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

Fluorine in Organic
Chemistry

Fluorine in Organic Chemistry Richard D. Chambers
© 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7


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

www.pdfgrip.com

Fluorine in Organic
Chemistry
Richard D. Chambers FRS
Emeritus Professor of Chemistry
University of Durham, UK


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

www.pdfgrip.com

ß 2004 by Blackwell Publishing Ltd
Editorial offices:
Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK
Tel: ỵ44 (0)1865 776868
Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia
Tel: þ61 (0)3 8359 1011
ISBN 1-4051-0787-1

Published in the USA and Canada (only) by
CRC Press LLC, 2000 Corporate Blvd., N.W., Boca Raton, FL 33431, USA
Orders from the USA and Canada (only) to
CRC Press LLC
USA and Canada only:
ISBN 0-8493-1790-8
The right of the Author to be identified as the Author of this Work has been asserted in accordance with
the Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise,
except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of
the publisher.
This book contains information obtained from authentic and highly regarded sources. Reprinted material
is quoted with permission, and sources are indicated. Reasonable efforts have been made to publish
reliable data and information, but the author and the publisher cannot assume responsibility for the
validity of all materials or for the consequences of their use.
Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are used
only for identification and explanation, without intent to infringe.
First published 2004
Library of Congress Cataloging-in-Publication Data is available
A catalogue record for this title is available from the British Library
Set in 10/12.5 pt Times
by Kolam Information Services Pvt. Ltd, Pondicherry, India
Printed and bound in India
by Gopsons Papers Ltd, Noida
The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and
which has been manufactured from pulp processed using acid-free and elementary chlorine-free
practices. Furthermore, the publisher ensures that the text paper and cover board used have met
acceptable environmental accreditation standards.
For further information on Blackwell Publishing, visit our website:

www.blackwellpublishing.com


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

www.pdfgrip.com

To
my wife Anne and our grandchildren,
Daniel, Benjamin, Alexandra, and Jack,
who give us so much pleasure


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page vii

www.pdfgrip.com

Contents

Foreword
by Professor George A. Olah
Preface
1
I

GENERAL DISCUSSION OF ORGANIC FLUORINE CHEMISTRY

General introduction
A Properties
B Historical development

II Industrial applications
A Introduction
B Compounds and materials of high thermal and chemical stability
1 Inert fluids
2 Polymers
C Biological applications
1 Volatile anaesthetics
2 Pharmaceuticals
3 Imaging techniques
4 Plant protection agents
D Biotransformations of fluorinated compounds
E Applications of unique properties
1 Surfactants
2 Textile treatments
3 Dyes
III Electronic effects in fluorocarbon systems
A Saturated systems
B Unsaturated systems
C Positively charged species
D Negatively charged species
E Free radicals
IV Nomenclature
A Systems of nomenclature
B Haloalkanes
References

xv
xvii
1
1

1
2
3
3
3
4
5
5
6
7
7
9
9
12
12
12
12
13
14
14
15
15
16
16
17
18
19

vii



Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page viii

www.pdfgrip.com
viii

2

Contents

PREPARATION OF HIGHLY FLUORINATED COMPOUNDS

I

23

Introduction
A Source of fluorine
II
Fluorination with metal fluorides
A Swarts reaction and related processes (halogen exchange using HF)
1 Haloalkanes
2 Influence of substituent groups
B Alkali metal fluorides
1 Source of fluoride ion
2 Displacements at saturated carbon
3 Displacements involving unsaturated carbon
Alkene derivatives
Aromatic compounds
C High-valency metal fluorides

1 Cobalt trifluoride and metal tetrafluorocobaltates
III Electrochemical fluorination (ECF)
IV Fluorination with elemental fluorine
A Fluorine generation
B Reactions
C Control of fluorination
1 Dilution with inert gases
D Fluorinated carbon
E Fluorination of compounds containing functional groups
V
Halogen fluorides
References

23
23
23
24
25
26
27
28
29
30
30
31
31
32
33
35
35

35
36
36
39
39
40
41

3

PARTIAL OR SELECTIVE FLUORINATION

47

I
II

Introduction
Displacement of halogen by fluoride ion
A Silver fluoride
B Alkali metal fluorides
C Other sources of fluoride ion
D Miscellaneous reagents
Replacement of hydrogen by fluorine
A Elemental fluorine
1 Elemental fluorine as an electrophile
B Electrophilic fluorinating agents containing O–F bonds
C Electrophilic fluorinating agents containing N–F bonds
D Xenon difluoride
E Miscellaneous

Fluorination of oxygen-containing functional groups
A Replacement of hydroxyl groups by fluorine
1 Pyridinium poly(hydrogen fluoride) – Olah’s reagent
2 Diethylaminosulphur trifluoride (DAST) and related reagents
3 Fluoroalkylamine reagents (FARs)

47
47
47
47
49
50
51
51
52
56
58
60
60
62
62
62
63
65

III

IV



Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page ix

www.pdfgrip.com
Contents

B
C

Replacement of ester and related groups by fluorine
Fluorination of carbonyl and related compounds
1 Sulphur tetrafluoride and derivatives
D Cleavage of ethers and epoxides
V
Fluorination of sulphur-containing functional groups
VI Fluorination of nitrogen-containing functional groups
A Fluorodediazotisation
B Ring opening of azirines and aziridines
C Miscellaneous
VII Addition to alkenes and alkynes
A Addition of hydrogen fluoride
B Direct addition of fluorine
C Indirect addition of fluorine
D Halofluorination
E Addition of fluorine and oxygen groups
F Other additions
References
4
I
II
III


THE INFLUENCE OF FLUORINE OR FLUOROCARBON
GROUPS ON SOME REACTION CENTRES

Introduction
Steric effects
Electronic effects of polyfluoroalkyl groups
A Saturated systems
1 Strengths of Acids
2 Bases
B Unsaturated systems
1 Apparent resonance effects
2 Inductive and field effects
IV The perfluoroalkyl effect
V
Strengths of unsaturated fluoro-acids and -bases
VI Fluorocarbocations
A Effect of fluorine as a substituent in the ring on electrophilic
aromatic substitution
B Electrophilic additions to fluoroalkenes
C Relatively stable fluorinated carbocations
1 Fluoromethyl cations
D Effect of fluorine atoms not directly conjugated with the
carbocation centre
VII Fluorocarbanions
A Fluorine atoms attached to the carbanion centre
B Fluorine atoms and fluoroalkyl substituents adjacent to the
carbanion centre
C Stable perfluorinated carbanions


ix

66
66
66
69
71
73
73
74
75
76
76
77
79
80
82
82
83

91
91
91
92
92
92
93
94
94
97

97
98
99
99
101
102
104
105
107
108
111
112


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page x

www.pdfgrip.com
x

Contents

D Acidities of fluorobenzenes and derivatives
E Acidities of fluoroalkenes
VIII Fluoro radicals
A Fluorine atoms and fluoroalkyl groups attached to the
radical centre
B Stable perfluorinated radicals
C Polarity of radicals
References
5


NUCLEOPHILIC DISPLACEMENT OF HALOGEN FROM
FLUOROCARBON SYSTEMS

Substituent effects of fluorine or fluorocarbon groups
on the SN 2 process
A Electrophilic perfluoroalkylation
II
Fluoride ion as a leaving group
A Displacement of fluorine from saturated carbon – SN 2 processes
1 Acid catalysis
2 Influence of heteroatoms on fluorine displacement
B Displacement of fluorine and halogen from unsaturated carbon –
addition–elimination mechanism
1 Substitution in fluoroalkenes
2 Substitution in aromatic compounds
References

113
115
115
115
117
117
118

122

I


122
126
128
128
129
131
131
132
133
135

6

ELIMINATION REACTIONS

137

I

b-Elimination of hydrogen halides
A Effect of the leaving halogen
B Substituent effects
C Regiochemistry
D Conformational effects
E Elimination from polyfluorinated cyclic systems
b-Elimination of metal fluorides
a-Eliminations: generation and reactivity of fluorocarbenes and
polyfluoroalkylcarbenes
A Fluorocarbenes
1 From haloforms

2 From halo-ketones and –acids
3 From organometallic compounds
4 From organophosphorous compounds
5 Pyrolysis and fragmentation reactions
B Polyfluoroalkylcarbenes
C Structure and reactivity of fluorocarbenes and
polyfluoroalkylcarbenes

137
137
138
139
140
142
144

II
III

147
147
147
149
149
151
151
154
156



Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xi

www.pdfgrip.com
Contents

1
2
References
7
I

II

Fluorocarbenes
Polyfluoroalkylcarbenes

POLYFLUOROALKANES, POLYFLUOROALKENES,
POLYFLUOROALKYNES AND DERIVATIVES
Perfluoroalkanes and perfluorocycloalkanes
A Structure and bonding
1 Carbon–fluorine bonds
2 Carbon–carbon bonds
B Physical properties
C Reactions
1 Hydrolysis
2 Defluorination and functionalisation
3 Fragmentation
D Fluorous biphase techniques
Perfluoroalkenes
A Stability, structure and bonding

B Synthesis
C Nucleophilic attack
1 Orientation of addition and relative reactivities
2 Reactivity and regiochemistry of nucleophilic attack
3 Products formed
4 Substitution with rearrangement – SN 20 processes
5 Cycloalkenes
6 Fluoride-ion-induced reactions
7 Addition reactions
8 Fluoride-ion-catalysed rearrangements of fluoroalkenes
9 Fluoride-ion-induced oligomerisation reactions
10 Perfluorocycloalkenes
D Electrophilic attack
E Free-radical additions
1 Orientation of addition and rates of reaction
2 Telomerisation
3 Polymerisation
F Cycloadditions
1 Formation of four-membered rings
2 Formation of six-membered rings – Diels–Alder reactions
3 Formation of five-membered rings – 1,3-dipolar cycloaddition
reactions
4 Cycloadditions involving heteroatoms
G Polyfluorinated conjugated dienes
1 Synthesis
2 Reactions
3 Perfluoroallenes

xi


156
158
159

162
162
162
162
162
163
163
163
164
166
166
167
167
169
171
172
172
176
176
183
185
186
187
188
190
191

196
197
202
203
205
205
209
212
214
214
214
216
218


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xii

www.pdfgrip.com
xii

Contents

III Fluoroalkynes and (fluoroalkyl)alkynes
A Introduction and synthesis
B Reactions
1 Perfluoro-2-butyne
Formation of polymers and oligomers
Reactions with nucleophiles
Fluoride-ion-induced reactions
Cycloadditions

Free-radical additions
References
8
I

FUNCTIONAL COMPOUNDS CONTAINING OXYGEN,
SULPHUR OR NITROGEN AND THEIR DERIVATIVES

Oxygen derivatives
A Carboxylic acids
1 Synthesis
2 Properties and derivatives
3 Trifluoroacetic acid
4 Perfluoroacetic anhydride
5 Peroxytrifluoroacetic acid
B Aldehydes and ketones
1 Synthesis
2 Reactions
Addition to C5O
Reactions with fluoride ion
C Perfluoro-alcohols
1 Monohydric alcohols
2 Dihydric alcohols
3 Alkoxides
D Fluoroxy compounds
E Perfluoro-oxiranes (epoxides)
F Peroxides
II Sulphur derivatives
A Perfluoroalkanesulphonic acids
B Sulphides and polysulphides

C Sulphur(IV) and sulphur(VI) derivatives
D Thiocarbonyl compounds
III Nitrogen derivatives
A Amines
B N–O compounds
1 Nitrosoalkanes
2 Bistrifluoromethyl nitroxide
C Aza-alkenes
D Azo compounds
E Diazo compounds and diazirines
References

218
218
222
222
222
223
223
224
226
227

236
236
236
236
238
240
241

242
243
243
243
246
251
254
254
255
257
258
259
264
265
265
270
272
272
275
275
277
277
278
278
284
284
287


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiii


www.pdfgrip.com
Contents

9

POLYFLUOROAROMATIC COMPOUNDS

I

xiii

296

Synthesis
A General considerations
B Saturation/re-aromatisation
C Substitution processes
1 Replacement of H by F
2 Replacement of 2N2ỵ by F: the BalzSchiemann reaction
3 Replacement of 2OH or 2SH by F
4 Replacement of Cl by F
II Properties and reactions
A General
B Nucleophilic aromatic substitution
1 Benzenoid compounds
Orientation and reactivity
Mechanism
2 Heterocyclic compounds
Pyridines and related nitrogen heterocyclic

(azabenzenoid) compounds
Polysubstitution
Acid-induced processes
3 Fluoride-ion-induced reactions
Polyfluoroalkylation
Other systems
4 Cyclisation reactions
C Reactions with electrophilic reagents
D Free-radical attack
1 Carbene and nitrene additions
E Reactive intermediates
1 Organometallics
Lithium and magnesium derivatives
Copper compounds
2 Arynes
3 Free radicals
4 Valence isomers
Nitrogen derivatives
References

296
296
297
298
298
300
300
300
306
306

307
307
310
311
315
315
320
321
325
325
332
332
336
338
338
341
341
342
346
346
349
351
353
358

10

ORGANOMETALLIC COMPOUNDS

365


I

General methods and synthesis
A From iodides, bromides and hydro compounds
1 Perfluoroalkyl derivatives
2 Derivatives of unsaturated systems

365
365
365
366


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 7:05pm page xiv

www.pdfgrip.com
xiv

Contents

B

From unsaturated fluorocarbons
1 Fluoride-ion-initiated reactions
II Lithium and magnesium
A From saturated compounds
B From alkenes
C From trifluoropropyne
D From polyfluoro-aromatic compounds

III Zinc and mercury
A Zinc
B Mercury
1 Perfluoroalkyl derivatives
2 Unsaturated derivatives
3 Cleavage by electrophiles
IV Boron and aluminium
A Boron
1 Perfluoroalkyl derivatives
2 Unsaturated derivatives
B Aluminium
V Silicon and tin
A Silicon
B Tin
VI Transition metals
A Copper
B Other metals
References

367
367
368
368
369
370
371
371
371
373
373

374
375
376
376
376
377
380
381
381
385
387
388
388
395

Index

399


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

www.pdfgrip.com

Foreword
by Professor George A. Olah
Nobel Laureate

Chambers’ book Fluorine in Organic Chemistry was published 30 years ago and became a
classic of the field. A revised and updated edition is a significant and authoritative

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

xv


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

www.pdfgrip.com

Preface

This book is a revision and update of one that was first published in 1973, followed by
two small reprintings. The original was prompted by Professor George Olah, during a year
that I spent as a Visiting Lecturer in Cleveland. My aim for the original edition was to
present an overview of organofluorine chemistry, in a way that corresponded with modern
organic chemistry. Of course this involved including a mechanistic basis of the subject,
which was still evolving at the time; to my knowledge, this was the first broad attempt to
do so. The original book appears to have served a useful purpose because, for a number of
years now, friends in the field have encouraged me to write an update.
In the intervening years since the first edition the subject has grown enormously, and
any idea of a single-author comprehensive volume would now be a preposterous undertaking. Consequently, I have concentrated attention on illustrating the principles of the

subject, and especially those concerning highly fluorinated compounds, where the chemistry is quite unusual. Inevitably, important areas are omitted: for example the impact of
fluorine as a label in biochemistry, which is outside my expertise. However, I hope that
there are enough key references to important areas that I have neglected.
Inevitably, my choice of illustrative examples is subjective and I apologise in advance
for all the beautiful examples that have not been included.
The considerable task of producing the manuscript would not have been completed
without the continued help of a long-term friend and collaborator, Dr. John Hutchinson, to
whom I am deeply indebted. Also, my sincere thanks to the Leverhulme Trust for an
Emeritus Fellowship, during the tenure of which the book was written. Thanks also to my
colleague, Dr Graham Sandford, for invaluable help and discussions, and to Dr Darren
Holling, Rachel Slater and Chris Hargreaves for reading the manuscript. Last, but not
least, thanks to my wife Anne for her continued forbearance.
Dick Chambers

xvii


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

www.pdfgrip.com

Chapter 1

General Discussion of Organic
Fluorine Chemistry

I

GENERAL INTRODUCTION


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

A


Properties

Fluorocarbon systems, in general, present no peculiar handling difficulties and the
familiar and powerful techniques of isolation, purification and identification in organic
Fluorine in Organic Chemistry Richard D. Chambers
© 2004 Blackwell Publishing Ltd. ISBN: 978-1-405-10787-7

1


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 2

www.pdfgrip.com
2

Chapter 1

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


B Historical development
It could be argued that fluorocarbon chemistry began with Moissan in 1890 when he
claimed to have isolated tetrafluoromethane from the reaction of fluorine with carbon,
but these results were in error [43, 44]. Swarts, a Belgian chemist, began his studies on the
preparation of fluorocarbon compounds [45] by exchange reactions around 1890 and
for about 25 years from 1900 he was virtually the only worker publishing in the field.
He continued until about 1938, and during that time he contributed a great deal in
outlining methods of preparation for a large number of partly fluorinated compounds. It
was on the foundation of Swarts’s work that Midgley and Henne [46] in 1930 were able
to apply fluoromethanes and ethanes as refrigerants, and this development gave the
subject some financial impetus for progress. Tetrafluoromethane was the first perfluorocarbon to be isolated pure; it was reported in 1926 by Lebeau and Damiens [47] but
not properly characterised by them until 1930 [48] and, in the same year, by Ruff and
Keim [49]. Swarts made trifluoroacetic acid [50] as early as 1922 and in 1931 reported
that the electrolysis of an aqueous solution of the latter gave pure perfluoroethane [51].
Nevertheless, the first liquid perfluorocarbons were not characterised until 1937, when
Simons and Block found that mercury promotes reaction between carbon and fluorine
[52]; they were able to isolate CF4 , C2 F6 , C3 F8 , C4 F10 (two isomers), cyclo-C6 F12 and
C6 F14 .
It was established that these compounds are very thermally and chemically stable and
this led to suggestions by Simons that these materials might be resistant to UF6 , which
was found to be the case. There then ensued a period of very rapid development in the
synthesis of fluorocarbon materials, the goal being stable lubricants and gaskets for use in
the gaseous diffusion plant for concentrating the 235 U isotope, using UF6 . These wartime
developments have been published in various collected forms [53–55]. Tetrafluoroethene
was obtained by Ruff and Bretschneider in 1933, who decomposed tetrafluoromethane in
an electric arc [56] while Locke et al. [57] developed a synthesis in 1934, which involved
zinc dehalogenation of CF2 Cl2CF2 Cl. Then the formation of polytetrafluoroethene [58]
was discovered in 1938 and in the same period chlorotrifluoroethene was found to
polymerise to give a very stable inert transparent polymer. The wartime efforts involved
development of these and other new materials. Nevertheless, even at the end of the



Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 3

www.pdfgrip.com
General Discussion of Organic Fluorine Chemistry

3

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

II


INDUSTRIAL APPLICATIONS

A

Introduction

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

B

Compounds and materials of high thermal and chemical
stability [29]

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


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 4


www.pdfgrip.com
4

Chapter 1

1 Inert fluids
The chlorofluorocarbons (CFCs) were introduced over 60 years ago as refrigerants [46] to
replace gases such as ammonia and sulphur dioxide. In 1974, at the peak of production,
900 000 tonnes of CFCs, principally CF2 Cl2 (CFC-12), CFCl3 (CFC-11) and CHFCl2
(CFC-22), were manufactured mainly for use as refrigerants, aerosols and foam blowing
agents. However, it was eventually recognised that the inertness of volatile CFCs is itself
a problem because they survive unchanged up to the stratosphere, where they dissociate
under short-wavelength solar ultraviolet radiation, releasing chlorine atoms which then
catalyse the decomposition of ozone to oxygen [66, 67]. Consequently, the Montreal
Protocol, which was introduced in 1987 and revised in 1990 and 1992, caused the
complete phase-out of production and use of the CFC range of compounds. This legislation forced refrigerant manufacturers to identify alternative ranges of non-toxic, stable
chemicals which, additionally, possess low ozone depletion potentials (ODPs) and low
global warming potentials (GWPs) to meet customer needs and regulatory requirements.
Hydrofluorocarbons (HFCs), being free of chorine atoms, have ODPs of zero, making
these products ideal systems for replacing CFCs. One of the major unsung achievements
of the chemical industry has been the rapid development to large-scale production of these
substitutes for CFCs; for example, CF3 CFH2 (HFC-134a) is an acceptable substitute for
CF2 Cl2 (CFC-12) in refrigeration applications.
Bromofluorocarbons possess outstanding fire-extinguishing ability: CF3 Br has been
used for automatic systems where the use of water is as potentially damaging as a fire, for
instance in art galleries and in libraries, or in aircraft where highly efficient non-toxic
agents are required. However, on an atom-to-atom basis bromine atoms are estimated to
be 40 times more effective at destroying ozone than chlorine atoms, and therefore the
Montreal Protocol required the complete phase-out of bromofluorocarbon use in 1994.

Alternative ‘in-kind’ replacements [68] of these halon fire extinguishers are being developed and currently CHF3 (DuPont) and CF3 CFHCF3 (Great Lakes), amongst others,
are on the market [69], but at the time of writing the problem of finding replacements for
bromofluorocarbons for application as fire-fighting agents in aircraft is largely unsolved.
Perfluorocarbon fluids, such as the Flutect range (F2 Chemicals Ltd), find many uses
in the electronics industry. For instance, the complete immersion of electronic components in a bath of perfluorocarbon fluid can efficiently cool overheated circuits and, by a
similar process, the airtight packaging around highly valuable and sensitive equipment
can be tested in complete safety for leaks.
Since perfluorocarbons are inert to microbiological attack, many potential medical uses
of these fluids have been investigated. The report by Clark in 1966 that perfluorocarbons
can dissolve significant amounts of oxygen [70] prompted the exciting suggestion that such
fluids could be used as ‘artificial blood’ [71] and the now-classic photograph of a rat
breathing under liquid perfluorocarbon has been reproduced countless times. Perfluorocarbons are immiscible with blood and do not dissolve the essential mineral nutrients required.
Consequently, emulsions of perfluorocarbons with an aqueous buffer solution containing
various surfactants have been formulated as potential blood substitutes. Although products
have been approved and marketed, there is no commercially successful emulsion.
The need to extend the liquid range of perfluorinated systems to very high molecular
weights was satisfied by the important introduction of perfluoropolyethers (PFPEs) [72]


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 5

www.pdfgrip.com
General Discussion of Organic Fluorine Chemistry

5

as high-boiling inert fluids, such as Krytoxt (DuPont), Fomblint (Ausimont) and
Demnumt (Daikin), for use in demanding environments and for long-term reliability
(Figure 1.1). These fluids have the longest liquid range known [73], remaining in fluid
form from À1008 C to 3508 C and, consequently, are used for the lubrication of many

diverse precision instruments, from the mechanisms of luxury watches to the moving
parts of geostationary satellites and even for computer discs.
F

CF3

O

OCF2CF2CF2
F

F

n

OCF2

n

Krytox® (DuPont)
Lubricants, coatings

Demnum® (Daikin)

n

OCF2CF2

m


Fomblin® (Ausimont)

Lubricants, vacuum pump oils

Figure 1.1

2

Polymers [73a]

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

C

Biological applications [29, 61, 62]


The physiological properties of many biologically significant molecules can be modulated if fluorine or fluorinated groups are incorporated into their structure [24, 78]; factors
affecting the change in biological activity of a substrate upon fluorination are complex
[79].


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

www.pdfgrip.com
6

Chapter 1

Table 1.1 Applications of fluoropolymers
Polymer

Monomer(s)

Applications

CF2=CF2

PTFE

FEP

CF2=CF2 + CF3CF=CF2

PFA


CF2=CF2 + RFOCF=CF2
F

Teflon AFt (DuPont)

CF2=CF2+ O
CF3

F

Optically clear, used in corrosive
environments where glass is
unsuitable, e.g. in computer chip
manufacture.
Optically clear, used in corrosive
environments, e.g. computer
chip manufacture.
Gaskets, seals, oils, coatings,
transparent inert covers.
Weather-resistant coatings; cable
insulation; piezo-electric devices.
Coatings, flexible films.
Elastomers used for sealants, Orings, fuel-resistant seals for
aircraft and automobiles.

O
CF3

CF2=CFO(CF2)nCF=CF2


Cytopt (Asahi)

PCTFE

CF2=CFCl

PVDF

CF2=CH2
CH2=CHF

PVF
VitonAt (DuPont)

CF2=CH2 + CF3CF=CF2
CF2ϭCF2 + F2CϭC

F

CF3

2

Nafiont (DuPont)

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

Fabrication by conventional melt
processing; wire and cable
insulators; heat-sealable film,
tubing.
Injection-moulded parts for use in
aggressive environments.

Membranes in chlor-alkali cells.

Ϫ

(OCF2CF)nO

CF2CF2X

Flemiont (Daikin)

Nafion, X ¼ CO2 H
Flemion, X ¼ SO2 H

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

CF3CHClBr


CF3CHClOCHF2

(CF3)2CHOCH2F

CF3CHFOCHF2

Fluothane®

Isoflurane®

Sevoflurane®

Desflurane®

Figure 1.2


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

www.pdfgrip.com
General Discussion of Organic Fluorine Chemistry

2

7

Pharmaceuticals

Fluorinated corticosteroids were the first successful commercial products where useful

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

leading member of a new family of selective serotonin re-uptake inhibitor (SSRI)
antidepressants, are in the world top 20 best-selling pharmaceuticals and achieve annual
sales in the region of US$1 billion each.

3

Imaging techniques

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


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 8

www.pdfgrip.com
8

Chapter 1
O
H

O
H

CF3

N


F
N
O
N

O

O

N

HO

H
OH

5-Fluorouracil
(anti-cancer)

N

N

Trifluridine®
(anti-viral)

N

O


N

OH

N

N

CO2H

F

F
N

N

N
H

F
Fluconazole®
(anti-fungal)

Ciprofloxacin®
(antibacterial)

O


H
O

OH

HO

N

CH2OH

CH3

CH3

F3C

F
O

Prozac®
(anti-depressant)

Betamethasone®
(anti-inflammatory)

Figure 1.3 Examples of drugs containing fluorine

molecule in a cell. Uptake of fluorine-18 gives a direct measure of the rate of glucose
metabolism in the part of the body under study. Similarly, 18 F-DOPA acts as a tracer for

DOPA, which is a neurotransmitter in the brain, and the PET study of the complex
metabolism and biodistribution of DOPA is hoped to provide a quantitative measure of
the dopaminergic neurons in the brain [84] (Figure 1.4).
Non-invasive monitoring of therapeutic agents can also be performed by 19 F magnetic
resonance imaging (MRI); the negligible natural fluorine background and the high
sensitivity of 19 F NMR spectroscopy has made possible the study of the in vivo action
and metabolic pathways of fluorine-containing drugs. For instance, 19 F MRI has demonstrated that 5-fluorouracil is metabolised to NH2 CH2 CHFCOOH.


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 9

www.pdfgrip.com
General Discussion of Organic Fluorine Chemistry

9

F

HO

CO2H
O

HO

OH
HO

F


NH2

HO
OH

18F-2-Fluorodeoxyglucose

18F-6-Fluoro-DOPA

(PET Scanning Agent)

(NMR Scanning Agent)

Figure 1.4

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

4

Plant protection agents [62]

Environmental concerns have imposed massive constraints on plant protection products,
and the impressive progress towards lower dose levels for effective control is another of
the unrecognised success stories of the chemical industry. Fluorinated molecules have
played an important role in these developments, leading to a range of successful herbicides, insecticides and fungicides [85]. Trifluralin (Dow), a herbicide used principally for
the control of grassy weeds in a wide range of crops, has been in use for over 25 years and
peak sales in the mid 1980s reached US$400 million per annum. Fusiladet is another
widely successful herbicide used for the control of weeds in broad-leaf crops at low

dosage rates. The pyrethroid derivative Cyhalothrint is a successful insecticide and the
fungicide sector contains five significant products with fluorine incorporated in the
substrate. Flutriafolt is used for protecting cereal crops and Flutolanilt is used mainly
in the Far East for controlling crop diseases (Figure 1.5).

D

Biotransformations of fluorinated compounds

As the occurrence of fluoride ion is so widespread, it is particularly surprising that
compounds containing carbon–fluorine bonds are rarely found in nature [1, 2]. Potassium
monofluoroacetate occurs in several tropical and sub-tropical plants located in the
southern hemisphere, such as Dichapetalum cymosum (South Africa, very toxic to
animals) and Oxylobium parviform (Australia). Some plants, such as soya bean (Glycine
max), are able to synthesise fluoroacetate when grown in fluoride-rich soil. A shrub
occurring in Sierra Leone, Dichapetalum toxicarium (ratsbane), is also poisonous, particularly the seeds, and this has been attributed to the occurrence of v-fluoro-oleic acid,
CH2 FðCH2 Þ7 CH5CHðCH2 Þ7 COOH [86]. Nucleocidin, an adenine-containing antibiotic,
has been isolated from the fermentation broths of a micro-organism Streptomyces calvus [1].
The fact that only 12 compounds containing C–F bonds have been found in nature so
far [87] leads to the questions of (a) whether this is a consequence of the difficulty of
forming C–F bonds in the first place, and (b) whether subsequent enzymic transformations in plants and animals are inhibited by the presence of C–F bonds. Fluorine, as
fluoride ion, although extremely abundant, is present in largely insoluble salts. Moreover,
fluoride ion is extensively hydrated because of the strength of hydrogen bonding, and in


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 10

www.pdfgrip.com
10


Chapter 1
NnPr2
O

NO2

O2N

O

F3C

OnBu
Me

N

CF3

O
Fusilade®

Trifluralin®
O

CN
O

F3C


O

Cl

Cyhalothrin®
OH
F

CF3
N

O

F

N

N

H

Flutriafol®

Flutolanil®

N

OiPr

Figure 1.5 Examples of plant-protecting agents containing fluorine


the hydrated state it is relatively unreactive as a nucleophile. It seems likely, therefore,
that the dearth of C–F bonds in nature is essentially due to a combination of these effects,
which inhibit C–F bond formation.
However, an exception to this situation is the formation of the toxin fluoroacetate,
which inhibits the Krebs cycle. Moreover, O’Hagan and co-workers have successfully
identified the first fluorinase enzyme, in the bacterium Streptomyces cattleya, which
catalyses the formation of a C–F bond [88] (Figure 1.6).
These results then raise the issue of how the fluoride becomes an active nucleophile in
this system: at this stage, the most likely scenario is that fluoride ion is drawn into
lipophilic sites on the enzyme and effectively de-solvated, to make it more reactive.
Exciting prospects for the future are indicated by the identification of this fluorinase
system [88].
In contrast, there are now many examples in the literature to indicate that, when
presented with organic compounds already labelled with fluorine, enzymes may be
tolerant to the presence of fluorine, depending on the number of C–F bonds and their
location [89, 90]. For example, baker’s yeast may lead to significant asymmetric reduction of carbonyl (Figure 1.7).
Likewise, various kinetic resolutions of fluorinated compounds have been achieved,
e.g. the acetate of 1,1,1-trifluoro-2-octanol has been transformed into (R)-1,1,1-trifluoro2-octanol (Figure 1.8).


Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:39pm page 11

www.pdfgrip.com
General Discussion of Organic Fluorine Chemistry
−
O

+
H3N


N
Me

S

N

+

O

HO

NH2

NH2

O

N

N

−

N

F


½88Š

N

F

Fluorinase

11

N

N

O

HO

OH

S-adenosylmethionine

OH
5'-FDA

O

O
+


NAD

OH

H

F

F
Fluoroacetaldehyde

Fluoroacetate

Figure 1.6

½89Š

OH
58%

CH2FCOPh
FH2C

Ph

R (90% ee)

Figure 1.7
OCOMe
F3C


CH2CO2Et

OH

Lipase MY
F3C

CH2CO2Et

OCOMe
F3C

½89Š

CH2CO2Et

(R) 96% ee

Figure 1.8

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