hypofluorites with electron-rich alkenes [137].
Some hypofluorites may be susceptible to spontaneous exothermic decomposition
(Figure 8.49) but, in spite of this, industry has mastered the application of intermediate
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 258
258 Chapter 8
CO + F2 (COF2) CF3COFF2
i, Cu Tube, 350�C
(CF3)2CO + F2CsF
−78�C(CF3)2CFOF 98%
CO2 + F2CsF
−78�CCF2(OF)2 99%
(CF3)3OH + F2
−20�C(CF3)3COF
CH3OH + F2 [CH3OF] CF3CFClOCH3
i ii
i, CH3CH2CN, −40�C, 1hrii, CF2=CFCl, −75�C to rt
i ½165, 166�
½167�
½168�
½169�
½170�
Figure 8.48
CF2(OF)2 CF4 + O2 ∆H0 = −360 kJ mol−1−184�C
N2
Figure 8.49
hypofluorites to make new perfluorinated ethers and industrially significant monomers.
Indeed, this chemistry illustrates well the view that an essential part of the skill of science
is to be able to operate potentially hazardous procedures while ensuring the complete
safety of the operators. For example, addition of RFOF to fluorinated alkenes (Figure 8.50)
has been exploited for the synthesis of important monomers (Figure 8.51) for copolymer-
isation (See Figure 8.78, page 269).
2 CF2=CF2 + CF2(OF)2 CF2(OCF2CF3)2 80−90% ½173�
Figure 8.50
Additions of CF3OF to sulphur dioxide and trioxide [165], at high temperatures, and to
carbon monoxide [174], on photolysis, have been described (Figure 8.52).
E Perfluoro-oxiranes (epoxides) [156, 158, 175]
Some reactions of epoxides with fluoride and perfluoroalkoxide ions were referred to in
Section IB, Subsection 2 (above), and the importance of polymers of these systems was
stressed. There are numerous publications or patents concerning the synthesis of these
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 259
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 259
FSO2CF2COF FSO2CF2CF2O−
FSO2CF2CF2OFi, ii
FSO2CF2CF2OCFClCF2ClFSO2CF2CF2OCF=CF2
iii
i, CsF; ii, F2; iii, CFCl=CFCl
i½137�
Figure 8.51
CF3OF + SO3 CF3OOSO2F + SO2FOOSO2F
CF3OF + CO CF3OCOF 86%hν
½165�
½174�
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, KOH, H2O/CH3OH, 30%H2O2, −78�C
CF3
OF F
F
25%i ½178�
Figure 8.53
CF2=CF2 + O2 (containing O3)
OF
F
F
F+ CF2CF2O
n
46% 18%
½181�
Figure 8.54
Bleaching powder has proved to be a very effective reagent for various epoxidations
[158, 182–184], and lithium t-butyl peroxide has been used as an epoxidising agent [185]
with electron-deficient alkenes (Figure 8.55).
A very unusual, but efficient, rearrangement of the dioxirane 8.56A to a diether 8.56B
occurs on heating, but the mechanism of the process is uncertain [186] (Figure 8.56).
An interesting use of trimethylamine as catalyst in combination with m-chloroperben-
zoic acid (mCPBA) or iodobenzene has been reported and is effective with alkenes having
perfluoroalkyl groups attached to the double bond [187] (Figure 8.57).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 260
260 Chapter 8
CF3CF2
F3C
CF3
CF2CF3
CF3CF2
F3C
F3C
F3C F3C F3C
F3C
F3C
F3C
F3C
F3C
CF3
CF2CF3
CF2CF3
O
Cl
CF3CF2 CF3
CF3
CF3
CF3 CF3
CF3
CF3
CF3
O
74%
Z : E = 1:1
OCl
O
Z + E
O
F
F
O
F CF3
F O
O
F F
O
O
F
i
i, t-BuOOLi, THF, −78�C to rt F
½158, 182�184�
½186�
Figure 8.55
F
F
O
O
F
F
OO
FF96%
i
ii
i, t-BuOOLi, THF, −78�C to rtii, Sealed tube, 220�C, 19 days
8.56A
8.56B
F3C
F3CF3C
F3C
F3C
F3C
CF3
CF3
CF3
CF3
CF3
CF3
½186�
Figure 8.56
Fluorinated oxiranes undergo a variety of ring-opening reactions with nucleophiles, the
most simple of which is formation of an acid fluoride. In most cases, terminal oxiranes
open to give an acid fluoride 8.58B rather than a ketone [156, 158] (Figure 8.58) and this
specificity of a ring opening is a puzzling feature; it may well be that, in forming an acid
fluoride, the strongest set of carbon–fluorine bonds is produced because the 2CF2O�
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 261
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 261
m-ClC6H4CO3H
m-ClC6H4CO2H
Me3N
Me3N-O
O
F
RFRF
RFRF
F CF3
CF3
RF = CF(CF3)2
½187�
Figure 8.57
RFCFCF2Nuc
O OF3C
F
F
F
RFCFCF2O
Nuc
−F− −F
−
RFCOCF2Nuc RFCFCOF
Nuc8.58A
8.58B
½156, 158�
Figure 8.58
group is isoelectronic with 2CF3. This would then be consistent with the well-known
order of decreasing carbon–fluorine bond strengths in the series 2CF3 >
2CF22 >CF2; see Chapter 7, Section IB.
Ring-opening oligomerisation of the oxirane derived from hexafluoropropene (see
Figure 8.47) forms the basis of the production of Krytoxt fluids (DuPont Co.), with
end-group stabilisation by direct fluorination etc. Clearly, achieving high-molecular-
weight material by this process is not easy.
For comparison, oxetanes are oligomerised in an analogous way to give intermediate
polyfluoro-polyethers that are then further fluorinated to give perfluoro-polyethers in the
process for the production of Demnumt fluids (Daikin Co.) [188] (Figure 8.59).
CF2=CF2 + (CH2O)nO
F
F
F
FH
H
F CH2CF2CF2O CH2CF2COFn-1
F CF2CF2CF2On
ii
i
iii
i, HFii, e.g. CsFiii, F2, 100−120�C
F
½188�
Figure 8.59
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 262
262 Chapter 8
Examples of other ring-opening reactions are illustrated in Figure 8.60.
F F
F
F
(CH3)3N
CH3OH +
F
FF
F3C
i, KF, 80�C, 4hr
+ F−
F−
[CF3CF2O]−
(CF3)2CFCOF
(CF3)2CCOFCF3CFCF2O−
N(CH3)3
CH3OH
[CF3CF(OCH3)COF]
CF3CF(OCH3)COOCH3
96%
N(CH3)3
++
97%
i, (CH3)3N, 100�C, 30hr
CF3COF + F−i
i
FF O
O
FF3C O
½179�
½189�
½178�
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).
FF
FF3C O
CF3C(C4H9)(OH).CF2C4H9
i, ii
[CF3C(O)CF2C4H9]C4H9Li+
i, BuLi, ii, H+
½156�
Figure 8.61
Ring opening with a strong protonic acid gives the corresponding alcohol [190] and this
is consistent with the idea that an intermediate carbocation, 8.62A, would be more stable
than 8.62B, where CF3 groups would certainly raise the energy of an adjacent carbocation
centre (Figure 8.62).
Conversely, cleavage with a Lewis acid catalyst gives a ketone [191, 192] (Figure
8.63). These are interesting reactions because they involve a 1,2-fluorine shift to a
positive centre (Figure 8.64), a process that is, of course, very well known for hydride
shifts. The conversion of hexafluoropropene oxide to hexafluoroacetone is probably the
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:06pm page 263
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 263
F
FF3C
F3C
O
H+
F
+ HF250�C
64hr(CF3)3COH
(CF3)2CCF2OH (CF3)2C(OH)CF2
++
8.63B 8.62A
FF3C
F3C
O
H+
½190�
Figure 8.62
OF
i, Al2O3, 150−300� C
OF
OC5F11
F
F
F
i, SbF5, 150� C, 18hr
i
iC5F11CO.CF3
½191�
½192�
Figure 8.63
O
F
Acid
C C
O
F
Acid
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 trifluoro-
methoxide, 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 hexafluoro-
acetone and hydrogen peroxide [107] (Figure 8.67).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 264
264 Chapter 8
2 CO + 3 F2AgF2
CF3OOCF3
2 (CF3)3COH + ClF3 (CF3)3COOC(CF3)3
C3F7COCl + t-BuOOH C3F7C(O)OOt-Bu
FC(O)OF + CsF CF2
O
O
O
F
F
(CF3)2C(OLi)2 + F2O
OF3C
F3C
O F
½194�
½194�
½194�
½195�
½196�
Figure 8.65
13COF213CF3O
OO
F F
13CF3O(OCF2O)nOC(O)F
13CF3OOC(O)FF
−F
nA
n = 1-3
13CF3OOCF2O
A
½197�
Figure 8.66
(CF3)2C(OH)OOH CF3OOH + CO2 + O2 ½107�
Figure 8.67
Also, intermediate peroxides are formed in the oxidation of perfluorinated alkenes,
e.g. in the photo-oxidation of perfluoroethene and perfluoropropene for the formation of
Fomblint (Ausimont Co.) perfluoro-polyether fluids [198, 199].
II SULPHUR DERIVATIVES [5, 7, 200, 201]
A Perfluoroalkanesulphonic acids
Trifluoromethanesulphonic acid is commercially available and is the most readily
obtained member of this series by electrochemical fluorination [202–205] (Figure 8.68),
since the yields of perfluoroalkanesulphonic acids decrease as the size of the alkyl group
increases.
The acids are very thermally stable; longer straight-chain derivatives are surface-active
[206]. This combination of properties appears to be responsible for the application of
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 265
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 265
CH3SO2ClEletrochemical
FluorinationCF3SO2F CF3SO2OH 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 ðH0Þ: CF3SO2OH (�13.8); FSO3H (�15.1); FSO3H=20%SbF5,
‘Magic Acid’ (�20); and H2SO4 (�11.1). Furthermore, the extreme electron-withdrawing
capacity of the CF3SO2 group [5, 209] is such that ðCF3SO2Þ2NH is the most acidic
amide known [4] and it leads to systems with remarkable C2H acidity, e.g.
ðCF3SO2Þ22CH2ðpKa ¼ �1Þ is more acidic than CF3CO2HðpKa ¼ 0:52Þ. Consequently,
perfluoroalkanesulphonic acids are outstanding Friedel–Crafts catalysts [208, 210]. More-
over, esters of trifluoromethanesulphonic acid, i.e. ‘triflates’, are super leaving groups
in nucleophilic displacement reactions and, as such, are extremely important in both
mechanistic and synthetic organic chemistry [208]. Significantly, the first example of
generating an aryl cation utilised both a triflate leaving group and the ionising ability of
trifluoroethanol as solvent [211] (Figure 8.69).
X
OSO2CF3
X X X X
OCH2CF3
X
i
i, 120�C, K2CO3, CF3CH2OHX = SiMe3
½211�
Figure 8.69
Moreover, the outstanding leaving-group ability of the nonofluorobutylsulphonyl
group, ‘nonaflate’, allows the conversion of hydroxyl to fluorine in some cases using
n-C4F9SO2F [212], which itself is obtained by electrochemical fluorination (Figure 8.70).
Triflate salts are important catalysts because the anions are poorly co-ordinating [214,
215] (Figure 8.71).
S
O O
C4F9SO2F 45%i
i, HF, E.C.F.
Ph(CH2)3OHii
Ph(CH2)3F 79%
ii, n-C4F9SO2F
½213�
½212�
Figure 8.70
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 266
266 Chapter 8
Me3SiCH2Li CH2(SO2CF3)2
[(CF3SO2)3C]3 M
[(CF3SO2)3CLi]i ii
i, (CF3SO2)2O, pentane, 0� Cii, t-BuLi (2 equiv), (CF3SO2)2O, −78� C
M2O3
M = Y, Sc
½214�
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).
(CF3SO2)2O CF3SO2OCF3
90%
Nuc-CF3
Nuci
i, Cat. SbF4(OSO2CF3)
½216�
Figure 8.72
Trifluoromethanesulphonic acid forms a very stable crystalline hydrate [205, 218] and
reacts vigorously with alcohols, ethers and ketones. Oxonium salts are formed and further
reaction may occur on heating (Figure 8.73).
CF3SO2OH + (C2H5)2O (C2H5)2OH(CF3SO3)
Figure 8.73
Perfluoralkanesulphonyl chlorides may be obtained from the corresponding iodides
[219] (Figure 8.74), and they will act as a source of perfluoroalkyl radicals under
pyrolysis or photolysis, by losing sulphur dioxide [220] (Figure 8.75).
n-C4F9I n-C4F9SO2Cl 80%i
i, SO2,Cl2,DMF,Ni
½219�
Figure 8.74
RFSO2Cl +RF Cl
SO2
CF3SO2Cl∆
∆
CF3Cl + SO2
CF3(CH3)3C
(CH3)3C�N=O
i
i, hν, or peroxides
N
O
CF3
½221�
½220�
Figure 8.75
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 267
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 267
Trifluoromethyl radicals may also be generated by electrolysis of salts of trifluoro-
methanesulphinic acid [222] (Figure 8.76).
CF3SO2 K−1e
E = 1.05VCF3SO2 CF3 + SO2
+1e
E = −0.8v
SO2
OMe OMe
OMe
OMe
OMeOMe
CF3
CF3
Total yield = ca.47%
½222�
Figure 8.76
Sulphur-containing compounds are also obtained from reactions involving fluoroalk-
enes. Polyfluoro-b-sultones are produced in reactions of fluoroalkenes with freshly
distilled sulphur trioxide [223, 224]; these sultones have a varied chemistry, including
nucleophilic ring opening to give sulphonic acid derivatives (Figure 8.77) (see
also Chapter 7, Section IID). This ring-opening reaction is important in the synthesis
of co-monomers for the production of Nafiont-type (DuPont) membranes [37]
(Figure 8.78). Resins of this type have allowed membrane cells to displace the ill-
famed mercury cells for chlor-alkali production. Also, Nafiont resin is a useful strong
acid and has been developed for solid-phase catalytic processes [225–227] (Figure 8.79).
CF2=CF2 + SO3
F
F
F
F 61%
i, F , (C2H5)3N
F
O
F
SO2
F
F
N(C2H5)3F
CO.FCF2SO2F
F (C2H5)3N
F
F
F
F 1, NaOH
2, Ion Exchange
F2CCO2H
SO2OH
F
F
F
F i
O
O
SO2
SO2
O SO2
½223�
½223�
½37, 223, 224�
Figure 8.77
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 268
268 Chapter 8
FCOCF2SO2F + F OCF2CF2SO2F
CF2=CFOCF2CF(CF3)OCF2CF2SO2F
i
ii
iii
Co-polymer
CF3
F
O
F
F
ii,
iii, CF2=CF2
i,
FCOCF(CF3)OCF2CF(CF3)OCF2CF2SO2F
iv, Hydrolysis
ivMembrane
∆, Na2CO3
½37�
Figure 8.78
n-BuONO2
R
NO2
15-98%i
R
+
i, Nafion H
C6H6 + CH2=CH2
i
i, Nafion H
C6H5C2H5
RSO3H ArH+i
RSO2Ar
30-82%R = alkyl or aryl
i, Nafion H, Reflux
½225�
½226�
½227�
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 + NaHSO3120�C
CHF2CF2SO3Na
CF3CF=CF2 + NaHSO3i
i, (C6H5COO)2, 120�C
CF3CFHCF2SO3Na 64%
½228�
½229�
Figure 8.80
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 269
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 269
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.
Sx + (CF3)2CFI243�C
[(CF3)2CF]2S 11% + [(CF3)2CF]2S2 34%
+ [(CF3)2CF]2S3 18%
½231�
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 CF3SSSCF3120�C ½232�
Figure 8.82
A series of cyclic sulphides is produced in reactions of fluoroalkenes and fluoroalkynes
with sulphur or sulphur halides [234–238]; some examples have been discussed in
Chapter 7 (Figure 8.83).
Sx + CF2=CF2
SS
SS
S
S
S
F
44% 10%
S
S
F 56%
N2
445�C
300�C 10hr
F ½234�
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).
Sx + CF2=CF2 + I2
S S
S
FF
39%
½236�
Figure 8.84
Direct syntheses of fluorocarbon–sulphur compounds from non-fluorinated starting
materials are limited, but bis(trifluoromethyl) disulphide may be obtained from carbon
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 270
270 Chapter 8
disulphide using iodine pentafluoride [239], or from thiophosgene using sodium fluoride
[240] (Figure 8.85).
CS2
IF5
195�C(CF3)2S2
76%
(CF3)2S3
7%
CSCl2
i, NaF, Sulpholan, 245�C
(CF3)2S2 + CS2
37%
i
½239�
½240�
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).
CH3SCH3 CCl3SCH3
PCl5 SbF5CF3SCH3
½242�
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, NaOCH3, 5−70�C
CH3SCF2CFClH
90%
ii, (CH3)2SO, KOH
CH3SCF=CFCl
CH3SCFClCFCl2CH3SCF2CF3iii, SbF3/SbF5
Cl2
i ii
iii
½243�
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).
CCl3SClNaF
SulpholanCF3SCl
PhMgBr + CF3SCl PhSCF3
Et2O52%
PhN(CH3)2 CF3SCl p-CF3SC6H4N(CH3)2 58%
½240�
½244�
½245�
Figure 8.88
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 271
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 271
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).
(CH3)2SElectrochemical
FluorinationCF3SF5 + (CF3)2SF4
CH3SHCoF3
250−275�CCF3SF5
CS2
F2/N2
48�CCF3SF5 CF3SF3 etc.
½246�
½247�
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 perfluoroalk-
anesulphonyl fluorides [250] (Figure 8.91).
CF3CF=CF2 + SF4 (CF3)2CFSF3 + [(CF3)2CF]2SF2CsF
100�C½249�
Figure 8.90
CF2=CF2 + SO2F2CsF
100�C(C2F5)2SO2 83%
CF3CF=CF2 + SO2F2CsF
Diglyme, 100�C(CF3)2CFSO2F etc
½250�
Figure 8.91
It has been shown that perfluoroalkylsulphur(II) compounds can be oxidised to corres-
ponding sulphur(IV) and sulphur(VI) compounds [251–254] (Figure 8.92).
Free-radical reactions of SF5Br provide a useful approach to sulphur(VI) compounds
[256] (Figure 8.93).
D Thiocarbonyl compounds
The most simple member of this class of compounds is thiocarbonyl fluoride [257, 258],
which is obtained from the thiophosgene dimer 8.94A, and then pyrolysis of 8.94B, to the
corresponding fluoro monomer [233] (Figure 8.94).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 272
272 Chapter 8
CF3SRF + ClF CF3SF2RF + Cl2−78�C
RF = CF3, C2F5, n-C3F7
(CF3)2SF2, −196�C
C2F6
(CF3)2SF2(CF3)2SO
Ar2S2i, ii, iii
ArSF5
Ar =
NO2
i, F2/N2(1:9 v/v), MeCN, −5�C
ii, F2, CH3CN, Micro-reactor
Ar =
F
NO2
iii, AgF2, CF2ClCFCl2, 60−130�C, Cu
½251�
½255�
½252�254�
Figure 8.92
SF5Br + CF2=CFPhhν
SF5CF2CFBrPh SF5CF2CF2PhAgBF4 ½256�
Figure 8.93
S
SCl
Cl
Cl
Cl S
SF
F
F
F2 CF2=S
i ii
i, SbF3/90�Cii, 457−500�C
8.94A 8.94B
½233�
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 + S445�C
(CF3)2C=S + HgF2
60%
½258�
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 273
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 273
C2F5CFICF3 (C2F5)CF3C=S
i, P2S5, 550�C
i ½258�
Figure 8.96
Hexafluorothioacetone does not readily form a hydrate, but dimerises readily, particu-
larly in the presence of base; high temperatures are then required to reverse the process
[258] (Figure 8.97).
600� C
Base
S
SF3C
F3C
CF3
CF3
2(CF3)2C�S 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 + F−
(CF3)2CF− Sx
(CF3)2CFS−
(CF3)2C=S
S
S
S
SO2F3CF3C
F3CF3C
CF3CF3
CF3CF3
(CF3)2C=SO2
ii, Quinuclidine
½259, 260�
Figure 8.98
Bistrifluoromethylthioketene has been obtained as a monomer; that is very unusual,
since thioketenes generally dimerise [261] (Figure 8.99).
EtOOC
EtOOC
COOEt
COOEt
i, SF4, HF, 125−200�C
S
S(CF3)2C C(CF3)2 70%
(CF3)2C=C=S 70%
750�C/1mm
i½261�
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 274
274 Chapter 8
S
S S
Ni
S
F3C F3C
F3CF3C
CF3 CF3
CF3CF3
CH2=CH2
S
S S
Ni
S
½262�
Figure 8.100
III NITROGEN DERIVATIVES
A Amines
Primary and secondary perfluoroalkylamines are relatively unstable systems with respect
to the elimination of hydrogen fluoride, although the situation is not as extreme as that
obtained with the corresponding alcohols. Consequently, CF3NH2 has been characterised
when generated at low temperatures [139] (Figure 8.101).
CF3NCl2 + HCl CF3NH2.HCl CF3NH2
Base ½139�
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 + NH3 HCF2CF2NH2
−2HFHCF2CN
N N
NR
R
R
R = CF2H
½230�
Figure 8.102
Addition of hydrogen fluoride [263, 264] to the imine CF3N5CF2 occurs and this
secondary system is reasonably stable, allowing some further reactions to be carried out
[263–265] (Figure 8.103). Other perfluorinated secondary amines have also been isolated
[266–268].
CF3N=CF2 + HF (CF3)2NH
(CF3)2NH
i, HNO3, (CF3CO)2O
(CF3)2N NO2i
½263, 264�
½264�
Figure 8.103
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 275
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 275
Systems in which the nitrogen is attached to carbon bearing only perfluoroalkyl groups,
rather than fluorine, are particularly stable but weak bases; for example, perfluoro-
t-butylamine is practically devoid of basic properties [269] (Figure 8.104). Diazotisation
of the amine gives a mixture of the alcohol and the nitroso derivative [270] (Figure
8.105).
(CF3)3CNO
i, H2/Pd black; ii, HI, Red P
(CF3)3CNHOHii
(CF3)3CNH2
i½269�
Figure 8.104
(CF3)3CNH2
i, HNO2, 0�C
(CF3)3COH + (CF3)3CNOi ½270�
Figure 8.105
Fluoroalkylbenzylamines are obtained by the Lewis-acid-catalysed reactions of fluoro-
alkylimines with aromatic compounds [270], and reactions also occur with alkenes [270,
271] (Figure 8.106).
(CF3)2C=NH + CH3OC6H5 CH3O C(CF3)2NH2
(CF3)2C=NH + CH2=CHCH3
i, AlCl3, 150�C
i, AlCl3, 100�C
CH2=CHCH2C(CF3)2NH2
(CF3)2C=NH + CH2=CHCH=CH2N
H
CF3
CF3i, 100�C, 13hr; ii, 150�C, 6hr
i
i
i, ii
½270�
½270�
½271�
Figure 8.106
The fluoroalkylbenzylamines are characterised by their particular inertness [270],
being devoid of the tendency towards oxidative decomposition that is generally charac-
teristic of amines. In fact, oxidation of methyl will occur in preference to that of an amino
group in these systems (Figure 8.107).
H3C C(CF3)2NH2 HOOC
i, Na2Cr2O7, H2SO4
C(CF3)2NH2
i½270�
Figure 8.107
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 276
276 Chapter 8
Perfluoro tertiary amines ðRFÞ3N are very inert systems and are more akin to perfluoro-
alkanes than amines. They are most directly obtained by electrochemical fluorination
[272, 273] (see Chapter 2, Section III) and, as inert volatile fluids, they are used
commercially as evaporation coolants for electronic apparatus.
Electron-diffraction studies on ðCF3CF2Þ3N have suggested susceptibility to attack at
the CF2 positions by electrophiles [274].
B N–O compounds
1 Nitrosoalkanes
Trifluoronitrosomethane may be obtained from photolysis of a mixture of trifluoroiodo-
methane and nitric oxide [275, 276] or from pyrolysis of trifluoroacetyl nitrite [277, 278]
(Figure 8.108).
CF3I + NO CF3NO 80%hν, Hg
(CF3CO)2O + N2O3 CF3COONO 92%
190�C
CF3NO + CO2
56%
½276�
½277, 278�
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).
CF3NOhν
CF3
NO
CF3NO
CF3
(CF3)2NO
(CF3)2NO CF3NO (CF3)2NONO + CF3
½276�
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].
CF3NO + CF2=CF2
N OF3C
F CF2CF2N(CF3)O n½280�
Figure 8.110
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 277
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 277
2 Bistrifluoromethyl nitroxide
Bistrifluoromethyl nitroxide, ðCF3Þ2NO, is a stable purple gas and is of particular interest
because, of course, nitroxides are stable free radicals. The nitroxide is prepared from
bistrifluoromethylhydroxylamine [283] by reaction with, for example, silver oxide [284]
(Figure 8.111) or potassium permanganate [285].
CF3NOhν
(CF3)2NONO (CF3)2NOH (CF3)2NOHCl, H2O AgO
Quantitative
½284�
Figure 8.111
A range of products containing ðCF3Þ2NO groups may be obtained by addition to
unsaturated compounds [286–289] (Figure 8.112).
(CF3)2NO + CF2=CFCF3 (CF3)2NOCF2CF(CF3)ON(CF3)2
i, 15 min., rt
F + (CF3)2NO C6F6-n[ON(CF3)2]n
n = 2,4,6i, Sealed tube, 150�C, 1−4hr
i
i½287�
½288�
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.
N OF3C
F
i, Si tube, 550�C, 5mm
CF3N=CF2
i[280]
(CF3)2NCOF CF3N=CF2 96%
i, Ni tube, 576�C
i[290]
(C2H5)2NH
i, Electrochem. fluorination; ii, (C5H5)2Fe
(C2F5)2NF C2F5N=CFCF3
i ii
[291]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 278
278 Chapter 8
Table 8.5 Contd
Reaction Ref.
(CF3)2C=NH + CCl4 (CF3)2CClN=CCl2 82%
ii
(CF3)2C=NCF3 + (CF3)2CFN=CF2
70 : 30 92% total
i
i, AlCl3, 65−100�C;ii, KF, Sulpholan
[292]
N
F
i, Mild Steel, 400−600�C
N
FN
CF3
F CF3CF2CF2CF=NCF3
i[293]
CF3CHFCF2N3 CF3CHFN=CF2 CF3CH=NCF3F
i, Pt, 270−280�C
i
[294, 295]
CBr2=NN=CBr2i, AgF2, 100�C
CF3N=NCF3 92%
AgF 70�C
CF2=NN=CFBr
i, AgF, 125�C
CF2=NN=CF2 33% overall
i
i
[296]
CCl2N=CCl2 2
HF NaF, 50�C
2CF2NHCF3 CF=NCF3 2
[297]
N
N
F
i, CoF3.CaF2, 80�CN
N
Fi
[298]
N
NF
i
N
NF
+F
N
NF
N
NF
N
NF
N
NF
N
NF
+ F2
i, CoF3.CaF2, 175�C[298]
N
NF
RF
RF
i
N
NF
RF
RF
83%
RF = CF(CF3)2i, CoF3.CaF2, 172�C
[299]
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
Polyfluoroaza-alkenes are even more susceptible to nucleophilic attack than
polyfluoroalkenes. Hydrolysis of CF25NCF3 occurs readily giving the isocyanate [302,
303], and a variety of reactions with nucleophiles have been recorded (Figure 8.113).
CF3N=CF2 CF3NCO 50%
i, H2O, 20�C, 24hr
CF3N=CF2 + CH2=CHCH2OH CF3NHCO2CH2CH=CH2 52%i
i, aq KF, Et2O
CF3N=CF2 + CH2=CHCH2OH CF3N=C(OCH2CH=CH2)2Et3N
i½302�
½304�
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.
CF3N=CF2
F(CF3)2N
i
ii
(CF3)2NCF=NCF3
(CF3)2COF
i, CF3N=CF2;ii, CsF, COF2, 100−150�C, 2hr
CF3N=CF2 + HgF2100�C, 15hr
[(CF3)2N]2Hg
½124, 305�
½264�
Figure 8.114
Contd
Table 8.5 Contd
Reaction Ref.
CF3CONHNHCOCF3 CF3CCl=NN=CClCF3
i
i, PhNMe2.HCl, POCl3
[300]
CF2=CFCF3
i, Et4N+N3
−, −5�C
CF3CHFCF2N3 + CF3CF=CFN3
Distil
N
F
FN
FF3C F3C
F
25%
<5% 25%
[301]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 280
280 Chapter 8
i
CF3N CF3N
CF3N
F
F
F
N
F3C F3C
F
F N
F
CF=NCF3
FN
CF3
N
NF
F
CF=NCF3
F
CF3
CF3
94%
ii
i, CsF, Sulpholan, −23�C
ii, CF3N=CFCF=NCF3
N
RF RF RF
F
N
F
N
F
Cs
i i
i, CsF, Sulpholan;ii, CH3I;iii, BF3.Et2O
RF = (CF3)2CF
8.114A 8.114B
ii iii
N
RF
F
CH3
8.114A + 8.114B Ratio 4:1
−F
CF3N=CF22 ½306�
½307�
Figure 8.114 Continued.
A remarkable rearrangement occurs in the conversion of 8.115A to 8.115B and a
mechanism has been advanced for the formation of a trifluoromethyl group [308] (Figure
8.115).
Stable salts of the ðCF3Þ2N�
anion have been described [309].
Oxaziridines have been obtained from perfluorinated aza-alkenes using a variety of
approaches, and they have been used in oxygen transfer and other reactions [310] (Figure
8.116).
Remarkably, perfluoroazapropene (8.117A) reacts with SbF5 to produce oligomers
[311, 312] (Figure 8.117). Further reaction of the cyclic trimer with SbF5 leads to the
loss of CF4 to give the stable cation 8.117B whereas, if the reaction is carried out in
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 281
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 281
N NF
N NF
N
N
N
N
F CF3
F F
F
N NF
N NF
F
N N
N
N
F F
F
F
FN N
N
N
F
F
F1
2
2
F
1
N N
N
N
FF3C
F
F
i
i, CsF, 150�C, 16hr
8.115A
8.115 B
½308�
Figure 8.115
CF3N=CF2 + CF3OOH CF3NHCF2OOCF3N
O
F3CF
F
+ COF2
BrCF2CF2N=CFCF3
O
NBrCF2CF2
CF3
F
O
NCF3CF2
CF3
F55 45:
i
i, m-CPBA, Sulpholan, 22�C
O
NRF
F
RF
R1SR2 R1SOR2 + RFN=CFRF
RF = n-C4F9
½310�
½310�
½310�
Figure 8.116
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 282
282 Chapter 8
CF3N=CF2 + SbF5
N
N
N
CF3
CF3
F (CF3)2NCF=NCF3
(CF3)2NCF2N=CFN(CF3)2
i, SbF5
N
N
NF3C CF3
−CF4, −F−
(CF3)2NCF
N
CFN(CF3)2
i, SbF5, SO2
−2CF4
2hr, 20�C
N
N
N
F3C CF3
CF3
F
F
F F
N
CF2F2C
F2C
NCF2
N
CF3
CF2
F2C
NC
N
CF3
CF3
F
F2CN
CN
CF3
CF3
F
N
N
NF3C CF3
CF3
F
CF2
NCF
NNF2C
CF3CF3
CF3
8.117B
8.117C
CF3N=CF2
8.117A
i
i
CF3N=CF2
F3C
F
½311�
½312�
½312�
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 283
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 283
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.
CF3CN C2F5N=NC2F5 90%i
i, AgF2, Ambient Temp.
C2F5CN C2F5CF2NCl2
i, ClF, −78 to −0�C
205�CC3F7N=NC3F7
85%
CF2(CN)2ClF
Cl2NCF2CF2CF2NCl2200−250�C
N NF
95%
i
½313�
½314�
½314�
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=NCF3hν 2CF3 + N2
2CF3 C2F6
½315�
Figure 8.119
E Diazo compounds and diazirines [316]
Stable diazoalkanes and diazirines (Figure 8.120, where X and Y are fluoroalkyl groups)
have been isolated, but no authenticated report is available of a diazoalkane where X or Y
is a fluorine atom, although difluorodiazirine is now well documented [316]. It has been
suggested that this is probably yet another result of the propensity of fluorine to favour the
formation of F2Cðsp3Þ bonds, rather than F2Cðsp2Þ, thus making the diazirine structure
thermodynamically preferred, although calculations have suggested that the diazo-
methane structure is slightly preferred for CF2N2 [317].
XC
Y
N NX
C
Y
N N
Diazoalkane
N
NX
Y
Diazirine
Figure 8.120
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 284
284 Chapter 8
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 + NH3
i, Pyridine, −25 to −30�C
(CF3)2C=NH 70%
(CF3)2C=NH + NH2NH2
i, P2O5, 0�C
(CF3)2C=NNH2 68%
(CF3)2C=NNH2
i, Pb(OAc)4, C6H5CN, 0�C
(CF3)2CN2 77%i
i
i
½103�
½103�
½318�
Figure 8.121
Diazotisation of hexafluoroisopropylamine has also been achieved [319] (Figure
8.122).
CF3CF=CF2 (CF3)2CFNO2
i, HF/HNO3; ii, H2, Pd, 70�C, 100atm
(CF3)2CHNH2 75%
(CF3)2CHNH2.HCl (CF3)2CN2 48%
i ii ½319�
½319�
Figure 8.122
Bis(perfluoroalkyl)diazoalkanes are surprisingly stable; for example, deliberate at-
tempts to detonate 2-diazoperfluoropropane failed [318]. It has been emphasised [316,
319] that this compound is less readily attacked by electrophilic reagents than diazoalk-
anes 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 hypo-
chlorite (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 F2C : and
CF3Þ2C : ,�
which have also been discussed earlier; see Chapter 6, Section IIIA.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 285
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 285
(CF3)2CN2 + CH2=CHCN
NN
F3C
F3C
F3C
F3C
CN
NH
N
CN
(Quant.)
(CF3)2CN2 + CH3C CCH3
60�C
NN
F3C
F3C
F3C
CH3
CH3
H3C
H3C
150�C
400�C
CF3
56%
½318�
½318�
Figure 8.124
CF2(NF2)2
i, (C5H5)2Fe, (C2H5)4NCl (or I)
N
NF
F
H2NCN(H2O)
i, F2, He, Buffered, 5−9�C
F2NCN 20%
F2NCN
N
N
F
F
F
F
N
NF
F
F
N
NF
F
CsF/24�C
i
i
½321�
½322�
½322�
Figure 8.125
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 286
286 Chapter 8
N
NF
F(CF3)2C(NH2)2
i, NaOCl, NaOH, 40−60�C
78%i
½323�
Figure 8.126
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294 Chapter 8
320 R.A. Mitsch, J. Heterocycl. Chem., 1966, 3, 245.
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Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:07pm page 295
Functional Compounds Containing Oxygen, Sulphur or Nitrogen and their Derivatives 295
Chapter 9
Polyfluoroaromatic Compounds
This chapter will deal mainly with the chemistry of highly fluorinated compounds,
although this will be prefaced by a more general summary of synthetic methods for the
introduction of fluorine into an aromatic system. A review of this topic by Brooke [1]
covers the area in considerable detail and we can only be selective in our discussion here.
I SYNTHESIS [1, 2]
A General considerations
An ideal process would, in principle, be one where elemental fluorine could be used as
indicated in Figure 9.1. Recent work with elemental fluorine has demonstrated that this is
a reasonable approach in some circumstances, e.g. when the opportunity for forming
isomers is limited. However, nucleophilic displacement of other halogens, or mobile
groups such as nitro, by fluoride ion, when the aromatic compound is susceptible to
nucleophilic attack, is a more versatile approach at the present time (Figure 9.2).
2ArH + F2 2ArF + HF
2HFElectrolysis
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(trifluoro-
methyl)benzene [6, 7], a reaction that was referred to in Chapter7, Section IIIB, Subsection 1.
6 CFBr3Pt
630−640� C9 Br2 + C6F6 55%
3 CF3C CCF3 C6(CF3)6
½4�
½6, 7�
Figure 9.3
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 296
296 Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
B Saturation/re-aromatisation
Examples of saturation and then re-aromatisation by dehydrohalogenation and
dehalogenation are given in Figure 9.4. Use of cobalt trifluoride [8] to form perfluorinated
C6Cl6i
i, F2, CF2ClCFCl2
C6ClxF12-x C6F6
C6F5ClC6F4Cl2C6F3Cl3ii, Fe, 330� C
x = mainly 5, 6, and 7
C6H6 C6H3F9 etc C6F6
KOH
C6H3F7 C6F5H
CH3
CoF3
CF3
CF3
FFe
460� C
CF3
CF3
F
H
H
H
H
Fi
i, Hg Cathode
2F−
CoF3
F
F
F
Fe
410� C
F
F
F
N NF
F
N
Fiii
i, Electrochemical Fluorinationii, Fe/600�C/,1mm
25%
ii
CH3
F
½16�
½17�
½18�
½13�
½19�
½15�
Figure 9.4
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 297
Polyfluoroaromatic Compounds 297
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).
S
H H
OH H
O
H H
H
SF
KOH
OF
KOH
O
KOH
H H
F
F
F F
½20�
½21�
½21�
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 reason-
ably regarded as electrophilic fluorinations are given in Figure 9.7. In the examples
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 298
298 Chapter 9
indicated, and others, the orientation of substitution is quite consistent with an electro-
philic aromatic substitution process.
F
"F" H
F H
H
F
F
9.6A
9.6B 9.6C
F H
Figure 9.6
COOH
F
F2
Solvent
COOH
FF
Solvent
98% H2SO4CH3CNCF2ClCFCl2
Yield, %
84530
NO2 NO2 NO2
Xi, F2, HCOOH, 10� C
X XF F F
X = OHX = F
70%53%
8%Trace
NO2 NO2 NO2
Me
i
Me MeF F F
81% 2%
i
i, F2, H2SO4, 10� C
½25�
½26�
½26�
Figure 9.7
Substitution in pyridine is more consistent with an addition–elimination process
(Figure 9.8).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 299
Polyfluoroaromatic Compounds 299
N N N
F
H
F F
i
i, F2, CFCl3, −78�C
−HF
N
i
NF
H
I
−HI
NCl Cl Cl F
N
I
Cl N F
F
b
b
a
70%
14%
i, IF5/2I2
a
½27�
½28�
Figure 9.8
The occurrence of radical intermediates is evident from the product of the fluorination
of benzene [29] and of tetrafluoropyrimidine [30] (Figure 9.9).
Xenon difluoride is reactive towards aromatic compounds [31], and selective fluoro-
desilylation using this reagent has also been reported [32] (Figure 9.10).
2 Replacement of 2Nþ2 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 de-
veloped that avoid isolating a solid diazonium salt [2] (Figure 9.12).
3 Replacement of 2OH or 2SH by F
Another alternative to the Balz–Schiemann reaction is now available through the thermal
decomposition of aryl fluoroformates or aryl thiofluoroformates [36–38], as indicated in
Figure 9.13. Fluoroformates are obtained in high yields but the pyrolysis step is quite
variable.
4 Replacement of Cl by F [39]
The most practicable and versatile laboratory and industrial route to polyfluoroaromatic
compounds involves the use of potassium fluoride in nucleophilic displacement of
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 300
300 Chapter 9
F F F F
n
F F F
n = 0, 20%n = 1, 40%
5% 8%
F
7%
N
NF
i
i, CoF3, CaF2, 183� C
N
NF
N
N
F
N
NF
+F
N
NF
Coupling etc
½29�
½30�
Figure 9.9
SiMe3 SiMe3
R
XeF
R
F
R
FXe
R
XeF2
CF3C6H5
XeF2meta-CF3C6H4F 71% para-CF3C6H4F 3% ½31�
½32�
Figure 9.10
ArH ArNO2 ArNH2
ArN2 BF4
HNO3
Ar BF4∆
−N2ArF + BF3
Figure 9.11
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 301
Polyfluoroaromatic Compounds 301
NH2COOH
N2COOH
F FCOOH
OHCOOH
i
i, NaNO2, HF/H2Oii, 58� C
ii ½2�
Figure 9.12
COCl2
i, AsF3, SbF3, or SiF4
COClF
ArXHCOClF
ArXCOF∆
ArF + COX
(X = O, S)or ArXCOCl
F
C6H5OH
i, COClF, Bu3N; ii, Pt Gauze, 800� C
C6H5OCOF
99%
iiC6H5F 70%
α-naphth.-OCOF∆
680� Cα
i
i
-naphth.-F 25%
½36�
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).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 302
302 Chapter 9
ArCl + KF ArF + KCl ½2�
Figure 9.14
C6Cl6(g) + 6KF(s) C6F6(g) + 6KCl(s)
∆H298 = −126 kJmol−1
C6Cl6(g) + 6NaF(s) C6F6(g) + 6NaCl(s)
∆H298 = +63 kJmol−1
½40�
Figure 9.15
NO2 NO2
Cl
Cl
F
F
71%i
i, KF, DMSO, phase transfer agent, heat
NO2 NO2
Cl F
82%i
i, KF, DMF, heat
Cl Cl
½2�
½2�
Figure 9.16
Cl F
i, KF, 195� C, NMP
Cl
Cl Cl
+ C6F4Cl2 + C6F5Cl
23% 34% trace
i ½42, 43�
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 perfluoro-
naphthalene from the perchloro compound (Figure 9.18).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 303
Polyfluoroaromatic Compounds 303
Cl Cl
i, KF, 235� C, Sulpholan
F F 52%i
½44�
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
NCl
N
N
NCl
H
F
N
N
N
H
Cl
Cl
Cl
F
−HCl
N
N
N
Cl
Cl
F
N
N
NF
HF etc
N N
N
ClN N
N
F
i, NaF, 245� C, Sulpholan
74%
HF
i½45�
½46�
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).
N
Cl
N
F
N
F
ClCl Cli
10 : 1i, KF, 200� C, Sulpholan
½47�
Figure 9.20
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 304
304 Chapter 9
C6F3Cl3 C6F6 11% + C6F5Cl 34% + C6F4Cl2 28%
+ C6F3Cl3 18% + C6F2Cl4 0.4%
C6Cl6 C6F6 21% + C6F5Cl 20% + C6F4Cl2 14%
+ C6F3Cl3 12%
i
i, KF, Autoclave, 450−500� C
N
Cl
N
F
N
F
Cl
68% 7%
i
i, KF/KCl Melt, 780� C
i, KF, Autoclave, 480� C
i
½40�
½48�
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 per-
fluoroquinoline [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.
N N
Cl4
N
Cl Cl
N
F F
Cl2, AlCl3
140−160� C87%
78%
71%KF
480˚C
PCl5 315� C
½52�
Figure 9.22a
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 305
Polyfluoroaromatic Compounds 305
N
F F
F F F F F F
F F
N
FN
N
NF
N
NF
N
N
F
N
N
N
N
N
N
N
N
NF
NN
NF
NN
NF
Figure 9.22b Perfluorinated heterocyclic systems obtained by Halex procedures [53]
II PROPERTIES AND REACTIONS
A General
Perfluorobenzene and perfluorobenzenoid compounds have boiling points that parallel
those of the corresponding hydrocarbons but, for perfluoropyridine and other perfluoro-
azabenzenoid compounds, the values are significantly lower than for their hydrocarbon
counterparts (Table 9.1).
The base strength of nitrogen in these perfluorinated systems is very considerably
reduced compared with their hydrocarbon counterparts so that, in the nitrogen systems, it
is clear that substitution of hydrogen for fluorine usually produces an overwhelming
reduction of intermolecular forces, which more than offsets the increase in molecular
weight.
Table 9.1 Boiling points of perfluoroaromatic compounds in comparison with hydrocarbon
counterparts
Compound Boiling point (8C) [54]
Boiling point of
perfluorinated derivative (8C) Ref.
Benzene 80.1 80.2 [55]
Toluene 110.6 102–103 [11]
p-Xylene 138 117–118 [11]
Pyridine 115.5 83.3 [55]
Quinoline 237.1 205 [52]
Isoquinoline 243.2 212 [52]
Pyridazine (1,2-diazine) 208 117 [56]
Pyrimidine (1,3-diazine) 123.5 89 [55]
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 306
306 Chapter 9
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 pre-
pared that undergo various nucleophilic aromatic substitution reactions. Taking perfluoro-
benzene 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 particu-
larly evident in this area how the chemistry of fluorocarbon systems helps to extend the
mechanistic framework of organic chemistry.
NucF
F Nuc
F
Nuc
F
9.23A
k1
k−1
k2
F5
Figure 9.23
1 Benzenoid compounds [1]
Hexafluorobenzene will react with a wide range of nucleophilic reagents, leading to
pentafluorophenyl compounds; some of these are given in Table 9.2, together with
some similar chemistry of other benzenoid systems. From these direct substitution
products, which are generally obtained in high yield, routes have been developed to
other important functional derivatives (Table 9.3). Some of these are included but other
important reactions, e.g. formation of organometallic compounds, will be covered in later
discussion and are not illustrated in this table.
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 307
Polyfluoroaromatic Compounds 307
Table 9.2 Reactions of perfluorobenzenoid compounds with nucleophilic reagents and some simple
interconversions
Reaction Ref.
Reactions starting from hexafluorobenzene
i, NaOCH3, MeOH; ii, AlCl3, 120� C
C6F5OCH3ii
C6F5OH
72% 58%
i
[63]
C6F5OH
i, KOH, t-BuOH 71%
i[5]
ii, Raney Ni, n-BuOHi, NaSH, Pyridine;
C6F5SH C6F5Hiii
[64]
ii, Cl2, H2O2
C6F5SO2Clii
[65]
ii, Me-nitrosourea, KOH, Et2O; iii, H2O2, CH3COOH
C6F5SCH3 C6F5SO2Meiiiii
[65]
ii, CF3CO3H, CH2Cl2i, aq. NH3, EtOH, 167� C;
C6F5NH2 C6F5NO2 85%i ii
[66, 67]
ii, HCl, Et2O
C6F5NH2HClii
[68]
NaOClC6F5N=NC6F5
[69]
ii, HCO3H, CH2Cl2
C6F5NO2 48%ii
[70]
ii, NaNO2, 80% HF; iii, Cu2Br2, HBr
C6F5N2 Fiii
C6F5Brii
[68]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 308
308 Chapter 9
Table 9.2 Contd
i, NH2NH2.H2O, EtOH; ii, Ca(OCl)2, C6H6
C6F5NHNH2
71%
C6F5C6H5
74%
i ii
[71]
NaOH
H
H
F 90% [72]
NO2Cl52%C6F5N3 [71]
LiAlH4C6F5H
[73]
i, (CH2OH)2, NaOH; ii, K2CO3, DMF, Reflux
F
OCH2CH2OH
ii
O
O
Fi [74]
Reactions of other perfluorobenzenoid compounds
i, NH2NH2, aq. EtOH; ii, LiAlH4, Et2O; iii, Fehling�s soln.
NHNH2
F F F F
ii
H
F F
iii
i
[75]
F F
i, LiAlH4, THF
F F
H
Hi
[76]
F F
i, C6F5O , DMAC
F F OC6F5
90 %
i[77]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 309
Polyfluoroaromatic Compounds 309
Table 9.2 Contd
F F
i, NH2NH2, aq. EtOH
F FH2NHN NHNH2
F FH2NHN
18%
72%
i
[78, 79]
a DMAC, dimethylacetamide.
Table 9.3 Nucleophilic substitution in C6F5X compounds
Orientation of product(%)
Substituent, X Nucleophile Ortho Meta Para Reference
H LiAlH4 7 1 92 [80]
NaOMe/MeOH 3 — 97 [81]
Me MeLi — — 100 [82]
MeO� — — 100 [83]
NH3 — — 100 [83]
CF3 LiAlH4 — — 100 [84]
NH3 — — 100 [84]
EtO� — — 100 [84]
NH2 NH3 — 100 — [66, 73]
NH3 — 87 13 [85, 86]
MeNH2 — 88 12 [86]
NO2 NH3 (ether) 70 — 30 [67]
NH3 (liq.) 33 — 67 [87]
MeNH2 (benzene) 77 — 23 [88]
MeOH ðEt2OÞ 8 — 92 [89]
MeOH ðEt2OÞ 50 — 50 [88]
NH2 NH3 — 100 — [66, 73]
NH3 — 87 13 [85, 86]
MeNH2 — 88 12 [86]
OH KOH — 100 — [73, 83, 90]
Orientation and reactivity: [1, 91]: Reactions of pentafluorophenyl derivatives are
particularly interesting because of the unusual orientation of substitution observed. This
area was pioneered by workers at the University of Birmingham (UK) [1, 17] and, in most
cases, for substitution in C6F5X derivatives the main (>90%) product arises from
displacement of a fluorine atom that is para to the substituent group X (for example,
where X ¼ H, CH3, SCH3, CF3, NðCH3Þ2, SO2CH3, NO2, C6F5, OC6F5, etc.). In a few
cases ðX ¼ NH2, 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 electron-
withdrawing groups activate; for example, C6F5NH2 and C6F5O� are strongly deacti-
vated. The magnitude of these effects, such as the relative reactivities of
NaOCH3ðCH3OH at 608C), have been recorded [92] and some relative rates towards
sodium pentafluorophenoxide (dimethylacetamide, 1068C) are shown in Table 9.4 [93].
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 310
310 Chapter 9
F
X Nuc
Nuc
F
X
F
X
Nuc
Nuc
+ F
+ F
e.g. X = H, CH3, CF3
e.g. X = NH2, O
Figure 9.24
Table 9.4 Relative rates of reaction of
C6F5X towards NaOC6F5, DMAC [93]
X Relative reaction rate
CF3 2.4 � 104
CO2C2H5 2.9 � 103
C6F5 7.3 � 102
Br 39
Cl 32
H 1
F 0.91
Clearly, therefore, there is a very wide spread in reactivity, as in electrophilic substitu-
tion 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 estab-
lish 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 311
Polyfluoroaromatic Compounds 311
F
Fδ
Nuc δ
ortho
meta
para
F
Nuc
ortho
meta
para
+ F
Figure 9.25
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).
Table 9.5 Ratios of measured rate constants (CH3O�=CH3OH, 588C) [91, 94]
Benzene derivatives compared kF=kH
F vs
F
F
H
para-F / para-H
(ie k/6)a
(Position of nucleophilic attack)
0.43
F vs
H
F
H
ortho-F / ortho- H
F H
57
F vs
H
F
H
meta- F / meta- H
F H
106
a Statistically corrected.
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 312
312 Chapter 9
C C F F
Strongly Stabilising Slightly de-stabilisingfor a planar system
Nuc F
F
δ −
δ −
δ −
F
Nuc F F
δ + F
δ −
meta-F para-F ortho-F
9.26A 9.26B 9.26C
Nuc
C
Figure 9.26
Taking the Meisenheimer complex as a model for the transition state associated with step
k1 (Figure 9.23), we can easily see why meta-F, which is adjacent to centres of high charge
density, is strongly activating. Likewise, the slightly deactivating influence of fluorine at
the para position (9.26B) is entirely consistent with the effect of fluorine directly attached
to a planar carbanion centre. However, we would have expected ortho- and para-F to have
similar effects, whereas this is clearly not the case. Consequently, it has been argued that the
effect of ortho-F (9.26C) is predominantly a polar influence, enhancing the electrophilic
character or ‘hardness’ of the carbon atom under attack. We might expect that the influence
of this ortho-F effect would diminish as the reactivity or ‘hardness’ of the nucleophile is
reduced, and the data contained in Table 9.6 support this case.
We can see, therefore, that nucleophilic attack para to the substituent in C6F5X
compounds (Table 9.3) stems from maximising the number of activating fluorine atoms
[95] (Figure 9.27), where attack para to X involves all of the ring fluorine substituents in
the positions that maximise their activating influence.
X
Fo o
m m
X
Fp o
m
o
4- activating F 3- activating F
Figure 9.27
Table 9.6 Comparison of kF=kH
Ortho Meta Para
MeO�=MeOH, 588CBenzene derivatives 57 106 0.43
Pyridine derivatives 79 30 0.33
NH3/dioxane, 258CPyridine derivatives 31 23 0.26
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 313
Polyfluoroaromatic Compounds 313
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).
pm
pp para
meta
ortho
F Nucpm
δ −
δ − δ −δ −
δ −pp
pm meta
ortho
orthopp
δ −δ −
δ −δ −
δ −
F
Nuc
pmF F F F
4- activating F 5- activating F
Figure 9.28
Clearly, attack at the b-position maximises the influence of fluorine substituents. These
same approaches can be used to account for the orientation of substitution in other
systems (Figure 9.29).
FF
F
F
FF
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 C6F5X 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).
NO O
H
NH2
F
½96�
Figure 9.30
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 314
314 Chapter 9
C6F5COOH
C
OBrMgO
F
MgBr
NHPh2PhNHMgBr
C
OBrMgO
F
MgBr
F
NH
Ph
C
OHO
F
NHPh
H
½97�
Figure 9.31
2 Heterocyclic compounds
Pyridines and related nitrogen heterocyclic (azabenzenoid) compounds: Polyfluoroaro-
matic nitrogen heterocyclic systems are all activated, relative to the corresponding
benzenoid compounds, towards nucleophilic aromatic substitution. The magnitude of
this activation is illustrated by the effects of a ring nitrogen, relative to C2F at the
same position, for attack by ammonia [91] (Figure 9.32).
NN
N
N
N N
N
NF F FF
1 37.4 2000 >105
Figure 9.32 Ratio of rate constants for attack by NH3 / aq. dioxane, 258C
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
N
F
OCH3 OCH3
OCH3 CH3O OCH3
OCH3
N
F
N
F
i, CH3ONa, CH3OH
i i[98, 99]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 315
Polyfluoroaromatic Compounds 315
Table 9.7 Contd
N
F
NH2
aq. NH3
N
F
N2 F
N
F
Br
CuBr
i, aq. HF, NaNO2, −20 to −25� C
N
F
NO2
CF3COOOH
N NF F
Cu, 230� C
i
[98, 100, 101]
N
F
OH
N
F
OH
10 1
N
F
OCH3
N
F
OCH3
i, KOH, t-BuOH; ii, KOH, CH3I, 100� C
i ii[102]
N
F
I
i, NaI, DMF, 150� C
i[103]
N
F
i, [π−C5H5Fe(CO)2]
π−C5H5Fe(CO)2
i [104]
Perfluoroisoquinoline
NF FLiAlH4
H
[105]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 316
316 Chapter 9
Table 9.7 Contd
NF F
OCH3
NF F
OCH3
CH3ONa
CH3O
CH3OH
[105]
NF Faq. NaOH
OH
NHF F
O
[106]
Perfluoroquinoline
N
F F
N
F F
i, CH3ONa, CH3OHOCH3
OCH3
AlCl3, 120� C AlCl3, 120� C
N
F F
N
F F
OH
NH
F F
O N
F F
O
OH
CH3
N
F F
OCH3
CH2N2, Et2O
i, H2SO4
ii, H2O
i
[52, 105, 106]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 317
Polyfluoroaromatic Compounds 317
(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 penta-
fluoropyridine (Figure 9.34).
Table 9.7 Contd
Miscellaneous
Perfluoro-3,3’-bipyridyl
i
OCH3
F
N N
F 88%
i, CNH3ONa, CH3OH
[107]
Perfluoropyridazine
i
N
NF
CH3O
N
NCH3O
CH3O
F also tri- andtetra-methoxyderivatives
i, CH3ONa, CH3OH
[108]
C6H5SNa
N
N 85%(SC6H5)4[108]
H+, H2O
N
NF
OH
N
NF
OH
Polymer[109]
Perfluoropyrimidine
aq NH3
N
N
NH2 NH2
F
N
NFor
H2N
[110]
N
N
OCH3
F
H3CO
i, CH3OH, Na2CO3
i[110]
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 318
318 Chapter 9
N
F
H
NH3/Dioxane
N
F
H
N
F
H
NH2
H2N
3.7 1
½76�
Figure 9.33
N
FNuc
F
δ+
δ−
o
m
o
m
N
Fo
m
o
m
F Nuc
N
F
Nuc
F
Figure 9.34 The activating influence of the F-substituent is maximised
The positions of the most favourable monosubstitution in attack by nucleophiles are
shown in Figure 9.35 for various systems; it is clear that directing effects by F have a
major influence on the orientation of attack.
N
F
N
FFN
FF FF
N
NF
N
NF
N
N
F
N
NFF
N
N
FF
N
N
FF F
cf
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).
N
F
Br
aq NH3
N
F
Br
NH2
½100�
Figure 9.36
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 319
Polyfluoroaromatic Compounds 319
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).
N
F
i, KOH, t-BuOHN
F
OH
X X X X
N
F
X X
OH
i
X = F, 90 10
X = Cl, 30 70
½102�
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.
N
F
i, NH3, Et2O
N
F
NH2
N
F
NH2i
N
F
NH2
NO2
27% 48% 25%
NO2 NO2
½101�
Figure 9.38
There are other cases [102, 107] where the subtle interplay of solvent and steric effects
has a profound effect on orientation of substitution.
Polysubstitution: Most groups introduced by nucleophilic substitution are subsequently
electron-donating and therefore deactivating towards further attack; for example, attack
on perfluoropyridine by methoxide becomes progressively more difficult but eventually
leads to 2,4,6-trisubstitution [98, 99] (Table 9.7). In this case R in 9.39A and 9.39B
(Figure 9.39) is electron-donating and so 9.39A is preferred. Examples will be discussed
later where the substituent is electron-withdrawing, for example, R ¼ CF2CF3, and then
2,4,5-trisubstitution occurs, indicating that in this case 9.39B is preferred to 9.39A.
The fact that the order of nucleophilic substitution is as indicated in Figure 9.40
allows the use of polyhalopyridines for synthesis of heterocyclic systems with unusual
substitution patterns [111]. Moreover, when this methodology is applied in combination
with palladium chemistry, the possibilities are extensive [112, 113] (Figure 9.41).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 320
320 Chapter 9
N
F
RF F
F
Nuc R
9.39A
N
F
RF F
F R
9.39B
Nuc
Figure 9.39
N
F
1
23
Figure 9.40
Remarkably, we note that orientation of substitution in 2,4,6-tribromodifluoropyridine
depends critically on the nature of the nucleophile. So-called ‘hard’ nucleophiles, e.g.
�OCH3 and NH3, give exclusive attack at the ‘hard’ electrophilic centres, i.e. C2F,
whereas ‘soft’ nucleophiles displace bromine. This is further evidence for the importance
of ion–dipole interactions, regarding attack at C2F bonds. Reactions of perfluoro-quinoline
and -isoquinoline with hard and soft nucleophiles have also revealed a sensitivity towards a
change in orientation of attack with the nature of the nucleophile [114] (Figure 9.42).
To account for these results, it has been suggested that the 1-position, i.e. the position
adjacent to the ring N, is the harder electrophilic site [114].
In the quinoline system the nature of the substituent groups also can govern the position
of entry of a nucleophile. When R in 9.43A (Figure 9.43) is electron-donating, methoxyl
for example, then a 2,4,7-trisubstituted compound 9.44A is obtained (Figure 9.44),
because 9.43A is preferred to 9.43B; but when R is electron-withdrawing, CFðCF3Þ2 for
example, then a 2,4,6-trisubstituted compound 9.44B is obtained [115] because perfluoro-
alkyl 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 321
Polyfluoroaromatic Compounds 321
N
Fi
N
F
Br Br
Br
N
F
H H
H
ii
i, HBr/AlBr3, 150� C; ii, Pd/C/H2(4Bar), Et3N, CH2Cl2, rt
N
F
Br Br
Br
Nuc
NBr Br
BrX1 X2
Nuc = NaOMe X1 = X2 = OMe
Nuc = NH3 X1 = F, X2 = NH2
N
F
Br Br
Br
i
N
F
Br
i, CuI/(Ph3P)3PdCl2, Et3N, RC CH (R = C3H7 or Ph)
C CRRC C
N
FNuc
N
F
Br Y2
Y1
Nuc = Et2NH; Y1 = Et2N, Y2 = Br
Y1 = Br, Y2 = Et2N
Y1 = PhS, Y2 = Br
3 :
2
Nuc = PhSH;
Br
Br Br
½112�
½112�
½112�
½112�
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 322
322 Chapter 9
NF F
NF F
NF F
NF F
X
X X
X
9.42A 9.42B 9.42C
Nucleophile
HS , DMF/(CH2OH)2 100%
PhS , EtOH 99% 1%
MeO , MeOH 93% 7%
4-NO2C6H4O , EtOH 100%
(X = SH)
(X = SPh)
(X = MeO)
(X = 4-NO2C6H4O)
Nuc
½114�
Figure 9.42
N
F F
N
F F
Nuc
9.43A 9.43B
FNuc
F etc
R R
etc
Figure 9.43
N
F F
OCH3
OCH3
OCH3
OCH3N
F F
CH3O
i, CH3O , CH3OH
N
F F
CF(CF3)2
CF(CF3)2 N
F F
CF(CF3)2
CF(CF3)2
CH3O
i
i, CH3O , CH3OH
i
9.44A
9.44B
½116�
Figure 9.44
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 323
Polyfluoroaromatic Compounds 323
N F
Acc
N F
Acc.
Nuc
N F
Acc.
Nuc
−F
N Nuc
Acc.
Acc. = Electron Acceptor
F F F
F
Figure 9.45
N
NF
N
NF
N
NF
N
NF
N
NF
N
NF
H
H2SO4
MeOMeOH
Et3OBF4
OMe
OMe
Et
MeO
MeO
70%
H2O
MeOH 35%
N
F F
N
F F
OMe N
F F
OMe
N
F F
H
N
F F
OMe
i
ii
iii
i, = MeONa/MeOH ii, = c. H2SO4 iii, = MeOH/Slow dilution
O
Et
½108, 109�
Figure 9.46
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 324
324 Chapter 9
9.47A 9.47B
CN
H F
NucCC
F F
Nucδ+
δ −
Figure 9.47
N
F F F F FF
N NCl
Cl
Cl
23% 57%
i, HCl, 100� C, Sulpholan
N
F Fxs BCl3
140� C
xs BBr3
150� CN
F
N
F
Br
F
Br
Cl
F
Cl
88% 91%
i½117�
½118�
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 poly-
fluoro-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 polyfluoro-
alkyl 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 325
Polyfluoroaromatic Compounds 325
N
N
F
Br
Br
i
iiN
N
F
C CC3H7
C CC3H7
i, CuI, (Ph3P)3PdCl2, Et3Nii, C3H7C CH
½112�
Figure 9.49
CF3CF=CF2
N
F
i, KF, Sulpholan
N
F
N
F
RF
RF RF
RF
RF
RF
F CF2=C CF3 C
CF3 C ArF F CF C Ar F
cf C ArH C Ar H
i
CF2=CF2
N
F
N
F
N
F
i, KF, Sulpholan
i
RF = CF(CF3)2
RF = CF2CF3
½120�
½121�
Figure 9.50
The rather complicated system that results in the pyridine system, after the trisubstitu-
tion stage has been reached using perfluoroisopropyl anions [116, 122–124, 128], is shown
in Figure 9.51. At lower temperatures, after disubstitution, further attack on 9.51D is
kinetically preferred at the 5-position through 9.51B, with the perfluoroalkyl groups now
controlling the orientation, as explained earlier. However, at higher temperatures, the
process becomes reversible with attack by fluoride ion occurring at the 5-position in
9.51A, leading to displacement of a perfluoroisopropyl group that can then re-enter, at
higher temperatures, at the 6-position via 9.51F. Attack by fluoride ion can also occur at the
4-position in 9.51A, giving the 2,5-derivative 9.51C. Finally, the situation is further
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 326
326 Chapter 9
complicated by the fact that the perfluoroisopropyl anion is in equilibrium with the
perfluoroalkene and this produces oligomers (see Chapter 7). The crowding that arises
from a perfluoroisopropyl group is reflected by the 19F NMR spectra where, for example,
for the compound 9.51D at �408C two geometric isomers 9.51D1 and 9.51D2 may be
detected [125, 126, 129], with the 4-substituent being essentially in two conformations.
−F−
F−
N
F
F−
N
F
F
N
FF
N
F
N
FCF(CF3)2 CF(CF3)2
RF
RF
RF
RF
RF
RF
RFRF
RF
RF
RF RF
RF RF
RF
RF
RF
RF
RF
N
F
N
FF
F
9.51A
9.51B
9.51C 9.51D
9.51E 9.51F
(CF3)2CF−F
−
CF3CF=CF2
Dimers and Trimers
RF = CF(CF3)2
CF3CF=CF2
½116, 122, 123�
Figure 9.51
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 327
Polyfluoroaromatic Compounds 327
N
F
CF CF3
CF3
CF3F3C
F N
F
C
CF3
F
F3C
F3C
F3C
F
9.51D1 9.51D2
½125, 126, 129�
Figure 9.51 Continued.
The 2-substituent is aligned preferentially with the CF3 groups towards nitrogen and it is
understandable, therefore, that the trisubstituted isomer 9.51E is more stable than 9.51A.
Tetrafluoroethene leads only to the 2,4,5-trisubstituted compound [124], which does
not rearrange, whilst perfluoroisobutene gives only the 2,4,6-trisubstituted compound; the
2,4,5-isomer, in this case, is probably very crowded. This variation in the orientation of
trisubstitution products obtained with the alkene used is related to the reversibility of the
process and to the crowding occurring in the 2,4,5-isomer. Carbanion stabilities decrease
in the series ðCF3Þ3C� > ðCF3Þ2CF� > CF3CF�2 and therefore reversibility and crowding
also follow this series (Figure 9.52).
CF2=CF2
N
F
i, CsF, Tetraglyme, 80�C
N
F
RF
RF
RF
N (RF)n
CF2=C(CF3)2
N
F
N
F
RF
RF RF
i
i
i, CsF, Tetraglyme
RF = CF2CF3
RF = C(CF3)3
½121, 124�
½124�
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 intramolecu-
lar, depending on the system. However, intramolecular anionic migrations of polyfluoro-
alkyl 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 328
328 Chapter 9
arising from nucleophilic attack at N in 9.53B, accompanied by loss of fluorine from a
tertiary site (Figure 9.53). A similar process occurs in the reaction of 2,3-dimethylbuta-
diene with 9.53B, giving the unusual spiro system 9.53D [131] (Figure 9.53), but without
the loss of fluorine.
NN
NCl
RF
RFRF
RF
RFRF RF
RF
RF
NN
NN
NN NN
N
CCF3F3C
F
9.53A 9.53B 9.53C
RF = C(CF3)3
NN
N
RFRF RF
RF
RF
RFRF
RF
RF
9.53B
i
i, CH2=CH(CH3)CH(CH3)=CH2
9.53D
NN
N
H3C CH3
NN
N
H3C CH3
½130�
½131�
Figure 9.53
Recent methodology, using amines as initiators to provide the active fluoride ion, inthe absence of a solvent, has made access to these sytems on a large scale quite
feasible [115].
A recent exciting development [132, 133] of this chemistry involves conversion of
perfluoro(4,5-di-isopropyl)phthalonitrile to corresponding metal perfluorophthalocyanine
complexes; for example, when perfluoro(4,5-di-isopropyl)phthalonitrile was melted with
zinc acetate at 1808C, a blue-green solid was obtained which was established as the
phthalocyanine derivative. These perfluoroalkyl derivatives are much more soluble than
other halogenated phthalocyanines and, moreover, they appear to be excellent sensitisers
for the production of singlet oxygen.
Reactions involving chlorotrifluoroethene and bromotrifluoroethene introduce further
complexities which are summarised in Figure 9.54 [134]. Direct substitution may occur
giving 9.54A, but this is frequently accompanied by loss of Cl or Br from the side chain
to give a pentafluoroethyl derivative 9.54B. Exchange is also possible (when X ¼ Br) to
give 9.54C, together with a vinyl anion that may then react to give 9.54F, which is also
able to form an anion 9.54E, and this anion can finally give a diaryl derivative 9.54D.
Results relating to this scheme are shown in Table 9.8.
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 329
Polyfluoroaromatic Compounds 329
CF2=CFXF
CF3CFX
X = Cl, Br
CF3CFX
F + ArFCFXCF3F
ArFCF2CF3
ArFF
CF2=CFX
CF3CFX2 + CF2CF
ArFF
ArFCF=CF2ArFCFCF3
F(ArF)2CFCF3
9.54A 9.54B
9.54C
9.54D 9.54E 9.54F
½134�
Figure 9.54
Table 9.8 Polyfluoroalkylations and related reactions
Reaction Ref.
N N
N
C3F6N N
N
F [CF(CF3)2]nF3−n
CsF
200−300�C
n = 1, 39%; n = 2, 51%; n = 3, 5%
[135]
N
N5 C3F6F
i, CsF, Sulpholan, 70� C
N
NF
RF
RFN
NF
RF
RF RFN
N
RF
RF RF
RF
6% 81% 3%
RF = CF(CF3)2
i+ +
[136]
N
F CF3CF=CFCF3
N
F
RF
RF
i
i, CsF, Sulpholan, 100� CRF = CF(CF3)CF2CF3
[137]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 330
330 Chapter 9
Table 9.8 Contd
N
NF CF2=CFCl
N
NF
CF3CF2
N
NCF3CF2
F
CF3CF2
i
i, CsF, Sulpholan, 90�C 57% 19%
[134]
N
F CF2=CFBri
i, CsF, Sulpholan, 90� C
N CFCF3F
2
+ CF3CFBr2 [134]
N
NF CF2=CFBr
i
i, CsF, Sulpholan, 90� C
N
NF
CF3CF2
N
NF
CF3CF2
CF3CF2
[134]
N
F CF3C CCF3i
N
F
CF3CC
F
CF3
N
F
CF3CC
CF3
Fn
n = 2 and 3i, CsF, Sulpholan, 110� C
[138]
i, CsF, SulpholanN
F EtO2CC CCO2Eti
N
F
EtCO2C
F
CO2Et
[138, 139]
Fi F
CF3CC
CF3
Fn
CN CN
i, CsF, DMF, 125� C
CF3C CCF3 [140]
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 331
Polyfluoroaromatic Compounds 331
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 SN20 type of displace-
ment of fluorine from 3-trifluoromethylquinoline occurs in reactions with sodium eth-
oxide [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.
N
CF3
N
CF2
HEtOOEt
i
i, NaOEt/EtOH/Reflux
N
CF2OEt
−F
N
CF=OEt
N
C(OEt)3
EtO etc
H2O
N
CO2Et
½141�
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 332
332 Chapter 9
ate is isolated before cyclisation. Polycyclic systems may be obtained from ortho-difunc-
tional compounds (Figure 9.61).
N
NF
RF RF
RF
N
N
RF
NMe2
Me2NN
NC
RF
NMe2
Me2N
CF3
F3C
F
N
NC
RF
N
Me2N
CF3
F3C
N
NC
RF
NMe2
N
CF3
F3C
H3C CH3
BF4 H2C
H3C
N
N
N
NMe
RFCH3
H
H
F3CCF3
i ii
iii
iv
(Yellow)
(Purple)
(Colourless)
i, Me2NH/DMF/Room Temp.ii, Standing or on addition of wateriii, BF3.Et2Oiv, Moist Acetone
RF = CF(CF3)2
½142�
Figure 9.56
CF3C CCF3 CF3CF=CCF3
CF3C CCF3
CF3CF=C(CF3)C(CF3)=CCF3
ArFF
ArFFCF3C CCF3
C(CF3)=CF(CF3)n
Polymer
+ F
Figure 9.57
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 333
Polyfluoroaromatic Compounds 333
RFO + ArX ArORF + X (X + Cl or F)
N N
N
Cl (CF3)2CO.KFDiglyme
−10� C N N
N
[OCF(CF3)2]3
86% conversion
½146�
Figure 9.58
F
SH
F
SC
C
COOEt
COOEt
F
SC
C
COOEt
COOEt
iii, −Fiv, H2SO4
i, ii
i, n-BuLi ii, EtOOCC CCOOEt
F
SCH
CH Cu
Quinoline
F CH3COCHCOOEt NaNaH
THFF
C
C
O CH3
H
COOEt
FC
C
HO CH3
COOEt
BaseFC
C
O CH3
COOEt
FC
C
O CH3
H
H
i, NaH.1THF, 2DMF reflux
FC
C
O CH3
Hi
½148�
½149�
½146, 150�
Figure 9.59
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 334
334 Chapter 9
FC
C
O CH3
H
H FC
C
HSCH3
H
FC
CS
H
i, H2S, EtOH, O� C
H
SH
CH3
ii, Pyridine, NaOH, Reflux
i
ii
½148�
Figure 9.60
Li Li
+ SCl2 or S2Cl2
F F F F
S
i
i, Et2O, hexane, −78� C
½151�
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).
N
F
X N
F
X
N
F
X
N
F
X
N
F
X
O
O
O
O
O
O
O
O O
O
i ii
i, Me3SiOCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days
X = CF(CF3)2, 94%X = OMe, 80%
X = CF(CF3)2, 64%X = OMe, 85%
ii, Me3SiOCH2CH2OCH2CH2OSiMe3, CsF, Monoglyme, Reflux, 2 days
½152�
Figure 9.62
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 335
Polyfluoroaromatic Compounds 335
C Reactions with electrophilic reagents
Displacement of Fþ from an aromatic system by electrophiles is obviously not a very
favourable process; indeed, fluorine might be considered as the worst possible leaving
group in a non-concerted process. Nevertheless, reactions of concentrated nitric acid with
perfluoro-aromatic compounds, for example perfluoronaphthalene, give quinones, or
addition products may be obtained using HNO3 in HF or NO2BF4 in Sulpholan [153].
Thus, perfluorinated systems will undergo reactions with some strong electrophiles to
give products that formally arise from electrophilic displacement of fluorine, whatever the
detailed mechanism may be (Figure 9.63).
F Fi
F F F F
CH3CH3
i, CH3F, SbF5, SO2ClF, 20� C
½1, 154�
Figure 9.63
Ring fission to the phthalic acid derivative has been observed [155] (Figure 9.64).
F F F
F NO2
F
F NO2
F
F
F
FF FF
COOH
COOH
F F
F
F
O
O
c. HNO3 H2O
F
F
O
F
O
i F
61%
71%
i, NO2+ (NO2BF4 or HNO3.HF)
½153, 155�
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 per-
fluorotoluene [161] (Figure 9.67).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 336
336 Chapter 9
O
O
FSF4
F
O
O
F
O
F
SbF5
SbF6
H2O
F F
F5
½156, 157�
Figure 9.65
F FSO3.SbF5
Oleum F F SO3.SbF5
C6F6 + O2AsF6 C6F6 AsF6 + O2
NO
C6F6 + NO AsF6
½158�
½159, 160�
Figure 9.66
CF3
CF3
F
i, H2SO4, SO3, 150� C, 12hr
CF3
Fi
COOH
COOH
F
CF2
F
CF3CF=CF2
CF2CF(CF3)2
F
i
i, SbF5, HF, 50-60� C
½18�
½161�
Figure 9.67
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 337
Polyfluoroaromatic Compounds 337
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 electro-
philic attack. Exclusive attack at pentafluorophenyl occurs, showing that the cumulative
activating effect of the ortho- and the para-fluorine substituents is dominant [168]
(Figure 9.70).
D Free-radical attack [169]
Photochemical chlorination of perfluorobenzene [170] and perfluoropyridine [171], and
reactions with bistrifluoromethyl nitroxide [171], give addition products, although the
C5N bond is very resistant to radical attack (Figure 9.71).
It is well known that free-radical aromatic substitution occurs readily when aryl
radicals are used, and extensive studies have been made using diaryl peroxides as the
source of these radicals. The effect of fluorine on the process may be considered in two
parts: first, most substituents may be expected to encourage the formation of radical
intermediate 9.72A in Figure 9.72; second, in reactions with hydrocarbon radicals, polar
effects should also increase reactivity, since the ring would be made more electrophilic.
The converse would be expected to apply with electrophilic radicals, e.g. CF3� or C6F5�.By contrast, it is not easy to predict the fate of radical 9.72A, once formed; fluorine atoms
are unlikely to be generated, but transfer of a fluorine atom to another species is possible.
Arylation of perfluorobenzene does indeed occur when dibenzoyl peroxide is used, but
ðC6F5COOÞ2 gives only tar: the scheme shown in Figure 9.73 has been proposed
[172–174].
In contrast, perfluoronaphthalene gives a mixture of products with benzoyl peroxide,
but they mainly arise from attack by C6H5CðOÞO� [173].
Cyclisation may be achieved in some electrochemical oxidations. These have been
formulated as radical substitutions [176, 177] (Figure 9.74).
Electrochemical reduction of polyhalopyridines has been observed; the position of
H-transfer corresponds with calculated spin and charge densities [179] (Figure 9.75).
Reductive defluorination will also occur under relatively mild conditions, in some
circumstances by electron transfer from metals, e.g. zinc [180, 181] (Figure 9.76).
1 Carbene and nitrene additions
Additions of carbenes to perfluorobenzene have been reported [182, 183] and tropylidene
structures for the products have been proposed (Figure 9.77).
Addition of difluorocarbene to perfluorobenzene has been proposed to account for the
formation of perfluorotoluene and other perfluoromethylbenzenes in the pyrolysis of
perfluorobenzene with potassium fluoride, or with polytetrafluoroethene as a difluoro-
carbene source [184, 185]. Indeed, Russian workers have studied the pyrolysis and
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 338
338 Chapter 9
F
H
F CH
3i, CHCl3, AlCl3, 150� C
F
H
i, Br2 (or I2), Oleum, 60−65� C
F
Br
F
H
F
NO2
i, HNO3, Sulpholan, BF3, 60−70� C
F
H
F
CH(CH3)2
i, C3H6, CBr4, AlBr3, 0� C
F F
Br
i, FeBr2.CCl4, Reflux
F F
NO2
i, HNO3, Oleum, 70� C
90-94%
F
H
3 F
C6F5
C6F5 C6F5
SbF5,F
i
i
i
i
i
i
½162�
½163�
½164, 165�
½166�
½1, 154�
½167�
½167�
Figure 9.68
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 339
Polyfluoroaromatic Compounds 339
E H
F5
Figure 9.69
C6F5HgC6Cl5
i, HCl, 100� C, 65hr, Sealed tube
C6Cl5Hg
C6Cl5HgCl + C6F5Hi
Cl−
+
F5
H
½168�
Figure 9.70
FCl2, hn
48hr
ClF
F
Cl
F Cl
Cl
F
Cl
F
Cl F
N
FCl2, hn
35hrN
ClF
F
Cl F
Cl
F
Cl F
½170�
½171�
Figure 9.71
R F
R F
F
R
F ?
9.72AF5
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 340
340 Chapter 9
F Ar
Ar F
F
Ar
ArCOOArCOOF
Ar F
Ar
Coupling
FF F
F5
½172, 174, 175�
Figure 9.73
C6F5NH2−e
C6F5NH2−H
C6F5NH
C6F5NH2
N
H2N
H
F F F
N
N
F F−e
etc
C
H2N
O
F F
N
C
F F
O
H
½177�
½178�
Figure 9.74
Insertion of nitrenes occurs readily and may lead to ring expansion and a variety of
rearrangements [195, 196] (Figure 9.82).
Cyanotetrafluorophenylnitrene gives very high yields of C2H insertion compounds
[197] (Figure 9.83).
E Reactive intermediates
1 Organometallics
Fluorocarbon organometallic compounds [198, 199] are discussed more generally in
Chapter 10, but polyfluoroaryl-lithium, -magnesium and -copper compounds are particu-
larly important in organic synthesis, as outlined below.
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 341
Polyfluoroaromatic Compounds 341
N
X
F
N
X
N
X
N
X
N
H
F
i
ii
i, Hg Cathode, DMF, Et4NBF4, −1.8V (SCE)ii, Hydroquinone
X = Cl, F
F4 F4
F4
H
½179�
Figure 9.75
F
CF3
CF3 CF3 CF3 CF3
CF3CH3
F
CF2(CH2)5CH3
F F
Hi
i, Zn (Cu), DMF, H2O, 1-Hexene, 65� C
COOH
F F
COOH
F F
H
i
i, Zn, aq.NH3, rt, 2hr
½180�
½181�
Figure 9.76
C6F6 + N2
hνF 30%
C6F6 + (CF3)2CN2
hνF
CF3
CF3
20%
½182�
½183�
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 342
342 Chapter 9
C6F6 + CF2CF2 n550�C
C6F6 + C6F6-n(CF3)n
n = 1,2,3
C6F5XCF2
C6F5CF2
CF2=CF2 C6F5CF2CF2CF2
F F
−F (?)
½185�
½186�
Figure 9.78
C6F6F
(KF)
F F
CF2
(a) Insertion
(b) Addition
C6F6
C6F6
C6F5CF3
F
F
F
FF
F
F
F
9.79A
F5
Figure 9.79
N
F CF2CF2 n
550� C
N
F
N
F
CF3 CF3F3C
60% 6%
N
F
CF3
85−90% +2- and 4- isomers N
F
i, KF, 8hr, 550−560� C
i
½193�
½189�
Figure 9.80
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 343
Polyfluoroaromatic Compounds 343
CNH3C
R
F3C
F3C
½194�
Figure 9.81
C6F5N3i
[C6F5N:]
N
F
N
N
F F
i, Flash Vac. Pyrolysis/300� C
C6F6 + N3CN45� C N NCF ½195�
½196�
Figure 9.82
CN
N3
F hν
CN
N
F
CN
N
F
H C6H11
75−80%
c-C6H12 ½197�
Figure 9.83
C6F5MgBrC6F5Br C6F5COOH
67%i, Mg, Et2O, or THF
CO2i
C6F5CH2CH2OH
O
½200�
½201�
Figure 9.84
Lithium derivatives [202] are more versatile and more convenient to use than the
Grignard reagents, although the report of serious explosions occurring with pentafluoro-
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 344
344 Chapter 9
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 polyfluor-
oaryl-lithium or polyfluoroarylmagnesium derivatives should be treated as poten-
tially 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 fluor-
ine 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 + n-BuLiEt2O
−78� CC6F5Li + n-BuBr
H
X
F
X = H or F
+ n -BuLiEt2O
−78� C
Li
X
F
½204�
½205, 208�
Figure 9.85
The use of some polyfluoroaryl-lithiums in organic synthesis is illustrated in Table 9.9;
these reagents have, of course, been used to make many corresponding derivatives of
other elements, but this will be illustrated in the next chapter.
Table 9.9 Some organic syntheses using polyfluoroaryl-lithiums
Reaction Ref.
C6F5Li
i, B(OMe)3, H2O2
C6F5OH 39%i
[209]
C6F5Li
i, S8; ii, H2O
C6F5SH 46%i, ii
[210]
C6F5Li
i, CO2; ii, H, E+t2O, <55� C
C6F5COOH 99%i
[205]
C6F5LiHCO(NMe2) C6F5CHO 61% [211]
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 345
Polyfluoroaromatic Compounds 345
Copper compounds [215]: An interesting contrast occurs between phenyl- and penta-
fluorophenyl-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).
Table 9.9 Contd
C6F5Li(MeO)2CO
(C6F5)2CO 70% + (C6F5)3COH [212]
OH
H
Fn-BuLi
OLi
Li
F
OH
COOH
Fi, CO2
ii, H+ 84% [209]
H
Br
Br
HF
F
Li
Br
Br
HF
FHOMe2C
Br
Br
HF
F
i ii
i, LDA, THF, −78� C; ii, Me2CO, −78� C
[207, 213]
NH
H
F
FCl
NH
Li
F
FCl
H
COOH
F
FCl
F
i ii, iii
i, LDA, THF, −78�C; ii, Me2CO, −78�C; iii, H+
[214]
Li Li
F FSCl2
F F
S
66% [212]
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 346
346 Chapter 9
C6F5MgBr + CuIEt2O [C6F5Cu]
DioxaneC6F5Cu.Dioxane
130� C −Dioxane
[C6F5Cu]4PhI
MeI200�C
C6F5C6H5
C6F5Me
C6F5C6F5
87%
39%
C6F5ClCu(I)Cl, Mg
THF
[C6F5Cu]MeCOCl
−5� CC6F5COMe 72%
C6F5C CC6F5
CBr2=CHBr
43%
C6F5Cl
i, n-BuLi, THF, −70� C
C6F5Li [C6F5Cu]Cu(I)I CF2=CFI
C6F5CF=CF2
55%
C6F5I + 2Cu C6F5Cu + CuIMonoglyme
rt
C6F5Cu + CH2I2 CH2(C6F5)2
i
½221�224�
½216, 219, 220�
½225�
½217�
½226�
Figure 9.86
C6F5Cu + CF3Cu C6F5CF2CF2Cu−30� C
DMF½227�
Figure 9.87
F
Li
F F S
X
X
X
X
XF
SX
−SX = H, Cl
½228�
Figure 9.88
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 347
Polyfluoroaromatic Compounds 347
In addition to these cycloaddition reactions with nucleophilic p-donors, tetrafluoro-
benzyne 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).
F
Li
FC6F5Li
F
Li
C6F5 C6F5
F
H
H½204�
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 decom-
position of pentafluorophenylmagnesium bromide at elevated temperatures in THF solu-
tion [230, 231] (Figure 9.90).
C6F5MgBr FC6F5MgBr
F F
MgBr
F F
MgBr
C6F5MgBr
C6F5F F
MgBr
C6F5
n
½230, 231�
Figure 9.90
This type of process appears to occur even more easily with trifluoropyridyne [232]
(Figure 9.91).
N
F
Br
i, n-BuLi, Et2O, −78� C
N
F
Li
N
F
Furan
n-BuLi
Polymer
i ½232�
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 348
348 Chapter 9
F F
SH
i, n-BuLi, Et2O, C6H8, 0�C
Br
F F
S
F
S
FF
S
F
70%
i ½233�
Figure 9.92
F
Li
FPhCH=N(Ph)O
O
NF
H
Ph
Ph
½234�
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 rad-
icals in a quantitative fashion by competition for the radicals between chlorobenzene and
benzene [237], giving kðC6H5Cl=C6H6Þ ¼ 0:72 in comparison with a value for phenyl
radicals kðC6H5Cl=C6H6Þ 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 inter-
esting contrast with the classical reduction of benzophenone to benzopinacol under the
same conditions (Figure 9.98). This difference between the two systems has been attrib-
uted to the greater resonance stabilisation of the radical 9.98A in comparison with 9.98B
and to electron-pair repulsions inhibiting the dimerisation of 9.98A.
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 349
Polyfluoroaromatic Compounds 349
F
O
O
O
OHg
300� CHg
Hg
HgF
F
F
83%
Hg
Hg
HgF
F
F
F F 39%Ag
~255� C
OF
O
O
F F 24%750� C
0.6mmHg
I
I
Fi
F
i, hν, Ne matrix, 3K
9.94A
½155�
½155�
½235�
½236�
Figure 9.94
C6F5NH2 + C5H11ONO C6F5
C6F5 + C6H5CH3 C6F5 C6H4CH3
o-(62.1), m-(21.5), p-(16.4)%
C6F5 + C6H5NO2 C6F5 C6H4NO2
o-(20.8), m-(53.4), p-(25.8)%
½237�
Figure 9.95
Pentafluorophenol is oxidised by lead tetra-acetate, giving products arising from
intermediate C6F5O� radicals [244, 245] (Figure 9.99).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 350
350 Chapter 9
i, Bleaching Powder, C6H6
C6F5COCl
i, NaOH, H2O2; ii, C6H6, 80� C
(C6F5COO)2 C6F5COOH+ C6F5C6F5
+ C6F5COOC6F5
C C6F5C6H5
i
i ii
6F5NHNH2½198�
½238, 239�
Figure 9.96
C6F5IS, 230� C
(C6F5)2S 70%
I
I
F S, 250� C
S
S
F F 60%
C6F5INMe Me
H
NMe Me
H
C6F5
70%hν
CH3CN
½241�
½241�
½242�
Figure 9.97
(C6F5)2COhν
(C6F5)2OH CC6F5
HO
(C6F5)2CHOH + Me2CO
etc
cf (C6H5)2C=O (C6H5)2COH
9.98A
9.98B
PhPh
OH
PhPhHO
Me2CHOH
Me2CHOH
F ½243�
Figure 9.98
4 Valence isomers [246–248]
Photochemistry of fluorinated aromatic systems has made an important contribution to the
study of valence isomers because it has been possible to isolate and characterise
some species on which there had previously only been speculation. Some of these, as
might be expected, are very unstable (sometimes, treacherously so) towards reverting to
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 351
Polyfluoroaromatic Compounds 351
C6F5OH C6F5Oi ii
O
F OC6F5
OF
OC6F5FF
iii
OF
OC6F5F
C6F5O
i, Pb(OAc)4ii, Dimerisationiii, C6F5O etc.
½244�
Figure 9.99
the corresponding aromatic form. This is the case with perfluorobenzene but, when
perfluoroalkyl groups are present, valence isomers have been isolated that are remarkably
stable and thus present some fascinating systems to organic chemistry.
Let us consider the possible effects of fluorine or fluorocarbon groups as substituents
on the transformation of a benzene derivative to a para-bonded species 9.100A, a
benzvalene 9.100B or a prismane 9.100C (Figure 9.100).
X = F or perfluoroalkyl
+ +
9.100A 9.100B 9.100C
X6
X6
X6 X6
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 tetrafluoro-
ethene than ethene (by about 73 kJmol�1). 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 kJmol�1 [249] but the enthalpy changes DH� for
photoisomerisation are much more varied, e.g. 214 [C6F6], 117 [C6ðCF3Þ6] and
35 kJmol�1½C6ðC2F5Þ6�. It appears that the thermal stability of valence isomers increases
with the number of perfluoroalkyl substituents. Not the least advantage of fluorocarbon
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 352
352 Chapter 9
systems is the stability of carbon–fluorine bonds. In this sense fluorine or fluorocarbon
groups are useful as ‘passive’ substituents [192], where skeletal rearrangements are being
observed, in order to obtain a minimum of side-reactions.
t-Butylfluoroacetylene is an extremely reactive compound that undergoes thermal
oligomerisation, giving a benzene derivative and valence isomers [250] (Figure 9.101).
F +
F F
F F
F
F
+
F
∆∆
(CH3)3CC CF½250�
Figure 9.101
The para-bonded isomer of perfluorobenzene may be formed by irradiation, in the
vapour phase, using 254 nm radiation [251–254] (Figure 9.102). Substituted benzenes,
C6F5XðX ¼ H, CH3, CF3, OCH3Þ [255], and trifluorobenzenes, C6H3F3 [256], all form
para-bonded species on irradiation.
Fhn
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(trifluoro-
methyl)benzene and hexakis(pentafluoroethyl)benzene [257–259] in the gas phase or in
solution. The sequence of formation of the isomers is shown in Figure 9.104.
Kinetic and thermodynamic data for valence isomers have been compared [249, 260].
The bicyclopropenyl isomer (Figure 9.105) has been prepared by a carbene addition
process; therefore, this system is quite unique in that all of the valence isomers are
known and fully characterised.
Nitrogen derivatives: A remarkable series of transformations has been discovered with
fluorinated pyridazines, giving pyrimidines and small amounts of pyrazines on pyrolysis
[262, 263] and pyrazines on photolysis [264]. Highly specific substituent labelling occurs
on pyrolysis and diazabenzvalenes, or vibrationally excited species approaching these,
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 353
Polyfluoroaromatic Compounds 353
+
F6
F6
9.103A
9.103A
9.103A
F6
F6
F4 F5
NaOMe
MeO OMe OMe
Br2 Br
Br
O3
H2OF F
F
F
COOH
COOH
P2O5
O
O
O
O
i, iii
i, hνii, hν, furan
½254�
½254�
½248�
Figure 9.103
(CF3)6
(CF3)6
>200nm<270nm
170� C
t1/2 9hr
170� Ct1/2 135hr
>200nm
>200nm
170� C
t1/2 129hr
(F3C)6
(CF3)6½258, 259�
Figure 9.104
CF3C CCF3 + CN
NF3C
Cl
(CF3)3 (CF3)3½261�
Figure 9.105
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 354
354 Chapter 9
have been suggested [192] in order to account for the results, although no valence isomers
have actually been isolated. Cycloaddition processes have been ruled out by N-15
labelling experiments. Furthermore, rearrangement is encouraged by free-radical promo-
tors, leading to the conclusion that these processes involve free-radical-promoted forma-
tion of diazabenzvalene derivatives [263] (Figure 9.106).
N
NF
RF RF RF
RFRFRF
RFRF
RF
RFRF
RF
N
NF
R
R
N
NF
R
N
NF
−R
NNF
N
NF
½263�
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.
N
N
F
RF
RF
RF
RF RF
RF
RF
RFRF
RF
RFRF
RF
F
254nm
gas phase
NN
F
FN
NF
F
+i
i
i = hν or heat
N
N
F
F
254nm
gas phase N
NF
RF
F
+
i
i = hν or heat
RF = F , CF(CF3)2 , CF2CF3 , CF(CF3)(C2F5)
N
NF
F
N
N
F
F
½264, 265�
½264, 265�
Figure 9.107
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 355
Polyfluoroaromatic Compounds 355
N
N
1
2
3
4
6
5
1
2
3
4
56
N
N
1
2
3
4
6
5 N
N
1
2
3
4
6
5
N
N
N
N
1
2
3
4
5
6
9.108A
Figure 9.108
Some of the valence isomers (e.g. 9.108A) have a half-life of a few minutes at 1008C.
In contrast, valence isomers of some polyfluorinated pyridine derivatives have substantial
stability [266] (Figure 9.109).
N
N N
(CF3CF2)5 (CF3CF2)5 (CF3CF2)5
>200nm >200nm
270nm½266�
Figure 9.109
Again, substituent labelling studies have enabled photochemical rearrangement mech-
anisms to be clearly associated with the intermediate valence isomers, in this case
involving azaprismane derivatives (Figure 9.110).
a
b b b
a
a
ab b
b c b a b c
b
c
c a c c a c
c
b
c
c
b b b b
c c ccN
N
N N N
N Nhν
heat
+ +
x x
xx
y
y
heatcleavage, x
heat cleavage, yheat cleavage, x
a = CF3CF2-; b = CF3-; c = (CF3)2CF
Rearrangement
½267�
Figure 9.110
In some cases, photochemically induced eliminations occur; in the case of fluorinated
1,2,3-triazines, this has generated azetes [268, 269] which have been trapped and even
observed by low-temperature isolation techniques [269] (Figure 9.111).
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 356
356 Chapter 9
F
F
F
F
−RFCN
N N N
N
iii
F
N N
N
Adduct
N
i
ii
NN
RFRF
RF
RFRF
F
F
RF
RF
RF
RF
RF
RF
RF
RF
RF
F
N
FF
RF
RF
RF
RF
i = hv; ii = furan; iii = 350� C
RF = CF(CF3)2
RF ½268, 269�
Figure 9.111
Thermal elimination of nitrogen presents a route to fluorinated alkyne derivatives [270]
(Figure 9.112).
N
N
YX
XY
∆XC CY
X = Y = C6F5 (90%);X = CF3CF2; Y = C6F5 88%
½270�
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).
S S
F3C
S
i
ii
i, hν; ii, heat or Pd Catalyst
O X
hνX
O
9.113A
X = F or CF3
(CF3)4
(CF3)4 (CF3)3
(CF3)3(CF3)3
½246�
½271�
Figure 9.113
Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 357
Polyfluoroaromatic Compounds 357
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Chambers: Fluorine in Organic Chemistry Final Proof 5.8.2004 8:15pm page 364
364 Chapter 9
Chapter 10
Organometallic Compounds
Organometallic compounds have been referred to at various points in this book and their
role as reactive intermediates, where significant, has been outlined. Frequent comparisons
have been made between the chemistry of functional-hydrocarbon and corresponding
functional-fluorocarbon systems with the aim of building up a picture of the effect of
fluorine as a substituent on the chemistry of various functional groups, reactive centres
and the like. Needless to say, a similar consideration of the effect of fluorine on the
properties of carbon–metal bonds is fascinating in itself and, over the years, striking
developments in this novel field of organometallic chemistry have been made. This book
is about organic chemistry and it cannot cover this field of inorganic chemistry as a whole.
What follows, therefore, is a discussion of systems that are largely of interest to, or useful
to, the organic chemist.
There are a number of reviews available [1–19], and other key references will be given
in the text. The earliest and still one of the most dramatic contrasts between hydrocarbon
and the corresponding fluorocarbon organometallic systems is that between dimethyl-
and bistrifluoromethyl-mercury [20]. The latter is a white crystalline solid (melting point
1638C) that is slightly soluble in water, whereas dimethylmercury is a covalent liquid
(boiling point 928C). In a less dramatic but more useful way, transition-metal compounds
[21] are generally more thermally stable with fluorocarbon groups attached. Attached
fluorocarbon groups often enhance the acceptor properties of a metal and the metal
generally becomes more susceptible to nucleophilic attack. The converse also applies:
that is, electrophilic attack becomes more difficult, especially in cases where a metal is
attached only to perfluoroalkyl or perfluoroaryl groups, although the situation is more
complicated with mixed derivatives.
I GENERAL METHODS OF SYNTHESIS
It will become clear that, in some cases, the classical routes to organometallics are not
available but, compensating for this, the different chemistry of, for example, unsaturated
fluorocarbons has often been exploited to provide quite new synthetic approaches.
A From iodides, bromides and hydro compounds
1 Perfluoroalkyl derivatives
Fluorocarbon organometallic chemistry began with the first syntheses of perfluoroalkyl
iodides (see Chapter 7, Sections IIC, Subsection 7, and IIE, Subsection 2, for current
methods). On the basis of classical methods, this might have been expected to lead
logically to the corresponding lithio derivatives and these, in turn, to a considerable
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 365
365Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
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-C3F7I i-C3F7Li + n-C4H9I
−LiF
CF3CF=CF2
CH3Li + C2F5I [C2F5Li] C2F5C(OH)PhCH3ii
88%
i, Et2O, −78�C
i
ii, PhCOCH3, H+ etc.
i
½22�
½23�
Figure 10.1
A warning has been given [24] about carrying out exchange reactions to form
pentafluoroethyl-lithium at very low temperatures, where violent decomposition has
been observed. The most likely explanation for these events is that solid perfluoroethyl-
lithium is precipitated at the low temperature and, of course, this is extremely unstable
with respect to formation of the metal fluoride. The same cautionary note may be made
for all fluorinated alkyl- or aryl-lithium compounds (see Chapter 9, Section IIE,
Subsection 1)
The carbon–iodine bond in perfluoroalkyl iodides is usually susceptible to homolytic
fission; this was exploited in early work on the synthesis of mercurials and in later work
relating to group IVB and transition-metal derivatives (Figure 10.2).
CF3I + Hg∆
CF3HgI
(CH3)3SnSn(CH3)3 + CF3I (CH3)3SnI + (CH3)3SnCF3
hν
½20�
½25�
Figure 10.2
2 Derivatives of unsaturated systems
Perfluoropropynyl [15, 26, 27] and perfluorovinyl [16, 28–30]-lithium and -magnesium
are considerably more stable than perfluoroalkyl derivatives, whilst the corresponding
perfluoroaryl derivatives may be used as effectively as in the hydrocarbon series, and
direct syntheses involving iodo compounds are also possible (Figure 10.3).
This quite definite trend towards increasing stability in a series from CF3Li, which may
have little more than a fleeting existence when generated, to RFLiðRF5C2F5, n- and
i-C3F7), CF5CFLi and C6F5Li is probably a reflection of the ease of elimination of metal
fluoride decreasing in this series; see also Chapter 6, Sections II and IIIA, Subsection 3
(Figure 10.4).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 366
366 Chapter 10
C6F5Hn-BuLi
C6F5LiHgCl2
(C6F5)2Hg
C6F5I
i, Zn (200�C) or Cd (230�C)
(C6F5)2M M = Zn or Cd
CF3CH2CF2Hi
(−LiF)[CF3CH=CFH]
i
(−LiF)
i
CF3C CLiii
Ph3SnC CCF3
i, n-BuLi; ii, Ph3SnCl
84%
CF3CFH2i
(−LiF)[CF2=CFH]
iCF2=CFLi
PhCH(OH)CF=CF2
iii, n-BuLi; ii, PhCHO, H
+ etc.
i
[CF3C CH] ½27�
½30�
½11�
½11�
Figure 10.3
CF3Li−LiF
[ CF2]etc
CF2=CFLi−LiF or [CF2=C ]
F
Li
−LiF F
[CF CF]
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 carb-
anions (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 367
Organometallic Compounds 367
F + [Re(CO)5]− F
Re(CO)5
N
NF + [πC5H5Fe(CO)2]
− N
NF
Fe(CO)2πC5H5
½6�
½6�
Figure 10.5
Subsection 6). Mercurials have been obtained by fluoride-ion-initiated reactions of per-
fluoroalkenes with mercury(II) chloride [31], and it is probable that the process could be
extended considerably (Figure 10.6).
F− + CF2=CFCF3 (CF3)2CF
−Hg[CF(CF3)2]2
i
i, HgCl2
½31�
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 perfluoro-
alkyl 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-C3F7Li
i-C3F7Li
i, H2SO4, Et2O
CF3CF=CF2 N.B. Little or no i-C3F7H formed
i, EtCHO, H2SO4
EtCH(i-C3F7)OH 53%
ICF2CF2I + [n-C4F9Li + MeCHO] [MeCH(OH)CF2-]2
i
i
i, ii
i, −80� C to −85� C ii, H+
66%½22�
½22�
½32�
Figure 10.7
The fact that exchange occurs to produce, in each case, the fluorocarbon derivative is
quite consistent with the general observation that exchange generally proceeds to give a
product where the metal is bonded preferentially to the most electronegative group [33].
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 368
368 Chapter 10
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.
H
FEt2O, −40�C
MeLi
Li
F
D
FD2O
F
O
Furan
I
F
Me
F
CH(OH)Me
F
I2i, MeCHO
MeIii, H
+
F
10.8A
½37�
Figure 10.8
This difference is obviously due to the difficulty in producing a double bond at a
bridgehead position. Nevertheless, elimination of lithium fluoride does occur, especially
at reflux temperatures; the bridgehead alkene 10.8A, which probably has only a transitory
existence or may even be more appropriately described as a diradical, may be trapped
with furan.
B From alkenes
Several perfluoroalkene derivatives have been made and used successfully in synthesis.
Trifluorovinylmagnesium bromide and the lithium derivative may be obtained [39–41]
from bromotrifluoroethene but preparation from HFC 134a, which involves metallation of
trifluoroethene generated in situ, is now the more accessible route (see Section IA).
However, direct metallation of fluorinated alkenes and fluorinated cycloalkenes has
also been reported [26, 28] (Figure 10.9).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 369
Organometallic Compounds 369
CF2=CFBr
i, Mg + I2, THF, ~ −22�C
CF2=CFMgH2SO4 CF2=CFH 43%
Me2SnCl2 + Mg
i, CF2=CFBr, THF, 0�C
Me2Sn(CF=CF2)2 65%
CF2=CFH + n-BuLi
i, Et2O or THF, −78�C
ii, CO2
iii, H+
CF2=CFLi + C4H10
ii
iii
CF2=CFCOOH 65%
(CF2)n (CF2)n
(CF2)n
F + MeLi−70�C
Et2OCH4 +
i, MeCHO
ii, H+
CH(OH)Me
n = 1, 23%n = 2, 42%n = 3, 63%
i
i
H
F
Li
F
i
½40�
½42�
½28�
½26�
Figure 10.9
C From trifluoropropyne [15]
The C2H bond in trifluoropropyne is sufficiently acidic to allow ready metallation via
Grignard or lithium reagents (Figure 10.10). However, the route from CF3CH2CF2H [27]
(Section IA, Subsection 2) is more direct.
CF3C CH + n-BuLi
i, C5H10, Et2O, −78�C
C4H10 + CF3C CLi
Et3SiCl
Et3SiC CCF3
i ½43�
Figure 10.10
A number of derivatives of metals have been synthesised [15]; the lithium and magne-
sium derivatives, especially, are capable of quite wide application.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 370
370 Chapter 10
D From polyfluoro-aromatic compounds [7, 17, 18, 21]
The generation of Grignard reagents and lithium derivatives was discussed in Chapter 9,
Section IIE, Subsection 1, and these reagents have already provided an impressive
number of derivatives, which are discussed in detail in reviews [7, 17, 18, 21]. Some
examples are shown in Figure 10.11 but more will be found in the following text.
The steric requirements of the ligands in 10.11A are considerable and this feature has
allowed a number of unusual systems to be synthesised [48].
C6F5MgBr
i, SiCl4, Et2O
(C6F5)4Si
C6F5MgBr i (C6F5)2Hg 73%
C6F5Li
i, BCl3, Pentane/Hexane, −78�C to rt
(C6F5)3B 50%
i
i, HgCl2, Et2O
i
F3C
CF3
CF3
F3C
CF3
CF3
F3C
CF3
CF3
Lin-BuLi MX2
2
M = Zn, Cd, Hg.
M
10.11A
½44�
½45�
½46�
½47, 48�
Figure 10.11
Metallation of less highly fluorinated systems has been reviewed [49].
III ZINC AND MERCURY
A Zinc
Less work had been done with zinc compounds, but enough to indicate a contrast with
lithium and magnesium derivatives. For example, perfluoro-n-propyl zinc iodides [50, 51]
and perfluoroisopropyl zinc iodides [22] can be obtained, and the n-propyl derivative
is even stable in dioxane at reflux. It should be noted that these compounds are stable
largely because they are solvated and it has not been possible to remove the solvent
completely. Zinc under these circumstances appears to be a very strong acceptor and
therefore the compounds decompose much more readily when formed in the free state
[52] (Figure 10.12).
Ultrasonic radiation of perfluoroalkyl iodides may be used to form zinc reagents which
undergo standard reactions (Figure 10.13).
Fluorovinylzinc reagents are especially useful [14] (Figure 10.14).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 371
Organometallic Compounds 371
n-C3F7I
i, Zn, Dioxane, 100�C,ii, Removal of Solvent
n-C3F7ZnI CF3CF=CF2~155�C
n-C3F7Ii
n-C3F7ZnI n-C3F7ZnI/dioxane
n-C3F7H 96%
H2O 100�C
n-C3F7ZnI/dioxanen-C3F7COCl
(n-C3F7)2CO
15%
i
ii
i, Zn, Dioxane, 100�C,ii, Removal of Solvent
ii
½51�
½50�
Figure 10.12
C3F7I +Ph
Br
Ph
C3F7
66%
i, Pd(Ph3P)4, Zn, THF
C3F7I +Ph Ph
71%BrC3F7
CF3I + HOCH2C CHi
CF3CH=CHCH2OH 61%
C2F5I + 51%C2F5
CF3I + PhCHODMF
PhCH.OHCF3 72%
CF3CCl3 + PhCODMF
Ph
OH
CCl2CF3
86%
i
i, Pd(Ac)2, Zn, THF
i
i, CuI, Zn, THF
i, Cp2TiCl2, Zn, THF
i
Zn
Zn
½53�
½53�
½53�
½53�
½53�
½54�
Figure 10.13
CF2=CFBrDMF
[CF2=CFZnBr]Me3SiCl
CF2=CFSiMe3 65%Zn ½55�
Figure 10.14
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 372
372 Chapter 10
Perfluoroarylzinc derivatives may be obtained directly from the corresponding iodide
and, sometimes, the chloride; they are also sufficiently stable to be produced by de-
carboxylation procedures (Figure 10.15).
C6F5I + Zn
C6F5Li + ZnCl2
(C6F5CO2)2Zn
(C6F5)2Zn
N
F
Cl
N
F
ZnCl
25%
½14�
½56�
Figure 10.15
Surprisingly, zinc has been inserted directly into C2F bonds using ultrasound tech-
niques, 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 hexa-
fluorobenzene is relatively unreactive in the process [57] (Figure 10.16).
F
CF3
iF
CF3
ZnCl
Br2 F
CF3
Bri, Zn, SnCl2, DMF, Ultrasound
½57�
Figure 10.16
B Mercury
1 Perfluoroalkyl derivatives
Perfluoroalkyl derivatives of mercury were the first fluorocarbon–organometallic com-
pounds to be reported. Alkylmercurials are valuable in that they are able to alkylate other
metals, but the toxicity of mercurials greatly inhibits the use of these systems. Perfluoro-
alkyl iodides react with mercury on heating or irradiation with ultraviolet light to give
perfluoroalkylmercury(II) iodides [58–60] (Figure 10.17).
An effective route to a number of bis(perfluoroalkyl)- and bis(perfluorocycloalkyl)-
mercurials involves fluoride-ion-induced reactions of fluoroalkenes [31]; this follows an
earlier method involving addition of mercury(II) fluoride to fluoroalkenes, e.g. using
anhydrous hydrogen fluoride as solvent [62] (Figure 10.18).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 373
Organometallic Compounds 373
CF3I + Hg
i, hν (150�C), or ii, ~275�C
CF3HgI80% (i)
22% (ii)
(CF3COO)2Hg
i, K2CO3, 120 to180�C
(CF3)2Hg
i or ii
i
½20�
½61�
Figure 10.17
CF3CF=CF2 + HgF2
i, Anhyd HF, 110�C
[(CF3)2CF]2Hg 60%
CF3CF=CF2 + HgCl2 [(CF3)2CF]2Hg 65%
i, KF, DMF, 40�C
(CF3)2C=CF2 + HgF2 [(CF3)3C]2Hg 66%i
i
i
i, KF, DMF, −78�C
½62�
½31�
½31�
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 + HgCl2Et2O (CF2=CF)2Hg 52%
C6F5MgBr + HgCl2Et2O (C6F5)2Hg 73%
N
F
COO Hg
2
∆
N
F
Hg
2
½41�
½45�
½64�
Figure 10.19
Pentafluorophenylmercurials can also be made by interesting direct mercuration pro-
cedures, 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 374
374 Chapter 10
C6F5H + Hg(OCOCF3)2150�C C6F5HgOCOCF3 85%
(C6F5)2Hg 72%
i
C6F5H + HgBr42−
+ 2 OH−
(C6F5)2Hg + 4Br− + 2H2O
i, EtOH, NaI, rt
½65�
½66�
Figure 10.20
These polyfluoroaryl groups enhance the acceptor properties of mercury and neutral
1:1 coordination complexes can be isolated with bipyridyl, 1,2-bis(diphenylphosphi-
no)ethane, 1,10-phenanthroline, and so on [45, 63].
Whereas bis(perfluoroalkyl)mercurials are cleaved by alkali, nucleophilic aromatic
substitution occurs with bis(pentafluorophenyl)mercury [67] (Figure 10.21).
(C6F5)2Hg + KOHt-BuOH
100�C(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)2HgS
250�C(C6F5)2S
(C6F5)2HgSn
260�C(C6F5)4Sn
82%
60%
½68�
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 four-
centre process [45] (Figure 10.23).
An order of susceptibility to electrophilic attack may be formulated as C6H5 >
C6F5 > C6Cl5 > CH3, which correlates with similar cleavage reactions of tin derivatives.
These reactions have applications in the synthesis of boron and aluminium compounds.
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 375
Organometallic Compounds 375
(C6F5)2Hg + HgCl2
C6F5Hg
Cl
HgCl
F2 C6F5HgCl
C6F5HgCH3
HCl (g)C6F5H + CH3HgCl
C6F5HgC6H5
HCl (g)C6H6 + C6H5H (trace) + C6F5HgCl
δ−
δ+
½45�
½45�
½45, 70�
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 per-
fluoroalkyl group attached to boron before success was achieved. Difficulty arises from
the propensity of a fluorine atom for migration from carbon to boron; for example, the
compound CF3BF2 has been isolated in low yields [71, 72] and delightfully described as
‘enduringly metastable’, with respect to formation of BF3. It is not clear, however,
whether this decomposition is intermolecular (10.24A), intramolecular (10.24B) or both
(Figure 10.24).
CF3BF2 CF
F
F
BF2or CF
F
F
BF2
10.24A 10.24B
Figure 10.24
This ease of migration of fluorine from carbon to boron has inhibited the development
of hydroboration techniques in fluorinated systems. However, when the carbon–fluorine
bond is sufficiently remote from the boron, then hydroboration works well and Markov-
nikov or anti-Markovnikov additions may be obtained, depending on the hydroborating
system; dicyclohexylborane, ChxÞ2BH�
, is less electrophilic but sterically more
demanding than dihaloboranes (Figure 10.25).
At the root of the instability of fluoroalkylboron compounds is the availability of a
vacant orbital on boron; it will be seen that when boron is co-ordinately saturated, as in
four-covalent boron derivatives (10.26A), or partially saturated by p bonding with
attached oxygen- or nitrogen-containing groups (10.26B), then the stability of perfluoro-
alkylboron compounds increases (Figure 10.26).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 376
376 Chapter 10
RF
OHRF
RFCHOH.CH3iii, ii i,ii
i, HBCl2, Hexane; ii, H2O2, alkaline; iii, (Chx)2BH, THF
86% yield (RF = C6F13) 90% yield (RF = C6F13)
95% Regioselective 99% Regioselective
80% yield (RF = CF3) 82% yield (RF = CF3)
94% Regioselective 99% Regioselective
½73, 74�
Figure 10.25
B RF
X
B
X
RF
10.26A 10.26B
X = O- or N<
X
B
X
RF
Figure 10.26
Several salts containing the anion ½RFBF3�� ðe:g: RF ¼ CF3, C2F5Þ have been isolated
[75a], as indicated below, while the tri-covalent derivatives 10.27A and 10.27B are not
readily decomposed; for example, 10.27A is recovered unchanged after heating to 1208C.
Furthermore, thermal decomposition of 10.27A or 10.27B gives n-C3F7H and not per-
fluoropropene, which would be formed if migration of fluorine to boron was still
important [76] (Figure 10.27).
2 Unsaturated derivatives
There is a marked increase in stability, with respect to formation of boron trifluoride,
along the series CF3BF2 � CF25CFBF2 < C6F5BF2 [71, 77, 78] and this can be related
to partial co-ordinative saturation of boron.
Trifluorovinylboron and pentafluorophenylboron halides are synthesised by electro-
philic cleavage from unsymmetrical tin compounds or mercurials [7, 17, 18] (Figure
10.28).
The formation of C6F5BF2 rather than ½C6F5BF3�� indicates that C6F5BF2 is a weaker
Lewis acid than BF3, i.e. CF3BF2 > BF3 > C6F5BF2. A complex salt 10.29A can,
however, be obtained by addition of C6F5BF2 to an aqueous solution of potassium
fluoride; the salt undergoes a novel elimination process on pyrolysis, giving polyphenyl-
enes 10.29B [79] (Figure 10.29).
Trifluorovinylboron derivatives are only stable for short periods when heated at 1008C,
and their partial decomposition to boron trifluoride occurs even on standing at room
temperature [77, 80].
Heating pentafluorophenylboron difluoride leads to disproportionation and not aryne
formation [78] (Figure 10.30).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 377
Organometallic Compounds 377
Me3SnCF3 Me3Sn(CF3BF3)
i, BF3, CCl4, −196 to −20�C
aq. KFK(CF3BF3) + Me3SnF
∆
[ CF2] + KBF4CF2=CF2 F F+ +
O
B
O
i, n-C3F7Li, −50�C, Et2O
O
B
O
Cl C3F7
30%
10.27A
120�C, 3hr
172�C,12hr
Unchanged
n-C3F7H
25%
n-C3F7Li(Me2N)2BC3F7(Me2N)2BX
10.27B
i
i
½75�
½76�
½76�
Figure 10.27
Me2Sn(CF=CF2)2
i, BCl3, rt
CF2=CFBCl2 + Me2SnCl2
93%
SbF3
CF2=CFBF2 59%
Me3SnC6F5
i, BF3 CCl4
Me3SnBF2 + C6F5BF2
Me3SnC6F5
BCl3C6F5BCl2 C6F5BF2
i
i
½77�
½78�
½78�
Figure 10.28
C6F5BF2 + KFH2O K(C6F5BF3)
300�CKBF4 + -(C6F4)-n
10.29B10.29A
½79�
Figure 10.29
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 378
378 Chapter 10
F
194�C
18hrBF3 + (C6F5)2BF
H2O
(C6F5)2BOH
71%
C6F5BF2 ½78�
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).
C6F5BCl2
i, H2O, Acetone, −78�C
C6F5B(OH)2
89%
H2OC6F5B(OH)2.OH2
H2O Base
C6F5B(OH)3C6F5H + H3BO3
i ½78�
Figure 10.31
Tris(pentafluorophenyl)boron forms etherates but it can also be obtained unco-
ordinated in a hydrocarbon solvent (Figure 10.32).
3 C6F5Li + BCl3
i, Pentane/Hexane, −78�C to rt
(C6F5)3B 50%
3 C6F5MgBr + BF3.OEt2
i, Toluene, Reflux
(C6F5)3B 80%
(C6F5)3B
i, C6F5Li, Et2O, Hexane, −78� Cii, Pyridine
(C6F5)4BLii
ii
(C6F5)3B.NC5H5
i
i
½46�
½81�
½46�
Figure 10.32
The contrast in thermal stability between ðC6F5Þ3B and CF3BF2 is significant; for
example, the pentafluorophenyl compound was recovered largely unchanged after heating
at 2708C for 168 h [82]. Tris(pentafluorophenyl)boron is, in effect, a novel Lewis acid
and it is a curious fact that this compound, which was first made over 40 years ago, has
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 379
Organometallic Compounds 379
only in the last few years become important as a co-catalyst for polymerisation [18].
Similarly, pentafluorophenylaluminium compounds have been developed for the same
purpose (see below), a salutary lesson to those who feel confident in predicting which
basic research areas will yield great practical returns on the sums invested.
B Aluminium
Factors analogous to those which limit the stability of perfluoroalkylboron compounds are
even more dominant in the case of aluminium. Indeed, no perfluoroalkyl derivatives of
tri-covalent aluminium have been obtained, although salts of the type Li½ðn-C3F7Þ2AlI2�are produced [83] in reactions of perfluoroalkyl iodides with LiAlH4.
Tris(trifluorovinyl)aluminium may be obtained as the trimethylamine complex, as
indicated in Figure 10.33.
3(CF2=CF)2Hg + 2Me3N.AlH3Et2O
(CF2=CF)3Al.NMe3 + 3H2 + 3Hg
½84�
Figure 10.33
Tris(pentafluorophenyl)aluminium is obtained as the etherate from either the Grignard
reagent in ether or the lithium derivative in ether/hexane [81, 85], whereas only complex
materials are obtained from pentafluorophenyl-lithium in hexane (Figure 10.34). At-
tempts to remove the ether from the etherate, 10.34A, inevitably led to explosions.
3C6F5MgBr + AlBr3Et2O
−20 to 0�C(C6F5)3Al.OEt2
10.34A
½81, 85�
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 1958C.
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, Petroleum, 70�C, 5days
C6F5AlBr2 + MeHgBr
C6F5HgMe
(C6F5)2AlBr + MeHgBr
10.35A
10.35B
i ½85�
Figure 10.35
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 380
380 Chapter 10
C6F5
AlBr
Br
BrAl
Br
C6F5
C6F5
AlC6F5
Br
BrAl
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 +
Hydrolysis
AlCHMe
CH2
Toluene
MeCH=CH2C6F5(C3H6)nH + C3H6 + C6F5H
10.37A
½86�
Figure 10.37
Tris(pentafluorophenyl)aluminium has been prepared by metathesis, [87] (Figure
10.38), and the toluene complex is used as a co-catalyst for alkene polymerisation.
Me3Al + B(C6F5)3 Me3B + (C6F5)3Al ½87�
Figure 10.38
V SILICON AND TIN
A Silicon
The Grignard or lithium route is of limited value for the preparation of perfluoroalkyl
derivatives. Much of the early work was concerned with the addition of silanes to
fluorinated alkenes [88, 89], leading to the preparation of important fluorinated poly-
siloxanes, manufactured by Dow Corning Co. (Figure 10.39).
The siloxane 10.39A chars at 150–2008C and 10.39B decomposes above 2008C to
give vinyl fluoride, while 10.39C only decomposes at temperatures in excess of 4008C.
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 re-
agent’ [92], has been widely investigated [93–96] as an intermediate for transferring the
trifluoromethyl group as a nucleophile, thus compensating for the deficiencies of poly-
fluoroalkyl Grignard or lithium derivatives. This approach also complements other
methods for transfer of trifluoromethide ion. A variety of procedures have now been
developed for the synthesis of this compound but the electrochemical procedure [93]
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 381
Organometallic Compounds 381
(Figure 10.41), or simply heating bromotrifluoromethane with ðCH3Þ3SiCl and alumin-
ium powder, is particularly effective [97] (Figure 10.42).
Et2SiCl2 + n-C3F7Li~−50�C
Et2Si(n-C3F7)2 10%
+
Et2Si(n-C3F7)Cl 17%
MeSiHCl2hν
MeCl2Si + H
MeCl2Si + CF2=CF2 MeCl2SiCF2CF2
MeSiHCl2
MeCl2SiCF2CF2H + MeCl2Si etc[MeSi(CF2CF2H)O]nH2O
SiHCl3 + CF2=CF2hν
HCF2CF2SiCl3H2O [HCF2CF2SiO1.5]n
SiHCl3 + CF2=CH2hν
HCF2CH2SiCl3H2O [HCF2CH2SiO1.5]n
SiHCl3 + CF3CH=CH2hν
CF3CH2CH2SiCl3H2O [CF3CH2CH2SiO1.5]n
10.39A
10.39B
10.39C
½34�
½90�
½91�
½91�
½91�
Figure 10.39
Si C
F
∆Si F + C
SiC
C
F
∆ Si F +
Figure 10.40
CF3Bri
Me3SiCF3
i, Me3SiCl, anisole - HMPA (5 : 1)Sacrificial Al anode, Bu4NPF6 ( electrolyte)
CF3Br + 2e CF3− + Br
−
CF3− + Me3SiCl Me3SiCF3 + Cl
−
Anode: 2/3 Al0 2e 2/3 Al3+
½93�
Figure 10.41
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 382
382 Chapter 10
CF3Br + Me3SiCl Me3SiCF3 62%i
i, Al powder, NMP, Heat
½97�
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].
C
R1 R2
O
CF3SiMe3+
NBu4 F−
FSiMe3
R1 R2
O NBu4F3C
CF3SiMe3
R1 R2
OF3C NBu4
SiMe
F3CMe
Me
C
R1 R2
O
R1 R2
TMSF3C
H+
R1 R2
OHF3C
½94�
Figure 10.43
Examples of the application of Ruppert’s reagent are shown in Figure 10.44, including
the especially interesting diastereoselective procedures.
The process and mechanism for nucleophilic transfer from Me3SiCF3 to electrophilic
sites are analogous to the clever use of DMF as a reservoir for trifluoromethide (10.45A),
formed by reaction of fluoroform with a base [96], in a process outlined in Figure 10.45;
they are also analogous to the use of iodoperfluoroalkanes with tetrakis(dimethylami-
no)ethene [99] (Figure 10.46).
Not surprisingly, trifluorovinyl groups are cleaved by aqueous potassium hydroxide
from, for example, ðCF25CFÞ4Si, Et2SiðCF5CF2Þ2 and Et3SiCF5CF2, which may be
obtained by the Grignard or lithium routes [100–104] (Figure 10.47).
However, with other nucleophiles attack also occurs at carbon in 10.48A, leading to
displacement of fluorine [102] (Figure 10.48).
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 383
Organometallic Compounds 383
RCOOCH3i, ii
RCOCF3
i, Me3SiCF3, THF, TBAF, −78�C
ii, H+ R = Ph 78% = C6H11 72%
N
Ph R1
R2
N
R1
R2
Ph
F3C
SiMe3
41 − 86%
i
i, Me3SiCF3, THF, TBAF
t-BuS
N
H
R1 R1
Oi
t-BuS
N
CF3O
Hi, Me3SiCF3, THF, TBAF, −55�C
R1 = p-ClC6H4 95%
= Ph 80%
= t-Bu 75%
(RS1S)/(RS1R)Yield
>99
97 : 3
99 : 1
½94�
½94�
½94, 98�
Figure 10.44
Ph2CO + CF3H Ph2C(OH)CF3 72%i
i, (Me3Si)3N / Me4NF, DMF
O R
R1
R1
CF3O
M
NO
F3C R
O
F3CNMe2
H
O
R R1
O
H
N(SiMe3)2
N(SiMe3)3O
Me2N
Me2N
H
CF3H
F
Me3SiF
OSiMe3
F3C RR1
N(SiMe3)3
10.45A +
½96�
Figure 10.45
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 384
384 Chapter 10
RFI + TDAE [RFI] RFSiMe3
55−81%
RF = C2F5, n-C3F7, n-C4F9
i
i, (Me2N)2C=C(NMe2)2 ii, Me3SiCl
+1e
ii
RF Transfer½99�
Figure 10.46
CF2=CFMgISiCl4
−15�C(CF2=CF)4Si
15%KOH
−110�CCF2=CFH ½100�
Figure 10.47
Et3SiCF=CF2 + RLiEt2O Et3SiCF=CFR + LiF
R = Ph 76%
= C4H9 79%
10.48A
½102�
Figure 10.48
B Tin [15]
Some syntheses of perfluoroalkyl and polyfluoroalkyl derivatives are shown in Figure
10.49.
Me3SnSnMe3 + RFIhν
or ∆Me3SnRF + Me3SnI
RF = CF3, C2F5, etc
n-Bu2SnH2 + 2CF2=CF2
90�C
4hrn-Bu2Sn(CF2CF2H)2 28%
Me3SnSnMe3 + CF2=CF2hν
Me3SnCF2CF2SnMe3
Me2SnCl2 + Mg
i, C2F5I, THF, rt
Me2Sn(C2F5)2 34%i
½25, 105�
½106�
½107�
½108�
Figure 10.49
A few general trends can be traced from reactions of these compounds. Hydrolytic
cleavage occurs readily and this may well involve a two-step process, that is, via a five-
co-ordinate species, such as 10.50A, rather than an SN2-type process (Figure 10.50).
Nucleophilic displacement of trifluoromethyl also occurs with iodide ion and this is a
useful method for generating difluorocarbene [109] (Figure 10.51) (see Chapter 6, Section
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 385
Organometallic Compounds 385
HO + Me3SnCF3 [(Me3Sn(OH)CF3]
CF3H + Me3SnOH + OH
10.50A
Figure 10.50
I + Me3SnCF3
i, NaI, DME, 80�C
Me3SnI + CF3
−F
CF2
F F
MeMe
MeMe
ii
ii, Me2C=CMe2
i ½109�
Figure 10.51
IIIA), although other perfluoroalkyltin compounds are not sources of the corresponding
carbenes [110].
Thermal decomposition, again, occurs readily and, in the case of ðCH3Þ3SnCF3,
difluorocarbene is probably formed (Figure 10.52); see Chapter 6, Section IIIA,
Subsection 3.
Me3SnCF3150�C
Me3SnF + CF2
CF2=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 ðCH3Þ3SnC6F5
to hydrolysis is very dependent on purity; in the presence of fluoride ion, rapid hydrolysis
occurs and a process involving initial co-ordination of fluoride ion, and other halide ions,
to tin has been suggested [111] (Figure 10.53).
Me3SnC6F5 + X−
[Me3(C6F5)SnX]−
[Me3(C6F5)SnX (H2O)]−
Me3SnOH + C6F5H + X−
½111�
Figure 10.53
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 386
386 Chapter 10
Perfluorovinyl [112] and perfluoromethyl derivatives apparently undergo similar cleav-
age with aqueous alcoholic potassium fluoride. Fluorocarbon tin compounds may be used
effectively in Stille coupling processes [15] (Figure 10.54).
Bu3SnCF=CF2 +
I
Y
i
CF=CF2
Y
15−87%i = Pd catalyst
½15�
Figure 10.54
Electrophilic cleavage of perfluorovinyl [42] and perfluorophenyl [111] from mixed
compounds occurs quite readily, although electrophilic attack is much more difficult in
the tetrakis derivatives such as tetrakis(pentafluorophenyl)tin. The order of ease of
electrophilic cleavage from tin has been established as CF25CF � C6H5 >
CH25CH > alkyl > perfluoroalkyl [42], and p-MeC6H4 > C6H5 > C6F5 > Me [111],
illustrating the effect of electron withdrawal by fluorine; nevertheless, quantitative work
on the acid cleavage of Me3SnC6F5 indicates a rate greater than might be expected from
the combined effects of the atoms on an additive basis [113]. The well-known exchange
reaction between tetra-alkyl- or tetra-aryl-tin compounds and tin(IV) is much more
difficult with tetrakis(pentafluorophenyl)tin [114] (Figure 10.55).
3(C6F5)4Sn + SnCl4 3(C6F5)3SnCl160�C
7days
(C6F5)4Sn + 3 SnCl4 4 C6F5SnCl3140�C
11 weeks
½114�
½114�
Figure 10.55
The trichloride is more effectively made by cleavage of methylpentafluorophenylmer-
cury [111] (Figure 10.56).
C6F5HgMe + 3 SnCl4 C6F5SnCl3 + MeHgCl20�C
20 hours½111�
Figure 10.56
Cleavage of tetrakis(pentafluorophenyl)tin does not occur with boron halides, but
pentafluorophenylboron halides can be obtained from ðCH3Þ3SnC6F5 [79].
VI TRANSITION METALS
Factors affecting the stability of transition-metal bonds to carbon are of continued interest
and fluorocarbon transition-metal derivatives are especially interesting [115–117] be-
cause of their generally enhanced stability, relative to hydrocarbon analogues. Factors
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 387
Organometallic Compounds 387
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 de-
carboxylation of salts of carboxylic acids [123–125] (Figure 10.58).
It was concluded, from the establishment of a crude r-value of þ0.46 for the reaction,
that the process may involve ½CF3CuI�� as an intermediate. A similar process may be
involved in the reaction of trifluoromethanesulphonyl chloride with copper (Figure
10.59).
Burton and co-workers, as part of a series of ground-breaking studies on fluorinated
organometallic systems [14], have established that trifluoromethyl derivatives may be
obtained by reaction of halofluoromethanes with copper and other metals. The process
involves electron transfer from the metal, with subsequent loss of halogen to form
difluorocarbene which, in turn, generates very active fluoride ion by reaction with the
solvent. The full process is indicated in Figure 10.60.
In an analogous manner trifluoromethylcopper has been generated from sulphonyl
fluorides (Figure 10.61).
Trifluorovinylcopper reagents are also stable and have been used in various useful
coupling reactions [15], especially in the synthesis of polyenes, where stereospecific
systems may be obtained (Figure 10.62).
Several procedures have been used to obtain pentafluorophenylcopper and this reagent
(again, much more stable than phenylcopper) may be used in coupling procedures (Figure
10.63).
B Other metals
Various approaches to other transition-metal derivatives have been applied which are not
covered here, but some involve reactions that exploit the properties of the fluorocarbon
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 388
388 Chapter 10
CF3I + Cui
[CF3Cu]PhI
PhCF3
NBr Br
n-C6F13I
Nn-C6F13 n-C6F13
i
i = Cu, DMSO, 125−130�C
I(CF2)3I + 2 ICH�CHCli
ClHC�CH(CF2)3CH�CHCl
i = Cu, Pyridine, 100� C
CHF2Cu + CH CCMe2Cl HCF2CH�C�CMe2
78%
i
i = DMF, −55� C
CF3Cu +
S S
i
i = DMF, HMPA, 70� C
N
NN
N
NH2
O
OAcOAc
AcO
Ii
CF3Cu +N
NN
N
NH2
O
OAcOAc
AcO
F3C
i = HMPA
i = DMF, ~135� C
I
CF3
½118�
½119�
½120�
½121�
½14�
½122�
Figure 10.57
CF3CF2CO2Na + p-ClC6H4I p-ClC6H4CF2CF3
i
i = DMF, HMPA, 170� C, Cu2I254%
½125�
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 389
Organometallic Compounds 389
CF3SO2Cl + Cu +
ClNO2
NO2
CF3
NO2
NO2
i
i = DMAC, Heat
½126�
Figure 10.59
CF2XY + M (Zn, Cd, Cu) MXY +
Me2NCHO Me2NCHF2 + CO
Me2NCHF2
F +
CF3
CF3
+ MXY CF3MX + (CF3)2M
[ CF2]
[ CF2]
[ CF2]
Me2N�CHF F
½14�
Figure 10.60
FSO2CF2I + PhIi
PhCCF3
i = Cu, DMF, 60−80� C. ~6Hr.
80%
FSO2CF2COOMei
[CuCF3]ii
PhCH�C(CF3)2
55 %i, CuI, DMF/HMPA, Pd(PPh3)4ii, PhCH�CBr2
½127�
½128�
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 penta-
fluoropyridine, 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 390
390 Chapter 10
F3C
F
F
Cu
F3C F3C
Ph
F
I F
F
F
Ph
CF3
54%
CF2=CFCu CF3C CCF3
F3C
Cu
CF3
I2
63%
(CF2)n(CF2)n
I I
(CF2)n
(CF2)n
(CF2)n (CF2)nCu
F
F
F
F3C
I
CF3
F
F
F
n = 2, 3
½15�
½15�
½129�
Figure 10.62
C6F5M + CuX C6F5Cu
C6F5I
Activated Cu
60� C
C6F5COOCu
C6F5H + LiCuMe2
M = Li, MgBr, CdXX = Cl, Br, I
C6F5Cu + CF2�CFI C6F5CF�CF2
C6F5Cu + CH2I2 (C6F5)2CH2
88%
70%
½15�
½15�
½15�
Figure 10.63
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 391
Organometallic Compounds 391
CF3CF=CF2 π-C5H5Fe(CO)2Na
CF3CF=CF�Fe(CO)2πC5H5 + NaF
THF
(CO)5Mn M CF2=CFCF2Cl (CO)5MnCF2CF=CF2
(CO)5MnCF=CFCF3
M = Li, Na
C6F6 + [π-C5H5Ru(CO)2] C6F5Ru(CO)2π-C5H5
½130�
½131; 132�
½133�
Figure 10.64
π-C5H5Co(CO)2 + CF3I π-C5H5Co(CO)(CF3)I + COBenzene
MeRe(CO)5 + CF2=CF2
hνMeCF2CF2Re(CO)5
Benzene(Ph3P)2Pt(CF=CFCl)2(Ph3P)4Pt + CF2=CFCl
½134�
½135�
½136�
Figure 10.65
N
FX
Br Br
F
X = Br, CF(CF3)2
i
N
FX
RC C C CR
F
R = Ph, C3H7
i = RC CH, CuI, (Ph3P)3PdCl2 , Et3N
CF3CFH2 + ZnCl2i
[CF2=CFZnCl]ii
CF=CF2
R
61−86%
i = LDA, THF, 15−20� Cii = RC6H4I, Pd(PPh3)4, Heat
½138, 139�
½140�
Figure 10.66
Contd
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 392
392 Chapter 10
Ar
H
F
Br
i Ar
H
F
Ph
E/Z ~1:1 100% Z isolated, 73%
Ar = p-FC6H4-
i, −20� C, 7 daysii, PhSnBr3, Pd[(PPh3)]4, CuI, DMF, rt
F
Bu3Sn
F
SiMe3
+ CF2=CFIi F
CF2�CF
F
SiMe3
i, Pd[(PPh)3]4, CuI, DMF, rt
Ph
H
F
Br
i, ii Ph
H
Br Ph
H
F
H
+
i, iii
Ph
H
F
COO n-Bu
F
i, Cl2Pd(PPh3)2ii, HCOOH, n-Bu3N, DMF, 35� Ciii, CO, 160psi, n-BuOH, n-Bu3N, 70� C
E/Z 1:1 100% Z
Ar
H
F
Br
High E/Z ratio
ii ½141�
½142�
½143�
RF
I
R 4
RF
R
4
i
i, PdCl2[PPh3]2 , Et3N, CuI
½144�
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 393
Organometallic Compounds 393
N
F
L2Pd(II) Br
F
X
N
F
Br Br
F
X
N
F
Br
F
X
R
L2Pd(0)
N
F
L2Pd(II) Br
F
X
Br
Et3NHBr
Et3N
H
X = Br, CF(CF3)2
N
F
L2Pd(II) Br
F
X
Br
L = Ph3P
R
H
R
R
½139�
Figure 10.67
i, Ni(COD)(PEt3)2
N
F
N
F
NiEt3P
PEt3
F
N
F
H
HCli
F F [Complex] F F
NiEt3P
PEt3
F
Heati
i, Ni(COD)(PEt3)2
½145�
½146�
Figure 10.68
Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 394
394 Chapter 10
Selective insertion into C2Cl occurs in competition with C2F, leading to further
useful processes (Figure 10.69).
[Ni(COD)2]
N
Cl
F
Ni PEt3Et3P
Cl
NF
N
I
F
I2−[Ni]
PEt3
MeLi
N
FMe
O
N
FMe
OHPEt3
Ni PEt3Et3P
Me
NF
CO−[Ni]
½147�
Figure 10.69
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133 T. Blackmore, M.I. Bruce and F.G.A. Stone, J. Chem. Soc. (A), 1968, 2158.
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135 J.B. Wilford, P.M. Treichel and F.G.A. Stone, Proc. Chem. Soc., 1963, 218.
136 M. Green, R.B.L. Osborn, A.J. Rest and F.G.A. Stone, J. Chem. Soc. (A), 1968, 2525.
137 J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic Synthesis, Wiley-
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138 R.D. Chambers, C.W. Hall, J. Hutchinson and R.W. Millar, J. Chem. Soc., Perkin Trans. 1,
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Chambers: Fluorine in Organic Chemistry Final Proof 7.8.2004 7:26pm page 398
398 Chapter 10
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
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
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 399
399Fluorine in Organic Chemistry Richard D. Chambers © 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7
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 400
400 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
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 401
Index 401
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 SO2F2, 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 402
402 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
SN1 SN2 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
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 403
Index 403
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 404
404 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 SN20 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
SN2 processes
effect of substituents, 122
F/Cl rate constant ratios, 129
fluoride as a leaving group, 128
transition-states, 128
SN20 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 SN2 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
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 405
Index 405
tetrafluoroethene (cont’d)
in polyfluoroalkylation, 328
radical additions, 198, 202–4
reactions with nucleophiles, 173–4, 177
reaction with SO2F2, 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 CF3H, 384
transfer from silicon, see Ruppert’s reagent
trifluoromethylation
transfer from CF3H, 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
Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:04pm page 406
406 Index