Organofluorine Chemistry

Organoﬂuorine Chemistry Kenji Uneyama Professor, Department of Applied Chemistry, Okayama University, Japan Organoﬂu...

Author: Kenji Uneyama

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Organoﬂuorine Chemistry

Kenji Uneyama Professor, Department of Applied Chemistry, Okayama University, Japan

Organoﬂuorine Chemistry

Organoﬂuorine Chemistry

Kenji Uneyama Professor, Department of Applied Chemistry, Okayama University, Japan

C 2006 K. Uneyama

Blackwell Publishing Ltd Editorial Ofﬁces: Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Tel: +44 (0) 1865 776868 Blackwell Publishing Professional, 2121 State Avenue, Ames, Iowa 50014-8300, USA Tel: +1 515 292 0140 Blackwell Publishing Asia Pty, 550 Swanston Street, Carlton, Victoria 3053, Australia Tel: +61 (0)3 8359 1011 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. First published 2006 by Blackwell Publishing Ltd ISBN-13: 978-14051-2561-1 ISBN-10: 1-4051-2561-6 Library of Congress Cataloging-in-Publication Data is available A catalogue record for this title is available from the British Library Set in 10/12pt Minion & Optima by TechBooks, New Delhi, India Printed and bound in India by Replika Press Pvt, Ltd, Kundli 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 Web site: www.blackwellpublishing.com

Contents

Preface

ix

1

1 1

2

Fundamentals in Organic Fluorine Chemistry 1.1 Some physical properties of organic ﬂuorine compounds 1.1.1 Effect of the ﬂuorine atom on the molecular orbital energy levels of organic molecules and refractive index 1.1.2 Boiling points 1.1.3 Miscibility 1.1.4 Lipophilicity 1.1.5 Gas solubility 1.1.6 Surface tension 1.1.7 Summary 1.2 Electronic effect 1.2.1 Electronic effects of the ﬂuorine atom: insight from Hammett substituent constants 1.2.2 Electronic effects on acidity, bond length, and bond energy of ﬂuoroorganic molecules 1.2.3 Halogen bonding 1.2.4 Electronic effect on the destabilization of carbonyl and imono groups 1.2.5 ␲–␲ Stacking of ﬂuoroaromatics 1.2.6 Increased p-character (Bent’s rule) and low-lying LUMO in carbon–ﬂuorine bonding orbitals 1.2.7 Negative hyperconjugation 1.2.8 Electron-donating effect (stabilization of carbocation) 1.2.9 Effect of ﬂuorine substituents on the structure, stability, and reactivity of ﬂuoroalkyl radicals 1.3 Steric effects of ﬂuorine substituents References Unique Reactions Induced by Fluorine 2.1 Nucleophilic substitution on ﬂuoroaromatic rings 2.2 SN 2 reactions of alkenes bearing a triﬂuoromethyl group

1 3 6 6 7 8 9 10 10 15 24 31 37 45 52 60 67 81 90 101 101 107

vi

Contents

2.3 2.4 2.5

Nucleophilic substitution on the gem-diﬂuoromethylene double bond Single electron transfer reaction of perﬂuoroalkyl halides Fluorine-activated electrophilic reagents (F–X and XFn ) 2.5.1 Halogen monoﬂuoride (F-halogen) 2.5.2 Bromine triﬂuoride (BrF3 ) 2.5.3 Iodine pentaﬂuoride (IF5 ) 2.5.4 Iodoarene diﬂuoride (ArIF2 ) 2.5.5 Benzeneselenenyl ﬂuoride (PhSeF) 2.5.6 tert-Butyl and methyl hypoﬂuorites 2.5.7 Hypoﬂuorous acid · MeCN complex (HOF · MeCN) References

3

4

5

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms 3.1 Reaction induced by F–Li interaction 3.1.1 Li–F interaction in aromatic C–F bonds 3.1.2 Li–F interaction in aliphatic C–F bonds 3.2 The ﬂuorine–aluminum interaction 3.3 Reactions induced by F–Si interaction 3.3.1 Fluoride-ion mediated desilylative alkylations 3.4 Reactions induced by B–F interaction 3.5 Reactions activated by a strong interaction between ﬂuorine and Sm, Yb, Sn, Ti References Hydrogen Bonding in Organoﬂuorine Compounds 4.1 Organoﬂuorine as a hydrogen-bonding acceptor 4.1.1 Deﬁnition and classiﬁcations of hydrogen bonds 4.1.2 Some examples of O –H · · ·F –C and N –H · · ·F –C hydrogen-bonding systems 4.1.3 Some examples on nonconventional hydrogen bonding: C –H · · ·F –C interactions 4.1.4 Summary of organic ﬂuorine as hydrogen-bonding acceptor 4.2 Hydrogen bonding of ␤-ﬂuorinated alcohols, its structural character, and utilization in organic syntheses 4.2.1 Use of TFE and HFIP for protonating agents and/or protonating solvents 4.2.2 Use of TFE and HFIP for cation-stabilizing solvents References Fluorinated Ligands for Selective Catalytic Reactions 5.1 Ligands with ﬂuorine-substituted aryl groups 5.1.1 Ligands for stereoselective reactions 5.1.2 Ligands for oleﬁn polymerization

112 121 126 126 127 128 128 130 130 131 133

139 140 140 144 147 152 153 159 165 168 173 173 173 175 177 179 180 182 184 184 186 186 186 197

Contents

5.2 5.3

Ligands and auxiliaries with ﬂuorinated alkyl groups Fluorinated ligands usable for catalytic reactions in scCO2 and ﬂuorous solvents References

6

7

vii

199 203 203

Fluorine in Drug Designs 6.1 Electron-withdrawing effect 6.2 Electron-withdrawing effect for lowering basicity of amines 6.3 ␲–␲ Stacking of polyﬂuorinated aromatic rings 6.4 Interaction of ﬂuorine in the C–F bond with an electron-deﬁcient center 6.5 Metabolic blocking 6.6 Increased hydrophobicity of ﬂuoroaryl groups 6.7 Mechanism-based design of bioactive molecules 6.8 Fluoroalkenes as isosteres of the amide bond 6.9 Summary References

206 206 209 209

Methods for Introduction of Fluorine-Functionality into Molecules 7.1 Monoﬂuorination 7.1.1 Electrophilic reagent: F2 , CsSO4 F, R2 NF, CF3 OF, RCO2 F, ArIF, XeF2 7.1.2 DAST (diethylaminosulfur triﬂuoride) and related reagents 7.1.3 Deoxoﬂuor: [(CH3 OCH2 CH2 )2 N-SF3 ] 7.1.4 Ring opening of epoxide 7.1.5 Haloﬂuorination 7.1.6 Selenoﬂuorination 7.1.7 Electrochemical ﬂuorination 7.1.8 Nucleophilic reagent 7.1.9 TASF [(Me2 N)3 S]+ [Me3 SiF2 ]− 7.1.10 Schiemann reaction 7.1.11 Others 7.1.12 Fluorinated building blocks 7.2 Diﬂuorination 7.2.1 Diﬂuorocarbene route and halodiﬂuoromethyl radicals and anions 7.2.2 Transformation of carbonyl group to –CF2 – 7.2.3 Fluorine addition –CH2 – (active methylene) −→ –CF2 – (diﬂuoromethylene) 7.2.4 7.2.5 Deﬂuorination from CF3 7.2.6 Diﬂuoromethyl synthetic blocks: Halodiﬂuoroacetate (XCF2 CO2 R) 7.3 Triﬂuoromethylation 7.3.1 CF− 3 anion from CF3 I, CF3 Br, CF3 H

223 223

212 212 213 215 218 219 220

223 233 238 239 240 242 243 245 247 248 249 250 257 257 263 267 267 268 275 292 292

viii

Contents

7.4

Index

7.3.2 FSO2 CF2 CO2 Me 7.3.3 CF3 -TMS 7.3.4 Others 7.3.5 · CF3 radicals 7.3.6 CF3 + equivalent 7.3.7 CF3 CH2 + equivalent 7.3.8 CO2 H −→ CS2 H or CS2 R −→ CF3 7.3.9 Triﬂuoromethyl building blocks 7.3.10 Imidoyl halides Perﬂuoroalkylation 7.4.1 Rf-Li perﬂuoroalkyl lithium 7.4.2 Rf-Zn perﬂuoroalkyl zinc 7.4.3 Sm-promoted perﬂuoroalkylation 7.4.4 Rf-Cu perﬂuoroalkyl copper 7.4.5 Rf-Ru 7.4.6 Miscellaneous 7.4.7 Polyﬂuorobenzene

296 296 301 302 308 308 310 311 315 324 324 325 326 327 329 329 334 337

Preface

“Small atom with a big ego” was the title of the ACS Symposium in San Francisco in 2000, where a number of current scientiﬁc and industrial aspects of ﬂuorine-related chemistry were discussed. This small atom has been providing mankind with a lot of beneﬁts, in r , freon, ﬂuoro-liquid crystals, pharmaceutical the form of special products such as Teﬂon and agrochemical compounds, and so on, all of which have their own unique properties created by the characteristic nature of ﬂuorine. Nowadays, organic ﬂuorine compounds have attracted a great deal of interest from the scientists involved in many ﬁelds of science and technology. This book was written with the following objectives: ﬁrst to support research scientists to get the comprehensive scientiﬁc information on ﬂuorine chemistry necessary for their current research works; secondly to support graduate students and scientists in industry, and hopefully in the other ﬁelds of science, to get systematic knowledge directive of design for new reactions and syntheses, and creation of novel ﬂuorinated advanced materials; and thirdly to encourage them to step into this attractive natural science of ﬂuorine chemistry. During my teaching at Okayama University, for over twenty years, and at various other universities in Japan as well as in the EU and USA, I talked about the science and chemistry of ﬂuoroorganic compounds, focusing on why ﬂuorine creates such unique properties in biologically active compounds and advanced materials, and also taught the scientiﬁc background of the unique phenomena. Most of the topics discussed were chosen from recent journals and were explained on the basis of fundamentals and principal concepts of organoﬂuorine chemistry. During these years of teaching I found that not only many young chemists but also expert chemists are strongly interested in ﬂuorine-related materials and that they have an image that this unique element potentially could create something new. At the same time I also knew that they, unfortunately, have only fragmentary but not systematic knowledge on ﬂuorine chemistry based on principal concepts and mechanistic backgrounds, deep understanding of which is essential and undoubtedly helpful for the future fruitful development of science and technology related to ﬂuorinated materials. I hope this concise book is useful in this regard. I am afraid there may be some incorrect and weak scientiﬁc descriptions, owing to my rather narrow knowledge and background in chemistry and science. I would appreciate any frank comments on this matter, which will be useful for the next edition of this book. Nevertheless, I am satisﬁed, in some sense, with the book written by a single author. There

x

Preface

is certainly a clear scientiﬁc stream that ﬂows through the entire book and also presents the author’s ideas and aims towards science and education. Finally, I deeply appreciate the strong support of many well-acquainted friends and colleagues, without whom this book would have never been completed. Professor G. B. Hammond (University of Louisville) recommended me to write this book and encouraged me. Professor J. M. Percy (Leicester University) kindly read almost all of the scripts and gave valuable comments and remarks that were extremely useful for the modiﬁcation of the scripts. Professor T. Katagiri (Okayama University) contributed much in writing Section 1.1 and Chapter 4, and discussing many subjects included in this book. Motoko Uneyama undertook the role of typing and checking the scripts. I also appreciate Dr. Y. Takagi, Dr. J. Takagi, Dr. T. Ono, and Dr. T. Korenaga for reading the scripts, and students from the Molecular Design Laboratory, Faculty of Engineering, Okayama University, for drawing the schemes. Kenji Uneyama

Chapter 1

Fundamentals in Organic Fluorine Chemistry

1.1

Some physical properties of organic ﬂuorine compounds

Organic ﬂuorine compounds often show unusual properties and behavior in comparison with nonﬂuorinated parent compounds. Thus, we can say, “ﬂuorine is a small atom with a big ego.” Such big effects have been called ﬂuorine magic. There have been many empirical rules and legends on the characteristic properties of organic ﬂuorine, especially in regard to the properties of intermolecular interaction. Some of these are rationalized by theories of physical and/or quantum chemistries, and some of these are just unsubstantiated rumors. Some important effects of the ﬂuorine atom on the properties of organic molecules are comprehensible from a quantum chemical point of view, while most of the effects on the properties of the compounds and materials are complicated by the cooperative work of these effects. In this chapter, we ﬁrst discuss the origin of the effects of the ﬂuorine atom on the basis of the molecular orbital theory. Then, we discuss some speciﬁc properties of the ﬂuorinated molecules and materials. This book treats these properties qualitatively. For quantitative discussions and estimations, see the advanced physical chemistry books [1, 2], and, for detailed values of the properties, see the comprehensive summaries [3–5].

1.1.1

Effect of the ﬂuorine atom on the molecular orbital energy levels of organic molecules and refractive index

The valence orbital (2s and 2p) energy levels of the ﬂuorine atom are stabilized remarkably well by a large positive charge of the nucleus and the absence of shielding effects by innershell electrons. The orbital energy level of the 2p lies at −18.6 eV. This is 5 eV lower than that of the proton’s 1s-orbital [6]. When we assume the molecular orbital of a ﬂuorinated compound or its parent compound from a fragmentation of the organic moiety and ﬂuorine or proton atoms, newly generated molecular orbitals could be illustrated as shown in Figure 1.1. Both newly generated HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) levels of ﬂuorinated compounds are lower than those of a hydrogen compound. These lower orbital energy levels of the ﬂuorinated compound indicate a high reactivity toward the reductant (electron donor to the LUMO) and a low reactivity toward the oxidant (electron acceptor from the HOMO). Moreover, a lower HOMO suggests strongly that the valence electrons captured by the molecular nuclei in the ﬂuorinated

2

Organoﬂuorine Chemistry

Figure 1.1 Orbital energy diagram of ﬂuorinated and nonﬂuorinated compounds.

compounds ﬂuctuate scarcely in the molecule. That is, the molecule becomes “small” and “hard”; thus, it has smaller electronic polarizability [7, 8]. The electronic polarizability could be estimated from the refraction of light through the materials and measured as a refractive index. The refractive indices of ﬂuorinated compounds are usually lower than those of the nonﬂuorinated analogs; perﬂuoro compounds show exceedingly low values. The low refractive index of ﬂuorinated plastic provides an advantage in optical ﬁber use. The propagation of light through a ﬁber with a low refractive index is faster. The speed of the light is in inverse proportion to the refractive index of the medium. The refractive index of the transparent plastic (CYTOP) is 1.34, and that of the fused quartz is 1.45. Thus, the propagation of light through the core of a ﬂuoroplastic ﬁber could be 8% faster than that in a glass ﬁber (see Figure 1.2). The relevant research topic in this ﬁeld would be the

Figure 1.2 A conceptual ﬁgure for the transport of light through ﬂuoroplastic ﬁber.

Fundamentals in Organic Fluorine Chemistry

3

development of a miscible compound with a relatively low refractive index to be used as a cladding for the grated index optical ﬁber [9]. The electronic polarizability is the origin of the van der Waals attractions: the less the polarizability, the less the van der Waals attraction. Therefore, the ﬂuorinated organic compounds usually have a smaller van der Waals interaction than do the nonﬂuorinated parent compounds. The small van der Waals attraction of a ﬂuoroorganic compound, which can be estimated by its refractive index, specializes the physical properties regarding the intermolecular interaction of ﬂuoroorganics [10].

1.1.2

Boiling points

Physical properties of the compounds and materials have been expressed by so many physical constants with a variety of physical dimensions and meanings. In this section, we mainly use a raw constant, refractive index, n D , for further discussions because of its popularity among organic chemists and its common use. Moreover, the constant is a physical constant of the compound or the materials, and not of the molecules. Thus, it would be a much more straightforward factor that demonstrates the properties of the real compounds semiquantitatively or qualitatively, although it is affected by temperature and wave frequencies in its measurements. The boiling point is one of the most common physical constants of organic compounds. To date, many empirical legends on the boiling point have been told in the ﬁeld of organic chemistry. The most popular one among them would be a principle that boiling points of structurally similar compounds mainly depend on their molecular weights. Actually, halogenated organic compounds attain higher boiling points along with their higher molecular weights. However, highly ﬂuorinated organic compounds such as perﬂuoroalkylated and triﬂuoromethylated compounds are exceptionally volatile and one must be careful in handling them. Triﬂuoroacetic acid boils at 72◦ C, which is 42◦ C lower than the boiling point of acetic acid. Di- and triﬂuorinated acetic acids boil at notably lower temperatures than those expected from the curve shown in Figure 1.3. Toluton–Hildebrand’s empirical rule indicates that the boiling points (K) linearly relate to the latent heat of vaporization [1, 11]. Thus the intermolecular attraction energy needs to be reconsidered for a better understanding of the boiling point, especially of ﬂuorinated organic molecules. Instead of following conventional classiﬁcations, it would be reasonable to classify the intermolecular forces into three categories on the basis of their origin [2]. The ﬁrst is the forces caused by the electronic polarization, i.e. van der Waals attraction, such as London dispersion (electronic polarization–electronic polarization) and Debye interaction (dipole– dipole-induced electronic polarization). The second is the forces caused by the electrostatic charges and/or the dipoles of the molecule; these forces are based on the molecular structure and are independent of electronic polarizability. And the last category is the forces caused by exchange of elemental particles, such as an electron (covalent bond) and a proton (hydrogen bond). In the series of acetic acids, interactions of the second and the last categories should be enhanced by ﬂuorination. On the other hand, interaction of the ﬁrst category may be depressed by ﬂuorination because of the smaller electronic polarizability of triﬂuoroacetic

4

Organoﬂuorine Chemistry

Figure 1.3 Boiling points of halogenated acetic acids as a function of molecular weight. Circles are ﬂuorinated acetic acids.

acid (n25 D = 1.284), which is far smaller than that of the parent nonﬂuorinated acetic acid (n20 D = 1.371). When the boiling points of halogenated acetic acids are correlated with refractive indices (n), a good linear correlation is observed, as shown in Figure 1.4, although a nonlinear correlation is shown between boiling points and molecular weights in Figure 1.3. This linear

Figure 1.4 Boiling points of halogenated acetic acids as a function of refractive index. Squares are ﬂuorinated acetic acids.

5

Fundamentals in Organic Fluorine Chemistry

Table 1.1 List of correlations of boiling points vs. refractive indices of substituted organic compounds [9] Number of points

Range of n

1-substituted pentanes 1-substituted hexanes substituted cyclohexanes 3-substituted 1,2-epoxypropanes 2-substituted ethanols 1-substituted acetones substituted acetic acids methyl substituted acetates ethyl substituted acetates substituted acetonitriles

5 5 5 5 8 7 9 6 6 7

1.360–1.495 1.376–1.492 1.415–1.548 1.368–1.482 1.289–1.571 1.300–1.470 1.284–1.501 1.290–1.458 1.307–1.503 1.333–1.574

713 775 648 698 392 679 664 687 672 441

78 75 107 75 229 80 161 107 126 207

0.975 0.983 0.936 0.788 0.946 0.988 0.953 0.933 0.902 0.840

monosubstituted benzenes 1,2-disubstituted benzenes 1,3-disubstituted benzenes 1,4-disubstituted benzenes 1,2,3-trisubstituted benzenes 1,2,4-trisubstituted benzenes 1,3,5-trisubstituted benzenes 1,2,3,5-tetrasubstituted benzenes pentasubstituted benzenes hexasubstituted benzenes 2-substituted anisoles 3-substituted anisoles 4-substituted anisoles 2-substituted anilines 3-substituted anilines 2-substituted pyridines 3-substituted pyridines

5 13 10 10 9 30 4 3 6 6 4 5 4 4 5 4 4

1.468–1.620 1.443–1.661 1.439–1.608 1.440–1.583 1.423–1.555 1.423–1.647 1.415–1.577 1.404–1.485 1.390–1.487 1.377–1.469 1.494–1.574 1.488–1.613 1.488–1.564 1.542–1.611 1.544–1.681 1.466–1.572 1.472–1.570

673 718 798 816 881 778 850 719 693 634 865 687 882 772 687 675 631

49 51 9 5 −9 40 −5 66 94 124 −2 96 3 29 90 77 88

0.987 0.987 0.983 0.893 0.990 0.882 0.974 0.994 0.930 0.971 0.997 0.999 0.997 0.995 0.985 0.918 0.930

Series of compounds

Intercept at Slope (K) n = 1.0 (K)

r

correlation clearly shows that the depressed van der Waals attraction by ﬂuorination is responsible for the low boiling points of di- and triﬂuoroacetic acids. The linear correlation between the refractive indices and the boiling points was found in 27 series of organic compounds with a wide range of structural variation, as summarized in Table 1.1. So long as the structures of a series of molecules resemble each other, these linear correlations have fair to excellent correlation coefﬁcients [9]. Except for hydrogen-bonded and apparently rod-shaped molecules, the main coherent forces of the liquids come from the electronic polarizability. The legend that “boiling points of organic compounds are mainly dependent on their molecular weights” is not satisfactory [12]. A molecule having a large molecular weight usually has a large molecular orbital and many more electrons and thus it has a large electronic polarizability, and it causes large intermolecular forces, resulting in a high boiling point. Meanwhile, ﬂuorine atoms in the molecule attract molecular orbitals and electrons near the

6

Organoﬂuorine Chemistry

atomic nuclei and thus induce a smaller electronic polarizability of the molecule to make the molecule hard and to lower the boiling point. Noteworthy is the fact that the substitution of hydrogen by ﬂuorine is the sole methodology to reduce the electronic polarizability.

1.1.3

Miscibility

Since the pioneering work on ﬂuorous biphase hydroformylation with a facile separation of the catalyst [13], the ﬂuorous biphase system has been a hot favorite of organoﬂuorine chemistry [14–22]. Thus, miscibility and immiscibility of two liquids are important physical properties for organoﬂuorine chemistry. Curran proposed a deﬁnition of the term ﬂuorous in 2002 [18]. His deﬁnition is based on “ﬂuorophilic” and “ﬂuorophobic” properties, which are controlled by the polarity of the compound. Here, the term polarity may contain not only the conventional polarity but also the electronic polarizability, because it was noted that hexaﬂuorobenzene, which has no dipole moment, is a nonﬂuorous compound. “Like dissolves like” is an extremely useful rule of thumb. Structurally similar molecules associate with a similar intermolecular interaction. Thus, a molecule in the liquid can be substituted by a structurally similar molecule, without a major change in intermolecular interactions. Ethanol dissolves in water because major interactions holding water molecules to each other and those of the ethanol are very similar, hydrogen bond interactions. On the other hand, water and carbon tetrachloride make a biphase system. The carbon tetrachloride molecules are cast aside because they cannot make enough hydrogen bonding interaction with water molecules to hold the molecules in the water phase. Thus, the carbon tetrachloride molecules hold themselves in the other phase by van der Waals interaction. Likewise, perﬂuorinated organic molecules would be cast aside from the “van der Waals interacted” organic phase, because they lack electronic polarizability to make enough van der Waals interaction. The electronic polarizabilities of the perﬂuorinated molecules would roughly be a half of that of the aromatic molecules. Thus, they still have a chance to mix with organic solvents under certain circumstances, such as higher temperature [23]. An empirical rule on the ﬂuorous tag describes that “longer ﬂuorous chains cause an increase in partition coefﬁcient to the ﬂuorous phase coupled with a decrease in absolute solubility in both organic and ﬂuorous phases” [24]. This description suggested a lack of attractive interaction of the ﬂuorous tag, a perﬂuoroalkyl chain, to the ﬂuorous phase. One may suppose a molecule with a ﬂuorous tag may construct a higher order structure, which would be like reverse micelle in oil.

1.1.4

Lipophilicity

It is a popular lore that the introduction of some ﬂuorine atoms or a short perﬂuoroalkyl group results in increasing lipophilicity. A classical parameter ␦, Hildebrand’s “solubility parameter,” which is the square root of the cohesive energy density, has been used for miscibility estimation [2]. If two liquids have similar values for ␦, i.e. if (␦1 −␦2 )2 is small, they are miscible.

Fundamentals in Organic Fluorine Chemistry

7

Here, the water has a big ␦ (around 48) [24], the organic solvent has a medium ␦ (around 20), and the ﬂuorous solvent has a small ␦ (around 12). The introduction of some perﬂuoroalkylated moiety with small ␦ into a highly hydrophilic molecule with a big ␦ would result in lowering the ␦ of the partially ﬂuorinated molecule to a medium ␦ value. This suppression of ␦ would result in higher partition coefﬁcient toward the organic phase, i.e. higher lipophilicity [24]. The lipophilicity is a ratio of solubility, with no absolute limits. A molecule with a small ␦ just loses a chance to dissolve in an aqueous phase, and is cast aside from the aqueous phase. The perﬂuoroalkyl moiety does not give an additional lipophilic attractive force to the molecule. The term ﬂuorophilic is based on the observations of a ﬂuorous biphase system [14–22], perﬂuorinated layers found in the liquid crystal phase [25], and a perﬂuorinated alkyl moiety highly aligned in the crystals of partially perﬂuorinated molecules. They let us imagine some unknown attraction force among the perﬂuorinated moieties. However, the origin of the attraction has never been explored. It is natural to understand that the perﬂuorinated organic molecules would be just cast aside from the “van der Waals interacted” organic phase. Nevertheless, there have been many experimental results on the preferred self-assembly used to construct highly ordered perﬂuoroalkyl layers. For example, an X-ray diffraction analysis study revealed that a C8 perﬂuoroalkyl moiety as a side chain of polyacrylate was found to be in alignment with the side chains, while a C12 nonﬂuoroalkyl moiety was needed for a similar alignment [26].

1.1.5

Gas solubility

Emulsions of perﬂuorinated hydrocarbons were studied extensively for oxygen transfer in blood substitute [27]. The key factor in this usage is the gas solubility. Generally, the gaseous molecule is a small molecule with a small electronic polarizability, thus it cannot have good interaction with organic compounds. On the other hand, the perﬂuorinated compound itself has a smaller electronic polarizability, thus it can dissolve gaseous molecules effectively, according to the rule “like dissolves like” [28]. Conventionally, a relationship between gas solubility and molar volume has been considered. Of course, the molar volume correlates to the ﬂuctuation of electrons around the molecules, i.e. electronic polarizability. Table 1.2 summarizes gas (He, H2 , O2 , N2 , and CO2 ) solubility to various solvents. Here, the solvents are arranged in the order of their refractive indices. One may ﬁnd the lower the refractive indices of the solvents (columns upward) or the higher the refractive indices of the gas (rows rightward), the higher the gas solubility. These trends are consistent with the “like dissolves like” rule. Because carbon dioxide is a much more “soft” gas than oxygen, a much larger amount of carbon dioxide than oxygen was dissolved in every solvent. Here we should note that the ratio of solubility of O2 /CO2 in n-C7 F16 was 1/4, while that in benzene was 1/12. That is, higher gas solubility with lower gas selectivity was attained by a lower refractive index of the solvent. A good correlation between the refractive indices of the solvents and the selectivities of the gas solubility was found (see Figure 1.5).

8

Organoﬂuorine Chemistry

Table 1.2 Gas solubility as mole fraction at 25◦ C (1 atm. partial pressure of gas × 104 ) [29, 30]

Solvent

n 20 D

He (1.000036)a

H2 (1.000132)a

O2 (1.000271)a

N2 (1.000297)a

CO2 (I .00045)a

n-C7 F16 n-hexane n-octane cyclo-hexane toluene m-xylene benzene C6 H5 -Cl

1.300 1.379 1.398 1.426 1.496 1.497 1.501 1.524

8.862 2.604 2.397 1.217 0.974 1.121 0.771 0.691

14.03 6.315 6.845 4.142 3.171 4.153 2.580 2.609

55.08 19.30 20.83 12.48 9.090 — 8.165 7.910

38.80 14.02 13.04 7.610 5.740 — 4.461 4.377

208.2 — — 76.00 101.3 — 97.30 98.06

a Refractive

1.1.6

index nD of each gas.

Surface tension

Gas solvation selectivity (O2/CO2)

The surface energy of a solid, ␥s , is commonly given in units of energy per unit area (mJ/m2 or erg/cm2 ), while that of a liquid, ␥ l , is given in tension per unit length (mN/m or dyn/cm). Their dimensions are the same as the surface free energy. Physical and physicochemical aspects of surface tension and surface energy have been discussed and described in many papers and books [1, 2]. In any case, the intermolecular forces that determine the surface energy of a liquid are the same as those that determine its latent heat of vaporization and boiling point [2]. Thus, one may expect ﬂuorination should reduce surface tension. The surface tension of a liquid is mainly controlled by the intermolecular interaction among the molecules. Thus, it can be determined directly from the properties of the molecule. However, the surface tension of the solid surface is affected by its structure and roughness. When the surface is rough enough to keep gases or vacuum on it, the mean polarizability becomes very low. The water droplets on such a rough surface contact the solid

Refractive index

Figure 1.5 Gas solvation selectivities (O2 /CO2 ) as a function of refractive index.

Fundamentals in Organic Fluorine Chemistry

9

part just at points. Thus, the droplet on such a surface becomes sphere shaped, like a droplet in the air. The lowest critical surface tension of the smooth surface was attained by alignment of perﬂuorocarboxylic acids on a platinum surface [31]. The critical surface tension was measured to be 7 mN/m, which is one-third of that of PTFE (poly(tetraﬂuoroethylene)) [32].

1.1.7

Summary

This section discusses how the ﬂuorine atom inﬂuences the physical and physicochemical properties of organic ﬂuorine compounds. One of the most important factors for a better understanding of such properties would be the low electronic polarizability (refractive index) of the molecules. Of course, we cannot disregard other effects such as the strong electronwithdrawing effect and stiff nature of the perﬂuoroalkyl moiety.

Fluorocarbon chains are stiffer than hydrocarbon chains

Unlike polyethylene, Teﬂon is one of the typical rigid polymers. Why are ﬂuorocarbon chains stiffer than hydrocarbon chains? Fluorocarbon chains have a higher energy barrier for the internal rotation around the carbon–carbon bond axis because of a slightly larger van der Waals radius of ﬂuorine than that of hydrogen (Table 1.44). In fact, the successive ﬂuorination of one of the methyl groups in ethane increases the energy barrier for

10

Organoﬂuorine Chemistry

the rotation of ﬂuorinated ethanes (2.9 and 3.9 kcal/mol for CH3 –CH3 and CF3 –CF3 , respectively) [1]. A model experiment is shown here to clarify the stiffness of the ﬂuorocarbon chains [2]. Diester 1 with two pyrene units shows an additional broad ﬂuorescence, characteristic of the intramolecular pyrene excimer (425–600 nm)(Chart A). Meanwhile, diester 2 with two pyrene units separated with a C8 F17 segment and 3 and 4 with one pyrene unit show only a weak emission in the region of 425–600 nm (Chart B). Since the excimer arises from the intramolecular interaction of two pyrene units, no excimer from 2 indicates that there exists no intramolecular interaction between pyrene units in 2, demonstrating that the stiffness of the ﬂuorocarbon chains does not allow the intramolecular interaction. 1. Gallaher, K.L., Yokozeki, A., and Bauer, S.H. (1974) J. Phys. Chem., 78, 2389–2395. 2. Eaton, D.F. and Smart, B.E. (1990) J. Am. Chem. Soc. 112, 2821–2823. Charts A and B were reprinted from [2] with permission from the American Chemical Society.

1.2 1.2.1

Electronic effect Electronic effects of the ﬂuorine atom: insight from Hammett substituent constants

Because of the large electronegativity of the ﬂuorine atom (electronegativity for halogens: F (4.0), Cl (3.0), Br (2.8), I (2.5)), ﬂuorine substituents are strongly inductively electron withdrawing and activate nucleophilic reactions on the reaction center. However, lone-pair electrons on the ﬂuorine atom sometimes play another important role of electron donation to the reaction centers through the ␲-bond so as to control reaction rates and regiochemistry of electrophilic reactions (Figure 1.6). They also interact strongly and speciﬁcally with highly electron-deﬁcient reaction species like protons through hydrogen bonding (as for hydrogen bonding with ﬂuorine substituents, see Chapter 4) and with metal cations and Lewis acids through coordination (the interactions between ﬂuorine and other atoms are

Figure 1.6 Transmission of electronic effect to the reaction center by ﬂuorine.

Fundamentals in Organic Fluorine Chemistry

11

summarized in Chapter 3). Therefore, ﬂuorine can turn many faces toward a variety of reactions.

1.2.1.1

Electronic effect of the ﬂuorine atom as a substituent

Most conventional measures for the electronic effect of substituents are provided as Hammett (␴) substituent constants, which are applicable to substituents on aromatic rings, and as Taft (␴ ∗ ) constants for substituents attached to aliphatic chains. In order to understand the electronic effect of ﬂuorine atoms, let us ﬁrst consider the electronic effects revealed by Hammett ␴ and Taft ␴ ∗ constants listed in Tables 1.3 [1] and 1.4 [28, 29]. The electronic effect of halogen atoms on the aromatic ring is somewhat complex since both the electron-withdrawing inductive effect and the electron-donating resonance effect are operative simultaneously. In fact, Taft ␴ ∗ values (␴ ∗ = 1.10, 1.05, 1.02, and 0.88 for CH2 F, CH2 Cl, CH2 Br, and CH2 I, respectively, see Table 1.4) for halogens increase incrementally as the electronegativity of the halogen atoms increases. Meanwhile, values of Hammett ␴ m and ␴ p are almost comparable except for the smallest ␴ p value (0.06) for ﬂuorine. The ␴ R values for halogens are all negative, which demonstrates that halogens are potentially electron donating in spite of their strong electronegativity when their electronic effects are transmitted through ␲-bonds. In particular, the electron-donating resonance effect (␴ R ) for ﬂuorine is markedly large (−0.39) as compared with that of other halogens (−0.19, −0.22, and −0.24 for Cl, Br, and I, respectively). The prominent electron-donating effect of ﬂuorine is due to the well-matched size of the 2p-orbital of the lone pair on the ﬂuorine with the carbon 2p-orbital; the 2p␲–2p␲ orbital overlap for the C–F bond is much more effective than the overlap of np␲–2p␲for the X–C bond (n = 3, 4, and 5,for X = Cl, Br, and I, respectively), which strengthens the electron-donating resonance interaction. The favored ortho- and para-orientations in the electrophilic substitution of haloaromatics are explained by the electron-donating effect of halogen atoms, in particular the ﬂuorine atom, although halogen substituents deactivate the aromatic ring and thus decrease the rates of electrophilic reaction as a result of the overall electron-withdrawing inductive effect of halogens. The rate enhancement and the high product-selectivity by ␣-ﬂuorine substitution are often observed in carbocation formation reactions (see Section 1.2.8). In summary, the electron-withdrawing inductive effect of ﬂuorine is observed only in the reactions wherein the reaction center is connected with the ﬂuorine atom only through ␴-bonds. The electron-donating effect of the ﬂuorine atom plays an important role in reactions in which the reaction center is connected with the ﬂuorine atom through a ␲bond (see Figure 1.6).

1.2.1.2 The electronic effect of triﬂuoromethyl and the related polyﬂuorinated alkyl groups All of triﬂuoromethyl and polyﬂuoroalkyl groups are net electron-withdrawing substituents irrespective of the ﬂuoro substituents being connected with the reaction center through either ␴-bond or ␲-bond, and no electron-donating effect arises from them (Figure 1.6). Successive increase of the number of ﬂuorine atoms in an alkyl group leads to an increasing electron-withdrawing inductive effect (␴ I = 0.01, 0.15, 0.29, and 0.38 for CH3 , CH2 F, CHF2 , and CF3, respectively). However, the inductive effect of perﬂuoroalkyl groups seems

12

Organoﬂuorine Chemistry

Table 1.3 Hammett and modiﬁed Swain–Luption constants [1] Substituent OCH3 OCH2 F OCHF2 OCF3 OCF2 CF3 OCOCH3 OCOCF3 SCH3 SCH2 F SCHF2 SCF3 SCF2 CF3 SeCF3 S(O)CH3 SO2 CH3 SO2 CF3 SO2 CI SO2 F SF3 SF5 NH2 NHCH3 N(CH3 )2 N(CF3 )2 P(CF3 )2 NHCOCH3 NHCOCF3 NHSO2 CH3 NHSO2 CF3 N(SO2 CF3 )2 SiH3 Si(CH3 )3 SiF(CH3 )2 SiF2 CH3 SiF3 SiCl3 Si(OCH3 )3 IO IF2 PF2 PF4 F Cl Br I CH3

␴m 0.12 0.20 0.31 0.38 0.48 0.39 0.56 0.15 0.23 0.33 0.40 0.44 0.44 0.52 0.60 0.83 1.20 0.80 0.70 0.54 −0.16 −0.21 −0.16 0.40 0.60 0.21 0.30 0.20 0.44 0.61 0.05 −0.04 0.12 0.29 0.54 0.48 0.09 0.58 0.85 0.49 0.63 0.34 0.37 0.39 0.35 −0.07

␴p −0.27 0.02 0.18 0.35 0.28 0.31 0.46 0.00 0.20 0.37 0.50 0.48 0.45 0.49 0.72 0.96 1.11 0.91 0.80 0.69 −0.66 −0.70 −0.83 0.53 0.69 0.00 0.12 0.03 0.39 0.83 0.10 −0.07 0.17 0.23 0.69 0.56 0.13 0.62 0.83 0.59 0.80 0.06 0.23 0.23 0.18 −0.17

␴I 0.29 0.29 0.37 0.39 0.55 0.42 0.58 0.23 0.25 0.32 0.36 0.42 0.43 0.52 0.53 0.74 1.16 0.72 0.63 0.47 0.08 0.03 0.15 (0.35) 0.55 0.31 0.38 0.28 0.45 0.50 0.06 0.01 0.12 0.32 0.47 0.44 0.10 0.55 0.82 0.44 0.54 0.45 0.42 0.45 0.42 0.01

␴R −0.56 −0.27 −0.19 −0.04 −0.27 −0.11 −0.12 −0.23 −0.05 0.05 0.14 0.06 0.02 −0.03 0.19 0.22 (−0.05) 0.19 0.17 0.12 −0.74 −0.73 −0.98 0.18 0.14 −0.31 −0.26 −0.25 −0.06 0.33 0.04 −0.08 0.04 −0.09 0.22 0.12 0.03 0.07 0.01 0.15 0.26 −0.39 −0.19 −0.22 −0.24 −0.18

Reference [2] [3] [4] [5] [3] [2] [3] [2] [3] [6] [7] [8] [9] [2] [2] [10] [11] [12] [13] [14] [2] [14] [2] [5] [15] [2] [16] [16] [3] [17] [13] [2] [3] [3] [14] [18] [3] [19] [13] [15] [13] [2] [2] [2] [2] [2]

13

Fundamentals in Organic Fluorine Chemistry

Table 1.3 (Continued ) CH2 F CHF2 CF3 CH2 Cl CHCl2 CCl3 CBr3 CH2 CH3 CH2 CF3 CF2 CF3 (CF2 )2 CF3 (CF2 )3 CF3 CF(CF3 )2 C(CF3 )3 C 6 H5 C6 H4 -3-F C6 H4 -4-F C6 F5 C6 Cl5 COCH3 COCF3 NO2 CN CO2 R CO2 H CHO COC6 H5 OH SH

0.12 0.29 0.43 0.11 0.31 0.40 0.28 −0.07 0.12 0.47 0.44 0.47 0.37 0.55 0.06 0.15 0.12 0.26 0.25 0.38 0.63 0.71 0.56 0.37 0.37 0.35 0.34 0.12 0.25

0.11 0.32 0.54 0.12 0.32 0.46 0.29 −0.15 0.09 0.52 0.48 0.52 0.53 0.55 −0.01 0.10 0.06 0.27 0.24 0.50 0.80 0.78 0.66 0.45 0.45 0.42 0.43 −0.37 0.15

0.15 0.29 0.38 0.13 0.31 0.38 0.28 0.00 0.15 0.44 0.42 0.44 (0.31) 0.53 0.12 0.19 0.17 0.27 0.27 0.32 0.54 0.65 0.51 0.34 0.34 0.33 0.31 0.33 0.30

−0.04 0.03 0.16 −0.01 0.01 0.09 0.01 −0.15 −0.06 0.08 0.06 0.08 0.22 0.02 −0.13 −0.09 −0.11 0.00 −0.03 0.17 0.26 0.13 0.15 0.11 0.11 0.09 0.12 −0.70 −0.15

[20] [20] [2] [6] [3] [6] [21] [2] [15] [22] [23] [22] [22] [8] [2] [23] [23] [24] [24] [2] [20] [2] [2] [25] [2] [26] [27] [2] [2]

to reach saturation; ␴ I s for CF2 CF3 , (CF2 )2 CF3 , and (CF2 )3 CF3 are essentially comparable (0.44, 0.42, and 0.44, respectively). The CF3 CH2 group (␴ I = 0.15) is electronically comparable with CH2 F (␴ I = 0.15), but is of course much less electron withdrawing than CF3 (␴ I = 0.38). Of particular importance is the rather large ␴ R value (0.16) for CF3 , which suggests a possible electron-withdrawing resonance effect by the CF3 group when the substituent is attached to a ␲-electron system, such as phenyl and vinyl groups (Figure 1.6 and Scheme 1.1A). Similar large positive ␴ R values are known for NO2 (0.13), CN (0.15), COCH3

Scheme 1.1

14

Organoﬂuorine Chemistry

Table 1.4 Aliphatic substituent constants (␴ ∗ ) Substituent R CF3 CHF2 CH2 F CCl3 CHCl2 CH2 CI CBr3 CHBr2 CH2 Br CH2 I CH2 CN CH2 OCH3 CH2 OPh CH2 OH CH2 Ph H CH3 CH2 CH3 n-C3 H7 i-C3 H7 C(CH3 )3 C– –CH CH–CH2 C6 H5 C6 F5 CHO COCH3 COPh a

pK a (RCO2 H)

Taft ␴∗a

␴(calcd)b

0.23 1.24 2.66 0.65 1.30 2.86 0.72 1.48 2.90 3.12 2.43 3.53 3.17 3.83 4.31 3.77 4.76 4.88 4.82 4.86 5.04 1.84 4.25 4.20 — 3.32 2.50 1.32

2.61 2.05 1.10 2.65 1.94 1.05 2.3 1.6 1.02 0.88 1.30 0.66 0.85 0.56 0.22 0.49 0 −0.10 −0.12 −0.19 −0.30 1.7 0.56 0.60 — 1.1 1.65 2.2

2.60 2.00 1.17 2.35 1.97 1.05 2.31 1.86 1.03 0.90 1.30 0.66 0.87 0.48 0.20 0.51 −0.07 −0.14 −0.10 −0.13 −0.23 1.65 0.57 0.60 1.50c 1.09 1.55 2.20

[28].

b Calculated c Calculated

on the basis of pKa values [29]. on the basis of ␯x=o of RCH2 OCOCH2 CH2 Ph [30].

(0.17), and SO2 CH3 (0.19), all of which are the typical electron-withdrawing conjugative substituents (Scheme 1.1B). Thus, nucleophilic reactions to the triﬂuoromethyl-substituted carbon–carbon double bond are highly activated by the CF3 group. The chemistry related to the negative hyperconjugation of a CF3 group is described in Section 1.2.7. The pentaﬂuorophenyl group (␴ I = 0.27, ␴ ∗ = 1.50) is more electronegative than phenyl (␴ 1 = 0.12, ␴ ∗ = 0.60) and the same as C6 Cl5 (␴ 1 = 0.27). Also it is slightly less electron withdrawing than the acetyl group (␴ I = 0.32, ␴ ∗ = 1.55). Taft ␴ ∗ for C6 F5 was modiﬁed to be 1.50 on the basis of Cohen’s method [29] by Korenaga and Sakai [30].

15

Fundamentals in Organic Fluorine Chemistry

Table 1.5 pK a of ␣-substituted acetic acids RCO2 H

CH3 CH2 F CH2 Cl CH2 Br CH2 I CH2 CN CH2 NO2 CHF2 CF3 CCl3

1.2.2

1.2.2.1

pK a

pK a

4.76 2.59 2.87 2.90 3.18 2.47 1.48 1.3 0.50 0.66

0.0 2.17 1.89 1.86 1.58 2.29 3.28 3.5 4.26 4.10

Electronic effects on acidity, bond length, and bond energy of ﬂuoroorganic molecules Acidity of ﬂuoroorganic molecules

Because of the powerful electronegativity of ﬂuorine, the introduction of a ﬂuorine atom into a molecule affects markedly the acidity, bond lengths, and bond energy of the molecule. As described in the last section, the electronic effect of ﬂuorine is largely dependent on whether ﬂuorine is attached to a ␴-electron system or to a ␲-electron system; only its inductive effect is crucial in the former case, while both inductive and electron-donating resonance effects are cooperative in the latter case. Table 1.5 shows pK a values of ␣-substituted acetic acids, where the ␣-substituent affects the acidity of the carboxyl group through inductive effects. Judging from the ␴ I value (0.45, 0.51, and 0.65 in Table 1.3) of ﬂuorine, cyano, and nitro groups, the pK a values (2.59, 2.47, and 1.48) of ﬂuoro-, cyano-, and nitroacetic acids are found to be reasonable [1]. Generally, an ␣-CF3 group enhances the acidity of aliphatic alcohols and carboxylic acids by 3.5–4.0 pK a units. The effect of ﬂuorine on an aromatic ring for the acidity of benzoic acids and phenols is somewhat complicated (Tables 1.6 and 1.7). In general, halogens enhance the acidity of halosubstituted benzoic acids and phenols, and the acid-strengthening effect of the halogen is dependent on the position of substitution (the order is ortho > meta > para). However, ﬂuorine is less effective compared to other halogens for strengthening the acidities of both benzoic acid and phenol [2]. The electrondonating effect of ﬂuorine through the ␲-electron system would have the effect of partially weakening the acidities. A very strange phenomenon was observed in the acidity of o-triﬂuoromethyl-substituted benzoic acid whose pK a is equal to that of the parent benzoic acid (Table 1.8) [3, 4]. The 2-ﬂuorobenzoic acid is the strongest among monoﬂuorobenzoic acids, and the same trends of acidity were observed in orthoﬂuoro [5] and triﬂuoromethylphenols [6] (Table 1.9). The unusual low acidity of o-CF3 -benzoic acid may arise from the suppression of the acid dissociation due to the Coulombic repulsion between carboxylate anion and

16

Organoﬂuorine Chemistry

Table 1.6 pK a of substituted benzoic acids

X

Ortho

Meta

Para

F Cl Br I

3.27 2.90 2.85 2.86

3.86 3.84 3.81 3.87

4.15 4.00 3.96 4.00

Table 1.7 pK a of substituted phenols

X

Ortho

Meta

Para

F Cl Br I

8.73 8.56 8.45 8.51

9.29 9.12 9.03 9.03

9.89 9.41 9.37 9.33

Table 1.8 Acidity difference between benzoic and F- or CF3 -benzoic acids

Xo

Xm

Xp

pK a

F H H CF3 H H

H F H H CF3 H

H H F H H CF3

−0.7 −0.3 −0.1 −0.0 −0.4 −0.4

17

Fundamentals in Organic Fluorine Chemistry

Table 1.9 Acidity difference between phenol and F- or CF3 -phenols

Xo

Xm

Xp

pK a

F H H CF3 F H

H F H H CF3 H

H H F H H CF3

−1.2 −0.7 −0.1 −1.7 −1.0 −1.3

the triﬂuoromethyl group, which is a kind of electron block. Meanwhile, the stronger acidity for p-CF3 –phenol than for m-CF3 –phenol could be due to the stabilization of phenolate anion by the negative hyperconjugation (refer to Section 1.2.7 for the negative hyperconjugation) of the triﬂuoromethyl group (Scheme 1.2).

Scheme 1.2

The successive replacement of hydrogen in methanol with triﬂuoromethyl groups increases acidities of the alcohols by about 3 pK a units (Table 1.10) [7]. Because of the small Table 1.10 pK a of some ﬂuoroalcohols Alcohol

pK a

CH3 OH CH3 CH2 OH CF3 CH2 OH CCl3 CH2 OH (CF3 )2 CHOH (CF3 )3 COH

15.1 15.9 12.4 12.3 9.3 5.4

18

Organoﬂuorine Chemistry

Table 1.11 pK a of ﬂuoroalanines

R

CH3

CH2 F

CHF2

CF3

pK a (CO2 H) pK a (NH2 )

2.3 9.9

2.4 9.8

1.5 8.4

1.2 5.3

size and the strong electronegativity of ﬂuorine; introduction of ﬂuorine into the suitable positions of amino acids and phosphonic acids affects their acidities and basicities enough to modify their biological activities. The pK a of some ﬂuoroalanines [8] and phosphonic acids [9] are listed in Tables 1.11 and 1.12. The ﬂuorine substituent also affects the acidity of carbon acids [10]. The methine proton of triﬂuoromethane (pK a = 30) [11] is much more acidic than methane (pK a = 47) and slightly more acidic than triphenylmethane (pK a = 32), although it is far less acidic than chloroform (pK a = 24). The calculation indicates that the increased number of ﬂuorine substitutions on the ␣-carbon of methane, acetonitrile, and nitromethane results in a substantial enhancement of the acidity of the carbon acids [12]. Here again successive replacement of ﬂuorine atoms with triﬂuoromethyl groups increases the acidity of the ␣proton by about 2–3 pK a units per replacement (Table 1.13). Pentaﬂuorocyclopentadiene [13] is more acidic by 2 pK a units compared to cyclopentadiene [14], and pentakistriﬂuoromethylcyclopentadiene [15] is much more acidic by 18 pK a units compared to the parent compound. Triﬂuoromethyl groups directly attached to the ␣-position on the charged center in carbanions strongly stabilize the ␣-carbanion, whereas the ␣-ﬂuorine atom is less effective for the stabilization of the ␣-carbanion. The carbanion of diﬂuoronitromethane is pyramidal, although the corresponding carbanion of the parent nonﬂuorinated compound is planar (Scheme 1.3) [12]. The planar structure of the ﬂuoromethide anion would increase Coulombic repulsion between the lone-pair electrons of the carbanion and ﬂuorine atoms. It is noticeable that there is a report that demonstrates that a ﬂuorine atom destabilizes the

Table 1.12 pK a of ﬂuorophosphonate monoester

X pK a

O

CH2

CHF

CF2

6.45

7.65

6.2

5.64

Fundamentals in Organic Fluorine Chemistry

Table 1.13 pK a of some carbon acids

30.5

28.2

25.2

21

∼32 X=F (27.2) X=CI (25.0)

24.2

−11

−2

∼14

∼16

19

20

Organoﬂuorine Chemistry

Scheme 1.3

␣-carbanion in some cases [16]. The ﬂuoro-substituted acetophenones, benzonitriles, and nitrobenzenes are electrochemically less easily reduced than the corresponding chlorides and bromides, which suggests that the radical anions of the ﬂuoroaromatics are less stable than those of the chloro- and bromoaromatics [17]. Fluorine also enhances the acidity of an sp2 -hybridized C−H bond in aromatic and alkenyl hydrocarbons (Table 1.13). Pentaﬂuorobenzene [18] and triﬂuoroethene [19] are much more acidic than the corresponding parent hydrocarbons (pK a = 43 and 44 for benzene and ethene, respectively). The ﬂuorination of amines has also a pronounced effect bringing about a signiﬁcant decrease in basicity. 2,2,2-Triﬂuoroethylamine (pK b = 3.3) is about 105 times less basic than the nonﬂuorinated ethylamine [20]. Perﬂuoroamines (Rf)2 NH and perﬂuoropyridine do not react with HCl and BF3 [21]. Successive ﬂuorination of the bridgehead carbons of 1-adamantamine 4 increases linearly the acidities of the conjugate acids, which suggests that the basicity of the ﬂuorinated amines decreases equally (Figure 1.7) [22].

Figure 1.7 Acidity dependence on ﬂuorine.

Fundamentals in Organic Fluorine Chemistry

21

The acidity enhancement by ﬂuorine substitution has been employed for the highly effective polymer Brønsted acid 6 and Lewis acid 11. The polymer Brønsted acid 6 catalyzed a variety of acid-catalyzed carbon–carbon bond formations more effectively than did Naﬁon H 7 (Scheme 1.4) [23]. The Lewis acids 11 and 13 could be prepared by simply mixing Brønsted acids 10 and 12 with allylsilane in excellent yields [24] (Scheme 1.5). The acidity of Lewis acids Me3 SiX could be estimated by the chemical shifts of 29 Si of the trimethylsilyl group and measured by the down ﬁeld chemical shift of the ␤-proton on coordinating with crotonaldehyde (Table 1.14). The order of Lewis acidity of Me3 SiX is C6 F5 CTf2 > NTf2 > OTf, which is the opposite of that of the Brønsted acidity of HX [pK a in AcOH: C6 F5 CHTf2 (1.5) < HNTf2 (0.67) < HOTf (−0.96)]. Both 11 [27] and 13 [24] are effective super Lewis acids for carbon–carbon bond formations.

Scheme 1.4

Scheme 1.5

22

Organoﬂuorine Chemistry

Table 1.14 Chemical shift differences on coordination of acids to carbonyl group HX C6 F5 CHTf2 HNTf2 HOTf

␦(H␤ )a

Me3 SiX

␦29 Sib

␦(H␤ )a

0.086 0.76 1.27

Me3 Si[C6 F5 CTf2 ] Me3 SiNTf2 Me3 SiOTf Me3 SiB(C6 F5 )4 c Me3 SiClO4 d Me3 SiCI

58.5 55.9 43.5 84.8 43.4 32.5

1.99 1.74 0.003

a

Chemical shift differences of H␤ of crotonaldehyde observed on protonation with HX and coordination with Lewis acid (Me3 SiX). Positive value of ␦(H␤ ) means a downﬁeld shift. b 29 Si Chemical shifts with larger positive values mean lower ﬁeld. c [25]. d [26].

General anesthetic

Highly volatile, chemically inert, nontoxic, and noninﬂammable ﬂuorohydrocarbon ethers have been employed as a general anesthetics. The CF3 or its equivalent groupactivated methine proton plays an essential role for the anesthetic action.

1.2.2.2

Bond energy and bond length

The carbon–ﬂuorine bond is the strongest of the carbon/other element bonds. Indeed, the strength of the bond is signiﬁcant in determining much of the chemistry of ﬂuorocarbon compounds. For example, the C–F bond strength is much greater than the C–Cl and the C–Br bond strengths and is almost twice the strength of the C–I bond (Table 1.15). Alkyl bromides and iodides undergo facile SN 1 and SN 2 reactions, but alkyl ﬂuorides are less reactive by 10−2 for SN 2 and by a factor of 10−4 –10−6 for SN 1 than the chlorides [28]. The reactions of alkyl ﬂuorides with strong nucleophiles mostly proceed via elimination (E2) rather than via nucleophilic substitution (SN 2).

23

Fundamentals in Organic Fluorine Chemistry

Table 1.15 Bond strength of R–X (kcal/mol) X R CH3 CH3 CH2 PhCH2 CF3 CF3 CF2 CCl3

H

F

Cl

Br

I

CH3

105 101 90 108 103 94

113 111 — 131 127 100

84 85 74 87 83 68

70 71 61 71 68 54

57 56 — 54 52 —

90 89 79 101 87 —

Replacement of alkyl groups in R–X with the triﬂuoromethyl group slightly strengthens the C–X bond. Increasing the number of the ␣-ﬂuorines in X–CFn X3−n (X = H or Cl) makes the C–X bond stronger (Tables 1.16 and 1.17). Greater use of the p-orbital of the hybrid orbital in the C–F bond of X–CFn X3−n makes the ratio of the s-orbital of the C–X bond larger and thus the bond stronger. It is noteworthy, however, that the carbon–halogen bonds of pentaﬂuoroethyl halides (halogen: Cl, Br, I) are weaker than those of ethyl halides and that the C–X bonds in X–CCl3 are much weaker than the C–H and C–X (X = halogen) bonds in X–CH3 , X–CH2 CH3 , and X–CF3 . The third-row elements such as sulfur and chlorine in C–X stabilize the ␣-carbon radical more substantially than do the second-row elements such as oxygen and ﬂuorine. The O–O bond in bistriﬂuoromethylperoxide is 8 kcal/mol stronger than that of dimethylperoxide presumably due to the lower degree of electrostatic repulsion between lone-pair electrons on both oxygen atoms. However, it is the opposite case for bis(perﬂuorot-butyl) peroxide, where the lower degree of electrostatic repulsion and the larger steric repulsion by the extremely bulky perﬂuoro-t-butyl groups are operative oppositely (Table 1.18) [29]. Table 1.16 Bond strength of H–C in CFn H4−n (kcal/mol) n

0

1

2

3

BE

105

101

103

108

Table 1.17 Bond strength of Cl–C in CFn Cl4−n (kcal/mol) n

0

1

2

3

BE

73

73

83

86

24

Organoﬂuorine Chemistry

Table 1.18 Bond strength of O–O in RO–OR (kcal/mol) CH3 CF3 (CH3 )3 C (CF3 )3 C

38 46 38 35

The effect of halogen on the C–H and C–C bond lengths in halohydrocarbons is somewhat complicated. The effect of ﬂuorination on the C–C bond length of polyﬂuoroethanes is summarized in Table 1.19 [30]. The increasing substitution of ﬂuorine at the same carbon makes the C–C bond shorter, but further additional substitution at both C1 and C2 carbons results in lengthening of the bond.

1.2.3

Halogen bonding

The strong electron-withdrawing nature of ﬂuorine atoms in molecules induces an interesting halogen bonding in which perﬂuoroalkyl iodides, formally Lewis bases, actually behave like Lewis acids. Perﬂuoroalkyl iodides strongly associate with Lewis bases, affording a crystalline 1:1 adduct in most cases. Typically, the halogen bonding is observed in a combined system of perﬂuoroalkyl, aryl, and vinyl iodides with Lewis bases such as amines, nitriles, N-oxides, P -oxides, S-oxides, and ethers. These interesting phenomena have been extensively disclosed by Resnati’s group. (One typical example is presented in the supplementary topic on p. 25.) Thus, mixing 1,4-diiodo-2,3,5,6-tetraﬂuorobenzene (1) with 1,2-bis(4pyridyl)ethane (2) in a 1:1 ratio gives a crystalline solid material. Also interesting is the fact that mixing 1, 2, and 1,4-hydroquinone in a ratio of 1:1:1 in THF (tetrahydrofuran) results in precipitation of a crystalline solid that consists of one-to-one linear chains of 1 and 2, while the unreacted 1,4-hydroquinone remains in the solution. This phenomenon demonstrates that the nonbonding association between 1 and 2 is much stronger than a conventional

˚ of C–C bond in CHn F3−n –CHmF3−m Table 1.19 Bond lengths (A) CH3 –CH3 CH3 –CH2 F CH3 CHF2 CH3 –CF3 CH2 F–CH2 F CH2 F–CHF2 CF3 –CH2 F CF3 –CHF2 CF3 –CF3 CHF2 –CHF2

1.513 1.504 1.498 1.494 1.503 1.500 1.501 1.524 1.545 1.518

Fundamentals in Organic Fluorine Chemistry

25

acid–base association between 1,4-hydroquinone and 2. Crystallographic analysis reveals that the linear chains of the two molecules align alternately (see the following textbox, crystal 3) [1].

Halogen bonding may arise from an expected electron deﬁciency of iodine atoms in perﬂuorinated aryl and alkyl iodides, which in turn is caused by the large electron deformation of the soft lone-pair electron on the iodine atom induced by electron-withdrawal through ␴-bonds. The fact that halogen bonding is strongest in iodides among halides suggests that the softness of the lone-pair electron on the iodine atom plays an essential role. A relatively large equilibrium constant (K eq = 10.7) for the equilibrium between 1-azabicyclo[2.2.2]octane (4) and perﬂuoropropyl iodide (5) in chloroform has been observed (Scheme 1.6) [2]. The preference of iodine over bromine for the halogen bonding is

26

Organoﬂuorine Chemistry

Scheme 1.6

supported by the fact that the much larger upﬁeld shifts of the diﬂuoroiodomethyl group are observed in 19 F NMR on mixing 1,2-dihalotetraﬂuoroethane with Lewis base solvents (Table 1.20) [2]. The interaction degree of the lone-pair electron of Lewis bases with the iodine atom of perﬂuorinated iodides is a measure of the electron-donating ability of Lewis base, which can be analyzed by measuring any upﬁeld chemical shifts of the ﬂuorine atom of the diﬂuorohalomethyl group in 1,2-dihalotetraﬂuoroethanes in a Lewis base as a solvent (Scheme 1.6). Table 1.20 summarizes upﬁeld chemical shifts, which are differences of the Table 1.20

19

F NMR chemical shift differences of 8 (X = I, Br) in Lewis base solvents ␦ (ppm)

Piperidine N-Methylpiperidine Morpholine N-Methylmorpholine Thiomorpholine THF Tetrahydrothiophene 3,6-Dioxaoctane 3,6-Dithiaoctane 1,3-Propanediol 1,3-Propanedithiol Pyridine Furan Thiophene Acetone DMSO HMPA Acetonitrile

X=I

X = Br

11.23 8.89 10.59 8.39 9.94 4.13 5.38 3.36 5.50 4.30 3.45 7.32 1.11 1.41 3.63 7.22 8.23 2.74

2.40 2.07 1.95 1.71 1.62 0.95 0.76 0.96 0.77 0.90 0.58 1.12 0.13 0.26 0.90 2.03 2.76 0.45

Fundamentals in Organic Fluorine Chemistry

27

chemical shifts between those in n-hexane and in any Lewis base solvents. It is clear that the iodine atom is more susceptible than the bromine atom in this electron-accepting interaction of perﬂuorinated alkylhalides [2]. The stronger interaction for iodides has been already demonstrated in the shorter interatomic distance (I < Br < Cl in C–X . . . NC–) between the halogen and the nitrogen of the cyano group in the packing structure of 1-halo2-cyanoacetylenes [3]. A combination of perﬂuoroalkyl iodide with either alkyl amines [1] or bipyridine [4] is also effective for halogen bonding. A one-to-one mixture of 1,2-diiodotetraﬂuoroethane (10) (mp = −27◦ C) with 1,2-ethylenediamine (11) (mp = −55◦ C) produces a crystal 12 whose melting point (mp = 105◦ C) is much higher than those of the mother compounds (10 and 11) [1]. On the other hand, a 1:1 mixture of 11 and 1,2-diiodoethane is a liquid. X-ray crystallographic analysis of crystal 14, which is obtained from a 1:1 mixture of 10 ˚ between nitrogen and iodine was and azacrown 13, revealed that the bond distance (2.80 A) ˚ of van der Waals radii of both nitrogen and iodine, much shorter than the sum (3.53 A) suggesting there exists a strong attractive force between the two atoms [5]. It is well known that halogen atoms of alkyl halides in general behave as a typical Lewis base. However, the iodine atom of 10 strongly associates with the nitrogen atom of amines, typical Lewis bases, and behaves as an active center for a Lewis acid (Scheme 1.7).

Scheme 1.7

The same Lewis acid type nature of the iodine atom is also demonstrated in ﬂuorovinyl iodide (15), which makes crystals 17 and 19, respectively, with N,N,N,N-tetramethylethylene

28

Organoﬂuorine Chemistry

diamine (16) and 1,4-bipyridine (18) [6]. The nitrogen atom of the cyano group of ␣, ␻dicyanoalkanes (21) can also participate in the halogen bonding with the iodine atom of ␣, ␻-diiodoperﬂuoroalkanes (20), although the halogen bonding in this case seems weaker than those of amines as evident from their lower melting points (Scheme 1.8) [7]. A strong interaction of perﬂuorobenzyl iodide with N,N,N,N-ethylenediamine has also been reported [8].

Scheme 1.8

Not only the nitrogen atom of amines and nitriles, but also the oxygen atom of N-oxide 23 [1], dioxane 25 [9], HMPA 27 [9], and aryl aldehyde 29 [10] associates strongly with the iodine of perﬂuorinated compounds as shown in Scheme 1.9. Here again the bond distance ˚ in cocrystal 26 is in between those of the covalent between iodine and oxygen (2.814 A) ˚ and the sum of the van der Waals radii of iodine and oxygen (3.500 A). ˚ The bond (2.140 A) bond angle of O–I–C is 177◦ , i.e. near 180◦ , and this reveals a favorable linear alignment of the three atoms involved in the halogen bonding. The bond distance between iodine and ˚ is shorter than that of crystalline nonﬂuorinated carbonyl oxygen in crystal 29 (2.95 A) ˚ [11]. Quite interesting is the bidentate bonding of the oxygen 4-iodobenzaldehyde (3.07 A) atom of HMPA (27), which interacts with two iodine atoms of 10 by using both lone-pair electrons on the oxygen atom, while the oxygen atom of dioxane associates with only one iodine atom of 10. This is due to the strong donor ability of the lone-pair electrons on the

Fundamentals in Organic Fluorine Chemistry

29

Scheme 1.9

oxygen atom of HMPA. This result is also supported by the larger upﬁeld shift of the F NMR chemical shift of 10 with HMPA (Table 1.20) [2]. Ferrocenyl amine (30), which has two different donor sites, gives crystals when mixed with 10 and the related ␣, ␻-diiodoperﬂuoroalkanes (31) [12]. Melting points of these crystals are moderate (43–80◦ C). Two iodine atoms of 31 interact with both cyclopentadiene and amino nitrogen, separately (Scheme 1.10).

30

Organoﬂuorine Chemistry

Scheme 1.10

Applications of the nonbonding interaction system to material and reaction sciences seem to be promising. The halogen bonding is able to induce liquid crystallinity from nonmesomorphic components. Thus, a 1:1 mixture of 33 and 34 (both colorless) in THF produces pale yellow crystals. Here again the iodine atom is the most effective for the halogen bonding because no complex formation was observed from the corresponding bromo- and chloropentaﬂuorobenzenes [13]. Resolution of enantiomers of racemic dibromoperﬂuoropropane (35) by diastereoselective crystallization through the halogen bonding is remarkable [14]. 1,2-Dibromoperﬂuoropropane melts at −95◦ C, while crystals formed by the halogen bonding between bromoﬂuoropropane (35) and amine hydrogenbromide (36) have a surprisingly high melting point of 105◦ C, which enables diastereoselective crystallization and resolution (Scheme 1.11).

Scheme 1.11

A strict alignment of electron donor module through the halogen bonding can be used for stereo-controlled [2 + 2] photochemical cycloaddition in a solid state. A combination of

Fundamentals in Organic Fluorine Chemistry

31

pentaerythritol ether (38) with trans-1,2-bis(4-pyridyl)ethene (39) in a mixture of CHCl3 and CCl4 produces a crystalline supramolecule in which two ethene moieties are ideally preorganized for the photochemical cycloaddition, both by intermolecular ␲–␲ stacking interaction and halogen bonding as shown in Scheme 1.12. Photolysis of the crystals provides stereoselectively tetrakis(4-pyridyl)cyclobutane in a quantitative yield [15].

Scheme 1.12

1.2.4

Electronic effect on the destabilization of carbonyl and imono groups

The stability of the carbonyl group of ketones and aldehydes is highly dependent on the electronic nature of the substituents on the carbonyl group. Because the polar carbonyl bond which contains the carbon of the carbonyl group is electron deﬁcient, the electron-donating substituents stabilize the carbonyl group, while the electron-withdrawing groups destabilize it. Perﬂuoro or polyﬂuoroalkyl ketones and aldehydes are in general unstable toward attack by nucleophiles [1]. Therefore, in aqueous or alcoholic solution they exist mostly as hydrates or hemiacetals, some of which are distillable without decomposition (1 and 2 in Scheme 1.13). Both diﬂuoroenolate (3) [2] and enamine (4) [3] are stable and isolable, although they decompose under basic conditions. Some typical examples are shown in Scheme 1.13.

Scheme 1.13

32

Organoﬂuorine Chemistry

Table 1.21 Calculated heat of hydration R1

R2

MNDO (kcal/mol)

CH3 CH2 F CHF2 CF3

CH3 CH3 CH3 CH3

−1.05 −6.86 −9.92 −12.19

CH3 CF3

H H

−7.75 −11.44

Equilibrium constants for hydrations of hexaﬂuoroacetone and acetone in water clearly reveal a big difference in hydration equilibrium constants between both ketones, as shown in Scheme 1.14 [4]. Likewise, calculated heats of hydration of ﬂuoroacetones and ﬂuoroacetaldehyde indicate that the energy gain for hydration increases with the increasing number of ﬂuorine substituents, as shown in Table 1.21 [5].

Scheme 1.14

The enol form (8) of the highly ﬂuorinated cyclopentanone (7) is more stable than the keto form (Scheme 1.15), demonstrating the powerful ﬂuorine effect on enolization [6]. It is well known that the transformation of the enol form (3) to the corresponding keto form was found not to be easy [2]. We all know that hemiacetals of ketones and aldehydes and enols of common ketones can exist only as intermediates and cannot be isolated as their stable form. However, the chemical nature of the highly ﬂuorinated aliphatic carbonyl compounds is totally different from that of the nonﬂuorinated ones. The unusual behavior of the ﬂuorinated carbonyl compounds sometimes induces interesting chemical reactions and leads to novel drug designs. Compare the well-known Grignard reaction of ethyl acetate (11a) with that of ethyl triﬂuoroacetate (11b). The former acetate provides 1,1-diphenylethanol even though 1 mol equivalent of phenyl magnesium bromide is employed. On the other hand, the latter gives triﬂuoromethyl phenyl ketone (13) in ether. The big reactivity difference between the two esters arises from the relative stability of the intermediates 12 and 14 in ether. The nonﬂuorinated adduct (14) is converted in situ rapidly under the usual Grignard reaction conditions to acetophenone (15), which readily

Fundamentals in Organic Fluorine Chemistry

33

Scheme 1.15

reacts more rapidly with another mole of the Grignard reagent, resulting in the formation of tert-alcohol (16). In contrast, the intermediate produced from ﬂuorinated ester (11b) is so stable in the reaction medium that it does not break down until work up; when in acid, it is converted to ketone 13. A similar reaction is also observed for diﬂuorinated acetate derivative 17 (Scheme 1.16) [7].

Scheme 1.16

The instability of the carbonyl group of perﬂuorinated ketones and aldehydes suggests, in other words, its high reactivity toward nucleophiles. The more reactive carbonyl groups react with nucleophiles much faster than do the less electrophilic ones. Triﬂuoromethylated ketones are more reactive to nucleophiles. Thus, a Diels–Alder reaction of cyclopentadiene

34

Organoﬂuorine Chemistry

with a 1:1 mixture of ␣, ␤-unsaturated ketones 19 and 20 affords the triﬂuoromethylated [4 + 2]cycloadduct (21) predominantly along with a small amount of adduct 22. However, the same reaction in the presence of Lewis acid (BF3 etherate) provides nonﬂuorinated cycloadduct 22 as the sole product (Scheme 1.17). The CF3 group in ketone 19 activates the carbon–carbon double bond for the Diels–Alder reaction, but lowers the Lewis basicity of the carbonyl group and makes the ketone 19 less sensitive to the Lewis acid catalysis for the reaction in comparison with 20.

Scheme 1.17

Likewise, the competitive reaction of aldehydes 23 and 24 with allyltributylstannane gives homoallylic alcohol (25) exclusively (Scheme 1.18). In contrast, nonﬂuorinated cycloadduct is produced mainly under the catalysis of BF3 etherate in methylene chloride. These results clearly demonstrate that ﬂuorinated carbonyl compounds are more reactive; however, there is a turnabout in the reactivity under the Lewis acid catalytic conditions because of the lower basicity of the carbonyl group than that of the nonﬂuorinated one.

Scheme 1.18

Fundamentals in Organic Fluorine Chemistry

35

The 13 C NMR study clearly reveals that acetophenone largely shifts to the downﬁeld when in association with BF3 , while no shift is observed in triﬂuoroacetophenone under the same conditions. This fact suggests that no association of the markedly weak Lewis basic carbonyl group of 27 with Lewis acid is observed under the NMR analysis conditions. The nonﬂuorinated carbonyl group associates strongly with Lewis acid to enhance the electrophilic reactivity, while the corresponding ﬂuorinated one does not (Scheme 1.19) [8].

Scheme 1.19

One of the successful utilizations of the difference in the relative stability between ﬂuorinated and nonﬂuorinated imines is an effective transformation of perﬂuorinated ketones to the perﬂuorinated amines via imines by base-catalyzed 1,3-proton-shift methodology [9]. The driving force for the proton shift from 31 to 32 arises from the relatively lower stability of perﬂuoroalkyl imines compared to benzylidene imines [9]. Soloshonok developed an asymmetric version of the transformation in which DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) catalyzes the asymmetric 1,3-proton shift of 31 to provide enantio-enriched ␤-aminoester (33), as shown in Scheme 1.20 [10].

Scheme 1.20

Thermolysis of hexacoordinated phosphorous compounds (34)results in elimination of either benzophenone or hexaﬂuoroisobutene depending on the electronic nature of substituents R in 34. The exclusive elimination of hexaﬂuoroisobutene rather than of hexaﬂuoroacetone from 34 (R = CF3 ) is presumably due to the lower thermodynamic stability of hexaﬂuoroacetone than of hexaﬂuoroisobutene (Scheme 1.21) [11]. The strong electrophilic nature of the triﬂuoroacetyl group functions as a key functional group in potent inhibitors for serine proteases, which have attracted a great deal of attention as therapeutic targets. The idea is based on the effective trapping of a serine hydroxyl group

36

Organoﬂuorine Chemistry

Scheme 1.21 Table 1.22 Peptidyl methyl and perﬂuoroalkyl ketone inhibitors of HCMV protease Inhibitor 37a–f a: R = CH3 b: R = H c: R = CH3 d: R = CH3

X = CH3 X = CH3 X = CF3 X = CF2 CF3

f: R = CH3

IC50 (␮M) 2100 5000 1.1 0.1

0.2

in the active site of the protease enzymes by the highly electrophilic perﬂuorinated acyl group incorporated within oligopeptides. A large number of peptidyl methyl and perﬂuoroalkyl ketone inhibitors of human cytomegalovirus proteases have been synthesized and subjected to biological tests (some results are given in Table 1.22) [12]. Both triﬂuoromethyl and pentaﬂuoroethyl ketones were found to be effective. The generally accepted mechanism of the competitive inhibition is depicted in Figure 1.8 with the example of a peptidyl triﬂuoromethyl ketone. Attack of the active site serine hydroxyl group on the reactive carbonyl group results in formation of a hemiketal with an appreciable lifetime.

Figure 1.8 Proposed mechanism for the serine-protease inhibitory action.

37

Fundamentals in Organic Fluorine Chemistry

top view

H

F

F F

F F

F

H H

H H

H

side view

C6F6

C6F6

Figure 1.9 Negative charge distribution on C6 F6 and C6 H6 .

1.2.5 1.2.5.1

␲–␲ Stacking of ﬂuoroaromatics ␲–␲ Stacking between aromatics

Perﬂuoroalkylation of arenes makes the aromatic ring electron deﬁcient and thus it interacts with electron-rich arenes and Lewis bases. Figure 1.9 shows the ␲-electron distribution on the hexaﬂuorobenzene and benzene ring. Most of the ␲-electrons in hexaﬂuorobenzene are withdrawn from the aromatic ring by ﬂuorine atoms to make the aromatic ring highly electron deﬁcient, while the ␲-electrons in benzene are localized inside the ring. Thus both the benzenes interact attractively in a face-to-face manner [1]. In 1960, the ␲–␲ interaction between benzene and hexaﬂuorobenzene was reported [2]. An equimolar mixture of hexaﬂuorobenzene and benzene forms a solid with a melting point of 23.7◦ C, which is much higher than that of either of the two benzenes (ca. 5◦ C). The C6 F6 –C6 H6 cocrystals show a face-to-face alternate packing with an interplanar distance (r ) of 3.4 A˚ and an intercentroid distance (d) of 3.7 A˚ [3] (see Scheme 1.22 and Figure 1.10). The same type of face-to-face interaction has been observed in the 1:1 complex between the highly electron-deﬁcient 1,3,5-trinitrobenzene and benzene [4]. In contrast, benzene crystallizes by itself in a face-to-edge manner. The structural feature of the hexaﬂuorobenzene–benzene ␲–␲ stacking can be explained on the basis of the quadrupole–quadrupole interaction ˚ to −5.6 kcal/mol (Scheme 1.23) [5]. The stabilization energies of –3.7 kcal/mol (r = 3.6 A) for the C6 F6 –C6 H6 dimer have been estimated by theoretical calculations [6]. The dipole moment of the C6 F6 –C6 H6 complex has been reported to be 0.44 D [7]. Association between hexaﬂuorobenzene and the benzene rings of bis(␩2 -benzene)2 chromium was observed not only through quadrupole–quadrupole interaction but also through charge transfer (Figure 1.11). The CT complex [Cr(␩2 -C6 H6 )2 + C6 F6 − ] was conﬁrmed by redox potential measurements, EPR, and IR spectroscopies. Fluoride ion formed from C6 F6 − in the complex was trapped as TMS-F with TMS-OTf. The distance of 3.48 A˚ between centroids of both C6 F6 and C6 H6 is close to that observed in the CT complex [Fe(␩5 -C5 Me5 )·TCNE] [8]. The CT complex formations were also reported in the reactions of hexaﬂuorobenzene with the electron-rich aromatics such as N, N-dimethylaniline [9] and 1,4-N, N, N , N -tetramethylphenylenediamine [10].

Scheme 1.22

Figure 1.10 Cocrystals of hexaﬂurobenzene and benzene. The relative orientation of successive molecules is neither fully staggered nor eclipsed. Reprinted from Ref. [3b] with permission from Wiley-VCH.

Scheme 1.23

39

Fundamentals in Organic Fluorine Chemistry

Figure 1.11 Packing diagram of [Cr(␩6 -C6 H6 )2 ·C6 F6 ]. Reprinted from Ref. [8] with permission from Royal Society of Chemistry.

1.2.5.2

C 6 F6 –Lewis base interaction

Theoretical studies have demonstrated that the electron-deﬁcient center of hexaﬂuorobenzene interacts with Lewis bases and anions [11]. In these complexes (1), the anion is positioned over the benzene ring along the C6 axis. The calculated distances between the anion and the centroid of C6 F6 are shorter than those between C6 F6 and C6 H6 (Table 1.23) [9]. The X-ray crystallographic analysis of crystals of (C6 F5 )2 Br+ BF4 − clearly reveals the ﬂuorine–␲ interaction (see Figure 1.12) [12]. The same type of attractive interaction between hexaﬂuorobenzene and the ﬂuorine atom in ﬂuoromethane has been proposed on the basis of theoretical calculation [13]. The anion–␲ interaction gives a rational explanation for the fact that hexaﬂuorobenzene reacts with the late transition metals to form stable complexes, stability of which would arise from the back donation of the d-electrons in the metals to ␲ ∗ −antibonding orbitals of the ﬂuorobenzene. The complexes react with oxidizing reagents to regenerate C6 F6 (Scheme 1.24) [14]. Table 1.23 The calculated distance between the anion and the centroid of C6 F6

X− E (kcal/mol)a ˚ b R (A) a

H−

F−

Cl−

Br−

CN−

CO3 −

−11.2 3.034

−18.8 2.669

−11.0 3.404

−13.2 3.479

−11.9 3.020

−28.4 3.011

Interaction energies without the basis set superposition error. distance.

b Equilibrium

40

Organoﬂuorine Chemistry

Figure 1.12 X-ray crystal structure of (C6 F5 )2 Br+ BF− 4 . Reprinted from Ref. [12] with permission from Wiley-VCH.

Scheme 1.24

A theoretical calculation suggests that the interactions of water molecules with hexaﬂuorobenzene and benzene are totally different. A water molecule approaches the center of hexaﬂuorobenzene through the oxygen as Lewis base, while with benzene the hydrogen acts as a Brønsted acid (Scheme 1.25) [15, 16]. Of particular interest is the ﬁnding that ab initio calculations show that the water molecule in a 1:1 mixture of hexaﬂuorobenzene and benzene

Scheme 1.25

Fundamentals in Organic Fluorine Chemistry

41

is stabilized as a trimer, where it interacts with hexaﬂuorobenzene through oxygen–␲ interaction and with benzene through OH · · · ␲-hydrogen bond (see 5 in Scheme 1.25) [16].

1.2.5.3

Molecular recognition and crystal engineering by ␲–␲ stacking

The ␲–␲ stacking interaction has been employed elegantly in crystal engineering studies and in the design of novel supramolecular architectures. The following are representative examples. Diphenylbutadiyne (6) and decaﬂuorodiphenylbutadiyne (7) are colorless crystalline compounds. Diacetylene 6 is completely photostable, while 7 produces only traces of a polymeric material upon UV irradiation. On the other hand, both 1:1 cocrystal 8 and homocrystal 9 photooligomerize (Scheme 1.26). The reactivity difference for photopolymerization may arise from the remarkably different packing structures among these crystals. Diacetylene 6 packs in a highly slanted manner (distance between the packed molecules, ˚ while cocrystals 8 have the much shorter distance (d = 3.69 A), ˚ close to the ideal d = 6.0 A), ˚ for the intermolecular reaction. The higher melting point of cocrystals 8 distance (3.4 A) (mp = 152◦ C) as compared with those of homocrystals 6 (mp = 87◦ C) and 7 (mp = 114◦ C) strongly suggests the tight packing of the cocrystals 8 [17]. Similarly, two-dimensional packing has been demonstrated for the stacking of 1,3,5-tris(perﬂuorophenylethnyl)benzene (10) and 1,3,5-tris(phenylethynyl)benzene (11) [18], which formed essentially planar cocrystals with less slippage (12 and 13), while both homocrystals of 10 and 11 formed slipped stacks with the terminal aryl rings twisted with respect to the plane of the central ring (Scheme 1.27).

Scheme 1.26

The stereospeciﬁc solid-state [2 + 2] photocyclization of cocrystals 14 proceeded in a stereospeciﬁc manner to form 15 [19]. The pentaﬂuorophenyl–phenyl ␲–␲ interaction in the solution state has been demonstrated in the Pd-catalyzed synthesis of acetylenic cyclophanes (17) via inter- and then intramolecular self-assembly as shown in the transformation of 16 to 17 (X = F, Y = H) (Scheme 1.28) [20]. The photochromic behavior of the diarylethene crystals can be controlled by crystal engineering, namely the use of the ␲–␲ stacking phenomenon. Pentaﬂuorophenyl substituted

42

Organoﬂuorine Chemistry

Scheme 1.27 Photographs of 12 and 13 reprinted from Ref. [18b] with permission from WileyVCH.

3-thienylperﬂuorocyclopentene (18) cocrystallizes with benzene and naphthalene to make a sandwiched packing structure (see 20 in Scheme 1.29). Upon irradiation with 370-nm light, the colorless homocrystals 18 and cocrystals of 18 with benzene turned blue and reddishpurple, respectively. The absorption maxima in the visible region are 630 and 555 nm for 19 and 19/benzene cocrystals, respectively. The crystal structure of the ring-closed 19/benzene cocrystals 20 revealed that the pentaﬂuorophenyl rings largely tilt to the molecular plane of the central part, while that in the homocrystal 19 is coplanar to the ␲-system of the central part [21]. The effective utilization of the ␲–␲ stacking phenomenon for drug designs is described in Section 6.3. Assembly of the macrocyclic dinuclear complex bearing 2,3,5,6-tetraﬂuoro-1,4phenylene moiety 21 includes electron-rich aromatics as a guest into its cavity. The complex (21) associates with the electron-rich aromatics more efﬁciently than with the electrondeﬁcient aromatics as shown in Scheme 1.30. A noteworthy fact is that 21 does not complex with nonaromatics, 1,4-dimethoxycyclohexane (Scheme 1.30, Table 1.24) [22].

Fundamentals in Organic Fluorine Chemistry

43

Scheme 1.28

1.2.5.4

Conformational ﬁxation

The interaction of the electron-deﬁcient C6 F6 with the electron-donor moieties can be used for conformational ﬁxation. The conformation of N-pyrimidin-2-ylhexaﬂuoro benzamide (23) is syn in its crystal state, and is in equilibrium between syn and anti in CDCl3 , where the syn-form is preferred at the lower temperature. The pyrimidine ring twists by 68◦ to make possible the interaction of its nitrogen with the C6 F5 plane (distance 3.39 A˚ for the nitrogen-centroid of the C6 F5 ring) [23]. On the other hand, the preferred conformation of nonﬂuorinated benzamide (25) is anti in both crystal and solution states (Scheme 1.31). N-Benzyl ketimine (27) forms an adduct 28 with trispentaﬂuorophenyl borane (26), the structure of which is rigid in solution, as evidenced by the observations of 15 separate ﬂuorine signals for the three pentaﬂuorophenyl groups in the 19 F NMR along with diastereotopic benzyl protons in the 1 H NMR at room temperature. The absence of fast exchange between the C6 F5 rings suggests that rotation about the B–N and B–C bonds is restricted in adduct 28. X-ray crystallographic analysis of 28 also reveals the ␲–␲ stacking with a distance of 3.052 A˚ between C-1 for the C6 F5 ring and C-1 for the benzylic phenyl group [24]. The same

Scheme 1.29

Scheme 1.30

Table 1.24 Association constants (L/mol) between 21 and various guest aromatics in D2 O

X = MeO MeOCH2 CN NO2

2680 560 80 30 No complexation

Fundamentals in Organic Fluorine Chemistry

45

Scheme 1.31

␲–␲ stacking interaction has been observed in the adduct of phenyl ketone derivatives with B(C6 F5 )3 (Scheme 1.32) [25].

Scheme 1.32

The remarkably low reactivity of tetraﬂuoroparacyclophane (29) to Friedel–Crafts acylation in comparison with para-xylene indicates the deactivation of the nonﬂuorinated aromatic ring of 29 because of electron-deﬁciency due to a through-space polarization (Scheme 1.33) [26]. The ␲–␲ stacking interaction between arenes and perﬂuoroarenes has been employed for modiﬁcation of the liquid crystals [27].

Scheme 1.33

1.2.6

Increased p-character (Bent’s rule) and low-lying LUMO in carbon–ﬂuorine bonding orbitals

Bent’s rule describes that atomic p-character concentrates in the orbitals directed toward electronegative substituents [1]. Therefore, a carbon–ﬂuorine bond bears a more p-character in the bonding orbital because of the strongly electronegative ﬂuorine atom. On the other

46

Organoﬂuorine Chemistry

Figure 1.13 Relative stability of C–F bond.

hand, the remaining carbon–carbon bond bears a more s-character. The rule also suggests that ﬂuorine prefers bonding to sp3 -hybridized orbitals rather than to sp2 - and sp-hybridized orbitals (Figure 1.13). Many of the structures and reactivities of ﬂuorocarbons follow this generalization. The preferred sp3 hybridization for saturated ﬂuorocarbons is a major driving force for the easy polymerization of TFE to PTEF with more exothermic enthalpy change (Scheme 1.34) [2]. The ␲-bond energy of tetraﬂuoroethylene is 52 kcal/mol, which is smaller than that of ethylene, 64–65 kcal/mol [3]. The easy [2 + 2] cycloadditions of gem-diﬂuoroalkenes (thermal concerted reactions of which are forbidden) proceed stepwise via biradical intermediates. The intermediacy of a biradical is supported by the fact that a 1:1 mixture of the cis- and trans-dideuteriocyclobutanes (7 and 8) was obtained in the [2 + 2] cycloaddition of TFE with cis- (4) and trans-dideuterioethylene (5) [4] (Scheme 1.34).

Scheme 1.34

The highly exothermic cesium ﬂuoride catalyzed isomerization of hexaﬂuorobutadiene (9) via 10 to hexaﬂuoro-2-butyne (11) is another example [5] that shows that the ﬂuorine atom is preferably bonded to the carbon atom through the sp3 -hybridized orbital rather than through the sp2 orbital [6]. And here again, Bent’s rule plays an important role in the isomerization [7]. The thermal reaction of hexaﬂuoro-1,3-butadiene provides perﬂuorotricyclo[3.2.0.02,6 ]octane (15) as a stable ﬁnal product via sequential intraand/or intermolecular cycloaddition at 200◦ C [8]. In contrast, the parent hydrocarbon (16)

Fundamentals in Organic Fluorine Chemistry

47

undergoes ring opening to provide 1,5-cyclooctadiene (17) [9]. These results strongly suggest that ﬂuorocarbon 15 is thermodynamically more stable than perﬂuorinated 1,5-octadiene (14), while the reverse is true for the corresponding hydrocarbon 16 (Scheme 1.35).

Scheme 1.35

1.2.6.1

Highly strained ﬂuorocarbon compounds

Kekule benzene analogues such as Dewar benzene, prismane, and benzvalene (Scheme 1.36) have been dream compounds as the synthetic targets of both structural and theoretical interest. However, the parent hydrocarbons have never been synthesized and isolated in a stable form. Replacement of all of the hydrogen atoms of the parent hydrocarbons with a ﬂuorine atom or triﬂuoromethyl group makes these interesting compounds stable and even isolable [8]. These ﬂuorocarbons, or cyclic compounds with carbon skeletons and ﬂuorine skins, so-called by Lemal [9], are unusually stabilized (Scheme 1.37). The question is why are the ﬂuorocarbons more stable than the corresponding hydrocarbons. First, no hydrogen, which is oxidizable, is involved and thus ﬂuorocarbons are less air sensitive. Secondly, the bond strength of a carbon–ﬂuorine bond is higher than that of a carbon–hydrogen bond. Thirdly, carbon–carbon bonds in ﬂuorocarbons are generally strengthened by the increased s-character of the hybridized carbon orbitals. Bent’s rule describes that the p-character concentrates in orbitals directed toward electronegative substituents [1]. Therefore, the

Scheme 1.36

48

Organoﬂuorine Chemistry

Scheme 1.37

rule suggests that a carbon–ﬂuorine bond bears more p-character in the bonding orbital because of the strongly electronegative ﬂuorine atom; on the other hand, the remaining carbon–carbon bond bears a more s-character to make the bond stronger. For example, the carbon–carbon bond in hexaﬂuoroethane is 7 kcal/mol stronger than that in ethane. In addition, highly perﬂuoroalkyl-substituted molecules are kinetically and thermodynamically stable due to sterical protection by the bulky perﬂuoroalkyl groups from any external attacks. Comparison of the half-lives of thermal isomerization of the perﬂuoroalkylated strained molecules (28 and 30) with those of the parent hydrocarbons (29 and 31) reveals an exceptionally high stability of these ﬂuorocarbons (Scheme 1.38) [10]. Both the strengthening C–C bond and the steric protection of the inner carbon skeleton by perﬂuoroalkyl groups are responsible. Thermal equilibrium between hexakis(pentaﬂuoroethyl)benzene (34) and its Dewar benzene isomer (35) suggests another factor to control the stability of densely substituted benzene. Nonbonding steric repulsion between neighboring bulky pentaﬂuoroethyl groups in 34 destabilizes the aromatic planar structure and so the equilibrium shifts toward the Dewar benzene 35 side, with K eq = 4.4 at 400◦ C [11]. The large positive entropy change observed in the equilibrium indicates a release of the nonbonding repulsive potential energy involved in the planar structure (Scheme 1.39). In contrast, thermal isomerization of hexakismethyl Dewar benzene (36) to 37 is strongly exothermic.

Fundamentals in Organic Fluorine Chemistry

49

Scheme 1.38

Scheme 1.39

The unusual high thermal stability is observed in highly ﬂuorinated [2.2.2]propellane (38) in contrast to the unstable hydrocarbon analogue (39). The ﬂuorinated propellane 38 is extremely thermally stable and so no change is observed even at 100◦ C for 10 h [12]. In contrast, nonﬂuorinated propellane 39 undergoes retrocycloaddition to yield dimethylenecyclohexanes (40) and (41) with a half-life of 25 min at 25◦ C (Scheme 1.40) [13].

50

Organoﬂuorine Chemistry

Scheme 1.40

1.2.6.2

Low-lying LUMO of highly ﬂuorinated hydroﬂuorocarbons

Since the white-colored teﬂon stirrer bar turns black on being used under Birch reduction conditions, it indicates that ﬂuorocarbons are reactive under reductive conditions though in general these are thermally, photochemically, and chemically stable. The low-lying LUMO of perﬂuorinated compounds induces unique reactions by accepting an electron from nucleophiles, in particular via electron transfer reactions (Scheme 1.41).

Scheme 1.41

Although propellane (42) is thermally stable, it is readily reduced even by a chloride ion in moist acetonitrile at room temperature. The reduced compound 43 would be formed by electron transfer to the low-lying LUMO of the ␴ ∗ -orbital of the carbon–carbon bond between both bridgeheads from the chloride ion, followed by trapping the dianion with the proton of water. Meanwhile, nucleophilic attack of the chloride ion to one of the bridgehead carbons followed by trapping the carbanion with water may produce another compound (44) (Scheme 1.42) [12]. Perﬂuorinated decalin (45) is also a good electron acceptor and therefore on reaction with thiophenoxide in DMI it completely transforms to phenylthiosubstituted naphthalene (47). Electron transfer from thiophenoxide to the LUMO of 45 induces deﬂuorination to make a carbon–carbon double bond in the molecule of 45, and then the successive electron transfer/elimination sequence produces perﬂuoronaphthalene (46) as an intermediate. The replacement of the ﬂuorine atom with a thiophenoxy group via

Fundamentals in Organic Fluorine Chemistry

51

Scheme 1.42

nucleophilic substitution on the aromatic ring of 46 affords the fully phenylthio-substituted naphthalene (47) [14]. Diels–Alder reaction of the highly strained alkene (48) with benzene is one of the strikingly unusual reactions. The driving force of the unusual cycloaddition would be a favorable electron transfer from benzene to the low-lying LUMO of the highly electron-deﬁcient double bond of 48 [15]. In contrast, the corresponding hydrocarbon (50) dimerizes and polymerizes rapidly at ambient temperature (Scheme 1.43) [16].

Scheme 1.43

Saturated perﬂuorocarbons are not only thermally stable, but also, in general, chemically unreactive. However, they undergo facile deﬂuorination on reaction with strong reducing agents such as alkali metals and benzene thiolates, which are employed for etching perﬂuoropolymers [17].

52

1.2.7

Organoﬂuorine Chemistry

Negative hyperconjugation

Since Roberts’ proposal in 1950 [1], the concept of negative hyperconjugation has been used to explain the chemical and physical properties and the reactions of the triﬂuoromethyl compounds, in particular, although the origin of the unique phenomenon has been queried on various grounds [2]. The interactions of the carbon–ﬂuorine bond with the ␤-carbanion 1, the lone-pair lobe of ␣-heteroatom substituent in 3, and the ␣-carbon–carbon double bond in 4 are typical systems for negative hyperconjugation in which the C–F bond cleaved form 2 in a so called double bond/no bond resonance was originally proposed as a contributed resonance structure (Scheme 1.44) [2]. Later on in terms of the molecular orbital theory, the negative hyperconjugation has been explained to be the interaction of the lone-pair electrons (n or p) of the anionic center or the neutral heteroatom with the antibonding (vacant ␴ ∗ CF ) and bonding (ﬁlled ␴CF ) orbitals of the ␤-C–F bonds (Figure 1.14) [3, 4]. Or, simply said it is the delocalization of the lone-pair electrons to the low-lying ␴ ∗ -antibonding orbital of the C–F bond (Figure 1.14A).

Scheme 1.44

It has been widely recognized that the hyperconjugation plays an important role either thermodynamically or kinetically (1) in the stabilization of ␤-carbanion 1, (2) in the shortening and strengthening of the C␣ –C␤ bond in the systems 1, 3, and 4 (see Scheme 1.44), and (3) in the high reactivity of the C–F bond in system 4.

Figure 1.14 2p-␴ ∗ overlap in negative hyperconjugation for ␤-ﬂuorocarboanion.

53

Fundamentals in Organic Fluorine Chemistry

This section begins with Roberts’ initial proposal. The dipole moment of p-N,Ndimethylaminobenzotriﬂuoride (5) (4.62 D) is 0.44 D units larger than the sum of (4.18 D) dipole moments of N,N-dimethylaniline (1.58 D) and benzotriﬂuoride (2.60 D). The acidity constants of substituted anilinium ions (8) suggest the additional electron-withdrawing effect of the triﬂuoromethyl group attached to an aromatic ring (Scheme 1.45, Table 1.25). The positive values of the pK a difference between para- and meta-substituted anilinium ions suggest that both nitro and triﬂuoromethyl groups on the para-position strongly stabilize the lone-pair electron on the amino nitrogen of 9 to strengthen the acidity of the anilinium ions (8). The extra dipole moment of 5 and the higher acidity of 8 with the p-CF3 group have been explained in terms of the negative hyperconjugation (see 5 and 6 in Scheme 1.45).

Scheme 1.45

Bond distances and bond angles in ﬂuorinated molecules often provide useful informations about the bonding state of the C–F bond related to the negative hyperconjugation. Calculations indicate that the C–C bond of 10 is shortened by 0.13 A˚ and the antiperplanar Table 1.25 Acidity constants of substituted anilinium ions 8 X

pK a pK a a a

H

p-Cl

m-Cl

p-NO2

m-NO2

p-CF3

m-CF3

4.57

4.15

3.67

1.11

2.45

2.57

3.46

−0.48

pK a = meta-pK a − para-pK a .

1.36

0.89

54

Organoﬂuorine Chemistry

C–F bond is lengthened by 0.13 A˚ as compared with those of the parent 1,1,1-triﬂuoroethane (11) (Scheme 1.46) [5]. The calculation also supports that an in-plane HOMO–LUMO mixing of a C–F ␴-antibonding orbital with the carbon lone pair yields hyperconjugative ␲-bonding in the anti conformation [6]. Similar phenomena were also conﬁrmed in the perﬂuorinated carbanions such as perﬂuorinated ethyl, isopropyl, and tert-butyl carbanions [7]. Likewise in the case of the C–C bond shortening in 10, the carbon–sulfur bonds in the sulfonylmethyl carbanions (12) (X = CH3 , CF3 , and F) are shortened as compared with those of the parent sulfones (13) [4]. Thus, the shortened distances of the C␣ –S bonds ˚ respectively) are larger for the ﬂuorinated carbanions (12b) and (12c) (0.142 and 0.131A, ˚ than that of the nonﬂuorinated carbanion (12a) (0.104 A). The calculation based on the more stable conformation of 14 rather than of 15 reveals that the lengthened distance (the S–X bond distance difference between the carbanion 12 and the neutral molecule 13) of ˚ for the S–F in 12c is larger than those (0.033 and the antiperiplanar S–X bond (0.092 A) ˚ 0.022A) of S–C bonds for 12a and 12b, respectively. Here again, the effect of the ﬂuorine atom located antiperiplanar to the lobe of the carbanion 12c is remarkable.

Scheme 1.46

Negative hyperconjugation is important in neutral system as well. The same phenomena of both the shortening of the C␣ –X bond and the lengthening of the C␣ –F bond antiperiplanar to the lobe of the lone pair on X in F–C␣ –X (X = heteroatom) system 3 are demonstrated in triﬂuoromethyl ethers, amines, and thioether [8]. The calculated bond shortenings of various triﬂuoromethyl ethers and related molecules (CF3 –X) at the level of G2MP2/6– 31G(d) are correlated with the calculated C–C bond dissociation energies (BDE) (Table 1.26) [8], although Kaupp has warned of the uncritical use of the relationship between bond distance and bond strength [9]. Quite interesting are the facts that (1) the bond strengthening effect by the heteroatoms (X = O and N) in CF3 –X is larger than that by the carbon, and (2) the effect is weaker for the third- and fourth-row elements (S and Br, respectively), if the differences of BDE between triﬂuoromethyl and methyl compounds for each substituent X are compared (see the values of the last row in Table 1.26).

55

Fundamentals in Organic Fluorine Chemistry

Table 1.26 Bond dissociation energies of triﬂuoromethyl ethers and related compounds (CF3 –X)a X in CF3 X or CH3 X

n-Pr

OCH3

OCF3

N(CH3 )2

SCH3

Br

CF3 CH3 (CF3 − CH3 )d

97.0 91.5 5.5

109.3 86.8 22.5

110.5 99.8 10.7

99.8b 83.2 16.6

78.4c 74.7 3.7

74.8 73.8 1.0

a

Calculated by G2MP2 method. of N(CF3 )3 . c BDE of S(CF ) . 3 2 d Difference of BDE between CF X and CH X. 3 3 b BDE

Measurement of the rotational barrier about the C–N bond in the F–C–N system is also a useful probe to gain information on negative hyperconjugation because the contribution of the double bond/no bond resonance would hinder the rotation. A number of theoretical predictions of the rotational barrier in the F–C–N system have been reported [3, 10]. An elegant NMR measurement of the energy barrier for the rotation-inversion process in the unsymmetrically substituted ␣-ﬂuoroamine, N-benzyl-N-methyl-␣-ﬂuoromethylamine (16), was reported by Lemal [11]. The contribution of the resonance structure 17 is assumed to increase the energy barrier for the rotation process (Scheme 1.47). The variable temperature experiment has shown that the proton signals of the ﬂuoromethyl group resolved into a doublet with J = 59.6 Hz corresponding to the geminal coupling with a ﬂuorine atom at –30◦ C, then to a pair of doublets at –75◦ C, and ﬁnally a clear pair of double-doublets as shown in Figure 1.15. Two protons on the ﬂuoromethyl group of 16 resolved into an AB-type double doublet as a result of the freezing of the rotation-inversion process at –100◦ C. The free energy of activation obtained by the NMR analysis was G ‡ = 10.1 kcal/mol, which is similar to the theoretically calculated values of 7.8 kcal/mol [10a, 10b] and 9.4 kcal/mol [5a] for the parent ﬂuoromethylamine and is larger than that of aminomethanol (6.6 kcal/mol) [3]. The author described that the rather big energy barrier for the rotation-inversion process of 16 could be partially attributed to the negative hyperconjugation.

Scheme 1.47

The C–O bond energy in CF3 OH is of interest because of its relevance to the atmospheric oxidation of hydroﬂuorocarbons. The computational results suggest that the CF3 O–H bond is much stronger than that of methanol and is comparable to the O–H bond strength in water. The CF3 group bonds strongly to the adjacent hydroxyl group, a typical ␲-donor group. Table 1.27 shows that (1) the successive substitution of hydrogens in methanol with

56

Organoﬂuorine Chemistry

Figure 1.15 NMR signals measured at 300 MHz in CCl3 F/C6 D5 CD3 (4:1) for the ﬂuoromethyl protons of 16 at various temperatures. Reprinted from Ref. [11] with permission from the American Chemical Society.

ﬂuorine or chlorine results in both shortening and strengthening of the carbon–oxygen bond [12], and (2) the degree of the C–O bond strengthening and shortening is larger for ﬂuoromethanols than for chloromethanols. The calculation reveals that the antiperiplanar conformations 18, 19, and 20 (Scheme 1.48) are the most stable conformation of mono, di, and triﬂuoromethanol as observed in ␤-ﬂuoroethyl carbanion (10) [13]. Table 1.27 Calculated bond distances and bond energies in CHn X3-n OH

C–O bond distancea BDE (RO–H)b BDE (R–OH)b BDE (R–H)b

CH3

CFH2

CF2 H

CF3

CCIH2

CCl2 H

CCl3

1.3984 104.4c 92.5c 104.9c

1.3631 105.3 105.4 100.1

1.3387 115.3 115.2 103.3

1.3297 118.2 118.3 107.1

1.3631 106.3 97.3 100.8

1.3458 111.7 99.2 98.4

1.3441 111.6 96.4 93.8

˚ RHF/6-31G level calculation, A. were estimated by MP2/6-31G level calculation, kcal/mol. c Experimental values, Ref. [13].

a

b BDE

Fundamentals in Organic Fluorine Chemistry

57

Scheme 1.48

In relation to the geometries of triﬂuoromethoxide, an important experimental result was obtained by the DuPont group [14]. The X-ray crystallographic analysis of ˚ tris(dimethylamino)sulfonium methoxide (22) revealed that (1) the C–O bond (1.227 A) ˚ (2) the bond anin 22 is, unusually, as short as the normal C–O double bond (1.23 A), gle of O–C–F is 116.2◦ , which deviates largely from that of the normal sp3 hybridization and is close to that of sp2 , and (3) the bond angle of F–C–F is smaller than that of the normal sp3 hybridization in spite of the expected unfavorable ﬂuorine–ﬂuorine repulsion (Scheme 1.49). The calculated geometric data of 23 are consistent with those of the observed (22). The calculated C–O bond length becomes shorter as the number of ␣-ﬂuorine atom increases (1.214 A˚ for 23, 1.222 A˚ for 24, and 1.245 A˚ for 25). All of these observed and calculated results of the geometries for triﬂuoromethoxide anion strongly support the negative hyperconjugation in the anion (26) (see Scheme 1.49) [14].

Scheme 1.49

58

Organoﬂuorine Chemistry

The thermodynamic and kinetic acidities of ␤-ﬂuorohydrocarbons are one of the useful measures for estimating a stabilization effect of ␤-carbanion by ﬂuorine substituents. Andreades ﬁrst suggested the double bond/no bond resonance for the tris(triﬂuoromethyl)methyl carbanion (27) in 1964. The relative H/D exchange reaction rates for (CF3 )3 CH, (CF3 )2 CFH, CF3 (CF2 )5 CF2 H, and CF3 H were 109 : 2 × 105 : 6:1, from which the respective pK a values were calculated to be 11, 20, 30, and 31 [15]. The relative acidities were explained in terms of the negative hyperconjugation on the basis of the numbers of double bond/no bond resonance contributors (29) (Scheme 1.50). However, the relative acidities can be also explained by the combination of the strong inductive effect of triﬂuoromethyl and perﬂuoroalkyl groups [16] and the destabilization of the carbanion by a repulsion with the lone-pair electrons on the ␣-ﬂuorine atom. The acidities of polyﬂuorinated bicyclic compounds, in which the resonance stabilization cannot operate because of the high strain of the bridgehead double bond, were studied so as to estimate the resonance and inductive effects separately. (Streitwieser et al. [17] concluded that the negative hyperconjugation was not necessary to explain the acidity of 27. But, it has also been pointed out that serious anomalies still existed; see Ref. [18].) Tatlow showed the relative rates (27:30:31 = 100:10:1) for the kinetic H/D exchange reaction of bicyclooctane 30 and heptane 31 in a neutral medium (D2 O/CD3 COCD3 ) [19]. The acyclic polyﬂuoride (27) is substantially more acidic than the related cyclic polyﬂuorides (30) and (31). Another important contribution to the acidity measurement for 27 and 31 was demonstrated by Koppel and Taft. The pulsed FT-ICR technique led to a conclusion that the acyclic ﬂuoride 27 is more acidic than the cyclic ﬂuoride 31 by many orders of magnitude [3].

Scheme 1.50

59

Fundamentals in Organic Fluorine Chemistry

˚ calculated for CH3 –X and CF3 –X(34) Table 1.28 Optimized bond lengths r (A) CH3 –X X

˚ r (A)

CH3 CH− 2 SiH3 SiH2 − NH2 NH− PH2 PH− OH O− SH S−

1.533 1.568 1.882 1.981 1.450 1.451 1.864 1.920 1.430 1.361 1.821 1.839

CF3 –X ˚ r (A) 0.035 0.099 0.001 0.056 −0.069 0.017

˚ r (A)

˚ r (A)

1.486 1.386 1.885 1.946 1.364 1.299 1.872 1.844 1.338 1.233 1.784 1.722

−0.100 0.061 −0.065 −0.028 −0.105 −0.062

On the basis of the above discussion, it is reasonable to consider the concept of negative hyperconjugation in the system related to the second-row elements shown in 1, 3, and 4. Since the second-row elements form a stronger ␲-conjugation system with the 2p-orbital on carbon than do the third-row elements, the question is whether the negative hyperconjugation is effective for systems like 34, which contain the third-row elements (Scheme 1.51) [20]. Examination of the bond lengths calculated for CH3 –X and CF3 –X (Table 1.28) provides information useful for evaluating the hyperconjugation in the third-row elements: (1) Bond lengths of C–X for CF3 –X are generally shorter than those for CH3 –X; (2) the C–X bond lengths for the anion of CH3 –X are longer than those for the neutral molecules, while in contrast, the C–X bond lengths for the anion of CF3 –X are shorter than those for the neutral molecules, except one for Si molecules; (3) the extent of the bond shortening for the anion of CF3 –X is larger for the second-row elements than for the third-row elements (see Table 1.28). The last point suggests the negative hyperconjugation, which induces the C–X bond shortening in CF3 –X due to the resonance contribution of 35, is less effective for the third-row element systems. The extent of the A–F bond lengthening in the AF3 –X system again gives us the same conclusion (Table 1.29) [21]. However, the situation is somewhat complex when A is the third-row element since the F–P bonds are shortened in both PF3 O and PF3 S.

Scheme 1.51

60

Organoﬂuorine Chemistry

Table 1.29 Calculated F–A bond lengthening in AF3 –X systema CF3 –O− CF3 –S− NF3 –O− NF3 –S− PF3 –O PF3 –S

+0.069 (CF3 –H) +0.033 (CF3 –H) +0.022 (NF3 ) −0.009 (NF3 ) −0.038 (PF3 ) –0.029 (PF3 )

a Bond

length change in comparison with ˚ reference molecule (A).

Fujita proposed that the negative hyperconjugation is unfavorable to explain nonstereoselective oxidation of ␣-ﬂuorosulﬁdes (36), which is a model for the third-row element system 34 [22]. Electrophilic attack anti to the C–F bond would be unfavorable due to the lowering of the HOMO level of the anti lone pair, if the negative hyperconjugation is signiﬁcant in the most stable conformation of 36. The results of the oxidation with both m-CPBA and t-BuOOH were opposite to the expectation (ratio of 37:38 = 70:30) (Scheme 1.52).

Scheme 1.52

From the discussion above, it is clear that the ﬂuorine-negative hyperconjugation is mostly signiﬁcant in the second-row element systems (Scheme 1.44).

1.2.8

Electron-donating effect (stabilization of carbocation)

“Does a ﬂuorine-substituent stabilize carbocation?” is an interesting question to be clariﬁed in this section. In spite of the strong electron-withdrawing nature of a ﬂuorine atom in molecules, the ﬂuorine atom stabilizes ␣-carbocation by releasing its lone-pair electrons to the vacant p-orbital of the carbocation. However, it destabilizes ␤-carbocation because of its strong electron-withdrawing nature (Scheme 1.53).

Scheme 1.53

Fundamentals in Organic Fluorine Chemistry

61

Table 1.30 Thermochemical properties related to ﬂuoromethyl carbocation stabilities R CH3 CH2 F CHF2 CF3 a

IP (R) (eV)a

D (R+ –H− ) (kcal/mol)

9.84 8.90 8.73 9.17

312.2 289.6 283.9 299.0

At 25◦ C.

Several criteria, including hydride afﬁnities of carbocations (R+ –H− heterolytic BDE) and adiabatic ionization potentials of the corresponding free radicals (Table 1.30), indicate the order of decreasing stability of ﬂuoromethyl carbocations to be CHF2 + > CH2 F+ > CF3 + > CH3 + (Scheme 1.54) [1].

Scheme 1.54

It is interesting to see completely different regiochemistries in nucleophilic and electrophilic reactions to 1,1-diﬂuoroethene as a model. Scheme 1.55 shows a typical electronic effect of the ﬂuorine atom as a substituent. Electrophiles mostly attack the ␤-carbon of 1,1-diﬂuoroethene generating ␣-diﬂuorinated carbocations as intermediates in contrast to regioselective nucleophilic additions on the ␣-carbon of 1,1-diﬂuoroethene generating ␤-ﬂuorocarbanions.

Scheme 1.55

Any electrophiles such as protons (1) [2], chloronium cations (2,3) [3, 4], benzene selenenyl (4) [5] and sulfenyl cations (5) [6], nitronium ion (6) [7], acyl cation (7) [8], hydroxylmethyl carbocation (8) [9], and even palladium species (9) [10] react at the methylene

62

Organoﬂuorine Chemistry

side of 1 regioselectively to generate diﬂuorinated carbocation-type intermediates, which are trapped with the counter anions of the electrophiles at the ␣-position, affording 1:1 adducts, respectively (see Scheme 1.56). The reaction of triﬂuoromethyl hypoﬂuorite, an electrophilic ﬂuorinating reagent, is an exception where the reaction mechanism is not straightforward to explain (10) [3]. Electrophilic attack on 1 from the electron-deﬁcient divalent oxygen side or radical addition of the triﬂuoro methoxyl radical may be involved. The reaction of 1,1-dichloro-2,2-diﬂuoroethene with triﬂuoroacetyl hypochlorite provides the corresponding 1:1 adduct in high yields with excellent regioselectivity (11) [4], which is opposite to that obtained from the reaction of 1 (12) (Scheme 1.57).

Scheme 1.56

Another question is whether the ﬂuorine-stabilized carbocation formation is preferred even in the electrophilic reaction to diﬂuoroalkylidene compounds. Sulfuric acid catalyzed

Fundamentals in Organic Fluorine Chemistry

63

Scheme 1.57

hydrolysis (13) [11] and Friedel–Crafts-type acylation (14) [12] of diﬂuorostyrenes (2 and 5) are shown in Scheme 1.58. Again the regiochemistry is strictly retained and therefore promotes an electrophilic attack at the ␤-carbon to the ﬂuorinated carbon, suggesting the ﬂuorine-stabilized carbocation formation is preferred over the benzylic carbocation formation.

Scheme 1.58

The computational study on ␣-triﬂuoromethyl cations reveals that the energy barrier to ﬂuorine migration in 8 via the hypothetical transition state 9 is only 3.2 kcal/mol, and the rearranged cation 10 is much more stable (by 16.4 kcal/mol) than 8 because of ␲-conjugation by ␣-ﬂuorines and hyperconjugation by ␤-hydrogens (Scheme 1.59) [13]. Intramolecular ﬂuorine migration from the aromatic triﬂuoromethyl group 12 to sp2 carbocation is also known (Scheme 1.60) [14]. The driving force for the ﬂuorine migration would be the formation of the more stable diﬂuorobenzyl carbocation 14. ␣-Fluorine stabilized carbocations 17–21 have been observed by NMR spectra [15] (Scheme 1.61). The ﬂuorine resonance of the ␣, ␣-diﬂuorobenzyl cation 17 formed by ionic chlorine abstraction in the SbF5 –SO2 system at –75◦ C appears as a triplet (J HF = 1 Hz) with the chemical shift strongly deshielded by 61 ppm from the starting chloride 16. The magnitude of this marked downﬁeld shift of the ﬂuorine suggests that a high degree of positive charge resides on the ﬂuorine because of its electron-donating resonance.

64

Scheme 1.59

Scheme 1.60

Scheme 1.61

Organoﬂuorine Chemistry

Fundamentals in Organic Fluorine Chemistry

65

␣, ␣-Diﬂuoroalkyl carbocation chemistry has been applied elegantly for the construction of ␤-ﬂuoro-␣, ␤-unsaturated cyclopentenone moieties by Ichikawa (Scheme 1.62) [16]. TMS–triﬂate-catalyzed Nazarov-type cyclization of 22 provides 27 exclusively. The cyclization of the pentadienyl carbocation intermediates proceeds exclusively via diﬂuoro-stabilized carbocation 23 rather than via 24 in the manner of a concerted cyclization–deprotonation sequence. A variety of ␣ -alkylidene-␤-ﬂuoro-␣, ␤-unsaturated cyclopentenones are synthesized in excellent yields (some are shown in Scheme 1.62).

Scheme 1.62

Monoﬂuorooleﬁn (31) also shows the same type of regioselectivity in the electrophilic addition of nitrosyl ﬂuoride. Regioselective addition of nitrosyl cation on the ␤-carbon of the cyclopentene ring of 31 and the subsequent trapping of the ﬂuoro-substituted carbocation with ﬂuoride ion provide oxime 32, which is hydrolyzed to ␣, ␣-diﬂuorocyclopentanone (33) (Scheme 1.63) [17]. Fluorine-stabilized carbocation chemistry was applied to the biomimetic cyclization of polyoleﬁns by Johnson (Scheme 1.64) [18]. The rates and product yields in the cyclization are signiﬁcantly controlled because of the electronic nature of the substituents attached in the middle carbon–carbon double bond of polyoleﬁn 34. The isobuylidene substituent accelerates the reaction rate and also provides the desired cyclized product 36 in a good yield.

66

Organoﬂuorine Chemistry

Scheme 1.63

Scheme 1.64

The stabilization of the carbocation intermediate 35 by the isobutylidene group must be a driving force to promote the reaction. The striking feature in the cyclization is a remarkable acceleration effect by the ﬂuorine substituent at the same carbon. The ﬂuorine substituent gives an excellent rate of acceleration and product yield. In contrast, the SnCl4 -catalyzed cyclization of nonsubstituted polyoleﬁn 34 (R = H) in hexane gives only 30% of the cyclized product in 20 min. The same type of rate-acceleration effect by the ␣-ﬂuorine substituent is known in electrophilic substitution on the aromatic ring. Fluorine accelerates bromination, while chlorine

Fundamentals in Organic Fluorine Chemistry

67

and bromine retard it. The intermediate cyclohexadienyl carbocation 39 would be stabilized by the electron-donating resonance effect of ﬂuorine. On the other hand, chlorine and bromine deactivate the aromatic ring by the inductive effect (Scheme 1.65) [19].

Scheme 1.65

1.2.9

1.2.9.1

Effect of ﬂuorine substituents on the structure, stability, and reactivity of ﬂuoroalkyl radicals Generation of perﬂuoroalkyl radicals

Perﬂuoroalkyl iodides (1) [1], perﬂuoroalkanoic acids (2), and perﬂuoroacylperoxides (3) are the most commonly used sources of perﬂuoroalkyl radicals (4). The perﬂuoroalkyl radicals afforded from 1 are summarized in Eq. (1) (Scheme 1.66). The Rf radicals can be generated either by thermal or by photochemical reactions of 1 [2], but more efﬁciently by the abstraction of iodine from 1 with radical initiators. The single-electron transfer (SET) reactions from nucleophiles or reductants to perﬂuoroalkyl iodides are also useful for Rf radical generation. (For SET reactions of perﬂuoroalkyl halides, see Section 2.4.) A variety of reducing reagents such as reductive metals, anionic species, and neutral reducing reagents, such as TDAE, along with electrochemical reduction have been employed for the purpose. (For details of generations and reactions of perﬂuoroalkyl radicals, see Sections 7.2–7.4.) Decarboxylation of perﬂuoroalkanoyl radicals (5) is another route to Rf radical generation. Electrooxidation of the carboxylate of 2 [3], reaction with xenon diﬂuoride [4], and Hunsdiecker reaction [5] have been used (Eq. 2 in Scheme 1.66). Photolysis of Burton’s esters (8), which are prepared from the reaction of 2 with 7, is useful [6]. Thermal and photochemical homolyses of perﬂuoroalkyl diacyl peroxides (3) are useful for Rf radical generation and their synthetic utilization (Eq. 3 in Scheme 1.66) [7]. The activation enthalpies for the homolysis of 3 are approximately 5 kcal/mol lower than for the corresponding hydrocarbon diacyl peroxides [8]. The acyl peroxides (3) accept an electron from electron-rich aromatics to form anion radicals (9), heterolysis of which generates Rf radicals. The Rf radicals (4)

68

Organoﬂuorine Chemistry

Scheme 1.66

combine with a cation radical of aromatics ArH formed in situ, affording perﬂuoroalkylated aromatics (10) [9, 10]. Photolysis of perﬂuoroalkylsulfonyl bromide (11) [10], perﬂuoroazoalkanes (12) [11], hexaﬂuoroacetone (13) [12], and N-nitroso-N-(triﬂuoromethyl)triﬂuoromethane sulfonamide (14) [13] also generates Rf radicals (Scheme 1.67).

Scheme 1.67

Fundamentals in Organic Fluorine Chemistry

69

Table 1.31 ESR hyperﬁne splitting constants for ﬂuorinated methyl radicals

a 13C a 19F

1.2.9.2

CH2 F

CHF2

CF3

54.8 64.3

148.8 84.2

272 143.7

Structure of ﬂuoroalkyl radicals

Fluorine substituents signiﬁcantly affect the structure and reactivity of ﬂuoroalkyl radicals [14, 15]. Triﬂuoromethyl radical (16) [16] is essentially tetrahedral, and other ﬂuoromethyl radicals [16a] are pyramidal, while methyl (15) and alkyl radicals are planar (Scheme 1.68). The 13 C hyperﬁne splittings (hfs) in ESR (electron spin resonance) give useful information on the geometry of carbon radicals. The values of the hfs are affected by the s-character of the singly occupied orbital on the radical carbon. The larger s-character induces large hfs, which indicates the increasingly pyramidal structure of the carbon radicals. Table 1.31 lists the hfs of some ﬂuoroalkyl radicals [16b]. The increasing number of ﬂuorine atoms on the ﬂuoromethyl radicals leads to larger hfs, indicating that the geometry of the methyl radicals changes from planar to pyramidal, and essentially tetrahedral. The value of 272 G for triﬂuoromethyl radical is close to that expected for its sp3 hybridization [16b]. The hfs with 19 F of the ﬂuoromethyl radicals also show the same increasing trend of the a 19F values. Fluorine substitution at the ␣-site of the radicals increases the energy barrier for the inversion of the geometry with energy barriers of 1, 7, and 25 kcal/mol calculated for CH2 F, CHF2 , and CF3 , respectively [17]. Such a strong substituent effect of ␣-ﬂuorine on the geometry of the radicals can be understood largely in terms of the ␴ inductive effect. Because of the strong electronegativity of the ﬂuorine atom, the thermodynamically favorable bonding between carbon and ﬂuorine atoms requires the increased p-character in the C–F ␴-bond, which results in the larger s-character in the unpaired electron lobe and the bending structure of the ﬂuoromethyl radicals.

Scheme 1.68

Taking into account the marked pyramidalization of carbon radicals by ␣-ﬂuorine substituents, it is interesting to see whether benzylic or allylic conjugation would make the ﬂuoroalkyl radicals planar or not. The observed a(19 F) hfs constants (42.6 and 39.7 G) for 1,1,3,3-tetraﬂuoroallyl radical [18] are smaller than that for CH3 CF2 radical (94.0 G)

70

Organoﬂuorine Chemistry

Table 1.32 Optimized structures for cation, radical, and anion of PhCX2 (X = H, F) calculated by UHF/3-21 G

Cation

Radical

Anion

17 ␪(◦ ) ␣FCa F (◦ ) ˚ C␣ –F (A) ˚ C␣ –C (A)

0 112.6 1.29 1.36

20.1 112.1 1.34 1.40

65.5 103.2 1.45 1.49

18 ␪(◦ ) ␣HCa H (◦ ) ˚ C␣ –H (A) ˚ C␣ –C (A)

0 116.9 1.07 1.36

0 117.8 1.07 1.42

0 117.1 1.08 1.39

[19] and are consistent with the radical being near planar. The ESR study of the ␣,␣diﬂuorobenzyl radical also exhibited a small a(19 F) hfs constant (51.4 G), which is consistent with near planar geometry [20]. However, calculation of the bending dependence of the hfs of the benzyl radical suggested some pyramidal distortion of the CF2 Ph radical [21]. In relation to the benzylic conjugation effect, the calculation of the geometry of a series of ␣,␣-diﬂuorobenzyl cations, radicals, and anions is worthy for elucidating the structures of the ﬂuorinated reactive species. Yoshida showed the bending angle ␪ between a phenyl plane and a plane of F–C–F, bond lengths of C␣ –F and C␣ –C (benzene), and angle of F–C–F in ␣,␣-diﬂuorobenzyl cation, radical, and anion (17) in comparison with those of a nonﬂuorinated benzyl species [22]. Based on the bending angle ␪, the calculation suggests that the diﬂuorobenzyl radical is slightly bending and the corresponding anion is pyramidal, nearly tetrahedral, while the cation is planar. In contrast, all of the nonﬂuorinated benzyl cations, radicals, and anions (18) are planar (Table 1.32). It is worth noting that all of the geometries, ␪, bond angles (FCF), and bond lengths (C␣ –F and C␣ –C) for the diﬂuorobenzyl species are totally different among the three species, while those for nonﬂuorinated benzyl species are quite similar, except the C␣ –C bond length (Table 1.32). Planarization by benzylic conjugation and pyramidalization by ﬂuorine inductive effect are operative conﬂictively and the degree of their predominance is highly dependent on the electron deﬁciency at the ␣-carbon in the diﬂuorobenzyl species. The planarity and the short C␣ –F and C␣ –C bond lengths in cation 17 strongly suggest that both ␲-conjugations of the phenyl group and the lone pair on the ﬂuorine atom with the vacant p-orbital on the ␣-carbon play an important role for the geometry of the cation 17. Both ␲-conjugations are less effective in radical 17, and the ﬂuorine inductive effect is predominant in anion 17 (Scheme 1.69). Generation and stereospeciﬁc reaction of ﬂuorocyclopropyl radicals provided experimental evidence for the nonplanarity of the ﬂuoroalkyl radical [23]. Hunsdiecker reaction

Fundamentals in Organic Fluorine Chemistry

71

Scheme 1.69

of both stereoisomers (19 and 20) provided bromo compounds (23 and 24) stereospeciﬁcally (Scheme 1.70). Retention of the stereochemistry on the ␣-carbon of ﬂuorocyclopropyl radicals (21 and 22) clearly indicates that the ␣-ﬂuorine atom enhances conﬁgurational stability of the ␣-ﬂuoro carbon radicals. ESR studies also demonstrated that 2,3-dimethyl1-ﬂuorocyclopropyl radicals (25 and 26) were conﬁgurationally stable at –108◦ C, while in contrast the corresponding hydrocarbon radicals (27 and 28) underwent rapid interconversion (Scheme 1.71) [24].

Scheme 1.70

Scheme 1.71

1.2.9.3

Stability of ﬂuoroalkyl radicals

Relative BDEs have been used to estimate the relative radical stabilities. Therefore, the smaller BDE is a measure for the higher stability of the radicals that are formed by the homolytic dissociation of the bond. For example, BDEs of a series of substituted alkyl C–H bonds decrease in the order of the degree of substitution, CH3 –H (104.8), CH3 CH2 –H (101.1),

72

Organoﬂuorine Chemistry

Table 1.33 Calculated C–H bond dissociation energies (BDE, kcal/mol) for some ﬂuorinated methanes: an evaluation of ␣-ﬂuorine substituent effect CH3 –H CH2 F–H CHF2 –H CF3 –H CH3 CH2 –H CH3 CF2 –H

104.8 101.2 103.2 106.7 101.1 99.5

Table 1.34 Calculated C–H bond dissociation energies (BDE, kcal/mol) for some ﬂuorinated ethanes: an evaluation of ␤-ﬂuorine substituent effect CH3 CH2 –H CH2 FCH2 –H CHF2 CH2 –H CF3 CH2 –H

97.7 99.6 101.3 102.0

(CH3 )2 CH–H (98.6), and (CH3 )3 C–H (96.4 kcal/mol) [25, 26], which apparently reﬂects the order of the increasing stability of the substituted alkyl radicals. The BDEs of the C–H bond of ﬂuoromethanes (see Table 1.33) suggest that one or two ␣-ﬂuorine substitution stabilizes the ﬂuoromethyl radicals, while in contrast, three ␣-ﬂuorine substitution destabilizes triﬂuoromethyl radical [25]. Likewise, ␣, ␣-diﬂuorination in ethane leads to the stabilization of the ␣, ␣-diﬂuoroethyl radical as compared with the ethyl radical. In contrast, ␤-ﬂuorine substitution destabilizes ␤-ﬂuoroethyl radicals (Table 1.34) [27]. Table 1.35 summarizes the calculated stabilization energies for substituted methyl radicals. The results of the calculations suggest that ﬂuorine substitution destabilizes the radical inductively, but slightly stabilizes ␣-radicals through resonance [28]. Table 1.35 Calculated stabilization energies (kcal/mol) for substituted methyl radical CH3 CH2 (CH3 )2 CH (CH3 )3 C CH2 F CHF2 CF3 CH2 FCH2 CHF2 CH2 CF3 CH2

3.3 5.8 8.0 1.6 0.6 −4.2 1.5 0.2 −1.3

73

Fundamentals in Organic Fluorine Chemistry

The kinetic data on the relative rate of the C–R bond homolytic cleavage from radical 30 relative to that of the C–CH3 bond reveal also the relative stability of ﬂuoro-substituted methyl radicals to the methyl radical (Scheme 1.72). Mono- and diﬂuoromethyl radicals were formed from 30 preferentially in comparison with methyl radicals. Here again, mono- and diﬂuoro-substitutions in ␣-substituted methyl radicals seem to stabilize the radicals [29].

Scheme 1.72

1.2.9.4

Reactivity of ﬂuoroalkyl radicals

The ionization potentials (IP), electron afﬁnities (EA), and absolute electronegativities of ﬂuoroalkyl radicals are useful in order to elucidate the nucleophilic and electrophilic reactivities of the ﬂuoroalkyl radicals. Table 1.36 summarizes available IP and EA data, indicating that (1) all of the ␣-ﬂuoromethyl radicals have lower IPs than methyl radicals in spite of the strong inductive effect of the ﬂuorine atom, and (2) triﬂuoromethyl and pentaﬂuoroethyl radicals are, of course, more electrophilic than methyl and ethyl radicals because of their higher values of EA [30]. The former result may arise from the electron-donating conjugation of lone-pair electrons on the ﬂuorine atom, and the latter is due to the strong inductive effect of the ﬂuorine atom. Both addition to ␲-bond of alkenes and hydrogen abstraction reactions are involved in most of the common reactions of radicals. The reactivities are mostly governed by these factors combined with electronic, steric, and bond-strengthening effects [31]. The relative reactivities of the electrophilic perﬂuoroalkyl radicals such as CF3 and C3 F7 radicals for addition to hydrogen abstraction in heptane are summarized in Table 1.37 [32]. The rate Table 1.36 Experimental ionization potentials, electron afﬁnities, and absolute electronegativities of some alkyl and ﬂuoroalkyl radicals (eV)

IP EA ␹a a␹

CH3 ·

CH3 CH2 ·

9.84 0.08 4.96

8.51 −0.39 4.06

= 1/2(IP + EA).

(CH3 )2 CH· 7.69 −0.48 3.61

(CH3 )3 C· 6.93 −0.30 3.32

CH2 F·

CHF2 ·

CF3 ·

CF3 CF2 ·

9.04

8.73

9.25

9.63

74

Organoﬂuorine Chemistry

Table 1.37 Relative rates of addition of perﬂuoroalkyl radicals to oleﬁns vs. their rates of hydrogen abstraction from heptane at 50◦ C Oleﬁn

CF3 ·

CH2 –CH2 CH2 –CHF CH2 –CF2 CHF–CF2 CF2 –CF2 CF2 –CFCF3

132 30 9 6 8 —

C2 F5 ·

C3 F7 ·

340 108 13 9 7 0.3

290 40 — — <0.3 —

Table 1.38 Regioselectivity in triﬂuoromethyl radical addition to oleﬁns Oleﬁn CH2 –CHF CH2 –CF2 CHF–CF2 CH2 –CHCI CHCI–CF2 CH2 –CHCH3 CH2 –C(CH3 )2 CH2 –CHCH–CH2 CF2 –CHCH3 CF2 –CHCF3 CF2 –CFCF3

k␣ : k ␤ 1: 0.09 1: 0.05 1: 0.50 1: 0.02 1: 11.5 1: 0.1 1: 0.08 1: <0.01 1: 50 1: 1.5 1: 0.25

of the addition reaction decreases with sharply increasing substitution of ﬂuorine atoms on ethylene as a result of the high electrophilicity of ﬂuoroalkyl radicals. Table 1.38 shows regiochemistry in the addition of triﬂuoromethyl radicals to ﬂuoroethylenes and related alkenes, and one can observe interesting substituent effects of ﬂuorine and chlorine atoms on the radicals [33]. The triﬂuoromethyl radical attacks favorably at the methylene site (␣-addition) of ﬂuoroethylenes (33) and related alkenes, generating radicals (34) at ␣-ﬂuoro-substituted or alkylated sites (Scheme 1.73, Table 1.38). The favored ␣-addition would arise from the

Scheme 1.73

75

Fundamentals in Organic Fluorine Chemistry

Table 1.39 Absolute rate constants for the addition of perﬂuoroalkyl radicals to alkenesa Alkenes

CF3

C2 F5

n-C3 F7

n-C7 F15

RCH2

(CH3 )3 C

CH2 –CHPh CH2 –C(CH3 )Ph CH2 –CH(CH2 )3 CH3 CH2 –CHCN

53 87

79 94 16 3.2

43 78 6.2 2.2

46 89 7.9 1.6

0.12 0.059 0.0002

0.13

a In

4.4

2.4

F113 at 298 ± 2 K; kadd /106 M−1 s−1 .

combined factors: stabilization of the radicals by ␣-ﬂuorine substitution, destabilization of the radicals 35 by ␤-ﬂuorine substitution, and unfavorable electron deﬁciency at diﬂuoromethylene carbon to electrophilic attack by the CF3 radical. The results obtained from a series of alkenes CHF–CF2 , CH2 –CHCl, and CF2 –CHCl suggest that the ␣-chlorine atom stabilizes ␣-substituted carbon radicals much more than does an ␣-ﬂuorine atom. Laser ﬂash photolysis (LFP) has enabled the direct measurement of absolute kinetic rates for the reactions of radicals in the liquid phase. The accumulated data indicate that the reactivity of nucleophilic radicals is best understood as deriving from an SOMO–LUMO interaction leading to charge transfer interactions [34]. In contrast, the reactivities of ﬂuoroalkyl radicals such as triﬂuoromethyl radicals, typical electrophilic radicals, would be somewhat different from the corresponding hydrocarbon radicals since the former radicals are electron deﬁcient and nonplanar ␴-radicals and the latter radicals are electron rich and planar ␲-radicals. The LFP studies provided the absolute rate constants for the addition of perﬂuoroalkyl radicals to alkenes in solution (Table 1.39) [35]. Perﬂuoroalkyl radicals add to electron-rich alkenes very fast with rate constants of the order of 106 M−1 s−1 and are much more reactive than nonﬂuorinated alkyl radicals. For example, n-C3 F7 radicals add to 1-hexene 30 000 times and to styrene 350 times faster than n-alkyl radicals [35]. The reactivities of perﬂuoroalkyl radicals to electron-rich alkenes are comparable among the radicals so far examined from CF3 to C7 F15 and are more than ten times larger than those to electron-deﬁcient alkenes (acrylonitrile).

1.2.9.5

High electrophilicity of ﬂuoroalkyl radicals

The high reactivities of perﬂuoroalkyl radicals to electron-rich alkenes appear to be due to the strong electrophilicities of the radicals and so there is a correlation between log kadd for the addition of perﬂuoroalkyl radicals to electron-rich alkenes and IPs of the alkenes. Figure 1.16 demonstrates a good linear correlation between the rate constants for the addition of C3 F7 radicals to alkenes and their IPs. The electrophilic character of n-perﬂuoroalkyl radicals was also conﬁrmed by an excellent linear free energy relationship between the rates of addition of perﬂuoroalkyl radicals and an electronic factor, the Hammett ␴ constants of the substituents on the phenyl ring of substituted styrenes (Figure 1.17) [36]. The negative ␳ value (−0.53) for the radical reaction supports the fact that the perﬂuorooctyl radical is an electrophilic reactant. The good linear correlation with Hammett ␴ values rather than with the Brown–Okamoto ␴ + value suggests that the charge separation of the styrenes in the transition state would be small even though the reactant radical is strongly electrophilic.

76

Organoﬂuorine Chemistry

Figure 1.16 Plot of log K add of C3 F7 radicals to IP values of alkenes. Reprinted from Ref. [36] with permission from the American Chemical Society.

A steric factor may be operative in the addition of sterically bulky radicals such as perﬂuorinated isopropyl and tert-butyl radicals to 1,2-disubstituted alkenes such as ␤-methylstyrene since these radicals react with the styrene more slowly than do triﬂuoromethyl radicals, but react much faster with styrene and ␣-methyl styrene than do triﬂuoromethyl radicals [37]. The hydrogen abstraction reaction of perﬂuoroalkyl radicals competes with addition to the ␲-bond in the radical reactions of alkenes, and the addition is mostly faster than the hydrogen abstraction reaction. For example, the values of kadd /kH for perﬂuoropropyl and perﬂuoroisopropyl radicals in the radical reaction of cyclohexene are 66 and 17, respectively [38]. Some of the rate-controlling factors in the hydrogen abstraction are enthalpic and polar factors. An enthalpic factor makes the hydrogen abstraction by perﬂuoroalkyl radicals thermally favorable due to the exothermicity of the reaction (Rf–H bonds are mostly stronger than C–H or X–H bonds of hydrocarbon substrates). However, a good match-up in the polarities between the reacting radicals and the abstractable X–H bonds is also important in the transition state of the hydrogen abstraction. Table 1.40 gives a comparison

Figure 1.17 Plot of log kadd of C8 F17 radicals to Hammett ␴ values of p-substituted styrenes. Reprinted from Ref. [36] with permission from the American Chemical Society.

77

Fundamentals in Organic Fluorine Chemistry

Table 1.40 Rate constants for hydrogen abstraction by RCH2 and C7 F15 radicalsa H-donor

Radical RCH2 b C7 F15 c a k × 104 H b At 25◦ C. c At

Et3 SiH

n-Bu3 GeH

(TMS)3 SiH

n-Bu3 SnH

PhSH

0.007 7.5

1 150

3.8 510

24 2030

1400 3

M−1s−1 .

30◦ C.

of the hydrogen abstraction reactivities between perﬂuoroheptyl and primary alkyl radicals. The ﬂuoroalkyl radicals abstract hydrogen from Si–H, Ge–H, and Sn–H >100 times faster than do the primary alkyl radicals [39]. The observed rate enhancements for hydrogen abstraction by perﬂuoroalkyl radicals are due to the higher exothermicity than that of the analogous alkyl radical reaction (BDEs for Rf–H and R–H are 107 and 98 kcal/mol, respectively [40]). It can also be observed from Table 1.40 that hydrotributylstannane is more useful for reducing perﬂuoroalkyl halides by the radical pathway than are hydrotriethylsilane and benzene thiol, while benzene thiol and hydrotributylstannane are useful for the alkyl radicals. One question answered in Table 1.40 is why benzene thiol can transfer hydrogen to the alkyl radicals faster than to the ﬂuoroalkyl radicals. Dolbier proposed the importance of the polar effect in the transition state of the hydrogen abstraction reaction [41]. Based on the electronegativities of the elements involved in the radical reaction (C = 2.5, H = 2.2, Si = 1.7, Ge = 2.0, Sn = 1.7, and S = 2.4), silanes, germanes, and stannanes are classiﬁed as electropositive hydrogen donors and benzene thiol as an electronegative hydrogen donor. Therefore, favorable polar transition states would be as shown in A and B in Scheme 1.74, where one can see opposite electron polarizations from H-donor to H-acceptor. The best correlation of log kH with Brown–Okamoto ␴ + values rather than with Hammett ␴ values (␳ = −0.56) support the fact that the electron-donating resonance effect is transmitted to the reaction center in the transition state of the hydrogen abstraction from substituted ben-

Scheme 1.74

78

Organoﬂuorine Chemistry

Table 1.41 ␣-Hydrogen abstraction by perﬂuoroalkyl radicals from alkoxides and alcohols in water Alkoxides and alcohols CH3 CH2 OH CF3 CH2 OH CF3 CH2 O− Na+ (CH3 )2 CHOH (CF3 )2 CHOH (CF3 )2 CHO− Na+

kH /103 M−1 s−1

Rel. rates

12 0.08 77 48 0.39 108

150 1 963 600 5 1350

zene thiols [41] by C17 F15 radicals. Electronic polarization in the transition state as shown in A, Scheme 1.74, can explain the ␣-hydrogen activation of alkoxides in hydrogen abstraction. The hydrogen donor abilities of ␣-hydrogens in alcohols are dramatically increased by 102 –103 times when the alcohols are anionized as metal alkoxides (see C in Scheme 1.74, Table 1.41) [42] Fluorine substitution enhances the reactivity of not only the sp3 carbon centered radicals, but also of the sp2 radicals such as substituted phenyl radicals toward organic hydrogen atom donors. Table 1.42 summarizes the relative reactivities of some ﬂuorine-substituted Table 1.42 Hydrogen abstraction by charged phenyl radicals from hydrogen donors Radicals

H-donors

0.14

0.24

0.51

0.003

0.07

0.21

0.03

0.13

0.18

0.002

0.18

0.32

79

Fundamentals in Organic Fluorine Chemistry

phenyl radicals toward four hydrogen atom donors. ortho-Fluorine substitution (radicals 37 and 38) dramatically activates the hydrogen abstraction from all of the four hydrogen donors, in particular from THF, a simple model of sugar moiety in DNA. On the basis of the greater sensitivity of THF (reactivity range >150 times) toward ﬂuorine substitution in the phenyl radical, Kenttamaa proposed that ﬂuorine substitution is likely to drastically increase the activity of those antitumor drugs whose action is based on DNA cleavage by polyatomic organic radicals [43].

1.2.9.6

Diﬂuorocarbene

Diﬂuorocarbene is electrophilic in its reactions with alkenes, carbanions, thiols, alkoxides, and other nucleophiles. But, it is the most stable and least electrophilic among dihalocarbenes in spite of the strong electron-withdrawing nature of ﬂuorine. Table 1.43 gives the EAs of halocarbenes, which is one of the measures for electrophilicity of the reactive species. The data demonstrate that diﬂuorocarbene has the lowest EA [44]. Fluorine atom substitution of CH2 actually decreases the EA from 0.652 eV for CH2 carbene to 0.550 eV and to 0.170 eV for CHF and CF2 carbenes, respectively. On the other hand, for chloro- and bromocarbenes it is the opposite case, where the increased number of halogens increases the EAs of the halocarbenes. The ﬂuorine atom thus withdraws electron density through the ␴-bond, but efﬁciently transfers electron density back to the vacant carbon p␲ -orbital through the ␲-conjugation. The better match in p-orbital size between carbon and ﬂuorine as compared with the other halogens is a key factor in the EA difference among the dihalocarbenes. The lower EA of diﬂuorocarbene suggests that the carbene would be less electrophilic and thus the most selective in the electrophilic attack to alkenes. In fact, the selectivity, which was obtained in the competitive cyclopropanation in a 1:1 mixture of 2-methylpropene and 2-methyl-2-butene, increased in the order of CBr2 < CClBr < CCl2 < CFCl < CF2 at 20◦ C, although the order was reversed at 120◦ C (CBr2 > CClBr > CCl2 > CFCl > CF2 ). The reason behind this reversal phenomenon is that activation enthalpies and activation entropies are changed in the same direction with variation of carbene substituents from ﬂuorine to bromine [45]. Another important property of dihalocarbenes is the singlet–triplet energy gap. The singlet diﬂuorocarbene is more stable than the triplet and the energy gap is the largest Table 1.43 Electron afﬁnities and the energy gap between singlet and triplet of the halocarbenes as determined by photoelectron spectroscopy Carbene

EA (eV) E ST (kcal/mol)

CHF:

CHCI:

CHBr:

CHI:

CF2 :

CCI2 :

CBr2 :

CH2 :

0.550 −14.7

1.213 −6.4

1.551

1.683

0.170 −56.7

1.596 −20.5

— −15.6

— 9.22

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Organoﬂuorine Chemistry

among halocarbenes (Table 1.43) [46], while the stable state for methylene carbene is a triplet (Scheme 1.75).

Scheme 1.75

CF3 radical as an active ﬁre extinguishing species

Triﬂuoromethyl radicals have been proposed to be active species for chemical ﬁre extinguishing [1, 2]. The radicals react with hydrogen atoms and hydroxyl radicals, main active species in the combustion zone (Scheme 1) in a similar mechanism as the bromine atoms which are formed by the thermolysis of halons (bromoﬂuorocarbons, such as CF3 Br, CF2 BrCl, CF2 BrCF2 Br). 1. (a) Fukaya, H., Ono T., and Abe, T. (1995) J. Chem. Soc., Chem. Commun., 1207–1208; (b) Fukaya, H., Ono T., and Abe, T. (1998) J. Compt. Chem., 19, 277–289; (c) Fukaya, H., Ono T., and Abe, T. (1999) Bull. Chem. Soc. Jpn., 72, 207–211. 2. There are two types of actions, physical and chemical ones for ﬁre ﬁghting. The former type of agents are water and carbon dioxide, which suppress the ﬁre by a physical action, i.e. cooling and diluting. Halons are one of the typical chemical ﬁre ﬁghting agents.

Fundamentals in Organic Fluorine Chemistry

81

Distillable stable radical

An unusually stable alkyl radical 1 was discovered in 1985. The radical was isolated in the course of the reaction of ﬂuorine gas with perﬂuoro 3-isopropyl-4-methyl-2-pentene and 3 - ethyl- 2,4- dimethyl-2-pentene at ambient temperature [1]. The radical 1 is stable at room temperature to dimerization, disproportionation, treatments with O2 , Cl2 , Br2 , I2 , or aqueous acid and base, and even heating at 70◦ C in GC. It only decomposes by elimination of a triﬂuoromethyl radical through ␤-scission on heating at 100◦ C, with a half-life of 60 min. 1. Scherer, K.V., Jr., Ono, T., Yamanouchi, K., Fernandez, R., and Henderson, P. (1985) J. Am. Chem. Soc., 107, 718–719.

1.3

Steric effects of ﬂuorine substituents

Fluorine is apparently one of the smallest substituents and has been recognized as a mimic of hydrogen. However, it is a misunderstanding to say that ﬂuorine is as small as hydrogen; ﬂuorine is undoubtedly larger than hydrogen. In particular, the triﬂuoromethyl group (CF3 ) is much larger than a methyl group. The steric sizes of atoms and substituents are somewhat dependent on how they are deﬁned or derived. van der Waals radii are one of the frequently used measures of atomic size. Thermodynamic conformational studies of the torsional process of substituted cyclohexanes, cyclophanes, and biaryls have provided information on relative steric sizes of substituents. Kinetic study of the acid-catalyzed hydrolysis of ␣substituted ethyl acetates was also used for estimating atomic or substituent sizes (Taft’s E s value) in a molecule. Steric sizes of atoms and substituents have been obtained under speciﬁc experimental or theoretical conditions and so these must be handled with care when one tries to estimate any steric effect of substituents in unrelated or different reactions. The steric size like van der Waals radius is an intrinsic molecular property with an absolute term, but the steric effect is an extrinsic phenomenon and thus is entirely dependent on the nature of the transition state for the particular reaction, which deﬁnes the degree of Coulombic interaction between the atom or group in question and other atoms or groups involved [1].

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Organoﬂuorine Chemistry

Table 1.44 Bondi’s van der Waals radii in angstroms H (1.20) C (1.70) Si (2.10)

N (1.55) P (1.80) As (1.85)

O (1.52) S (1.80) Se (1.90) Te (2.06)

F (1.47) CI (1.75) Br (1.85) I(1.98)

He (1.40) Ne (1.54) Ar (1.88)

van der Waals radii of atoms have been derived from the selected most reliable X-ray crystallographic data. Table 1.44 is a summary of Bondi’s van der Waals radii [2]. The van der Waals radius of the ﬂuorine atom is 1.47, which is the second smallest except the noble gases, but apparently larger than that of hydrogen (1.20). Radii for symmetric substituents of the type AX3 have been calculated by Charton and are listed in Table 1.45 [3]. Here again, the CF3 group is much larger than the methyl group, and smaller than the tert-butyl group. Taft’s E s values are summarized in Table 1.46 (a large negative value of E s means a bigger steric effect); these were obtained from the acid-catalyzed hydrolysis rates of ␣-substituted ethyl acetates and have been used as a measure for the steric effect of substituents in reactions [4]. The E s value for the CH2 F group is comparable with that of the CH2 Cl group, and is smaller than those of the CH2 Br and CH2 SCH3 groups. However, as it is larger than those of the CH2 CH3 and CH2 OCH3 groups, these data are somewhat confusing. The diﬂuoromethyl group (−0.67) seems to be larger than the isopropyl group (−0.47) and smaller than the isobutyl group (−0.93). The triﬂuoromethyl group (−1.16) is comparable with the sec-butyl group (−1.13) and smaller than the tert-butyl group (−1.54). Discussion of the physicochemical sizes of substituents on the basis of conformational analysis of the torsional process of substituted cyclohexanes, cyclophanes, and diaryl derivatives have been summarized by Schlosser [5]. The energies required for the conformational exchange of an equatorial position to the axial position for each substituent in cyclohexane are listed in Table 1.47 [6]. For ﬂuorine, the energy difference between the axial and equatorial environment is negligibly small as compared with methyl, while that of CF3 seems larger than that of i -Pr so far observed in the cyclohexane torsional system. From the Table 1.45 Calculated van der Waals radii for AX3 symmetric substituents X

r max A˚

r min A˚

Me CF3 CCl3 CBr3 Me3 C Me3 N+ Me3 Si SO3 −

2.23 2.743 3.408 3.670 3.150 3.114 3.987 2.852

1.715 2.107 2.579 2.760 2.435 2.417 2.60 2.186

Fundamentals in Organic Fluorine Chemistry

Table 1.46 Taft’s steric substituent constants E s for aliphatic substituents in RCO2 Et Substituent

Es

CH3 CH3 CH2 CH3 OCH2 CH3 SCH2 FCH2 CICH2 BrCH2 ICH2 n-C3 H7 i-C3 H7 n-C4 H9 c-C6 H13 PhCH2 CF2 H CF3 CCl2 H CCl3 CBr3 i-C4 H9 s-C4 H9 CH3 CH(Ph) t-C4 H9 t-C4 H9 CH2 (Ph)2 CH

0.00 −0.07 −0.19 −0.34 −0.24 −0.24 −0.27 −0.37 −0.36 −0.47 −0.39 −0.79 −0.38 −0.67 −1.16 −1.54 −2.06 −2.43 −0.93 −1.13 −1.19 −1.54 −1.74 −1.76

Table 1.47 Conformational energies G ◦ ax/eq (kcal/mol) of selected substituents

X H F OCH3 CH3 CH(CH3 )2 CF3

G ◦ ax/eq 0.00 0.15 0.65 1.7 2.1 2.4

83

84

Organoﬂuorine Chemistry

Table 1.48 Energy barriers to axial torsion

X H F OH CH3 CH(CH3 )2 CF3

G ◦ (kcal/mol) 10.6 14.2 16.1 19.3 22.2 22.0

energy analysis of the torsional process around the biaryl axis for ortho-substituted 6-aryl1,1,5-trimethylindanes (Table 1.48) [7] and 4,5-disubstituted 9,10-dihydrophenanthrenes (Table 1.49) [8], it can be said that ﬂuorine is rather closer to hydrogen than to methyl. However, opposite energy barriers were observed in the same type of biaryl system bearing phosphorus substrates, 6,6 -disubstituted 2,2 -bis(diphenylphosphino)biphenyls [9] and the torsional system of the cyclophanene system (Scheme 1.76) [10], which may arise from electronic repulsion between the lone-pair electrons of the phosphorus and ﬂuorine atoms. Care must be taken to interpret such an energetic torsional process, where some electron repulsion must be involved. These steric dissimilarities between hydrogen and ﬂuorine, and methyl and triﬂuoromethyl groups, often result in a noticeable difference of reactivity and product selectivity in a number of reactions. Table 1.49 Energy barriers to axial torsion

X H F OCH3 CH3 CF3

G ◦ (kcal/mol) 4.1 10.3 15.6 23.4 >29

Fundamentals in Organic Fluorine Chemistry

85

Scheme 1.76

Although the size of ﬂuorine is small, it was found to be large enough to control the stereoand regiochemistries in some selected reactions. For instance, endo-diﬂuoronorbornene (4) underwent very smooth photochemical dibromination (they are inert under ionic bromination conditions in the dark [11]), where endo-4 provided a cis-dibromide (6) as the sole product. Similarly, predominant cis-dibromination of 9, in which the endo-side was blocked by cyano and chloro groups occurred (Scheme 1.77). In contrast to this, exo-5 gave a 1:1 mixture of stereoisomers 7 and 8 [11]. The ﬁrst and subsequent second bromines approach endo-4 from the less hindered direction, although trans-addition of bromine to norbornene is a normal radical reaction pathway [12].

Scheme 1.77

Terminal gem-diﬂuoro-substitution affects the rate of some reactions in a steric manner. Scheme 1.78 shows thermal Cope rearrangement of the particular bis-diﬂuorodienes (10) (d, l ) and (11) (meso), where the activation enthalpies of ﬂuorodienes (X = F) are compared with those of the corresponding hydrocarbons (X = H). For the d, l -isomers, ﬂuoroalkene 10 reacted faster with the lower activation enthalpy than did the corresponding hydrocarbon 10 (X = H) (Scheme 1.78). The rearrangement of 10 would proceed via chair-like

86

Organoﬂuorine Chemistry

Scheme 1.78

transition-state (12), which involves less steric hindrance by ﬂuorine. The driving force for the favorable reaction of the ﬂuoro-compound derives from the transformation of the thermally less stable sp2 CF2 group to the more stable sp3 CF2 group [13]. In contrast, the rearrangement of ﬂuoro-compound 11 (X = F) to the meso-isomer was unfavorable as compared with the parent compound 11 (X = H). Moreover, the activation enthalpy difference between the d, l -isomer and meso-isomer for ﬂuoro-compounds was extremely large (27.1 kcal/mol). The lower reactivity of meso-ﬂuoro compound 11 (X=F) could be explained in terms of signiﬁcant steric hindrance in the boat-like transition state 13 [14]. Introduction of at least one ﬂuorine atom to the methyl group of acetophenone leads to a dramatic change in conﬁgurational preference of the corresponding N-(1-phenethyl)imines (16, 17, and 18) from syn to anti, where the syn conﬁguration of the methyl group to the N-phenethyl group is preferred in the parent nonﬂuorinated imine 15 (Scheme 1.79) [15]. The stereochemistry was conﬁrmed by NOE analysis in 1 H NMR for 16 and 17, and

Scheme 1.79

87

Fundamentals in Organic Fluorine Chemistry

Table 1.50 Regioselectivity in hydrogenolysis of bis(1-phenylethyl)amines (23) X

R a/b

2-CF3

3-CF3

4-CF3

3,5-bis-CF3

4-CF3

3-F

4-F

3,5-bis-F

H >99/1

H >99/1

H >99/1

H >99/1

t-Bu 60/40

H >99/1

H >99/1

H >99/1

X-ray crystallographic analysis for 18 [15]. The ﬂuorinated imines 16, 17, and 18 provided (S, S) amines (20) exclusively on reduction with NaBH4 , where hydride attacked from the less hindered face via the preferred conformation 19. Regioselective Pd-catalyzed hydrogenolysis of 20 afforded enantiomerically pure 2-ﬂuoro-, 2,2-diﬂuoro-, and 2,2,2triﬂuoro-1-phenylethylamines [16]. A sterically bulky substituent on an aromatic ring inhibits a favorable adsorption of aromatic substrates onto the catalyst surface for hydrogenation [17]. Therefore, ethanediol bisbenzyl ethers (21) underwent regioselective C–O bond cleavage at the nonsubstituted site, affording 22 predominantly (Scheme 1.80) [18]. Extension of this approach enabled the synthesis of almost enantiomerically pure 1-(ﬂuorinated phenyl)ethylamines (24) via the regioselective hydrogenation of 23 (Scheme 1.81, Table 1.50) [19, 20], where the nonsubstituted benzylic site was cleaved exclusively. The catalytic reduction of 4-CF3 -4 -t-Bu amine (23) (X = CF3 , R = t-Bu) provided a mixture of 1-(4-CF3 -phenyl)ethylamine (24) and 1-(4-t-Bu-phenyl)ethylamine (60:40), demonstrating that both CF3 and t-Bu groups on phenyl are sterically bulky. It is also interesting to see that even a single ﬂuorine atom on a phenyl group governs completely the regiochemistry for the C–N bond cleavage, although some electronic effect may cooperate for the reduction (Table 1.50).

Scheme 1.80

Scheme 1.81

88

Organoﬂuorine Chemistry

Steric bulkiness of substituents in ketones (25), for example, makes it possible to differentiate two pairs of lone-pair electrons (a or b in 25) on carbonyl oxygen for coordinating with the Lewis acidic center of boron in oxazaborolidine (28). The complex (29) formed from 28 with catecholborane binds ketone (32) stereospeciﬁcally by using the lone-pair electrons at the less hindered side so as to direct the smaller substituent RS toward the bulky N-tertbutyl group. The intramolecular hydride transfers to the favorably coordinated carbonyl group as shown in 30, Scheme 1.82, results in asymmetric reduction of ketones. Reduction of triﬂuoromethyl and methyl ketones (25) (R = CF3 or CH3 ) by this system afforded the corresponding alcohols (26 or 27) with an opposite stereochemistry (Scheme 1.82).

Scheme 1.82

89

Fundamentals in Organic Fluorine Chemistry

less hindered site

hindered site a

b

a

b

a

b

Figure 1.18 Corey–Pauling–Koltun (CPK) model of triﬂuoro- and trichloromethyl phenyl ketones. Reprinted from Ref. [21(b)] with permission from Elsevier.

CPK (Corey–Pauling–Koltun) models clearly indicate that space b in 25 (R = CH3 ) is wide enough for effective coordination with ketone; on the other hand, space b is blocked when a triﬂuoromethyl group is present (Figure 1.18). The smaller substituent in 25 is methyl for R = CH3 , but aryl for R = CF3 , respectively [21]. In molecular orbital terms, lone-pair electrons on carbonyl oxygen are delocalized into the antibonding orbital ␴ ∗ -orbital of the C–C bond between carbonyl and trihalomethyl groups. X-ray crystallographic analysis indicates the carbonyl group bends toward the CX3 group as shown in 34 [22]. Since the steric effect deﬁnes the Coloumbic interaction in the transition state between two atoms or substituents involved, the steric effect of the triﬂuoromethyl group always appears unusually large in nucleophilic reactions. The CF3 group undoubtedly inhibits the access of nucleophiles to the reaction center. One of the unsolved problems in organoﬂuorine chemistry is how to realize stereospeciﬁc nucleophilic substitution of the hydroxy group or its modiﬁed leaving groups of secondary triﬂuoromethyl carbinols [CF3 CH(OR1 )R2 ]. The difﬁculty of the nucleophilic substitution may arise from the steric shielding of the central carbon atom of the secondary alcohols and electronic repulsion between the CF3 group, a huge block of electrons and incoming nucleophiles [23]. The diastereoselectivity in the cyclopropanation via intramolecular nucleophilic substitution of the hydroxy group with cyano- and phenyl-stabilized carbanion in 40 was found to be governed by electronic interaction of the CF3 group and electron density at both 2- and 6-positions of the phenyl ring as shown in 41 (Scheme 1.83) [24].

Scheme 1.83

90

Organoﬂuorine Chemistry

A keen human nose as an excellent sensor for an odor An interesting estimation of steric bulkiness of substituents was tried on the basis of comparison of odorous change by substituent size. The idea was based on the concept that the interaction between the receptor in a biosystem and the chemical excitant is primarily dependent on the steric matching. The concept suggests the small ﬂuorine substituent should cause little difference in odor change [1]. In fact the olfactory evaluation of raspberry ketones (42) and exaltones (43) revealed that the odorous properties of the ﬂuorinated compounds (X=F) generally resembled the parent compounds (X=H), but the corresponding methyl ones were strongly different from those of the parent compounds [1–3]. A striking odorous change by replacement of the methyl group with the triﬂuoromethyl group in (R)-citronellol has also been reported, suggesting again a big dissimilarity in the steric size between methyl and triﬂuoromethyl groups. 1. Schlosser, M. (1999) In V.A. Soloshonok, (ed), Enantiocontrolled Synthesis of Fluoro-organic Compounds: Stereochemical Challenges and Biomedical Targets Wiley, New York, pp. 613–659. 2. Schlosser, M., and Michel, D. (1996) Tetrahedron, 52, 99–108. 3. Michel, D., and Schlosser, M. (2000) Tetrahedron, 56, 4253–4260.

References References to Section 1.1 1. Reinhard, M., and Drefahl, A. (1999) Handbook for Estimating Physicochemical Properties of Organic Compounds. Wiley-Interscience, New York. 2. Israelachivili, J.N. (1985) Intermolecular and Surface Forces, 2nd edn. Academic Press, New York. 3. Hudlicky, M. (1992) Chemistry of Organic Fluorine Compounds, 2nd edn. Ellis Horwood PTR Prentice Hall, New York. 4. Hudlicky, M., and Pavlath, A.E. (eds) (1995) Chemistry of Organic Fluorine Compounds II, ACS Monograph 187. American Chemical Society, Washington, DC. 5. Wrast R.C. (ed) (1977) CRC Handbook of Chemistry and Physics, 58th edn. CRC Press, Cleveland, OH. 6. Atkins, P. (1994) Physical Chemistry, 5th edn. Freeman, New York, p. 488. 7. Atkins, P. (1994) Physical Chemistry, 5th edn. Freeman, New York, pp. 760–762. 8. Pearson, R.G. (1997) Chemical Hardness. Wiley-VCH, Weinheim. 9. Noritomi, M. Murofushi, H., Nakashima, N. (2004) Bull. Chem. Soc. Jpn., 77, 2121–2127. 10. Katagiri, T., and Uneyama, K. (2001) Bull. Chem. Soc. Jpn., 74, 1409–1410. 11. Hildebrand, J.H. (1939) J. Chem. Phys., 7, 233–235.

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12. Bradley, D.C. (1954) Nature, 174, 323. 13. Horvath, I.T., and Rabai, J. (1994) Science, 266, 72–75. 14. Studer, A., Hadida, S., Ferritto, R., Kim, S.Y., Jeger, P., Wipf, P., and Curran, D.P. (1997) Science, 275, 823–826. 15. Fish, R.H. (1999) Chem. Eur. J., 5, 1677–1680. 16. Cavazzini, M., Montanari, F., Pozzi, G., and Quici, S. (1999) J. Fluorine Chem., 94, 183–193. 17. Hope, E.G., and Stuart, A.M. (1999) J. Fluorine Chem., 100, 75–83. 18. Gladysz, J.A., and Curran, D.P. (2002) Tetrahedron, 58, 3823–3825. 19. Tzschucke, C.C., Markert, C., Bannwarth, W., Roller, S., Hebel, A., and Haag, R. (2002) Angew. Chem., Int. Ed. Engl., 41, 3964–4000. 20. Sandford, G. (2003) Tetrahedron, 59, 437–454. 21. Zhang, W. (2003) Tetrahedron, 59, 4475–4489. 22. Fache, F. (2004) New J. Chem., 28, 1277–1283. 23. Beier, P., and O’Hagan, D. (2002) Chem. Commun., 1680–1681. 24. Kiss, L.E., Kovesdi, I., and Rabai, J. (2001) J. Fluorine Chem., 108, 95–109. 25. Duan, M., Okamoto, H., Petrov, V.F., and Takenaka, S. (1999) Bull. Chem. Soc. Jpn., 72, 1637– 1642. 26. Yamaguchi, F. (2004) In Fusso Kagaku Nyumon (An Introduction to Fluorine Chemistry). Sankyo, Tokyo, 2004, pp. 260–278. 27. Deschamps, J., Costa Gomes, M.F., and Padua, A.A.H. (2004) J. Fluorine Chem., 125, 409–413. 28. Gross, U., Papke G., and R¨udiger, S. (1993) J. Fluorine Chem., 61, 11–16. 29. Dack, M.R.J. (1975) Technique of Chemistry, Vol. 8, Solutions and Solubility, Part 1. Wiley, New York. 30. Lide, D.R. (ed) (1993) CRC Handbook of Chemistry and Physics, 74th edn. CRC Press, Boca Raton, FL, E-224. 31. Nishino, T. (1999) J. Adhension Soc. Jpn., 36, 170–175. 32. Hare, E.H., Shafrn, E.G., and Zisman, W.A. (1954) J. Phys. Chem., 58, 236–239.

References to Section 1.2.1 1. Reliable data on electronic substituent constants are summarized in the following review: Hansch, C., Leo, A., and Taft, R.W. (1991) Chem. Rev., 91, 165–195. 2. McDaniel, D.H., and Brown, H.C. (1958) J. Org. Chem., 23, 420–427. 3. Perrin, D.D., Dempsey, B., and Serjeant, E.P. (1981) pKa Prediction for Organic Acids and Bases. Chapman and Hall, London. 4. Van Poucke, R., Pollet, R., and De Cat, A. (1966) Bull. Soc. Chim. Bel., 75, 40–51. 5. Fawcett., F.S., and Sheppard, W.A. (1965) J. Am. Chem. Soc., 87, 4341–4346. 6. Exner, O. (1966) Coll. Czech. Chem. Commun., 31, 65–89. 7. Sheppard, W.A. (1963) J. Am. Chem. Soc., 85, 1314–1318. 8. Kondratenko, N.V., Popov, V.I., Kolomeitsev, A. A., Saenko, E.P., Prazhdo, V.V., Lutskii, A.E., and Yagupolskii, L.M. (1980) Zh. Org. Chem., 16, 1215–1221. 9. Boloshchuk, V.G., Yagupolskii, L.M., Syrova, G.P., and Bystrov, V.F. (1967) Zh. Obsh. Khim, 37, 2591. 10. Kondratenko, N.V., Kolomeitaev, A.A., Potov, V.L., Ilchenko, A.Y., Korzhenevakaya, N.G., Pirgo, M.D., Titov, E.V., and Yagupolskii, L.M. (1983) Zh. Obsh. Khim., 53, 2254EE. 11. Bray, P.J., and Barnes, R.G. (1957) J. Chem. Phys., 27, 551–560. 12. Kalfus, K., Vecera, M., and Exner, O. (1970) Coll. Czech. Chem. Commun., 35, 1195–1207. 13. Yagupolskii, L.M., Ilchenko, A.Y., and Kondratenko, N.V. (1974) Russ. Chem. Rev., 43, 64–94. 14. Hogben, M.G., and Graham, W.A.G. (1969) J. Am. Chem. Soc., 91, 283–291.

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15. Sheppard, W.A., and Sharts, C.M. (1969) Organic Fluorine Chemistry. W.A. Benjamin, New York, p. 348. 16. Exner, O., and Lakomy, J. (1970) Coll. Czech. Chem. Commun., 35, 1371–1386. 17. Yagupolskii, L.M., Gandelsman, L.Z., and Nazaretyan, V.P. (1974) Zh. Org. Khim., 10, 889–890. 18. Kondratenko, N.V., Syrova, G.P., Popov, V.L., Sheinker, Y.N., and Yagupolskii, L.M. (1971) Zh. Obsh. Khim., 41, 2056–2060. 19. Yagupolskii, L.M., Popov, V.L., Pavlenko, N.V., Maletina, I.I., Mironova, A.A., Gavrilova, R.Y., and Orda, V.V. (1986) Zh. Org. Khim., 22, 2169–2173. 20. Yagupolskii, L.M., Ilchenko, A.Y., and Kondratenko, N.V. (1974) Russ. Chem. Rev., 43, 32EE, 64– 94. 21. Sheppard, W.A. (1967) Trans. N.Y. Acad. Sci., 29, 700–710. 22. Sheppard, W.A. (1965) J. Am. Chem. Soc., 87, 2410–2420. 23. Charton, M. (1981) Prog. Phys. Org. Chem., 13, 119–251. 24. Sheppard, W.A. (1970) J. Am. Chem. Soc., 92, 5419–5422. 25. Little, W.F., Reilley, C.N., Johnson J.D., Lynn, K.N., and Sanders, A.P. (1964) J. Am. Chem. Soc., 86, 1376–1381. 26. Jaffe, H.H. (1953) Chem. Rev., 53, 191–261. 27. White, W.N., Schlitt, R., and Gwynn, D.J. (1961) Org. Chem., 26, 3613–3615. 28. Taft, R.W., Jr. (1956) In M.S. Newman (ed), Steric Effects in Organic Chemistry. Wiley, New York, pp. 556–675. 29. Aliphatic substituent constants (␴ ∗ ) originally provided by Taft were modiﬁed with improved accuracies by Cohen: Takahashi, S., Cohen, L.A., Miller, H.K., and Peake, E.G. (1971) J. Org. Chem., 36, 1205–1209. 30. Korenaga, T., Kadowaki, K., Ema, T., and Sakai, T. (2004) J. Org. Chem., 69, 7340–7343.

References to Section 1.2.2 1. Lide, D.R. (ed) (2003) CRC Hand Book of Chemistry and Physics. CRC Press, Boca Raton, FL. 2. The electronic effect of ﬂuorine on the acidities of organoﬂuorine molecules is reviewed: Schlosser, M. (1998) Angew. Chem., Int. Ed. Engl., 110, 1496–1513. 3. For F-benzoic acids: Strong, L.E., Brummel, C.L., and Lindower, P. (1987) J. Solution Chem., 16, 105–124. 4. For CF3 -benzoic acids: (a) Yagupolskii, L.M., and Yagupolskaya, L.N. (1960) Dokl. Akad. Nauk SSSR, 134, 1381–1383 [Chem. Abstr., 1961, 55, 11352i]; (b) Roberts, J.D., Webb, R.L., and MaElhill, E.A. (1950) J. Am. Chem. Soc., 72, 408–411. 5. (a) Bennett, G.M., Brooks, G.L., and Glasstone, S. (1939) J. Chem. Soc., 1821–1826; (b) Hodgson, H.H., and Smith, R. (1939) J. Chem. Soc., 263–266. 6. Seiler, P., and Wirt, J. (1972) Helv. Chem. Acta, 55, 2693–2712. 7. (a) Abraham, M.H., Grellier, P.L., Prior, D.V., and Duce, P.P. (1989) J. Chem. Soc., Perkin Trans. 2, 699–711; (b) Murto, J. (1971) In S. Patai (ed), The Chemistry of the Hydroxyl Group. Interscience, New York, Part 2. 8. Kukhar, V.P. (1994) J. Fluorine Chem., 69, 199–205. 9. O’Hagan, D., and Rzepa, H.S. (1997) Chem. Commun., 645–652. 10. Streitwieser, A., Holtz, D., Ziegler, G.R., Stoffer, J.O., Brokaw, M.L., and Guibe, F. (1976) J. Am. Chem. Soc., 98, 5229–5234. 11. Stoffer, G.R., Brokaw, J.O., and Guibe, F. (1976) J. Am. Chem. Soc., 98, 5229–5234. 12. Castejon, H.J., and Wiberg, K.B. (1998) J. Org. Chem., 63, 3937–3942. 13. Paprott, G., and Seppelt, K. J. Am. Chem. Soc., 106, 4060–4061. 14. Streitwieser, A., and Nebenzahl, L.L. (1976) J. Am. Chem. Soc., 98, 2188–2190.

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References to Section 1.2.3 1. Corradi, E., Meille, S.V., Messina, M.T., Metrangolo, P., and Resnati, G. (2000) Angew. Chem., Int. Ed. Engl., 39, 1782–1786. 2. Messia, M.T., Metrangolo, P., Panzeri, W., Ragg, E., and Resnati, G. (1998) Tetrahedron Lett., 39, 9069–9072. 3. Lommerse, J.P.M., Stone, A.J., Taylor, R., and Allen, F.H. (1996) J. Am. Chem. Soc., 118, 3108–3113. 4. Corradi, E., Meille, S.V., Messina, M., Metrangolo, P., and Resnati, G. (1999) Tetrahedron Lett., 40, 7519–7523. 5. (a) Amico, V., Meille, S.V., Corradi, E., Messina, M.T., and Resnati, G. (1998) J. Am. Chem. Soc., 120, 8261–8262; (b) Lunghi, A., Cardillo, P., Messina, T., Metrangolo, P., Panzeri, W., and Resnati, G. (1998) J. Fluorine Chem., 91, 191–194. 6. Burton, D.D., Fontana, F., Metrangolo, P., Pilati, T., and Resnati, G. (2003) Tetrahedron Lett., 44, 645–648. 7. Metrangolo, P., Pilatib, T., Resnati, G., and Stevenazzia, A. (2004) Chem. Commun., 1492–1493. 8. Zhu, S.-H., Xing, C.-H., Xu, W., and Li, Z.-T. (2004) Tetrahedron Lett., 45, 777–780. 9. Chu, Q., Wang, Z., Huang, Q., Yan, C, and Zhu, S. (2001) J. Am. Chem. Soc., 123, 11069–11070. 10. Leroy, J., Schollhorn, B., Syssa-magale, J.-L., Boubekeur, K., and Palvadeau, P. (2004) J. Fluorine Chem., 125, 1379–1382. 11. Britton, D., and Young, V.G., Jr. (1997) Acta Cryst., C53, 1359–1362. 12. Amati, M., Lelj, F., Liantonio, R., Metrangolo, P., Luzzati, S., Pilati, T., and Resnati, G. (2004) J. Fluorine Chem., 125, 629–640. 13. Nguyen, H.L., Horton, P.N., Hursthouse, M.B., Legon, A.C., and Bruce, D.W. (2004) J. Am. Chem. Soc., 126, 16–17. 14. Farina, A., Meille, S.V., Teresa, M., Metrangolo, P., Resnati, G., and Vecchio, G. (1999) Angew. Chem. Int. Ed. Engl., 38, 2433–2436. 15. Caronna, T., Liantonio, L., Logothetis T.A., Metrangolo, P., Pilati, T., and Resnati, G. (2004) J. Am. Chem. Soc., 126, 4500–4501.

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References to Section 1.2.4 1. Linderman, R.J., and James, E.A. (1991) J. Fluorine Chem., 53, 79–91. 2. Osipov, S.N., Golubev, A.S., Sewald, N., Michel, T., Kolomiets, A.F., Fokin, A.V., and Burger, K. (1996) J. Org. Chem., 61, 7521–7528. 3. Mae, S., Amii, H., and Uneyama, K. (2001) Tetrahedron Lett., 41, 7893–7896. 4. (a) Guthrie, J.P. (1975) Can. J. Chem., 53, 898; (b) For calculations of hydration energies for a variety of carbonyl compounds: Wiberg, K.B., Morgan, K.M., and Maltz, H. (1994) J. Am. Chem. Soc., 116, 11067–11077. 5. Linderman, R.J., Tennyson, S.D., and Shults, D.A. (1994) Tetrahedron Lett., 35, 6437–6440. 6. (a) Lindner, P.E., and Lemal, D.M. (1997) J. Am. Chem. Soc., 119, 3259–3266; (b) Lindner, P. E., and Lemal, D.M. (1996) J.Org. Chem., 61, 5109–5115; (c) Correa, R.A., Lindner, P.E., and Lemal, D.M. (1994) J. Am. Chem. Soc., 116, 10795–10796. 7. Gouault, S., Guerin, C., Lemoucheux, L., Lequeux, T., and Pommelet, J.-C. (2003) Tetrahedron Lett., 44, 5061–5064. 8. Asao, N., Asano, T., and Yamamoto, T. (2001) Angew. Chem. Int. Ed. Engl., 40, 3206–3208. 9. (a) Soloshonok, V.A., and Ono, T. (1996) Tetrahedron Lett., 52, 14701–14712; (b) Soloshonok, V.A., and Kukhar, V.P. (1997) Tetrahedron Lett., 53, 8307–8314. 10. (a) Soloshonok, V.A., and Ono, T. (1997) J. Org. Chem., 62, 3030–3031; (b) Soloshonok, V.A., Ono, T., and Soloshonok, I.V. (1997) J. Org. Chem., 62, 7538–7539. 11. Kawashima, T., Watanabe, K., and Okazaki, R. (1997) Tetraedron Lett., 38, 551–554. 12. LaPlante, S.R., Bonneau, P.R., Aubry, N., Cameron, D.R., Deziel, R., Grand-Maitre, C., Plouffe, C., Tong, L., and Kawai, S.H. (1999) J. Am. Chem. Soc., 121, 2974–2986.

References to Section 1.2.5 1. Review for the ␲–␲-interaction: Meyer, E.A., Castlellano, R.K., and Diederich, F. (2003) Angew. Chem., Int. Ed. Engl., 42, 1210–1250. 2. Patrick, C.R., and Prosser, G.S. (1960) Nature, 187, 1021. 3. (a) Overell, J.S.W., and Pawley, G.S. (1982) Acta Crystallogr. Sect., B, 38, 1966–1972; (b) Williams, J.H., Cockcroft, J.K., and Fitch, A.N. (1992) Angew. Chem., Int. Ed. Engl., 31, 1655–1657. 4. Lawrey, D.M.G., and McConnell, H.J. (1952) J. Am. Chem. Soc., 74, 6175–6177. 5. (a) Collings, J.C., Roscoe, K.P., Thomas, R.L., Batsanov, A.S., Stimson, L.M., Howard, J.A.K., and Marder, T.B. (2001) New J. Chem., 25, 1410–1417; (b) Dahl, T. (1994) Acta Chem. Scand., 48, 95–106; (c) Williams, J.H. (1993) Acc. Chem. Res., 26, 593–598. 6. (a) West, A.P., Jr., Mecozzi, S., and Dougherty, D.A. (1997) J. Phys. Org. Chem., 10, 347–350; (b) Hernandez-Trujillo, J., Colmenares, F., Cuevas, G., and Costas, M., (1997) Chem. Phys. Lett., 265, 503–507; (c) Lozman, O.R., Bushby R.J., and Vinter, J.G. (2001) J. Chem. Soc., Perkin Trans. 2, 1446–1452; (d) Lorenzo, S., Lewis, G.R., and Dance, I. (2000) New J. Chem., 24, 295–304. 7. Steed, J.M., Dixon, T.A., and Klempeter, W. (1979) J. Chem. Phys., 70, 4940–4946. 8. Aspley, C.J., Boxwell, C., Buil, M.L., Higgitt, C.L., Long, C., and Perutz, R.N. (1999) Chem. Commun., 1027–1028. 9. Beaumont, T.G., and Davis, K.M.C. (1967) J. Chem. Soc. B, 1131–1134. 10. Dahl, T. (1979) Acta Chem. Scand. A, 33, 665–669. 11. (a) Alkorta, I., Rozas, I., and Elguero, J. (2002) J. Am. Chem. Soc., 124, 8593–8598; (b) Mascal, M., Armstrong, A., and Bartberger, M.D. (2002) J. Am. Chem. Soc., 124, 6274–6274; (c) Alkorta, I., Rozas, I., and Elguero, J. (1997) J. Org. Chem., 62, 4687–4691; (d) Alkorta, I., Rozas, I., and Elguero, J. (2002) J. Fluorine Chem., 101, 233–238. 12. Quinonero, D., Garau, C., Rotger, C., Frontera, A., Ballester, R., Costa, A., and Deya, P.M. (2002) Angew. Chem., Int. Ed. Engl., 41, 3389–3392.

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References to Section 1.2.7 1. Roberts, J.D., Webb, R.L., and McElhill, E.A. (1950) J. Am. Chem. Soc., 72, 408–411. 2. Banks, R.E., and Tatlow, C.J. (1994) In R.E. Banks, B.E. Smart, and J.C. Tatlow (eds), Organoﬂuorine Chemistry, Principles and Commercial Applications. Plenum Press, New York. 3. Koppel, I.A., Pihl, V., Koppel, J., Anvia, F., and Taft, R.W. (1994) J. Am. Chem. Soc., 116, 8654– 8657. 4. Raabe, G., Gais, H.-J., and Fleischhauser, J. (1996) J. Am. Chem. Soc., 118, 4622–4639. 5. (a) Schleyer, P.R., and Kos, A.J. (1983) Tetrahedron, 93, 1141; (b) Apeloig, Y. (1981) J. Chem. Soc., Chem. Commun., 396–399. 6. Friedman, D.S., Francl, M.M., and Allen, L.C. (1985) Tetrahedron, 41, 499–506. 7. Dixon, D.A., Fukunaga, T., and Smart, B.E. (1986) J. Am. Chem. Soc., 108, 4027–4031. 8. Fukaya, H., Ono, T., and Abe, T. (2001) J. Phys. Chem. A., 105, 7401–7404. 9. Kaupp, M., and Riedel, S. (2004) Inorganica Chem. Acta, 357, 1865–1872. 10. (a) Schleyer, P.v.R., Jemmis, E.D., and Spitznagel, G.W. (1985) J. Am. Chem. Soc., 107, 6393–6394; (b) Radom, L., Hehre, W.J., Pople, J.A. (1972) J. Am. Chem. Soc., 94, 2371; (c) Dill, J.D., Schleyer, P.v.R., and Pople, J.A. (1976) J. Am. Chem. Soc., 98, 1663–1668. 11. Rahman, M.M., Lemal, D.M., and Dailey, W.P. (1988) J. Am. Chem. Soc., 110, 1964–1966. 12. Schneider, W.F., Nance, B.I., and Wallington, T.J. (1995) J. Am. Chem. Soc., 117, 478–485. 13. Atkinson, R., Baulch, D.L., Cox, R.A., Hampson, R.F., Jr., Kerr, J.A., and Troe, J. (1992) J. Phys. Chem., 21, 1125–1568 14. Farnham, W.B., Smart, B.E., Middleton, W.J., Calabrese, J.C., and Dixon, D.A. (1985) J. Am. Chem. Soc., 107, 4565–4567. 15. Andreades, S. (1964) J. Am. Chem. Soc., 86, 2003. 16. (a) Klabunde, K.J., and Burton, D.J. (1972) J. Am. Chem. Soc., 94, 5985; (b) Holtz, D. (1971) Prog. Phys. Org. Chem., 8, 1. 17. (a) Streitwieser, A., and Holtz, D. (1967) J. Am. Chem. Soc., 89, 692; (b) Streitwieser, A., Holtz, D., Ziegler, G.R., Stoffer, J.O., Brokaw, M.L., and Guibe, F. (1967) J. Am. Chem. Soc., 89, 5229. 18. Tatlow, J.C. (1995) J. Fluorine Chem., 75, 7–34. 19. Sleigh, J.H., Stephenes, R., and Tatlow, J.C. (1979) J. Chem. Soc., Chem. Commun., 921–922. 20. Magnusson, E. (1986) J. Am. Chem. Soc., 108, 11–16. 21. Reed. A.E., and Schleyer, P.v.R. (1990) J. Am. Chem. Soc., 112, 1434–1445. 22. Fujita, M., Suzuki, M., Ogata, K., and Ogura, K. (1991) Tetrahedron Lett., 32, 1463–1466.

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16. 17. 18.

19.

Blint, R.J., McMahon, T.B., and Beauchamp, J.L. (1974) J. Am. Chem. Soc., 96, 1269–1278. Marial-Hodebar, L., Tordeux, M., and Wakselman, C. (1998) J. Chem. Res., Syn., 192–193. Johri, K.K., and DesMarteau, D.D. (1983) J. Org. Chem., 48, 242–250. Tari, I., and DesMarteau, D.D. (1980) J. Org. Chem., 45, 1214–1217. Piettre, S., De Cock, C., Merenyi, R., and Viehe, H.G. (1987) Tetrahedron 43, 4309–4319. Feiring, A.E. (1980) J. Org. Chem., 45, 1958–1961. Baasner, B., Hagemann, H., and Klauke, E. (1984) Ger. Offen, DE. 3 305 201; Chem. Abstr., (1985) 102, 5684. Archibald, T.G., and Baum, K. (1990) J. Org. Chem., 55, 3562–3565. Feiring, A.E. (1978) J. Fluorine Chem., 12, 471–479. Li, A.R., and Chen, Q.Y. (1997) Synthesis, 1481–1488. Hayashi, S., Nakai, T., and Ishikawa, N. (1980) Chem. Lett., 651–654. Suda, M., (1980) Tetrahedron Lett., 21, 2555–2556. Charpentier, M., Fossey, J., Tidwell, T.T., and Wolfe, S. (1987) Can. J. Chem., 65, 473–481. Ferraris, D., Cox, C., Anand, R., and Leckea, T. (1997) J. Am. Chem. Soc., 119, 4319–4320. (a) Olah, G.A., Cupas, C.A., and Comisarow, M.B. (1966) J. Am. Chem. Soc., 88, 362–364; (b) Olah, G.A., and Comisarow, M.B. (1969) J. Am. Chem. Soc., 91, 2955–2961; (c) Olah, G.A., Stephenson, M., Shih, J.G., Krishnamurthy, V.V., and Prakash, G.K.S., (1988) J. Fluorine Chem., 40, 319– 329. Ichikawa, J., Miyazaki, S., Fujiwara, M., and Minami, T. (1995) J. Org. Chem., 60, 2320–2321. Ripcka, W. (1971) US Patent 3,634,466; Chem. Abstr., (1972) 76, 99924. (a) Johnson, W.S., Chenera, B., Tham, F.S., and Kullnig, R.K. (1993) J. Am. Chem. Soc., 115, 493– 497; (b) Johnson, W.S., Fletcher, V.R., Chenera, B., Bartlett, W.R., Tham, F.S., and Kullnig, R.K. (1993) J. Am. Chem. Soc., 115, 497–504. Mare, P.B.D.L., and Ridd, J.H. (1959) Aromatic Substitution. Butterworths. London.

References to Section 1.2.9 1. (a) Tarrant, P. (1984) J. Fluorine Chem., 25, 69–74; (b) Haszeldine, R.N. (1986) J. Fluorine Chem., 33, 307–313; (c) Wakselman, C. (1994) In R.F. Banks, B.E. Smart, and J.C. Tatlow (eds), Organoﬂuorine Chemistry, Principle and Commercial Applications. Plenum, New York, pp. 177–194. 2. Sosnovsky, G. (1964) Free Radical Reactions in Preparative Organic Chemistry. Macmillan, New York. 3. (a) Uneyama, K. (1991) Tetrahedron, 47, 555–562; (b) Kislyi, V.P., Grinberg, V.A., Kurykin, M.A., Kagramanov, L.D., German, K.S., Semenov, V.V. (1992) J. Fluorine Chem., 58, 228. 4. Tanabe, Y., Matsuo, N., Ohno, N. (1988) J. Org. Chem., 53, 4582–4585. 5. Haszeldine, R.N. (1951) J. Chem. Soc., 584–587. 6. Barton, D.H.R., Lacher, B., and Zard, S.Z. (1988) Tetrahedron, 42, 2315–2328. 7. (a) Yoshida, M., and Kamigata, N. (1990) J. Fluorine Chem., 49, 1–20; (b) Gumprecht, W.H., and Dettre, R.H. (1975) J. Fluorine Chem., 40, 930–934. 8. Zhao, C., Zhou, R., Pan, H.J., Qu, Y., Wu, C., and Jiang, X. (1982) J. Org. Chem., 47, 2009–2013. 9. (a) Yoshida, M., Yoshida, T., Kamigata, N., and Kobayashi, M. (1988) Bull. Chem. Soc. Jpn., 61, 3549–3552; (b) Ref. 8. 10. Huang, W.Y. (1992) J. Fluorine Chem., 58, 1–8. 11. Chambers, W.J., Tullock, C.W., and Coffman, D.D. (1962) J. Am. Chem. Soc., 84, 2337–2343. 12. (a) Sangster, J.M., and Thynne, J.C.J. (1969) J. Phys. Chem., 73, 2746–2750; (b) Charles, S.W., and Whittle, E. (1960) Trans. Faraday Soc., 56, 794–801. 13. Umemoto, T., Ando, A. (1986) Bull. Chem. Soc. Jpn., 59, 447–452.

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14. An excellent review for more detailed information on ﬂuoroalkyl radicals: Dolbier, W.R., Jr., (1996) Chem. Rev., 96, 1557–1584. 15. Smart, B.E. (1995) In M. Hudlicky, S.E. Paviath (eds), Chemistry of Organic Fluorine Compounds II, ACS Monograph 187. American Chemical Society, Washington, DC, pp. 979–1010. 16. (a) Fessenden, R.W., and Schuler, R.H. (1965) J. Chem. Phys., 43, 2704–2718; (b) Krusic, P.J., and Bingham, R.C. (1976) J. Am. Chem. Soc., 98, 230–232; (c) Deardon, D.V., Hudgens, J.W., Johnson, R.D., III, Tsai, B.P., and Kafaﬁ, S.A. (1992) J. Phys. Chem., 96, 585–594; (d) Yamada, C., and Hirota, E. (1983) J. Phys. Chem., 78, 1703–1711; (e) Morokuma, K., Pendersen, L., and Karplus, M. (1968) J. Chem. Phys., 48, 4801–4802. 17. Bernardi, F., Cherry, W., Shaik, S., and Epiotis, N.D. (1978) J. Am. Chem. Soc., 100, 1352–1356. 18. Smart, B.E., Krusic, P.J., Meakin, P., and Bingham, R.C. (1974) J. Am. Chem. Soc., 96, 7382–7383. 19. Korth, H.G., Trill, H., and Sustmann, R. (1981) J. Am. Chem. Soc., 103, 4483–4489. 20. Kispert, L.D., Lui, H., and Pittman, C.U., Jr. (1973) J. Am. Chem. Soc., 95, 1657–1659. 21. Beregovaya, I.V., Schehegoleva, L.N., and Platonov, V.E. (1990) Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 26, 510–517. 22. Yoshida, M., Morishita, A., Sumida, D., Iyoda, M., Aoki, K., and Ikuta, S. (1996) Bull. Chem. Soc. Jpn., 69, 2019–2023. 23. (a) Ishihara, T., Hayashi, K., Ando, T., and Yamanaka, H. (1975) J. Org. Chem., 40, 3264–3267; (b) Ando, T., Yamanaka, H., Namigata, F., and Funasaka, W. (1970) J. Org. Chem., 35, 33–38; (c) Walborsky, H.M., and Collins, P.C. (1976) J. Org. Chem., 41, 940–943. 24. Kawamura, T., Tsumura, M., Yokomichi, Y., and Yonezawa, T. (1977) J. Am. Chem. Soc., 99, 9251–8256. 25. McMillen, D.F., and Golden, D.M. (1982) Ann. Rev. Phys. Chem., 33, 493–532. 26. Lide, D.B. (ed), (1995–96) CRC Handbook of Chemistry and Physics, 76th edn. CRC Press, Boca Raton, FL, pp. 9–63. 27. Martell, J.M., Boyd, R.J., and Shi, Z. (1993) J. Phys. Chem., 97, 7208–7215. 28. (a) Pasto, D.J., Krasnansky, R., and Zercher, C. (1987) J. Org. Chem., 52, 3062–3072; (b) Pasto, D.J. (1988) J. Am. Chem. Soc., 110, 8164–8175. 29. Jiang, X.K., Li, X.Y., and Wang, K.Y. (1989) J. Org. Chem., 54, 5648–5650. 30. (a) DePuy, C.H., Bierbaum, W.M., and Damrauer, R. (1984) J. Am. Chem. Soc., 106, 4051–4053; (b) Bartmess, J.E., Scott. J.A., and Melver, R.T., Jr. (1979) J. Am. Chem. Soc., 101, 6047–6049; (c) Christodoulides, A.A., McCorkie, D.L., and Christodoulides, L.G. (1984) In L.G. Christodoulides (ed), Electron–Molecule Interactions and Their Applications, Vol 2. Academic Press, Orlando, pp. 423–641. 31. Tedder, J.M., and Walton, J.C. (1976) Acc. Chem. Res., 9, 183–191. 32. Serov, S.I., Zhuraviev, M.V., and Sass, V.P. (1981) J. Org. Chem., USSR, 17, 48–52. 33. (a) Tedder, J.M., and Walton, J.C. (1980) Tetrahedron, 36, 701–707; (b) Tedder, J.M. (1982) Angew. Chem., Int. Ed. Engl., 21, 401–410; (c) Ref. 33. 34. (a) Fisher, H. (1986) In H.G. Viehe, Z. Janousek, and R. Merenyi (eds), Substitution Effects in Radical Chemistry, Reidel, Derdrect, pp. 123–142; (b) Heberger, K., Walbiner, M., and Fisher, H. (1992) Angew. Chem., Int. Ed. Engl., 31, 635–636. 35. Avila D.V., Ingold, K.U., Lusztyk, J., Dolbier, W.R., Jr., and Pan, H.Q. (1993) J. Am. Chem. Soc., 115, 1577–1579. 36. Avila D.V., Ingold, K.U., Lusztyk, J., Dolbier, W.R., Jr., Pan, H.Q., and Muir, M. (1994) J. Am. Chem. Soc., 116, 99–104. 37. Avila D.V., Ingold, K.U., Lusztyk, J., Dolbier, W.R., Jr., Pan, H.Q., and Muir, M. (1996) Tetrahedron, 52, 12351–12356. 38. Brace, N.O. (1963) J. Org. Chem., 28, 3093–3102. 39. (a) Newcomb, M. (1993) Tetrahedron, 49, 1151–1176; (b) Rong, X.X., Pan, H.Q., Dolbier, W.R., Jr., and Smart, B.E. (1994) J. Am. Chem. Soc., 116, 4521–4522.

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40. McMillen, D.F., and Golden, D.M. (1982) Annu. Rev. Phys. Chem., 33, 493. 41. Dolbier, E.R., Jr., and Rong, X.X. (1995) J. Fluorine Chem., 72, 235–240. 42. Cradlebaugh, J.A., Zhang, L., Shelton, G.R., Litwinienko, G., Smart, B.E., Ingold, K.U., and Dolbier, W.R., Jr. (2004) Org. Biomol. Chem., 2, 2083–2086. 43. Li, R., Smith, R.L., Kenttamaa, H.I. (1996) J. Am. Chem. Soc., 118, 5056–5061. 44. Murray, K.L., Leopoid, D.G., Miller, M.T., and Lineberger, W.C. (1988) J. Chem. Phys., 89, 5442– 5453. 45. Giese, B., Lee, W.-B., and Meister, J. (1980) Liebigs Ann. Chem., 725–735. 46. Irikura, K.K., Goddard, W.A., III, and Beauchamp, J.L. (1992) J. Am. Chem. Soc., 114, 48–51.

References to Section 1.3 1. 2. 3. 4. 5. 6.

7. 8.

9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Smart, B.E. (2001) J. Fluorine Chem., 109, 3–11. Bondi, A. (1964) J. Phys. Chem., 68, 441–451. Charton, M. (1969) J. Am. Chem. Soc., 91, 615–618. Taft, R.W., Jr. (1956) In Newman, M.S. (ed), Steric Effects in Organic Chemistry. Wiley, New York, pp. 556–675. Schlosser, M., and Michel, D. (1996) Tetrahedron, 52, 99–108. (a) Anderson, P. (1962) Acta Chem. Scand., 16, 2337–2340; (b) Eliel, E.L., and Martin, R.J.L. (1968) J. Am. Chem. Soc., 90, 689–697; (c) Hirsch, J.A. (1967) In N.L. Allinger, and E.L. Elier (ed), Topics in Stereochemistry. Wiley Interscience, New York, pp. 199–222; (d) Lewin, A.H., and Winstein, S. (1962) J. Am. Chem. Soc., 84, 2464–2465; (e) Armitage, B.J., Kenner, G.W., and Robinson, M.J.T. (1964) Tetrahedron, 20, 747–764; (f) Celotti, J.C., Reisse, J., and Chiuedoglu, G. (1966) Tetrahedron, 22, 2249–2269; (g) Della, E.W. (1966) Tetrahedron Lett., 7, 3347–3351; (h) Della, E.W. (1967) J. Am. Chem. Soc., 89, 5221–5224; (i) Allinger, N.L., and Freibert, L.A. (1960) J. Am. Chem. Soc., 82, 2393–2394; (j) Booth, H., and Everett, J.R. (1980) J. Chem. Soc., Perkin Trans. 2, 255–259; (k) Shephard, M.J., and Paddon-Row, M.N. (1993) Aust. J. Chem., 46, 547–560. Bott, G., Field, L.D., and Sternhell, S. (1980) J. Am. Chem. Soc., 102, 5618–5626. (a) Cosmo, R., and Sternhell, S. (1987) Aust. J. Chem., 40, 35–47; (b) Mislow, K., Glass, M.A.W., Hopps, H.B., Simon, E., and Wahl, G.H. (1964) J. Am. Chem. Soc., 86, 1710–1733; (c) Yamamoto, O., and Nakanishi, H. (1973) Tetrahedron, 29, 781–787. (a) Desponds, O., and Schlosser, M. (1996) J. Organomet. Chem., 507, 257–261; (b) Desponds, O., and Schlosser, M. ( 1996) Tetrahedron Lett., 37, 47–48. Mitchell, R.H., Bodwell, G.J., Vinod, T.K., and Werawarna, K.S. (1988) Tetrahedron. Lett., 29, 3287–3290. Smart, B.E. (1973) J. Org. Chem., 38, 2027–2035. For radical addition of CCl4 ,:Osborne, C.L., Van Auken, T.V., and Trecker, D.J. (1968) J. Am. Chem. Soc., 90, 5806–5813. Dolbier, W. R., Jr., Atly, A.C., and Phanstiel, O., IV. (1987) J. Am. Chem. Soc., 109, 3046–3050. Dolbier, W. R., Jr., and Palmer, K.W. (1993) J. Am. Chem. Soc., 115, 9349–9350. Ishii, A., Miyamoto, F., Higashiyama, K., and Mikami, K. (1998) Tetrahedron Lett., 39, 1199–1202. Kanai, M., Ueda, K., Yasumoto, M., Kuriyama, Y., Inomiya, K., Otsuka, T., Katsuhara, Y., Higashiyama, K., and Ishii, A. (2005) J. Fluorine Chem., 126, 377–383. Held, G., Bassent, M.P., Titmus, S., and King, D.A. (1996) J. Chem. Phys., 105, 11305–11312. Gaunt, M.J., Yu, J., and Spenar, J.B. (1998) J. Org. Chem., 63, 4172–4173. For CF3 -substituted amines 24: Kanai, M., Yasumoto, M., Kuriyama, Y., Inomiya, K., Katsuhara, Y., Higashiyama, K., and Ishii, A. (2003) Org. Lett., 5, 1007–1010. For F-substituted amines 24: Kanai, M., Yasumoto, M., Kuriyama, Y., Inomiya, K., Katsuhara, Y., Higashiyama, K., and Ishii, A. (2004) Chem. Lett., 33, 1424–1425.

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21. (a) Corey, E.J., Cheng, X.-M., Cimprich, K.A., and Sarshar, S. (1991) Tetrahedron Lett., 32, 6835– 6838; (b) Corey, E.J., Link, J.O., and Bakshi, R.K. (1992) Tetrahedron Lett., 33, 7107–7110. 22. Corey, E.J., Link, J.O., Sarshar, S., and Shao, Y. (1992) Tetrahedron Lett., 33, 7103–7106. 23. (a) Katagiri, T., and Uneyama, K. (2000) J. Fluorine Chem., 105, 285–293; (b) Katagiri, T., and Uneyama, K. (2003) Chirality, 15, 4–9. 24. (a) Katagiri, T., Irie, M., and Uneyama, K. (2000) Org. Lett., 2, 2423–2425; (b) Katagiri, T., Yamaji, S., Handa, M., Irie, M., and Uneyama, K. (2001) Chem. Commun., 2054–2055.

Chapter 2

Unique Reactions Induced by Fluorine

2.1

Nucleophilic substitution on ﬂuoroaromatic rings

Substitutions on aromatic rings mostly occur via electrophilic mechanisms. However, the strong electron-withdrawing inductive effect exerted by ﬂuorine makes nucleophilic substitutions on aromatic rings possible. The reactivity of the aryl halides decreases in the order of ﬂuoride > chloride > bromide > iodide, which is entirely opposite to that observed in the SN 2 reactions of aliphatic halides. The big difference arises from the extent of bond breaking between carbon and halogen atoms at the transition state. Addition and elimination pathways (1 → 2 → 3) are involved in the mechanism of aromatic nucleophilic substitution, in which addition is rate-determining (Scheme 2.1). Therefore, the sterically small and strong electron-withdrawing ﬂuorine atom activates the addition step. Meanwhile, bond breaking between carbon and halogen atoms plays an important role in the transition state for the SN 2 so that aliphatic iodides react the fastest among aliphatic halides in SN 2. Table 2.1 clearly

Scheme 2.1

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Organoﬂuorine Chemistry

Table 2.1 Effect of 4-halogens X

R

Yield (%)

F Cl Br I

4-CN 4-CN 4-CN 4-CN

94 80 48 27

Table 2.2 Effect of 4-substituents X

R

F F F F F F

4-NO2 4-SO2 Ph 4-CO2 Et 4-Ph 4-Br H

Yield (%) 98 79 74 62 55 33

demonstrates the order of the reactivity of 4-cyanoarylhalides with the conjugate base of indol [1]. Table 2.2 shows that substituents that stabilize the intermediate cyclohexadienyl anion (2) by resonance effects in turn enhance the reactivity of 4-substituted arylﬂuorides (5). Similar priority of ﬂuorine substituents for nucleophilic substitution on aromatic rings was observed in pyridine rings. The lithium amides undergo nucleophilic substitution to 2-ﬂuoropyridine (7), affording 2-aminopyridines in reasonable yields (Scheme 2.2). Quite in contrast, lithium amide attacks on the C-6 position rather than on the C-2 position of 11 (X = Cl or Br) to give the ring-opened product 13 as a ﬁnal product via intermediate 12 [2]. Fluorine-activated aromatic nucleophilic substitutions are highly useful for the syntheses of functionalized and multisubstituted aromatic compounds via both inter- and

Scheme 2.2

Unique Reactions Induced by Fluorine

103

intramolecular substitutions as shown in Scheme 2.3. Both large and medium ring heterocycles (15) [3] and (17) [4] can be prepared in good yields. Even nonactivated arylﬂuoride (18) cyclizes smoothly, affording 20 in excellent yield [5]. Weak nucleophiles such as amide and pyridinyl nitrogens attack ﬂuorinated aromatic carbon intramolecularly to give cyclic pyridinium salt (22) [6].

Scheme 2.3

Fluorine-promoted stepwise polymerization of 4-ﬂuorophenol derivative (23) provides a polyaryl ether (26) [7] where the ﬂuorine atom plays an essential role in the activation of the reactive site in the chain extension step (Scheme 2.4). Aryl ﬂuorides in general are much more reactive than other aryl halides. However, it is noticeable that the reactivity is sometimes controlled by the hard–soft principle of nucleophiles. Scheme 2.5 indicates some of the results. Soft nucleophiles attack the carbon–bromine bond

104

Organoﬂuorine Chemistry

Scheme 2.4

preferentially, while hard ones prefer the carbon–ﬂuorine bond [8]. Of course, lithium– halogen exchange reactions occur exclusively on the bromine atom when aromatic bromide reacts with butyl lithium (Scheme 2.5).

Scheme 2.5

The ﬂuorine-activation protocol for nucleophilic substitution on an aromatic ring has been utilized for the syntheses of hexa-substituted aromatic compounds (Scheme 2.6). The sterically small and inductively strong ﬂuorine atom must play a crucial role at the last step of introducing a sixth substituent on penta-substituted benzenes. Hexa-substituted phenylthiobenzenes (34) [9], vinylthiobenzenes (35) [10], pyridinylbenzenes (36) [11], phenoxybenzenes (37) [12], triﬂuoroethoxybenzenes (38) [12], and pentaﬂuoroethylbenzenes

Unique Reactions Induced by Fluorine

105

Scheme 2.6

(39) [13] have been synthesized from hexaﬂuorobenzene (Scheme 2.6). The sequential addition proceeds stepwise ﬁrst via the 1,4-position [13] and 1,2,4,5-tetrasubstitution and then via hexa-substitution. One of the more interesting applications for the stepwise addition is shown in the synthesis of 44 [14]. Bis-lithium species (45) reacts with hexaﬂuorobenzene at adjacent carbons to form phenanthrene ring (46) in good yield (Scheme 2.7) [15]. Of particular interest is the facile methanolysis of the ﬂuoroaromatics bearing highly activating groups like the diazonium [16] and nitro [17] groups. These reactions occur at room temperature, even under acidic conditions. The methoxyl substitution is useful for the preparation of meta-ﬂuorophenol derivatives (50) from available ﬂuoroanilines (47) via diazonium salt (Scheme 2.8).

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Organoﬂuorine Chemistry

Scheme 2.7

Scheme 2.8

Fluorine-activated coupling reagents for peptide synthesis Alkenyl and arylﬂuorides (F−C=C) are reactive and so one can imagine that the moiety of (F−C=X) (X=O, NR) should also be reactive. Acyl ﬂuorides have greater stability than the corresponding chlorides toward neutral oxygen nucleophiles such as water and methanol, but appear to be equal reactivity toward anionic nucleophiles and amines [1]. Cyanuric ﬂuoride 2 is a mild reagent for the preparation of acyl ﬂuorides [2]. The protected amino acids can be transformed into the corresponding amino alcohols without racemization by the reduction of acyl ﬂuorides 3 [3].

Generation of acyl ﬂuorides of the protected amino acids and the in situ coupling for the peptide synthesis have been achieved by the use of ﬂuoroformamidium salts, a new class of coupling reagents. Both 5 and 6 are easily prepared, and are nonhygroscopic, stable to handling under ordinary conditions, but reactive enough to transform carboxylic acids 8 to acyl ﬂuorides 9 under very mild conditions, which can be coupled with amine 10 [4, 5].

Unique Reactions Induced by Fluorine

107

1. (a) Bender, M.L., Jones, J.M. (1992) J. Org. Chem., 27, 3771–3774; (b) Swain, C.G., Scott, C.B. (1953) J. Am. Chem. Soc., 75, 246–248. 2. Olah, G.A., Nojima, M., Kerekes, I. (1973) Synthesis, 487–488. 3. Kototos, G., Noula, C. (1996) J. Org. Chem., 61, 6994–6996. 4. Carpino, L.A., El-Faham, A. (1995) J. Am. Chem. Soc., 117, 5401–5402. 5. El-Faham, A. (1998) Chem. Lett., 671–672.

2.2

SN 2 reactions of alkenes bearing a triﬂuoromethyl group

A triﬂuoromethyl group attached to a double bond lowers the LUMO and thus accelerates nucleophilic addition to the bond. The addition occurs mostly at the ␤-position because of the stabilization of the carbanions formed in the addition by both inductive and negative hyperconjugation effects, which also apply to the carbanion-like transition states formed in concerted reactions. (The negative hyperconjugation is discussed in Section 1.2.7.) In aprotic solvents, SN 2 reactions proceed generally via deﬂuorination to give functionalized 1,1-diﬂuoroalkenes (2) (Scheme 2.9). Triﬂuoropropene derivatives (3) with either electronwithdrawing or electron-donating substituents (R) at the ␣-carbon undergo smooth SN 2 reactions on reacting with carbon and heteroatom anions as shown in Scheme 2.10 (Table 2.3) [1–4]. 2-Triﬂuoropropenylsilane (5) reacts with a variety of nucleophiles to give 1,1-diﬂuoro2-silylalkenes (6) via an SN 2 reaction, which can be transformed to 1,1-diﬂuoroalkenes

Scheme 2.9

108

Organoﬂuorine Chemistry

Table 2.3 SN 2 -type reactions to CF3 -alkenes R H H CO2 H Ph, alkyl

Reagent

Nu

Yield of 4 (%)

Reference

(R3 Si)2 /TBAF PhLi (PhMgBr/CuBr) RMgBr R Li or R2 NLi

R3 Si Ph Ph, alkyl Ph, (alkyl)2 N

56–84 83 (21) 43–53 60–93

1 2 3 4

Scheme 2.10

(7) by replacement of the silyl group with electrophiles (Scheme 2.11) [5]. The reactions of 1-substituted-3,3,3-triﬂuoropropenes (8) [6] and (10) [7] with Grignard reagents need higher temperatures or longer reaction times as compared with 3 and 5, presumably because of the steric hindrance at the reaction sites (Scheme 2.12). Triﬂate (10) can be transformed to ␣-ﬂuoro-␣,␤-unsaturated esters (12) in good yields [7].

Scheme 2.11

Carbon–heteroatom double bonds bearing CF3 groups are also good substrates that accept nucleophiles at the heteroatom site, leading to ﬂuoroalkenes via formal SN 2 reactions (Scheme 2.13) [8, 9]. An electron is a tiny and powerful nucleophile that is easily accepted into a CF3 -bearing ␲system because of the low-lying LUMO. Either electrochemical reduction [9] or magnesium metal reduction [10] is useful for the C–F bond activation via the formal supply of one

109

Unique Reactions Induced by Fluorine

CF3

CF2 RMgBr

H

R

F NMe2

F RT/5–8 h

NMe2

8

H

9

F3C OTf F

THF/reflux 57-- 85%

10

F

solid acid R

F 11

(76%)

O

OH

F

R–MgBr

R : Ph (91%), Pr (55%), PhCH CH

EtO

R

EtOH, reflux 85 –87%

F 12

Scheme 2.12

Scheme 2.13

electron. Deﬂuorination and the subsequent trapping of the anion with TMSCl provide diﬂuoroalkenes (18) (Scheme 2.14). In particular, deﬂuorination brought about by the Mg–TMSCl–DMF system is reliable for the purpose [11]. Diﬂuoroenol silyl ethers [12], enamines [13], phenyl-1,1-diﬂuoroacetate [14], diﬂuorinated Danishefsky diene [15], and trimethylsilyldiﬂuoromethyl benzenes [16] can be prepared in good to excellent yields. The one-pot synthesis of 22 from 21 is of great interest. Deﬂuoro-dechlorinative double silylation occurs under very mild conditions to afford compound 22, a useful synthetic intermediate, in which two different silyl groups can be replaced with various electrophiles in a stepwise manner [17]. Highly functionalized ␣-iminoesters (27) can be synthesized via 25 and 26 in excellent yields as shown in Scheme 2.15.

110

Organoﬂuorine Chemistry

Scheme 2.14

Scheme 2.15

Although the mechanism is not a formal SN 2 reaction, the base-catalyzed 1,4-eliminations of 31 proceed smoothly and generate the diﬂuorinated orthoquinodimethane-type intermediates (28) [18]. Likewise, 29 [19] and 30 [20] have been generated. All of these intermediates are very reactive toward nucleophilic alkylation at the diﬂuoromethylene site. The overall chemical transformations provide a variety of highly functionalized ﬂuoroheterocycles (Scheme 2.16).

Unique Reactions Induced by Fluorine

Scheme 2.16

111

112

Organoﬂuorine Chemistry

Figure 2.1 Enhanced electrophilic reactivity of diﬂuoroethene.

2.3

Nucleophilic substitution on the gem-diﬂuoromethylene double bond

Fluoroalkenes and gem-diﬂuoroalkenes in particular are highly reactive toward nucleophilic attack at the diﬂuorinated carbon. Some of the driving forces for the facile nucleophilic attack on gem-diﬂuoromethylene carbon are as follows: (i) high electron deﬁciency on the gemdiﬂuoromethylene carbon, (ii) thermodynamical instability of sp2 -hybridized ﬂuoroalkenes [1, 2] in comparison with sp3 -hybridized ﬂuoroalkanes, and (iii) stable sp3 -hybridized ␤-ﬂuorocarbanions (Figure 2.1). The high reactivity of 1,1-diﬂuoroalkenes to nucleophiles is suggested by the polar nature of the double bond. 13 C NMR chemical shifts are shown in Figure 2.2 [2] where a marked deshielding of the ␣-carbon and a big chemical shift difference between ␣- and ␤-carbons for ﬂuoroalkenes are shown suggesting high electron deﬁciency (high reactivity to nucleophiles) on the ␣-carbon. Nucleophiles therefore attack exclusively at the gem-diﬂuoromethylene carbon of diﬂuoroalkenes to form ␤-ﬂuorocarbanions (1). The chemical fates of 1 are mostly dependent on the structures of the alkenes and the reaction conditions. The typical reaction pathways of 1 are classiﬁed into three as shown in Scheme 2.17. In aprotic solvents, the carbanions (1) undergo deﬂuorination, affording ␣-substituted monoﬂuoroalkenes (2). Meanwhile, in protic solvents or in the presence of electrophiles in aprotic solvents, the carbanions (1) can be trapped with a proton or an electrophile to give addition products (3). The third case is SN 2 -type addition where substrates must have a leaving group on the ␥ -carbon of 1 such as an alkoxy or an acyloxy group.

Figure 2.2

13

C NMR chemical shifts.

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113

Scheme 2.17

Scheme 2.18

Some typical reactions of 1,1-diﬂuoroethene with nucleophiles are summarized in Scheme 2.18. Alkoxides [3], trialkylsilyl anion [4], ester enolates [5], and diphenylphosphinyl anion [6] attack the gem-diﬂuorinated carbon of 5. However, it is noteworthy that nucleophilic substitution and proton abstraction are in some cases competitive, and thus s -butyl lithium abstracts the ␤-vinylic proton predominantly to generate vinyllithium. The lithium species can be trapped with an aldehyde, providing diﬂuoroallyl alcohol, which is then hydrolyzed to ␣,␤-unsaturated carboxylic ester (11) [7] (Scheme 2.19). Some synthetically useful examples are shown in Schemes 2.20 and 2.21. Tetrathiafulvalene derivative (14) is prepared from diﬂuorinated derivative (13) [8]. An elegant intramolecular version was demonstrated by Ichikawa, which provided a range of cyclized compounds (17), including dihydrofurans, thiophenes, pyrroles, and cyclopentenes, and also corresponding benzo derivatives (20) [2].

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Organoﬂuorine Chemistry

Scheme 2.19

Scheme 2.20

Scheme 2.21

The striking feature in this cyclization is the fact that two ﬂuorine substituents are essential; the corresponding monoﬂuoro compound (22) (R1 = Bu, X = O) reacted very slowly and yielded the desired benzofuran in only 17% yield (at 60◦ C, 2 h for the diﬂuoro compound, and at 80◦ C, 43 h for the monoﬂuoro compound) (Scheme 2.21). A large amount (80%) of the starting material (23) was recovered, without the desired cyclized product (20), at 60◦ C for 8 h in the case of the chloro compounds [2]. Moreover, a remarkable chemoselectivity was

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115

observed for cyclization of ␣-substituted ␤,␤-diﬂuoroacrylate (24) in contrast to nonﬂuorinated acrylate (26) [2]. Baldwin reported the cyclization of dimethyl 4-methyleneglutamate (26) to ␥ -lactam (27), showing difﬁculty for 5-endo-trig cyclization of 26 [9]. (A favored sp3 hybridization for ﬂuorohydrocarbons in comparison with sp2 hybridization is discussed in Section 1.2.6.) In contrast, the diﬂuorinated acrylate (24) undergoes facile intramolecular nucleophilic attack on the diﬂuoromethylene carbon, leading to the exclusive formation of a dihydropyrrole ring (25) as shown in Scheme 2.22 [2].

Scheme 2.22

The acceleration of nucleophilic addition by a ﬂuorine atom on the vinylic carbon can be applied for designing a microbial inhibition system. Scheme 2.23 shows a proposed mechanism for deoxy-amination of chorismate (28) via sequential SN 2 -type additions by

Scheme 2.23

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Organoﬂuorine Chemistry

amino group. (6S)-6-Fluoroshikimate strongly inhibits 4-amino-deoxychorismate (ADC) synthase. The ﬂuorine atom in 31 enhances irreversible addition of the amino group of the enzyme (from 31 to 32). However, it is eliminated from 32 to form a stable aromatic molecule which is not converted to ADC [10]. The shikimic pathway is an attractive target for antimicrobial agents as it is present in microorganisms, but not in mammals. The use of a ﬂuorine atom in the system would be promising for the purpose. Another well-known reaction for nucleophilic addition to 1,1-diﬂuoroalkenes is SN 2 type addition where substrates have a leaving group on the 3-carbon. Acyloxy and alkoxy groups are among the typical leaving groups and the reaction occurs both inter- and intramolecularly. Some examples are shown in Scheme 2.24. Methyl Grignard reagent cleanly attacks with the aid of Cu(I) on the diﬂuoromethylene carbon of 34 via SN 2 [11]. Exceptionally interesting is the reaction of diﬂuoro ␲-allyl palladium species (38) in which preferential ␥ -attack occurs [12].

Scheme 2.24

Sigmatropic rearrangements of diﬂuoroalkenes such as Claisen rearrangement of enol ether (40) [13], [2,3]sigmatropic rearrangement of carbanion (43) [14], and [2,3]sigmatropic rearrangement of sulfenate (46) [15] are intramolecular versions of the SN 2 reaction. They proceed smoothly to give functionalized diﬂuoroketone precursors (41), (44), and (47), respectively (Scheme 2.25). An interesting aza-Claisen rearrangement of ﬂuorinated enamines is described in the textbox given later in this chapter. Nucleophilic addition of alkyl lithium to diﬂuorovinyl-substituted epoxide (48) proceeds on the diﬂuoromethylene carbon via the addition–ring opening pathway [16]. However, trimethylaluminum reagent transfers the methyl group at the carbon remote from the diﬂuorinated carbon of 50 presumably via the Lewis acid catalyzed ring opening–addition mechanism as shown in Scheme 2.26.

Unique Reactions Induced by Fluorine

[3,3]

Scheme 2.25

Scheme 2.26

117

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Organoﬂuorine Chemistry

The third reaction pattern in nucleophilic reaction to diﬂuoroalkenes is addition. Protic nucleophiles such as amines and alcohols add sometimes to the diﬂuoroalkenes in a manner of 1,2-addition to the double bond where both nucleophilic moiety and proton are incorporated into the double bond (Scheme 2.27). A diﬂuoromethylene moiety is potentially a carbonyl synthon and a diﬂuoroalkylidene moiety is a synthon of an amide [17] and an ester (53) [18]. 1,1-Diﬂuoro-2-aminoalkenes (52) (R1 = amino moiety) would be transformed to dipeptides (53) (RX = amino ester, R1 = amino moiety) on reacting with amino esters. This idea was realized by the reaction of 60 with a variety of amino esters, leading to a practical synthesis of triﬂuoroalanine dipeptides (62) as shown in Scheme 2.27 [19].

Scheme 2.27

It should be noted that some highly ﬂuorinated alkenes are poisonous [20]. Perﬂuoroisobutene (PFIB; 63), a by-product of Teﬂon manufacture, is one of the most toxic among them and is more toxic than phosgene. Other ﬂuorinated alkenes such as hexaﬂuorocyclobutene (HFCB; 64) and tetraﬂuorocyclopropene (73) are toxic by inhalation. PFIB has

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119

a high afﬁnity for thiols in the lung. A rapid fall of cysteine and glutathione levels in the lung was observed in rodents exposed to PFIB. The origin of the toxicity is considered to be the rapid reaction between these perﬂuoroalkenes and cellular components such as cysteine via the addition–elimination pathway as described above. Some inhalation toxicities of ﬂuorobutenes in mice and rats are shown in Schemes 2.28 and 2.29 [21]. Timperley demonstrated experimentally the relation between toxicity and reactivity toward the thiols of these highly ﬂuorinated alkenes. Both PFIB and phosgene react rapidly with 2 mol of propane thiol to give dithiolated compounds 65 and 67, respectively (Scheme 2.30). In connection with similar reactivities, it is suggestive that the symptoms caused by inhalation of both PFIB and phosgene are quite similar and N-acetylcysteine is effective for alleviating the symptoms of both PFIB and phosgene. Polyﬂuorinated cyclobutenes (69) with more reactive sites are much more toxic as shown in Scheme 2.28. And the strained small ring cycloalkene is potentially more toxic [22] (Scheme 2.29).

Scheme 2.28

Scheme 2.29

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Organoﬂuorine Chemistry

Scheme 2.30

Fluorine-accelerated Claisen rearrangement and unusual behavior in aza-Claisen rearrangement Fluorine substituents on the C−C double bond greatly accelerate Claisen rearrangement. For instance, diﬂuorovinyl prenyl ether 83 rearranges at 100◦ C, while nonﬂuorinated vinyl prenyl ether rearranges at 200◦ C [1]. The chemoselective transformation of 76 to 75 reveals also a favorable ﬂuorine-directed rearrangement [2].

The temperature required for aza-Claisen rearrangement is about 100–150◦ C higher than those for the corresponding ethers [3]. The trend is the same in the rearrangment of ﬂuorinated compounds as shown below. The totally unique products formation observed in aza-Claisen rearrangement of ﬂuorinated enamines as compared with those of ethers suggests a different mechanism via, not a concerted six-membered transition state, but a stepwise radical pathway [4].

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121

1. Rhoads, S.J., and Raulins, N.R. (1975). In W.G. Dauben (ed), Org. React. Vol. 22, John Wiley & Sons, Inc., New York, p. 1. 2. Garayt, M.R., and Percy, J.M. (2001). Tetrahedron Lett., 42, 6377–6380. 3. Tarbell, D.S. (1960). In R. Adams (ed), Org. React. Vol. 1, John Wiley & Sons, Inc., New York, p. 1. 4. Amii, H., Ichihara, Y., Nakagawa, T., Kobayashi, T., and Uneyama, K. (2003). Chem. Commun., 2902–2903.

2.4

Single electron transfer reaction of perﬂuoroalkyl halides

The reaction of triﬂuoromethyl iodide with arene thiolates provides triﬂuoromethyl aryl sulﬁdes via a single electron transfer (SET) reaction rather than the SN 2 reaction, which is the only formal mechanism (Scheme 2.31). In general, perﬂuoroalkyl (Rf –X), tert-alkyl, and vinyl and aromatic halides are strongly deactivated for the replacement of halogens with

Scheme 2.31

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Organoﬂuorine Chemistry

Scheme 2.32

nucleophiles via SN 2 reactions. As for perﬂuoroalkyl halides, several factors such as the increased bond strength of the carbon–halogen bond in Rf –X by ﬂuorine substitution and the repulsion by ␣,␣-diﬂuorine atoms against approaching electron-rich nucleophiles to the ␣carbon are considered to be responsible for the rate retardation of the SN 2 pathway. Instead, SET reactions [1] that are initiated by electron transfer from SET reagents to the highly electron-deﬁcient halogen atom, in particular the iodine atom in perﬂuoroalkyl iodides, occur smoothly. In the SET reaction, the carbon–halogen bond is cleaved heterolytically to generate perﬂuoroalkyl radicals (2) and halide ions initiating the reaction as shown in Scheme 2.32 [2]. Then, ﬂuorinated carbon radicals (2) react electrophilically with nucleophiles to generate the anion radicals (3) which transfer an electron to the halides (1), affording the ﬁnal product (4) and also propagating the chain reaction via the radical (2) [3]. The mechanism shown in Scheme 2.32 for the overall transformation of 1 to 4 is named SRN 1 (unimolecular radical nucleophilic substitution) and was ﬁrst proposed by Kornblum [4] and Russell [5] in 1966. The SET reactions can be initiated by organic anions such as carbanions and heteroatom anions, reducing organic reagents such as tetrakis(N,N-dimethylamino)ethene, low valent metal, and electrochemical reduction. Irradiation by UV light is sometimes useful for the acceleration of SET reactions, but it is not necessarily required when good electron donors, for instance thiolates instead of thiols, are used. The chain reactions of, in particular, less reactive perﬂuoroalkyl bromides are inhibited by species such as nitrobenzene, para-dinitrobenzene, and hydroquinone [3, 6]. The reactivity order of perﬂuoroalkyl halides

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123

(I > Br > Cl > F) is in agreement with the order of the leaving ability of halide ions and also supports an SET reaction mechanism [7]. The intermediacy of the radicals (2) in the chain process is demonstrated by radical trapping with norbornene in the course of the perﬂuoroalkylation of 2-nitro-2-propyl carbanion with perﬂuorooctyl iodide (Scheme 2.33) [8].

Scheme 2.33

Perﬂuoroalkylation of the carbanions from acetylacetone [9] and malonates [10] are shown in Scheme 2.34 where intermediates 7 and 9 underwent further dehydroﬂuorination under the basic conditions [11].

Scheme 2.34

A number of perﬂuoroalkylations of thiolates from aliphatic, aromatic, and heteroaromatic thiols were reported by Boiko [12], where the substitution with primary and secondary perﬂuoroalkyl iodides afforded the desired products in 60–85% yield, but no reaction occurred with tert-Rf-I [12c]. Some of the related reactions are shown in Schemes 2.35 [13] and 2.36 [14].

Scheme 2.35

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Organoﬂuorine Chemistry

Scheme 2.36

Electrochemically reducible nitro- and cyanoarenes are used as mediators for SRN 1 perﬂuoroalkylation of heteroaromatics such as uracils (17) [15], purines (18), pyrimidines (19) [16], indoles (20), and imidazoles (21) [17] where the electroreductively generated arene anion radicals initiate the SET reaction [18] (Scheme 2.37).

Scheme 2.37

Because of the radical mechanism for SET reactions, introduction of both a perﬂuoroalkyl group and a heteroatom moiety to the carbon–carbon double [17–20] and even triple [21] bonds is possible. The initially generated perﬂuoroalkyl radicals add ﬁrst to oleﬁns to form a new radical intermediate (23), which then couples with anions (22) to form new anion radicals (24). The formation of the product (25) and the chain propagation via electron transfer from anion radicals (24) to perﬂuoroalkyl halides constitutes a chain reaction as shown in Scheme 2.38. Sulfur [19], selenium [20], tellurium [21], and phosphorus [22] anions (22) have been employed for these reactions [23]. Some synthetic applications are shown in Schemes 2.39–2.41. 1,1-Addition of perﬂuoroalkyl iodides to isonitriles (26) provides perﬂuoroalkyl imidoyl iodides (27) [24], which have been employed as useful reactive intermediates for triﬂuoromethylated amino acids and heterocycles [25]. Stereo-controlled perﬂuoroalkylation [26] and bromodiﬂuoromethylation [27] of the enolates (28) and (30) give diastereomerically enriched ﬂuoro-building blocks (29) and (31).

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125

Scheme 2.38

35−93% Scheme 2.39

Scheme 2.40

Reduction of chlorodiﬂuoromethylketones (32) with tetrakis(N,N-dimethylamino)ethene (35) produced carbanion (33) via two-electron reduction, which underwent aldol reaction with aldehydes to form 34 [28]. On the other hand, one-electron reduction of 32 with thiolates produced 36 via radical 35 [29] (Scheme 2.41).

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Organoﬂuorine Chemistry

Scheme 2.41

2.5

Fluorine-activated electrophilic reagents (F–X and XFn )

Reagents that consist of ﬂuorine bonded to another heteroatom are highly reactive because of the lone pair electron repulsion between X and F, and thus have been employed effectively to introduce either X or F to target molecules (Scheme 2.42). Whether X in the reagent (X–F) behaves electrophilically is dependent on the relative electron-withdrawing nature of X compared to F. Fluorine-activated electrophilic reagents (type A) are described in this section, and another type of reagent (type B), electrophilic ﬂuorinating reagents, is summarized in Chapter 7, Section 7.1. Fluorine-activated electrophilic reagents (type A) are mostly unstable and are generated in situ and used directly.

Scheme 2.42

2.5.1

Halogen monoﬂuoride (F-halogen)

Halogen monoﬂuorides are generated by the reaction of halogens with ﬂuorine gas diluted with nitrogen. They are strongly electrophilic becasue of their attachment to the most

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127

electronegative ﬂuorine atom. In particular, iodine monoﬂuoride is an extremely activated electrophilic iodine species for aromatic iodination, although molecular iodine itself is less electrophilic in comparison with chlorine and bromine. It is, therefore, a promising alternative to molecular iodine. The X–F reagents react smoothly even with electron-deﬁcient carbon–carbon double bonds [1, 2] and aromatics [3, 4] to transfer halogens (X) electrophilically (Scheme 2.43). The I–F reagent protonated with conc. H2 SO4 is still a more activated iodine transfer reagent, providing 3-iodo-1-triﬂuoromethylbenzene (5) and 1,4diiodo-2,3,4,5-tetraﬂuorobenzene (7) in 83 and 86% yields, respectively [4].

Scheme 2.43

2.5.2

Bromine triﬂuoride (BrF3 )

Bromine triﬂuoride (BrF3 ) is commercially available and has been used for transformations of carbonyl group equivalents such as C=NR, C=S, and C(SR)2 to the CF2 group, and SR and OH groups to the CF moiety [Caution: BrF3 should be treated with care because it reacts violently with solvents such as water and acetone. All reactions were conducted with diluted BrF3 ] [5]. Bromine in BrF3 is extremely electron-deﬁcient and thus electrophilic so that it interacts at ﬁrst with the lone-pair electrons on nitrogen and sulfur atoms as a Lewis acid and then activates or cleaves the carbon–heteroatom bonds with concomitant transfer of one of the ﬂuorine atoms in BrF3 to the carbon (Scheme 2.44). Various hydrazines [5], oximes [6], thioketones [7], and thioacetals [8] can be transformed to the corresponding diﬂuoromethylene moieties. One of the synthetic applications is shown in Scheme 2.44, where 2-triﬂuoromethylcarboxylates (16) were synthesized in overall yields of 20–35% from 11 [9].

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Organoﬂuorine Chemistry

Scheme 2.44

2.5.3

Iodine pentaﬂuoride (IF5 )

Iodine pentaﬂuoride (bp = 100.5◦ C, mp = 9.4◦ C) is a hazardous and extremely moisturesensitive reagent. However, a solution of IF5 in Et3 N–3HF (IF5 /Et3 N/HF = 1:1:3) is easy to prepare and handle, and is not moisture-sensitive with a low vapor pressure as compared with its neat form. The 19 F NMR of IF5 in CH2 Cl2 reveals one doublet and one quintet with relative intensity of 4:1 [10]. The theoretical calculation and the 19 F NMR data suggest that the structure of IF5 is likely to be slightly bent-square pyramidal. The reagent IF5 /Et3 N/3HF is a powerful and selective ﬂuorinating reagent for the replacement of the hydroxyl group of alcohols and carboxylic acids with ﬂuorine, diﬂuorination of carbonyl equivalents such as thiocarbonyl compounds, imines, hydrazones, and thioacetals, and diﬂuorination of the C–H bond of active methylene compounds [11], the mechanism of which is shown in Scheme 2.45 [12]. Depending on the structure of substrates, arylsulfenyl group migration was observed during the polyﬂuorination (22–24, Scheme 2.45) [13].

2.5.4

Iodoarene diﬂuoride (ArIF2 )

Iodoarene diﬂuorides (25) [14] react mostly with active methylene compounds, alkyl iodides, alkenes, and alkynes in a similar manner to IF5 and BrF3 to transfer one or two ﬂuorines. A striking feature of the reaction of ArIF2 is a regio- and stereoselective 1,2-transfer of ﬂuorine and areneiodonium moiety to the carbon–carbon triple bond leading to 2-ﬂuoro-1alkenyl iodonium salts (26) [15]. The Pd-catalyzed cross-coupling reactions of the iodonium salts (26) provide a variety of functionalized ﬂuoroalkenes (27) regioselectively as shown in Scheme 2.46 [16]. Because of the combination of oxidizability and ﬂuorine-transfer ability

Unique Reactions Induced by Fluorine

Scheme 2.45

Scheme 2.46

129

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Organoﬂuorine Chemistry

of ArIF2 , deiodinative ring expansion with stereoselective ﬂuorination was observed in iodomethylcyclic ethers (28). The reaction occurred in four- to six-membered cyclic ethers and provided the ﬂuorinated one-carbon expanded cyclic ethers in 50–87% yields [17]. Fluorination accompanied by C–S bond cleavage in cephalosporin esters (32) is also a subject of interest [18].

2.5.5

Benzeneselenenyl ﬂuoride (PhSeF)

Benzeneselenenyl ﬂuoride is generated by the action of XeF2 with diphenyl diselenide in CH2 Cl2 and employed in situ (Scheme 2.47) [19, 20]. The reagent is highly electrophilic to transfer both PhSe and F moieties to carbon–carbon double [19] and triple bonds [21]. Because of the strong electrophilicity of PhSeF, it adds to ␣,␤-unsaturated ketones and esters to transfer the PhSe moiety mostly at the ␣-position [22]. Formation of 2,4,6-tri-tertbutylbenzeneselenenyl ﬂuoride was detected by 19 F and 77 Se NMR spectroscopies, which clearly differentiated ArSeF from ArSeF3 [23].

Scheme 2.47

2.5.6

tert-Butyl and methyl hypoﬂuorites

Nonﬂuorinated alkyl hypoﬂuorites (ROF) are mostly unstable and decompose through HF elimination with formation of the corresponding carbonyl compounds. However, tertbutyl [24] and methyl hypoﬂuorites (RO+ · · · F− ) [25] can be generated and employed in situ for alkoxy-ﬂuorination of alkenes. The relatively higher stability of both hypoﬂuorites comes from the nonavailability of ␣-hydrogens which are reactive to the radical hydrogen abstraction [26]. Both of the hypoﬂuorites add to carbon–carbon double bonds regio- and stereoselectively as shown in Scheme 2.48. The anti-addition mode (37–39) is in sharp contrast to the syn-addition mode of electrophilic ﬂuoroalkoxy and acetoxy reactions of ﬂuorinated alkyl and acetyl hypoﬂuorites (Rf O− · · · F+ , 40–41) [27].

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131

Scheme 2.48

2.5.7

Hypoﬂuorous acid · MeCN complex (HOF · MeCN)

The HOX reagents (X = Cl, Br, I) are well known as oxidizing and halo-hydroxylation reagents, in which halogens act as electrophiles (HO− X+ ). In contrast, hypoﬂuorous acid (HOF) is polarized oppositely so as to make the hydroxyl group highly electropositive and thus electrophilic because of the strong electron-withdrawing nature of ﬂuorine. Therefore, HOF is an excellent electrophilic hydroxylating and oxygen transfer reagent that enables unique reactions otherwise difﬁcult [28, 29]. Rozen is the pioneering chemist who succeeded in the generation and synthetic utilization of the relatively more stable and synthetically more feasible HOF · MeCN reagent. The reagent HOF · MeCN is generated by simply passing ﬂuorine through aqueous acetonitrile and can exist for a few hours at 0◦ C, long enough to run a variety of reactions [30]. In particular, the oxygen transfer reaction with HOF · MeCN is remarkable. The highly electron-deﬁcient fumaric ester (42) can be epoxidized stereospeciﬁcally [31]. Even the less stable cyclooctatetraene (44) can be transformed to tetraoxide quantitatively [32], while enol silyl ethers (47) are ␣-hydroxylated smoothly [33]. The less oxidizable thiophenes (50) are oxidized at room temperature within 20 min, providing the sulfones (51) almost quantitatively [34, 35], while some aromatic rings (52) are also epoxidized directly [36] (Scheme 2.49). The amino groups of amino esters (54) [37] and azides (56) [38] are also substrates for easy oxidation to nitro compounds. Baeyer-Villiger oxidation of ketones (58) proceeds at 0◦ C over 4 h to give a mixture of esters (60) and (61) via a dioxirane intermediate, intermediacy of which was proposed on the basis of the complete scrambling of the ester oxygen with heavy oxygen in H18 OF [39] (Scheme 2.50). Direct C–H bond activation leading to hydroxylation of aliphatic [40] and aromatic [41] C–H bonds is possible on reacting hydrocarbons (62) and (64) with HOF · MeCN (Scheme 2.51).

132

Scheme 2.49

Organoﬂuorine Chemistry

Unique Reactions Induced by Fluorine

133

Scheme 2.50

Scheme 2.51

References References to Section 2.1 1. Smith, W.J., and Sawyer, J.S. (1996) Tetrahedron Lett., 37, 299–302. 2. Pasumansky, L., Hernandez, A.R., Gamsey S., Goralski, C.T., and Singaram, B. (2004) Tetrahedron Lett., 45, 6417–6420. 3. Schultz, A.G., and Guo, Z. (1995) Tetrahedron Lett., 36, 659–662. 4. Ouyang, X., Chen, Z., Liu, L., Dominguez, C., and Kiselyov, A.S. (2000) Tetrahedron, 56, 2369– 2377. 5. Lysen, M., Kristensen, J.L., Vedso, P., and Begtrup, M. (2002) Org. Lett., 4, 257–259.

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6. (a) Rocca, P., Marsais, F., Godard, A., and Queguiner, G. (1993) Tetrahedron Lett., 34, 7917–7918; (b) Arzel, E., Rocca, P., Marsais, F., Godard, A., and Queguiner, G. (1998) Tetrahedron Lett., 39, 6465–6466. 7. Yokozawa, T., Suzuki, Y., and Hiraoka, S. (2001) J. Am. Chem. Soc., 123, 9902–9903. 8. Chambers, R.D., Hoskin, P.R., Sandford, G., Yuﬁt, D.S., and Howard, J.A.K. (2001) J. Chem. Soc., Perkin Trans. 1, 2788–2795. 9. Suenaga, Y., Kuroda-Sowa, T., Maekawa, M., and Munakata, M. (2000) J. Chem. Soc., Dalton Trans., 3620–3623. 10. Gostevskaya, V.I., Gavrilova, G.M., Afonin, A.V., and Amosova, S.V. (2001) Russ. J. Org. Chem. (Translation of Zhurnal Organicheskoi Khimii), 37, 388–389. 11. Weiss, R., Pomrehn, B., Hampel, F., and Bauer, W. (1995) Angew. Chem. Int. Ed. Engl., 34, 1319– 1321. 12. Zhang, Y.F., Kirchmeier, R.L., and Shreeve, J.M. (1994) J. Fluorine Chem., 68, 287–292. 13. Flowers, W.T., Haszeldine, R.N., and Kemp, J.E.G. (1969) J. Chem. Soc., Chem. Commun., 203. 14. Mayor, M., and Lehn, J.M. (1997) Helv. Chim. Acta, 80, 2277–2285. 15. Cho, D.M., Parkin, S.R., and Watson, M.D. (2005) Org. Lett., 7, 1067–1068. 16. Takechi, N., Fukai, Y., Oka, K., and Huisgen, R. (1996) Chem. Lett., 23–24. 17. Bolto, B.A., Liveris, M., and Miller, J. (1956) J. Chem. Soc., 750–753.

References to Section 2.2 1. Hiyama, T., Obayashi, M., and Sawahata, M. (1983) Tetrahedron Lett., 24, 4113–4116. 2. For PhLi: (a) Fontanelli, R., and Sianesi, D. (1965) Ann. Chim. (Roma), 55, 862–871; For PhMgBr: (b) Kendrick, D.A., and Kolb, M. (1989) J. Fluorine Chem., 45, 265–272; (c) Bergstrom, D.E., Ng, M.W., and Wong, J.J. (1983) J. Org. Chem., 48, 1902–1903. 3. (a) Fuchikami, T., Shibata, Y., and Suzuki, Y. (1986) Tetrahedron Lett., 27, 3173–3176; (b) Kitazume, T., and Ohnogi, T. (1988) Synthesis, 614–615; (c) Kitazume, T., Ohnogi, T., Miyauchi, H., and Yamazaki, T. (1989) J. Org. Chem., 54, 5630–5632. 4. (a) Begue, J-P., Bonnet-Delpon, D., and Rock, M.H. (1996) J. Chem Soc., Perkin Trans. 1, 1409–1413; (b) Begue, J.-P., Bonnet-Delpon, D., and Rock, M.H. (1995) Tetrahedron Lett., 36, 5003–5006. 5. Ichikawa, J., Ishibashi, Y., and Fukui, H. (2003) Tetrahedron Lett., 44, 707–710. 6. (a) Park, H.M., Uegaki, T., Konno, T., Ishihara, T., and Yamanaka, H. (1999) Tetrahedron Lett., 40, 2985–2988; (b) Yamanaka, H., Uegaki, T., Ishihara, T., Kubota, T., and Gupton, J.T. (1999) J. Fluorine Chem., 97, 101–108. 7. Funabiki, K., Sawa, K., Shibata, K., and Matsui, M. (2002) Synlett, 1134–1136. 8. Uneyama, K., Yang, F.-Y., Hirama, S., and Katagiri, T. (1996) Tetrahedron Lett., 37, 2045–2048. 9. Portella, C., and Shermolovich, Y. (1997) Tetrahedron Lett., 38, 4063–4064. 10. (a) Chaussard, J., Folest, J.C., Nedelec, J.Y., Perichon, J.H., Sibille, S., and Troupel, M. (1990) Synthesis, 369–381; (b) Uneyama, K., Maeda, K., Kato, T., and Katagiri, T. (1998) Tetrahedron Lett., 39, 3741–3744; (c)Uneyama, K., and Kato, T. (1998) Tetrahedron Lett., 39, 587–590; (d) Clavel, P., Leger-Lambert, M.-P., Biran, C., Spirau, F.S., Bordeau, M., and Marzouk, R. (1999) Synthesis, 829–834. 11. Uneyama, K., and Amii, H., (2002) J. Fluorine Chem., 114, 127–131. 12. Amii, H., Kobayashi, T., Hatamoto, Y., and Uneyama, K. (1999) Chem. Commun., 1323–1324. 13. Mae, M., Amii, H., and Uneyama, K. (2000) Tetrahedron Lett., 41, 7893–7896. 14. Amii, H., Kobayashi, T., and Uneyama, K. (2000) Synthesis, 2001–2003. 15. Amii, H., Kobayashi, T., Terasawa, H., and Uneyama, K. (2001) Org. Lett., 3, 3103–3105. 16. Amii, H., Hatamoto, Y., Seo, M., and Uneyama, K. (2001) J. Org. Chem., 66, 7216–7218. 17. Kobayashi, T., Nakagawa, T., Amii, H., and Uneyama, K. (2003) Org. Lett., 5, 4297–4300.

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18. (a) Kiselyov, A.S., and Strekowski, L. (1994) Tetrahedron Lett., 35, 7597–7600; (b) Strekowski, L., Kiselyov, A.S., and Hojjat, M. (1994) J. Org. Chem, 59, 5886–5890; (c) Smith, L., and Kiselyov, A.S. (1999) Tetrahedron Lett., 40, 5643–5646; (d) Kiselyov, A.S., and Dominguez, C. (1999) Tetrahedron Lett., 40, 5111–5114. 19. Betley, J.R., Cesaro-Tadic, S., Mekhalﬁa, A., Rickard, J.H., Denham, H., Partridge, L.J., Pluckthun, A., and Blackburn, G.M. (2002) Angew. Chem. Int. Ed., 41, 775–777. 20. (a) Kiselyov, A.S. (2001) Tetrahedron Lett., 42, 3053–3056; (b) Kiselyov, A.S. (2001) Tetrahedron, 57, 5321–5326; (c) Kiselyov, A.S. (1995) Tetrahedron Lett., 36, 493–496.

References to Section 2.3 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

15. 16. 17.

18.

19. 20. 21. 22.

Stothers, J.B. (1972) Carbon-13 NMR Spectroscopy. Academic Press, New York, p. 183. Ichikawa, J., Wada, Y., Fujisawa, M., and Sakoda, K. (2002) Synthesis, 1917–1936. Murata, J., Tamura, M., and Sekiya, A. (2002) Green Chem., 4, 60–63. Hanamoto, T., Harada, S., Shindo, K., and Kondo, M. (1999) Chem. Commun., 2397–2398. Crouse, G.D., and Webster, J.D. (1992) J. Org. Chem., 57, 6643–6646. Hanamoto, T., Shindo, K., Matsuoka, M., Kiguchi, Y., and Kondo, M. (2000) J. Chem. Soc., Perkin Trans. 1, 103–107. (a) Tellier, F., and Sauvetre, R. (1993) Tetrahedron Lett., 34, 5433–5436; (b) Sauvetre, R., and Normant, J.F. (1981) Tetrahedron Lett., 22, 957–958. Gimbert, Y., Moradpour, A., Dive, G., Dehareng, D., and Lahlilt, K. (1993) J. Org. Chem., 58, 4685–4690. Baldwin, J.E. (1976) J. Chem. Soc., Chem. Commun., 734. Bulloch, B.M.M., Jones, M.A., Parker, E.J., Osborne, A.P., Stephens, E., Davies, G.M., Coggins, J.R., and Abell, C. (2004) J. Am. Chem. Soc., 126, 9912–9913. Tellier, F., and Sauvetre, R. (1995) J. Fluorine Chem., 70, 265–270. Shi, G.-Q., Huang, X.-H., and Zhang, F.-J. (1995) Tetrahedron Lett., 36, 6305–6308. (a) Patel, S.T., Percy, J.M., and Wilkes, R.D. (1995) Tetrahedron, 51, 11327–11336; (b) Broadhurst, M.J., Percy, J.M., and Prime, M.E. (1997) Tetrahedron Lett., 38, 5903–5906. (a) Patel, S.T., Percy, J.M., and Wilkes, R.D. (1996) J. Org. Chem., 61, 166–173; (b) Kariuki, B.M., Owton, W.M., Percy, J.M., Pintat, S., Smith, C.A., Spencer, N.S., Thomas, A.C., and Watson, M. (2002) Chem. Commun., 228–229. Blades, K., Patel, S.T., Percy, J.M., and Wilkes, R.D. (1996) Tetrahedron Lett., 37, 6403–6406. Yamazaki, T., Ueki, H., and Kitazume, T. (2002) Chem. Commun., 2670–2671 (a) Bailey, P.D., Boa, A.N., Crofts, G.A., Vandiepen, M., Helliwell, M., Gammon, R.E., and Harrison, M.J. (1989) Tetrahedron Lett., 30, 7457–7460; (b) England, D.C., Melby, L.R., Dietrich, M.A., and Lindsey, R.V., Jr. (1960) J. Am. Chem. Soc., 82, 5116–5122. (a) Takaoka, A., Iwakiri, H., and Ishikawa, N. (1979) Bull. Chem. Soc. Jpn., 52, 3377–3380; (b) Ishikawa, N., Takaoka, A., Iwakiri, H., Kubota, S., and Kagaruki, S.R.F. (1980) Chem. Lett., 1107–1110. Guo, Y., Fujiwara, K., Katagiri, T., and Uneyama, K. (in press) Org. Lett. Timperley, C.M. (2004) J. Fluorine Chem., 125, 685–693. Maidment, M.P., Patel, S.K., Upshall, D.G., and Timperley, C.M. (1999) J. Appl. Toxicol., 19, 113–123. Timperley, C.M. (2000) In R.E. Banks (ed), Fluorine Chemistry at the Millennium: Fascinated by Fluorine. Elsevier, Amsterdam, pp. 499–537.

References to Section 2.4 1. Review of nucleophilic substitution reactions by electron transfer: Rossi, R.A., Pierini, A.B., and Penenory, A.B. (2003) Chem. Rev., 103, 71–167.

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2. As for the SET reaction mechanism, three kinds of electron transfer (ET) processes are proposed; a path via radical anion intermediates, dissociative ET, and associative ET: Wakselman, C. (1992) J. Fluorine Chem., 59, 367–378. See also Ref. 1. 3. The chain reaction was ﬁrstly proposed for the reaction of perﬂuoroalkyl iodides with arene thiolates by Wakselman: Wakselman, C., and Tordeux, M. (1984) J. Chem. Soc., Chem. Commun., 793–794. 4. Kornblum, N., Michel, R.E., and Kerber, R.C. (1966) J. Am. Chem. Soc., 88, 5662–5663. 5. Russell, G.A., and Dannen, W.C. (1966) J. Am. Chem. Soc., 88, 5663–5665. 6. (a) Medebielle, M., Pinson, J., and Saveant, J.M. (1991) J. Am. Chem. Soc., 113, 6872–6879; (b) Wakselman, C., and Tordeux, M. (1985) J. Org. Chem., 50, 4047–4051. 7. Long, Z., and Che, Q.Y. (1998) J. Fluorine Chem., 91, 95–98. 8. Feiring, A.E. (1985) J. Org. Chem., 50, 3269–3274. 9. Yagupolskii, L.M., Matyushecheva, G.I., Pavlenko, N.V., and Boiko, V.N. (1982) J. Org. Chem. U.S.S.R., 18, 10–14. 10. (a) Chen, Q.Y., and Qiu, Z.J. (1986) J. Fluorine Chem., 31, 301–317; (b) Guo, Y., and Chen, Q.Y. (2001) Acta Chim. Sin., 59, 1730–1734. 11. Ethyl acetoacetate anion provided the substitution products in 70–75% yields: Chen, Q.Y., and Qiu, Z. (1987) J. Fluorine Chem., 35, 1730–1734. 12. (a) Boiko, V.N., Shchupak, G.M., and Yagupolskii, L.M. (1977) J. Org. Chem. U.S.S.R. (Engl. Transl.), 13, 972–975; (b) Boiko, V.N., and Shchupak, G.M. (1994) J. Fluorine Chem., 69, 207–212; (c) Popov, V.I., Boiko, V.N., Kondratenko, N.V., Sambur, V.P., and Yagupolskii, L.M. (1977) J. Org. Chem. U.S.S.R. (Engl. Transl.), 13, 1985–1988; (d) Popov, V.I., Boiko, V.N., Kondratenko, N.V., and Yagupolskii, L.M. (1982) J. Fluorine Chem., 21, 365–369; (e) Feiring, A.E. (1984) J. Fluorine Chem., 24, 191–203. 13. Burkholder, C.R., Dolbier, W.R., Jr., and Medebielle, M. (2000) J. Fluorine Chem., 102, 369–376. 14. Boiko, V.N., Dashevskaya, T.A., Shchupak, G.M., and Yagupolskii, L.M. (1979) J. Org. Chem. U.S.S.R. (Engl. Transl.), 15, 347–350. 15. Medebielle, M., Oturan, M.A., Pinson, J., and Saveant, J.M. (1993) Tetrahedron Lett., 34, 3409– 3412. 16. Medebielle, M., Pinson, J., and Saveant, J.M. (1992) Tetrahedron Lett., 33, 7351–7354. 17. Medebielle, M., Pinson, J., and Saveant, J.M. (1990) Tetrahedron Lett., 31, 1279–1282. 18. Medebielle, M., Oturan, M.A., Pinson, J., and Saveant, J.M. (1996) J. Org. Chem., 61, 1331– 1340. 19. Uneyama, K., and Kitagawa, K. (1991) Tetrahedron Lett., 32, 3385–3386. 20. Uneyama, K., and Kitagawa, K. (1991) Tetrahedron Lett., 32, 375–378. 21. Tellurium: Uneyama, K., and Kanai, M. (1991) Tetrahedron Lett., 32, 7425–7426. 22. Vaillard, S.E., Postigo, A., and Rossi, R.A. (2004) Organometallics, 23, 3003–3007. 23. Ueda, Y., Kanai, M., and Uneyama, K. (1994) Bull. Chem. Soc. Jpn., 67, 2273–2277. 24. Yu, H.-W., and Huang, W.-Y. (1996) Tetrahedron Lett., 37, 7999–8002. 25. Review of the chemistry of triﬂuoroacetimidoyl halides: Uneyama, K. (1999) J. Fluorine Chem., 97, 11–25. 26. Iseki, K., Takahashi, M., Asada, D., Nagai, T., and Kobayashi, Y. (1995) J. Fluorine Chem., 74, 269–271. 27. Katagiri, T., Handa, M., Matsukawa, Y., Dileep Kumar, J.S., and Uneyama, K. (2001) Tetrahedron Asym., 12, 1303–1311. 28. Burkholder, C., Dolbier, W.R., Jr., Medebielle, M., and Ndedi, A. (1998) Tetrahedron Lett., 39, 8853–8856. 29. Burkholder, C., Dolbier, W.R., Jr., Medebielle, M., and Ait-Mohand, S. (2001) Tetrahedron Lett., 41, 3459–3462.

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References to Section 2.5 1. (a) Rozen, S., and Brand, M. (1986) J. Org. Chem., 51, 3607–3611; (b) Rozen, S., and Zamir, D. (1991) J. Org. Chem., 56, 4695–4700; (c) Rozen, S., Brand, M., and Zamir, D. (1987) J. Am. Chem. Soc., 109, 896–897. 2. For aromatic bromination: Rozen, S., Brand, M., and Lidor, R. (1988) J. Org. Chem., 53, 5545–5547. 3. Rozen, S., Zamir, D., Menachem, Y., and Brand, M. (1988) J. Org. Chem., 53, 1123–1125. 4. Chambers, R.D., Skinner, C.J., Atherton, M.J., and Moillient, J.S. (1996) J. Chem. Soc., Perkin Trans. 1, 1659–1664. 5. Rozen, S., Mishani, E., and Bar-Haim, A. (1994) J. Org. Chem., 59, 2918. 6. Rozen, S., and Ben-David, I. (2001) J. Org. Chem., 66, 496–500. 7. (a) Rozen, S., and Mishani, E. (1993) J. Chem. Soc., Chem. Commun., 1761–1762; (b) Rozen, S., and Mishani, E. (1994) J. Chem. Soc., Chem. Commun., 2081; (c) Ben-David, I., Rechavi, D., Mishani, E., and Rozen, S. (1999) J. Fluorine Chem., 97, 75–78. 8. (a) Hagooly, A., Sasson, R., and Rozen, S. (2003) J. Org. Chem., 68, 8287–8289; (b) Sasson, R., Hagooly, A., and Rozen, S. (2003) Org. Lett., 5, 769–771; (c) Hagooly, A., Ben-David, I., and Rozen, S. (2002) J. Org. Chem., 67, 8430–8434. 9. Hagooly, A., and Rozen, S. (2004) Chem. Commun., 594–595. 10. Yoneda, N., and Fukuhara, T. (2001) Chem. Lett., 222–223. 11. Yoneda, N. (2004) J. Fluorine Chem., 125, 7–17. 12. Ayuta, S., Yoneda, N., Fukuhara, T., and Hara, S. (2002) Bull. Chem. Soc. Jpn., 75, 1597–1601. 13. Ayuba, S., Fukuhara, T., and Hara, S. (2003) Org. Lett., 5, 2873–2874. 14. Preparation of ArIF2 : Cl2 and then HgO/HF aq., or Cl2 and then NaOH followed by HF aq.: Carpenter, M. (1966) J. Org. Chem., 31, 2688–2689; XeF2 : Zupan, M., Pollak, A. (1975) J. Chem. Soc., Chem. Commun., 715–716; Electrochemical oxidation in Et3 N–3HF or in Et3 N–5HF: Fuchigami, T., Fujita, T. (1994) J. Org. Chem., 59, 7190–7192; Hara, S., Hatakeyama, T., Chen, S.Q., Ishii, K., Yoshida, M., Sawaguchi, M., Fukuhara, T., Yoneda, N. (1998) J. Fluorine Chem., 87, 185–192. 15. Hara, S., Yoshida, M., Fukuhara, T., and Yoneda, N. (1998) J. Chem. Soc., Chem. Commun., 965– 966. 16. (a) Yoshida, M., Hara, S., Fukuhara, T., and Yoneda, N. (2000) Tetrahedron Lett., 41, 3887–3890; (b) Hara, S., Yamamoto, K., Yoshida, M., Fukuhara, M., and Yoneda, N. (1999) Tetrahedron Lett., 44, 7815–7818; (c) Yoshida, M., Yoshikawa, S., Fukuhara, T., Yoneda, N., and Hara, S. (2001) Tetrahedron, 57, 7143–7148. 17. Inagaki, T., Nakamura, Y., Sawaguchi, M., Yoneda, N., Ayuba, S., and Hara, S. (2003) Tetrahedron Lett., 44, 4117–4119. 18. Motherwell, W.B., Greaney, M.F., Edmunds, J.J., and Steed, J.W. (2002) J. Chem. Soc., Perkin, Trans. 1, 2816–2826. 19. (a) Uneyama, K., and Kanai, M. (1990) Tetrahedron Lett., 31, 3583–3586; (b) Lermontov, S.A., Zavorin, S.I., Pushin, A.N., Chekhlov, A.N., Zeﬁrov, N.S., and Stang, P.J. (1993) Tetrahedron Lett., 34, 703–706; (c) Uneyama, K. (2000) J. Organomet. Chem., 611, 158–163. 20. Halogen–ﬂuorine exchange reactions such as AgF–PhSeBr, AgF–PhSeCl–MeCN have been used also for the generation of PhSeF equivalent: Nicolaou, K.C., and Claremon, N.A. (1985) Tetrahedron, 41, 4835–4841; (b) Tomoda, S., and Usuki, Y. (1998) Chem. Lett., 1235–1236; (c) Mccarthy, J.R., Natteus, D.P., and Barney, C.L. (1990) Tetrahedron Lett., 31, 973–977; (d) Saluzzo, C., Alvernhe, G., and Anker, D. (1990) Tetrahedron Lett., 31, 663–667. 21. (a) Saluzzo, C., Alvernhe, G., Anker, D., and Haufe, G. (1990) Tetrahedron Lett., 31, 2127–2130; (b) Poleschner, H., Heydenreich, M., Spindler, K., and Haufe, G. (1994) Synthesis 1043–1049; (c) Usuki, Y., Iwaoka, M., and Tomoda, S. (1992) Chem. Lett., 1507–1510. 22. Uneyama, K., Hiraoka, S., and Amii, H.(2000) J. Fluorine Chem., 102, 215–218. 23. Poleschner, H., and Seppelt, K. (2004) Chem. Eur. J., 10, 6565–6574.

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24. 25. 26. 27. 28.

29. 30. 31. 32. 33.

34. 35. 36. 37.

38. 39. 40. 41.

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Ben-David, I., Mishani, E., and Rozen, S. (1998) J. Org. Chem., 63, 4632–4635. Rozen, S., Mishani, E., Kol, M., and Ben-David, I. (1994) J. Org. Chem., 59, 4281–4284. Rozen, S., and Bar-Haim, A. (1995) J. Fluorine Chem., 74, 229–231. (a) Rozen, S., and Lerman, O. (1980) J. Org. Chem., 45, 4122–4125; (b) Rozen, S., Lerman, O., Kol, M., and Hebel, D., (1985) J. Org. Chem., 50, 4753–4758. (a) Reviews for chemistries of HOF · MeCN: Rozen, S. (1988) Acc. Chem. Res., 21, 307–312; (b) Rozen, S., (1996) Acc. Chem. Res., 29, 243–248; (c) Rozen, S. (1996) Chem. Rev., 96, 1717– 1736. Review for elemental ﬂuorine and related ﬂuorinating reagents in organic synthesis: Purrington, S.T., and Kagan, B.S. (1986) Chem. Rev., 86, 997–1018. Rozen, S., and Brand, M. (1986) Angew. Chem., Int. Ed. Engl., 25, 554–555. Rozen, S., and Kol, M. (1990) J. Org. Chem., 55, 5155–5159. Golan, E., Hagooly, A., and Rozen, S. (2004) Tetrahedron Lett., 45, 3397–3400. (a) Dayan, S., Bareket, Y., and Rozen, S. (1999) Tetrahedron, 55, 3657–3667; (b) Rozen, S., and Bareket, Y. (1996) J. Chem. Soc., Chem. Commun., 627–628; (c) For MeO: Rosen, S., Mishani, E., and Kol, M. (1992) J. Am. Chem. Soc., 114, 7643–7645. (a) Rozen, S., and Bareket, Y. (1997) J. Org. Chem., 62, 1457–1462; (b) Rozen, S., and Bareket, Y. (1994) J. Chem. Soc., Chem. Commun., 1959. (a) Rozen, S., and Bareket, Y. (1994) Tetrahedron Lett., 35, 2099–2102; (b) Beckerbauer, R., and Smart, B.E. (1995) J. Org. Chem., 60, 6186–6187. Rozen, S., Bareketa, Y., and Blimb, J. (1997) Tetrahedron Lett., 38, 2333–2337. (a) Rozen, S., Bar-Haim, A., and Mishani, E. (1994) J. Org. Chem., 59, 1208–1209; (b) For oxidation of aromatic amines: Kol, M., and Rozen, S. (1991) J. Chem. Soc., Chem. Commun., 567–568; (c) Golan, E., and Rozen, S. (2003) J. Org. Chem., 68, 9170–9172. Rozen, S., and Carmeli, M. (2003) J. Am. Chem. Soc., 125, 8118–8119. Rozen, S., Bareket, Y., and Kol, M. (1993) Tetrahedron, 49, 8169–8178. Rozen, S., Bareket, Y., and Kol, M. (1989) J. Am. Chem. Soc., 111, 8325–8326. Kol, M., and Rozen, S. (1993) J. Org. Chem., 58, 1593–1595.

Chapter 3

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

There are many unique and otherwise difﬁcult reactions that are induced essentially by the strong interaction between ﬂuorine and a special atom. Because of its hardness, ﬂuorine interacts strongly with alkaline and alkaline earth metal ions, and in particular with neutral group III elements. Table 3.1 lists the strengths of chemical bonds between ﬂuorine and other atoms, as a measure for the interaction between ﬂuorine and other atoms [1]. The theoretically calculated ﬂuoride afﬁnity also serves as a measure of interaction between a ﬂuoride ion and an inorganic Lewis acid [2]. Complexation of crown ethers and the corresponding azamacrocycles with metal ions is well known, where heteroatoms in crown molecules strongly coordinate with metal ions to extract metal ions from aqueous to organic phase. Therefore one can imagine that a wellarranged cyclic array of C–F bonds or crown ethers with C–F bonds at proper positions would participate in the coordination of metal ions. This phenomenon was demonstrated by Plenio in 1994 [3]. The crown ether (1) formed a stoichiometric 1:1 metal–ligand complex, which was analyzed by 19 F NMR chemical shift changes. However, no conclusion about the relative or absolute stabilities of the complexes in solution was obtained [3a]. In the solid state, an X-ray structure of the cesium ion (bond angle of C–F–Cs = 161.1◦ ) in the complex of cryptand (2) has been reported [4]. The 19 F–133 Cs spin coupling was observed in 19 F NMR for the complex of cryptand (2), with cesium ion in CDCl3 –CD3 CN at −30◦ C, and the presence of this coupling is evidence of the metal–ﬂuorine interaction [5]. The question is what is the driving force for the complexation of metal ions with the C–F bond, since ﬂuorine is a hard atom and thus has a higher ionization potential than do oxygen and nitrogen, which would weaken the coordination. The coordination ability is dependent on the electron-donating ability ␯D (cm−1 ) of heteroatom molecules. This can be estimated from the CH3 OD IR stretching vibration change on their interacting with CH3 OD [6]. The smaller electron-donating ability ␯D (cm−1 ) and the larger dipole moment of the C–F bond as compared with those of C–O and C–N bonds (Table 3.2) suggest that the C–F–metal interaction arises from a dipole–cation interaction. The potential energy for the metal cation–dipole interaction is estimated by Eq. (1) shown in Scheme 3.1, where ε, Q, and ␮ are permittivity, charge of metal ion, and dipole moment of the C–F bond, respectively [7]. The equation suggests that the C–F bond can interact even with soft metal ions such as silver and thallium and that the interaction would be weakened in a solvent with a high dielectric constant. Therefore, the less polar solvents are useful for C–F–metal interaction controlled stereo- and regioselective reactions [8].

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Table 3.1 Strengths of chemical bonds between ﬂuorine and atom (kcal/mol) H Li Na K Rb Cs

136 138 124 119 118 123

Be Mg Ca Sr Ba

138 110 126 130 140

B Al Ga ln Ti Sm

181 159 138 121 136 135

C Si Ge Sn Pb

132 132 116 112 85

N P As Sb Bi

82 105 98 105 62

O S Se Te

53 82 81

F Cl Br I

38 61 60 65

Table 3.2 Dipole moment ␮ and electron donating ability ␯D

Ph-F (C2 H5 )2 O (C2 H5 )3 N

3.1

␮(D)

␯D (cm−1 )

1.61 1.15 0.77

−15 78 238

Reaction induced by F–Li interaction

Both lithium and ﬂuorine atoms are classiﬁed as hard atoms, and both associate strongly with each other [9]. The Li–F bond strength is 138 kcal/mol, which is comparable with that of the H–F bond (136 kcal/mol) and is slightly stronger than that of the C–F bond (132 kcal/mol). The Li–F interaction seems to be the strongest of the ﬂuorine–alkali metal interactions on simply observing the F–M bond strengths (Na 124, K 119, Rb 118, and Cs 123 kcal/mol, respectively). The lithium ion interacts not only with ﬂuoride ion, but also with a neutral ﬂuorine atom in a carbon–ﬂuorine bond, which is a hard and effective donor, like an oxygen atom in an ether or a carbonyl group. Such Li–F interactions can play a crucial role in controlling the rate and regio- and/or stereochemical outcomes of the reactions of ﬂuoroorganic compounds.

3.1.1

Li–F interaction in aromatic C–F bonds

An example of the Li–F interaction in the solid state of a ﬂuoroaromatic compound is ˚ shown in Scheme 3.2. The two Li–F interatomic lengths are in the range of 2.27–2.39 A, both of which are in between dmin and dmax (see Table 3.3). A bond length threshold up to which CF–metal interactions are credible is summarized in Table 3.3 [10]. The threshold was used in a search for CF–metal interactions in the Cambridge Crystallographic Structure Database. Ab initio calculations on the lithiation of ﬂuorobenzene with lithium hydride predicted that ortho-lithiation would proceed preferentially with a lower activation energy of 6.5 kcal/mol as compared with para-lithiation [11]. The calculation also indicated that the C–F

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

141

Scheme 3.1

Scheme 3.2

bond in ortho-lithiated 7 is lengthened relative to that in para-lithiated 8. The distance ˚ is much shorter that the sum of the van der Waals (vdW) radii of Li–F in 7 (1.901 A) ˚ suggesting that an attractive interaction exists between lithium and ﬂuorine in 7 (3.29 A), (Scheme 3.3). The regioselective ortho-lithiation can be applied to the synthesis of 2,4-diﬂuorobenzoic acid (10) from 1,3-diﬂuorobenzene (9) as shown in Scheme 3.4. The initial lithiation takes place at the most acidic and chelation-stabilized 2-position and then the second lithiation

142

Organoﬂuorine Chemistry

Table 3.3 Metal–ﬂuorine bond parameters Metal

˚ a r ion (A)

˚ b d min (A)

˚ c d max (A)

Li+ Na+ K+ Rb+ Cs+ Ca2+

0.59 1.02 1.51 1.66 1.81 1.06

2.06 2.49 2.98 3.13 3.28 2.53

2.47 3.07 3.47 3.67 3.87 3.13

a

The ionic radius of the metal ion. The sum of the ionic radius of the metal and van der Waals radius of ﬂuorine. c The sum of the van der Waals radius of ﬂuorine and ionic van der Waals radius of the metal. b

Scheme 3.3

occurs at the 4-position after silylation at C-2. The trimethylsilyl group acts as a blocking group for C-2 [12].

Scheme 3.4

The two examples show that the base-catalyzed proton abstraction occurs mostly at the ortho-position, i.e. the most acidic position in ﬂuoroaromatics. However, the assumption has proved incorrect in some cases. Schlosser proposed a concept of “regioselectivity through mechanism-based substrate–reagent matching” [13] (an example is shown in Scheme 3.5).

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

143

Scheme 3.5

In the lithiation of ﬂuoroanisoles (15) and (16) and their derivatives, butyllithium exclusively deprotonates the less acidic protons from the position ortho to the alkoxyl group. On the other hand, deprotonation takes place at the more acidic site, i.e. the ortho-position next to the ﬂuorine substituent on reaction of the substrates with super bases, such as BuLi–tBuOK or BuLi–N,N,N ,N ,N -pentamethyldiethylenetriamine, in which lithium cation is stabilized by chelation in the combined base-system (Scheme 3.5) [14]. The lithium cation interacts preferentially with the more Lewis basic alkoxyl oxygen to locate butyllithium close to the position ortho to the alkoxyl group, enhancing kinetic deprotonation (see 17 in Scheme 3.5). However, the extent of solvent coordination (THF) around lithium sometimes governs the stability and reactivity of the lithium species (Scheme 3.6). Lithium species (18) undergoes benzyne formation to form either 3-ﬂuoro or 3-chlorobenzyne, depending on the concentration of THF in toluene. The less THF-coordinated lithium species (19) favors the additional interaction with ﬂuorine and enhances LiF elimination to produce 3-chlorobenzyne (23), while the fully THF-coordinated lithium species (18) eliminates chloride as a better leaving group to form 3-ﬂuorobenzyne (22) [15].

Scheme 3.6

144

3.1.2

Organoﬂuorine Chemistry

Li–F interaction in aliphatic C–F bonds

Crystallographic analysis of the lithiated 1,3,5-tris(triﬂuoromethyl)benzene (24) revealed that the lithium ion interacts with two ﬂuorine atoms from each ortho-triﬂuoromethyl group to afford a dimer as shown in 27 (see Scheme 3.7). The observed Li–F distances were ˚ which are much shorter than the 3.29 A˚ estimated from the in the range of 2.227–2.293 A, sum of the vdW radii of the two atoms, suggesting a strong interaction between ﬂuorine and lithium [16]. The lithiated species (25) was transformed to other metal species (26) by the lithium–metal exchange reaction with appropriate metal halides [17]. The Li–F coupling (2.4 Hz) was observed in 19 F NMR of Li[Al(OC(Ph)(CF3 )2 )4 ] in solution [18]. However, the fact that the ﬂuorine atoms of all of the triﬂuoromethyl groups interacting with lithium were magnetically equivalent suggests the lability of the lithium ion in solution, which turns out to be a highly active catalyst for carbon–carbon bond formations.

Scheme 3.7

Many Li–F chelation-controlled regioselective reactions have been reported. Chelationcontrolled lithiation can be used for the regioselective trimethylsilylation of triﬂuoromethylated 1-phenylpyrazoles (28) (Scheme 3.8) [19]. For example, lithiation of nontriﬂuoromethylated pyrazole (28) (R1 = R2 = CH3 ) with BuLi (Eq. 3) in THF at 0◦ C takes place at the ortho-position of the phenyl ring to give 30 (78%) preferentially, in which the lithium ion is chelated with N-2 of the pyrazole ring. On the other hand, bistriﬂuoromethylated pyrazole was lithiated exclusively at C-4 with 1.2 equivalents of BuLi to give 29 (95%). Meanwhile, pyrazole (28) (R1 = CH3 , R2 = CF3 ) provided a mixture of 4-TMS (11%) and 2 -TMS 31 (32%), and 28 (R1 = CF3 , R2 = CH3 ) gave 32 (37%). Activation of 4-CH in 29 arises from both increased acidity and stabilization of lithium intermediate (29) by chelation with the ﬂuorine atom of the CF3 group. Similar chelation was observed in ortho-lithiated triﬂuoromethoxybenzene (33). The lithium species seems to be more stable but less reactive as compared with 34 in which two ﬂuorines are conformationally ﬁxed in an unsuitable location for chelation with lithium

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

145

Scheme 3.8

[20]. Therefore, 33 provided a trace amount of ethylene oxide adduct (35), whereas 34 afforded 36 in a satisfactory yield. However, 33 gave adducts with halogens, alkyl halides, aldehydes, and ketones in good to excellent yields. The lithium cation in 33 is unable to participate in Li-coordinated activation of oxirane oxygen for the oxirane ring opening (Scheme 3.9).

Scheme 3.9

2-Bromotriﬂuoromethylbenzene (37) was kinetically lithiated at the less acidic site the 3-position rather than at the more acidic site the 6-position with lithium 2,2,2,2tetramethylpiperidide, a sterically bulky amide at −100◦ C. However, a noteworthy fact is that the lithium species (38) undergoes lithium migration at −75◦ C to form thermodynamically more stable 2-lithio-species (39) (Scheme 3.10)[21].

Scheme 3.10

146

Organoﬂuorine Chemistry

The Li–F chelation is also useful for stereoselective reactions. In particular, chelation between lithium of enolates and a ﬂuorine of a triﬂuoromethyl group results in conformational ﬁxation of substrates, leading to markedly enhanced stereoselection. This concept has often been employed to achieve stereocontrol in ﬂuorinated enolate chemistry. Morisawa reported Li–F chelation-controlled stereoselective ␣-hydroxylation of enolate of 40 [22]. The oxidant approaches from the less hindered side of the Li–F chelated enolate intermediate (41), affording anti-alcohol (42) exclusively (Scheme 3.11). The syn-alcohol (45) was prepared by NaBH4 reduction of ketoester (43) via a reaction course predicted by Felkin–Anh’s model (44).

Scheme 3.11

Reduction of the related ketone (46) afforded syn-alcohol preferentially with NaBH4 , LiAlH4 , red-Al, DIBAL-H, LiBH(Et)3 , and KBH(Bu)3 in ether, but afforded anti-alcohol (48) in particular with AlEt3 –Bu3 SnH in toluene. Triethylaluminum chelates both with carbonyl oxygen and a ﬂuorine of the triﬂuoromethyl group to ﬁx the conformation of the ketone (46) (see 47 in Scheme 3.11), leading to accepting hydride from the opposite side of the methyl group [23]. Stabilization of the lithium enolate by intramolecular chelation with ﬂuorine of the C–F bond has been demonstrated by calculation. The (Z)-enolate (49) of ﬂuoroacetaldehyde is more stable than the (E )-enolate (50) [24]. Likewise, the double ﬂuorine-chelated (Z)enolate (51) of 4,4,4-triﬂuorobutanal is the most stable among the lithium enolates (51–54) [25] (see Table 3.4).

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

147

Table 3.4 Calculated energies for the intramolecular F–Li interaction

1,4-Addition of lithium enolate (56) to triﬂuorocrotonate (55) proceeded smoothly in almost quantitative yields with excellent stereoselectivity. The intramolecular chelation in 57 retards the retro-aldol reaction. On the other hand, nonﬂuorinated crotonate (59) provided 60 in a poor yield because of the faster retro-aldol reaction [26]. The stereochemistry of the chelated intermediate (57) was proven by trapping 57 as its ketenesilylacetal (61). Pd-catalyzed Ireland–Claisen rearrangement of 61 proceeded stereospeciﬁcally to give a single stereoisomer (62), suggesting a rigid control of the three consecutive stereocenters (Scheme 3.12) [27]. The stereochemistry of ␣-alkylation of ester (63) seems to be governed not simply by a steric bulkiness of substituent R, but by stereochemically oriented attack of electrophiles to the chelated intermediates (64). The less bulky ﬂuoromethyl compound provided higher stereoselectivity than did the isopropyl analogue, in spite of the smaller Taft’s steric factor of the CH2 F group (Scheme 3.13) [28]. It can be seen from Table 3.5 that one ﬂuorine in substituent R is good enough to control the stereochemistry for the ␣-alkylation. The Li–F chelation-enabled stereoselective generation of cis-2-lithio-3-CF3 -oxiranes (70) leads to the preparation of CF3 -substituted tetra-substituted oxiranes (67) in a stereoselective manner. The Li–F chelation controlled a stereospeciﬁc SN 2-type replacement of chlorine with alkyl group via 68, followed by stereospeciﬁc oxirane-ring formation via 69, resulting in the formation of 67 in excellent diastereomeric excess (Scheme 3.14) [29].

3.2

The ﬂuorine–aluminum interaction

The ﬂuorine–aluminum bond energy is 159 kcal/mol, which is the second strongest of the ﬂuorine–metal bonds (F–Ba, F–Li, F–Ti, F–Si = 140, 138, 136, 132 kcal/mol, respectively) and so both atoms interact strongly with each other. Bis (2,2,6,6tetramethylpiperidino)aluminum halides (X = Cl, Br, I, and F) have been synthesized

148

Organoﬂuorine Chemistry

Scheme 3.12

Scheme 3.13

by the reactions of lithium 2,2,6,6-tetramethylpiperidide with aluminum halides for 1 (X = Cl, Br, and I) and with AgBF4 for 1 (X = F), respectively, and characterized to ﬁnd whether they are stable as monomers or oligomers. The aluminum compounds with Cl, Br, and I were planar and monomeric as tris(amino)aluminums with bulky amino groups such as Al[N(i Pr)2 ]3 and Al[N(SiMe3 )2 ]3 . The corresponding aluminum ﬂuoride was dimeric, containing a ﬂuoride bridge with Al–F bond lengths of 1.829 and 1.835A˚ as shown in structure 2 (Scheme 3.15) [1].

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

149

Table 3.5 Isolated yields and diastereoselectivities for the alkylation of 57 E -X R CF3 CHF2 CH2 F i-Pr

Steric factors

Mel

PhCH2 Br

Allyl-I

Es

E s

67 (90) 58 (88) 50 (82) 50 (56)

79 (80) 45 (84) 41 (84) 31 (48)

82 (68) 61 (72) 49 (62) 77 (28)

−1.16 −0.67 −0.24 −0.47

−0.78 −0.32 −0.20 −0.48

Scheme 3.14

Scheme 3.15

The strong F–Al interaction sometimes induces the abstraction of ﬂuoride anion from the carbon–ﬂuorine bond, which is not easy because of the strong C–F bond as shown in 3 (Scheme 3.15). Trialkylaluminum reagents are therefore useful for the C–F bond activation. Alkylation at the tertiary carbon of 4 with ketenesilylacetal (5) is such an example (Scheme 3.16) [2]. The C–F bond activation with aluminum reagents has been extensively employed for the synthesis of C-glycosides (8). Benzyl protected 2-ﬂuorogycoside (7) was methylated and cyanated with high ␣-preference under mild conditions [3]. Likewise, alkenyl transfer was

150

Organoﬂuorine Chemistry

Scheme 3.16

achieved with retention of the ene-geometry in a high yield [4]. Amino transfer occurred exclusively in the reaction of 7 with dimethyl(N-allylamino)aluminum, affording 8 in quantitative yields [5]. Starting from ␤-furanosyl ﬂuoride (9), the coupling proceeded with the retention of the conﬁguration at the anomeric center (Scheme 3.17) [6].

Reagent

Condition

X

Yield (%) (␣ : ␤)

AlMe3 AlMe2 CN AlH3 Al(i-Bu)2 CH=CHC6 H13 AlMe2 NHCH2 CH=CH2

Toluene, 0◦ C Toluene, 0◦ C Et2 O, 0◦ C Toluene, 0◦ C CH2 Cl2 , 0◦ C

Me CN H CH=CHC6 H13 NHCH2 CH=CH2

95 (>20:1) 96 (10:1) 90 85 (2.6:1) quant (2:1)

Scheme 3.17

Fluoride-displacement reactions with alkyl aluminum reagents allow the regio- and/or stereoselective alkylation of ﬂuoroorganic compounds. The reaction of diﬂuorinated alkenediol 12 with trialkylaluminum in the presence of CuI2 and LiCl proceeded smoothly in THF at 0◦ C, affording 13 with complete Z-and syn-selectivity (Scheme 3.18). And its reaction with copper reagent Me2 CuLi occurred with lower diastereoselectivity (syn:anti = 2:1 for the Z-isomer) and no alkylation occurred in the absence of CuI·2LiCl [7]. The chelation of aluminum involving both oxygen and ﬂuorine is crucial for rate enhancement [8] and stereocontrol. Coordination between ﬂuorine and aluminum also controls the stereoselective reduction of ␣, ␣-diﬂuoro-␤-hydroxyketones (15). The reduction of 15 with DIBAL-H in THF–hexane

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

151

Scheme 3.18

or Al(i -PrO)3 in benzene provided anti-diols (17) selectively. While, the reduction under zinc chelation conditions with DIBAL-H provided syn-diols preferentially. The transitionstate (16) for the Wagner–Meerwein–Pondorf–Verley reduction of (15) is proposed as shown in Scheme 3.19 [9].

Scheme 3.19

The regioselectivity in ring-opening alkylation of oxirane (18) with trialkylaluminum is highly dependent on the ortho-substituent (X) on the phenyl ring (Scheme 3.20). 2 -Fluorooxirane (18) (X = F) was alkylated exclusively at the terminal carbon to give 2-alcohol (20). On the other hand, nonﬂuorinated oxirane (18) (X = H) produced both regioisomers in an almost 1:1 ratio [10]. The chelated intermediate (19) was proposed on the basis of 13 C NMR analysis. The chemical shifts of C-1 and C-2 indicated strong deshielding (7.3–9.6 ppm), while that of the ﬂuorinated C-2 position indicated slight shielding (1.0 ppm). This NMR result suggests an electron donation from oxygen to ﬂuorine through the bridged aluminum in 19. The same type of trimethylaluminum-promoted ring opening of 3,3,3-triﬂuoropropene oxide (21) with a variety of nucleophiles via 22 has been reported [11]. The stereospeciﬁc (inversion of stereochemistry) substitution of ﬂuorine with amino group has been achieved (Scheme 3.21), where activation of a C–F bond with aluminum reagent plays an essential role for the unique reaction [12].

152

Organoﬂuorine Chemistry

Scheme 3.20

Scheme 3.21

3.3

Reactions induced by F–Si interaction

Because of the availability of a pentacoordinate state for silicon, many interesting silicon molecules with ﬂuorine bridges between silicon atoms have been synthesized and characterized. Both bridged and nonbridged ﬂuorine in 1 [1], 2 [2], 3 [3], and 4 (Scheme 3.22) are spectroscopically equivalent in 19 F and 29 Si NMR. For instance, the 29 Si NMR signal appears at −83.6 ppm as a sextet and the 19 F NMR signal as a sharp singlet at −115.4 ppm, with satellite signals due to two 29 Si nuclei for the bridged ion (4). These spectral data suggest a rapid intramolecular silicon–ﬂuorine ion exchange synchronized with the ring inversion in 4 [4]. Hexakis(ﬂuorodimethylsilyl)benzene (7) shows interesting NMR phenomena in solution. 29 Si NMR shows a triplet at 0◦ C, which does not change into a doublet of doublets at the low temperature limit of toluene-d8 (Figure 3.1), suggesting each silicon interacts with two ﬂuorine atoms equally, although the lengths of the two Si–F bonds in the solid state are signiﬁcantly different (see 8 in Scheme 3.23). It is noteworthy that the 29 Si NMR spectrum of 7 at 55◦ C exhibits a heptet, indicating the silicon interacts with six ﬂuorine

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

153

Scheme 3.22

atoms equally. All the ﬂuorine atoms migrate throughout the ring by a combination of Si–F alternation and free rotation of SiMe2 F groups. It may be said that the ﬂuorine atoms move like a merry-go-round (Scheme 3.23) [5].

3.3.1

Fluoride-ion mediated desilylative alkylations

Because of the available pentacoordinate state for silicon, ﬂuoride ion and neutral ﬂuorine in C–F bonds coordinate much more strongly to tetravalent silicon than to carbon, in spite of the comparable bond strengths of Si–F and C–F (132 kcal/mol). Therefore, most of the ﬂuoride-ion-mediated reactions proceed via high valent silicate intermediates. The synthetic potential of the ﬂuoride-ion-mediated reactions has been exploited in a number

Figure 3.1 29 Si NMR of 7 in toluene-d8 . Reprinted from Ref. [5] with permission from the American Chemical Society.

154

Organoﬂuorine Chemistry

Scheme 3.23

of unique reactions, such as desilylative alkynylation [6], allylation [7], acylmethylation [8], and carboalkoxymethylation [9] with alkynylsilanes, allylsilanes, enol silyl ether, and ketene silyl acetals, respectively (see Eq. 2 in Scheme 3.24). Because of the mild reaction conditions, unstable and thus reactive synthetic intermediates can be elegantly generated by the ﬂuorine-mediated reaction and can undergo C–C bond formation. Some functionalized silanes used for ﬂuoride-ion-mediated desilylative alkylations are shown in Schemes 3.24 and 3.25. Aldol reaction and alkylation of ketones at the ␣-position via enol silyl ethers (11) under neutral conditions are good examples [8]. Ortho-quinodimethane (15) is afforded at room temperature and undergoes [4 + 2] cycloaddition [10]. In contrast, the thermal ring opening of benzocyclobutane requires a much higher temperature (180–190◦ C) [11]. The ﬂuorine-mediated Si–C activation protocol was the preferred method for the formation of tetraﬂuoro-para-quinodimethane (19), which then dimerizes to octaﬂuoro-paracyclophane (20) [12]. Azomethine ylide (22) can be generated from 21 by AgF catalysis and is used for heterocycles syntheses [13]. Triﬂuoroacetimidoyl carbanion equivalent (26) was generated from 24 via intermediate (25) and was stable even at 40–50◦ C, i.e. stable enough to be alkylated with a variety of electrophiles [14] in contrast to the corresponding lithium species unstable at −50◦ C. Lithium in 29 migrates to 30 at temperatures above −50◦ C [15]. ␣-Halo-␣-metal organic species are so unstable that they undergo facile ␣-elimination of the halogen as a result of the halogen–metal interaction (see 34 in Scheme 3.25) and are thus useless for ␣-alkylation. Instead, ␣-halosilanes (31) are effective intermediates for ␣-halocarbanions, which can be alkylated [16]. Triﬂuoromethyl lithium and magnesium have never been employed for synthetic reactions because of their instability. Instead triﬂuoromethyltrimethylsilane (36) has been extensively used as a nucleophilic triﬂuoromethylating reagent [17]. It enables the introduction of a CF3 group into a variety of electrophilic substrates [18]. For example, see 39 in Scheme 3.25 for sulﬁnyl group-directed diastereoselective triﬂuoromethylation [19]. Fluoride-ion-mediated generation of benzyne from silylaryl triﬂates (41) [20] is mild and excellent in chemical yields and so it has been employed for a variety of electrophilic (42) [21], nucleophilic (43) [22], and cycloaddition reactions [23] (Scheme 3.26). N-Phenylations of sulfonamides (44), amines (45) [24], azirines [25], oxazoles [26], pyrroles [27], and imidazoles [28] with benzyne from 41 are also known.

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

Scheme 3.24

155

156

Organoﬂuorine Chemistry

Scheme 3.25

Although the ﬂuoride-mediated generation of carbanion equivalents from silanes is generally applicable, desilylation requires forcing conditions in some cases. For the milder allylation with allyl silanes, bis(allyl)silane (46) has been proposed, where the chelated form (47) enhances generation of allylic anion and thus facilitates an effective allylation of benzaldehyde, otherwise the yield of 48 was very poor (4%) with allyltrimethylsilane [29]. The chelated structure (47) is supported by 19 F NMR observation of the lower ﬁeld shift of TBAF by 4.31 ppm on combining it with 46 in CDCl3 . The concept of biscoordination of ﬂuoride ion with silicon was applied for the cleavage of the carbon–ﬂuorine bond of aliphatic ﬂuorides with lithium naphthalide in the presence of 1,2-bis(trimethylsilyl)benzene (49) [30]. The reaction conditions in the absence of 49 or in the presence of monosilane (trimethylphenylsilane) are useless for the purpose. The C–F bond cleavage occurs probably due to electron transfer from the naphthalide anion to the C–F bond activated by the biscoordination (see 50 in Scheme 3.27).

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

157

Scheme 3.26

Scheme 3.27

Stannylsilane (51) reacts selectively with ﬂuoride ion on the silicon site, generating stannyl anion, which can cleave vinyl and aryl iodides under very mild conditions to give vinyl and aryl anions, respectively. Likewise, other halides and cyanide ions attack selectively at the harder silicon site of 51, chemoselectivity of which can be explained on the basis of HSAB theory. An application of the stannyl anion chemistry for the synthesis of (–)-cephalotaxine (56) via spirocyclization is shown in Scheme 3.28 [31]. The oxidative transformation of alkylsilanes bearing an alkoxyl group as a substituent on silicon to alkanols (Tamao oxidation) has often been employed in the syntheses of natural products because of the mild reaction conditions and retention of conﬁguration (generally, Tamao oxidation requires at least one alkoxy or electron-withdrawing heteroatom group on the central silicon atom, but no alkoxy substituents are needed for the oxidative Si–C

158

Organoﬂuorine Chemistry

Scheme 3.28

bond cleavage of the strained four-membered siletanes) [32, 33]. This reaction also involves F-mediated activation of a Si–C bond [34]. Calculations suggest that the pentacoordinated ﬂuorosilicate (58) lowers activation energy for the nucleophilic attack of hydrogen peroxide to silicon and (59) is stabilized [35]. Stereospeciﬁc synthesis of polyalcohol (64) is shown in Scheme 3.29 [36]. Palladium-catalyzed cross couplings of organoﬂuorosilanes with vinyl [37] and aryl [38] halides and triﬂates are known, where the activation of the Si–C bond by ﬂuoride ion plays an essential role in the coupling. The pentacoordinated ﬂuoroorganic silanes promote the transmetallation to the aryl halide–palladium complexes strongly. At least one ﬂuorine

Scheme 3.29

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

159

Scheme 3.30

substituent is needed on silicon for the reaction, since trimethylalkyl and vinyl silanes are not reactive (Scheme 3.30). The ﬂuorine–silicon interaction is useful for controlling the stereochemistry in the reactions of organosilicon compounds. Nucleophilic substitution of one of the gem-ﬂuorines in diﬂuoroalkene (68) proceeds stereoselectively via an addition–elimination pathway, where the ﬂuorine trans to the (trimethylsilyl)methyl group is replaced with nucleophiles exclusively (Scheme 3.31) [39]. The conformation of the carbanion intermediate (69) was ﬁxed so as to make interaction of the silyl group with ﬂuorine and location of the other ﬂuorine anti to the lobe of lone-pair electrons possible. The through space interaction between silicon and ﬂuorine was supported by the observation of the coupling (J Si−F = 16.4 Hz) between Si–F in 29 Si NMR of ethyl 3-ﬂuoro-2-silylmethyl-3-phenylpropionate. In contrast, LiAlH4 reduction of 2-alkyl-3,3-diﬂuoropropenoate in THF provided a 1:1 stereoisomeric mixture [40].

Scheme 3.31

3.4

Reactions induced by B–F interaction

Boron is one of the hardest atoms and makes the strongest covalent bond (181 kcal/mol, Table 3.1) with ﬂuorine and so the trivalent organic and inorganic boron compounds strongly interact both with ﬂuoride ion and the organic ﬂuorine in carbon–ﬂuorine bonds. The calculated ﬂuoride afﬁnity proposed by Christe et al. [1] is also one of the measures for the interaction between ﬂuoride ion and Lewis acids. Organic boron molecules with multidentate Lewis acidic sites such as (2) and (3) bind strongly with ﬂuoride ion so as to form a pyramidalized chelate (4) (Scheme 3.32). The incorporation of the anion into a medium-sized cyclic structure releases ring strain via the pyramidalization of planar boron centers. It is interesting to see the binding energies of

160

Organoﬂuorine Chemistry

Scheme 3.32

1, 2, and 3 with anions in relation to the role of MAO and B(C6 F5 )3 (5) as catalysts for abstracting hydride or alkide and generating highly reactive carbocation species for oleﬁn polymerization. Table 3.6 lists the binding energies calculated by the Hartree–Fock method, using 3-21G and 6-31 +G∗ basis sets [2]. Binding with hard anions such as hydride, ﬂuoride, and methyl anion results in larger binding energies. In particular, perﬂuorinated cyclic trisborane (3) yields much higher energy (555.3 kJ/mol) on binding with methyl anion than that of tris(pentaﬂuorophenyl)borane (472.7 kJ/mol), a conventional oleﬁn polymerization catalyst [3]. The sensing of ﬂuoride ion is potentially useful for biological and industrial applications. The strong afﬁnity of a boron atom toward ﬂuoride ion is thus useful for the sensing, which can be detected by electrochemical, ﬂuorescent, and colorimetric changes. Katz ﬁrst proposed bidentate 1,8-naphthalenediylbis(dimethylborane) (6) as a ﬂuoride sponge and isolated the ﬂuorodiborate as (Me2 N)3 S+ salt [4]. The bisborane (6) binds ﬂuoride ion much more strongly than does monoborane (9) and so 6 abstracts ﬂuoride ion from 7 instantly on mixing 7 with 6 (Scheme 3.33). It is interesting to see whether boron or silicon binds ﬂuoride ion more strongly in the mixed bidentate ligand (10). The crystal structure (11) revealed boron bound ﬂuoride almost covalently, while silicon interacted weakly with the ion. Meanwhile, in the solution state, the observation of the Si–F coupling as a doublet in 29 Si NMR of the ﬂuoride complex (11) suggested there exists a bonding interaction Table 3.6 Calculated binding energy for anion (kJ/mol) Borane 2 3 5

H−

F−

Cl−

Br−

CH3−

359.0 692.3 —

307.9 595.7 —

107.3 385.4 —

73.1 338.9 —

298.3 555.3 472.4

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

161

Scheme 3.33

between silicon and ﬂuorine [5]. The fact that binding is more favorable with boron than with silicon in 11 is reasonable on the basis of the larger bond energy of B–F than of Si–F, or larger ﬂuorophilicity of boron than of silicon. Complexation of both cation and anion with heterotopic host molecules makes metal halides more soluble in organic solvent. The concept was demonstrated by using 1,3-xylyl[21]crown-6 bearing catecolboronyl moiety on C-2 as a bifunctional Lewis acid–Lewis base host; a stoichiometric amount of KF dissolved in methylene chloride within 4 h with quantitative formation of adduct (12) [6]. This remarkable dissolution of KF in methylene chloride is noteworthy since [18]crown-6 or 1,3xylyl[21]crown-6 itself chelates with at most a trace amount of KF in methylene chloride. The strength of the B–F bond is decisive in the binding process. Tris(9-anthryl)borane (13) is highly sensitive for colorimetric ﬂuoride ion detection (␮M scale) because it is both air- and water-stable due to the steric protection around a bulky anthryl moiety and has an intense orange color due to the extended ␲-conjugation through the boron atom [7]. Once it binds with ﬂuoride ion, it turns colorless since the tetravalent borate (14) no longer has the extended ␲-conjugation, which can be detected readily by eye (Scheme 3.34). The UV–vis absorption changes induced by the addition of TBAF in THF are shown in Fig. 3.2. The functionalized boronic acids (15 and 16) are useful for sensing ﬂuoride ion in aqueous solution. Electrochemical redox is used for the detection of ﬂuoride ion with ferrocenylboronic acid (15) [8] and for ﬂuorescence detection with aminoboronic acid (16) [9]. Molecule (16) can effectively detect concentration of ﬂuoride ion in the range of 5–30 mM, where the ﬂuoride adduct is stabilized by the additional hydrogen bonding with protonated amine at pH 5.5 as shown in structure 17 (Scheme 3.35). Fluoride-ion-promoted B–C bond activation has been employed for transition-metalcatalyzed C–C bond formation. For example, palladium-catalyzed homocoupling of vinyl bromide (18) is mediated by bis(pinacolato)diboron (19), which is activated by ﬂuoride ion

162

Organoﬂuorine Chemistry

Scheme 3.34

Figure 3.2 UV–vis absorption change of 13 upon addition of TBAF. Reprinted from Ref. [7] with permission from the American Chemical Society.

Scheme 3.35

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

163

Scheme 3.36

during the mediatory process (Scheme 3.36) [10]. The original coupling reaction was developed using potassium phenoxide as a promoter [11]. Fluoride ion activates the diboron more efﬁciently than phenoxide. Nucleophilic attack of the diboron–ﬂuoride ion complex to vinyl palladium species produces 2-phenylvinyl boronic ester (23), which is subsequently activated again with ﬂuoride ion and is allowed to react with another vinyl palladium, affording (1E ,3E )-diene (20) as the ﬁnal product. The stereochemistry (1E ,3E ) is totally different from that of the dienes (1Z,3Z) obtained by Burton via homocoupling of 1-bromo-1-ﬂuoroethenylbenzenes mediated by bis(tributyltin) [12]. Cyanuric acid (27) catalyzes stereocontrolled 1,4-addition of alkenylboronic acid (25) to ␣, ␤-unsaturated ketone (26), where the C–C bond formation would proceed via alkenyl ﬂuoro alkoxy borane intermediate [13] (Scheme 3.37).

Scheme 3.37

The strong afﬁnity of boron to ﬂuorine sometimes induces C–F bond cleavage of tertalkyl ﬂuorides and allyl ﬂuorides (29) [14]. The catalytic amount of BF3 etherate (2 mol%) is good enough to cleave the C–F bond in methylene chloride at −20◦ C, generating the corresponding carbocations which then undergo C–C bond formation with enol silyl ethers (30) leading to ␤-alkyl and ␤-allyl ketones (31). Replacement of one of the three ﬂuorine atoms in benzotriﬂuoride (32) with bromine was achieved by the reaction of BBr3 with 32 at reﬂux (Scheme 3.38) [15].

164

Organoﬂuorine Chemistry

Scheme 3.38

Tris(pentaﬂuorophenyl)borane (35) is a powerful Lewis acid with a hard boron center. It interacts strongly with hard Lewis basic centers and abstracts hard anion such as methyl anion and hydride to initiate selective reactions that are otherwise difﬁcult to achieve. The B(C6 F5 )3 -promoted early transition-metal-catalyzed oleﬁn polymerizations are typical reactions [16]. The B(C6 F5 )3 –Ph3 SiH system is useful for hydro-silylation of the carbonyl group, in which the boron of 35 activates the Si–H bond rather than the carbonyl group (see 40 in Scheme 3.39) and reduces even the ester carbonyl group effectively [17]. A number

Scheme 3.39

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

165

of applications of 35 as Lewis acid have been explored [18]. 1,4-Addition of 42 to 41 is one such example (Scheme 3.39).

3.5

Reactions activated by a strong interaction between ﬂuorine and Sm, Yb, Sn, Ti

The strong interaction between samarium and ﬂuorine accelerates electron transfer from Sm(II) to the carbonyl group through chelation of Sm(II) with both ﬂuorine and oxygen atoms (see 1 in Scheme 3.40) [1]. The rate enhancement by o-methoxy-, o-amino-, and o-ﬂuoro groups for the reduction of the carbonyl group of substituted acetophenones is remarkable. In particular, the ortho-ﬂuorine atom enhances the rate most markedly and its rate enhancement is 100 times larger than that exerted by a para-ﬂuorine substituent. The biggest negative entropy of activation was found for o-ﬂuoroacetophenone (−45 cal/mol K) as compared with others (−22, −17, and −32 cal/mol K for o-MeO, o-NH2 , and o-Cl, respectively), suggesting an ordered transition-state structure like 1 for the reaction. The driving force for chelation may arise from the strong bond energy between samarium and ﬂuorine (Sm–F = 135 kcal/mol, Sm–O = 135 kcal/mol, and Sm–Cl = 101 kcal/mol). The model of selective chelation has been extended to the chelation of a ﬂuorine atom involving the triﬂuoromethyl group. Thus, the N-triﬂuoroacetyl group accelerates Sm(II)-promoted N – N bond cleavage of N-triﬂuoroacetylhydrazines (3) remarkably [2]. The reducibility for the N-triﬂuoroacetyl group is comparable with that for the N-benzoyl group. However, the authors claim easy deprotection of the N-triﬂuoroacetyl group of 5 to liberate the free amino group with the retention of the stereochemistry on the chiral carbon bearing the amino group under mild conditions (K2 CO3 in MeOH–H2 O) is useful. A selective activation of the C–F bond by Yb(OTf)3 has been employed in an elegant C–O bond forming reaction for joining ring E and ring H fragments of Ciguatoxin (Scheme 3.41) [3]. The activation of the C–F bond in 8 by ytterbium triﬂate is much more effective than

Scheme 3.40

166

Organoﬂuorine Chemistry

Scheme 3.41

the conventional C–Cl bond activation in 9 by silver ion. Moreover, ␣-ﬂuorosulﬁde (8) is more stable than the chlorosulﬁde (9) and can be handled easily and stored. Fluoride-ion-catalyzed activation of tetravalent stannanes has been employed for organic syntheses. Ligand exchange reactions on iodine (III) of aryl-␭3 -iodanes [4] and bromanes [5] with 1-alkynylsilanes, stannanes, and boranes constitute an efﬁcient method for the synthesis of 1-alkynyl(aryl)-␭3 -iodanes and bromanes (13). Judging from the much stronger Si–F and Sn–F bonds (132 and 112 kcal/mol, respectively), in comparison to the Br–F (60 kcal/mol) bond and the polar nature of the Br–F bond, it seems that coordinative interaction of ﬂuorine in the Br–F bond with tetravalent silicon in 11 and tin in alkynylstannane (15), and subsequent ﬂuorine migration via four-membered cyclic transition states (14) and (15), would be a driving force in the ligand exchange reactions (Scheme 3.42). Fluoride ion activation of aryltrimethylstannane is important for the enantioselective catalytic arylation of aldimine (16) (Scheme 3.43) [6]. Titanium enolates (20) of triﬂuoromethyl ketones (19) are stable and can be alkylated anti-selectively at the ␣-carbon in

Scheme 3.42

Reactions Activated by a Strong Interaction Between Fluorine and Other Atoms

167

Scheme 3.43

contrast to lithium enolates (24), which undergo facile deﬂuorination, although enolates (20) decompose at the higher temperature of −78◦ C [7]. Calculation at the B3LYP/631LAN level reveals the structural differences between titanium (22) and lithium enolates (24) (see Scheme 3.44). The bond angles Ti–O–C in 22 and Li–O–C in 24 are 170.2◦ and 121.9◦ , respectively, suggesting the Ti–O–C is almost linear, while Li–O–C is bent. The Ti–F bond ˚ which is much longer than the sum of the vdW radii of ﬂuorine length in 22 is 3.38 A, ˚ is shorter than ˚ but the Li–F bond length (1.95 A) and ionic radii of titanium (2.10 A), ˚ The bond angle and length in 22 indicate the corresponding sum of the vdW radii (2.08 A). that the Ti–F interaction exists, but is weak, which makes the titanium enolate more stable against deﬂuorination.

Scheme 3.44

The titanium–ﬂuorine bond is extremely polar due to the considerable difference in electronegativity (Ti = 1.3, F = 4.0). The high polarity and strength of the Ti–F bond and the small size of ﬂuorine in diﬂuorobinaphthol titanium catalyst (26) (X = F) create a reasonable asymmetric space and help to activate both the carbonyl oxygen of aldehydes and the carbon–silicon bond of allylsilanes (see 28 in Scheme 3.45) for enantioselective allylation. The catalytic system afforded homoallyl alcohols in high enantioselectivity as compared with the corresponding iso-propoxy catalyst (26) (X = i -PrO) (Scheme 3.45) [8]. Transition-metal-catalyzed C–F bond activations are currently hot topics for further development [9].

168

Organoﬂuorine Chemistry

Scheme 3.45

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34. (a) Tamao, K., Hayashi, T., and Ito, Y. (1991) In A.R. Bassindale and P.P. Gaspar (ed), Frontiers of Organosilicon Chemistry. Royal Society of Chemistry, Cambridge, pp. 197–207; (b) Jones, G.R., and Landais, I. (1996) Tetrahedron, 52, 7599–7662. 35. Mander, M.M., and Norrby, P.-O. (2002) Chem. Eur. J., 8, 5043–5048. 36. Tamao, K., Nakajima, T., Sumiya, R., Arai, H., Higuchi, N., and Ito, Y. (1986) J. Am. Chem. Soc., 108, 6090–6093. 37. Hatanaka, Y., and Hiyama, T. (1989) J. Org. Chem., 54, 270–276. 38. (a) Matsuhashi H., Kuroboshi, M., Hatanaka, Y., and Hiyama, T. (1994) Tetrahedron Lett., 35, 6507–6510; (b) Hatanaka, Y., and Hiyama, T. (1991) Synlett, 845; (c) Hatanaka, Y., and Hiyama, T. (1990) Tetrahedron Lett., 31, 2719–2722. 39. Huang, X.-H., He, P.-Y., and Shi, G.-Q. (2000) J. Org. Chem., 65, 627–629. 40. Watanabe, S., Sugahara, K., Fujita, K., Sakamoto, M., and Kitazume, T. (1993) J. Fluorine Chem., 62, 201–206.

References to Section 3.4 1. Christe, K.O., Dixon, D.A., McLemore, D., Wilson, W.W., Sheehy, J.A., and Boatz, J.A. (2000) J. Fluorine Chem., 101, 151–153. 2. Aldridge, S., Fallis, I.A., and Howard, S.T. (2001) Chem. Commun., 231–232. 3. Deck, P.A., Beswick, C.L., and Marks, T.J. (1998) J. Am. Chem. Soc., 120, 1772–1784. 4. Katz, H.E. (1985) J. Org. Chem., 50, 5027–5032. 5. Katz, H.E. (1986) J. Am. Chem. Soc., 108, 7640–7645. 6. Reetz, M.T., Niemeyer, C.M., and Harms, K. (1991) Angew. Chem., Int. Ed. Engl., 30, 1472–1474. 7. Yamaguchi, S., Akiyama, S., and Tamao, K. (2001) J. Am. Chem. Soc., 123, 11372–11375. 8. Dusemund, C., Samankumara, K.R.A., and Shinkai, S. (1995) J. Chem. Soc., Chem. Commun., 333–334. 9. Cooper, C.R., Spencer, N., and James, T.D. (1998) Chem. Commun., 1365–1366. 10. Eddarir, S., and Rolando, C. (2004) J. Fluorine Chem., 125, 377–380. 11. (a) Takahashi, K., Takagi, J., Ishiyama. N., and Miyaura, N. (2000) Chem. Lett., 126–127; (b) Takagi, J., Takahashi, K., Ishiyama, T., and Miyaura, N. (2002) J. Am. Chem. Soc., 124, 8001–8006. 12. Xu, J., and Burton, D.J. (2002) Tetrahedron Lett., 43, 4565–4567. 13. Hara, S., Shudoh, H., Ishimura, S., and Suzuki, A. (1998) Bull. Chem. Soc. Jpn., 71, 2403–2408. 14. Hirao, K., Fujita, K., Yorimitsu, H., Shinokubo, H., and Oshima, K. (2004) Tetrahedron Lett., 45, 2555–2557. 15. Prakash, G.K.S., Hu, J., Simon, J., Bellew, D.R., and Olah, G.A. (2004) J. Fluorine Chem., 125, 596–601. 16. (a) Piers, W.E., and; Chivers, T. (1997) Chem. Soc. Rev., 26, 345–354; (b) Marks, T.J. (1992) Acc. Chem. Res., 25, 59–65; (c) Yang, X., Stern, C.L., and Marks, T.J. (1991) J. Am. Chem. Soc., 113, 3623–3625. 17. Parks, D.J., and Piers, W.E. (1996) J. Am. Chem. Soc., 118, 9440—9441. 18. (a) Ishihara, K., Hanaki, N., and Yamamoto, H. (1993) Synlett, 127–129; (b) Ishihara, K., Hanaki, N., Funahashi, M., and Yamamoto, H. (1995) Bull. Chem. Soc. Jpn., 68, 1721–1730.

References to Section 3.5 1. Prasad, E., and Flowers, R.A., II (2002) J. Am. Chem. Soc., 124, 6357–6361. 2. Ding, H., and Friestad, G.K. (2004) Org. Lett., 6, 637–640.

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3. Inoue, M., Yamashita, S., and Hirama, M. (2004) Tetrahedron Lett., 45, 2053–2056. 4. (a) Ochiai, M. (2003) In T. Wirth (ed), Topics in Current Chemistry, Vol. 224. Springer, Berlin, p. 5; (b) Stang, P.J. (2003) J. Org. Chem., 68, 2997–3008. 5. Ochiai, M., Nishi, Y., Goto, S., Shiro, M., and Frohn, H.J. (2003) J. Am. Chem. Soc., 125, 15304– 15305. 6. Hayashi, T., and Ishigedani, M. (2000) J. Am. Chem. Soc., 122, 976–977. 7. Itoh, Y., Yamanaka, M., and Mikami, K. (2004) J. Am. Chem. Soc., 126, 13174–13175. 8. Gauthie, D.R., Jr., and Carreira, E.M. (1996) Angew. Chem., Int. Ed. Engl., 35, 2363–2365. 9. For Yb: Deacon, G.B., Forsyth, C.M., and Sun, J. (1994) Tetrahedron Lett., 35, 1095–1098; for Rh: Ishii, Y., Chatani, N., Yorimitsu, S., and Murai, S. (1998) Chem. Lett., 157–158.

Chapter 4

Hydrogen Bonding in Organoﬂuorine Compounds

Hydrogen bondings are of fundamental importance in nature. They determine the higher order structures of proteins and control the dynamic processes of molecular recognition events by DNAs, peptides, and sugar chains. They are also one of the major interactions between pharmaceuticals and their target biomolecules. That is, the hydrogen-bonding properties of the organic molecules directly correlate to the pharmacological activities. Therefore, the inﬂuence of a ﬂuorine atom on the hydrogen-bonding properties is of great interest in the molecular design of pharmaceuticals. In spite of the potential demands in molecular design, the inﬂuence of the ﬂuorine atom toward hydrogen bonding has remained unsolved. In this chapter, we ﬁrst discuss the possibility of organoﬂuorine as a hydrogen-bonding acceptor. Then, some properties of highly acidic proton donors, such as ␤-ﬂuorinated alcohols and amines, and their use in organic reactions are summarized.

4.1

Organoﬂuorine as a hydrogen-bonding acceptor

The question “how good is organic ﬂuorine (ﬂuorine in a C–F bond) as a hydrogen bond acceptor?” [1] still remains unanswered [1–3]. There is no question that the ﬂuoride ion itself acts as a strong hydrogen acceptor to construct one of the strongest hydrogen-bonding systems [4–7]. Metal ﬂuorides also act as hydrogen-bonding acceptors to some extent [8]. Some interactions of organic ﬂuorine with metal species have often been reported and conﬁrmed by NMR J couplings [9, 10]. However, the possibility of the action of organic ﬂuorine as a hydrogen-bonding acceptor is still controversial [1–3]. This situation is due to the ambiguous deﬁnition and scope of the hydrogen bond itself.

4.1.1

Deﬁnition and classiﬁcations of hydrogen bonds

Over the last two decades, there has been a remarkable progress in elucidating hydrogenbonding structures and energies. X-ray diffraction analysis and computational calculation have been employed for estimation of the interactions [4–7]. Interestingly, these highly accurate estimations of the structures and the energies spread the scope of hydrogen bondings; i.e. potential hydrogen bondings have been found in hardly ever imagined hydrogen bonding donor–acceptor pairs such as the C–H· · ·␲ system [11, 12]. This nonconventional category of hydrogen bonding includes C–H· · ·F–C interactions [13–15].

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The hydrogen bondings are currently classiﬁed into three types: “strong” [4] (or “very strong” [6]), “moderate” [4] (“medium” or “strong” [6]), and “weak” hydrogen bonds (Scheme 4.1), although there is no clear cutoff line in the boundaries between them [4–6]. (The data on hydrogen bond systems summarized in Scheme 4.1 have been taken from Ref. [6].)

Scheme 4.1

The strong hydrogen bond is mostly a covalent interaction with shorter bond distance, highly linear A–H· · ·B angle, and high bond energy, e.g. proton sponges and HF complexes. The interactive force of the moderate hydrogen bond consists of a combination of covalent and electrostatic interactions. The bond has a bond distance that is almost the sum of

Hydrogen Bonding in Organoﬂuorine Compounds

175

the van der Waals radii of B and A, and has a moderate bond energy that is similar to that found in alcohols, phenols, and the amides in biological systems. The weak hydrogen bond arises mostly from an electrostatic interaction and thus it has a longer bond distance and a smaller bonding energy, e.g. O–H· · ·F–C and C–H· · ·F–C interactions [6]. The weak hydrogen-bonding system does not exchange its proton and therefore it is no more a genuine hydrogen bond; it is an electrostatic attraction of positive charge on the hydrogen and negative charge on the heteroatom. When one deﬁnes hydrogen bonds broadly, including “weak” ones, then organic ﬂuorine could be considered a hydrogen-bonding acceptor. On the other hand, when one considers orbital interaction (bond path or exchange of the proton) is essential for “genuine” hydrogen bonding, organic ﬂuorine cannot be considered a hydrogen-bonding acceptor. The orbital levels of the lone pairs of the ﬂuorine atom lie at so low a level (i.e. “hard”) that it seems tough to interact with that of soft proton donors [2, 3].

4.1.2

Some examples of O –H · · ·F –C and N –H · · ·F –C hydrogen-bonding systems

Some evidence for a weak hydrogen bond between an O–H· · ·F–C or N–H· · ·F–C system would be a short H· · ·F distance and/or O· · ·F or N· · ·F distance, and an estimated negative charge distribution on the ﬂuorine atom. A spectral analysis of 2-ﬂuorophenol revealed that ˚ is shorter than the s-cis conformer is a stable form in which the distance of OH· · ·F (2.235 A) the sum of the van der Waals radii of ﬂuorine and hydrogen [16]. The distance of OH· · ·F ˚ where the hydroxyl group in tetraﬂuoro-1,4-benzhydroquinone is much shorter (2.02 A), is more acidic. An observation of spin–spin coupling between proton and ﬂuorine by 19 F NMR and/or 1 H NMR would be the most direct and convincing evidence. However, there has been only one report on such H–F spin–spin couplings in the compound 3, and only a few reports described broadening of the spectra. Meanwhile, the interaction of metal with organic ﬂuorine (M· · ·F–C) with spin–spin coupling has often been reported (Scheme 4.2) [10, 17–19]. Dynamic interaction of organic ﬂuorine with a metal species has been summarized well in Ref. [17].

Scheme 4.2

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To date, there has been only one report on the observation of spin–spin coupling between the proton and the organic ﬂuorine of an O–H· · ·F–C system in 3 (Scheme 4.3) [20]. Crystallographic analysis of the compound shows that the angle of F· · ·H–O = 131.6◦ , which lies on the borderline between moderate and weak hydrogen-bonding systems (see Scheme 4.1).

Scheme 4.3

In 1997, Dunitz surveyed comprehensively the possible hydrogen bonds to organic ﬂuorine in crystal structures of small molecules [2]. And, he pointed out only two possible and three potential examples of O–H· · ·F–C hydrogen bonds, which have short enough H· · ·F distances. The one possible intermolecular hydrogen-bonding acceptor is an anion species and thus it has a bigger negative charge not only on the anion center but also on the conjugated organic ﬂuorine atom (Scheme 4.4) [21]. And another is the dimeric ␣-ﬂuoroalcohol (5) (Scheme 4.4) [22].

Scheme 4.4

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177

He also pointed out 12 possible N–H· · ·F–C hydrogen bonds [2]. The hydrogen bond donors (N–H) among these could roughly be classiﬁed into four: N–H of amides (6) (Scheme 4.5), Lewis acid coordinated amine (8), aniline (10), and ammonium (9). Howard et al. showed another hydrazine proton donor (7) [23]. All these have acidic amino protons and thus could protonate negatively charged organic ﬂuorine atoms.

Scheme 4.5

A perﬂuoalkyl group is a sort of electron block and thus a good proton acceptor. Sekiya demonstrated an intermolecular hydrogen bonding between perﬂuorocyclohexane and substituted phenols. The chemical shift of the phenolic hydroxyl group moved to lower ﬁeld in proportion to the ratio of perﬂuorocyclohexane. No chemical shift change was observed in the absence of the ﬂuorocarbon (Figure 4.1) [24].

4.1.3

Some examples on nonconventional hydrogen bonding: C –H · · ·F –C interactions

Spontaneous ionic scission of the C–H bond is rare. Even a C–H moiety activated by neighboring electron-withdrawing groups cannot be cleaved by a weak Lewis base such as organic ﬂuorine. Thus, the C–H· · ·F–C system cannot be a genuine hydrogen bond. Meanwhile, organic hydrogen in a C–H bond has a small positive charge. A large positive charge could be seen in the C–H moiety activated by neighboring electron-withdrawing

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Figure 4.1 Chemical shift change of hydroxyl proton of p-Cl–P when in contact with ﬂuorocyclohexane. ␦H = ␦H ( p-Cl–P in the absence of FCy) – ␦H ( p-Cl–P in the presence of FCy).

groups. Thus, an electrostatic attraction between a positive charge on the acidic hydrogen and a negative charge on the organic ﬂuorine is presumable [18–20, 25]. Recently, a through space H–F coupling was reported (Scheme 4.6) [26]. The coupling seemed to be dominated by the distance between the ﬂuorine atom and the hydrogen. The orbital interaction between these will be a theme of future discussions.

Scheme 4.6

Except for the example shown above, C–H· · ·F–C is understood as an electrostatic attraction (a weak hydrogen bond). Detailed study on the orientation of ﬂuorinated benzenes in the crystal showed that C–H· · ·F–C interactions play an important role in stabilizing speciﬁc crystal packing (Scheme 4.7) [27]. The C–H· · ·F distances observed are in the range ˚ which are comparable to the sum of the van der Waals radii of ﬂuorine and of 2.47–2.65 A, hydrogen. A comparison of the structures of ﬂuorobenzenes with those of the corresponding chloro, bromo, and iodo benzenes proved that the ﬂuorine atom behaves differently from the other halogens. Fluorine seems to form C–H· · ·F–C interactions rather than F· · ·F contacts, whereas the heavier halogens seem to prefer the formation of X· · ·X interactions. Another comparison of 4-ﬂuorophenylacetylene with other 4-halogenated (chloro, bromo, and iodo) phenylacetylenes showed a similar difference in behavior of the ﬂuorine

Hydrogen Bonding in Organoﬂuorine Compounds

179

Scheme 4.7

atom from the other halogens (see Figure 4.2). Fluorine acts as an acceptor of the ethynyl proton, while other halogens do not. Other halogens seemed to aggregate by themselves, and a triple bond acts as a proton acceptor [28].

4.1.4

Summary of organic ﬂuorine as hydrogen-bonding acceptor

The weak hydrogen bonding with organic ﬂuorine acceptors has not been well recognized nor utilized as a product-determining factor. From an energetic point of view, the interaction would potentially be applicable for such a purpose. The estimated hydrogen-bonding energy of the H2 O proton donor with the CH3 F proton acceptor is 2.38 kcal/mol [1], which is comparable to that for selectivity with 95% de [29]. Cooperative and/or additive works of the weak hydrogen-bonding interaction play a crucial role for the determination of crystal and polymer structures [30]. Here again, we should note that the weak hydrogen bonding with organic ﬂuorine is an electrostatic interaction due to its negative charge, and is not a genuine hydrogen bond.

Figure 4.2 Crystal packing of 4-halophenylacetylenes. Packing difference by halogen.

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Organoﬂuorine Chemistry

Thus, it would be a far-reaching interaction rather than a genuine hydrogen bond controlled by the orbital.

4.2

Hydrogen bonding of ␤-ﬂuorinated alcohols, its structural character, and utilization in organic syntheses

Because of the strong electron-withdrawing effect of the ﬂuorine atom, the acidity of ﬂuorinated alcohols increases with the number of ﬂuorine atoms on the ␤-positions. The acidity of 2,2,2-triﬂuoroethanol (TFE; pK a = 11.4 [31]) is comparable to that of alkanethiols (pK a = 10–11 [32]) and the acidity of 1,1,1,3,3,3-hexaﬂuoro-2-propanol (HFIP; pK a = 9.3 [31]) is comparable to that of phenols (pK a = 8–11 [32]). Thus, these ﬂuorinated alcohols can be good proton donors in a hydrogen-bonding system. The ␣ scale of the TFE is 1.51 and that of HFIP is 1.96, which is larger than that of ethanol (0.83), acetic acid (1.12), or water (1.17) [33, 34]. Here, the ␣ scale of solvent hydrogen bond donor acidities describes the ability of the solvent to donate a proton in a solvent–solute hydrogen-bonding system [33]. Meanwhile, ﬂuorinated alcohols cannot be good proton acceptors due to their electrondeﬁcient lone pairs on the oxygen atoms. The ␤ scale of both TFE and HFIP is 0.00, which is apparently smaller than those of ethanol (0.77), ether (0.47), water (0.18), or even toluene (0.11) [33]. Here, the ␤ scale, i.e. the hydrogen-bond acceptor basicity of a solvent, describes the ability to accept a proton (donate an electron pair) in a solute–solvent hydrogen-bonding system [4]. These acidities (pK a [31, 34]), hydrogen-bonding parameters (␣ and ␤ scale Table 4.1 Melting points of β-ﬂuorinated alcohols and their nonﬂuorinated parentsa

a

Catalog Handbook of Fine Chemicals, Aldrich, Milwaukee, 1996.

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Hydrogen Bonding in Organoﬂuorine Compounds

Table 4.2 Some parameters on TFE, HFIP, EtOH, and water Compounds TFE HFIP Ethanol Water

pK a

␣

␤

␣H

␤H

N

N1

11.4 9.3 15.9 15.7

1.51 1.96 0.83 1.17

0.00 0.00 0.77 0.18

0.57 0.77 0.33 0.33

0.18 0.03 0.44 0.38

−2.78 −4.23 0 —

1.23 — 7.44 5.20

[33, 34]), other hydrogen-bonding parameters (␣H and ␤H scale [35]), and nucleophilicities (N [34] and N1 [36]) are summarized in Table 4.2. Table 4.2 shows that TFE and HFIP have high proton-donating ability but small protonaccepting ability or nucleophilicity. However, this description of these ␤-ﬂuorinated alcohols seems inconsistent with the fact that their melting points are higher than those of nonﬂuorinated alcohols (Table 4.1). The most striking example of the cooperative ionic hydrogen-bonding chain was found in the crystals of triﬂuorolactates (Figure 4.3). Every distance between the hydroxyl oxygen of the neighboring molecules was found to be 2.82 A˚ [37, 38]. This distance is short enough to be regarded as a genuine moderate hydrogen bond [4]. This hydrogen-bonding system constructs homochiral association of the molecules not only in the solid state but also in

Figure 4.3 A schematic view of hydrogen-bonding system of isopropyl triﬂuorolactate.

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the liquid state; the compound experienced discrimination of its enantiomeric excess in the course of distillation [25].

4.2.1

Use of TFE and HFIP for protonating agents and/or protonating solvents

Triﬂuoroethanol has been used to denature proteins and to stabilize structures in peptides via protonation. Direct interactions of the triﬂuoroethanol with the peptide chain have been inferred from changes in NMR chemical shift and line width. Site-speciﬁc interaction has not yet been demonstrated experimentally in solution [39, 40]. Neutron diffraction studies on a similar protonation of lysozyme by ethanol indicate that triﬂuoroethanol is likely to bind to the carbonyl oxygen on the main chain of the peptide. It is inferred that such a sitespeciﬁc interacting nature of triﬂuoroethanol resulted in the enhancement of intramolecular hydrogen bonding of the amide group in the peptide to minimize its exposure to the alcohol. A structural transition from ␤-sheet to ␣-helix of the Taiwan cobra poison peptide, which is induced by an interaction of triﬂuoroethanol, has been reported [41]. Details on the effects of triﬂuoroethanol on peptides and proteins are summarized in Ref. [42]. A chiral ␤,␤,␤-triﬂuoro-2-propanol (14) was used for asymmetric protonation of lithium enolate (15) (Scheme 4.8) [43]. The determining factor for the product chirality in this reaction was found to be the chirality of carbinol carbon, but another chirality of the sulﬁnyl sulfur also affects the enantiomeric excess of the product. Thus, a binary chelation of the chiral ﬂuorinated alcohol to the lithium was suggested.

Scheme 4.8

The acidic nature of HFIP was used for deprotection of the DMT group of 17 with acid-sensitive nucleotides (Scheme 4.9) [44]. Similarly, the alcohol was used as the catalytic solvent for Diels–Alder reaction of acid-sensitive acrolein (Scheme 4.9) [45]. ␤-Fluorinated alcohols, TFE and HFIP, have often been used as catalytic solvents for epoxidation reactions under mild conditions [34]. The merit of these ﬂuorinated alcohols is, surely, their resistant nature toward oxidation. Another merit of their use in oxidation reactions has often been said to be their catalytic activities via protonation of an active oxygen species, such as H2 O2 . Experimental and computational studies indicate that the protonated hydrogen peroxide, H3 O2 + , which is generated by the action of H2 O2 with a strong acid, is a very powerful oxidant. In contrast, weak acids such as TFE appear to

Hydrogen Bonding in Organoﬂuorine Compounds

183

Scheme 4.9

Scheme 4.10

participate in the activation of H2 O2 in their nondissociated forms (Scheme 4.10) and activate the oxygenation to a double bond by hydrogen bonding to the oxidant [46]. A computational study on the transition state suggested protonation of an oxygen atom as well as some participation of electrostatic interaction of a negatively charged ﬂuorine atom to the positively charged proton. The cooperative interaction may result in “push–pull” activation of H2 O2 . The TFE- or HFIP-activated H2 O2 oxidant promotes not only epoxidation [34, 47, 48], but also Baeyer–Villiger oxidation [48], oxidation of sulﬁdes to sulfoxide [34, 49], and oxidation of thiols to disulﬁdes [5, 50]. The nature of the weaker nucleophilicity and higher acidity of TFE as compared with ethanol is useful as a solvent for Pd-catalyzed asymmetric hydrogenation of triﬂuoromethylimines [51].

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Organoﬂuorine Chemistry

4.2.2

Use of TFE and HFIP for cation-stabilizing solvents

The highly polar nature of TFE and HFIP enables dissolution of ionic species and ion pairs. Moreover, the low or nonnucleophilic nature as well as low-lying HOMO of the solvents stabilizes cation and radical cation intermediates in the solvents. The stabilization of a cation by an acidic solvent has been considered to be due to the protonation of nucleophilic impurities and thus suppresses their reactivity toward cation species. Therefore, the cation-stabilizing ability has been considered to be proportional to the strength as an acid of the solvent. Meanwhile, the half-life time of aromatic cation radical species in HFIP is a few ten or hundred times longer than that in triﬂuoroacetic acid (TFA) [52]. This is a paradoxical result because TFA is less nucleophilic and a much stronger acid than HFIP. (This would be a future problem to be solved.) In any event, TFE and HFIP are inert to oxidants and anodic oxidation [53]. This property of the ﬂuorinated alcohol solvents has been widely used for mechanistic studies in oxidative reactions as well as organic syntheses [53–58].

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

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27. (a) Thalladi, V.R., Weiss, H.C., Blaser, D., Boese, R., Nangia, A., and Desiraju, G.R. (1998) J. Am. Chem. Soc., 120, 8702–8710; (b) Desiraju, G.R. (2002) Acc. Chem. Res., 35, 565–573. 28. Weiss, H.C., Boese, R., Smith, H.L., and Haley, M.M. (1997) Chem. Commun., 2403–2404. 29. Seyden-Penne, J. (1995) Chiral Auxiliaries and Ligands in Asymmetric Synthesis. Wiley, New York, p. 4. 30. Guru Row, T.N. (1999) Coord. Chem. Rev., 183, 81–100. 31. Hudlicky, M. (1992) Chemistry of Organic Fluorine Compounds, 2 edn. PTR/Prentice Hall, New York, p. 550. 32. Smith, M.B., and March, J. (2001) Advanced Organic Chemistry, 5th edn. Wiley, New York, pp. 329– 331. 33. Kamlet, M.J., Abboud, J.L.M., Abraham, M.H., and Taft, R.W. (1983) J. Org. Chem., 48, 2877–2887. 34. Begue, J.P., Bonnet-Delpon, D., and Crousse, B. (2004) Synlett, 18–29. 35. Smart, B.E. (2001) J. Fluorine Chem., 109, 3–11. 36. Minegishi, S., Kobayashi, S., and Mayr, H. (2004) J. Am. Chem. Soc., 126, 5174–5181. 37. Katagiri, T., and Uneyama, K. (2001) Chem. Lett., 1330–1331. 38. Katagiri, T., Duan, M., Mukae, M., and Uneyama, K. (2003) J. Fluorine Chem., 120, 165–172. 39. Cammers-Goodwin, A., Allen, T.J., Oslick, S.L., McClure, K.F., Lee, J.H., and Kemp, D.S. (1996) J. Am. Chem. Soc., 118, 3082–3090. 40. Kentsis, A., and Sosnick, T.R. (1998) Biochemistry, 37, 14613–14622. 41. Jayaraman, G., Kumar, T.K.S., Arunkumar, A.I., and Yu, C. (1996) Biochem. Biophys. Res. Commun., 222, 33–37. 42. Matthias. B. (1998) Quart. Rev. Biophy., 31, 297–355. 43. Kosugi, H., Hoshino, K., and Uda, H. (1994) Phosphorus, Sulfur, Silicon Relat. Elem., 95/96, 401– 402. 44. Leonard, N.J., and Neelima (1995) Tetrahedron Lett., 36, 7833–7836. 45. Cativiela, C., Garcia, J.I., Mayoral, J.A., and Salvatella, L. (1994) Can. J. Chem., 72, 308–311. 46. de Visser, S.P., Kaneti, J., Neumann, R., and Shalk, S. (2003) J. Org. Chem., 68, 2903–2912. 47. (a) van Vliet, M.C.A., Arends, I.W.C.E., and Sheldon, R.A. (2001) Synlett, 1305–1307; (b) van Vliet, M.C.A., Arends, I.W.C.E., and Sheldon, R.A. (2001) Synlett, 248–250. 48. (a) Neimann, K., and Neumann, R. (2000) Org. Lett., 2, 2861–2863; (b) Kobayashi, S., Tanaka, T., Amii, H., and Uneyama, K. (2003) Tetrahedron, 59, 1547–1552. 49. Ravikumar, K.S., Bonnet-Delpon, D., and Begue, J.P. (1998) Tetrahedron Lett., 39, 3141–3144. 50. Kesavan, V., Bonnet-Delpon, D., and Begue, J.P. (2000) Synthesis, 223–225. 51. Abe, H., Amii, H., and Uneyama, H. (2001) Org. Lett., 3, 313–315. 52. (a) Eberson, L., Hartshorn, M.P., Persson, O., and Radner, F. (1996) Chem. Commun., 2105–2112; (b) Eberson, L., Hartshorn, M.P., and Persson, O. (1995) J. Chem. Soc., Perkin Trans. 2, 1735–1744. 53. (a) Matsumura, Y., Yamada, M., Kise, N., and Fujiwara, M. (1995) Tetrahedron, 51, 6411–6418; (b) Matsumura, Y., Tomita, T., Sudoh, M., and Kise, N. (1994) Tetrahedron Lett., 35, 1271–1274. 54. Kita, Y., Tohma, H., Hatanaka, K., Takeda, T., Fujita, S., Mitoh, S., Sakurai, H., and Oka, S. (1994) J. Am. Chem. Soc., 116, 3684–3691. 55. Kita, Y., Tohma, H., Inagaki, M., Hatanaka, K., and Yakura, T. (1991) Tetrahedron Lett., 39, 4321– 4324. 56. Ciminale, F., Lopez, L., and Farinola, G.M. (1999) Tetrahedron Lett., 40, 7267–7270. 57. Burdisso, M., Gandolﬁ, R., Toma, L., and Oberti, R. (1991) Tetrahedron, 47, 6725–6736. 58. McClelland, R.A., Mathivaqnan, N., and Steenken, S. (1990) J. Am. Chem. Soc., 112, 4857–4861.

Chapter 5

Fluorinated Ligands for Selective Catalytic Reactions

Organometal-promoted catalytic asymmetric reactions have been a central research area for over 20 years. The design and synthesis of highly sophisticated ligands and their application to organic reactions enable homogeneous catalytic asymmetric reactions for the syntheses of complex natural products. Fluorine substituents provide a unique and essential property otherwise difﬁcult to the ligands and thus enhance yield, selectivity, and recyclability in the desired catalytic reactions. This chapter describes an overview of ﬂuorinated ligands, including recent advances.

5.1 5.1.1

Ligands with ﬂuorine-substituted aryl groups Ligands for stereoselective reactions

The right balance between the steric and electronic effects of a ligand is essential for optimizing a selectivity in organometallic catalytic reactions. A sterically bulky triﬂuoromethyl group located in a suitable position in a ligand controls access of reagents to the substrates coordinated to the metal complexes, thus inducing high stereoselection. Likewise, reasonable modiﬁcation of electron deﬁciency or Lewis acidity of the central metal by the ligands enhances the reaction rate and also increases the product selectivity. For instance, incorporation of halogens at the 6,6 -positions of BINOL increases enantioselectivity of the ene reaction by increasing the Lewis acidity of the BINOL-titanium catalysts [1]. OctaﬂuoroBINOL (1) has been found to be much more stable even under both basic and acidic conditions than nonﬂuorinated BINOL, which is racemized in both basic and acidic media [2], suggesting the usefulness of 1 for recycle use. Surprisingly, the ligand (1) is so stable that no racemization was observed even on keeping the aqueous NaOH solution of 1 at 100◦ C for 24 h although replacement of a ﬂuorine atom with a hydroxyl group was observed in a small extent [3]. Octaﬂuorinated BINOL is much more efﬁcient for enantioselective sulfoxidation (75% ee) in CH2 Cl2 than the nonﬂuorinated BINOL (3% ee) (Scheme 5.1) [4]. Interestingly, tetraﬂuorination of one of the two naphthyl rings is good enough to induce an enantioselectivity (80% ee at 0◦ C with catalyst 2; Table 5.1) [5]. A quite strange yet very interesting phenomenon of the stereochemical outcome was observed in asymmetric oxidation of phenyl alkyl sulﬁdes with para-substituted (R,R)-1,2diarylethane-1,2-diol-Ti(IV) catalyst (Scheme 5.2). Both electron-donating (MeO) and, in particular, electron-withdrawing (CF3 ) substituents decreased enantioselectivity, although

187

Fluorinated Ligands for Selective Catalytic Reactions

Scheme 5.1

Table 5.1 Enantioselective sulfoxidation in BINOL/Ti(IV) system Ligand (R)-BINOL (3) (R)-F8 BINOL (1) (R)-F4 BINOL (2) (R)-7-MeO-F3 BINOL (R)-7-t-Bu-F3 BINOL

Scheme 5.2

Time (h)

Yield (%)

ee (%)

42 4.5 2 3 2

69 77 78 49 32

3 75 80 28 27

188

Organoﬂuorine Chemistry

the reason for such a stereochemical outcome is unclear. It is needed to clarify any associated structure of the sulﬁdes with peroxide bound with the metal complex in the transition state so as to evaluate the effect of the ﬂuorine substituent [6]. A mixed catalyst of (R)-1 and nonﬂuorinated (S)-3 improved an enantioselectivity in the ene reaction of ethyl glyoxylate (9) with alkenes dramatically (Scheme 5.3, Table 5.2). The synergistic effect of the mixed ligands of the opposite enantiomers (R)-1 and nonﬂuorinated (S)-3 is interesting and has been discussed in detail [7].

Scheme 5.3

The introduction of electron-withdrawing substituents on the aromatic ring of BINOL highly enhances the Lewis acidity of the metal complex and thus increases the reaction rates and also the stereoselectivity. Achievement of the higher enantioselectivity by introduction of the pentaﬂuoroethyl group on 6- and 6 -positions of BINOL is one of the successful examples for enantioselective hetero Diels–Alder reaction of the rather unreactive 1,3-pentadiene (13). The chiral 6,6 -C2 F5 -BINOL(11c)-zirconium catalyst provided cycloadduct (14) in high yields with excellent enantioselectivities (87–98% ee) (Scheme 5.4, Table 5.3). In contrast, none of the desired products was obtained by the use of unsubstituted BINOL [8], demonstrating the marked efﬁciency of the strong electron-withdrawing group on the 6-position for the asymmetric reaction. This is the ﬁrst example of the enantioselective preparation of trans-2,3-disubstituted 2,3-dihydro-4H-pyranone derivatives by hetero Diels–Alder reaction as a key step. The polymer-supported Zr catalyst (12) is useful for asymmetric aza-Diels–Alder cycloaddition of benzaldehyde imine to Danishefsky diene [9]. The 6-substituted BINOL-Zr(IV) catalyst is useful for the enantioselective anti-preferred aldol reaction of benzaldehyde with ketene silyl thioacetal (15) (Scheme 5.5) [10]. The calculated charge densities on the oxygen atoms of the BINOL derivatives revealed that there is a good correlation between the charge density and the reactivity of 6-substituted BINOL [10]. Brønsted acid assisted chiral Lewis acid catalysts (BLA) are designed for the asymmetric Diels–Alder reaction [11]. Both BLA (17) [11] and (18) [12] were employed in Table 5.2 Enantioselective-ene reaction in BINOL-Ti(IV) system R Ph Ph Me Et c-hex c-pen

Ligand

Yield (%)

ee (%)

(S)-1 (R)-1 + (S)-3 (R)-1 + (S)-3 (R)-1 + (S)-3 (R)-1 + (S)-3 (R)-1 + (S)-3

53 95 57 71 47 59

92 99 99 99 99 99

189

Fluorinated Ligands for Selective Catalytic Reactions

Scheme 5.4

Table 5.3 Enantioselective catalytic hetero Diels–Alder reaction of 13 R Ph Ph 4-MeC6 H4 4-ClC6 H4 PhCH–CH PhCH2 CH2

Scheme 5.5

Ligand

Yield (%)

cis/trans

ee (%)

11a 11e 11c 11c 11c 11c

Trace Quant 93 99 78 68

– 1/12 1/7 1/9 1/7 1/9

– 98 90 97 87 87

190

Organoﬂuorine Chemistry

Scheme 5.6

the enantioselective catalytic Diels–Alder reaction of methacrolein with cyclopentadienes (Scheme 5.6). In some cases, triﬂuoromethylated BLA (18) provided a higher enantioselectivity than 17. It is quite interesting, however, that the absolute conﬁguration of the cycloadduct (21) obtained using 17 is opposite to that of product 24 obtained using 18. Catalysts (25) are the Lewis acid–Lewis base bifunctional catalysts in which Lewis acidAl(III) moiety activates acyl iminium ion and the Lewis base (oxygen of phosphine oxide) does TMSCN, simultaneously (Scheme 5.7). Halogen atoms at the 6-position enhanced both yields and enantioselectivity in Reissert-type cyanation of the imino part of 26. However, the order for the activation is not parallel to the electronegativity of the halogen atoms and, moreover, the strong electron-withdrawing triﬂuoromethyl group provided unexpectedly the worst result for the activation [13]. It is not simple to explain this phenomenon only in terms of the increased Lewis acidity of the metal center. Triﬂuoromethylated BINOLzirconium catalysts (28) for asymmetric hetero Diels–Alder reaction (Scheme 5.8) [14], triﬂuoromethylated arylphosphine-palladium catalyst (32) for asymmetric hydrosilylation (Scheme 5.9) [15], and ﬂuorinated BINOL-zinc catalyst (35) for asymmetric phenylation (Scheme 5.10) [16] are known. The weak coordination of phosphine ligands with palladium enhances enantioselectivity in catalytic asymmetric [4 + 2]cycloaddition of a vinylallene (39) with butadiene [17]. Palladium complex modiﬁed by a ferrocene-derived chiral monophosphine ligand was employed as a template in which the strong electron-withdrawing ﬂuorine substituents on the phenyl ring play an important role for the stereoselection (Table 5.4). The initially formed palladacyclopentene intermediate (41) couples with butadiene before undergoing a ring-ﬂipping stereoisomerization (Scheme 5.11).

Scheme 5.7

Scheme 5.8

Scheme 5.9

192

Organoﬂuorine Chemistry

Scheme 5.10 Table 5.4 Asymmetric Diels–Alder reaction of 39 X H H H H F CF3

Scheme 5.11

Y

Yield (%)

ee (%)

H OMe F CF3 H H

82 30 90 77 74 85

51 40 63 52 71 83

Fluorinated Ligands for Selective Catalytic Reactions

193

Scheme 5.12

Fluorine substituents on the aromatic ring in chiral quaternary ammonium salts also play an important role for the improvement of enantioselectivity in asymmetric alkylations of the Schiff base of glycine esters in an aqueous biphase system. Dolling ﬁrst demonstrated asymmetric methylation of indanone (44) by cinchonidine ammonium salt (43) (Scheme 5.12) [18]. Ooi and Maruoka developed an efﬁcient phase transfer catalyst (46a–e), which consisted of chiral N-spiro ammonium salts with binaphthalene skeleton. 3,3 -(3,4,5Triﬂuorophenyl)ammonium salt (46e) provided a perfect stereoselection in benzylation of benzophenone Schiff base of glycine tert-butyl ester (47) (Scheme 5.13, Table 5.5) [19]. The perfect stereoselective alkylation is applicable for a variety of alkyl bromides in the presence of 1 mol% of the catalyst (46e). Not only monoalkylation but also the consecutive double alkylation of 49 was successful to give 50 in excellent enantioselectivities (Scheme 5.14) [20]. The protocol is useful for the enantioselective aldol reaction of 47 with aldehyde (51) [21] and ␣-imino ester [22], in which catalysts (46f) and (46g) were effective (Scheme 5.15) [23]. Fluorine substitution is obviously valuable for improved enantioselection in the ammonium-catalyzed alkylation in the biphase system. However, it is not clear to estimate which factor, the electronic or steric effect, is more important in each reaction. The remarkable enhancement of both yield and enantioselectivity by the substitution of two phenyl groups on the 3- and 5-position of the phenyl group (R = Ph in 46b and R = 3,5-diphenyl in 46d in Table 5.5) suggests an importance of the steric effect and so the substitution of three ﬂuorine atoms in 3,4,5-triﬂuoro compound (46e) may affect the enantioselection through the steric effect that arises from a Coulombic repulsion between the enolate anion of 47 and the lone pair electrons on ﬂuorine atoms. The related non-spiro quaternary ammonium salt (53) is also usable for asymmetric alkylation of 47 [24]. The preference of the steric effect was also demonstrated by the 1,4-addition of silyl nitronate (54) to cinnamaldehyde (55) where the sterically bulky substituents CF3 and t-Bu provided higher regio-, stereo- (syn/anti), and enantioselectivities (Scheme 5.16, Table 5.6) [25]. The recent advances in the design of atropisomeric diphosphane ligands reveal that the steric property of the ligands is controlled by the dihedral angle ␪ of the biaryl backbone; the narrower dihedral angle seems to provide the higher enantioselectivity [26]. Scheme 5.17 and Table 5.7 indicate a relation between the dihedral angle of ligands (58–62) and the enantioselectivity in asymmetric hydrogenation of triﬂuoro-1,3-diketones (64). The asymmetric hydrogenation with nonﬂuorinated BINAP (58) [27] was unsuccessful for the

194

Organoﬂuorine Chemistry

Scheme 5.13

Table 5.5 Benzylation of 47 with PTC-46a–e 46a–e: R 46a: H 46b: Ph 46c: ␤-Np 46d: 3,5-Ph2 -C6 H3 46e: 3,4,5-F3 -C6 H2

Yield (%)

ee (%)

76 43 95 91 90

73 81 96 98 99

Scheme 5.14

Scheme 5.15

Scheme 5.16

Table 5.6 Effect of substituents on the regio and enantioselectivity of 1,4-addition of silyl nitronate 54 to 55

ee (%) of 56 X 46f 46h 46i 46j 46k

F CF3 Me i-Pr t-Bu

Scheme 5.17

Yield (%)

56/57

syn/anti

syn

anti

98 99 99 98 99

3.1/1 16/1 2.4/1 10/1 19/1

66/34 76/24 67/33 76/24 76/24

41 90 33 88 94

12 52 19 59 74

197

Fluorinated Ligands for Selective Catalytic Reactions

Table 5.7 Comparison of diﬂuorphos and other ligands in the Ru-catalyzed hydrogenation of perﬂuoroalkyldiketones 64

Dihedral angle θ(◦ ) ␲-aciditya Substrate

BINAP

MeO-BIPHEP

SYNPHOS

SEGPHOS

DIFLUORPHOS

86 2017

72 2014

71 2012

67 2016

67 2023

59 76 88

70 81 98

Enantioselectivity of 65 or 66 [ee (%)]

64ab 64bb 64cc

23 44 91

40 57 87

49 63 85

␲-acidity as ␯ (CO) cm−1 of [RhCI (diphosphane)(CO)] complex. The higher the carbonyl stretching frequency, the higher the ␲-acidic character of the phosphane. b Product 65. c Product 66.

a

purpose. Table 5.7 shows that the ee is closely related to the dihedral angle ␪, and not to the ␲acidity of the ligands, that is, it increases as the angle ␪ decreases. However, DIFLUORPHOS (62) provided better ee than SEGPHOS (61) even though the dihedral angles of both ligands were the same. It seems that an atypical combination of a narrow dihedral angle and a stronger electrodeﬁcient character of the ligands works in this catalytic hydrogenation. It is obvious that ﬂuorine or ﬂuoroalkyl modiﬁcation on the aryl moiety of ligands is useful for improving the stereoselectivity, but it is yet unclear which effect, steric or electronic, is preferentially operative in each catalytic reaction.

5.1.2

Ligands for oleﬁn polymerization

Fluorinated ligands have often been employed in oleﬁn polymerization. Fluorine substituents on the aromatic ring in well-reﬁned Kaminsky-type metallocence catalysts for oleﬁn polymerization play an important role in controlling the activity of the catalysts, molecular weight, tacticity, and molecular weight distribution of the polymers [28]. The catalyst (67),

Scheme 5.18

198

Organoﬂuorine Chemistry

Table 5.8 Ethylene polymerization with bis(phenoxyimine) titanium dichloride 68a Catalyst X = 68a 68b 68c 68d 68e 68f 68g a

2-F 4-F 2,6-F2 2,4,6-F3 3,5-F2 3,4,5-F3 2,3,4,5,6-F5

TOFb

Mn /103

Mw /Mn

76 3160 492 1440 19 000 26 500 21 500

13 000 128 000 64 000 145 000 129 000 98 000 424 000

1.06 2.18 1.05 1.25 1.78 1.99 1.13

Toluene (250 mL), cat (0.5–5.0 mmol), MAO (1.25 mmol), 1 or 5 min at 50◦ C. frequency in min−1 atm−1 .

b Turnover

bis[N-(3-tert-butylsalicylidene)anilinato]zirconium(IV) dichloride (Scheme 5.18), exhibited an excellent activity (519 kg PE/mmol × h for Zr-67) in comparison with that (27 kg PE/mmol Zr × h) of Cp2 ZrCl2 /MAO [29]. Table 5.8 shows the effect of the ﬂuorine substituent on the N-phenyl group of phenoxy-imino titanium catalyst (68) and reveals that both meta-substitution and the increased number of ﬂuorine substitutions dramatically increase turnover numbers of the catalysts [30]. The activity enhancement may be attributed to the increased electrophilicity of the active Ti species. Fluorine substituents strongly affect not only enhancement of the catalyst activity, but also molecular weight and molecular weight distribution of the polymers. The titanium catalyst (68) bearing a pentaﬂuorophenyl group with methylaluminoxane (MAO) exhibited living polymerization with ethylene even at 50◦ C to afford high molecular weight polymer (Mw = 423 000) with a narrow molecular weight distribution (Mw /Mn = 1.13; see Table 5.8). The molecular weight is one of the highest and the turnover frequency (TOF) is three orders of magnitude greater than that observed for the living polymerization of ethylene [26]. Noteworthy is the fact that the ortho-ﬂuorine substitution controls highly the living polymerization of ethylene (smaller Mw /Mn in Table 5.8). The livingness with a narrow molecular weight distribution was also observed in the polymerization of propylene by the use of catalysts 68 [31] and 69 [32]. Here, again, ortho-ﬂuorine substitution in catalysts 69b, 69e, 69i, and 69j promoted the living polymerization. The increased number of ﬂuorine substitutions led to higher syndiotacticity [32]. Calculation of the structure of catalyst 68 suggested that the ortho-ﬂuorine substituent and a ␤-hydrogen of the n-propyl group, which represents a model of a growing polymer chain, ˚ which was well within the range of nonbonding were located at a distance of 2.276–2.362 A, ˚ The ﬂuorine–␤-hydrogen interactions, and that the C–H␤ bond was elongated (1.113 A). interaction would disfavor ␤-hydrogen transfer to the titanium center and thus promote the usual chain propagation leading to the living polymerization. Transition metal complexes of bis(phosphane)s with the densely ﬂuorinated aryl groups catalyze polymerization (Scheme 5.19). The electron-withdrawing nature of ﬂuorine substituents makes the ligands and metal complexes electron-deﬁcient and thus provides to the complexes high ␲-acceptor capacity. The catalysts 70a–c convert norbornene (71) to the corresponding polymer much more efﬁciently than do nonﬂuorinated catalysts, DPPE and DPPP-Pd complexes (Scheme 5.19) [33]. The related DPPP-Pd catalysts bearing four m-CF3 substituents on one ligand side activated high ethylene/propylene/CO terpolymerization,

Fluorinated Ligands for Selective Catalytic Reactions

199

Scheme 5.19

affording high activity (13–14 kg/mol Pd × h) and ultra high molecular weight (Mw = 800 000 g/mol) in comparison to the performances with 3-CH3 and 3-F ligands [34].

5.2

Ligands and auxiliaries with ﬂuorinated alkyl groups

A number of aliphatic series of triﬂuoromethylated and perﬂuoroalkylated auxiliaries and ligands have been proposed. Here again, both the strong electron-withdrawing effect and steric bulkiness of the triﬂuoromethyl group play an essential role for rate enhancement and stereocontrol. Since the ﬁrst asymmetric reduction of ketones with chiral borohydrides by Itsuno et al. [1], a number of studies on the asymmetric reduction of ketones with chiral borane reagents have been demonstrated [2]. Corey’s oxazaborolidines are some of the most successful reagents [3]. The effect of ﬂuorine substituents was examined in the asymmetric reduction of acetophenone with LiBH4 by the use of chiral boronates (73) obtained from substituted phenyl boronic acid and tartaric acid [4]. Likewise, 3-nitro, ﬂuorine, and triﬂuoromethyl groups on the 3- or 4-position provided enhanced stereoselection (Scheme 5.20). N-Heptaﬂuorobutyryl oxazaborolidines (76) are excellent catalysts for a novel carbon– carbon bond formation between silyl allenolates (77) and aldehydes, the transition state structure of which is shown in 78 (Scheme 5.21) [5]. The stereoselectivity is dramatically affected by N-substituents on the oxazaborolidine ring as suggested by Corey who proved that the N-substituents control the orientation of boron–aldehyde coordination [6]. Among the N-substituents, perﬂuoroacyl groups provide excellent results, while the acetyl group induces no desired reaction under the same conditions.

200

Organoﬂuorine Chemistry

Scheme 5.20

Scheme 5.21

Asymmetric ketene–aldehydes cycloaddition leading to the enantiomerically enriched ␤-lactones (83) is catalyzed effectively by triﬂuoromethanesulfonylated aluminum Lewis acid (80), which controls the stereochemistry much more efﬁciently than the corresponding tosylated catalyst (Scheme 5.22) [7]. The lactones (83) are useful precursors for the enantiomerically enriched ␤-amino acids (84). The N-Triﬂuoromethanesulfonyl group increases Lewis acidity of (S,S)diazaaluminolidine (85a), which associates with 3-acryloyl-1,3-oxazolidine-2-one conformationally tightly so as to control the preferred one-side access of the diene in the transition state 86 of the reaction of 87 with 88, as shown in Scheme 5.23 [8]. The same catalysts (85a–c) have been employed for asymmetric radical allylation on the quaternary carbon of coumarin derivatives [9]. Highly triﬂuoromethylated diols (90 and 91) have

Fluorinated Ligands for Selective Catalytic Reactions

201

Scheme 5.22

Scheme 5.23

been employed for asymmetric ring-closing metathesis with chiral molybdenum alkylidene complexes where the recovered diene acetate (96) was enantiomerically enriched (84% ee after 90% conversion) (Scheme 5.24) [10]. Steric repulsion between the triﬂuoromethyl group and the acetoxy group destabilizes the intermediate (92) and thus would retard RCM (ring close metathesis) for the (S)-acetate. Triﬂuoromethylamino alcohol (98) [11] is a ligand useful for chiral zinc reagents in which the bulkiness of the triﬂuoromethyl group controls the stereochemistry. Both the asymmetric Reformatsky reaction [12] and ethylation [13] of benzaldehyde are catalyzed by the chiral zinc reagent with 98

202

Organoﬂuorine Chemistry

Scheme 5.24

Scheme 5.25

(Scheme 5.25). Replacement of the CF3 group in 98 with the methyl group sharply decreases the enantioselectivity to less than 50% ee. N,N -Substituted-N,N -ethylenetartramides (101) are more prominent enantioselective allylation reagents than the parent diisopropyltartarate (102) (Scheme 5.26) [14]. Both reaction rate and yield of allylation with N-triﬂuoroethyl borane (101c) are more satisfactory as compared with the corresponding N-benzyl and N-cyclohexylmethyl boranes (101a and 101b), although the stereoselection is comparable among the three reagents.

Fluorinated Ligands for Selective Catalytic Reactions

203

Scheme 5.26

5.3

Fluorinated ligands usable for catalytic reactions in scCO2 and ﬂuorous solvents

One of the current frontiers in synthetic organic chemistry concerns the use of environmentally friendly solvents such as water and supercritical carbon dioxide (scCO2 ) and recyclable solvents such as ﬂuorous solvents and ionic liquids. In particular, homolytic catalytic reactions require rational designs for organometallic complexes soluble in solvents. Perﬂuoroalkyl groups attached to the core ligand molecules have been used for successful modiﬁcation to organometallic catalysts soluble in scCO2 and ﬂuorous solvents. Excellent reviews on homogeneous catalysis in scCO2 [1], ﬂuorous biphase chemistry [2], coordination chemistry of the carbon–ﬂuorine unit in ﬂuorocarbons [3], and ﬂuorous chiral ligands for novel catalytic systems [4] are useful for reference.

References References to Section 5.1 1. Mikami, K., and Shimizu, M. (1992) Chem. Rev., 92, 1021–1050. 2. Kyba, E.P., Gokel, G.W., de Jong, F., Koga, K., Sousa, L.R., Siegel, M.G., Kaplan, L., Sogah, G.D.Y., Cram, D.J. (1977) J. Org. Chem., 42, 4173–4184. 3. (a) Yudin, A.K., Martyn, J.P., Pandiaraju, S., Zheng, J., Lough A. (2000) Org. Lett., 2, 41–44; (b) Chen, Y., Yekta, S., Yudin, A.K. (2003) Chem. Rev., 103, 3155–3211. 4. Martyn, L.J.P., Pandiaraju, S., Yudin, A.K. (2000) Organomet. Chem., 603, 98–104. 5. Yekta, S., Krasnova, L.B., Mariampillai, B., Picard, C.J, Chen, G., Pandiaraju, S., Yidin, A.K. (2004) J. Fluorine Chem., 125, 517–525. 6. Superchi, S., Donnoli, M.I., Rosini, C. (1998) Tetrahedron Lett., 39, 8541–8544. 7. Pandiaraju, S., Chen, G., Lough, A., Yudin, A.K. (2001) J. Am. Chem. Soc., 123, 3850–3851. 8. Yamashita, Y., Saito, S., Ishitani, H., Kobayashi, S. (2002) Org. Lett., 4, 1221–1223.

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Organoﬂuorine Chemistry

9. Kobayashi, S., Kusakabe, K., Ishitani, H. (2000) Org. Lett., 2, 1225–1227. 10. Yamashita, Y., Ishitani, H., Shimizu, H., Kobayashi, S. (2002) J. Am. Chem. Soc., 124, 3292– 3302. 11. (a) Ishihara, K., Yamamoto, H. (1994) J. Am. Chem. Soc., 116, 1561–1562; (b) Ishihara, K., Kurihara, H., Matsumoto, M., Yamamoto, H. (1998) J. Am. Chem. Soc., 120, 6920–6930; (c) Ishihara, K., Kurihara, H., Yamamoto, H. (1996) J. Am. Chem. Soc., 118, 3049–3050. 12. Ishihara, K., Kondo, S., Kurihara, H., Yamamoto, H., Ohashi, S., Inagaki, S. (1997) J. Org. Chem., 62, 3026–3027. 13. Takamura, M., Funabashi, K., Kanai, M., Shibasaki, M. (2000) J. Am. Chem. Soc., 122, 6327–6328. 14. Kobayashi, S., Kusakabe, K., Ishitani, H. (2000) Org. Lett., 2, 1225–1227. 15. Hayashi, T., Hirase, S., Kitayama, K., Tsuji, H., Torii, A., Uozumi, Y. (2000) Chem. Lett., 1272– 1273. 16. Huang, W.-S., Pu, L. (2000) Tetrahedron Lett., 41, 145–149. 17. Murakami, M., Minamida, R., Itami, K., Sawamura, M., Ito, Y. (2000) Chem. Commun., 2293– 2294. 18. Dolling, U.H., Davis, P., Grabowski, E.J.J. (1984) J. Am. Chem. Soc., 106, 446–447. 19. (a) Ooi, T., Kameda, M., Maruoka, K. (1999) J. Am. Chem. Soc., 121, 6519–6520; (b) Ooi, T., Kameda, M., Tannai, H., Maruoka, K. (2000) Tetrahedron Lett., 41, 8339–8342; (c) Ooi, T., Kameda, M., Maruoka, K. (2003) J. Am. Chem. Soc., 125, 5139–5151. 20. Ooi, T., Takeuchi, M., Kameda, M., Maruoka, K. (2000) J. Am. Chem. Soc., 122, 5228–5229. 21. Ooi, T., Taniguchi, M., Kameda, M., Maruoka, K. (2002) Angew. Chem. Int. Ed., 41, 4542–4544. 22. Ooi, T., Kameda, M., Fujii, J., Maruoka, K. (2004) Org. Lett., 6, 2397–2399. 23. Reviews on this subject: (a) Ooi, T., Maruoka, K. (2004) Kagaku to Kogyo (Tokyo, Japan) 57, 711–715 ; (b) Ooi, T., Maruoka, K. (2004) Acc. Chem. Res., 37, 526–533; (c) Maruoka, K., Ooi, T. (2003) Chem. Rev., 103, 3013–3028; (d) Ooi, T., Maruoka, K. (2003) Yuki Gosei Kagaku Kyokaishi (J. Synth. Org. Chem.), 61, 1195–1206. 24. Lygo, B., Allbutt, B., James, S.R. (2003) Tetrahedron Lett., 44, 5629–5632. 25. Ooi, T., Morimoto, K., Doda, K., Maruoka, K. (2004) Chem. Lett., 33, 824–825. 26. (a) Zhang, Z., Qian, H., Longmire, J., Zhang, X. (2000) J. Org. Chem., 65, 6223–6226; (b) Saito, T., Yokozawa, T., Ishizaki, H., Moroi, T., Sayo, N., Miura, T., Kumobayashi, H. (2001) Adv. Synth. Catal., 343, 264–267; (c) Duprat de Paule, S., Jeulin, S., Ratovelomanana-Vidal, V., Genet, J.-P., Champion, N., Dellis. P. (2003) Tetrahedron Lett., 44, 823–826. 27. Jeulin, S., Duprat de Zpaule, S., Ratovelomanana-Vidal, V., Genet, J.-P., Champton, N., Dellis. P. (2004) Angew. Chem. Int. Ed., 43, 320–325. 28. Makio, H., Kashima, N., Fujita, T. (2002) Adv. Synth. Catal., 344, 477–493. 29. (a) Matsui, S., Mitani, M., Saito, J., Tohi, Y., Makio, H., Tanaka, H., Fujita, T. (1999) Chem. Lett., 1263–1264; (b) Matsui, S., Mitani, M., Saito, J., Matsukawa, N., Tanaka, H., Fujita, T. Chem. Lett., 554–555; (c) Matsui, S., Mitani, M., Saito, J., Tohi, Y., Makio, H., Matsukawa, N., Takagi, Y., Tsuru, K., Nitabaru, M., Nakano, T., Tanaka, H., Kashiwa, N., Fujita, T. (2001) J. Am. Chem. Soc., 123, 6847–6849. 30. (a) Saito, J., Mitani, M., Mohri, J., Yoshida, Y., Matsui, S., Ishii, S., Kojoh, S., Kashima, N., Fujita, T. (2001) Angew. Chem. Int. Ed., 40, 2918–2920. 31. Mitani, M., Mohri, J., Yoshida, Y., Saito, J., Ishii, S., Tsuru, K., Matsui, S., Furuyama, R., Nakano, T., Tanaka, H., Kojho, S., Matsugi, T., Kawashima, N., Fujita, T. (2002) J. Am. Chem. Soc., 124, 3327– 3336. 32. Mason, A.F., Tian, J., Hustad, P.D., Lobkovsky, E.B., Coates, G.W., Isr. J. Chem., 42, 301–306. 33. Wursche, R., Debaerdemaeker, T., Klinga, M., Rieger, B. (2000) Eur. J. Inorg. Chem., 2063– 2070. 34. Meier, U.W., Hollmann, F., Thewalt, U., Klinga, M., Leskela, M., Rieger, B. (2003) Organometallics, 22, 3905–3914.

Fluorinated Ligands for Selective Catalytic Reactions

205

References to Section 5.2 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Hirao, A., Itsuno, S., Nakahama, S., Yamazaki, N. (1981) J. Chem. Soc., Chem. Commun., 315–317. Deloux, L., Srebnik, M. (1993) Chem. Rev., 93, 763–784. Corey, E.J., Helal, C.J. (1998) Angew. Chem. Int. Ed., 37, 1986–2012. Suri, J., Vu, T., Hernandez, A. (2002) Tetrahedron Lett., 43, 3649–3652. Li, G., Wei, H.-X., Phelps, B.S., Purkiss, D.W., Kim, S.H. (2001) Org. Lett., 3, 823–826. Corey, E.J., Loh, T.-P., Roper, T.D., Azimioara, M.D., Noe, M.C. (1992) J. Am. Chem. Soc., 114, 8290–8292. (a) Nelson, S.G., Peelen, T.J., Wan, Z. (1999) J. Am. Chem. Soc., 121, 9742–9743; (b) Nelson, S.G., Spencer, K.L. (2000) Angew. Chem. Int. Ed., 39, 1323–1325. Corey, E.J., Sarshar, S., Bordner, J. (1992) J. Am. Chem. Soc., 114, 7938–7939. Murakata, M., Jono, T., Hoshino, O. (1998) Tetrahedron: Asym. 9, 2087–2092. Fujimura, O., Grubbs, R.H. (1998) J. Org. Chem., 63, 824–832. Katagiri, T., Takahashi, S., Fujiwara, Y., Ihara, H., Uneyama, K. (1999) J. Org. Chem., 64, 7323–7329. Fujiwara, Y., Katagiri, T., Uneyama, K. (2003) Tetrahedron Lett., 44, 6161–6163. Katagiri, T., Fujiwara, Y., Takahashi, S., Ozaki, N., Uneyama, K. (2002) Chem. Commun., 986–987. Roush, W.R., Grover, P.T. (1995) J. Org. Chem., 60, 3806–3811.

References to Section 5.3 1. Jessop, P.G., Ikariya, T., Noyori, R. (1999) Chem. Rev., 99, 475–493. 2. (a) Horvath, I.T. (1998) Acc. Chem. Res., 31, 641–650; (b) Hope, E.G., Stuart, A.M. (1999) J. Fluorine Chem., 100, 75–83; (c) Mikami, K. (ed) (2005) Green Reaction Media in Organic Synthesis. Blackwell Publishing Ltd, Oxford. 3. Plenio, H. (1997) Chem. Rev., 97, 3363–3384. 4. Pozzi, G., Shepperson, I. Coord. Chem. Rev., 242, 115–124.

Chapter 6

Fluorine in Drug Designs

A great number of examples have shown that the introduction of a ﬂuorine atom or a ﬂuoro-functional group into an organic molecule induces a dramatic change in its chemical, physical, and also pharmacological properties. The unique properties of ﬂuoroorganic molecules may arise from the greatest electronegativity of the ﬂuorine atom, the largest strength of the carbon–ﬂuorine bond, low polarizability due to the hardness of the carbon– ﬂuorine bond, high lipophilicity of ﬂuoroalkyl and aryl groups, along with the second smallest atomic size of the ﬂuorine atom. These factors are operative singly or sometimes cooperatively to affect the pharmacological properties of the ﬂuorinated molecules. The following examples explain the pharmacological action mechanism of the ﬂuorinated molecules in an organism on the basis of the factors discussed in detail in Chapters 1–4.

6.1

Electron-withdrawing effect

Prostanoids are produced in human internal organs and play a variety of physiological functions in the human body. Pharmacological modiﬁcation of prostanoids by partial ﬂuorination has long been a subject of active investigation to develop novel medicines. Partial ﬂuorination on C-7 or C-10 of prostacyclines (PGI2 ) makes their half-life much longer under the physiological conditions of the human body. Nonﬂuorinated PGI2 is hydrolyzed very fast due to the acid-sensitive enol ether moiety and is converted to the inactive ketone (3). gem-Fluorination on C-7 and C-10 improves the half-lives of 4 [1] and 5 [2] dramatically, as shown in Scheme 6.1. The hydroxyl group on C-15 has long been regarded to be essential for pharmacological activity. However, gem-diﬂuoro-PGF 7 was found to be more potent for the reduction of intraocular pressure [3]. TXA2 (8) is known to be very unstable with a half-life of 30 s; however, 10,10-diﬂuoro-TXA2 (9) can be synthesized as a stable form [4]. The stability of 9 as compared with 8 may be due to rate retardation of ring opening of the acetal moiety of 9 under physiological conditions. The triﬂuoromethyl group also provides possible stability for the hydrolytic metabolism of artemisinin (10)—a potential therapeutic agent for malaria, which is one of the major parasitic diseases in many tropical and subtropical regions, causing more than one million deaths each year. Compound 10 has two acetal functionalities that are labile under physiological conditions. The 10-triﬂuoromethyl artemisinin derivatives (12 and 13) are more active and metabolically more stable than 10 and 11 (Scheme 6.2). The improvement in biological activity of the CF3 compounds could be due to factors such as better hydrolytic stability, higher stability for oxidative metabolism, and higher lipophilic character [5].

Scheme 6.1

Scheme 6.2

208

Organoﬂuorine Chemistry

Fluorination at the C-9 position increases the activity of 9␣-ﬂuorodihydrocortisone (14) (X = F) as compared with nonﬂuorinated cortisone [6]. Fluorine at the C-9 position makes the oxidative metabolism of the 11-hydroxyl group to a carbonyl group slow since it is well known that electron-withdrawing group such as ﬂuorine at the ␤-position deactivates oxidation of alcohols (Scheme 6.3).

Scheme 6.3

The ketones polyﬂuorinated at the ␣-position are profoundly destabilized due to the strong electron-withdrawing nature of the polyﬂuoroalkyl groups and their hydrated forms are mostly more stable (Section 1.2.4). This unique property of polyﬂuorinated ketones is useful for trapping active nucleophilic groups in enzymes, which is the essential action mode for enzyme inhibition. Scheme 6.4 shows a schematic drawing for the action mechanism for serine protease inhibition by oligopeptidyl triﬂuoromethyl ketones. The acceleration for trapping the hydroxyl group in the serine moiety by the triﬂuoroacetyl group and the enhanced stabilization of the intermediate hemiacetal (20) by the triﬂuoromethyl group lead to a remarkable inhibition 103 times more active as compared to the corresponding acetyl compound [7].

Scheme 6.4

Fluorine in Drug Designs

209

A nitro group on the C-6 aryl group of 21 was implicated in potential toxicity upon chronic administration, and so it was replaced with 3,4-diﬂuoro- and 2,4-diﬂuorophenyl groups. Compounds 22 and 23 showed similar binding afﬁnities at the ␣-1a adrenoceptors and antagonism of A-61603-induced contractions in isolated prostate tissue, suggesting that the 3,4-diﬂuoro- and 2,4-diﬂuorophenyl groups act as a bioisostere of an aromatic nitro group (Scheme 6.5) [8].

Scheme 6.5

6.2

Electron-withdrawing effect for lowering basicity of amines

The strong electron-withdrawing effect of ﬂuorine lowers the basicity of amines as discussed in Section 1.2.2. Fluorination at the ␥ -carbon of cyclic amines lowers their basicity by about more than 1 pK a unit, which in turn improves oral bioavailabilities of the amines. An important feature of typical antipsychotic drugs is their relative afﬁnities to serotonin 5-HT2 and dopamine D2 receptors. Fluorination of the piperidine ring of 24 at C-4 increases binding to the 5-HT2 receptor and also its bioavailability (Table 6.1). Additional ﬂuorination at C-6 of the indole ring (compound 27) leads to the further increase in binding and bioavailability and was also effective for blocking metabolism leading to 6-hydroxyindole derivative (26) [9]. Similar oral absorption enhancement by ﬂuorination of amines (30) has been demonstrated by 5-HT1D agonists targeted for the treatment of migraine (Table 6.2) [10].

6.3

␲–␲ Stacking of polyﬂuorinated aromatic rings

The ﬂuorinated aromatic sulfonamides (31) bind tightly to carbonic anhydrase (CA) II enzyme and show their inhibitory activity. The activities K d for ﬂuorinated inhibitors of carbonic anhydrase increase in the order of non-F, 2-F, 2,5-F2 , 3,4,5-F3 , 2,3,5,6-F4 , and 2,3,4,5,6-F5 in 31 (1.8, 0.73, 0.55, 0.55, 0.53, 0.44 nM, respectively). The increased activity is due to their hydrophobicity and speciﬁc contacts between the ﬂuoroaromatic ring and the Phe131 site of the protein [11]. The octanol/water partition coefﬁcients (log P ) measure the hydrophobicity of each compound and increase with the level of ﬂuorine substitution.

210

Organoﬂuorine Chemistry

Table 6.1 Afﬁnity and bioavailability of 3-piperidinylindoles

Indoles

24

25

27

28

29

5-HT2A a

0.99

0.43

0.06

18

3.3

b

F(%)

Poor

18

pK a a Afﬁnities

80

10.4

8.5

at human cloned 5-HT2A receptor. calculated from dosing at 0.5–2 mg/kg iv and po.

b Bioavailability

A 19 F NMR spectrum of the pentaﬂuorobenzyl amide bound to the enzyme shows that the ortho and meta ﬂuorines are shielded in the bound state, relative to their chemical shift when not bound. The NMR data suggest a possible binding conformation as shown in 32 in Scheme 6.6. Such an interaction was also clariﬁed by X-ray crystal structure analysis of isozyme CAII bound with sulfonamide (37) [12]. The ␲–␲-stacking strategy has been Table 6.2 pK a , IC50 , and bioavailabilities of 30

X

Y

Z

pK a

IC50 (nM)

Bioavailability

H F F F

H H F F

CH2 CH2 CH2 OCH2

9.7 8.7 6.7 5.9

0.3 0.9 78 8.5

Poor Good — Good

211

Fluorine in Drug Designs

Scheme 6.6

employed to improve the physiological activity of heterocyclic sulfonamides (37), (38), and (39) to CAII inhibition, which showed a potent reduction of the intraocular pressure in hypertensive rabbits. However, as discussed in Section 2.1, the pentaﬂuorobenzenesulfonyl group is highly reactive toward thiol groups of cysteine, glutathione, and hydroxyl and amino groups involved in proteins [13], which results in severe ocular side effects. One way to overcome this problem is to use 2,3,5,6-tetraﬂuorosulfonyl or pentaﬂuorophenylaminocarbonyl groups instead of the sulfonamide for 38 and 39, respectively [14]. Sulfonamides with these substituents showed excellent inhibition and no attack by thiol (Scheme 6.7 and Table 6.3) [14].

Scheme 6.7

Table 6.3 Carbonic anhydrase II inhibition dataa Compound

34

35

36

R

—

CH3

Ph

Ki (nM)

9

14

17

a Human

cloned isozymes.

37

38

39

1.5

3.6

0.7

212

6.4

Organoﬂuorine Chemistry

Interaction of ﬂuorine in the C–F bond with an electron-deﬁcient center

Fluorine in the carbon–ﬂuorine bond (C–F) interacts with an acidic proton (hydrogen bonding; Chapter 4), metal ions (chelation with metal ions; Chapter 3), and other electrondeﬁcient centers such as the carbon atom of carbonyl and cyano groups. This unique phenomenon has been employed for the binding enhancement of ﬂuoro compounds within the active site of enzymes. In recent developments, X-ray crystallographic analysis revealed the interaction of thrombin inhibitors with a protein backbone as shown in Scheme 6.8 [15]. N-(4-Fluorobenzyl)succinimide derivative (40) showed higher thrombin inhibition activity (4-F, 2-F, 3-F, 4-Cl, and H = 0.057, 0.50, 0.36, 0.19, 0.31 ␮M, respectively). The X-ray crystal analysis of 40 cocrystallized with thrombin showed close contact of the ﬂuorine with both ˚ and an acidic ␣-hydrogen (2.1 A). ˚ N-(4-Fluorobenzyl)succinimide carbonyl carbon (3.5 A) (41), a model compound for the inhibitor (40), crystallized as a dimer form, in which inter˚ between ﬂuorine and the carbonyl carbon was shorter molecular contact distance (2.94 A) ˚ than the sum of the van der Waals radii (3.3 A).

Scheme 6.8

6.5

Metabolic blocking

Benzyl anilino and phenoxy groups in drug molecules are oxidatively metabolized at C-4 to the corresponding 4-hydroxy moieties. The metabolic hydroxylations of aromatic hydrocarbons proceed via oxirane intermediates in which the oxygen comes from molecular oxygen and not from water [16]. Suppression of facile metabolism is necessary to modify drug candidate molecules since it is believed that good activity in an in vivo tumor model for instance would require concentrations of the drug in blood sufﬁcient to provide sustained inhibition for 24 h. Fluorination at the C-4 position is useful for retardation of oxidative metabolism. Because of the electron-withdrawing nature of the ﬂuorine on the aromatic ring, the atom deactivates the aromatic ring toward electrophilic attack (Section 1.2.8) although it controls markedly the regiochemistry of the electrophilic substitution.

Fluorine in Drug Designs

213

4-Aminoquinazoline (42) showed antitumor activity against A431 human tumor xenografts in nude mice and is a lead molecule for the inhibition of epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity, which was a potential for treating human cancer [17]. However, compound 42 is rapidly metabolized with a half-life of 1 h to 4-hydroxy (43) and 3-hydroxymethyl compounds. Fluorination on C-4 enhanced the halflife much longer to maintain high concentration in the blood for 24 h. Compound 44 has a good oral bioavailability and inhibits the growth of a broad range of human solid tumor xenografts [18]. Celecoxib (46) is a COX II inhibitor, which was designed by removing the 4-ﬂuorosubstituent from 45 so as to adjust the half-life to an acceptable level (Scheme 6.9) [19].

Scheme 6.9

6.6

Increased hydrophobicity of ﬂuoroaryl groups

A ﬂuorine atom on the aromatic ring increases the hydrophobicity of a molecule, which affects the stronger binding ability of the molecule to the hydrophobic pocket of the enzyme, and thus enhances the potency. HMG–CoA (3-hydroxy-3-methylglutaryl–coenzyme A, a source of isoprenoids and cholesterols in biosynthesis) reductase (HMGR) catalyzes the

214

Organoﬂuorine Chemistry

Scheme 6.10

cholesterol biosynthesis. Statins 48 are HMGR inhibitors with inhibition constant values in the nanomolar range. The bulky and hydrophobic moieties of compactin and statins occupy the HMG–CoA-binding pocket and part of the binding surface for CoA, and thus block access of the substrate HMG–CoA to HMGR. Crystal structure analyses of the HMGR complexed with statins demonstrated that binding of the ﬂuorophenyl group to the hydrophobic pocket plays an important role in assuming potency [20] (Scheme 6.10). The stronger activity enhanced by similar hydrophobic binding with 4-ﬂuorophenyl substituent was observed in 50 for the inhibition of tumor necrosis factor-␣ production [21] and in 51 for the inhibition of IL-1 [22] (Scheme 6.11).

Scheme 6.11

215

Fluorine in Drug Designs

Table 6.4 pK a , water solubility, ether solubility, and bioactivity of some sulfonamides

CF3 SO2 NH2 52 pK a Water sol. wv% Pether Kd(CAI) (nM)

6.3 >10 0.003 <2

8.9 0.17 0.10 9.3

6.7 0.21 1.08 208

Both high water solubility and lipophilicity are needed to provide the requisite bioavailability for drugs. Triﬂuoromethanesulfonamide (52) is one of the most potent inhibitors of carbonic anhydrase isozyme II (CAII) and is very soluble in water, but it is toxic and less bioavailable. A trial was carried out to increase both these properties by introducing CF2 group into acetazolamide (53), which has been used for glaucoma therapy although it is poorly soluble in water [23]. Table 6.4 shows that the CF2 group provides 53 higher solubility and bioavailability (given as Pether ).

6.7

Mechanism-based design of bioactive molecules

The small size of the ﬂuorine atom induces minimal change in the steric volume and the structural shape of molecules when one of the hydrogen atoms in the molecule is replaced with a ﬂuorine atom. The correct structural volume and shape of molecules are essential for molecular recognition, but the small change in these in the ﬂuorinated molecules allow a living organism to incorporate them as normal necessary substrates. However, the totally different chemical reactivity of the carbon–ﬂuorine bond involved in the ﬂuorinated molecules in comparison with the carbon–hydrogen bond results in unusual metabolism in the living organism, sometimes resulting in inhibition of normal enzyme activity. This phenomenon, which is called “mimic effect,” has often been used for drug design. Figure 6.1

Figure 6.1 iso-Density surface graphics of Tegafur and the corresponding nonﬂuorinated molecule.

216

Organoﬂuorine Chemistry

shows computer graphics of Tegafur and its nonﬂuorinated uracil derivative, both of which look quite similar. The former is an anticancer drug, and the latter is not. Because of the similarity in the shape and volume of 5FU with the normal uracil, it is incorporated into an organism and transformed into the FUTR (5-ﬂuorouridine triphosphate) as a part of ribonucleic acid (false RNA), which behaves differently in a growing cancer cell. Another important action of 5FU is inhibition of deoxythymidine phosphate synthesis, which is essential for biosynthesis of DNA. The dUMP is transformed into deoxythymidine monophosphate (dTMP) by the reaction with folic acid under thymidylate synthetase catalysis conditions. The corresponding ﬂuoro-molecule reacts with folic acid in a similar manner, but further reaction of the intermediate (59) to thymidine is blocked because of the unavailability of hydrogen at the C-5 position (Scheme 6.12) [24].

Scheme 6.12

Triﬂuorothymidine derivatives are expected to also be potent as antiviral agents owing to their irreversible reaction with thymidylate synthetase (Scheme 6.13) [25]. The ␣triﬂuoromethylacrylates are signiﬁcantly reactive toward nucleophiles via an SN 2 addition reaction (see Section 2.2) and so triﬂuorothymidine derivatives (61) react with the nucleophilic groups of enzymes such as thiohydroxyl, hydroxyl, and amino groups. Successive trapping of the amino groups in the enzyme with the diﬂuoromethylene moiety of the intermediate (62) occurs spontaneously to produce a modiﬁed enzyme covalently bound with ﬂuorothymidine, which is inactive to normal enzyme reaction (see Section 2.3 for nucleophilic reaction to diﬂuoroalkenes).

Fluorine in Drug Designs

217

Scheme 6.13

The high reactivity of ﬂuoroalkenes with nucleophiles such as amines has been used for the design of enzyme-trapping agents. The diﬂuoromethylornithine (65) acts as an ornithine decarboxylase inhibitor by the action mechanism shown in Scheme 6.14. Ornithine is one of the sources of spermines and spermidines, both of which are used for DNA packaging in the organism, and it is transformed to putrescine (1,4-diaminobutane) via 70 under catalysis by pyridoxal phosphate. Diﬂuoromethylornithine (65) is transformed to Schiff base (67) similarly and subsequently to ﬂuoroalkene (68) via decarboxylativedeﬂuorination. The active ﬂuoroalkene (68) immediately traps the amino group in the decarboxylase leading to the dead-end adduct (69) for the amine synthesis cycle as shown in Scheme 6.14 (65−→67−→68−→69) [26].

Scheme 6.14

2 -Deoxy-2 -ﬂuoromethylene nucleosides are potential inhibitors of ribonucleoside diphosphate reductase (RDPR), which catalyzes the essential biosynthesis path of deoxyribonucleoside in the DNA synthesis system. Initial hydrogen abstraction at the C-3 position by tyrosyl radical has been proposed for the RDPR catalysis system (see from 71 to 73 in

218

Organoﬂuorine Chemistry

Scheme 6.15) [27]. Meanwhile, the intermediate radical (75) produced from 2 -deoxy-2 ﬂuoromethylene nucleoside (74) would be hydrogenated again via 76 to 77, which would undergo dehydroﬂuorination leading to the ␣, ␤-unsaturated cyclopentenone system (78). The enone form (78) is reactive enough to trap a thiol group on the enzyme, resulting in the dead end to the DNA synthesis system [28]. The existence of the radical intermediates was clariﬁed by detailed ESR analysis.

Scheme 6.15

The terminal ﬂuorooleﬁne group is a useful functionality in the design of mechanismbased enzyme inhibitors [29]. The deﬂuorinative formation of quinone methide intermediates (82) from 80 and their trapping of active enzyme has been proposed as a method for afﬁnity labeling of ␤-glycosidases as shown in Scheme 6.16 [30].

6.8

Fluoroalkenes as isosteres of the amide bond

The use of nonhydrolyzable amide isosteres represents important constituents in peptidomimetics for medicinal and/or biological use since one of the major drawbacks in the use of peptides as therapeutic agents is their rapid degradation by peptidases.

Fluorine in Drug Designs

219

Scheme 6.16

Figure 6.2 Charges calculated using AM1 for the dipeptide Ala-Pro and the related dipeptide alkene isosteres.

Fluoroalkenes have been recognized as one of the possible nonhydrolyzable mimetics of amides on the basis of the similarity of charge distribution of the amide bond with the ﬂuoroalkene moiety (Figure 6.2) [31] and their dipole moments (3.7 and 0.97 D for N-methylacetamide and (E )-2-ﬂuoro-2-butene, respectively) [32]. A comparison of the receptor-binding ability of neuropeptide substance P (SP) with some related isosteres with ﬂuoroalkenyl moiety is shown in Table 6.5, which demonstrates the effectiveness of replacement of the amide bond with ﬂuoroalkenyl moiety [33].

6.9

Summary

The unique chemical and physical properties of the ﬂuorine atom and the ﬂuoro-functional groups, such as the greatest electronegativity of the ﬂuorine atom, the greatest strength of the carbon–ﬂuorine bond, low polarizability due to the hardness of the carbon–ﬂuorine bond, high lipophilicity of ﬂuoroalkyl and aryl groups, along with the second smallest atomic size of the ﬂuorine atom, sometimes provide a molecule with promising biological activity. Recent

220

Organoﬂuorine Chemistry

Table 6.5 Receptor binding of substance P and ﬂuoroalkene isosteres X

IC50 1.3 nM

2 nM Y=F

0.8 nM

Y=H

>10 nM

advances in basic and mechanistic chemistry and science on ﬂuoroorganic compounds and also in synthetic organoﬂuorine chemistry enable us to design mechanism-based potent bioactive compounds [34].

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Chapter 7

Methods for Introduction of Fluorine-Functionality into Molecules (Summary from publications for the last ﬁfteen years)

7.1

Monoﬂuorination

7.1.1 7.1.1.1

Electrophilic reagent: F2 , CsSO4 F, R2 NF, CF3 OF, RCO2 F, ArIF, XeF2 CsSO4

Rozen, S., and Gal, C. (1987) J. Org. Chem., 52, 4928–4933.

Stavber, S., Planinsek, Z., and Zupan, M. (1989) Tetrahedron Lett., 30, 6095–6096.

Stavber, S., and Zupan M. (1990) Tetrahedron, 46, 3093–3100.

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(a) Stavber, S., and Zupan, M. (1990) Tetrahedron Lett., 31, 775–776; (b) Michalski, T.J., Appleman, E.H., Bawman M.K., Hunt, J.E., and Norris, J.R. (1990) Tetrahedron Lett., 31, 6847–6850.

Stavber, S., and Zupan, M. (1991) J. Org. Chem., 56, 7347–7350.

7.1.1.2

XeF2

Stavber, S., Sket, B., Zajc, B., and Zupan, M. (1989) Tetrahedron, 45, 6003–6010.

Huang, X., Blackburn, B.J., Au-Yeung, S.C.F., and Janzen, A.F. (1990) Can. J. Chem., 48, 477–479.

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225

Wnuk, S.F. (1993) Tetrahedron, 49, 9877–9936.

Robins, M.J., Mullah, K.B., Wnuk, S.F., and Dalley, N.K. (1992) J. Org. Chem., 57, 2357–2364.

On the mechanism of activation of XeF2 by hydroxy group on glass-wares: Ramsden, C.A., and Smith, R.G. (1998) J. Am. Chem. Soc., 120, 6842–6843.

Patrick, T.B., Khazaeli, S., Nadji, S., H-Smith, K., and Reif, D. (1993) J. Org. Chem., 58, 705–708.

7.1.1.3

(RSO2 )2 NF

(a) Differding, E., and Lang, R.W. (1989) Helv. Chim. Acta., 72, 1248–1252; (b) Differding, E., and Ruegg, M. (1991) Tetrahedron Lett., 32, 3815–3818; (c) Differding, E., and Wehrli, M. (1991) Tetrahedron Lett., 32, 3819–3822.

(a) Davis, F.A., and Han, W. (1991) Tetrahedron Lett., 32, 1631–1634; (b) Davis, F.A., and Han, W. (1992) Tetrahedron Lett., 33, 2253–2256.

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(a) Resnati, G., and DesMarteau, D.D. (1991) J. Org. Chem., 56, 4925–4929; (b) Resnati, G., and DesMarteau, D.D. (1992) J. Org. Chem., 57, 4281–4284; (c) Xu, Z.-Q., DesMarteau, D.D., and Gotoh, Y. (1991) J. Chem. Soc., Chem. Commun., 179–181.

(a) Padova, A., Roberts, S.M., Donati, D., Marchioro, C., and Perboni, A. (1995) J. Chem. Soc., Chem. Commun., 661–662; (b) Padova, A., Roberts, S.M., Donati, D., Marchioro, C., and Perboni, A. (1996) Tetrahedron, 52, 263–270.

Snieckus, V., Beaulieu, F., and Mohri, K. (1994) Tetrahedron Lett., 35, 3465–3468.

Enders, D., Faure, S., Potthoff, M., and Runsink, J. (2001) Synthesis, 2307–2319.

Boger, D. L., Brunette, S.R., and Garbaccio, R.M. (2001) J. Org. Chem., 66, 5163–5173.

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Iorg, B., and Savignac, P. (2000) Synlett, 561–576; (b) Iorg, B., and Savignac, P. (2002) Synlett, 447–450.

Cabrera, I., and Apple, W.K. (1995) Tetrahedron, 51, 10205–10208.

Yield (%) ee (%)

63 70

<5 35

31 <10

Differding, E., and Lang, R.W. (1988) Tetrahedron Lett., 29, 6087–6090.

R

Yield (%) ee (%)

Me

Et

Bn

69 74

70 72

79 88

Takeuchi, Y., Suzuki, T., Satoh, A., Shiragami, T., and Shibata, N. (1999) J. Org. Chem., 64, 5708–5711.

228

7.1.1.4

Organoﬂuorine Chemistry

Acyl hypoﬂuorites (RCO2 F) X Cl

Cl

H

NO2 CO2 Et

Y H Cl H CH3 Yield (%) 85 80 80 >85

CH3 >85

Rozen, S., and Hebel, D. (1990) J. Org. Chem., 55, 2621–2623.

Habel, D., Kirk, K.L., Cohen, L.A., and Labroo, V.M. (1990) Tetrahedron Lett., 31, 619–622.

(a) Hebel, D., and Rozen, S. (1987) J. Org. Chem., 52, 2588-2590; (b) AcOF in MeCN: Rosen, S., Bareket, Y., and Kol, M. (1993) J. Fluorine Chem., 61, 141–153.

7.1.1.5

CF3 OF

Belanger, P.C., Lan, C.K., Willams, H.W.R., Dutresne, C., and Sheigetz, J. (1988) Can. J. Chem., 66, 1479–1482.

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229

Sekiya A., and Ueda, K. (1990) Chem. Lett., 609–612.

(a) Shellhamer, D.F., Carter, D.L., Chianco, M.C., Harris, T. E., Henderson, R.D., Low, W.S.C., Metcalf, B.T., Willis, M.C., Heasley, V.L., and Chapman, R.D. (1991) J. Chem. Soc., Perkin Trans., 2, 401–403; (b) Zeﬁrov, N.S., Gakh, A.A., Zhdankin, V.V., and Stang, P.J. (1991) J. Org. Chem., 56, 1416–1418.

7.1.1.6

Ar-IF2

Edmunds, J.J., and Motherwell, W.B. (1989) J. Chem. Soc., Chem. Commun., 881–882.

Caddick, S., Motherwell, W.B., and Wilkinson, J.A. (1991) J. Chem. Soc., Chem. Commun., 674–675.

(a) Hara, S., Nakahigashi, J., Ishii, K., Sawaguchi, M., Sakai, H., Fukuhara, T., and Yoneda, N. (1998) Synthesis, 495–496; (b) Review: Sawaguchi, M., Hara, S., and Yoneda, N. (2000) J. Fluorine Chem., 105, 313–317.

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(a) Yoneda, N., and Fukuhara, T. (2001) Chem. Lett., 222–223; (b) Review: van Steenis, J.H., and van der Gen, A. (2002) J. Chem. Soc., Perkin Trans., 1, 2117–2133.

(a) Hara, S., Yamamoto, K., Yoshida, M., Fukuhara, T., and Yoneda, N. (1999) Tetrahedron Lett., 40, 7815–7818; (b) Yoshida, M., Hara, S., Fukuhara, T., and Yoneda, N. (2000) Tetrahedron Lett., 41, 3887–3890; (c) Review for p-Tol-IF2 : Sawaguchi, M., Hara, S., and Yoneda, N. (2000) J. Fluorine Chem., 105, 313–317.

Greaney, M.F., and Motherwell, W.B. (2000) Tetrahedron Lett., 41, 4463–4466 and 4467–4470.

Koen, M.J., Guyader, F.L., and Motherwell, W.B. (1995) J. Chem. Soc., Chem. Commun., 1241–1242.

7.1.1.7

FClO3

Takeuchi, Y., Nagoya, K., and Koizumi, T. (1989) J. Org. Chem., 54, 5453–5459.

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Fujiwara, H., and Takeuchi, Y. (2002) J. Fluorine Chem., 117, 173–176.

7.1.1.8

F-TEDA-BF4 (SelectﬂuorTM )

Banks, R.E. (1998) J. Fluorine Chem., 87, 1–17.

R

–NHCO2 Et –NHAC –OMe Yield (%) ortho/para

88 1/2.3

84 2/1

83 1/2.4

Poss, A.J., and Shia, G.A. (1999) Tetrahedron Lett., 40, 2673–2676.

Chamber, R.D., Parsons, M., Sandford, G., and Bowden, R. (2000) Chem. Commun., 959–960.

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Greedy, B., and Gouverneur, V. (2001) Chem. Commun., 233–234.

(a) Cahard, D., Audouard, C., Plaquevent, J.-C., Toupet, L., and Roques, N. (2001) Tetrahedron Lett., 42, 1867–1869; (b) Takeuchi, Y., Suzuki, T., Satoh, A., Shiragami, T., and Shibata, N. (1999) J. Org. Chem., 64, 5708–5711.

Cahard, D., and Audouard, C. (2000) Org. Lett., 2, 3699–3701.

(a) Umemoto, T., and Tomizawa, G. (1986) Bull. Chem. Soc., Jpn., 59, 3625–3629; (b) Ihara, M., Kai, T., Taniguchi, N., and Fukumoto, K. (1990) J. Chem. Soc., Perkin Trans., 1, 2357–2358; (c) Umemoto,

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T., Fukami, S., Tomizawa, G., Harasawa, K., Kawada, K., and Tomita, K. (1990) J. Am. Chem. Soc., 112, 8563–8575; (d) Umemoto, T., Harasawa, K., Tomizawa, G., Kawada, K., and Tomita, K. (1991) Bull. Chem. Soc., Jpn., 64, 1081–1092; (e) Umemoto, T., Harasawa, K., and Tomizawa, G. (1991) J. Fluorine Chem., 53, 369–386.

Ihara, M., Taniguchi, N., Kai, T., Satoh, K., and Fukumoto, K. (1992) J. Chem. Soc., Perkin Trans., 1, 221–227.

7.1.2

DAST (diethylaminosulfur triﬂuoride) and related reagents

7.1.2.1

(a) Kozikowski, A.P., Fauq. A.H., and Rusnak, J.M. (1989) Tetrahedron Lett., 30, 3365–3368; (b) Kozikowski, A.P., Fauq, A.H., Powis, G., and Melder, D.C. (1990) J. Am. Chem. Soc., 112, 4528– 4531; (c) Cottaz, S., Apparu, C., and Driguez, H. (1991) J. Chem. Soc., Perkin Trans., 1, 2235–2241; (d) Coe, D.M., Parry, D.M., Roberts, S.M. and Storer, R. (1991) J. Chem. Soc., Perkin Trans., 1, 2373–2377; (e) Dellac, C.G., Gosselin, G., and Im bach, I-L. (1991) Tetrahedron Lett., 32, 79–82; (f) Battistini, C., Giordani, A., Ermoli, A., and Franceschi, G. (1990) Synthesis, 900–904; (g) Green, K., and Blum, D.M. (1991) Tetrahedron Lett., 32, 2091–2094; (h) Coe, D.M., Myers, P.L., Parry, D.M., Roberts, S.M., and Storer, R. (1990) J. Chem. Soc., Chem. Commun., 151–153; (i) Murakata, C., and Ogawa, T. (1990) Tetrahedron Lett., 31, 2439–2442; (j) Borthwick, A.D., Biggadike, K., Holman, S., and Mo, C.L. (1990) Tetrahedron Lett., 31, 767–770; (k) Marecek, J.F., and Prestwich, G.D. (1989) Tetrahedron Lett., 30, 5401–5404; (l) Posner, G.H., Cho, C.-G., Anjeh, T.E.N., Johnson, N., Horst, R.L., Kobayashi, T., Okano, T., and Tugawa, N. (1995) J. Org. Chem., 60, 4617–4628; (m) Kuroboshi, M., Yamada, N., Takabe, Y., and Hiyama, T. (1995) Tetrahedron Lett., 36, 6271–6274;

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(n) Matsumura, Y., Wang, S.-Z., Shimada, T., Morizawa, Y., and Yasuda, A. (1995) Synlett, 260–262; (o) Zhu, G.-D., Haver, D.V., Jurriaans, H., and DeClercq, P.J. (1994) Tetrahedron, 50, 7049–7066; (p) Kozikowski, A.P., Powis, G., Fauq, A.H., Tuckmantel, W., and Gallegos, A. (1994) J. Org. Chem., 59, 963–971.

(a) Heckmap, B.M. Veeneman, G.H., van der Marel, G.A., van Beckel, C.A.A., and van Boom, J.H. (1995) Tetrahedron, 51, 5657–5670; (b) Ballereau, S., Guedat, P., Spless, B., Rehnberg, N., and Schlewer, G. (1995) Tetrahedron Lett., 36, 7449–7450; (c) Canfarini, F., Giolitti, A., Guide A., Pasqui F., Pestellini, V., and Arcamone, F. (1993) Tetrahedron Lett., 34, 4697–4700.

Guest, A.W., Milner, P.H., and Southgate, S. (1989) Tetrahedron Lett., 30, 5791–5794.

(a) Kuroboshi, M., and Hiyama, T. (1990) Chem. Lett., 1607–1610; (b) Geld, M.H., Lin, Y., Pickard, M.A., Song, Y., and Vederas, J.C. (1990) J. Am. Chem. Soc., 112, 4923–4942; (c) Hudlicky, M., and Merola. J.S. (1990) Tetrahedron Lett., 31, 7403–7406; (d) Buckle, D.R., Houge-Frydrych, C.S.V., Pinto, I.L., Smith, D.G., and Tedder, J.M. (1991) J. Chem. Soc., Perkin Trans., 1, 63–70; (e) Kiegiel, J., Wovkulich, P.M., and Uskokovic, M.R. (1991) Tetrahedron Lett., 32, 6057–6060; (f) Buist, P.H., and Adeney, R.A. (1991) J. Org. Chem., 56, 3449–3452.

(a) Kusumoto, T., Hanamoto, T., Sato, K., Hiyama, T., Takahara, S., Shoji, T., Osawa, M., Kuniyama, T., Nakamura, K., and Fujisawa, T. (1990) Tetrahedron Lett., 31, 5343–5344.

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Gharbaui, T., Legraverend, M., Ludwig, O., Bisagni, E., Aubertin, A-M., and Chertanova, L. (1995) Tetrahedron, 51, 1641–1652.

Gree, D.M., Kermarrec, J.M., Martelli, J.T., Gree, R.L., Lellouche, J-P., and Toupet, L.J. (1996) J. Org. Chem., 61, 1918–1919.

Jeong, L.S., and Marquet, V.E. (1995) Chem. Lett., 301–302.

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Hann, G.L., and Sampson, P. (1989) J. Chem. Soc., Chem. Commun., 1650–1651.

Kuroboshi, M., Furuta, S., and Hiyama, T. (1995) Tetrahedron Lett., 36, 6121–6122.

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Xu, Y., and Prestwich, G.D. (2002) J. Org. Chem., 67, 7158–7161.

Bildstein, S., Ducep, J.B., Jacobl, D., and Zimmermann, P. (1995) Tetrahedron Lett., 36, 5007–5010.

Aghmiz, M., L., Diaz, Y., Jana, G.H., Matheu, M.I., Echarri, R., Castillon, S., and Jimeno, M.L. (2001) Tetrahedron, 57, 6733–6743.

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7.1.2.3

RS(O)n –CH2 R −→ RS(O)n –CHFR

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Robins, M.J., and Wnuk, S.F. (1993) J. Org. Chem., 58, 3800–3801.

238

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Deoxoﬂuor: [(CH3 OCH2 CH2 )2 N-SF3 ]

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Singh, R.P., and Shreeve, J.M. (2002) J. Fluorine Chem., 116, 23–26.

Singh, R.P., Twamley, B., Majumdar, U., and Shreeve, J.M. (2001) J. Org. Chem., 66, 6263–6267.

Doi, M., Nishi, Y., Kiritoshi, N., Iwata, T., Nago, M., Nakano, H., Uchiyama, S., Nakagawa, T., Wakamiya, T., and Kobayashi, Y. (2002) Tetrahedron, 58, 8453–8459.

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Mase, T., Houpis, I.N., Akao, A., Dortiotis, I., Emerson, K., Hoang, T., Iida, T., Itoh, T., Kamei, K., Kato, S., Kato, Y., Kawasaki, M., Lang, F., Lee, J., Lynch, J., Maliares, P., Molina, A., Nemoto, T., Okada, S., and Beamer, R. (2001) J. Med. Chem., 66, 6775–6786.

7.1.4

Ring opening of epoxide

(a) HF-SbF5 : Berrier, C., Jacquesy, J.C., Jouannet, M.P., and Vidal, Y. (1990) Tetrahedron, 46, 815–826; (b) (i -Pr)2 NH(HF)3 : Takano, S., Yanase, M., and Ogasawara, K. (1989) Chem. Lett., 30, 1689–1690; Muehlbacher, M., and Poulter, C.D. (1988) J. Org. Chem., 53, 1026–1030; (c) HFPy: Sutherland, J.K., Watkins, W.J., Baiky, J.P., Chapman, A.K., and Daves, G.H. (1989) J. Chem. Soc., Chem. Commun., 1386–1387; Suga, H., Hamatani, T., and Schlosser, M. (1990) Tetrahedron, 46, 4247–4254; (d) KHF2 -TBAH2 F3 : Landini, D., and Penso, M. (1990) Tetrahedron Lett., 31, 7209–7212.

(a) Kanemoto, S., Shimizu, M., and Yoshida, H. (1987) Tetrahedron Lett., 28, 663–666; (b) Kanemoto, S., Shimizu, M., and Yoshida, H. (1989) Bull. Chem. Soc., Jpn., 62, 2024–2031.

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7.1.5

Haloﬂuorination

Shimizu, M., Nakahara, Y., and Yoshioka, H. (1989) J. Chem. Soc., Chem. Commun., 1881–1882.

Alvernhe, G., Anker, D., Laurent, A., Haute, G., and Beguin, C. (1988) Tetrahedron, 44, 3551–3563.

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Eddarir, S., Mestdagh, H., and Rolando, C. (1991) Tetrahedron Lett., 32, 69–72.

(a) Alvernhe, G., Laurent, A., and Haute, G. (1987) Synthesis, 562–564; (b) Suga, H., Hamatani, T., Guggisberg, Y., and Schlosser, M. (1990) Tetrahedron, 46, 4255–4260; (c) Suga, H., Hamatani, T., and Schlosser, M. (1990) Tetrahedron, 46, 4247–4254.

Shellhamer, D.F., Horney, M.J., Pettus, B.J., Pettus, T.L., Stringer, J.M., and Heasley, V.L. (1999) J. Org. Chem., 64, 1094–1098.

Barrier, C., Jacquesy, J.C., Jouannetand, M.P., and Vidal, Y. (1990) Tetrahedron Lett., 46, 815–826.

Shimizu, M., Okamura, M., and Fujisawa, T. (1991) Bull. Chem. Soc. Jpn., 64, 2596–2598.

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(a) Tomoda, S., and Usuki, Y. (1989) Chem. Lett., 1235–1236; (b) Usuki, Y., Iwaoka, M., and Tomoda, S. (1992) Chem. Lett., 1507–1510; (c) Saluzzo, C., Alvernhe, G., and Anker, D. (1990) Tetrahedron Lett., 31, 663–666; (d) McCorthy, J.R., Matthems, D.R., and Barney, C.L. (1990) Tetrahedron Lett., 31, 973–976.

(a) Uneyama, K., and Kanai, M. (1990) Tetrahedron Lett., 31, 3583–3586; (b) Lermontov, S.A., Zavorin, S.I., Pushin, A.N., Chekhlov, A.N., Zeﬁrov, N.S., and Stang, P.J. (1993) Tetrahedron Lett., 34, 703– 706.

Poleschner, H., Heydenreich, M., Sprinder, K., and Haufe, G. (1994) Synthesis, 1043–1049; Saluzzo, C., Alvernhe, G., Anker, D., and Haufe, G. (1990) Tetrahedron Lett., 31, 2127–2130.

Laali, K.L., Fiedlera, W., and Regitz, M. (1997) J. Chem, Soc., Chem. Commun., 1641–1642.

Lermontov, S.A., Zavorin, S.I., Bakhtin, I.V., Pushin, A.N., Zeﬁrov, N.S., and Stang, P.J. (1998) J. Fluorine Chem., 87, 75–83.

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243

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Laurent, E., Lefranc, H., and Tardivel, R. (1984) Nouv. J. Chim., 8, 345–348.

Ventalon, F.M., Faure, R., Laurent, E.G., and Marquet, B.S. (1994) Tetrahedron: Asymmetry, 5, 1909– 1912.

Suda, K., Hotoda, K., Aoyagi, M., and Takanami, T. (1995) J. Chem. Soc, Perkin Trans., 1, 1327–1329.

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(a) Laurent, E., Marquet, B., Tardivel, R., and Thiebault, H. (1987) Tetrahedron Lett., 28, 2359–2362; (b) Kabore, E., Chebli, S., Faure, R., Laurent, E., and Marquet, B. (1990) Tetrahedron Lett., 31, 3137– 3140.

Brigaud, T., and Laurent, E. (1990) Tetrahedron Lett., 31, 2287–2290.

Hanack, M., and Wilhelm, B. (1989) Angew. Chem., Int. Ed. Engl., 28, 1057–1058.

R t-Bu, n-Pen, 3-Hex, Cyclohex 66%

70%

89%

84%

Yoneda, N., Chen, S.-Q., Hatakeyama, T., Hara, S., and Fukuhara, T. (1994) Chem. Lett., 849–850.

Fuchigami, T., Fujita, T., and Konno, A. (1994) Tetrahedron Lett., 35, 4153–4156.

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7.1.8

245

Nucleophilic reagent

Metal F

Yield (%)

Cs

Rb

K

Na

Li

67

40

37

0

0

Gorgues, A., Stephan, D., and Cousseau, J. (1989) J. Chem. Soc., Chem. Commun., 1493–1494.

Langa, U., and Senning, A. (1991) Chem. Ber., 124, 1879–1880.

Langhals, E.F. (1994) Tetrahedron: Asymmetry, 5, 981–986.

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Pilcher, A.S., Ammon, H.L., and Deshong, P. (1995) J. Am. Chem. Soc., 117, 5166–5167.

7.1.9

TASF [(Me2 N)3 S]+ [ Me3 SiF2 ]−

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Omotowa, B.A., and Shreeve, J.N.M. (2000) Organometallics, 19, 2664–2670.

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Galow, T.H., Rodrigo, J., Cleary, K., Cooke, G., and Rotello, V.M. (1999) J. Org. Chem., 64, 3745–3746.

7.1.10

Schiemann reaction

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(a) Kanakarajan, K., Halder, K., and Czarnik, A.W. (1998) Synthesis, 566–568; (b) Haroutounian, S.A., Dizio, J.P., and Katzenellenbogen, J.A. (1991) J. Org. Chem., 56, 4993–4996.

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7.1.11

Others

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De Meio, G.V., and Pinhey, J.T. (1990) J. Chem. Soc., Chem. Commun., 1065–1066.

Purrington, S.T., and Pittman, J.H. (1987) Tetrahedron Lett., 28, 3901–3904.

Kanie, K., Tanaka, Y., Shimizu, M., Kuroboshi, M., and Hiyama, T. (1997) J. Chem. Soc., Chem. Commun., 309–310.

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Hashimoto, T., Prakash, G.K.S., Shih, J.G., and Olah, G.A. (1987) J. Org. Chem., 52, 931–933.

7.1.12

Fluorinated building blocks

Shimizu, M., Yamada, N., Takebe, Y., Hata, T., Kuroboshi, M., and Hiyama, T. (1998) Bull. Chem. Soc., Jpn., 71, 2903–2921.

Hata, T., Shimizu, M., and Hiyama, T. (1996) Synlett, 831–832.

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Hanamoto, T., Shindo, K., Matsuoka, M., Kiguchi, Y., and Kondo, M. (2000) J. Chem. Soc., Perkin Trans., 1, 103–107.

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Huang, X.-H., He, P.-Y., and Shi, G.-Q. (2000) J. Org. Chem., 65, 627–629.

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Zhang, Q., and Lu, L. (2000) Tetrahedron Lett., 41, 8545–8548.

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Chevrie, D., Lequeux, T., and Pomelet, J-C. (2002) Tetrahedron, 58, 4759–4767.

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Yoshida, M., Ota, D., Yoshikawa, S., Fukuhara, T., Yoneda, N., and Hara, S. (2002) J. Chem. Soc., Perkin Trans., 1, 384–389.

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Wada, Y., Ichikawa, J., Katsume, T., Nohiro, T., Okauchi, T., and Minami, T. (2001) Bull. Chem. Soc., Jpn., 74, 971–977.

Munyemana, F., Frisque-Hesbain, A., Devos, A., and Ghosez, L. (1989) Tetrahedron Lett., 30, 3077– 3080.

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7.2 7.2.1

Diﬂuorination Diﬂuorocarbene route and halodiﬂuoromethyl radicals and anions

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7.2.1.1

CICF2 CO2 –metal (metal = Na, Li, K)

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7.2.1.2 CF2 )

Generation of - CBrF2 and : CF2 by reduction of CF2 Br2 (- CBrF2 −→:

Balcerzak, P., Freborynski, M., and Jonczyk, A. (1991) J. Chem. Soc., Chem. Commun., 826.

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Roland, A., Durand, T., Egron, D., Vidal, J-P., and Rossi, J-C. (2000) J. Chem. Soc., Perkin Trans., 1, 245–251.

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7.2.1.3

Generation and reaction of ·CF2 Br radical

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7.2.2

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7.2.4

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Brook rearrangement

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7.2.6 7.2.6.1

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Diﬂuoroalkenes, alkynes, and arenes

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7.3

Triﬂuoromethylation

7.3.1 7.3.1.1

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Qiu, X.-L., and Qing, F.-L. (2002) J. Chem. Soc. Perkin Trans., 1, 2052–2057.

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Stahly, G.P., and Bell, D.R. (1989) J. Org. Chem., 54, 2873–2877.

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Ru-catalyzed cleavage of C–S bond in CF3 SO2 X

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Radically initiated generation of CF3 radical

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7.3.5.4

Electrochemical oxidation of TFA

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CF3 CH2 + equivalent

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Triﬂuoromethyl building blocks CF3 -alkenes

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CF3 -alkynes

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TFPO

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Triﬂuoromethylaziridines

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7.3.9.5

Imidoyl halides

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CF3 CO derivatives

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EWG

Rf = CF3 C6 F 5

CHO

COCH3

CO2 Et

CN

40 95

65 70

20 70

0 75

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Triﬂuoromethyl alcohols and amines

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Others

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Perﬂuoroalkylation Rf-Li perﬂuoroalkyl lithium

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Rf-Zn perﬂuoroalkyl zinc

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Lang, R.W. (1988) Helv. Chim. Acta., 71, 369–373.

7.4.3

Sm-promoted perﬂuoroalkylation

Lu, X., Ma, S., and Zhu, J. (1988) Tetrahedron Lett., 29, 5129–5130.

Ma, S., and Lu, X. (1990) Tetrahedron, 46, 357–364.

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Rf-Cu perﬂuoroalkyl copper

Hung, M.-H. (1990) Tetrahedron Lett., 31, 3703–3706.

Burton, D. J., Hartgraves, G.A., and Hsu, J. (1990) Tetrahedron Lett., 31, 3699–3702.

Kitagawa, O., Taguchi, T., and Kobayashi, Y. (1989) Chem Lett., 389–392.

Okano, T., Uekawa, T., and Eguchi, S. (1989) Bull. Chem. Soc. Jpn., 62, 2575–2579.

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Nenajdenko. V.G., Varseev, G.N., Korotchenko, V.N., Shastin, A.V., and Balenkova, E.S. (2004) J. Fluorine Chem., 125, 1339–1345.

Elsheimer, S., Slattery, D.K., Michael, M., Weeks, J., and Topoleski, K. (1989) J. Org. Chem., 54, 3992– 3993.

Tamura, M., and Sekiya, A. (1989) Chem. Lett., 231–234.

Berthod, M., Mignani, G., and Lemaire, M. (2004) Tetrahedron: Asymmetry, 15, 1121–1126.

Clark, J.H., McClinton, M.A., Jone, C.W., Landon, P., Bishop, D., and Blade, R.J. (1989) Tetrahedron Lett., 30, 2133–2136.

Chen, Q.-Y., and Wu, S.-W. (1989) J. Chem. Soc., Chem. Commun., 705–706.

Methods for Introduction of Fluorine-Functionality into Molecules

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7.4.5

Rf-Ru

Kamigata, N., Fukushima, T., and Yoshida, M. (1990) Chem. Lett., 649–650.

Kamigata, N., Fukushima, T., and Yoshida, M. (1990) Chem. Lett., 649–650.

7.4.6

Miscellaneous

Urata, H., Kosukegawa, O., Ishii, Y., Yugari, H., and Fuchikami, T. (1989) Tetrahedron Lett., 30, 4403– 4404.

Miller, A.O., Peters, D., Zur, C., Frank, M., and Miethchen, R. (1997) J. Fluorine Chem., 82, 33–38.

330

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Urata, H., Ishii, Y., and Fuchikami, T. (1989) Tetrahedron Lett., 30, 4407–4410.

(a) Uneyama, K., and Watanabe, H. (1991) Tetrahedron Lett., 32, 1459–1462; (b) Yu, H.-B., and Huang, W.-Y. (1998) J. Fluorine Chem., 87, 69–73

Lim, C., Burton, D.J., and Wesolowski, C.A. (2003) J. Fluorine Chem., 119, 21–26.

Fujita, M., and Hiyama, T. (1988) Bull. Chem. Soc. Jpn., 61, 3321–3322.

Chambers. R.D., Jaouhari, R., and Hagan, D.O. (1988) J. Chem. Soc. Chem. Commun., 1169–1170.

Heinze, P.L., and Burton, D.J. (1988) J. Org. Chem., 53, 2714–2720.

Methods for Introduction of Fluorine-Functionality into Molecules

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Takeyama, Y., Ichinose, Y., Oshima, K., and Utimoto, K. (1989) Tetrahedron Lett., 30, 3159–3162.

R R

H H

H n-Des

n-C7 H15 H

Ph H

Yield(%)

66

99

59

77

C6 F13 I (4 eq.), Et3 B (4 eq.) Ichinose, Y., Oshima, K., and Utimoto, K. (1988) Chem. Lett., 1437–1440.

Kitazume, T., and Ikeya, T. (1988) J. Org. Chem., 53, 2349–2350.

Servi, S. (1990) Synthesis, 1–25.

332

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Keumi, T., Shimada, M., Takahashi, M., and Kitajima, H. (1990) Chem. Lett., 783–786.

Yoshida, M., Yoshida, T., Kamigata, N., and Kobayashi, M. (1988) Bull. Chem. Soc. Jpn., 61, 3549–3552.

Rong, G., and Keese, R. (1990) Tetrahedron Lett., 31, 5615–5616.

Chambers, R.D., Shepherd, T., and Tamura, M. (1988) Tetrahedron, 44, 2583–2590.

Methods for Introduction of Fluorine-Functionality into Molecules

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Shen, Y., Zhang, Y., and Jiang, G.-F. (2002) Synthesis, 714–716.

Petrov, V.A. (2001) Tetrahedron Lett., 42, 3267–3269.

Nixon, P.G., Mohtasham, J., Winter, R., Gard, G.L., Twamley, G.B., and Shreeve, J.M. (2004) J. Fluorine Chem., 125, 553–560.

Markowicz, M.W., and Dembinski, R. (2004) Synthesis, 80–86.

Palacios, F., Alonso, C., Rubiales, G., and Villegas, M. (2004) Tetrahedron Lett., 45, 4031–4034.

Facchetti, A., Mushrush, M., Yoon, M.-H., Hutchison, G.R., Ratner, M.A., and Marks, T.J. (2004) J. Am. Chem. Soc., 126, 13859–13874.

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Lumbierres, M., Moreno-Manas, M., and Vllribora, A. (2002) Tetrahedron, 58, 4061–4065.

Stang, S.L., Meier, R., Rocaboy, C., and Gladysz, J.A. (2003) J. Fluorine Chem., 119, 141–149.

Liu, J.-T., and Zhao. F-L. (2003) Synthesis, 2307–2310.

7.4.7

Polyﬂuorobenzene

Wang, J., Lin, K.-Y., and Matteucci, M.D. (1998) Tetrahedron Lett., 39, 8385–8388.

Cayo, L.M., and Suto, M.J. (1996) Tetrahedron Lett., 37, 4915–4918.

Methods for Introduction of Fluorine-Functionality into Molecules

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Kamigata, N., Yoshinaga, M., and Shimizu, T. (1998) J. Fluorine Chem., 87, 91–95.

Parks, D.J., and Piers, W.E. (1996) J. Am. Chem. Soc., 118, 9440–9441.

Burton, D.J., and Jairaj, V. (2004) J. Fluorine Chem., 125, 673–680.

Li, H., Li, L., Marks, T.J., Liable-Sands, L., and Rheingold, A.L. (2003) J. Am. Chem. Soc., 125, 10788– 10790.

Facchetti, A., Yoon, M-H., Stern, C.L., Katz, H.E., and Marks, T.J. (2003) Angew. Chem., Int. Ed. Engl., 42, 3900–3903.

336

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Dunn, A.R., Dmochowski, I.J., Winkler, J.R., and Gray, H.B. (2003) J. Am. Chem. Soc., 125, 12450– 12456.

Jonhson, S.A., Liu, F-Q., Suh, M.C., Zurcher, S., Haufe, M., Mao, S.S.H., and Tilley, T.D. (2003) J. Am. Chem. Soc., 125, 4199–4211.

Zhang, J.M., Yang, W., Song, L.-P., Cai, X., and Zhu, S-Z. (2004) Tetrahedron Lett., 45, 5771–5773.

Sorokin, V.I., Ozeryanskii, V.A., and Pozhasrskii, A.F. (2004) Eur. J. Org. Chem., 766–769.

Index

abstraction of ﬂuoride ion, 149 acetyl hypoﬂuorite, 130 acyl ﬂuoride, 106 aluminum ﬂuoride, 148 anesthetics, 22 anti-bonding orbital of the C–F bond, 52 arylﬂuoride, 102 asymmetric hydrogenation, 183 asymmetric protonation, 181 asymmetric Reformatsky reaction, 201 Bent’s rule, 45 benzeneselenenyl ﬂuoride, 130 benzotriﬂuoride, 163 B–F interaction, 159 bioisostere, 209 biscoordination of ﬂuoride ion, 156 bond dissociation energy, 72 Bondi’s van der Waals radii, 82 bromo triﬂuoride, 127 2-bromo-3,3,3-triﬂuoropropene, 311 C–F bond activation, 149 C–F bond strength, 23 C–H–␲ interaction, 173 C–H–F-C interaction, 173 Claisen rearrangement, 116 Columbic interaction, 89 cyanuric ﬂuoride, 106, 163 decaﬂuorodiphenylbutadiyne, 41 dehydroﬂuorination, 123 deoxoﬂuor, 238 dibromodiﬂuoromethane (CF2 Br2 ), 259 1,1-dichloro-2,2-diﬂuoroethene, 62 diethylaminosulfur triﬂuoride (DAST), 233, 264 diﬂuorinated carbocation, 62 2,2-diﬂuoro-1-phenylethylamine, 87 10,10-diﬂuoro-TXA2 , 206

1,1-diﬂuoroacetate, 109 2,4-diﬂuorobenzoic acid, 141 diﬂuorobenzyl anion, 70 diﬂuorobenzyl cation, 70 diﬂuorobenzyl radical, 70 diﬂuorocarbene, 79 1,1-diﬂuoroethene, 61 diﬂuoroenol silyl ether, 109 diﬂuoroenolate, 31 diﬂuoroiodomethyl group, 26 diﬂuoromethyl building block, 275 diﬂuoromethylornithine, 217 diﬂuoronitromethane, 18 diﬂuorostyrene, 62 dihalocarbene, 79 1,2-dihalotetraﬂuoroethane, 26 electron afﬁnity, 73 electronic polarizability, 3 ethyl triﬂuoroacetate, 32 Felkin–Anh’s model, 146 ﬁre extinguishing species, 80 ﬂuoride sponge, 160 ﬂuorinated ligand, 186 ﬂuorinated propellane, 49 ﬂuorine in drug design, 36, 206 ﬂuorine–aluminum bond, 147 ﬂuorine–␲ interaction, 39 ﬂuorine-stabilized carbocation, 65 2-ﬂuoro-1-phenylethylamine, 87 ﬂuoroacetaldehyde, 146 ﬂuoroalanine, 18 ␤-ﬂuoroalcohol, 176 ﬂuoroalkyl radical, 67 ﬂuoroanisole, 143 ﬂuoroaryl group, 213 3-ﬂuorobenzyne, 143 1-ﬂuorocyclopropyl radical, 70

338

9␣-ﬂuorodihydrocortisone, 208 ﬂuoroformamidium salt, 106 2-ﬂuorogycoside, 149 ﬂuoromethyl carbocation, 61 2-ﬂuorophenol, 175 4-ﬂuorophenol, 103 4-ﬂuorophenylacetylene, 179 1-(ﬂuorophenyl)ethylamine, 87 ﬂuorophilic, 6 ﬂuorophilicity, 161 ﬂuorophosphonate, 18 2-ﬂuoropyridine, 102 ﬂuorosilicate, 158 5-ﬂuorouridine triphosphate, 216 ﬂuorous, 6 ﬂuorous biphase, 203 ﬂuorous tag, 6 5FU, 216 F-mediated activation of Si–C bond, 158 F–Si interaction, 152 ␤-furanosyl ﬂuoride, 150 gas solubility, 7 gem-diﬂuoromethylene, 112 gem-diﬂuoro-PGF, 206 halodiﬂuoroacetate, 275 halogen monoﬂuoride, 126 halon, 80 Hammett substituent constant, 10, 12, 13 hexaﬂuoro-2-butyne, 46 1,1,1,3,3,3-hexaﬂuoro-2-propanol (HFIP), 180, 182 hexaﬂuoroacetone, 32 hexaﬂuorobenzene, 6, 37, 105 hexaﬂuorobutadiene, 46 hexaﬂuorocyclobutene, 118 hexakis(ﬂuorodimethylsilyl)benzene, 152 hexakis(triﬂuoromethyl)benzvalene, 48 hexakis(triﬂuoromethyl)prismane, 48 hydrogen bonding, 173 hydrogen ﬂuoride triethylamine complex (Et3 N·(3HF)), 243 hydrophobicity, 209, 213 hypoﬂuorous acid, 131 iodine monoﬂuoride, 127 iodine pentaﬂuoride, 128 iodoarene diﬂuoride (Ar-IF2 ), 128, 229 ionization potential, 73 Ireland–Claisen rearrangement, 147 laser ﬂash photolysis, 75 Li–F chelation, 144 Li–F interaction, 140

Index

“like dissolves like” rule, 7 low-lying LUMO, 45, 50 m-ﬂuorophenol, 105 methyl hypoﬂuorite, 130 miscibility, 6 monoﬂuorination, 223 N-(4-ﬂuorophenyl) succinimide, 212 N-ﬂuorosulfonimide, 225 N-triﬂuoroacetyl group, 165 negative hyperconjugation, 14, 52, 107 nucleophilic substitution on ﬂuoroaromatics, 101 octaﬂuoro-BINOL, 186 octaﬂuoro-para-cyclophane, 154 octanol/water partition coefﬁcient (log P ), 209 organic ﬂuorine, 173 pentacoordinated ﬂuoroorganic silane, 158 pentaﬂuoroethyl benzene, 104 pentaﬂuoroethyl-BINOL, 188 pentakistriﬂuoromethylcyclopentadiene, 18 perﬂuoroacylperoxide, 67 perﬂuoroalkyl halide, 122 perﬂuoroalkyl imidoyl iodide, 124 perﬂuoroalkyl iodide, 67 perﬂuoroalkyl lithium, 324 perﬂuoroalkyl radical, 67, 68, 73 perﬂuoroalkylation, 123, 324 perﬂuorocyclohexane, 177 perﬂuorodecalin, 51 perﬂuoro-Dewar benzene, 48 perﬂuoroisobutene, 118 perﬂuoropropene, 74 phosphonodiﬂuoromethane derivative, 283 1,3-proton shift, 35 pyridinium ﬂuoride, 232 refractive index, 2 ␣-scale, 180 ␤-scale, 180 Schiemann reaction, 248 Selectﬂuor (F-TEDA-BF4 ), 231 Si–F bond, 152 sigmatropic rearrangement, 116 single-electron transfer (SET) reaction, 67, 121 singlet–triplet energy gap, 79 S N 2 , 107 S R N 1 reaction, 124 stable radical, 81 ␲–␲ stacking, 37 strained ﬂuorocarbon, 47 structure of ﬂuoroalkyl radicals, 69

Index

Taft substituent constant, 11, 14 Taft’s E s value (steric factor), 82, 147 TASF [(Me2 N)3 S]+ [Me3 SiF2 ]− , 247 TBAT [Bu4 N+ Ph3 SiF2 − ], 240 Tegafur, 216 tert-butyl hypoﬂuorite, 130 tetrabutylammonium ﬂuoride (TBAF), 161, 268 tetrabutylammonium ﬂuoride 2HF complex (TBAH2 F3 ), 265 2,3,5,6-tetraﬂuoro-1,4-phenylene moiety, 42 tetraﬂuoro-1,4-benzhydroquinone, 175 tetraﬂuorocyclopropene, 118 tetraﬂuoroethene, 46 tetraﬂuoro-para-cyclophane, 45 tetraﬂuoro-para-quinodimethane, 154 tetrakis(N,N-dimethylamino)ethene, 122, 125 3-thienylperﬂuorocyclopentene, 42 titanium-ﬂuorine bond, 167 triﬂuoroacetic acid, 184 triﬂuoroacetimidoyl carbanion, 154 triﬂuoroacetimidoyl halides, 315 triﬂuoroacetophenone, 35 triﬂuoroacetyl group, 208 triﬂuoroacetyl hypochlorite, 62 triﬂuoroalanine dipeptide, 118 triﬂuorocrotonate, 147 2,2,2-triﬂuoroethanol (TFE), 180, 182 2,2,2-triﬂuoroethylamine, 20 triﬂuoroethoxybenzene, 104

339

triﬂuorolactate, 181 triﬂuoromethane, 18 triﬂuoromethanesulfonylate, 200 triﬂuoromethanol, 56 triﬂuoromethyl artemisinin, 206 triﬂuoromethyl aryl sulﬁde, 121 triﬂuoromethyl group, 11 triﬂuoromethyl hypoﬂuorite, 228 triﬂuoromethyl radical, 69 triﬂuoromethylamino alcohol, 201 triﬂuoromethylation, 154, 292 triﬂuoromethylimine, 183 triﬂuoromethyltrimethylsilane, 154 2,2,2-triﬂuoro-1-phenylethylamine, 87 triﬂuoropropene oxide (TFPO), 314 triﬂuoropropene, 107 3,3,3-triﬂuoropropene oxide, 151 triﬂuorothymidine, 216 tris(9-anthryl)borane, 161 tris(pentaﬂuorophenyl)borane, 160, 164 trispentaﬂuorophenyl borane, 43 van der Waals attraction, 3 van der Waals radius, 82 Wagner–Meerwein–Pondorf–Verley reduction, 151 xenon diﬂuoride, 224, 242 ytterbium triﬂate Yb(OTf)3 , 165