Modern Fluoroorganic Chemistry [2 ed.] 3527331662, 9783527331666

Table of contents :
Modern Fluoroorganic Chemistry
Contents
Preface to the Second Edition
Preface to the First Edition
Abbreviations
1 Introduction
1.1 Why Organofluorine Chemistry?
1.2 History
1.3 The Basic Materials
1.3.1 Hydrofluoric Acid
1.3.2 Fluorine
1.4 The Unique Properties of Organofluorine Compounds
1.4.1 Physical Properties
1.4.2 Chemical Properties
1.4.3 Ecological Impact
1.4.3.1 Ozone Depletion by Chlorofluorocarbons
1.4.3.2 Greenhouse Effect
1.4.4 Physiological Properties
1.4.5 Analysis of Fluorochemicals: 19F NMR Spectroscopy
References
Part I Synthesis of Complex Organofluorine Compounds
2 Introduction of Fluorine
2.1 Perfluorination and Selective Direct Fluorination
2.2 Electrochemical Fluorination (ECF)
2.3 Nucleophilic Fluorination
2.3.1 Finkelstein Exchange
2.3.2 "Naked" Fluoride
2.3.3 Lewis Acid-Assisted Fluorination
2.3.4 The "General Fluorine Effect"
2.3.5 Amine–Hydrogen Fluoride and Ether–Hydrogen Fluoride Reagents
2.3.6 Hydrofluorination, Halofluorination, and Epoxide Ring Opening
2.4 Synthesis and Reactivity of Fluoroaromatic Compounds
2.4.1 Synthesis of Fluoroaromatic Compounds
2.4.2 Reductive Aromatization
2.4.3 The Balz–Schiemann Reaction
2.4.4 The Fluoroformate Process
2.4.5 Transition Metal-Catalyzed Aromatic Fluorination
2.4.6 The Halex Process
2.4.7 Think Negative! – "Orthogonal" Reactivity of Perfluoroaromatic and Perfluorooleflnic Systems
2.4.8 The "Special Fluorine Effect"
2.4.9 Aromatic Nucleophilic Substitution
2.4.10 Activation of the Carbon–Fluorine Bond by Transition Metals
2.4.10.1 Electrophilically Activated Arylation by Fluoroarenes
2.4.11 Activation of Fluoroaromatic Compounds by Ortho-Metalation
2.5 Transformations of Functional Groups
2.5.1 Hydroxy into Fluoro
2.5.1.1 Two-Step Activation–Fluorination
2.5.1.2 a, a-Difluoroalkylamine and a-Fluoroenamine Reagents
2.5.1.3 Sulfur Tetrafluoride, DAST, and Related Reagents
2.5.1.4 Amine–Hydrogen Fluoride Reagents
2.5.2 Conversion of Carbonyl into gem-Difluoromethylene
2.5.2.1 Sulfur Tetrafluoride, DAST, and Related Reagents
2.5.3 Carboxyl into Trifluoromethyl
2.5.4 Oxidative Fluorodesulfuration
2.6 "Electrophilic" Fluorination
2.6.1 Xenon Difluoride
2.6.2 Perchloryl Fluoride and Hypofluorides
2.6.3 "NF"-Reagents
References
3 Perfluoroalkylation
3.1 Radical Perfluoroalkylation
3.1.1 Structure, Properties, and Reactivity of Perfluoroalkyl Radicals
3.1.2 Preparatively Useful Reactions of Perfluoroalkyl Radicals
3.1.3 "Inverse" Radical Addition of Alkyl Radicals to Perfluoroolefins
3.2 Nucleophilic Perfluoroalkylation
3.2.1 Properties, Stability, and Reactivity of Fluorinated Carbanions
3.2.2 Perfluoroalkyl Metal Compounds
3.2.3 Perfluoroalkylsilanes
3.3 "Electrophilic" Perfluoroalkylation
3.3.1 Properties and Stability of Fluorinated Carbocations
3.3.2 Arylperfluoroalkyliodonium Salts
3.3.3 Perfluoroalkyl Sulfonium, Selenonium, Telluronium, and Oxonium Salts
3.3.4 Fluorinated Johnson Reagents
3.4 Difluorocarbene and Fluorinated Cyclopropanes
References
4 Selected Fluorinated Structures and Reaction Types
4.1 Difluoromethylation and Halodifluoromethylation
4.2 The Perfluoroalkoxy Group
4.3 The Perfluoroalkylthio Group and Sulfur-Based Super-Electron-Withdrawing Groups
4.4 The Pentafluorosulfanyl Group and Related Structures
References
5 The Chemistry of Highly Fluorinated Olefins
5.1 Fluorinated Polymethines
5.2 Fluorinated Enol Ethers as Synthetic Building Blocks
References
Part II Fluorous Chemistry
6 Fluorous Chemistry
6.1 Fluorous Biphase Catalysis
References
7 Fluorous Synthesis and Combinatorial Chemistry
7.1 Fluorous Synthesis
7.2 Separation on Fluorous Stationary Phases
7.3 Fluorous Concepts in Combinatorial Chemistry
References
Part III Applications of Organofluorine Compounds
8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds
8.1 Polymers and Lubricants
8.2 Applications in the Electronics Industry
8.3 Fluorinated Dyes
8.4 Liquid Crystals for Active Matrix Liquid Crystal Displays
8.4.1 Calamitic Liquid Crystals: a Short Introduction
8.4.2 Functioning of Active Matrix LCDs
8.4.2.1 The Physical Properties of Nematic Liquid Crystals
8.4.3 Why Fluorinated Liquid Crystals?
8.4.3.1 Improved Mesophase Behavior by Lateral Fluorination
8.4.3.2 Fluorinated Polar Groups
8.4.3.3 Improved Reliability
8.4.3.4 Fluorinated Bridge Structures
8.4.4 Conclusion and Outlook
8.5 Fluorine in Organic Electronics
8.5.1 Organic Field Effect Transistors (OFETs)
8.5.2 Organic Light-Emitting Diodes (OLEDs)
References
9 Pharmaceuticals and Other Biomedical Applications
9.1 Why Fluorinated Pharmaceuticals?
9.2 Lipophilicity and Substituent Effects
9.3 Hydrogen Bonding and Electrostatic Interactions
9.4 Stereoelectronic Effects and Conformation
9.5 Metabolic Stabilization and Modulation of Reaction Centers
9.6 Bioisosteric Mimicking
9.7 Mechanism-Based "Suicide" Inhibition
9.8 Fluorinated Radiopharmaceuticals
9.9 Inhalation Anesthetics
9.10 Blood Substitutes and Respiratory Fluids
9.11 Contrast Media and Medical Diagnostics
9.12 Agricultural Chemistry
References
Appendix A: Typical Synthetic Procedures
A.1 Selective Direct Fluorination
A.1.1 General Remarks
A.1.2 Fluorination of Diethyl Malonate (1) to Diethyl Fluoromalonate (2)
A.1.3 Synthesis of Bis(4-nitrophenyl)tetrafluorosulfurane (4) (Isomeric Mixture: 15% trans–85% cis)
A.1.4 Isomerization to trans-4
A.2 Hydrofluorination and Halofluorination
A.2.1 General Remarks
A.2.2 Synthesis of the Liquid Crystal 6
A.2.3 Synthesis of 8
A.3 Electrophilic Fluorination with F-TEDA–BF4 (Selectfluor)
A.3.1 Synthesis of the Fluorosteroid 11
A.3.2 Synthesis of Diethyl Fluorophenylmalonate (13)
A.4 Fluorinations with DAST and BAST (Deoxofluor)
A.4.1 General Remarks
A.4.2 General Procedure for Fluorination of Alcohols
A.4.3 General Procedure for Fluorination of Aldehydes and Ketones
A.5 Fluorination of a Carboxylic Acid with Sulfur Tetrafluoride
A.5.1 General Remarks
A.5.2 Synthesis of 4-Bromo-2-(trifluoromethyl)thiazole (23)
A.6 Generation of a Trifluoromethoxy Group by Oxidative Fluorodesulfuration of a Xanthogenate
A.6.1 Synthesis of the Liquid Crystal 25
A.7 Oxidative Alkoxydifluorodesulfuration of Dithianylium Salts
A.7.1 Dithianylium Triflate (27)
A.7.2 Synthesis of 28 from the Dithianylium Salt 27
A.7.3 Synthesis of 28 from the Ketenedithioketal 29
A.8 Electrophilic Trifluoromethylation with Umemoto's Reagents
A.8.1 Trifluoromethylation of the Trimethylsilyldienol Ether 30
A.9 Nucleophilic Trifluoromethylation with Me3SiCF3
A.9.1 Nucleophilic Trifluoromethylation of Ketone 33
A.10 Transition Metal-Mediated Aromatic Perfluoroalkylation
A.10.1 Copper-Mediated Trifluoromethylation of 36 Using Silane Reagents
A.10.2 Palladium-Mediated Trifluoromethylation of Aryl Chloride 41
A.11 Copper-Mediated Introduction of the Trifluoromethylthio Group
A.11.1 Preparation of Trifluoromethylthio Copper Reagent 43
A.11.2 Reaction of CuSCF3 with 4-Iodoanisole (44)
A.12 Substitution Reactions on Fluoroolefins and Fluoroarenes
A.12.1 Preparation of a, b-Difluoro-b-chlorostyrenes (47)
A.12.2 Preparation of a, b-Difluorocinnamic Acid (48)
A.12.3 ortho-Metalation of 1,2-Difluorobenzene (49) with LDA
A.13 Reactions with Difluoroenolates
A.13.1 Preparation of the Trimethylsilyl Difluoroenol Ether 52
A.13.2 Addition of 52 to Carbonyl Compounds
References
Appendix B: Index of Synthetic Conversions
Index

Citation preview

Peer Kirsch Modern Fluoroorganic Chemistry

Related Titles Wirth, T. (ed.)

Ojima, I. (ed.)

Organoselenium Chemistry Synthesis and Reactions

Fluorine in Medicinal Chemistry and Chemical Biology

2012

2009

ISBN: 978-3-527-32944-1

ISBN: 978-1-4051-6720-8

Petrov, V. A.

Mohr, F. (ed.)

Fluorinated Heterocyclic Compounds

Gold Chemistry

Synthesis, Chemistry, and Applications 2009 ISBN: 978-0-470-45211-0

Applications and Future Directions in the Life Sciences 2009 ISBN: 978-3-527-32086-8

Peer Kirsch

Modern Fluoroorganic Chemistry Synthesis, Reactivity, Applications

Second, Completely Revised and Enlarged Edition

The Author Prof. Dr. Peer Kirsch Merck KGaA Liquid Crystals R&D Chemistry Frankfurter Str. 250 64293 Darmstadt Germany

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978-3-527-33166-6 ePDF ISBN: 978-3-527-65138-2 ePub ISBN: 978-3-527-65137-5 mobi ISBN: 978-3-527-65136-8 oBook ISBN: 978-3-527-65135-1 Cover Design Grafik-Design Schulz, Fußg¨onheim Typesetting Laserwords Private Limited, Chennai, India Printing and Binding Markono Print Media Pte Ltd, Singapore Printed in Singapore Printed on acid-free paper

v

To Annette and Alexander

‘‘The fury of the chemical world is the element fluorine. It exists peacefully in the company with calcium in fluorspar and also in a few other compounds; but when isolated, as it recently has been, it is a rabid gas that nothing can resist.’’ Scientific American, April 1888.

‘‘Fluorine leaves nobody indifferent; it inflames emotions be that affections or aversions. As a substituent, it is rarely boring, always good for a surprise, but often completely unpredictable.’’ M. Schlosser, Angew. Chem. Int. Ed. 1998, 37, 1496–1513.

VII

Contents

Preface to the Second Edition XIII Preface to the First Edition XV Abbreviations XVII 1 1.1 1.2 1.3 1.3.1 1.3.2 1.4 1.4.1 1.4.2 1.4.3 1.4.3.1 1.4.3.2 1.4.4 1.4.5

Introduction 1 Why Organofluorine Chemistry? 1 History 1 The Basic Materials 3 Hydrofluoric Acid 3 Fluorine 5 The Unique Properties of Organofluorine Compounds 7 Physical Properties 7 Chemical Properties 13 Ecological Impact 15 Ozone Depletion by Chlorofluorocarbons 15 Greenhouse Effect 17 Physiological Properties 18 Analysis of Fluorochemicals: 19 F NMR Spectroscopy 20 References 21 Part I

2 2.1 2.2 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5

Synthesis of Complex Organofluorine Compounds

Introduction of Fluorine 27 Perfluorination and Selective Direct Fluorination 27 Electrochemical Fluorination (ECF) 34 Nucleophilic Fluorination 36 Finkelstein Exchange 36 ‘‘Naked’’ Fluoride 36 Lewis Acid-Assisted Fluorination 39 The ‘‘General Fluorine Effect’’ 41 Amine–Hydrogen Fluoride and Ether–Hydrogen Fluoride Reagents 42

25

VIII

Contents

2.3.6 2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6 2.4.7 2.4.8 2.4.9 2.4.10 2.4.10.1 2.4.11 2.5 2.5.1 2.5.1.1 2.5.1.2 2.5.1.3 2.5.1.4 2.5.2 2.5.2.1 2.5.3 2.5.4 2.6 2.6.1 2.6.2 2.6.3

3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.2.3 3.3 3.3.1 3.3.2 3.3.3

Hydrofluorination, Halofluorination, and Epoxide Ring Opening 43 Synthesis and Reactivity of Fluoroaromatic Compounds 46 Synthesis of Fluoroaromatic Compounds 46 Reductive Aromatization 47 The Balz–Schiemann Reaction 47 The Fluoroformate Process 49 Transition Metal-Catalyzed Aromatic Fluorination 49 The Halex Process 55 Think Negative! – ‘‘Orthogonal’’ Reactivity of Perfluoroaromatic and Perfluoroolefinic Systems 55 The ‘‘Special Fluorine Effect’’ 58 Aromatic Nucleophilic Substitution 59 Activation of the Carbon–Fluorine Bond by Transition Metals 63 Electrophilically Activated Arylation by Fluoroarenes 63 Activation of Fluoroaromatic Compounds by Ortho-Metalation 64 Transformations of Functional Groups 67 Hydroxy into Fluoro 67 Two-Step Activation–Fluorination 68 α, α-Difluoroalkylamine and α-Fluoroenamine Reagents 68 Sulfur Tetrafluoride, DAST, and Related Reagents 71 Amine–Hydrogen Fluoride Reagents 73 Conversion of Carbonyl into gem-Difluoromethylene 74 Sulfur Tetrafluoride, DAST, and Related Reagents 74 Carboxyl into Trifluoromethyl 77 Oxidative Fluorodesulfuration 78 ‘‘Electrophilic’’ Fluorination 85 Xenon Difluoride 85 Perchloryl Fluoride and Hypofluorides 86 ‘‘NF’’-Reagents 88 References 98 Perfluoroalkylation 107 Radical Perfluoroalkylation 107 Structure, Properties, and Reactivity of Perfluoroalkyl Radicals 107 Preparatively Useful Reactions of Perfluoroalkyl Radicals 110 ‘‘Inverse’’ Radical Addition of Alkyl Radicals to Perfluoroolefins 115 Nucleophilic Perfluoroalkylation 118 Properties, Stability, and Reactivity of Fluorinated Carbanions 118 Perfluoroalkyl Metal Compounds 120 Perfluoroalkylsilanes 130 ‘‘Electrophilic’’ Perfluoroalkylation 139 Properties and Stability of Fluorinated Carbocations 139 Arylperfluoroalkyliodonium Salts 142 Perfluoroalkyl Sulfonium, Selenonium, Telluronium, and Oxonium Salts 149

Contents

3.3.4 3.4

Fluorinated Johnson Reagents 156 Difluorocarbene and Fluorinated Cyclopropanes References 160

4 4.1 4.2 4.3

Selected Fluorinated Structures and Reaction Types 169 Difluoromethylation and Halodifluoromethylation 169 The Perfluoroalkoxy Group 172 The Perfluoroalkylthio Group and Sulfur-Based Super-Electron-Withdrawing Groups 176 The Pentafluorosulfanyl Group and Related Structures 179 References 188

4.4

5 5.1 5.2

156

The Chemistry of Highly Fluorinated Olefins 193 Fluorinated Polymethines 193 Fluorinated Enol Ethers as Synthetic Building Blocks References 205 Part II

Fluorous Chemistry

207

6 6.1

Fluorous Chemistry 209 Fluorous Biphase Catalysis References 224

7 7.1 7.2 7.3

Fluorous Synthesis and Combinatorial Chemistry 227 Fluorous Synthesis 227 Separation on Fluorous Stationary Phases 232 Fluorous Concepts in Combinatorial Chemistry 233 References 242 Part III

8 8.1 8.2 8.3 8.4 8.4.1 8.4.2 8.4.2.1 8.4.3 8.4.3.1 8.4.3.2 8.4.3.3 8.4.3.4

198

209

Applications of Organofluorine Compounds 245

Halofluorocarbons, Hydrofluorocarbons, and Related Compounds 247 Polymers and Lubricants 249 Applications in the Electronics Industry 256 Fluorinated Dyes 258 Liquid Crystals for Active Matrix Liquid Crystal Displays 260 Calamitic Liquid Crystals: a Short Introduction 260 Functioning of Active Matrix LCDs 261 The Physical Properties of Nematic Liquid Crystals 264 Why Fluorinated Liquid Crystals? 267 Improved Mesophase Behavior by Lateral Fluorination 267 Fluorinated Polar Groups 269 Improved Reliability 274 Fluorinated Bridge Structures 275

IX

X

Contents

8.4.4 8.5 8.5.1 8.5.2

Conclusion and Outlook 279 Fluorine in Organic Electronics 281 Organic Field Effect Transistors (OFETs) 281 Organic Light-Emitting Diodes (OLEDs) 290 References 293

9 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10 9.11 9.12

Pharmaceuticals and Other Biomedical Applications 299 Why Fluorinated Pharmaceuticals? 299 Lipophilicity and Substituent Effects 300 Hydrogen Bonding and Electrostatic Interactions 303 Stereoelectronic Effects and Conformation 306 Metabolic Stabilization and Modulation of Reaction Centers Bioisosteric Mimicking 316 Mechanism-Based ‘‘Suicide’’ Inhibition 325 Fluorinated Radiopharmaceuticals 329 Inhalation Anesthetics 333 Blood Substitutes and Respiratory Fluids 334 Contrast Media and Medical Diagnostics 335 Agricultural Chemistry 336 References 340

A.1 A.1.1 A.1.2 A.1.3 A.1.4 A.2 A.2.1 A.2.2 A.2.3 A.3 A.3.1 A.3.2 A.4 A.4.1 A.4.2 A.4.3 A.5 A.5.1 A.5.2 A.6

310

Appendix A: Typical Synthetic Procedures 351 Selective Direct Fluorination 351 General Remarks 351 Fluorination of Diethyl Malonate (1) to Diethyl Fluoromalonate (2) 352 Synthesis of Bis(4-nitrophenyl)tetrafluorosulfurane (4) (Isomeric Mixture: 15% trans–85% cis) 352 Isomerization to trans-4 353 Hydrofluorination and Halofluorination 353 General Remarks 353 Synthesis of the Liquid Crystal 6 354 Synthesis of 8 354 Electrophilic Fluorination with F-TEDA–BF4 (Selectfluor) 355 Synthesis of the Fluorosteroid 11 355 Synthesis of Diethyl Fluorophenylmalonate (13) 355 Fluorinations with DAST and BAST (Deoxofluor) 356 General Remarks 356 General Procedure for Fluorination of Alcohols 356 General Procedure for Fluorination of Aldehydes and Ketones 357 Fluorination of a Carboxylic Acid with Sulfur Tetrafluoride 358 General Remarks 358 Synthesis of 4-Bromo-2-(trifluoromethyl)thiazole (23) 358 Generation of a Trifluoromethoxy Group by Oxidative Fluorodesulfuration of a Xanthogenate 358

Contents

A.6.1 A.7 A.7.1 A.7.2 A.7.3 A.8 A.8.1 A.9 A.9.1 A.10 A.10.1 A.10.2 A.11 A.11.1 A.11.2 A.12 A.12.1 A.12.2 A.12.3 A.13 A.13.1 A.13.2

Synthesis of the Liquid Crystal 25 358 Oxidative Alkoxydifluorodesulfuration of Dithianylium Salts 359 Dithianylium Triflate (27) 359 Synthesis of 28 from the Dithianylium Salt 27 360 Synthesis of 28 from the Ketenedithioketal 29 360 Electrophilic Trifluoromethylation with Umemoto’s Reagents 361 Trifluoromethylation of the Trimethylsilyldienol Ether 30 361 Nucleophilic Trifluoromethylation with Me3 SiCF3 362 Nucleophilic Trifluoromethylation of Ketone 33 362 Transition Metal-Mediated Aromatic Perfluoroalkylation 362 Copper-Mediated Trifluoromethylation of 36 Using Silane Reagents 362 Palladium-Mediated Trifluoromethylation of Aryl Chloride 41 363 Copper-Mediated Introduction of the Trifluoromethylthio Group 364 Preparation of Trifluoromethylthio Copper Reagent 43 364 Reaction of CuSCF3 with 4-Iodoanisole (44) 364 Substitution Reactions on Fluoroolefins and Fluoroarenes 365 Preparation of α, β-Difluoro-β-chlorostyrenes (47) 365 Preparation of α, β-Difluorocinnamic Acid (48) 365 ortho-Metalation of 1,2-Difluorobenzene (49) with LDA 365 Reactions with Difluoroenolates 366 Preparation of the Trimethylsilyl Difluoroenol Ether 52 366 Addition of 52 to Carbonyl Compounds 367 References 367 Appendix B: Index of Synthetic Conversions Index

373

369

XI

XIII

Preface to the Second Edition Within the few years since the first edition, the landscape of fluorine chemistry has changed dramatically: it is no longer the domain of a highly specialized (and often quite courageous) community, but the field has attracted the attention of mainstream organic and bioorganic chemists. The value of fluorine substitution in bioactive compounds and other functional materials has been widely recognized beyond the boundaries of the traditional fluorine chemistry community. Consequently, the variety of available synthetic methodology has exploded. A review with a reasonable degree of completeness has become impossible, and even the selection of the most significant developments is a very difficult task. The scope of this book is not to offer a complete review of available methods, but to provide an introduction and a representative overview over the rapidly evolving field for the interested newcomer. It should be used as an entry point for a detailed in-depth study, but it is not intended as a stand-alone encyclopedia of fluorine chemistry. Therefore, there are many omissions, and the selection of the most interesting new developments has often been a matter of taste of the author. The focus of the second edition is application fields where fluorine is essential for function, and also the chemistry needed to access such compounds. This applies not only to the material sciences but of course also to the biomedical field. On the synthetic side, the most remarkable new development is a huge variety of transition metal-catalyzed methods for the introduction of fluorine and fluorinated groups. From the conceptual side, the author’s choice of the most important new developments has been covered. From the application side, two new areas have been added: fluorinated dyes as one of the first areas of the industrial application of fluorine chemistry was recognized as a gap in the previous edition. In the last 10 years, the field of organic electronics has developed tremendously, and also here fluorine chemistry has found a very specific range of applications. A short review of the role and function of fluorine chemistry in this rapidly developing field has been added. The author would like to thank the friends and colleagues who have provided their help and valuable input during the update of the text. In particular,

XIV

Preface to the Second Edition

Matthias Bremer, Alois Haas, Ingo Krossing, David O’Hagan, Gerd R¨oschenthaler, Georg Schulz, Peter and Marina Wanczek, John Welch, and Yurii Yagupolskii supported my project with information and critical discussions. From Wiley-VCH, Anne Brennf¨uhrer and Lesley Belfit provided me with steady support and encouragement. Most of all, I owe my gratitude to my wife Annette and my son Alexander, who received much less attention than they deserved and who provided an environment where I could make the time for writing a book on top of many other things. Seeheim-Jugenheim January 2013

Peer Kirsch

XV

Preface to the First Edition The field of fluoroorganic chemistry has grown tremendously in recent years, and fluorochemicals have permeated nearly every aspect of our daily lives. This book is aimed at the synthetic chemist who wants to gain a deeper understanding of the fascinating implications of including the highly unusual element fluorine in organic compounds. The idea behind this book was to introduce the reader to a wide range of synthetic methodology, based on the mechanistic background and the unique chemical and physicochemical properties of fluoroorganic compounds. There are quite some barriers to entering the field of preparative fluoroorganic chemistry, many based on unfounded prejudice. To reduce the threshold to practical engagement in fluoroorganic chemistry, I include some representative synthetic procedures which can be performed with relatively standard laboratory equipment. To point out what can be achieved by introducing fluorine into organic molecules, a whole section of this book is dedicated to selected applications. Naturally, because of the extremely wide range of sometime highly specialized applications, this part had to be limited to examples which have gained particular importance in recent years. Of course, this selection is influenced strongly by the particular ‘‘taste’’ of the author. I could not have completed this book without help and support from friends and colleagues. I would like to thank my colleagues at Merck KGaA, in particular Detlef Pauluth for his continuous support of my book project, and Matthias Bremer and Oliver Heppert for proof reading and for many good suggestions and ideas how to improve the book. The remaining errors are entirely my fault. G. K. Surya Prakash, Karl O. Christe, and David O’Hagan not only gave valuable advice but also provided me with literature. Gerd-Volker R¨oschenthaler, G¨unter Haufe, and Max Lieb introduced me to the fascinating field of fluorine chemistry. Andrew E. Feiring and Barbara Hall helped me to obtain historical photographs. Elke Maase from Wiley-VCH accompanied my work with continuous support and encouragement.

XVI

Preface to the First Edition

In the last 18 months I have spent most of my free time working on this book and not with my family. I would, therefore, like to dedicate this book to my wife Annette and my son Alexander. Darmstadt May 2004

Peer Kirsch

XVII

Abbreviations acac aHF AIBN AM ASV ATPH

Acetylacetonate ligand Anhydrous hydrofluoric acid Azobis(isobutyronitrile) Active matrix ‘‘Advanced super-V’’ Aluminum tri[2,6-bis(tert-butyl)phenoxide]

BAST BINOL Boc Bop-Cl BSSE BTF

N,N-Bis(methoxyethyl)amino sulfur trifluoride 1,1 -Bi-2-naphthol tert-Butoxycarbonyl protecting group Bis(2-oxo-3-oxazolidinyl)phosphinic chloride Basis set superposition error Benzotrifluoride

CFC COD CSA Cso CVD cVHP

Chlorofluorocarbon Cyclooctadiene Camphorsulfonic acid Camphorsulfonyl protecting group Chemical vapor deposition Chicken villin headpiece subdomain

DABCO DAM DAST DBH DBPO DEAD DCC DCEH DEC DFI DFT DIP-Cl DMAc DMAP DME DMF DMS DMSO DSM

Diazabicyclooctane Di(p-anisyl)methyl protecting group N,N-Diethylamino sulfur trifluoride 1,3-Dibromo-5,5-dimethylhydantoin Dibenzoyl peroxide Diethyl azodicarboxylate Dicyclohexylcarbodiimide Dicarboxyethoxyhydrazine N,N-Diethylcarbamoyl protecting group 2,2-Difluoro-1,3-dimethylimidazolidine Density functional theory β-Chlorodiisopinocampheylborane N,N-Dimethylacetamide 4-(N,N-Dimethylamino)pyridine 1,2-Dimethoxyethane N,N-Dimethylformamide Dimethyl sulfide Dimethyl sulfoxide Dynamic scattering mode

XVIII

Abbreviations DTBP dTMP dUMP

Di-tert-butyl peroxide Deoxythymidine monophosphate Deoxyuridine monophosphate

ECF ED EPSP ETFE

Electrochemical fluorination Effective dose 5-Enolpyruvylshikimate-3-phosphate Poly(ethylene-co-tetrafluoroethylene)

FAR FDA FDG FET FFS FITS FRPSG FSPE F-TEDA

α-Fluorinated alkylamine reagents Fluorodeoxyadenosine Fluorodeoxyglucose Field effect transistor Fringe field switching Perfluoroalkyl phenyl iodonium trifluoromethylsulfonate reagents Fluorous reversed-phase silica gel Fluorous solid-phase extraction N-Fluoro-N  -chloromethyldiazoniabicyclooctane reagents

GWP

Global warming potential

HFCF HFC HFP HMG+ HMPA HSAB

Hydrofluorocarbon Hydrofluorocarbon Hexafluoropropene Hexamethylguanidinium cation Hexamethylphosphoric acid triamide Hard and soft acids and bases (Pearson concept)

IPS ITO

In-plane switching Indium tin oxide

LC LCD LD LDA

1. Liquid crystal 2. Lethal concentration Liquid crystal display Lethal dose Lithium diisopropylamide

MCPBA MEM MOM MOST MVA

m-Chloroperbenzoic acid Methoxyethoxymethyl protecting group Methoxymethyl protecting group Morpholino sulfur trifluoride Multi-domain vertical alignment

NAD+ /NADH NADP+ /NADPH NBS NCS NE NFPy NFTh NIS NLO NMP NPSP

Nicotinamide adenine dinucleotide, oxidized/reduced form Nicotinamide adenine dinucleotide phosphate, oxidized/reduced form N-Bromosuccinimide N-Chlorosuccinimide Norepinephrine N-Fluoropyridinium tetrafluoroborate N-Fluoro-o-benzenedisulfonimide N-Iodosuccinimide Nonlinear optics N-Methylpyrrolidone N-Phenylselenylphthalimide

Abbreviations

OD ODP OFET OLED OPV OTFT

Ornithine decarboxylase Ozone-depleting potential Organic field effect transistor Organic light-emitting diode Organic photovoltaics Organic thin-film transistor

PCH PCTFE PDA PET PFA PFC PFMC PFOA PFOB PFOS phen PI PIDA pip+ PLP PNP PPVE PTC PTFE PVDF PVPHF P3DT

Phenylcyclohexane Polychlorotrifluoroethylene Personal digital assistant 1. Positron emission tomography 2. Poly(ethylene terephthlate) Perfluoropolyether Perfluorocarbon Perfluoro(methylcyclohexane) Perfluorooctanoic acid Perfluoro-n-octyl bromide Perfluorooctylsulfonic acid Phenanthroline Polyimide Phenyliodonium diacetate 1,1,2,2,6,6-Hexamethylpiperidinium cation Pyridoxal phosphate Purine nucleoside phosphorylase Poly(heptafluoropropyl trifluorovinyl ether) Phase transfer catalysis Polytetrafluoroethylene (TeflonTM ) Poly(vinylidene difluoride) Poly(vinylpyridine) hydrofluoride Poly(3-dodecylthiophene)

QM/MM QSAR

Quantum mechanics/molecular mechanics Quantitative structure–activity relationships

SAH SAM

S-Adenosylhomocysteine hydrolase 1. S-Adenosylmethionine 2. Self-assembled monolayer Sodium bis(methoxyethoxy)aluminum hydride Supercritical carbon dioxide Supercritical fluid chromatography Single electrton transfer Superfluorinated material Solid-phase extraction Super-twisted nematic

SBAH scCO2 SFC SET SFM SPE STN TADDOL TAS+ TASF TBAF TBDMS TBS

α,α,α ,α -Tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol Tris(dimethylamino)sulfonium cation Tris(dimethylamino)sulfonium difluorotrimethylsiliconate, (Me2 N)3 S+ Me3 SiF2 − Tetrabutylammonium fluoride tert-Butyldimethylsilyl protecting group See TBDMS

XIX

XX

Abbreviations

THP TIPS TLC TMS TN TPP TPPO TR

O-(Benzotriazol-1-yl)-N,N,N  ,N  -tetramethyluronium tetrafluoroborate Tetrakis(dimethylamino)ethylene 2,2,6,6-Tetramethylpiperidine-N-oxide Thin film transistor 1. Tetrahydrofuran 2. Tetrahydrofolate coenzyme Tetrahydropyranyl protecting group Triisopropylsilyl protecting group Thin-layer chromatography Trimethylsilyl protecting group Twisted nematic Triphenylphosphine Triphenylphosphine oxide Trypanothione reductase

VHR

Voltage holding ratio

ZPE

Zero point energy

TBTU TDAE TEMPO TFT THF

1

1 Introduction 1.1 Why Organofluorine Chemistry?

Fluorine is the element of extremes, and many fluorinated organic compounds exhibit extreme and sometimes even bizarre behavior. A large number of polymers, liquid crystals, and other advanced materials owe their unique property profile to the influence of fluorinated structures. Fluoroorganic compounds are almost completely foreign to the biosphere. No central biological processes rely on fluorinated metabolites. Many modern pharmaceuticals and agrochemicals, on the other hand, contain at least one fluorine atom, which usually has a very specific function. Perfluoroalkanes, especially, can be regarded as ‘‘orthogonal’’ to life – they can assume a purely physical function, for example, oxygen transport, but are foreign to the living system to such an extent that they are not recognized and are completely ignored by the body. Although fluorine itself is the most reactive of all elements, some fluoroorganic compounds have chemical inertness like that of the noble gases. They sometimes cause ecological problems not because of their reactivity but because of the lack of it, making them persistent in Nature on a geological time scale. All these points render fluoroorganic chemistry a highly unusual and fascinating field [1–14], providing surprises and intellectual stimulation in the whole range of chemistry-related sciences, including theoretical, synthetic, and biomedical chemistry and materials science.

1.2 History

Because of the hazardous character of hydrofluoric acid and the difficult access to elemental fluorine itself, the development of organofluorine chemistry and the practical use of fluoroorganic compounds started relatively late in the nineteenth century (Table 1.1). The real breakthrough was the first synthesis of elemental fluorine by Henri Moissan in 1886 [15], but the first defined fluoroorganic compound, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

2

1 Introduction Table 1.1

Dates and historical key events in the development of fluoroorganic chemistry.

Time

Key event

1764

First synthesis of hydrofluoric acid from fluorspar and sulfuric acid by A. S. Marggraf, repeated in 1771 by C. Scheele Synthesis of benzoyl fluoride as the first fluoroorganic compound by A. Borodin First synthesis of elemental fluorine by H. Moissan (Nobel Prize in 1906) by electrolysis of an HF–KF system Beginning of halofluorocarbon chemistry by direct fluorination (H. Moissan) and Lewis acid-catalyzed halogen exchange (F. Swarts) Access to fluoroarenes by the Balz–Schiemann reaction Refrigerants (Freon, in Germany Frigen), fire extinguishing chemicals (Halon), aerosol propellants. Fluorinated dyes with enhanced color fastness. Polymers (PTFE = Teflon), electrochemical fluorination (H. Simons) Manhattan Project: highly resistant materials for isotope separation plants, lubricants for gas centrifuges, and coolants Fluoropharmaceuticals, agrochemicals, artificial blood substitutes, respiratory fluids, and chemical weapons Gases for plasma etching processes and cleaning fluids for the semiconductor industry The Montreal Protocol initiates the phasing-out of CFCs Fluorinated liquid crystals for active matrix liquid crystal displays (AM-LCDs) Fluorinated photoresists for the manufacture of integrated electronic circuits by 157 nm photolithography

1863 1886 1890s 1920s 1930s 1940s 1941–1954 1950s 1980s 1987 1990s 2000s

benzoyl fluoride, had already been prepared and described by the Russian chemist, physician, and composer Alexander Borodin in 1863 [16]. Industrial application of fluorinated organic compounds started at the beginning of the 1930s with the introduction of chlorofluorocarbons (CFCs) as refrigerants [17]. The major turning point in the history of industrial fluoroorganic chemistry was the beginning of the Manhattan Project for development of nuclear weapons in 1941 [18]. The Manhattan Project triggered the need for highly resistant materials, lubricants, and coolants and the development of technology for handling extremely corrosive fluoroinorganic compounds. The consumption of hydrofluoric acid as the main precursor of all these materials soared, accordingly, during the 1940s. After 1945, with the beginning of the Cold War, various defense programs provided a constant driving force for further development of the chemistry and use of organofluorine compounds. In the 1950s and 1960s, more civilian applications of fluorinated pharmaceuticals and materials moved to the forefront [19]. The prediction of the ozone-depleting effect of CFCs in 1974 [20] and the subsequent occurrence of the hole in the ozone layer over the Antarctic in 1980 enforced a drastic reorientation of industrial fluoroorganic chemistry. With the Montreal Protocol in 1987, the phasing-out of most CFCs was initiated. Some of the refrigerants and cleaning chemicals could be replaced by other fluorine-containing

1.3 The Basic Materials

chemicals (for example, hydrofluorocarbons, HFCs and fluorinated ethers), but in general the fluorochemical industry had to refocus on other fields of application, for example, fluoropolymers, fluorosurfactants, and fluorinated intermediates for pharmaceuticals and agrochemicals [19]. A major and rapidly growing market segment is fluorine-containing fine chemicals for use as intermediates in pharmaceuticals and agrochemistry. Another application in which fluorochemicals have started to play an increasingly dominant role in the last few years is the electronics industry. Relevant compounds include plasma etching gases, cleaning fluids, specialized fluoropolymers, fluorinated photoresists for manufacturing integrated circuits by the currently emerging 157 nm photolithography, and liquid crystals for application in liquid crystal displays (LCDs).

1.3 The Basic Materials

Naturally occurring fluorine is composed of the pure 199 F isotope. Its relative abundance in the Earth’s crust as a whole is 0.027% by weight (for comparison, that of Cl is 0.19% and that of Br is 6 × 10−4 % by weight). Because of the extremely low solubility (solubility product 1.7 × 10−10 at 298 K) of its most important mineral, fluorspar (CaF2 ), the concentration of fluoride in seawater is very low (about 1.4 mg l−1 ) [21]. The most abundant natural sources of fluorine are the minerals fluorspar and cryolite (Na3 AlF6 ). Fluorapatite [Ca5 (PO4 )3 F = ‘‘3Ca3 (PO4 )2 ·CaF2 ’’] is, with hydroxyapatite [Ca5 (PO4 )3 OH], a major component of tooth enamel, giving it its extreme mechanical strength and life-long durability. Minor quantities of hydrogen fluoride, fluorocarbons, and even polytetrafluoroethylene (PTFE) are released by volcanoes [22]. Even elemental fluorine (F2 ) occurs in Nature, as an inclusion in fluorspar (about 0.46 mg of F2 per gram of CaF2 ). The so-called ‘‘stinkspar’’ or ‘‘antozonite,’’ which has been irradiated with γ -radiation from uranium ore, releases a pungent smell on rubbing or crushing [23]. Despite the relatively high abundance of fluorine in the lithosphere, only very few fluoroorganic metabolites have been identified in the biosphere [24]. No central metabolic process depending essentially on fluorine is yet known. It might be speculated that the reason for this unexpected phenomenon is the poor solubility of CaF2 , with Ca2+ ions being one of the central components essential for the existence of any living organism. Another reason might also be the very high hydration enthalpy of the small fluoride anion, which limits its nucleophilicity in aqueous media by requiring an energetically demanding dehydration step before any reaction as a nucleophile [24]. 1.3.1 Hydrofluoric Acid

Hydrofluoric acid is the most basic common precursor of most fluorochemicals. Aqueous hydrofluoric acid is prepared by reaction of sulfuric acid with fluorspar

3

4

1 Introduction Physicochemical properties of hydrofluoric acid [25] (the vapor pressure and density correspond to a temperature of 0 ◦ C).

Table 1.2

Property Boiling point (◦ C) Melting point (◦ C) HF vapor pressure (Torr) Density (g cm−3 )

Anhydrous HF

40% HF–H2 O

19.5 −83.4 364 1.015

111.7 −44.0 21 1.135

(CaF2 ). Because HF etches glass with the formation of silicon tetrafluoride, it must be handled in platinum, lead, copper, Monel (a Cu–Ni alloy developed during the Manhattan Project), or plastic (e.g., polyethylene or PTFE) apparatus. The azeotrope contains 38% w/w HF and it is a relatively weak acid (pK a 3.18, 8% dissociation), comparable to formic acid. Other physicochemical properties of hydrofluoric acid are listed in Table 1.2. Anhydrous hydrofluoric acid (aHF) is obtained by heating Fremi’s salt (KF·HF) as a liquid, boiling at 19.5 ◦ C. Similarly to water, aHF has a liquid range of ∼100 ◦ C and a dielectric constant ε of 83.5 (at 0 ◦ C). Associated by strong hydrogen bonding, it forms oligomeric (HF)n chains with a predominant chain length n of 6–7 HF units [25b]. In contrast with aqueous HF, pure aHF is a very strong acid, slightly weaker than sulfuric acid. Like water, aHF undergoes autoprotolysis with an ion product c(FHF− ) × c(HFH+ ) of 10−10.7 at 0 ◦ C. In combination with strong Lewis acids, for example, as AsF5 , SbF5 , or SO3 , aHF forms some of the strongest known protic acids. The best known example is ‘‘magic acid’’ (FSO3 H–SbF5 ), which can protonate and crack paraffins to give tert-butyl cations [25]. Apart from its use as a reagent, aHF is also an efficient and electrochemically inert solvent for a variety of inorganic and organic compounds. The dark side of hydrofluoric acid is its toxicity and corrosiveness. Aqueous and anhydrous HF readily penetrate the skin and, because of its locally anesthetizing effect, even in very small quantities, it can cause deep lesions and necroses [26, 27]. An additional health hazard is the systemic toxicity of fluoride ions, which interfere strongly with calcium metabolism. Resorption of HF by skin contact (from a contact area exceeding 160 cm2 ), inhalation, or ingestion leads to hypocalcemia with very serious consequences, for example, cardiac arrhythmia. The most effective, specific antidote to HF and inorganic fluorides is calcium gluconate, which acts by precipitating fluoride ions as insoluble CaF2 . After inhalation of HF vapor, treatment of the patient with dexamethasone aerosol is recommended, to prevent pulmonary edema. Even slight contamination with HF must always be taken seriously, and after the necessary first-aid measures a physician should be consulted as soon as possible. It should also be kept in mind that some inorganic (e.g., CoF3 ) and organic fluorinated compounds (e.g., pyridine–HF, NEt3 ·3HF, N,N-diethylamino sulfur

1.3 The Basic Materials

trifluoride (DAST)) can hydrolyze on contact with the skin and body fluids, liberating hydrofluoric acid with the same adverse consequences. Nevertheless, when the necessary, relatively simple precautions are taken [26], hydrofluoric acid and its derivatives can be handled safely and with minimum risk to health. 1.3.2 Fluorine

Despite the ubiquitous occurrence of fluorides in Nature, elemental fluorine itself proved to be quite elusive. Because of its very high redox potential (approximately +3 V, depending on the pH of aqueous systems), chemical synthesis from inorganic fluorides was impeded by the lack of a suitable oxidant. Therefore, Moissan’s first synthesis of fluorine in 1886 by electrolysis of a solution of KF in aHF in a platinum apparatus [28, 29] was a significant scientific breakthrough, and he was awarded the Nobel Prize for Chemistry in 1906 for his discovery (Figure 1.1).

Figure 1.1 The apparatus used by Moissan for the first isolation of elemental fluorine by electrolysis of an HF–KF system in 1886 [28].

5

6

1 Introduction

Fluorine is a greenish yellow gas, melting at −219.6 ◦ C and boiling at −188.1 ◦ C. It has a pungent smell reminiscent of a mixture of chlorine and ozone and is perceptible even at a concentration of 10 ppm. It is highly toxic and extremely corrosive, especially towards oxidizable substrates. Most organic compounds spontaneously combust or explode on contact with undiluted fluorine at ambient pressure. Because of its high reactivity, fluorine reacts with hot platinum and gold, and even with the noble gases krypton and xenon. In contrast to hydrofluoric acid, dry fluorine gas does not etch glassware. Because of its extreme reactivity and hazardous nature, for many chemical transformations fluorine is diluted with nitrogen (typically 10% F2 in N2 ). In this form, the gas can be stored without undue risk in passivated steel pressure bottles. Reactions can be conducted either in glassware or in fluoropolymer (PTFE or perfluoropolyether (PFA)) apparatus. If some elementary precautions are taken (for details, see Appendix A), reactions with nitrogen-diluted fluorine can be conducted safely in an ordinarily equipped laboratory. Fluorine owes its unparalleled reactivity, on the one hand, to the ease of its homolytic dissociation into radicals (only 37.8 kcal mol−1 , compared with 58.2 kcal mol−1 for Cl2 ) and, on the other hand, to its very high redox potentials of +3.06 and +2.87 V in acidic and basic aqueous media, respectively [30]. Fluorine, as the most electronegative element (electronegativity 3.98) [31], occurs in its compounds exclusively in the oxidation state −1. The high electron affinity (3.448 eV), extreme ionization energy (17.418 eV), and other unique properties of fluorine can be explained by its special location in the periodic system as the first element with p orbitals able to achieve a noble gas electron configuration (Ne) by uptake of one additional electron. For the same reason, the fluoride ion is also the smallest (ion radius 133 pm) and least polarizable anion. These very unusual characteristics are the reason why fluorine or fluorine-containing nonpolarizable anions can stabilize many elements in their highest and otherwise inaccessible oxidation states (e.g., IF7 , XeF6 , KrF2 , O2 + PtF6 − , N5 + AsF6 − ). A purely chemical synthesis of elemental fluorine was achieved by K. O. Christe in 1986 [32] (Scheme 1.1), just in time for the 100th anniversary of Moissan’s first electrochemical fluorine synthesis. Nevertheless, in his paper Christe remarked that all the basic know-how required for this work had already been available 50 years earlier. The key to his simple method is a displacement reaction between potassium hexafluoropermanganate [33] and the strongly fluorophilic Lewis acid antimony pentafluoride at 150 ◦ C.

2 KMnO4 + 2 KF + 10 HF + 3 H2O2 K2MnF6 + 2 SbF5

Scheme 1.1

74%

50% aq. HF

>40% 150 °C

2 K2MnF6 + 8 H2O + 3 O2

2 KSbF6 + MnF3 + ½ F2

The first ‘‘chemical’’ synthesis of fluorine [32].

1.4 The Unique Properties of Organofluorine Compounds

Nowadays, industrial fluorine production is based on Moissan’s original method [21]. In the so-called ‘‘middle-temperature method,’’ a KF·2HF melt is electrolyzed at 70–130 ◦ C in a steel cell. The steel cell itself is used as the cathode; the anodes are specially treated carbon blocks (S¨oderberg electrodes). The voltage used is 8–12 V per cell [34]. During the Cold War, the major use of elemental fluorine was in the production of uranium hexafluoride for separation of the 235 U isotope. Nowadays, the production of nuclear weapons has moved into the background and large quantities of fluorine are used for preparation of chemicals for the electronics industry [for example, WF6 for CVD (chemical vapor deposition), SF6 , NF3 , and BrF3 as etching gases for semiconductor production, and graphite fluorides as cathode materials in primary lithium batteries] and for making inert polyethylene gasoline tanks in the automobile industry.

1.4 The Unique Properties of Organofluorine Compounds

Fluoroorganic and, especially, perfluorinated compounds are characterized by a unique set of unusual and sometimes extreme physical and chemical properties. These are utilized in a variety of different applications ranging from pharmaceutical chemistry to materials science [35]. 1.4.1 Physical Properties

The physical properties of fluoroorganic compounds are governed by two main factors: (i) the combination of high electronegativity with moderate size and the excellent match between the fluorine 2s or 2p orbitals with the corresponding orbitals of carbon and (ii) the resulting extremely low polarizability of fluorine [36]. Fluorine has the highest electronegativity of all the elements (3.98) [31], rendering the carbon–fluorine bond highly polar with a typical dipole moment of around 1.4 D, depending on the exact chemical environment (Table 1.3). The apparently contradictory observation that perfluorocarbons (PFCs) are among the most nonpolar solvents in existence [e.g., ε = 1.69 for C6 F14 (3) compared with 1.89 for C6 H14 (1); Table 1.4 can be explained by the fact that all local dipole moments within the same molecule cancel each other, leading in total to a nonpolar compound. In semifluorinated compounds, for example, 2, in which some local dipole moments are not compensated, the effects of the resulting overall dipole moment are mirrored by their physicochemical properties, especially their heats of vaporization (Hv ) and their dielectric constants (ε). The low polarizability and the slightly larger size of fluorine compared with hydrogen (23% larger van der Waals radius) also have consequences for the structure and molecular dynamics of PFCs. Linear hydrocarbons have a linear zigzag conformation (Figure 1.2). PFCs, in contrast, have a helical structure, because of the steric repulsion of the electronically ‘‘hard’’ fluorine substituents

7

8

1 Introduction Comparison of the characteristics of carbon–halogen and carbon–carbon bonds (electronegativities from Ref. [31]; van der Waals radii from Ref. [37]; atom polarizabilities from Ref. [38]).

Table 1.3

Property

X

Bond length C–X (pm) Binding energy C–X (kcal mol−1 ) Electronegativity Dipole moment C–X, μ (D) van der Waals radius (pm) Atom polarizability, α (10−24 cm−3 )

H

F

Cl

Br

I

C

109 98.0 2.20 (0.4) 120 0.667

138 115.7 3.98 1.41 147 0.557

177 77.2 3.16 1.46 175 2.18

194 64.3 2.96 1.38 185 3.05

213 50.7 2.66 1.19 198 4.7

— ∼83 2.55 — — —

Table 1.4 Comparison of selected physicochemical properties of n-hexane (1) and its perfluorinated (3) and semifluorinated (2) analogs [36].

F F

F F F F F F F

F 1

F F F F

F

F F F F F F

2

3

μ Property B.p. (◦ C) Heat of vaporization, Hv (kcal mol−1 ) Critical temperature, T c (◦ C) Density, d25 (g cm−3 ) Viscosity, η25 (cP) Surface tension, γ 25 (dyn cm−1 ) Compressibility, β (10−6 atm−1 ) Refractive index, nD 25 Dielectric constant, ε

1

2

3

69 6.9 235 0.655 0.29 17.9 150 1.372 1.89

64 7.9 200 1.265 0.48 14.3 198 1.190 5.99

57 6.7 174 1.672 0.66 11.4 254 1.252 1.69

Steric repulsion F F F F 1

(a)

F FF (b)

3

F F

F

Figure 1.2 The zigzag conformation of octadecane (a) compared with the helical perfluorooctadecane (b), modeled at the PM3 level of theory [39, 40].

1.4 The Unique Properties of Organofluorine Compounds

bound to carbon atoms in the relative 1,3-positions. Whereas the hydrocarbon backbone has some conformational flexibility, PFCs are rigid, rod-like molecules. This rigidity can be attributed to repulsive stretching by the 1,3-difluoromethylene groups. Another consequence of the low polarizability of PFCs is very weak intermolecular dispersion interactions. A striking characteristic of PFCs is their very low boiling points, compared with hydrocarbons of similar molecular mass. For example, n-hexane and CF4 have about the same molecular mass (Mr 86 and 88 g mol−1 , respectively), but the boiling point of CF4 (−128 ◦ C) is nearly 200 ◦ C lower than that of n-hexane (69 ◦ C). If the homologous hydrocarbons and PFCs are compared (Figure 1.3), it is apparent they have very similar boiling points, even though the molecular mass of the PFCs is about four times higher than that of the corresponding hydrocarbons. In contrast to typical hydrocarbon systems, branching has a negligible effect on the boiling points of PFCs (Figure 1.4). Perfluorinated amines, ethers, and ketones usually have much lower boiling points than their hydrocarbon analogs. An interesting fact is that the boiling points of PFCs are only 25–30 ◦ C higher than those of noble gases of similar molecular mass (Kr, Mr 83.8 g mol−1 , b.p. −153.4 ◦ C; Xe, Mr 131.3 g mol−1 , b.p. −108.1 ◦ C; and Rn, Mr 222 g mol−1 , b.p. −62.1 ◦ C). In other aspects also, for example, their limited chemical reactivity, PFCs resemble the noble gases. Another consequence of the low polarizability of PFCs is the occurrence of large miscibility gaps in solvent systems composed of PFCs and hydrocarbons. The occurrence of a third, ‘‘fluorous,’’ liquid phase in addition to the ‘‘organic’’ and ‘‘aqueous’’ phases has been extensively exploited in the convenient and supposedly ecologically benign ‘‘fluorous’’ chemistry, which is discussed in detail in Sections 6 and 7. 200

Boiling point (°C)

150 100 50 0 –50 –100 –150 –200 1

2

3

4

5

6

7

8

9

10

Chain length n (for CnH2n+2 or CnF2n+2) Figure 1.3 The boiling points of homologous alkanes () compared with those of the corresponding perfluoroalkanes () [36].

9

1 Introduction

4

5

6

40 35 Boiling points (°C)

10

36.1

30 25

30.1

29.3

27.9

29.5

20 15 10 9.5

5 0 4

5

6

Figure 1.4 Boiling points of linear and branched isomers of perfluoropentane (white bars) and pentane (gray bars) [36].

Another very prominent characteristic resulting from their weak intermolecular interaction is the extremely low surface tension (γ ) of the perfluoroalkanes. They have the lowest surface tensions of any organic liquids (an example is given in Table 1.4) and therefore wet almost any surface [36]. Solid PFC surfaces also have extremely low surface energies (γ c ). Thus, PTFE (Teflon) has a γ c value of 18.5 dyn cm−1 , which is the reason for the antistick and low-friction properties used for frying pans and other applications. That this effect is directly related to the fluorine content becomes obvious on comparison of the surface energies of poly(difluoroethylene) (25 dyn cm−1 ), poly(fluoroethylene) (28 dyn cm−1 ), and polyethylene (31 dyn cm−1 ). If only one fluorine atom in PTFE is replaced by more polarizable chlorine, the surface energy of the resulting poly(chlorotrifluoroethylene) jumps to 31 dyn cm−1 , the same value as for polyethylene [41]. The decisive aspect of achieving low surface energies seems to be a surface which is densely covered by fluorine atoms. Accordingly, the lowest surface energies of any material observed are those of fluorinated graphites (C2 F)n and (CF)n , ∼6 dyn cm−1 [42]. Monolayers of perfluoroalkanoic acids CF3 (CF2 )n COOH also have surface energies ranging between 6 and 9 dyn cm−1 if n ≥ 6 [41b]. The same effect is observed for alkanoic acids containing only a relatively short perfluorinated segment [at least CF3 (CF2 )6 ] at the end of their alkyl chain, which is then displayed at the surface. When a hydrophilic functional group is attached to a PFC chain, the resulting fluorosurfactants (e.g., n-Cn F2n + 1 COOLi, with n ≥ 6) can reduce the surface tension of water from 72 to 15–20 dyn cm−1 compared with 25–35 dyn cm−1 for analogous hydrocarbon surfactants [43].

1.4 The Unique Properties of Organofluorine Compounds

Most unusual types of surfactant are the so-called diblock amphiphiles F(CF2 )m (CH2 )n H, which have both hydrocarbon and PFC moieties. At the interface between an organic and a ‘‘fluorous’’ phase (e.g., a liquid PFC), they show the behavior of typical surfactants [44], for example, micelle formation. Whereas intermolecular interactions between perfluoroalkanes are very weak, fairly strong electrostatic interactions are observed for some partially fluorinated hydrocarbons (HFCs), because of local, noncompensated carbon–fluorine dipole moments. The most pronounced effects of this kind are observed when bonds to fluorine and hydrogen arise from the same carbon atom. In such circumstances, the polarized C–H bonds can act as hydrogen-bond donors with the fluorine as the acceptor. The simplest example of this effect is difluoromethane. If the boiling points of methane and the different fluoromethanes are compared (Figure 1.5), the nonpolar compounds CH4 and CF4 are seen to have the lowest boiling points; the more polar compounds CH3 F and CHF3 boil at slightly higher temperatures. The maximum is for CH2 F2 , which has the strongest molecular dipole moment and which can – at least in principle – form a three-dimensional hydrogen-bond network similar to that of water with the C–H bonds acting as the hydrogen-bond donors and C–F bonds as the acceptors (Figure 1.6) [45]. A different type of strong electrostatic interaction is observed between arenes and perfluoroarenes (a detailed discussion of this phenomenon can be found in Ref. [47]). Benzene (m.p. 5.5 ◦ C; b.p. 80 ◦ C) and hexafluorobenzene (m.p. 3.9 ◦ C; b.p. 80.5 ◦ C) are known to have very similar phase-transition temperatures. In contrast, an equimolar mixture of both compounds gives a crystalline 1:1 complex melting at 23.7 ◦ C, which is about 19 ◦ C higher than those of the individual components [48]. In contrast to C6 H6 and C6 F6 , which crystallize in an edge-to-face, fishbone pattern, C6 H6 ·C6 F6 co-crystals contain both components in alternating, tilted parallel, and Number of fluorine substituents n (CH4-nFn) 0

1

2

3

4

0

2.5 1.85

1.97

Boiling point (°C)

–40

2

1.65 –51.6

–60

1.5

–80

–78.6

–82.2

–100 –128

–120 –140

0 –180

0.5

–161

–160

1

Dipole moment μ (D)

–20

0 0

Figure 1.5 Boiling points (gray bars) and dipole moments (D) (, numerical values in italics) of methane and the different fluoromethanes CH4 – n Fn [36].

11

12

1 Introduction

+0.22

–0.44 H H

–0.90

H H

F H +0.53

–0.39

+0.17

F H

+1.58

F

F

F

F

μ

(a)

δ – δ+ F H

δ– δ+ F H

F H

F H (b)

Figure 1.6 (a) Comparison of the distribution of natural partial charges q (e) on CH4 , CH2 F2 , and CF4 (MP2/6–31+G** level of theory) [46] and (b) the calculated structure (AM1) of a doubly

hydrogen-bridged difluoromethane dimer. The electrostatic potential (red denotes negative and blue positive partial charges) is mapped on the electron isodensity surface [40].

Figure 1.7 X-ray crystal structure of the benzene–hexafluorobenzene 1:1 complex, measured at 30 K in the lowest-temperature modification [49b].

approximately centered stacks with an interlayer distance of about 3.4 A˚ and a centroid–centroid distance of about 3.7 A˚ (Figure 1.7). Neighboring stacks are slightly stabilized by additional lateral Caryl –H···F contacts [49]. Similar structures have been observed for a variety of other arene–perfluoroarene complexes [47], indicating that this kind of interaction is a generally occurring phenomenon for this type of structure [50]. Evidence based on structural [49] and spectroscopic data [51] and on quantum chemical calculations [52] (Figure 1.8) indicates that the observed arene–perfluoroarene interactions are mainly the consequence of strong quadrupolar electrostatic attraction [53]. The usual interactions driving ‘‘aromatic stacking forces,’’ for example, dispersion interactions with a distance dependence of r −6 , seem to play an additional major role in this phenomenon. The occurrence of a charge-transfer complex between electron-rich benzene and electron-deficient hexafluorobenzene can, on

1.4 The Unique Properties of Organofluorine Compounds

F

H H H

H

F

H

F

Figure 1.8 Schematic representation of the complementary quadrupole moments of benzene (a) (−29.0 × 10−40 C m−2 ) and hexafluorobenzene (b) (+31.7 × 10−40 C m−2 ) [53]. The color pictures show the electrostatic potentials mapped on the isodensity surfaces

F F

H

(a)

F

(b) (B3LYP/6–31G* level of theory) [40, 46]. In benzene (far left), the largest negative charge density (coded in red) is located above and below the plane of the π -system. In contrast, in hexafluorobenzene, these locations carry a positive partial charge (coded in blue).

the other hand, be excluded by spectroscopic data. The quadrupole moments of benzene (−29.0 × 10−40 C m−2 ) and hexafluorobenzene (+31.7 × 10−40 C m−2 ) have a very similar order of magnitude but with their different signs the compounds form a complementary pair, interacting with a distance dependence of r −5 . The directionality of the quadrupolar interaction is considered to be the main force driving preference for the sandwich-like arrangement of the complementary arenes in the solid state. Ab initio and density functional theory (DFT) calculations gave estimates between −3.7 and −5.6 kcal mol−1 (assuming an interplanar distance of ˚ for the interaction energy between a parallel, but slightly shifted heterodimer 3.6 A) as found in the crystal structure. The interaction within the heterodimer was estimated to be 1.5–3 times stronger than within the corresponding benzene or hexafluorobenzene homodimers. Another interesting result from the calculations is that the contribution of the dispersion interactions to the overall binding energy of the heterodimer is even stronger than that of the electrostatic interaction. Electrostatic interactions resulting from the polarity of the carbon–fluorine bond play an important role in the binding of fluorinated biologically active compounds to their effectors [54] (discussed in detail in Section 9) and for the mesophase behavior of fluorinated liquid crystals [55] (Section 8.4). The consequences of the low polarizability of perfluorinated molecular substructures have been put into commercial use for CFC refrigerants, fire-fighting chemicals, lubricants, polymers with anti-stick and low-friction properties, and fluorosurfactants. 1.4.2 Chemical Properties

The most obvious characteristic of fluoroorganic compounds is the extreme stability of the carbon–fluorine bond [56]. The stability increases with increase in the number of fluorine substituents bound to the same carbon atom. This increase

13

14

1 Introduction

F F

F F

F

+

F

F F

Figure 1.9 Resonance stabilization of the carbon–fluorine bond in tetrafluoromethane, and electrostatic and steric shielding against nucleophilic attack on the central carbon atom. The electrostatic potentials are mapped on the electron isodensity surface (calculation at the MP2/6–31+G* level of theory [40, 46]; red denotes negative and blue positive partial charges).

in stability is reflected in the lengths of the C–F bonds in the series CH3 F (140 pm) > CH2 F2 (137 pm) > CHF3 (135 pm) > CF4 (133 pm) [calculation at the MP2/6–31+G(d,p) level of theory] [46]. The main reason for this stabilization is the nearly optimum overlap between the fluorine 2s and 2p orbitals and the corresponding orbitals of carbon; this allows the occurrence of dipolar resonance structures for multiply fluorine-substituted carbon (Figure 1.9). The consequences for chemical reactivity of this ‘‘self-stabilization’’ of multiple fluorine substituents on the same carbon atom are discussed in more detail in Section 2.3.4. In addition to this thermodynamic stabilization, in PFCs additional kinetic stability is derived from the steric shielding of the central carbon atom by a ‘‘coating’’ of fluorine substituents. The three tightly bound lone electron pairs per fluorine atom and the negative partial charges are an effective electrostatic and steric shield against any nucleophilic attack targeted against the central carbon atom. PFCs are, therefore, extremely inert against basic hydrolysis. PTFE, for example, can even withstand the action of molten potassium hydroxide. At high temperatures, PFCs are attacked by strong Lewis acids, for example, aluminum chloride. In such reactions, decomposition is initiated by the removal of a fluoride ion from the fluorous ‘‘protection shield,’’ rendering the resulting carbocation open to nucleophilic attack. Another mode of degradation of PFCs is by strong reducing agents at elevated temperatures. Thus PFCs are decomposed on contact with molten alkali metals and also on contact with iron at 400–500 ◦ C. The latter type of reaction has even been utilized for the industrial synthesis of perfluoroarenes by reductive aromatization of perfluorocycloalkanes (Section 2.4.2). Because of its strongly negative inductive effect, fluorine substitution tends to increase dramatically the acidity of organic acids [57, 58] (Table 1.5). For example, the acidity of trifluoroacetic acid (pK a = 0.52) is four orders of magnitude higher than that of acetic acid (pK a = 4.76). Even very weak acids, for example, tertbutanol (pK a = 19.0), are converted by fluorination into moderately strong acids [(CF3 )3 COH, pK a = 5.4]. The inductive effect of fluorination also reduces the basicity of organic bases by approximately the same order of magnitude (Table 1.6). In contrast with basicity, the nucleophilicity of amines is influenced much less by fluorinated substituents. Other effects of fluorine substitution in organic compounds include a strong influence on lipophilicity and the ability of fluorine to participate in hydrogen bonding either as a hydrogen-bond acceptor or as an inductive activator of a

1.4 The Unique Properties of Organofluorine Compounds Table 1.5

Acidities (pK a ) of organic acids in comparison with their fluorinated analogs [58].

Acid

pK a

CH3 COOH CF3 COOH C6 H5 COOH C6 F5 COOH CH3 CH2 OH CF3 CH2 OH (CH3 )2 CHOH (CF3 )2 CHOH (CH3 )3 COH (CF3 )3 COH C6 H5 OH C6 F5 OH

4.76 0.52 4.21 1.75 15.9 12.4 16.1 9.3 19.0 5.4 10.0 5.5

Table 1.6 Basicities (pK b ) of organic bases in comparison with their fluorinated analogs [58].

Base

pK b

CH3 CH2 NH2 CF3 CH2 NH2 C6 H5 NH2 C6 F5 NH2

3.3 8.1 9.4 14.36

hydrogen-bond donor group. This behavior has a substantial effect on the biological activity of fluorochemicals and is discussed in more detail in Section 4.5. 1.4.3 Ecological Impact

Despite or, better, because of their extreme chemical stability, PFCs and halofluorocarbons have a dramatic impact on the global environment; this was nearly impossible to predict when the substances were first introduced into industrial mass production and ubiquitous use. 1.4.3.1 Ozone Depletion by Chlorofluorocarbons Because of their extreme stability against all kinds of aggressive chemical agents, for example, radicals, PFCs, and halofluorocarbons are not degraded in the lower layers of the atmosphere as are other pollutants. After several years, or even decades, they finally reach the stratosphere at altitudes of 20–40 km [59, 60]. In this layer, under the influence of short-wave UV irradiation, ozone is formed continuously (Scheme 1.2). This stratospheric ozone plays an essential role in

15

16

1 Introduction

O2

O + O

hν

O3 + M*

O + O2 + M

Scheme 1.2 Mechanism of ozone formation in the stratosphere [59]. Dioxygen is photochemically split into atomic oxygen, which adds to another dioxygen molecule. The excess energy from the recombination is carried away by a collision partner (M).

HOCI HO

H2O

HCI

hν

O3

CI H3C CH4 F3C

hν hν

HO

O2 O2 HOO

H2O CIO

O2 O NO2 NO hν

NO2

CIONO2

CF3CI Figure 1.10

Catalytic ozone degradation by CFCs in the stratosphere [59].

preserving life on Earth by absorbing the short-wavelength UV radiation which would otherwise lead to an increase in photochemically induced mutations in most life forms. For humans, overexposure to short-wave UV irradiation results in a dramatically increased risk of skin cancer. Many crops and other plants also react rather sensitively towards an increase in UV exposure. Although CFCs are highly stable in the lower atmospheric layers, in the stratosphere they are slowly photolyzed by the ambient short-wavelength UV radiation, which also drives ozone formation. The bonds in CFCs most susceptible to photolytic dissociation are the carbon–chlorine bonds; chlorine and perfluoroalkyl radicals are liberated. The chlorine radicals react with ozone with the formation of oxygen and chlorooxide radicals, which are recycled back to chlorine radicals by reaction with atomic oxygen, nitrous oxide, nitric oxide, or hydroperoxy radicals (Figure 1.10). Chlorine radicals also react with stratospheric methane to give hydrochloric acid, which is rapidly re-oxidized to chlorine by hydroxyl radicals. In summary, stratospheric ozone is depleted, in a catalytic process, faster than it can be replenished by the natural, UV-driven process [60]. It has also been speculated that the concomitantly generated perfluoroalkyl radicals play a minor role in ozone depletion but, in contrast with chlorine, the trifluoromethyl radical, for example, is cleared from the atmosphere relatively quickly via its irreversible conversion to carbonyl difluoride (CF2 O) [61]. Whereas bromine (arising from bromofluorocarbon-based fire-fighting chemicals, for example, CF2 Br2 ) has a similar effect to chlorine, fluorine radicals do not contribute very much to ozone depletion, because they are rapidly removed from the catalytic cycle by irreversible formation of highly persistent hydrofluoric acid.

1.4 The Unique Properties of Organofluorine Compounds

When Molina and Rowland made their prediction in 1974, world production of CFCl3 and CF2 Cl2 was ∼0.3 and 0.5 Mton a−1 , respectively; fluorocarbon production in the United States was growing by 8.7% per year around 1970 [60]. Six years later, and every year since then, the predicted hole in the ozone layer was detected over Antarctica, when the chlorine concentration in the same atmospheric layer was ∼2000 pmol mol−1 [62]. After this clear evidence of the deleterious effects of CFCs, in 1987 this class of substance and most bromofluorocarbons were banned from further industrial use in the Montreal Protocol (ratified by the first 29 states in 1989). The lifetime of stratospheric CFCs lasts several decades. Although first effects of their phasing out are already becoming visible, full recovery of the ozone layer can be expected no earlier than ∼2040. Because CFCs had many essential functions in all aspects of our daily life (for example, refrigerants, foaming agents, or propellants for aerosol cans), subsequent to the Montreal Protocol an intensive search for potential replacements was initiated. CFC replacements so far include hydrofluorocarbons (for example, CF3 CFH2 , marketed as HFC-134a), hydrochlorofluorocarbons (HCFCs), and partially fluorinated ethers (for example, CH3 OCF3 ). These substances are much less stable to attack by radicals in the lower atmosphere and therefore cannot reach the stratosphere where they would deplete the ozone layer [63]. 1.4.3.2 Greenhouse Effect In addition to their long atmospheric lifetime, fluorocarbons also have strong infrared absorption bands between 1000 and 1400 cm−1 , where the atmosphere is relatively transparent. This IR absorption is used for analytical determination of the concentration of the different organofluorine compounds in the stratosphere. The infrared absorption of CFCs is much stronger than that of carbon dioxide, rendering them a potential contributor to global warming (Table 1.7). On the other hand, because of the relative quantities of the different greenhouse gases released into the atmosphere, CFCs and related compounds (for example, cyclic perfluoroalkanes [64] and SF6 , used as an insulating gas in high-voltage installations) have a negligible effect on global warming. For example, in 2000, emissions of CO2 were 200 000 times greater than the combined emissions of HFCs and PFCs [62]. However, since the quantities of first-generation CFC replacements, such as HFC-134a, are expected to grow rapidly, over the past decade more attention has been devoted to the development of a second generation of replacements with significantly reduced global warming potential (GWP) [66a, 67]. Examples are hydrofluoroolefins (HFOs), such as trans-1,3,3,3-tetrafluoro-1-propene (HFO1234ze), as a potential replacement for HFC-134a as a blowing agent and as a propellant (Scheme 1.3). Another replacement, in particular for use in automotive air conditioners, is 2,3,3,3-tetrafluoro-1-propene (HFO-1234yf). Also chlorinated compounds, such as 1-chloro-3,3,3-trifluoro-1-propene (HFO-1233zd), are under development for refrigeration. Despite their chlorine content, such chloroolefins have an ODP of close to zero. Some of the most potent fluorine-containing greenhouse gases are not produced on purpose but are by-products of industrial processes. Thus, trifluoromethane

17

18

1 Introduction Atmospheric lifetimes, global warming potential (GWP), and ozone-depleting potential (ODP) of different fluorochemicals. The GWP of a material is the integrated radiative forcing over 100 years after release of 1 kg divided by the integrated radiative forcing over the same period from release of 1 kg of carbon dioxide [62, 65, 66a].

Table 1.7

Compound

Atmospheric lifetime (years)

CF4 C2 F6 CF3 Cl (CFC-13) C2 F5 Cl (CFC-115) CF3 Br (Halon 1301) SF5 CF3 SF6 CHF3 (HFC-23) CH2 FCF3 (HFC-134a) C4 F9 OC2 H5 (HFE-7200) HFO-1234yf HFO-1234ze HFO-1233zd

F F

F F

HFO-1234yf

50 000 10 000 640 1 700 65 1 000 3 200 243 13.6 0.77 — — —

F F

F F

HFO-1234ze

Cl F

F F

GWP

ODP

5 700 11 400 14 000 10 300 6 900 17 500 22 200 14 800 1 600 55 4 6 7

— — 1.0 0.6 10.0 — — — — — — — —

Scheme 1.3 Second-generation CFC replacements with reduced global warming potential [64].

HFO-1233zd

(CHF3 ) is a product of overfluorination during the technical production of HCFC22 (CHClF2 ), and CF4 and C2 F6 are mostly formed during aluminum production by melt electrolysis of cryolite (Na3 AlF6 ). Most of the SF6 and the similarly greenhouse potent SF5 CF3 [65] released into the atmosphere are by-products from electrochemical fluorination processes. It has been proposed to make use of the greenhouse potential of CFCs for the ‘‘terraforming’’ of Mars [66b]. Addition of 400 ppb to the Martian atmosphere would lead to a 70 K increase in its surface temperature. 1.4.4 Physiological Properties

In their interaction with living organisms, the behavior of organofluorine compounds is again extreme. Most aliphatic PFC, CFCs, and related compounds are essentially ‘‘ignored’’ by organisms [68]. Because of their generally low reactivity, comparable to that of the noble gases, they are not metabolized. Because they are quite volatile and do not dissolve readily either in aqueous (e.g., blood) or fatty (e.g., nervous system) compartments of the body, they are usually not even recognized as ‘‘foreign’’ but just exhaled through the lungs. This inertness results in some

1.4 The Unique Properties of Organofluorine Compounds

unique opportunities for medical applications, which will be discussed in detail in Sections 9.9 and 9.10. A very few fluorine-containing substances are, on the other hand, extremely toxic. The most (in)famous of these are fluoroacetic acid (LD50 4.7 mg kg−1 in rats, LD100 5 mg kg−1 in humans [68] – the doses after which 50 or 100%, respectively, of the tested individuals die) and perfluoroisobutene (LC50 < 1 ppm – the concentration in ambient air for 4 h after which half of the tested individuals die). Fluoroacetic acid [69] has been identified as the toxic component of the South African plant gifblaar (Dichapetalum cymosum) [70]. Its mechanism of action is based on inhibition of the citric acid cycle, the main source of metabolic energy in all animals [71]. In this cycle, fluoroacetate can replace acetate as a substrate of aconitase, an enzyme complex which usually forms citrate by addition of acetate to α-oxoglutarate. The resulting fluorocitrate is binds tightly to the enzyme, but cannot be further converted to cis-aconitate and isocitrate [72], thus inhibiting aconitase. It must also be remembered that some fluoroorganic compounds are, if ingested, degraded to toxic metabolites. This phenomenon occurs with ω-fluoro fatty acids, aldehydes, alcohols, amines, and related compounds – because of metabolic oxidation of fatty acids by stepwise cleavage of C2 units, ω-fluoro fatty acids with an even number of carbon atoms end up as toxic fluoroacetate [e.g., F(CH2 )15 COOH, which has an LD50 of 7 mg kg−1 in mice]. Odd-numbered ω-fluoro fatty acids are metabolized to the less critical 3-fluoropropionate. This phenomenon is known as the ‘‘alternating’’ toxicity of ω-fluoro fatty acids [72] (Scheme 1.4). Perfluoroisobutene is the most toxic fluorinated compound yet discovered, with an LC50 of less than 1 ppm [73]. The target organs of the compound are the liver and lungs. Inhalation can cause lethal edema even 1–2 days after the end of exposure. Perfluoroisobutene is assumed to add to the thiol group of glutathione (Gly–Cys–γ Glu), a tripeptide which serves as a ubiquitous intracellular antioxidant and which is also used by the liver to clear toxins and their metabolites as S-conjugates by renal excretion (Scheme 1.5). The mechanism of toxicity is considered to be linked to the electrophilicity of perfluoroisobutene, causing depletion of intracellular antioxidant nucleophiles [74]. Pretreatment with N-acetylcysteine offers a certain degree of protection against its lethal effects [75]. The toxicity of perfluoroisobutene and other (less toxic) perfluoroolefins is of some practical relevance in daily life, because these compounds can also be formed at elevated temperatures during pyrolysis of PTFE (‘‘polymer fume fever’’), which is widely used as an anti-stick coating for household appliances [76]. Some widely used fluorosurfactants have recently become the focus of environmental concern. Compounds such as perfluorooctylsulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have environmental lifetimes on a nearly geological time scale. Traces of these substances have been found to be present in the remotest locations on Earth and the source of the contamination remains unclear [77]. There is some evidence of negative physiological effects of these widely used fluorosurfactants. In particular, PFOA has attracted some critical attention as a potential developmental toxin in rats [67] or as an immune suppressant in humans [78].

19

20

1 Introduction First cleavage site

O S-CoA

R

FAD

Oxidation

FADH2 O S-CoA

R

H2O

Hydratation

OH O S-CoA

R

NAD+

Oxidation

NADH + H+ O

O

S-CoA

R

HS-CoA

Thiolysis Next cleavage site R

O

+ S-CoA

O S-CoA

Scheme 1.4 The ‘‘alternating’’ toxicity of ω-fluorocarboxylic acids can be explained by the oxidative metabolism of fatty acids in C2 units. Only if the number of carbon atoms is even is the final oxidation product the highly toxic fluoroacetate [72]. Odd-membered ω-fluoro fatty acids are metabolized to the less toxic 3-fluoropropionate.

F3C F

F3 C

CF3 F

Glutathione-SH

S

H

CF3 F F

Gly-Cys-γ-Glu

Scheme 1.5

Formation of the toxic glutathione–perfluoroisobutene adduct.

Some major producers have, therefore, already started to replace these surfactants by more readily degradable alternative compounds [79]. 1.4.5 Analysis of Fluorochemicals: 19 F NMR Spectroscopy

Naturally and exclusively occurring 199 F has a nuclear spin of 1/2, and an NMR sensitivity only 20% less than that of 1 H. This renders 19 F NMR spectroscopy the method of choice for the analysis and elucidation of the structure of fluorinated

References

NF3

F2

SF6

CF4 BF3 δ

+500

+400

+300

+200

+100

0

–100

–200

ArF =C-F C(O)F

CFH2

CF2 CF2H

CF3

CHF

CF =N-F CFCI3

CF3COOH

C6F6

CFH3 δ

+150

+100

Figure 1.11 [80].

+50 19 F

0

–50

–100

–150

–200

–250

–300

chemical shifts for different fluorochemicals and fluorinated fragments

compounds [80, 81] (Figure 1.11). Depending on their chemical environment, the 19 F resonances of fluoroorganic and fluoroinorganic compounds cover a range of over 400 and 700 ppm, respectively. CFCl3 is typically used as a reference standard. References 1. Chambers, R.D. (1973) Fluorine in Or-

2.

3.

4.

5.

6.

ganic Chemistry, John Wiley & Sons, Inc., New York. Hudlicky, M. (1976) Chemistry of Organic Fluorine Compounds – A Laboratory Manual with Comprehensive Literature Coverage, Ellis Horwood, New York. Banks, R.E. (1982) Preparation, Properties and Industrial Applications of Organofluorine Compounds, Ellis Horwood, New York. Knunyants, I.C. and Yakobson, G.G. (1985) Syntheses of Fluoroorganic Compounds, Springer, Berlin. Banks, R.E., Sharp, D.W.A., and Tatlow, J.C. (1986) Fluorine: The First Hundred Years (1886–1986), Elsevier Sequoia, Lausanne. Olah, G.A., Chambers, R.D., and Surya Prakash, G.K. (1992) Synthetic

7.

8.

9.

10.

11.

Fluorine Chemistry, John Wiley & Sons, Inc., New York. Kitazume, T., Yamazaki, T., and Taguchi, T. (1993) Fusso no Kagaku (Chemistry of Fluorine), Kodansha Scientific, Tokyo. Banks, R.E., Smart, B.E., and Tatlow, J.C. (1994) Organofluorine Chemistry, Plenum Press, New York. Smart, B.E. (ed.) (1996) Special issue on organofluorine chemistry. Chem. Rev., 96, 1557–1823. Chambers, R.D. (1997) Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates, Topics in Current Chemistry, vol. 192, Springer, Berlin. Chambers, R.D. (1997) Organofluorine Chemistry: Techniques and Synthons, Topics in Current Chemistry, vol. 193, Springer, Berlin.

21

22

1 Introduction 12. Soloshonok, V.A. (2000) Enantio-

13.

14.

15.

16. 17.

18.

19.

20. 21.

22.

23.

24. 25.

controlled Synthesis of Fluoro-Organic Compounds – Stereochemical Challenges and Biomedicinal Targets, John Wiley & Sons, Inc., New York. Hiyama, T. (2000) Organofluorine Compounds: Chemistry and Applications, Springer, Berlin. B´egu´e, J.-P. and Bonnet-Delpon, D. (2008) Bioorganic and Medicinal Chemistry of Fluorine, John Wiley & Sons, Inc., New York. (a) Moissan, H. (1886) C. R. Acad. Sci., 102, 1534; (b) Moissan, H. (1886) C. R. Acad. Sci., 103, 202; (c) Moissan, H. (1886) C. R. Acad. Sci., 103, 256. Borodine, A. (1863) Ann. Chem. Pharm., 126, 58–62. Elliott, A.J. (1994) in Organofluorine Chemistry: Principles and Commercial Applications (eds R.E. Banks, B.E. Smart, and J.C. Tatlow), Plenum Press, New York, pp. 145–157. (a) Rhodes, R. (1986) The Making of the Atomic Bomb, Simon and Schuster, New York; (b) Rhodes, R. (1995) Dark Sun: The Making of the Hydrogen Bomb, Simon and Schuster, New York. For an overview on applications of fluoroorganic compounds: (eds R.E. Banks, B.E. Smart, and J.C. Tatlow) (1994) Organofluorine Chemistry: Principles and Commercial Applications, Plenum Press, New York. Molina, M.J. and Rowland, F.S. (1974) Nature, 249, 819. Banks, R.E. (1986) in Fluorine: The First Hundred Years (1886–1986) (eds R.E. Banks, D.W.A. Sharp, and J.C. Tatlow), Elsevier Sequoia, Lausanne, pp. 2–26. Gribble, G.W. (2002) in Handbook of Environmental Chemistry, Part N, vol. 3, (ed. A.H. Neilson), Springer, Heidelberg, 121ff. Schmedt auf der G¨unne, J., Mangstl, M., and Kraus, F. (2012) Angew. Chem. Int. Ed., 51, 7847–7849. Harper, D.B. and O’Hagan, D. (1994) Nat. Prod. Rep., 11, 123–133. (a) Olah, G.A. (2001) A Life of Magic Chemistry, John Wiley & Sons, Inc., New York, p. 96; (b) McLain, S.E, Benmore, C.J., Siewenie, J.E., Urquidi, J. and

26. 27. 28.

29. 30.

31. 32. 33.

34.

35. 36.

37. 38. 39.

40.

Turner, J.F.C. (2004) Angew. Chem. Int. Ed., 43, 1952–1955. Peters, D. and Miethchen, R. (1996) J. Fluorine Chem., 79, 161–165. Finkel, A.J. (1973) Adv. Fluorine Chem., 7, 199. Flahaut, J. and Viel, C. (1986) in Fluorine: The First Hundred Years (1886–1986) (eds R.E. Banks, D.W.A. Sharp, and J.C. Tatlow), Elsevier Sequoia, Lausanne, pp. 27–43. Kr¨atz, O. (2001) Angew. Chem. Int. Ed., 40, 4604–4610. Hollemann, A.F. and Wiberg, E. (1985) Lehrbuch der Anorganischen Chemie, 33rd edn, Walter de Gruyter, Berlin, pp. 387–448. Sen, K.D. and Jorgensen, C.K. (1987) Electronegativity, Springer, New York. Christe, K.O. (1986) Inorg. Chem., 25, 3721–3722. (a) Weinland, R.F. and Lauenstein, O. (1899) Z. Anorg. Allg. Chem., 20, 40; (b) Bode, H., Jenssen, H., and Bandte, F. (1953) Angew. Chem., 65, 304; (c) Chaudhuri, M.K., Das, J.C., and Dasgupta, H.S. (1981) J. Inorg. Nucl. Chem., 43, 85. (a) Groult, H. (2003) J. Fluorine Chem., 119, 173–189; (b) Groult, H., Devilliers, D., and Vogler, M. (1997) Trends in the fluorine preparation process. Proc. Curr. Top. Electrochem., 4, 23–39; (c) Rudge, A.J. (1971) in: Industrial Electrochemical Processes, (ed. A.T. Kuhn), Elsevier, Amsterdam, pp. 1–69. Johns, K. and Stead, G. (2000) J. Fluorine Chem., 104, 5–18. (a) Smart, B.E. (1994) in Organofluorine Chemistry: Principles and Commercial Applications, (eds R.E. Banks, B.E. Smart, and J.C. Tatlow), Plenum Press, New York, pp. 57–88; (b) Dunitz, J.D. (2004) ChemBioChem, 5, 614–621. Bondi, A. (1964) J. Phys. Chem., 68, 441. Nagel, J.K. (1990) J. Am. Chem. Soc., 112, 4740. Wavefunction (1998) Spartan SGI Version 5.1.3, Wavefunction, Inc., Irvine, CA. Fl¨ukinger, P., L¨uthi, H.P., Portmann, S., and Weber, J. (2002) MOLEKEL 4.2, Swiss Center for Scientific Computing, Manno.

References 41. (a) Wu, S. (1982) Polymer Interface and

42.

43.

44.

45.

46.

47.

Adhesion, Marcel Dekker, New York; (b) Pittman, A.G. (1972) Fluoropolymers, in High Polymers, (ed. L.A. Wall), Chapter 13, vol. 25, John Wiley & Sons, Inc., New York. Watanabe, N., Nakajima, T., and Touhara, H. (1988) Graphite fluorides, Studies in Inorganic Chemistry, vol. 8, Elsevier, Oxford. (a) Shinoda, K., Hato, M., and Hayasaki, T. (1972) J. Phys. Chem., 76, 909; (b) Kuneida, H. and Shinoda, K. (1976) J. Phys. Chem., 80, 2468; (c) Guo, W., Brown, T.A., and Fung, B.M. (1991) J. Phys. Chem., 95, 1829. (a) Russell, T.P., Rabolt, J.F., Twieg, R.J., Siemens, R.L., and Farmer, B.L. (1986) Macromolecules, 19, 1135; (b) Twieg, R.J., Russell, T.P., Siemens, R., and Rabolt, J.F. (1985) Macromolecules, 18, 1361; (c) Tirnberg, M.P. and Brady, J.E. (1988) J. Am. Chem. Soc., 110, 7797. Caminati, W., Melandri, S., Moreschini, P., and Favero, P.G. (1999) Angew. Chem. Int. Ed., 38, 2924–2925. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A. Jr., Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., and Pople, J.A. (1998) Gaussian 98, Revision A.6, Gaussian, Inc., Pittsburgh, PA. Meyer, E.A., Castellano, R.K., and Diederich, F. (2003) Angew. Chem. Int. Ed., 42, 1210–1250.

48. Patrick, C.R. and Prosser, G.S. (1960)

Nature, 187, 1021. 49. (a) Overell, J.S.W and Pawley, G.S.

50.

51.

52.

53.

54.

55. 56. 57. 58. 59. 60. 61.

(1982) Acta Crystallogr., Sect. B, 38, 1966–1972; (b) Williams, J.H., Cockcroft, J.K., and Fitch, A.N. (1992) Angew. Chem., 104, 1666–1669; (1992) Angew. Chem. Int. Ed., 31, 1655–1657. (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) Salonen, L.M., Ellermann, M., and Fiederich, F. (2011) Angew. Chem. Int. Ed., 50, 4808–4842. (a) Beaumont, T.G. and Davis, K.M.C (1967) J. Chem. Soc. B, 1131–1134; (b) Lamposa, J.D., McGlinchey, M.J., and Montgomery, C. (1983) Spectrochim. Acta, Part A, 39, 863–866. (a) West, A.P. Jr., Mecozzi, S., and Dougherty, D.A. (1997) J. Phys. Org. Chem., 10, 347–350; (b) Hern´andez-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. (a) Dahl, T. (1994) Acta Chem. Scand., 48, 95–106; (b) Williams, J.H. (1993) Acc. Chem. Res., 26, 593–598. McCarthy, J. (2000) Utility of fluorine in biologically active molecules: tutorial, division of fluorine chemistry. Presented at the 219th National Meeting of the American Chemical Society, San Francisco, CA, March 26, 2000. Kirsch, P. and Bremer, M. (2000) Angew. Chem. Int. Ed., 39, 4216–4235. O’Hagan, D. (2008) Chem. Soc. Rev., 37, 308–319. Schlosser, M. (1998) Angew. Chem. Int. Ed., 37, 1496–1513. Smart, B.E. (2001) J. Fluorine Chem., 109, 3–11. Rowland, F.S. (1996) Angew. Chem. Int. Ed. Engl., 35, 1786–1798. Molina, M.J. and Rowland, F.S. (1974) Nature, 249, 810–812. Ko, M.J.W., Sze, N.-D., Rodriguez, J.M., Weisenstein, D.K., Heisey, C.W.,

23

24

1 Introduction

62. 63. 64.

65.

66.

67. 68.

69.

70.

Wayne, R.P., Biggs, P., Canosa-Mas, C.E., Sidebottom, H.W., and Treacy, J. (1994) Geophys. Res. Lett., 21, 101. McCulloch, A. (2003) J. Fluorine Chem., 123, 21–29. McCulloch, A. (1999) J. Fluorine Chem., 100, 163–173. Paul, A., Wannere, C.S., Casalova, V., Schleyer, P.v.R., and III Schaefer, H.F. (2005) J. Am. Chem. Soc., 127, 15457–15469. Sturges, W.T., Wallington, T.J., Hurley, M.D., Shine, K.P., Shira, K., Engel, A., Oram, D.E., Penkett, S.A., Mulvaney, R., and Brenninkmeijer, C.A.M. (2000) Science, 289, 611–613. (a) U.S. Environmental Protection Agency (2011) Global Warming Potentials of ODS Substitutes, http://www. epa.gov/docs/ozone/geninfo/gwps.html (accessed 10 September 2012); (b) Gerstell, M.F., Francisco, J.S., Yung, Y.L., Boxe, C., and Aaltonee, E.T. (2001) Proc. Natl. Acad. Sci. U. S. A., 98, 2154–2157. Hogue, C. (2011) Chem. Eng. News, 89(31), 31–33. Ulm, K. (2000) in Houben-Weyl: OrganoFluorine Compounds, (eds B. Baasner, H. Hagemann, and J.C. Tatlow), vol. E10a, Georg Thieme, Stuttgart, pp. 33–58, and references cited therein. Zhu, X., Robinson, D.A., McEwan, A.R., and O’Hagan, D. (2007) J. Am. Chem. Soc., 129, 14597–14604. Marais, J.S.C. (1944) Onderstepoort J. Vet. Sci. Anim. Ind, 20, 67.

71. Stryer, L. (1988) Biochemistry, Freeman,

3rd edn., New York, pp. 373–396. 72. Peters, R.A. (1957) Adv. Enzymol. Relat.

Sub. Biochem., 113–159. 73. Makulova, I.D. (1965) Gig. Tr. Prof.

Zabol., 9, 20–23. 74. Lailey, A.F., Hill, L., Lawston, I.W.,

75. 76. 77.

78.

79.

80.

81.

Stanton, D., and Upshall, D.G. (1991) Biochem. Pharmacol., 42, S47–S54. Lailey, A.F. (1997) Hum. Exp. Toxicol., 16, 212–216. Waritz, R.S. and Kwon, B.K. (1968) Am. Ind. Hyg. Assoc. J., 29, 19–26. Martin, J.W., Smithwick, M.M., Braune, B.M., Hoekstra, P.F., Muir, D.C.G., and Mabury, S.A. (2004) Environ. Sci. Technol., 38, 373–380. Grandjean, P., Andersen, E.W., Budtz-Jørgensen, E., Nielsen, F., Mølbak, K., Weihe, P., and Heilmann, C. (2012) JAMA, 307, 391–397. Peschka, M., Fichtler, N., Hierse, W., Kirsch, P., Montenegro, E., Seidel, M., Wilken, R.D., and Knepper, T.P. (2008) Chemosphere, 72, 1534–1540. Fields, R. (1986) in Fluorine: The First Hundred Years (1886–1986) (eds R.E. Banks, D.W.A. Sharp, and J.C. Tatlow), Elsevier Sequoia, Lausanne, p. 287, and references cited therein. Berger, S., Braun, S., and Kalinowski, H.-O. (1994) 19F-NMR-Spektroskopie, NMR-Spektroskopie von Nichtmetallen, vol. 4, Georg Thieme, Stuttgart.

25

Part I Synthesis of Complex Organofluorine Compounds

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

27

2 Introduction of Fluorine

2.1 Perfluorination and Selective Direct Fluorination

Shortly after their first isolation of elemental fluorine in 1886, Moissan and his co-workers treated several organic substrates with this highly reactive gas. All these experiments, either at room temperature or at liquid nitrogen temperature, resulted in sometimes violent explosions. No major defined reaction products could be isolated. A plausible, first explanation for these discouraging results was proposed by W. Bockem¨uller in the 1930s, on the basis of thermochemical considerations. The energy released by formation of the highly stable carbon–fluorine bonds (∼116 kcal mol−1 ) is considerably greater than the energy needed for dissociation of carbon–carbon (∼83 kcal mol−1 ) or carbon–hydrogen bonds (∼99 kcal mol−1 ) [1]. A second problem is the extremely low homolytic dissociation energy of elemental fluorine (only 37 kcal mol−1 ), which allows the ready initiation of uncontrollable radical chain reactions, even at low temperatures and in the absence of light [2]. The first defined fluoroaliphatic compounds obtained by direct fluorination of organic substrates in liquid reaction media were characterized by Bockem¨uller [3] in the early 1930s and published with his thermochemical analysis. To control the immense reaction enthalpy, the fluorine gas was diluted with nitrogen or carbon dioxide. The organic substrate was dissolved in a cooled inert solvent, for example, CCl4 or CF2 Cl2 . A similar line of work was pursued in the United States by L. A. Bigelow [4], who studied the reaction of arenes with fluorine gas. In an alternative approach, volatile organic substrates were fluorinated in the gas phase on contact with a copper mesh. This work was pioneered by K. Fredenhagen and G. Cadenbach in the early 1930s [5] and then continued by N. Fukuhara and L. A. Bigelow [6] as part of the Manhattan Project (Figure 2.1). Vapor-phase fluorination finally permitted the preparation of (relatively) defined polyfluorination products from aliphatic hydrocarbons, benzene, or acetone. A modern, improved version of this general method, the LaMar (Lagow– Margrave) process, uses a nickel reactor with different temperature zones and Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

28

2 Introduction of Fluorine F2

D

H E

L

+

G C L I

A

O

M P N2

B K

Figure 2.1 Fluorination apparatus used by Fukuhara and Bigelow for the perfluorination of a variety of organic substrates [6]. Courtesy of the American Chemical Society.

silver-doped copper filings as a catalytic contact (Scheme 2.1). During the reaction, the concentration of fluorine in proportion to inert gas is slowly increased [7]. Another method used to control the high reaction enthalpy of fluorination is to coat the organic substrate as a thin film on sodium fluoride powder and reaction in a moving bed reactor with fluorine gas, diluted with nitrogen or helium. A slow, stepwise increase in the fluorine concentration also allows the clean perfluorination of fairly complex substrates [9] (Scheme 2.2). The first pure and fully characterized perfluorocarbons (PFCs) were obtained by the reaction of graphite with fluorine gas, yielding mainly carbon tetrafluoride [10]. An improved procedure, less prone to accidents, was reported by J. H. Simons and L. P. Block in 1937: passage of fluorine over graphite impregnated with catalytic amounts of mercuric chloride furnished a mixture of various PFCs in a controllable and reproducible reaction, proceeding ‘‘steadily and without explosions’’ [11]. The industrial-scale procedure probably most important for the synthesis of PFC-based solvents was developed during the Manhattan Project [12] (Figure 2.2). In the so-called cobalt trifluoride process (subsequently commercialized by F2 Chemicals as the Flutec process) [13], the large fluorination enthalpy is harnessed by dividing the reaction into two less exothermic steps. In the first step, CoF2 is oxidized with fluorine, at 350 ◦ C, to CoF3 . In the second step, the organic substrate is introduced and fluorinated by the CoF3 at a suitable temperature. The CoF2 formed is regenerated (i.e., reoxidized) to CoF3 in the next reaction cycle.

2.1 Perfluorination and Selective Direct Fluorination

RF-CH2-CH3

RF-CH2-CHF2

2 F2

RF-CH2-CF2

F

RF-CH-CF2H F

RF-CF2-CF2H F2

F

RF-CHF-CF2

RF-CF-CF2H

F

RF-CHF-CF2H

RF = CF3CF2CF2(CF3)2C−

RF-CF2-CF3

58%

F

F2/N2; temperature gradient

CF3 F3C

87%

F

F2/N2; temperature gradient

n-C7H15

CF3

F3C

62%

n-C7F15

F2/N2; temperature gradient

“Light Pennsylvania Paraffin Lubrication Oil”

12%

perfluorinated lubricant

F2/N2; temperature gradient

Scheme 2.1 Gas-phase perfluorination of a variety of hydrocarbons by the LaMar process. At the top the proposed mechanism of free radical direct fluorination of alkanes is shown [8].

F O

O 20%

O

O O

F2/He; −90 °C to r.t.

O F O F3C F 3C

F O F F O F O

CF3 CF3

Scheme 2.2 After adsorption by solid sodium fluoride, complex and sensitive organic compounds can be cleanly perfluorinated [9].

The cobalt trifluoride process is of particular value for the industrial perfluorination of organic substrates and it is based on the finding of Ruff and co-workers in the 1920s that high-valence metal fluorides such as AgF2 , CoF3 , and MnF3 are highly effective oxidative fluorination agents. Typical product distributions and the nature of the various rearrangement products indicate that the mechanism of the CoF3 and related processes involves single-electron transfers and carbocationic intermediates [14] (Scheme 2.3).

29

2 Introduction of Fluorine

30

B

A

D

C

A. Outlet tube B. Precipitator head C. Dust-settling tower D. High voltage electrode E. Inlet manifold F. Hydrocarbon feed inlet

G. Fluorine inlet H. Reactor end casting I. Bearing housing J. Shaft drive sprocket K. Inspection port L. Agitator paddle

E G

F

H I

J

M. Thermocouple well N. Reactor shell O. Agitator shaft P. Thermocouple fitting Q. Packing gland R. Shaft bearing S. Outlet port

N

K

O

S

L

M

P

Q

R

Figure 2.2 Schematic representation of the apparatus used to perform the cobalt trifluoride process [13]. Courtesy of the American Chemical Society.

step 1:

2 CoF2 + F2

−53 kcal·mol−1

2CoF3

step 2 :

R-H + 2 CoF3

−53 kcal·mol−1

R-F + HF + 2 CoF2

+·

C H

C H + CoF3

− H+ Oxidation

R′ C F

CoF3

+ R′ C

rearrangement

C

F· transfer CoF3 CoF3

+ F· transfer C CoF3

CF3CF2CF2CF2CF2CF3 (76%) CoF3, 360 °C

F3 C CF2CF3 F CF3CF2 (5%)

C F

F3 C F F3 C

C F

CF2CF2CF3 (11%)

F3C F3 C CF2CF3 F3C (1%)

Scheme 2.3 Two-step perfluorination of organic substrates by the cobalt trifluoride (Flutec) process. The mechanism is assumed to involve single-electron transfers and carbocationic intermediates [8].

2.1 Perfluorination and Selective Direct Fluorination

Figure 2.3 X-ray structure of C60 F18 obtained by selective fluorination of C60 with K2 PtF6 without solvent at 230–330 ◦ C [15].

Although the cobalt trifluoride process is most suitable for the production of industrial-scale quantities of PFCs, other high-valence metal fluorides are also attractive additions to the methodology toolbox for selective fluorination on a laboratory scale. K2 PtF6 was used for the selective fluorination of buckminsterfullerene (C60 ) to the partially fluorinated fluorofullerene C60 F18 , which was not accessible by other methods [15] (Figure 2.3). A major disadvantage of such metal fluorides, with extremely strong oxidizing power, in routine application is, nevertheless, the need to work either with volatile substrates in the gas phase or to use either no solvent at all or anhydrous hydrofluoric acid (aHF) as the only stable reaction medium. On the laboratory scale, the tendency of elemental fluorine to initiate radical chain reactions resulting in tar formation can be controlled by the appropriate choice of solvent. The solvent system CFCl3 –CHCl3 , sometimes with an additional 10% of ethanol, serves as an effective radical scavenger. The reaction enthalpy is controlled by dilution of the substrate in this solvent, by dilution of the fluorine gas with nitrogen or helium, and by use of a low reaction temperature. Under these conditions, the selective fluorination of cyclohexane derivatives in the tertiary axial position is possible in reasonable yields [16] (Scheme 2.4), supposedly by an electrophilic mechanism.

OAc

60% 10% F2/N2,

H +

Fδ Fδ−

CHCl3/CFCl3 (1:1);

OAc F

−78 °C

Scheme 2.4 Direct fluorination of aliphatic compounds in the tertiary position by an electrophilic mechanism [16].

31

32

2 Introduction of Fluorine

Under similar conditions, selective addition of fluorine to double bonds, even with complex organic substrates such as steroids, can also be achieved [17] (Scheme 2.5). O

O 35% 1% F2/N2, CFCl3/CHCl3/ EtOH (5:4:1); −75 °C

F F

O

O

H3C H3C

H H

AcO

Cl

Scheme 2.5 [17].

H3C H3C

40%

H

5% F2/N2, CFCl3, NaF; −78 °C

H AcO

Cl

F

H

Cl

F H

Cl

Selective direct fluorination of double bonds in complex organic compounds

One of the first examples of the industrial application of selective direct fluorination was the synthesis of the cytostatic 5-fluorouracil. In the most commonly used process, the precursor uracil is treated with nitrogen-diluted fluorine in hot water and the intermediate fluorohydrin is subsequently dehydrated either by heating the aqueous solution to 100 ◦ C or with sulfuric acid [18] (Scheme 2.6). O HN O

F

HN N H

Scheme 2.6

O

O

F2/N2 (2:1), H2O; 90 °C

O

78%

N H

OH

reflux, 16 h

F

HN O

N H

Direct fluorination process for industrial-scale production of 5-fluorouracil [18].

Towards the end of the 1990s especially, there have been great advances in the selective direct fluorination of even sensitive organic substrates. Some of the methods introduced by R. D. Chambers and co-workers are even fulfilling the requirements of robust and reproducible industrial processes, and the resulting products have become commercially available. The selective fluorination of β-dicarbonyl derivatives is best achieved in acetonitrile, which, because of its stability, is a particularly suitable solvent for direct fluorination. Typical reaction temperatures are conveniently in the range 0–5 ◦ C. With dialkyl malonates, addition of catalytic amounts of copper(II) nitrate allows the selective formation of the monofluoromalonates almost without difluorinated by-products [19] (Scheme 2.7). Enol acetates are cleanly converted into the respective α-fluoroketones [20]. Although clean, direct fluorination of aromatic compounds is possible [21], the selectivity of this process is not yet high enough for commercialization. Arenes

2.1 Perfluorination and Selective Direct Fluorination F EtO

OEt O

O

10% F2/N2, CH3CN,

O O Cu O O

OEt O

10 mol% Cu(NO3)2·5 H2O;

OEt

EtO

EtO

78%

O EtO

5 °C

OEt

O

OAc

F

56% 10% F2/N2, CH3CN; 0 °C

Scheme 2.7 Selective direct α-fluorination of carbonyl compounds. Copper salt catalysis supposedly acts via formation of the copper enolate complex [19, 20]. The formation of the corresponding copper complex of monofluoromalonate, the precursor of difluorinated products, is energetically disfavored.

are best fluorinated in acidic solvents such as sulfuric acid or formic acid, to obtain an electrophilic mechanism (Scheme 2.8). The main obstacle to large-scale industrial application of the potentially inexpensive direct fluorination of aromatic compounds is the difficult separation of the regioisomers and other by-products with higher or lower fluorine content. OMe

OMe

OMe

F

F

F +

10% F2/N2,

NO2

HCOOH; 10% C

δ+

F Fδ H

NO2

NO2

(50%)

(20%)

−

O

H O

Scheme 2.8 ‘‘Electrophilic’’ direct fluorination of activated arenes in acidic solvents [21].

Another approach to the control of the large reaction enthalpies in technical-scale direct fluorination is the use of microreactors [22]. These have three advantages compared with conventional arrangements: (i) the high surface-to-volume ratio for contact between the gas and liquid phases is especially advantageous for direct fluorinations, because it permits good mixing of the reactants and good temperature control; (ii) because the actual reaction volume is very small, the risk of runaway reactions or explosions is significantly reduced; and (iii) scale-up to industrial throughput is conveniently accomplished by the parallel operation of as many microreactors as necessary. Computational studies (P. Kirsch, unpublished work, 2003) on the structure and charge distribution of hydrogen-bonded F2 suggest a more differentiated view on the supposedly ‘‘electrophilic’’ mechanism of direct fluorination of aliphatic and aromatic hydrocarbons. Ab initio calculations indicate that even for the complex of F2 with the extremely strong hydrogen-bond donor HF as a model system, the energy of complex formation is very low – only 0.38 kcal mol−1 (MP2/6–31+G**//MP2/6–31+G** level of theory, ZPE, and BSSE correction) [23]

33

34

2 Introduction of Fluorine −0.439

0.434

0.016

2.157 95.9 −0.011

Scheme 2.9 Calculated gas-phase structure (MP2/6–31+G**//MP2/6–31+G** level of theory, ZPE and BSSE correction) (P. Kirsch, 2003, unpublished work) [23, 25] of the ˚ and F2 ···HF complex, with the length (A) angle (◦ ) of the central hydrogen bond and

the induced Mulliken partial charges (e). The natural partial charges on the F2 fluorine atoms are −0.02e and +0.02e, respectively. The formation of the complex is slightly exothermic by 0.38 kcal mol−1 .

(Scheme 2.9). Because of the low polarizability of the fluorine molecule, only very small partial charges are induced by the acceptance of a weak hydrogen bond from HF. This polarization alone (a natural charge of qF = +0.02e for the more electrophilic fluorine atom) seems to be too small to change the course of direct fluorination reactions from a radical to a polar electrophilic mechanism as proposed by Rozen and Gal [16] and Chambers and Spink [21a]. Experimentally, the achievement of a ‘‘clean’’ reaction when using polar protic solvents strongly suggests a pathway not involving free radicals. A detailed mechanistic study indicates that the key to ‘‘electrophilic’’ direct fluorination is not the direct polarization of F2 but the stabilization of the transition-state complex leading along a polar reaction trajectory by an electrostatic (hydrogen) bridge [24]. 2.2 Electrochemical Fluorination (ECF)

Another important technical process for the production of a variety of perfluorinated organic compounds – electrochemical fluorination (ECF) – was also developed during the Manhattan Project. This process was pioneered by J. H. Simons and co-workers in 1941 but published only after declassification in 1949 [26]. For ECF, the organic substrate is dissolved in aHF at 0 ◦ C and a current is passed through the solution at a potential of 4.5–6 V. Sometimes additives are used to increase the conductivity. In this voltage range, at the nickel anode, where the fluorination occurs, no fluorine gas is evolved, but hydrogen is evolved at the steel cathode, which is usually also the reaction vessel. With increasing fluorination, the solubility of the products in aHF decreases and, finally, the perfluorinated products formed at the anode become immiscible with aHF and form a separate phase which is denser than the solvent. They can, therefore, be easily removed from the bottom

2.2 Electrochemical Fluorination (ECF)

of the reaction vessel. Because the process depends crucially on the solubility of the substrate in aHF (which for many organic compounds is typically around 4% at 0 ◦ C), in contrast to the CoF3 process, it is applicable only for the perfluorination of functionalized organic compounds such as ether, amine, carboxylic, and sulfonic acid derivatives. ECF provided, for the first time, at reasonable cost, commercial quantities of the technically important trifluoroacetic acid and trifluoromethyl- and perfluorooctylsulfonic acids (Scheme 2.10). ECF

Ether

perfluoroether

R-COF

RF-COF

e.g. CF3COOH

R-SO2F

RF-SO2F

e.g. CF3SO3H, C8F17SO3H

R-NH2

RF-NF2

R2NH

(RF)2NF (RF)3N; e.g. N(C3F7)3

R3N

Scheme 2.10 Technically relevant conversions by the Simons ECF process (RF = perfluoroalkyl).

The Simons ECF process was subsequently developed into an industrial production process by the 3M Company. It currently provides the precursors to the palette of more than 250 large-scale fluorine-containing compounds produced by this company [27]. These products include fluorosurfactants, fire-fighting chemicals, perfluorinated solvents, and artificial blood substitutes. The electrochemical formation of high-valence nickel fluorides with strong fluorinating power at a nickel anode has been discussed as the key to the mechanism of ECF [28] (Figure 2.4). This hypothesis is supported by the findings of Bartlett et al. that chemically generated NiF3 and NiF4 in aHF are also very effective perfluorinating reagents [29]. Film (NiF4 or NiF4 ) F− F Ni F

HF F e− e−

H C R

F C R

F Ni

F

F Ni anode

F−

Figure 2.4 Proposed mechanism of the electrochemical fluorination (ECF) process. The organic substrate is oxidatively fluorinated by high-valence nickel fluorides at the anode surface [28].

35

36

2 Introduction of Fluorine

2.3 Nucleophilic Fluorination

For industrial chemistry, the various methods used for nucleophilic fluorination are probably the most important route to fluorinated fine chemicals. In aliphatic nucleophilic substitution (SN ) reactions, fluoride as the leaving group is the most inert halogen (order of nucleofugicity I > Br > Cl > F), because of the very strong carbon–fluorine bond and the high charge density of the liberated fluoride ion. The behavior of the fluoride ion as a nucleophilic species is, however, bizarre – depending on the reaction environment it can act either as an extremely poor nucleophile (in a protic solvent) or as a very powerful nucleophile (in polar aprotic solvents, especially with large lipophilic cations). 2.3.1 Finkelstein Exchange

The fact that fluoride is a poor leaving group in aliphatic nucleophilic substitutions and the high volatility of fluoroaliphatic compounds are the keys to the Finkelstein synthesis of alkyl fluorides. An alkyl iodide, bromide, or tosylate is heated in a polar solvent with an alkali metal fluoride and the volatile alkyl fluoride is removed by distillation during the reaction [30] (Scheme 2.11). For safe handling of primary alkyl fluorides, it must be kept in mind that the even-membered compounds of this series are toxic, because they can be oxidatively metabolized to the poisonous fluoroacetate [31]. R OTs

60-80% KF, (HOCH2CH2)2O; 120 °C

R F

Scheme 2.11 Finkelstein exchange of tosylates by fluoride. The volatile alkyl fluoride is removed from the reaction mixture by distillation [30].

The nucleophilic reactivity of alkali metal fluorides decreases in the order CsF > RbF > KF > NaF > LiF, because of the increasing lattice energy of the fluorides with decreasing ion radius of the cation (CsF 177.7; RbF 186.4; KF 194.0; NaF 218.4; LiF 247.0 kcal mol−1 ) [32]. To avoid this problem, crown ethers or phasetransfer catalysts with large, lipophilic cations are often used to render nucleophilic fluorinations more efficient. 2.3.2 ‘‘Naked’’ Fluoride

Generally, the fluoride ion – as it occurs in solutions of alkali metal fluorides in polar protic solvents – is not a very nucleophilic species. Because of the unique position of fluorine in the periodic system, it is the smallest possible monoanion with the largest negative charge density. The fluoride ion therefore acts as an

2.3 Nucleophilic Fluorination

extremely strong hydrogen-bond acceptor. This and its low polarizability are the reasons for the relatively moderate nucleophilicity in protic solvents. In contrast, in polar aprotic environments where no potential hydrogen bond donors are available and no close interaction with the cation occurs, fluoride acts as a very potent nucleophile and as a strong base. Suitable systems are, for example, fluorides with large organic cations (socalled ‘‘naked’’ fluorides) in polar aprotic solvents such as acetonitrile or 1,2dimethoxyethane. The basicity of the ‘‘naked’’ fluoride ion is so large that, in the solid state of the corresponding salts, many usually fairly stable organic cations, for example, the tetrabutylammonium cation, are decomposed by a deprotonationinduced mechanism. Many crystal structures of fluorides with organic counter-ions show the fluoride ion in close, hydrogen-bonding-like contact with, for example, dimethylamino groups. Similar interaction and deactivation are the reason for the reduced nucleophilicity of such salts in solvents which are usually considered ‘‘aprotic’’ (e.g., acetone). For this reason, discussion continues about whether truly ‘‘naked’’ fluorides exist at all. The quest for naked fluoride has its counterpart on the cationic side with the search for truly uncoordinated lithium cations, which are not deactivated by interactions with solvent or anion and thus limited in their Lewis acidity. Preparatively, it is sometimes not possible to remove traces of hydrogen-bonded water or alcohols from the fluorides without decomposing the organic cation. Under such conditions, the fluoride is generated in the last step of the synthesis by Me4N+BF4−

Thermolysis; − BF3

N SF4

Me4N+F−

+

S N Me2NSiMe3

Me3SiF2−

N TASF

NH4Cl + NaCl + PCl5 + POCl3

72% 1. reflux; − HCl 2. Me2NH, PhCl;

(Me2N)3P+

P(NMe2)3 BF4−

N

F−

KF, MeOH; − KBF4

r.t., 7 d 3. NaBF4, H2O

N +

N N

F + F

N

P(NMe2)4+ F−

N

N N N

F−

98%

SiMe3 CH3CN; −30 °C

N

+

N

N N

Me3SiF2−

N

to r.t., 2 h

Scheme 2.12 Sources of ‘‘naked’’ fluorides and some examples of their syntheses [TASF = tris(dimethylamino)sulfonium difluorotrimethylsiliconate] [34–39].

37

38

2 Introduction of Fluorine

thermolyzing the corresponding tetrafluoroborates (e.g., for Me4 N+ F− ). Another stabilization strategy is to use kinetically labile difluorotrimethylsiliconates [e.g., in tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF)] or difluorotriphenylstannates [33] as sources of ‘‘semi-naked’’ fluoride ions. A very effective means of increasing the nucleophilicity of ‘‘naked’’ fluorides is efficient charge distribution over a large organic cation, for example, tetrakis(dialkylamino)phosphonium or -phosphazenium ions (Scheme 2.12). Naked fluoride can also be generated in situ by a chemical reaction with more readily available anhydrous components: the reaction of hexafluorobenzene with tetrabutylammonium cyanide forms fluoride ions by aromatic nucleophilic substitution of fluoride by cyanide, which is much more easily obtainable in an anhydrous state [40]. The fluoride solution can be either isolated or used in situ (Scheme 2.13). N F F

F

F

+ − F Bu4N CN ,

polar aprotic solvent; −35 °C to r.t.

F

N

N

N

N

N + “truly anhydrous” Bu4N+F− Scheme 2.13 In situ generation of ‘‘truly anhydrous’’ tetrabutylammonium fluoride by reaction of cyanide anions with hexafluorobenzene [40].

An industrially important application of the lipophilic tetrakis(dimethylamino) phosphonium fluoride is as a phase-transfer catalyst in the Halex process for the technical synthesis of fluoroarenes. In contrast with alkali metal fluorides, even the moderately active tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF) is an effective reagent for the nucleophilic ring opening of epoxides (Scheme 2.14). BnO BnO BnO

O epoxidation

BnO BnO BnO

O O

53% Bu4N+F−, THF

BnO BnO BnO

O

F

OH

Scheme 2.14 Nucleophilic ring opening of 1,2-anhydro-α-D-hexopyranose derivatives with tetrabutylammonium fluoride (TBAF) [41].

Because of the strong basicity of the fluoride ion, in nucleophilic SN 2 reactions elimination usually occurs as a dominant side reaction. On the other hand, the basicity of the ‘‘naked’’ fluoride can be used for synthetic purposes, for example, for deprotonation of phosphonium salts to the corresponding ylides in a system based on potassium fluoride with catalytic amounts of 18-crown-6 in acetonitrile.

2.3 Nucleophilic Fluorination

2.3.3 Lewis Acid-Assisted Fluorination

There are two principal ways of increasing the reactivity of the fluoride ion as a nucleophile. The first is to inhibit any deactivating hydrogen bonding or other coordination by choice of a suitable lipophilic counter-ion and reaction medium, rendering the fluoride ‘‘naked.’’ The alternative is to increase the nucleofugicity of the leaving groups – in technically relevant cases usually halogen – by activation with Brønsted or Lewis acids. The use of Lewis catalysts increases the reaction rate of nucleophilic exchange dramatically. The thermodynamic direction of the reaction is again determined by the strong carbon–fluorine bond. The pioneering work in this field was performed by F. Swarts starting from 1892. Treatment of different haloalkanes with HF in the presence of Lewis acids such as SbF3 , SbF5 , AgF, HgF2 , and AlF3 yielded mixtures of partially and fully fluorinated alkanes, depending on the exact reaction conditions (Scheme 2.15). Stoichiometric amounts of the Lewis catalysts themselves can also serve as the fluoride source [42]. SbF3Br2

CCl4, CHCl3

(hydro)chlorofluorocarbon mixtures

SbF3, SbCl5 AgF

Scheme 2.15 Lewis acid-assisted halogen exchange of chloroalkanes to (hydro)chlorofluorocarbons (CFCs and HCFCs).

The catalytic halogen exchange works especially well in the benzylic position of aromatic compounds, giving access to a variety of industrially important fluorinated solvents [43, 44] and intermediates [45] (Scheme 2.16). CF3

CF3

CCl3 HF, SbF3

H2, catalyst HNO3, H2SO4

CF3

CF3

NO2

H2, catalyst

NH2

CrO3

CF3COOH

Scheme 2.16 Catalytic nucleophilic fluorination of benzotrichloride and subsequent synthesis of other fluorinated fine chemicals [45].

The chemistry developed by Swarts has over many years also been the foundation of the quantitatively most significant branch of industrial fluoroorganic chemistry, the production of chlorofluorocarbon refrigerants (Freon, in Germany Frigen) [46]

39

40

2 Introduction of Fluorine

and fire-fighting agents (Halon), which started in the 1930s. The most important CFCs are Freons 11 (CFCl3 ), 12 (CF2 Cl2 ), 113 (CF2 ClCFCl2 ), and 114 (CF2 ClCF2 Cl). Later hydrochlorofluorocarbons (HCFCs) such as Freon 22 (CHF2 Cl) were also introduced into the market. Typically, these substances were synthesized with anhydrous hydrofluoric acid as the source of fluoride and catalytic amounts of SbCl5 at temperatures below 200 ◦ C. The nomenclature of CFCs is discussed in Section 8. A newer field of application of Swarts fluorination in carbohydrate chemistry is the synthesis of glycosyl fluorides from the corresponding bromides [47] (Scheme 2.17). AcO AcO AcO

Br O

AcO AcO AcO

O

Br O

AcO AcO AcO

88% AgF, CH3CN;

Br 25 °C OAc O

AcO AcO

ZnF2, CH3CN;

OAc

O

AcO AcO

45%

O

O AcO

AcO

O

O AcO

AcO

AcO Br 70 °C

O

83% CF3ZnBr·2CH3CN,

AcO AcO O+

O

AcO Br CH2Cl2; r.t.

OAc

O

AcO AcO

F

AcO

OAc

OAc AcO AcO

F OAc

OAc

O

F

AcO

CH3 [CF2ZnBr·2CH3CN]+F−

CF3ZnBr·2CH3CN

Scheme 2.17 Synthesis of a variety of glycosyl fluorides by Lewis acid-assisted nucleophilic substitution of the corresponding bromides. The trifluoromethylzinc bromide bis(acetonitrile) complex acts as the fluoride source and electrophilic catalyst at the same time [47].

Glycosyl fluorides [48] are among the most versatile building blocks in modern carbohydrate and glycoconjugate chemistry [49]. In glycosylation reactions they serve as the glycosyl donor. A fluoride ion is readily abstracted by ‘‘hard’’ Lewis acids BnO

O

F

+

BnO HO R acceptor

+

H

O

R

Lewis acid promoter

BnO OBn donor

BnO BnO

BnO

Scheme 2.18

O

O

OBn

OR OBn

General mechanism of glycosylation by means of glycosyl fluorides [50].

2.3 Nucleophilic Fluorination

(promoters). The glycosyl acceptor subsequently adds to the resulting resonancestabilized carbocation intermediate. A large variety of Lewis acids can be used as promoters [50], most commonly BF3 ·OEt2 [51], SnCl2 –AgOTf [52], Me3 SiOTf [53], and, more recently, Cp2 HfCl2 –AgOTf [54] (Scheme 2.18). 2.3.4 The ‘‘General Fluorine Effect’’

At elevated reaction temperatures, Lewis catalysts cause a certain amount of intermolecular and intramolecular halogen migration. Not only hydrofluoric acid can be used as the fluoride source, but also other fluoroaliphatic compounds, for example, fluoromethyl ethers [55] (Scheme 2.19). F3C OCHClF F3C

Sevofluorane, cat. SbCl5

58%

F3C

F3C OCHF2 F3C

F3C OCHCl2 F3C

2 Sevofluorane, cat. SbCl5

OCH2F F3C Sevofluorane

92%

Scheme 2.19 Use of Sevofluorane as a fluoride source for the synthesis of inhalation anesthetics [55].

One clear tendency is apparent from the equilibrium product distribution of Lewis acid-induced transfluorination and halogen scrambling: if fluorine can migrate it will always tend to ‘‘concentrate’’ at one carbon atom. Most preferred reaction products are trifluoromethyl derivatives, followed by geminal difluoromethyl derivatives. This thermodynamic product control is often referred to as the ‘‘general’’ fluorine effect (Scheme 2.20). CF2Cl-CFCl2

80% AlBr3, 80 °C,

CF3 -CCl3

30 min

CF2Br-CHFCl

CF2Br-CFClBr

90% AlCl3, 50 °C 90% AlBr3, 0 °C

CF3 -CHClBr

CF3 -CClBr2

Scheme 2.20 The ‘‘general’’ fluorine effect in Lewis acid-induced halogen scrambling. For example, in the first example the formation of CF3 CCl3 is energetically preferred by about 5.6 kcal mol−1 (calculation on the B3LYP/6–31G*//B3LYP/6–31G* level of theory) [23].

The reason for this energetic preference for fluorine accumulation at the same sp3 center is ‘‘self-stabilization’’ by formation of possible ionic resonance structures, as already discussed in Section 1.4.2.

41

42

2 Introduction of Fluorine

2.3.5 Amine–Hydrogen Fluoride and Ether–Hydrogen Fluoride Reagents

Hydrofluoric acid itself is one of the most hazardous reagents used in fluorine chemistry, possibly more so than elemental fluorine itself. Reasons are the low boiling point of aHF (19.5 ◦ C) and its topical and systemic toxicity in combination with its local anesthetizing effect. To permit safer and more convenient handling of this reagent of central importance, several attempts have been made to ‘‘stabilize’’ the hydrogen-bonding network of the strongly associated liquid HF by adding hydrogen-bridge acceptors, for example, tetraalkylureas, amines, or ethers (Scheme 2.21). F H F H F H F

F−H

F

−

H F H F H F H

H

F H F H F H F

N

(a)

H−F

+

(b)

Scheme 2.21 Postulated structures of strongly associated amine–HF reagents. (a) 19 F NMR studies of pyridine·9HF (70% HF–pyridine) indicate a poly(hydrogen fluoride) network with each fluorine surrounded by four hydrogen atoms [56c]. (b) The proposed structure of the complex NEt3 ·3HF [57].

The first published example of such ‘‘tamed hydrofluoric acid’’ was pyridinium poly(hydrogen fluoride), also known as ‘‘Olah’s reagent’’ [56]. The stoichiometric complex pyridine·9HF containing 70% HF is a strongly acidic liquid stable up to 55 ◦ C. Like anhydrous HF, pyridine–HF etches glass and is highly toxic but, because of its lower vapor pressure, handling is much safer. It was soon found that by changing the ratio of amine to HF the acidity and nucleophilicity of this and similar reagents could be modified in a wide range. A further improvement of safety and ease of handling was the use of polyvinylpyridine as a solid base [58]. Of course, the general concept does not only work with pyridine as a hydrogenbridge acceptor. Other complexes, such as NEt3 ·3HF [57, 59] and Bu4 N+ (H2 F3 )− [60], have also found widespread practical application, because they are slightly basic or neutral and have no HF vapor pressure above the liquid. Triethylamine tris(hydrogen fluoride) (b.p. 78 ◦ C without decomposition at 1.5 mbar) does not etch glass and can be handled in ordinary glassware even at elevated temperatures. A more recent development, more acidic variants of ‘‘tamed HF,’’ are HF-dialkyl ether complexes such as Me2 O·2HF [61]. As a result of these developments, in preparative fluoroorganic chemistry there usually is no longer any need to use anhydrous hydrofluoric acid. This most hazardous reagent can usually be replaced by some kind of ‘‘tamed HF’’ with custom-tailored acidity and nucleophilicity.

2.3 Nucleophilic Fluorination

43

2.3.6 Hydrofluorination, Halofluorination, and Epoxide Ring Opening

Many amine–hydrofluoric acid reagents still have sufficient acidity to add to carbon–carbon double and triple bonds to yield hydrofluorination products. Olah’s reagent (70% HF–pyridine) [56] and its polymer-based analog [58] are especially widely used as less hazardous alternatives to anhydrous hydrofluoric acid. By selection of the right co-solvent, it is even possible to modulate the reactivity of 70% HF–pyridine so that highly selective, partial hydrofluorination of systems with several double bonds becomes feasible [62] (Scheme 2.22). F 35% 70% HF-pyr, THF; 20 °C 75%

F

70% HF-pyr, THF; 20 °C

F

F F

56% longer reaction time

PVPHF, CFCl3; 15 °C, 72 h

F 26%

C5H11

H7C3

122 equiv. 70% HF-pyr, CH2Cl2; r.t., 18 h

6%

C5H11 F

4 equiv. 70% HF-pyr, CH2Cl2; −15 °C to 10 °C, 1 h

F

F

Scheme 2.22 Hydrofluorination of olefins and acetylenes with 70% HF–pyridine and polyvinylpyridine hydrofluoride (PVPHF) [56a, 58, 62].

For halofluorination of multiple bonds, there is no need for a strongly acidic fluorination reagent. The selection of suitable amine–HF reagents therefore becomes broader than for hydrofluorination. There is also a wide choice of electrophiles for initiating the reaction. The acidic 70% HF–pyridine [56b] or the more neutral NEt3 ·3HF [63] are most commonly used as fluoride sources. The most common electrophiles are the halogenating reagents N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS) (Scheme 2.23). The trans stereochemistry of the halofluorination product indicates the formation of a three-ring, bridged

44

2 Introduction of Fluorine +

X

X

X+

AgF

F

F

F

(FHF)−

Scheme 2.23 Mechanism of the halofluorination reaction [X+ = electrophile, e.g., N-halosuccinimide, (MeSSMe2 )+ BF4 − , NPSP]. If the group X is bromine or iodine, it can be replaced by fluorine in situ with AgF [64–66].

intermediate which is subsequently opened by attack of a fluoride ion [64]. Occasionally, the 1-fluoro-2-haloalkane formed initially is converted in situ into the corresponding 1,2-difluoroalkane by further reaction with silver fluoride. Alternatively, several non-halogen electrophiles, for example, dimethyl (methylthio)sulfonium tetrafluoroborate [65] and N-phenylselenylphthalimide (NPSP), have been used [66]. The phenylselenyl moiety can be removed later, either by using m-chloroperbenzoic acid (MCPBA) to give fluoroalkenes or by radical reduction to furnish the fluoroalkane (Scheme 2.24). 85%

F

NBS, 70% HF-pyr, sulfolane; r.t., 30 min

Br Br

90% NBS, 70% HF-pyr, sulfolane; r.t., 30 min

F F

95% NCS, 70% HF-pyr, sulfolane; r.t., 30 min

Cl F

75% 1. NIS, 70% HF-pyr, Et2O; 0 °C, 30 min

F

2. AgF; r.t., 2 h

O

O

O

O

55% NPSP, NEt33HF,

F

CH2Cl2; r.t.

H3C H3C

C8H17

H H

H

Scheme 2.24 63–66].

H3C 96%

H

SePh

F

H3C

(MeSSMe2)+BF4−, NEt33HF, CH2Cl2; 0 °C

H H

MeS

C8H17

H

H

Examples of halofluorinations and mechanistically similar reactions [56b,

2.3 Nucleophilic Fluorination

45

Another, mechanistically related, reaction is the perfluorination of acetylene derivatives with NO+ BF4 − in 70% HF–pyridine [67] (Scheme 2.25).

H+

N O

75%

N OH +

NO+BF4−,

F

F

70% HF-pyr

NO+

OH N

HO F F−

F

F F

F

N

F

HO

H+

NO

+

N

N

OH

F

F

F

F

F−

F F

Scheme 2.25 Nitrosonium ion-induced fluorination of tolane derivatives to the corresponding diphenyltetrafluoroethylenes [67].

Opening of epoxides to give β-fluoroalcohols can also be achieved by use of amine–HF reagents. Because of the very different acidity and nucleophilicity of the various reagents, the stereoselectivity of the reaction can be modulated [68]. With neutral to basic reagents, the ring opening proceeds via nucleophilic attack of a hydrofluoride ion on the more electropositive carbon of the epoxide ring (SN 2-like) [69]. If an acidic complex is used, the primary step is protonation of the oxygen, followed by nucleophilic ring opening (SN 1-like) [70] (Scheme 2.26). F

OH

O

F

O

O

+

(35%)

70% HF-pyr

OH

O (26%)

+ oligomers (38%)

H O+ O F HO

O

OH O

F

Scheme 2.26 Ring opening of oxiranes with the acidic amine–HF reagent 70% HF–pyr is poorly selective and leads to the formation of oligomeric by-products [71].

46

2 Introduction of Fluorine

Ring opening with milder but more selective reagents such as NEt3 ·3HF or KHF2 –18-crown-6 proceeds significantly more slowly but it can be catalyzed by electrophilic transition metal complexes. With a chiral salen catalyst, even the enantioselective synthesis of chiral fluorohydrins can be achieved [71]. This type of reaction is of enormous interest for the enantioselective synthesis of fluoropharmaceutical compounds (Scheme 2.27).

O cat*

O cat*

SN1-like

HF

+

OH

O δ

+

cat*

F−

δ+

O

F

O cat* O cat*

H+

F

OH

OH

92% conversion

SN2-like

+

KHF2, 18-crown-6, A,

F

DMF; 60 °C, 80 h

Cl

(55% ee) 89:11 (20% ee)

H

H N

N Cr O

O Cl

t Bu

t Bu tBu

t Bu

A Scheme 2.27 [71].

Enantioselective oxirane ring opening with a chiral Lewis acid catalyst (cat*)

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds 2.4.1 Synthesis of Fluoroaromatic Compounds

Fluorinated arenes [72] are widely used as precursors for the synthesis of agrochemicals and pharmaceuticals [73] with a volume of several thousand tons per year [74]. More than 20% of the pharmaceuticals currently in clinical testing contain

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds

fluorinated aromatic substructures; for some types of agrochemical the proportion even exceeds 50% for newly introduced compounds. 2.4.2 Reductive Aromatization

Perfluoroaromatic compounds can be obtained by reductive aromatization of readily accessible perfluorocycloaliphatic precursors [75]. Defluorination can be accomplished by contact with hot (500 ◦ C) iron or iron oxide. After reducing the perfluoroaliphatic compound, the metal surface can be regenerated by passage of hydrogen gas. This method has been scaled up to a continuous flow process for the industrial synthesis of a variety of perfluorinated aromatic compounds (Scheme 2.28). F

F

F

Fe, 500 °C 52% Fe, 500 °C

F

44%

Fe, 660 °C

F CF3

CF3

CF3

CF3 F

F

CF3

F

CF3

CF3 F

F

10% Fe, 750 °C

F F

F

Scheme 2.28 Industrial-scale methods for reductive defluorination–aromatization of perfluorocycloaliphatic precursors, which again are accessible by the cobalt trifluoride process [76].

Reductive agents other than iron can also lead to aromatization or partial desaturation of perfluorocycloaliphatic derivatives. Photochemically activated ammonia (NH3 –Hg*) as the reducing agent leads to subsequent aminolysis products [77]. Others are complex catalytic systems which achieve the defluorination even at room temperature [8, 78] (Scheme 2.29). 2.4.3 The Balz–Schiemann Reaction

One of the earliest means of introducing fluorine selectively into specific positions of aromatic compounds is the Balz–Schiemann reaction [79], which dates back to the 1920s. An isolated aryldiazonium tetrafluoroborate is thermolyzed at up to 120 ◦ C

47

48

2 Introduction of Fluorine

CN

CF3

NH2

HN F

F Hg*, NH3

CF3

CF3 F

F

1. 4 equiv. Mg-anthracene, THF; r.t. 2. CO2

F

F

62% Na, Ph2CO,

H F

+

COOH

COOH F

F

THF

F F

F

40% Cp2ZrF2, Al, HgCl2,

F

F

F

THF; r.t.

CF3

CF3 F

+ 2 FeCp*2 + 2 LiOTf

F Zn,hn

+ 2 [FeCp*2]+OTf−

CF3 Zn

2 FeCp*2

F CF3

Zn2+

2 [FeCp*2]+

F

Scheme 2.29 Reductive defluorination–aromatization under milder reaction conditions suitable for laboratory-scale synthesis of perfluoroolefins and related products. Hg* = photochemically excited mercury; Cp* = pentamethylcyclopentadienyl [77, 78].

to yield the corresponding fluoroaromatic compound. Because of the infamously hazardous nature of isolated diazonium salts, the scope of the classical variant of the Balz–Schiemann reaction was limited to the small scale. The high exothermicity of the reaction is most conveniently controlled by diluting the diazonium salt with a solid inert medium such as sea sand. In addition to the danger to the experimenter, the reproducibility of the reaction yield is poor. In recent variants, more useful on a technical scale, the diazonium salt is not isolated but generated in situ by treating a solution of a suitable aromatic amine precursor in aqueous hydrofluoric acid or in 70% HF–pyridine with NaNO2 at 0–5 ◦ C. The resulting diazonium salt solution is subsequently thermolyzed at 55–160 ◦ C [56c, 80, 81] (Scheme 2.30).

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds N BF4− N+

NH2

F + N2

sand, Δ; − NaBF4

1. HCl, NaNO2 2. HBF4 80-95%

70% HF-pyridine, NaNO2; 0 °C (20 min), 55 °C (1 h)

Scheme 2.30 Balz–Schiemann fluorination of aryldiazonium tetrafluoroborates. A recent variant works in 70% HF–pyridine, avoiding isolation of the explosive diazonium salt [79–81].

2.4.4 The Fluoroformate Process

An alternative means of technical-scale access to fluoroarenes is the fluoroformate method. Starting from the corresponding phenol, a fluoroformate is generated by reaction with carbonyl chloride fluoride and subsequently catalytically decarboxylated to the aryl fluoride, in the gas phase, by contact with hot platinum [82] (Scheme 2.31). A newer, ‘‘greener’’ variant of the fluoroformate process has recently been introduced by Rhodia. In this approach, the fluoroformate is formed by the (catalyzed) reaction of the phenol with CO2 in HF, and the expensive platinum catalyst is replaced by an aluminum-based material. O

X

F

O

OH

COClF; 60-90 °C

X

F

Pt gauze; 700-800 °C, 1-3 s

+ CO2 X

Scheme 2.31 Synthesis of selectively fluorinated aromatic compounds from phenols via the fluoroformate. Under optimized conditions, depending on the nature of the substituents X, the yields are nearly quantitative [82].

2.4.5 Transition Metal-Catalyzed Aromatic Fluorination

One of the many drawbacks of the classic Balz–Schiemann synthesis is the generation of large quantities of undesired waste products such as NaBF4 , NaCl, or HCl. Another method, developed at DuPont [83], is based on the coppercatalyzed oxidative fluorination of aromatic compounds with hydrofluoric acid in the presence of oxygen (Scheme 2.32).

49

50

2 Introduction of Fluorine F

CuF2+

+ HF + Cu0

450-550 °C

½ O2, 400 °C H2 O

HF

Scheme 2.32 Oxidative fluorination of benzene by CuF2 which is regenerated by reaction with HF and O2 at 400 ◦ C [83].

The thermodynamic force driving this process is the formation of water as the only stoichiometric byproduct. The intermediately formed CuF2 acts as the fluorinating agent at temperatures around 500 ◦ C. The resulting copper is subsequently recycled by reaction with hydrofluoric acid and oxygen at 400 ◦ C. The reaction–regeneration cycles can be repeated without loss of activity of the copper reagent. The same process can also be used for the waste-efficient and costeffective industrial production of other fluorinated arenes such as fluorotoluenes and difluorobenzenes. Most aromatic fluorination methods require relatively harsh reaction conditions. Therefore, the transition metal-catalyzed fluorination of arene precursors such as bromides, triflates, boronic acids, and tin organyls under mild conditions has been a long-sought target [84]. One central application for a highly site-specific aromatic fluorination under mild conditions is the preparation of 18 F-labeled compounds for positron emission tomography (PET; see also Section 9.8) [85]. SnBu3

F

OH

NaX: X = OTf or HCO3

Reductive elimination

R R

+ NaHCO3

Transmetalation

F AgIIL

H2O

R

AgI catalyst

R

Bu3Sn(HCO3) AgI AgIm

R

n

n

[AgII]

Oxidation

PF6− N+ N

Scheme 2.33

N+ N+

Cl F

Cl 2 PF6−

Proposed mechanism for the silver-catalyzed oxidative fluorination [84a].

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds

First approaches in this direction are mainly based on the reaction of electrophilic fluorination reagents with metal organic compounds [86], arylstannanes [87], or boronates [88]. In particular, the silver-catalyzed fluorination of arylstannanes provides high yields and proceeds at low reaction temperatures (Schemes 2.33 and 2.34). However, the requirement for relatively expensive electrophilic fluorination reagents puts some practical limit on the large-scale use of these methods.

F

SnBu3 R

R

5.0 mol% Ag2O, 2.0 equiv. NaHCO3, 1.0 equiv. NaOTf, 1.5 equiv. F-TEDA-PF6, acetone; 65 °C F O

O flavanone (90%)

O

Me AcO

F

Me

Me Me

N COOMe H NHBoc Boc-Tyr-Phe-OMe (92%)

OH O OH Me

O O

MeO

NH O O F

O O Me

Me O Rifamycin Sa (65%)

Scheme 2.34 Electrophilic, silver-catalyzed fluorination of arylstannanes [87]. The names under the molecules refer to the nonfluorinated parent molecules. a 20 mol% of AgOTf, 2 equiv. of NaOTf, and 5 equiv. of methanol were used.

As a less expensive alternative to silver catalysis, aryl iodides can also be converted into the corresponding fluorides using copper-based catalysts [89]. Palladium(II)-mediated catalytic cycles for the introduction of fluoride into arenes are critically impeded by the high stability of the Pd-F bond preventing reductive fluoroarene elimination as the final step [90]. Alternative approaches via Pd(IV) intermediates require the use of electrophilic fluorination reagents (Section 2.6.3) [91]. The design of a palladium complex using a sterically demanding phosphane

51

52

2 Introduction of Fluorine

ligand [92] provided the necessary breakthrough [92] and made it possible for the first time to use inexpensive alkali metal fluorides as the fluoride source instead of electrophilic fluorination reagents (Schemes 2.35 and 2.36).

LnM Y

X Oxidative addition

Reductive elimination

Ln M

LnM

Y

X

Transmetalation

M′ Y M′

LnM

X

Y Ease of C-Y reductive elimination C-C

>

C-N

Early development (since 1960s)

>

C-O

>

C-F

Recent development (2000s)

Increasing difficulty in Pd-catalyzed C-Y cross-coupling Scheme 2.35 General catalytic cycle for transition metal-catalyzed aryl fluorination. L = ligand, M = transition metal (e.g., Pd), M = alkali metal (e.g., Cs), X = leaving group (e.g., TfO− , I− , Br− ). Scheme adapted from Ref. [84a].

The key is a T-shaped palladium complex (Figure 2.5) as the catalytically active species which eliminates the fluoroarene readily, completing the catalytic cycle at moderate reaction temperatures. The sterically demanding and electron-rich, socalled BrettPhos ligand [92] shields one coordination site of the palladium complex, impeding dimerization. Another approach to incorporate 18 F from [18 F]fluoride into aromatic compounds is to use a combination of two palladium complexes [93]: the aromatic substrate is activated via a Pd(II) complex, whereas the fluorine is introduced via an electrophilic Pd(IV) complex that is generated from a precursor complex by ligand exchange by [18 F]fluoride (Schemes 2.37 and 2.38).

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds 6 mol% t BuBrettPhos,

2 mol% [(cinnamyl)PdCl]2 (= 4 mol% “Pd”, Pd:L = 1:1.5)

OTf R

F R

+ CsF toluene; temp., 12 h

O Me2N

F

F

O2N

F

83% (2%) 2 mol% “Pd” 110 °C

84% (1%) C6H12, 130 °C

82% (2%) 110 °C

Ph O 63% (2%) 80 °C

F

CH3

Ph

H AcO

F H3C

N

H3C CF3 83% ( Br > I, is in the opposite order to that for aliphatic nucleophilic substitution. Even if no −M electron-withdrawing substituents are present, however, aromatic fluorine can be replaced. The ease of this replacement increases with the degree of fluorination. Perfluoroaromatic compounds such as hexafluorobenzene or pentafluoropyridine are especially highly reactive toward a variety of nucleophiles (Scheme 2.47).

S S

S

S

S

+ 6NaF S

N NaSPh, various solvents; 25 °C, 2 d

86%

N

F F

F F

F F

92%

N

N+ N+

N+

N+

N+

(OTf −)6 + 6 Me3SiF

DMAP, Me3SiOTf, CH3CN; 80 °C

N

N+

N

N Scheme 2.47 The complete nucleophilic replacement of all fluorine atoms can be driven, for example, by the strong nucleophilicity of the thiolate anion and the lattice energy of the formed NaF (top) [104], or by removal of the competing expelled nucleophilic fluoride with the volatile Me3 SiF (bottom right) [105].

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds

By analogy with the ‘‘hydrocarbon world,’’ high selectivity is also observed in the regiochemistry of the second substitution in perfluoroaromatic compounds (Scheme 2.48). For hexafluorobenzene, a second nucleophilic replacement always occurs in the position para to the first substituent. A similar, clear preference is also observed for perfluoronaphthalene [106]. N

N

F F

F F

F F

F

F HNMe2 /i-PrOH (3:7); r.t.

F

F F

NaSMe, MeOH; reflux, 6 h

F F

F

F F

pyrrolidine; r.t., 27 d

pyrrolidine, DMEU; 90 °C, 21 d

F SCH3

F

N F

F

F

F N

N

88%

F

N

F

23%

F

F

F

F

F

F

quant.

F

N

N F

F

Scheme 2.48 Regioselectivity of the stepwise nucleophilic replacement of fluorine in perfluoroaromatic systems [107–109].

Rationalization of the observed selectivity can be based on several considerations [106]. The negative charge of the intermediate adduct (analogous to the -complex in electrophilic aromatic substitution) has to be stabilized. This stabilization occurs mostly as a result of the combined inductive effects of the remaining fluorine atoms. This inductive effect must overcompensate the concomitant strongly destabilizing p–π repulsion of the sp2 -bound fluorine atoms, which is most significant in the Nu−

o F F m

X

X

X

F

Fm

p F

Fp

mF F o

Fo

mF

F

o F

Nu−

Scheme 2.49 Regioselectivity of a second nucleophilic aromatic substitution in perfluoroaromatic systems. The negatively charged primary addition product is stabilized best by fluorine in the ortho position (o), second best in the meta position (m), and least in

F m F o F Nu−

the para position (p). Only for attack of the nucleophile in the para position (see box) is the complex stabilized by two ortho and two meta fluorines. Nu− = nucleophile; X = first substituent, for example, OMe, NMe2 [106].

61

62

2 Introduction of Fluorine

positions ortho and para to the site of nucleophilic attack. Most effective for overall stabilization of the negatively charged intermediate (Scheme 2.41) is fluorine in the ortho position; meta-fluorine is less effective and fluorine in the para position is least effective (Scheme 2.49). Systematic exploitation of the different susceptibilities of the different positions of perfluoroaromatic compounds can be used as a tool for the combinatorial synthesis of (fluoro)aromatic compounds. The feasibility of this concept was demonstrated by Chambers and co-workers, who used the pentafluoropyridine system as an example [110] (Scheme 2.50). Further differentiation of the reactivity towards hard and soft nucleophiles was achieved by partial replacement of fluorine by bromine in this system. Br 70%

F

Br F

F F

N

F

F

F

91% HBr, AlBr3; 150 °C

1 equiv. NaOMe, MeOH; r.t.

Br

N

Br

Br Br

N

PhSH, K2CO3,

Br

85%

CH3CN; reflux

10 equiv. NaOMe, MeOH; r.t.

Br

N

Br

Reaction with hard nucleophile F

F Br

OMe

MeO

quant.

SPh Reaction with soft nucleophile

OMe

F

N

Br

Scheme 2.50 A variety of conversions starting from the pentafluoropyridine system as a molecular scaffold, for example, for combinatorial chemistry [110].

If the reaction temperatures are increased, less active aromatic compounds with fewer fluorine atoms or other inductively activating groups can also be used as substrates for nucleophilic replacement of fluorine [111] (Scheme 2.51). CF3 OH O

H NHMe

F

CF3

NaH, CH3CONMe2; 100 °C

H NHMe

Scheme 2.51 Nucleophilic replacement of fluorine in only partially fluorinated systems is an important tool for synthesis of pharmaceuticals, for example, (S)-norfluoxetine, a serotonin reabsorption inhibitor [111].

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds

2.4.10 Activation of the Carbon–Fluorine Bond by Transition Metals

Because of the extraordinary strength of the carbon–fluorine bond, transition metal-mediated activation of fluoroalkanes and arenes is not easy to achieve. Nevertheless, activation of the C–F bond in highly electron-deficient compounds such as 2,4,6-trifluoropyrimidine, pentafluoropyridine, and hexafluorobenzene is possible with stoichiometric amounts of bis(triethylphosphano)nickel(0) [112] (Scheme 2.52). Subsequently, Herrmann and co-workers [113] described a variant of the Kumada–Corriu cross-coupling reaction [114] between fluorobenzene and aryl Grignard compounds which uses catalytic amounts of nickel carbene complexes. Hammett analysis of the relative kinetic rate constants indicated that the reaction proceeds via initial oxidative addition of the fluoroaromatic reactant to the nickel(0) species. Perfluoroarylnickel complexes have also been used in order to initiate Suzuki-like reactions between boronic acids and perfluoroarenes [115]. F

N

F

F

N

F N

N F

1. [Ni(cod)2]

Et3P

2. PEt3, C6H14

Ni

PEt3

F

(a)

X

X F + BrMg-Ar

Ar + MgBrF

5 mol% [Ni], THF, r.t., 18 h

N [Ni] =

Ni N

2

(b)

Scheme 2.52 Transition metal-mediated activation of the aromatic carbon–fluorine bond and subsequent reactions. Above: stoichiometric reaction of electron-deficient fluoroarenes with Ni(0) complexes [112]. Below: Ni(0) carbene-catalyzed Kumada–Corriu coupling between fluoroarenes and aryl Grignard compounds [113].

2.4.10.1 Electrophilically Activated Arylation by Fluoroarenes The immense affinity between fluoride and aluminum- [116] or silicon-based [117] electrophiles has been utilized for the activation of fluoroarenes as electrophilic arylation agents. Although this type of reaction works only for intramolecular arylations, it is a valuable tool for the synthesis of complex polycyclic aromatic hydrocarbons (PAHs), which are of great interest in the materials sciences as organic semiconductors (Scheme 2.53).

63

64

2 Introduction of Fluorine

F

F

quant. Al2O3; 150 °C, 120 h

F 49% 10 mol% i Pr3Si+ [CB11H6Cl6]−, Me2Si(Mes)2, PhCl; 110 °C, 8 h

F

Scheme 2.53 Electrophilic cyclization of fluorinated arenes to polycyclic aromatic hydrocarbons, using fluorophilic aluminum or silylium electrophiles [116, 117].

2.4.11 Activation of Fluoroaromatic Compounds by Ortho-Metalation

Inductively electron-withdrawing substituents in aromatic compounds increase the thermodynamic acidity of the other aromatic hydrogen atoms. These hydrogen atoms can be abstracted by strong bases such as lithium diisopropylamide (LDA) and BuLi and ‘‘super-bases’’ (e.g., BuLi–KOt Bu) [118], leading to aryl metal compounds. The metal atom – usually lithium – is also stabilized by favorable electrostatic and electron-donating interactions with the lone electron pairs of neighboring groups (Scheme 2.54). The observed ortho selectivity of the metalation of suitably substituted aromatic compounds is, therefore, usually kinetically induced [119]. In biphenyl systems, the site-directing effect can also result in clean lithiation at the ortho position of the neighboring phenyl ring [120]. X

X

Li Lithium base

X

X

Li

Lithium base

Scheme 2.54 Directed ortho lithiation of aromatics carrying an inductively electronwithdrawing substituent (X = CONi Pr2 , OMe, NMe2 , F, OCF3 ). The reaction product is stabilized by interaction of the lone electron pairs of the group X with the neighboring lithium [118, 120].

2.4 Synthesis and Reactivity of Fluoroaromatic Compounds

F

F

Li + LiF

> −20 °C

BuLi/KOtBu, Et2O; −100 °C

+ + polymers

Scheme 2.55 ortho-Lithiation of fluorobenzene and subsequent aryne formation with elimination of lithium fluoride.

F

F

F F

Cl

F

F

F

F

F

F

S F

BuLi, C6H14; −15 °C

OMe

S

F

OMe −15 °C to r.t.

F

F

F F

F F

OMe F

NBS,CH3CN;

F

r.t.

OMe Br

F

F OH OH F

OCF3

OCF3

OCF3 74%

Br

LDA, THF; −78 °C to r.t.

O

O

71% 93%

OCF3

32% HCl; 75 °C

OH OCF3

Zn, HOAc; 120 °C

OCF3

+ OH

1:8

Scheme 2.56 Synthesis of naphthalene derivatives via fluorinated arynes [124, 125].

65

66

2 Introduction of Fluorine

Directed ortho-metalation is induced, for example, by diisopropylamido or alkoxy groups, which strongly stabilize the metal–organic species by -donation [121]. Fluorine is also highly effective as a strongly ortho-directing, acidity-enhancing substituent [122]. Whereas many aryllithium species are stable up to room temperature and above, ortho-fluorolithio arenes are stable at low temperatures only. If heated above about −30 ◦ C, they tend to decompose violently to the corresponding aryne and lithium fluoride [123] (Scheme 2.55). The dominant force driving aryne formation is the high lattice energy of lithium fluoride (247 kcal mol−1 ). In contrast with being a mere hazard, aryne formation by LiF elimination has been put to synthetic use in the otherwise very difficult preparation of fluorinated naphthalene derivatives [124, 125] (Scheme 2.56). Ortho-metalation is a tool of high value not only for the derivatization of fluorinated arenes – the aryl lithium species can subsequently be converted into a variety of useful synthetic intermediates. The choice of the right combination of base and solvent permits the highly selective derivatization of halogenated arenes; this cannot yet be achieved by any other means [126] (Scheme 2.57). F

F

F

F LDA, THF; −78 °C

F F

Li

CO2

COOH Br

Br

F

F Br BuLi, THF; −78 °C

(a)

F

COOH

Li Li

F

F

COOH F

F

"halogen Li shuffling"

LiTMP; −100 °C

(b)

CO2

I

I F

F

F

F

F CO2

I

I

F

F CO2; F

F

Br

(c)

F

F BuLi, solvent; −70 °C

solvent = Et2O

COOH COOH

Li Li

transmetalation solvent = THF

F

F

F

F

CO2

Scheme 2.57 Selective derivatization of fluoroarenes by different base–solvent combinations. If additional stability can be gained, for example, as a result of two ortho fluorines, transmetalation often occurs (b and c). Occasionally (c) this can be suppressed by the right choice of reaction solvent [126].

2.5 Transformations of Functional Groups

One complication, which sometimes leads to highly specific but unexpected reaction products, is transmetalation and so-called ‘‘halogen shuffling.’’ The primary metalation product with no ortho-directing neighbor (or only one) can gain additional stability by transmetalation, leading to a product with two stabilizing ortho substituents. This effect is more likely in strongly coordinating solvents, for example, THF, and can be suppressed by changing the reaction medium to diethyl ether, which leads to higher aggregation and lower reactivity of the metal organic species [127]. Occasionally, the order of the ortho-directing strength of different substituents does not allow access to the desired substitution pattern by a direct route. In such circumstances, a protective group strategy is necessary to block temporarily the most acidic positions of the intermediates. A convenient group for traceless aromatic blocking is the trimethylsilyl group, which is readily removable by the use of inorganic fluorides (e.g., cesium fluoride in N,N-dimethylformamide) [128] (Scheme 2.58). SiMe3 58%

F3C

F

47%

OEt

1. n-BuLi, THF; −70 °C 2. B(OMe)3; −70 °C to r.t.

F3C

1. n-BuLi, THF; −70 °C 2. I2, THF; −70 °C to r.t.

F

3. n-BuLi, Et2O; −70 °C

3. 30% H2O2, HOAc

OEt F3C

F

4. Me3SiCl, Et2O; −70 °C to r.t.

4. EtBr, K2CO3, EMK; reflux

SiMe3 59% 1. n-BuLi, KOtBu, THF; −78 °C 2. I2, THF; −78 °C to r.t.

I F3C

OEt F

60% 1. H7C3CycPhB(OH)2,

OEt

H7C3

cat. Pd(PPh3)4,

F3C

F

2 N aq. Na2CO3, toluene; 50 °C, 18 h 2. CsF, DMF; 80 °C, 1 h

Scheme 2.58 Example of the synthesis of a fluorinated liquid crystal via stepwise derivatization of 2-fluorobenzotrifluoride, making use of a trimethylsilyl-blocked intermediate [128].

2.5 Transformations of Functional Groups 2.5.1 Hydroxy into Fluoro

The first unsuccessful attempts to convert alcohols directly into alkyl fluorides were documented in 1782, when Scheele treated ethanol with hydrofluoric acid vapor obtained from the reaction of fluorspar (CaF2 ) with sulfuric acid [129]. Despite this

67

68

2 Introduction of Fluorine

and other early failures, a variety of successful and convenient strategies designed to solve this general synthetic problem have been developed, especially since the 1920s. 2.5.1.1 Two-Step Activation–Fluorination First reports of the activation of alcohols with nucleofugic leaving groups date back to the early 1800s. In 1835, Dumas and P´eligot [130] heated ‘‘chauffant doucement,’’ a mixture of dimethyl sulfate and potassium fluoride, to furnish methyl fluoride. Subsequently, the same principal method was used to obtain ethyl fluoride [131] and other alkyl fluorides. Nowadays, activation of alcohols with more nucleofugic leaving groups, for example, mesylate, tosylate, or triflate, and subsequent nucleophilic SN 2 substitution by fluoride under clean inversion, have become a standard tool, particularly when fluorination with defined stereochemistry is required (Scheme 2.59). OTf

OH Ph N OH

Ph N

Tf2O, pyridine;

OTf

−80 °C

Ph N

Bu4NF, VTHF;

F

−20 °C to r.t

O

O

O

O

O

O O

O O HO O

F

90%

Tf2O, CH2Cl2, pyridine

O

TASF, CH2Cl2

TfO O

TASF =

O F O O

NMe2 + S Me3SiF2− Me2N NMe2

Scheme 2.59 Examples of the activation–fluorination procedure for substrates with stereogenic centers [132, 133].

2.5.1.2 α,α-Difluoroalkylamine and α-Fluoroenamine Reagents A more convenient approach to the exchange of hydroxy groups by fluorine is one-step activation–substitution – the alcohol is treated with a sufficiently electrondeficient, fluorine-containing reagent which condenses with it, with liberation of a fluoride ion. This ion, in turn, effects nucleophilic replacement of the now present leaving group. Stereochemically, this process results in clean inversion at the carbon center. The first examples of this kind were the α,α-difluoroalkylamine reagents introduced by Yarovenko et al. [134] and Ishikawa and co-workers [135]. They are conveniently obtained by reaction of dimethylamine with either chlorotrifluoroethylene or perfluoropropene, respectively, and are fairly effective for conversion of aliphatic alcohols to alkyl fluorides (Scheme 2.60). Another useful addition to the methodic toolbox was the more stable α-fluoroenamine reagent introduced by

2.5 Transformations of Functional Groups H3C

F F3C

F F

H3C

CH3

F

F

H

HNMe2

F

N

CF3

N

−

F

H

F

H3 C

+ CH3

N

F

F

CH3 F

+ HF

CF3

CF3

(a) F Cl

F Cl

F

(b)

N

HNMe2

F

N (c)

N +

Cl

F

F

F

N

COCl2

O

N

NaF

F

Cl

α-fluoroenamines. (b) The dimethyl(2chloro-1,2-difluorovinyl)amine reagent has a more defined composition. (c) Synthesis of an α-fluoroenamine fluorination reagent [134–136].

Scheme 2.60 The most usual fluorinated amine reagents and their syntheses. (a) the perfluoropropene-based reagent exists as an equilibrium mixture of an α,αdifluoroalkylamine and the two isomeric

Ghosez and co-workers [136], which enables several highly selective conversions to be achieved (Scheme 2.61). An advantage of this reagent is that it acts in a neutral reaction medium, thus also allowing the transformation of acid-sensitive substrates. F

OH 86% F

H3 C

Ni Pr2 CHCl3; r.t.

H3C

H 3C

H3C 61%

H3C

H H

HO

H3C

H

Ni Pr2 CH2Cl2; reflux

H3C

H

OH

H3C

H3C CHCl3; r.t.

H F

+ 71% F

2

OBn 99%

O BnO

H 100% inversion

H

29%

OBn BnO BnO

H

F

F Ni Pr

H3C

F

H3C

F

H3C

Ni Pr2

OH

BnO BnO

O BnO

F

CH2Cl2; r.t.

Scheme 2.61 Examples of the fluorination of alcohols with α,α-difluoroalkylamines or αfluoroenamines. Synthesis of cycloalkyl fluorides, fluorosteroids, fluoroterpenes, and glycosyl fluorides with α-fluoroenamines [136, 137].

69

70

2 Introduction of Fluorine

N

N

+

F

N

F

H O

O

N O

R

+ F-R

R

R

F−

O

+

N F− O

R

Scheme 2.62 Mechanism of activation and reaction of α-fluoroenamine reagents. The SN 2 mechanism of the replacement of the imidoester leaving group by the fluoride ion results in a clean inversion.

The mechanism of the primary condensation (Scheme 2.62) is again based on the relative instability of fluorine at sp2 centers. In α-fluoroenamines, the p–π destabilization is even increased by the +Iπ effect of the p-donating dialkylamino group. Addition of the alcohol coverts the sp2 center into a very electron-rich sp3 center and the fluoride ion is expelled, facilitated by the combined π-donation from the dimethylamino and alkoxy groups. The resulting imido ester is, in turn, a nucleofugic leaving group which is replaced by the fluoride ion. The most F F KCl

ROH,RC(O)R N

N fluorination DFI

RF, RCF2R

KF −

Cl

N

O

Cl N+

N

N

COCl2

CO2 87%

OH

F

DFI, CH3CN; r.t., 1 h

HO

NO2

62% DFI, CH3CN;

F

NO2

85 °C, 15 h

CHO

82% DFI, CH3CN;

CHF2

85 °C, 8 h

Scheme 2.63 The fluorination reagent 2,2-difluoro-1,3-dimethylimidazolidine (DFI) and its mechanism of activation [138].

2.5 Transformations of Functional Groups

significant side reactions with all α-fluoroenamine reagents are elimination and, in allylic systems, rearrangements. A more recent development of the same general type of reagent is 2,2-difluoro1,3-dimethylimidazolidine (DFI), which is even more reactive, because of the stabilizing effects of two nitrogen atoms at the active center [138] (Scheme 2.63). By reaction with the inexpensive phosgene and subsequent nucleophilic fluorination, the reagent can be recycled on an industrial scale. 2.5.1.3 Sulfur Tetrafluoride, DAST, and Related Reagents Probably the most versatile reagent for one-step exchange of hydroxy groups by fluorine, and for many other conversions, is sulfur tetrafluoride, SF4 [139]. Sulfur tetrafluoride first converts the alcohol into a covalent intermediate with a nucleofugic group, which is subsequently replaced by a liberated fluoride ion, with inversion (SN 2 mechanism). The sulfur tetrafluoride is converted into sulfonyl fluoride; only two fluorine atoms are used for the reaction (Scheme 2.64). F− R

OH

R O SF3

SF4

SN2 reaction

R F + HF + SOF2

under inversion

Scheme 2.64 Reaction of alcohols with SF4 with formation of alkyl fluorides, HF, and sulfonyl fluoride.

Despite its versatility, SF4 has some major disadvantages. It is a highly toxic gas (m.p. −121 ◦ C, b.p. −38 ◦ C) and must therefore be handled under pressure in an autoclave [140]. In order to overcome these difficulties, less volatile analogs of SF4 have been synthesized by replacing one fluorine atom with a dialkylamino group (Scheme 2.65). S8 F2

S2Cl2

SF4

KF, Cl2, CH3CN, 80 °C

+ Me3SiF N DAST SF3

84% Me3SiNEt2, CFCl3; −70 °C

O N MOST SF3

O

O N Deoxofluor SF3

Scheme 2.65 Synthesis of diethylamino sulfur trifluoride (DAST) [141], morpholino sulfur trifluoride (MOST), and bis(methoxyethylamino) sulfur trifluoride (BAST) (commercialized by Air Products, Inc. under the brand name Deoxofluor) and its analogs.

The reactivity of N,N-diethylamino sulfur trifluoride (DAST) (b.p. 46–47 ◦ C) [141] is slightly lower than that of SF4 , but its handling in small-scale reactions is much

71

72

2 Introduction of Fluorine

easier (Scheme 2.66). Because of the relative instability of the sulfur–nitrogen bond, DAST can explode violently when heated over about 50 ◦ C. 90% OH

F

DAST, CH2Cl2; −78 °C

F

OH

+

DAST, CH2Cl2; −78 °C

H

(70%)

(30%) H

3%

OH

DAST, CH2Cl2; −78 °C, 2 h

H

BnO

BnO O

BnO

Scheme 2.66 142].

F

OH

O

98% Deoxofluor, CH2Cl2; r.t., 30 min

OBn

BnO

F α:β = 28:72 OBn

Examples for fluorinations of alcohols with DAST and its analogs [62, 141,

Frequently occurring side reactions are elimination and rearrangements of the carbon skeleton [141], because of the intermediate formation of carbocationic species. With the aim of obtaining a fluorination reagent which can be safely handled on a larger scale, other derivatives such as the morpholino sulfur trifluoride (MOST) and the methoxyethyl analog (Deoxo-Fluor™) were developed [142]. Deoxo-Fluor also decomposes at elevated temperatures, but it does so without a thermal runaway reaction and subsequent explosion. This renders the reagent safe enough for application in the industrial production of fluoropharmaceuticals and advanced materials. The lower reactivity of DAST and its analogs compared with SF4 can be attributed to its greater steric requirements and to the less strong inductive effect of the dialkylamino moiety. This becomes obvious from failed attempts to fluorinate hydroxy groups in sterically crowded positions [143] (Scheme 2.67). BnO

BnO Tf2O

BnO

O OBn OH

O

F OBn

DAST

BnO

BnO

BnO

50%

O

Bu4N+F–, THF; −10 °C

OBn OTf

Scheme 2.67 Attempted fluorination of a sterically crowded ribose derivative with DAST, and successful reaction by a two-step activation–fluorination procedure [143].

2.5 Transformations of Functional Groups

A chiral analog of DAST, (S)-2-(methoxymethyl)pyrrolidin-1-yl sulfur trifluoride [144], was prepared and studied to achieve enantioselection in the fluorination of chiral alcohols by double stereodifferentiation (Scheme 2.68). The desired effect was observed, but not to a preparatively useful extent. H

H H13C6

CH3 OSiMe3

0.5 equiv.

H13C6

C5H11

F + H3C CH3

8% ee

OMe N SF3 −78 °C

Scheme 2.68 Achievement of minor kinetic resolution in the fluorination of racemic trimethylsilyl ethers with a chiral DAST analog [144].

The more recently introduced reagents XtalFluor™ [145] and FluoLead™ [146] avoid the decomposition hazard of DAST-derived compounds either by converting them into a more stable sulfiminium salt or by eliminating the labile sulfur–nitrogen bond completely. Both reagents are solids which can be handled under ambient air (Scheme 2.69), and they show the same reactivity as their predecessor DAST. N SiMe3

89% 1. SF4, CH2Cl2; −78 °C to r.t. 2. BF3·THF; r.t. 3. Filtration

79%

+

N S

F BF4–

O

F XtalFluor-E

+

F

BF4– F XtalFluor-M N S

S S

S2Cl2, cat. ZnCl2, HOAc; r.t.

82%

KF, Cl2, CH3CN; 0 °C to r.t.

SF3 Fluolead

Scheme 2.69 Synthesis of the fluorination reagents XtalFluor-E™, XtalFluor-M™ [145], and Fluolead™ [146]. These reagents are crystalline, relatively insensitive to moisture, and do not pose an explosion hazard.

2.5.1.4 Amine–Hydrogen Fluoride Reagents For exchange of tertiary alcohols, direct fluorination without activation can be achieved by use of aHF or other sources of acidic fluoride (Scheme 2.70). This type of reaction in an acidic medium proceeds via a stabilized carbocation by an SN 1 mechanism. Fluoride addition is often reversible, and the stereochemistry of the

73

74

2 Introduction of Fluorine

H3C

H3C H3C

H3C OH

O

HO H HO

70% HF-pyr, CH2Cl2; −35 °C

F H

H3C

H3C

H H

70% HF-pyr, CH2Cl2; −35 °C

H H

H O

F

OH Scheme 2.70

H3C

H3C

HO H O

O

HO

Fluorination of tertiary steroid alcohols with 70% HF–pyridine [147, 148].

reaction is controlled thermodynamically only by the relative free enthalpies of the possible product isomers. Potential leaving groups other than hydroxy can also be activated with acidic amine–HF complexes, if a sufficiently stabilized carbocation is formed as a reaction intermediate. Thus, glycosyl fluorides can be conveniently prepared from a variety of different glycosidic precursors, because of the stability of the intermediately formed glycosyl cation [149, 150] (Scheme 2.71). OBn

OBn O

BnO BnO

70% HF-pyr,

F BnO α:β = 97:3

BnO OAc CH Cl ; 0°C 2 2 OPiv PivO PivO

O PivO

N N N

OPiv 71%

COOtBu

70% HF-pyr, CH2Cl2; −30 °C to −10 °C

COOtBu RO

+

OR

O

F

PivO

O RO

RO

PivO PivO

RO

O

RO

O

BnO BnO

89%

RO

+

OR

Scheme 2.71 Synthesis of glycosyl fluorides with 70% HF–pyridine from different activated precursors [149, 150].

2.5.2 Conversion of Carbonyl into gem-Difluoromethylene 2.5.2.1 Sulfur Tetrafluoride, DAST, and Related Reagents Sulfur tetrafluoride is also the reagent of choice [139] for the conversion of aldehydes, ketones, and ester carbonyl functions into gem-difluoromethylene groups [151]

2.5 Transformations of Functional Groups

(Scheme 2.72). The reactivity of SF4 is further enhanced by addition of Lewis acid catalysts (for example, BF3 ) or simply by conducting the reaction in aHF as solvent. O

CHF2 90% SF4, HF; r.t.

F3C O

F5C2O

O O O O

75%

OCF2CF3

CF3 SF4, HF;

100−175 °C, 10 h

O

F5C2O

F3C F

HOOC

COOH

80%

HOOC

COOH

SF4, HF; 240 °C

F

F

O F

F O

F

F

F

Scheme 2.72 Reaction of aldehydes, esters, and carboxylic acid anhydrides with SF4 [139a, 152, 153].

On the basis of analysis of typical by-product spectra, Dmowski postulated a mechanism for the reaction [154]. In aHF as solvent, the SF3 + species is generated in a solvolytic equilibrium. The strongly electrophilic SF3 + ion adds to the carbonyl oxygen, making the α-carbon atom highly electrophilic. A fluorine atom is then

Protolytic equilibrium:

δ + δ− SF4·HF

SF4 + HF

SF3+ + (FHF)– R

R

δ+ O HF δ−

O + HF

Competitive reaction:

R

R fluorination: R

O + SF3+

R

Possible competing reaction, depending on R:

R + O R SF2 (FHF)– F

R R

R H R

R

R +

hydride shift

R

R

H F

F F

H H F + (FHF)–

(FHF)–

F

R R

+

H R

F + SOF2

H F +

+

F R

H H F

Scheme 2.73 Proposed mechanism for fluorination of carbonyl compounds to the corresponding gem-difluoromethylene derivatives [154].

75

76

2 Introduction of Fluorine

transferred intramolecularly to the carbon and sulfonyl fluoride is expelled. The resulting resonance-stabilized (by π-donation from fluorine lone electron pairs) αfluorocarbenium ion adds fluoride from ambient (FHF)− ions (Scheme 2.73). The formation of typical by-products, mostly rearrangement products, can be explained on the basis of this mechanism. The more convenient reagents DAST, XtalFluor, and Fluolead can also be used to fluorinate aldehydes and some ketones in high yields (Scheme 2.74). The reaction does not work for sterically hindered ketones, or for esters or anhydrides, even under harsh conditions. CHF2

CHO 72% DAST, CH2Cl2; 25 °C, 18 h

(a)

O

CH3

CH3

CH3 O DAST, benzene; 78 °C, 24 h

CH3

F F

(b)

O

F + F

F F

O

CH3

CH3

(60%)

(15%)

F F

70% DAST, CH2Cl2; 5 °C, 18 h

(c)

82%

O O O

XtalFluor-E, NEt3·3HF, (CH2Cl)2; reflux, 2 h 81%

O

F F

O

Fluolead, 70% HF-pyr, CH2Cl2; 0 °C to r.t., 3 h

(d)

F

F

60%

O

SF4, CH2Cl2; 120 °C, 18 h

F

F

O O

(e)

Traces DAST, neat, cat. ZnI2; 60 °C, 2 h

F

F

Scheme 2.74 (a–d) Conversion of carbonyl compounds to difluoromethylene derivatives by DAST [141], XtalFluor™ [145], and Fluolead™ [146]. (e) Limits of the reactivity of DAST compared with SF4 . Source: P. Kirsch, A. Ruhl, and R. Sander, 2002, unpublished work.

As in the fluorination of alcohols, here also the most important side reactions are elimination and rearrangements. As demonstrated for pivaldehyde as an example (Table 2.1), the product distribution depends critically on the choice of

2.5 Transformations of Functional Groups Dependence on the solvent of the mechanism of fluorination of pivaldehyde with DAST and of the formation of side products [141].

Table 2.1

H3C

CH3 CHO CH3

H3C

HF

H3C H H3C OH H3C F

H

+

CH3

H3C

–OSF NEt 2 2

F Polar, basic solvent

H3C

H

H

Solvent

CCl3 F Pentane CHCl3 CH2 Cl2 Xylene THF Pivaldehyde Diglyme

H3C H3C H3C

H + –OSF2NEt2

F

Polar, nonbasic solvent

F

F H H3C CH3 H3C F

8

9

CH3 H

DAST

H3C H OSF2NEt2 H3C H 3C F

Nonpolar solvent

H 3C H H3C F H3C F 10

GLC yield (%) 8

9

10

88 87 72 72 64 65 60 30

2 3 3 2 8 20 10 32

10 10 25 26 28 15 30 38

a suitable reaction solvent. Nonpolar solvents (CFCl3 , pentane, or CH2 Cl2 ) favor the formation of the desired fluorides whereas polar solvents (THF or diglyme), which can stabilize cationic intermediates, favor elimination and rearrangement products. 2.5.3 Carboxyl into Trifluoromethyl

The conversion of carboxyl groups into trifluoromethyl groups proceeds in two steps. The first step, exchange of the hydroxy group by fluorine, can be accomplished easily by use of less potent fluorination agents such as α-fluoroenamines or DAST. Subsequent conversion of the carboxylic acid fluoride into the trifluoromethyl

77

78

2 Introduction of Fluorine

group requires more drastic conditions and can be achieved only with SF4 . The most convenient procedure is the one-step direct reaction of carboxylic acids with SF4 in aHF as solvent (Scheme 2.75). For most aliphatic and aromatic carboxylic acids, excellent yields can be obtained even at room temperature or below.

OH

F

O

O R

R

Mild conditions: α-fluoroenamines, DAST, SF4

Drastic conditions: SF4, aHF

F

H

CF3

SF4, aHF; r.t., 18 h

H

F F

H

70%

COOH

R

H

Scheme 2.75 Conversion of carboxylic acids to the corresponding trifluoromethyl compounds by sulfur tetrafluoride [139a]. Source: P. Kirsch, A. Ruhl, and R. Sander, 2002, unpublished work.

A major side-reaction of the fluorination of carboxylic acids is the formation of bis(α,α-difluoroalkyl) ethers, presumably (Scheme 2.76) via cationic intermediates. Fluorination: R

R O + SF3+

F

F

R + O F SF2 (FHF)– F

+

F + SOF2

R F

F F

Competing ether formation: R

R O + RCF2+

F

F

–

(FHF)

+

O CF2R

RCF2OCF2R

Scheme 2.76 Mechanism of the fluorination of carboxylic acids to trifluoromethyl derivatives, and the competing formation of bis(α,α-difluoroalkyl) ethers [154].

2.5.4 Oxidative Fluorodesulfuration

A very generally applicable method for converting a variety of different functional groups into their partially or fully fluorinated analogs is the oxidative fluorodesulfuration of thiocarbonyl compounds, dithiolanes, dithianes, and dithianylium salts. The principal method was initially discovered in the 1970s [155, 156]; since the beginning of the 1990s, it has been systematically developed into a valuable tool for fluoroorganic synthesis [157–162].

2.5 Transformations of Functional Groups

79

The general concept is that sulfur is introduced into the organic substrate as a direct synthetic precursor of fluorine. The sulfur compound is then treated with a thiophilic, ‘‘soft’’ electrophilic oxidant, for example, electrophilic halogenation agents such as NBS, NIS, 1,3-dibromo-5,5-dimethylhydantoin (DBH), Br2 , SO2 Cl2 [157], F2 [163], IF5 [164], BrF3 [165], 4-MePhIF2 [166], nitrosyl cations (NO+ BF4 − ) [160], or F-TEDA [167] in the presence of a fluoride source (50 or 70% HF–pyridine [157], HF–melamine [158], and NEt3 ·3HF [161]). The chemical oxidant can also be replaced by electrochemical oxidation [168, 169]. The sulfur species is thus activated by S-halogenation into a nucleofugic leaving group, which is substituted by fluoride. The fluorodesulfuration of thiocarbonyl compounds is supposed to follow a similar principal pathway. The mechanism depicted in Scheme 2.77 [156] is tentative, derived, and made plausible by molecular modeling and by analysis of the complete product spectrum, including side reactions. The extruded sulfur species cannot be expected to be stable in the presence of a substantial excess of oxidant and the typical subsequent aqueous work-up conditions. O

HS BF3·OEt2, CH2Cl2

F

F

S

S

NBS, 70% HF-pyr; –78 °C to r.t. or NO+BF4–, 70% HF-pyr

SH

or 10% F2/N2, I2, CH3CN

+ X+

– XSCH2CH2SX

F

+ X+

SX

SX

+

S

SX

X + F S

+

S X

S

F S

F Scheme 2.77 Proposed mechanism of oxidative fluorodesulfuration of dithiolanes [156, 167]. X+ represents electrophilic bromine ‘‘Br+ ’’, iodine ‘‘I+ ’’, the nitrosyl cation NO+ , or ‘‘F+ ’’.

From the viewpoint of ‘‘atom economy’’ [170], dithiolane, or dithiane fluorodesulfuration chemistry suffers from a drawback – as a result of oxidation of the

80

2 Introduction of Fluorine

sulfurous protecting (and activating) group, a relatively large part (by molecular mass) of the starting material is lost and cannot be recovered or recycled. Many varieties of fluorodesulfuration of protected (or activated) carbonyl compounds are known. Some contain an intermediate reductive step, leading to a monofluoromethylene instead of a gem-difluoromethylene group [160]. It has been demonstrated several times that different sulfur species (thiocarbonyl or thioether) can be selectively oxidized by careful choice of thiophilic oxidant and the acidity of the reaction medium. In thioesters or xanthogenates, the thiocarbonyl group is fluorodesulfurated in a neutral to mildly acidic medium [Bu4 N+ (H2 F3 )− ] with a relatively mild oxidant (NIS), whereas oxidation of the remaining α-difluorothioether requires a strongly acidic medium (70% HF–pyridine) and a more powerful oxidant (DBH) (Scheme 2.78). It seems that after oxidation of the thiocarbonyl group the resulting gem-difluoromethylene moiety deactivates the remaining sulfur against further thiophilic attack.

O Ph

H S Ph 1. PhSH, BF3Et2O, CH2Cl2

79%

Ph

Ph

H F

NO+BF4–, 60% HF-pyr; 0 °C

Ph

Ph

2. Et3SiH

O O

O

72%

S

+

–

Bu4N (H2F3) , DBH, CH2Cl2

F F

O F F

61%

SMe

Bu4N+(H2F3)–, NIS, CH2Cl2; 0 °C

S SMe

83%

Bu4N+(H2F3)–, DBH, CH2Cl2; 0 °C

CF3

63% Bu4N+(H2F3)–, DBH, CH2Cl2; 0 °C

Br

Bu4N+(H2F3)-, NBS, CH2Cl2; –78 to 0 °C

SMe

O S

62%

O O

70% HF-pyr, DBH, CH2Cl2; –78 to 0 °C

OCF3

70% HF-pyr, DBH, CH2Cl2; –78 to 0 °C

O

F F

Br

62%

S

SMe

O

44%

Br F

Cl 75% NEt3·5HF, CH2Cl2; electrochemical oxidation: 3.4 F·mol-1

O

O O

Scheme 2.78 Examples of the versatility of the different varieties of fluorodesulfuration reactions [160, 169, 171, 172].

2.5 Transformations of Functional Groups

81

In carbohydrate chemistry, fluorodesulfuration has become a convenient tool for switching between different, ‘‘orthogonal’’ modes of glycosidic activation [173] (Scheme 2.79). AcO AcO AcO

OAc O F

SPh

I CH3 F –78 °C to r.t., CH2Cl2

OAc O

AcO AcO AcO

a:b = 91:9

F

F +

S

Ph

OAc O

AcO AcO AcO

56%

PhCH3

I F

OAc

OAc AcO AcO

O

SPh

OAc

AcO I2, 10% F2/N2, AcO CH3CN, r.t.

O OAc

F

Scheme 2.79 Syntheses of glycosyl fluorides from thioglycosides by oxidative fluorodesulfuration [159, 166].

Orthogonal glycosidic activation is essentially based on the application of Pearson’s HSAB (hard and soft acids and bases) concept [174]. Under typical conditions 1st coupling (conditions A)

O

2nd coupling (conditions B)

O O

SR

O

HO

O O

F HO

SR

F introduction of hydrophobic tag (conditions A or B)

O O

O

O O

O

O

O O

n

O

n

O

X

X = SR or F

Cleavage and deprotection

Repeat

HO

(OH)4 (OH)3

O O

O

Polymer support

(OH)3 O

O

n

O

Hydrophobic tag

Scheme 2.80 Principle of ‘‘orthogonal’’ glycosidic activation on a polymer [e.g., poly(ethylene glycol)] support. To facilitate purification, a hydrophobic tag [e.g., 2(trimethylsilyl)ethyl] is introduced [173]. Conditions A are for thioglycoside activation and conditions B for activation of glycosyl fluorides.

82

2 Introduction of Fluorine

for activation of thioglycosides into glycosyl donors with ‘‘soft’’ Lewis acids (e.g., the MeOTf–MeSSMe system, with MeSSMe2 + as the activating species), glycosyl fluorides are inert. On the other hand, activation of glycosyl fluorides with ‘‘hard’’ Lewis acids (e.g., the Cp2 HfCl2 –AgOTf system, with Cp2 HfCl+ as the activating species) does not affect thiogylcosides present in the same reaction mixture (Scheme 2.80). Orthogonal glycosidic activation is an important step in the direction of automated oligoglycoside synthesis [175]. The fluorodesulfuration of dithioesters has also been used for the ‘‘traceless’’ solid-phase synthesis of trifluoromethyl arenes [176], which play a central role in pharmaceutical chemistry. The conversion of a solid-phase supported dithioester into a trifluoromethyl function is a useful tool for combinatorial drug design (Scheme 2.81). S

Br S

O

1. iPrMgCl·LiCl

O O

OH

2. CS2

R

Cl

Cl

3. KI,

, Et3N

4. pyridinium p -toluenesulfonate

S CF3

O

S

R

O

O

NIS, 70% HF-pyr

R

O

Scheme 2.81 Introduction of aromatic trifluoromethyl substituents via fluorodesulfuration of a traceless dithioester linker [176].

Since the late 1990s, fluorodesulfuration has gained importance as a valuable synthetic tool, especially for the preparation of liquid crystals [177, 178]. The H

H OH

H7C3

1. NaH,THF 2. CS2

H

H7C3

O S

3. MeI 1. NaH, THF + 2. S F3C S

–

SCH3

H

DBH, 50% HF-pyr, CH2Cl2; 0 °C OTf

(a)

H H7C3

H H7C3 H

OCF3 H

O S

CF3 S

54% 1. 70% HF-pyr, CH2Cl2; –70 °C

(b)

H H7C3

OCF2CF3 H

2. DBH; –70 °C to r.t.

Scheme 2.82 Synthesis of liquid crystals by oxidative fluorodesulfuration of xanthogenates (a) [178] and by the oxidative alkoxydifluorodesulfuration of dithianylium salts (b) [179].

2.5 Transformations of Functional Groups

83

methodology allows convenient access to aliphatic trifluoromethyl ethers and, more recently, to α,α-difluoroalkyl [161a] and perfluoroalkyl ethers also [179] (Scheme 2.82). The alkoxydifluorodesulfuration of dithianylium salts [180] has some very special advantages compared with other known fluorodesulfuration routes via thionoesters [161]. (i) Dithianylium salts are easily accessible. They can be prepared from either carboxylic acids or acid chlorides [181] and isolated by simple precipitation as stable, crystalline solids. (ii) Many aliphatic thionoesters (as the alternative substrate for oxidative fluorodesulfuration) are unstable and tend to eliminate the corresponding alkoxy moiety, forming even more unstable thioketenes. (iii) Typical liquid crystalline mesogenic core structures are based on trans-1,4-cyclohexane substructures. Making use of the reversibility of the formation of aliphatic dithianylium salts, the thermodynamically preferred trans-4-alkylcyclohexyl dithianylium salts

H11C5

O

S S

70% 2-trimethylsilyl-1,3-dithiane, n-BuLi, THF; –20 °C to r.t.

H11C5

in situ generation

1. CF3SO3H, CH2Cl2; –70 °C, 5 min 2. –70 °C to r.t., 30 min +

S

S H11C5

H COOH

H11C5 H

80-90% isolated yield 1. HS(CH2)3SH, CF3SO3H, toluene/i-octane (1:1); azeotropic removal of H2O

+

S

H11C5 S F3PhOH, NEt3, CH2Cl2; –78 °C

2. Precipitation with Et2O

H11C5

S

F

O S

F F 85-90%

1. NEt3·3HF; –78 °C 2. Br2; –78°C to r.t.

F H H11C5

CF2O

F

H F

Scheme 2.83 Synthesis of α,α-difluoroether-linked liquid crystals by oxidative alkoxydifluorodesulfuration of dithianylium salts. The intermediate dithioortho ester is only stable at temperatures below about −50 ◦ C [161a].

84

2 Introduction of Fluorine

can be conveniently obtained by protonation and subsequent equilibration of the corresponding ketenedithioketals. The in situ formation of dithianylium salts by protonation of ketenedithioketals is also useful for the generation of simple 2-alkyl-1,3-dithianylium salts which do not crystallize. Mechanistically, the only difference from the chemistry depicted in Scheme 2.77 is the formation of a dithioorthoester as the central sulfur-containing intermediate; if this is generated from strongly electron-deficient perfluoroalkyl dithianylium salts (Scheme 2.83), it can be isolated at room temperature. For alkyl or aryl dithianylium salts with less fluorination, the dithioorthoester is a labile intermediate which is only stable at low temperatures (up to about −50 ◦ C). This intermediate is subsequently fluorodesulfurated to yield the corresponding α,α-difluoroether. Dithianylium salts in combination with oxidative fluorodesulfuration chemistry are also useful reagents for the synthesis of gem-difluoromethylene analogs of carboxylic acid derivatives other than esters. If the fluorodesulfuration is conducted in the presence of other O- or N-nucleophiles, the corresponding α,α-difluoroalkyl compounds are obtained in reasonable to good yields (Scheme 2.84). F

78% 1. tBuOOH (90% in toluene), NEt3, CH2Cl2; –70 °C 2. NEt3·3HF; –70 °C 3. DBH; –70 °C to –10 °C 89% 1. Me3SiN3, CH2Cl2; 0 °C +

S

H7C3

F

O O

F H7C3

F +

N N N

+ – 2. Bu4N F , THF, 0 °C

−

3. NEt3·3HF; –70 °C 4. DBH; –70 °C to –20 °C

R CF3SO3–

S

14% 1. imidazole, NEt3, CH2Cl2; -70 °C

F H11C5

F N N

2. NEt3·3HF; –70 °C 3. DBH; –70 °C to –20 °C 11% 1. (S)-1,1′-bis(2-naphthol), NEt3, CH2Cl2; –65 °C 2. NEt3·3HF; –65 °C

O F C3H7 O

3. DBH; –65 °C to –20 °C

Scheme 2.84 Fluorodesulfuration of dithianylium salts in the presence of different O- and N-nucleophiles allows convenient access to a variety of α,α-difluoroalkylated products (R = n-C3 H7 or n-C5 H11 ) [161b].

O’Hagan and co-workers found that fluorodesulfuration not only is a versatile tool for the synthetic organic chemist but also – in a nonoxidative variant – but also so far is the only known pathway in Nature for enzymatic incorporation of inorganic fluoride ions into secondary metabolites [182] (Scheme 2.85). As the key step of this enzymatic reaction sequence, a trialkylsulfonium ion [S-adenosylmethionine (SAM)] reacts with inorganic fluoride in a nucleophilic replacement with methionine as the leaving group.

2.6 ‘‘Electrophilic’’ Fluorination

+

COO–

H3N

NH2

NH2 N +

S

O

H3C

N

N F

N

SAM HO

N O

N 5 ′- FDA

F –, fluorinase

OH

N

N

HO

OH Unknown steps

O H F Aldehyde dehydrogenase

NAD+

Transaldolase PLP

OH

O

COO–

O F

F

+

NH3

Scheme 2.85 Biological fluorodesulfuration and subsequent enzymatic conversions. SAM = S-adenosylmethionine, 5 -FDA = 5 -fluorodesoxyadenosine, NAD+ = nicotinamide adenine dinucleotide, PLP = pyridoxal phosphate [182].

2.6 ‘‘Electrophilic’’ Fluorination

The discovery of Fried and Subo [183] in the 1950s that incorporation of fluorine substituents into 9α-fluorocortisone acetate dramatically increased its therapeutic effect provided a strong stimulus for interest in fluorinated pharmaceuticals. One valuable component still missing from the toolbox of methods in organofluorine chemistry was a generally applicable method for the electrophilic fluorination of sensitive organic substrates under mild conditions. 2.6.1 Xenon Difluoride

One of the first reagents used for electrophilic fluorination was xenon difluoride (XeF2 ) [184], a solid which is easy to handle and which can be used in solvents that are relatively inert towards oxidation, for example, acetonitrile and dichloromethane. The reactivity is mostly determined by its strong oxidizing power, rendering its mode of action more oxidative than electrophilic fluorination. With XeF2 , not only are typical ‘‘electrophilic’’ fluorinations of aromatic compounds possible, but also the Hunsdiecker-like fluorodecarboxylation of carboxylic acids and fluorinative rearrangements of carbonyl compounds to difluoromethyl ethers [185–187] (Scheme 2.86).

85

86

2 Introduction of Fluorine

F 60% XeF2, HF, CH2Cl2; r.t.

(FHF)– O

O + XeF2

R OH

HF

O Xe F

FXe δ+ δ– F Xe F +

R-F + CO2 + Xe + (FHF)–

R

A Route a

CHO

+ O

F O XeF

H F-

H

O +

H F

F– + Xe

F OH Route b

H

O

CHF2

Scheme 2.86 Fluorination reactions with xenon difluoride (A = catalytic amount of SiF4 as a Lewis acid) [185–187].

2.6.2 Perchloryl Fluoride and Hypofluorides

The first electrophilic fluorination reagent with industrial relevance was perchloryl fluoride (FClO3 ) [188] (Scheme 2.87), a gas (m.p. −147.8 ◦ C, b.p. −46.7 ◦ C) which is thermally stable up to 500 ◦ C [189]. It was used commercially from the beginning of the 1960s for the production of fluoropharmaceuticals, in particular fluorosteroids. KClO4 + 2HF + SbF5 Scheme 2.87

40–50 °C

FClO3 + KSbF6 + H2O

Synthesis of perchloryl fluoride [189].

FClO3 owes its reactivity to the fluorine bound to a strongly electronegative chlorine in its highest oxidation state. Although FClO3 allows the selective synthesis of complex organic compounds such as fluorocorticoids (Scheme 2.88), its high oxidation potential in combination with organic solvents poses a constant threat of explosion. On contact with alcohols, in particular, the extremely shock-sensitive alkyl perchlorates are formed. Another class of powerful electrophilic fluorination reagents, which are slightly less risky to use, are the hypofluorites or ‘‘OF’’-reagents, with fluorine activated by electronegative oxygen groups [190]. The most prominent examples of these hypofluorites are CH3 COOF (m.p. −96 ◦ C, b.p. ∼53 ◦ C) [191], CF3 COOF [192], and

2.6 ‘‘Electrophilic’’ Fluorination

H3C OAc H3C

H3C

H H

FClO3

H

OAc

H3 C

AcO

H H

H

O F

Scheme 2.88 Synthesis of fluorosteroids by electrophilic fluorination with perchloryl fluoride.

CF3 OF [193] (Scheme 2.89), all highly toxic, low-boiling liquids or gases at room temperature. In addition to their toxicity, the hypofluorites tend to detonate in contact with organic solvents and are therefore not safe enough for industrial use. CF3COOF + NaF·H2O

O CF3COONa

F3C

H2O

OF

F2

NaF

CO + CsF

F2

F3CO–Cs+

N

CH3

F3C

H O F

N

ONa F F2 OF

F 3C

O

O CH3

CF3O– H H F

N

H

CH3

+

60%

N

CF3

CH3

F + F2CO + HF

CF3OF

CF3

OF F OF

F3COF + CsF

CF3O·· …Cs+ …F–…F·

F2

O

O H

F 3C

CF3

CF3

Scheme 2.89 Representative syntheses of a variety of OF-reagents and the mechanism proposed for the selective electrophilic ortho fluorination of aromatic acetamides [194].

Acetyl hypofluorite has achieved particular importance as a fluorinating agent for the rapid synthesis of positron-emitting 18 F radiopharmaceuticals and diagnostics with a half-life of 109.7 min (Scheme 2.90). The compound is readily available by the ‘‘dry column’’ method, that is, by passing gaseous F2 or 18 F19 F through a column packed with solvated KOAc·2HOAc [195]. OAc AcO AcO

OH

OH

O 1. AcO18F 2. hydrolysis

HO HO

O 18

F

+ OH

Scheme 2.90 Synthesis of 2-[18 F]fluorodeoxyglucose [196].

HO HO

18 F

O

minor

OH

87

88

2 Introduction of Fluorine

2.6.3 ‘‘NF’’-Reagents

Towards the end of the 1980s, the intensive search for less hazardous electrophilic fluorination agents produced a number of different sub-classes of so-called ‘‘NF’’-reagents [197–199] (Scheme 2.91). The concept underlying these reagents is based on work dating back to the late 1950s when the synthetic potential of N-fluoroamines such as perfluoro-N-fluoropiperidine [200] or, later, NF4 + and N2 F+ was explored [201]. The NF-reagents derive their fluorinating power from fluorine bound to electronegative nitrogen, occasionally additionally activated either by strongly electron-withdrawing groups such as carbonyl or sulfonyl or by nonstabilized positive charges in the same molecule. The great advantage of all these NF-reagents compared with the previous generation of electrophilic fluorination reagents is that most are solid, nonvolatile compounds which are not explosive. The commercial availability of reagents such as those depicted in Scheme 2.91 triggered an avalanche of experimental work on electrophilic fluorination in subsequent years [202]. CH2Cl

N

O O S NNa S O O

+

N

N CH2Cl2, BF3, 10% F2/N2

2BF4–

+ N

F F-TEDA-BF4 (Selectfluor)

CH3CN, BF3, 10% F2/N2

N

N

+

N F NFPy

10% F2/N2, CHCl3/CFCl3

O O S NF S O O NFTh

B2F7–

Scheme 2.91 The most important classes of commercially available electrophilic fluorination reagents of the NF-type and their syntheses [202].

The mechanism of electrophilic fluorination (real electrophilic ‘‘F+ ’’ transfer versus a two-step single-electron/fluorine radical transfer; Scheme 2.92) has been a matter of controversy for some time [203]. There is, however, a general consensus

SN2

– X

– Nu

F

Nu F + X–

X F + Nu– –. ET

X F

+ Nu .

Scheme 2.92 Possible mechanisms for electrophilic fluorination – two-step electron transfer/fluorine radical transfer or SN 2 nucleophilic substitution mechanism [203].

2.6 ‘‘Electrophilic’’ Fluorination

89

that the high enthalpy of formation of the F+ cation in the gas phase (420 kcal mol−1 ) precludes a truly ‘‘electrophilic’’ mechanism. A mechanism proceeding via a pure SN 2 pathway at the electrophilic fluorine also seems unlikely [203b]. Detailed studies of product distribution for NF-type reagents under different reaction conditions indicate a two-step mechanism via an electron transfer with subsequent fluorine radical transfer [199b] (Scheme 2.93).

F

O

+

N R

+

a: R = SiMe3, Ac +

N

N F

OR

OR

PyrF+

a

Fb

1. e – transfer 2. F· transfer

+

charge transfer complex

OR

b: R = alkyl

OR +

N

Scheme 2.93 Proposed mechanism of electrophilic fluorination with N-fluoropyridinium salts [199b].

Additional evidence for the two-step oxidation–fluorination mechanism is the correlation observed between the fluorinating ‘‘power’’ and the first reduction potential of different NF-reagents. Systematic studies by cyclic voltammetry [204] (Scheme 2.94) reflect not only the different reactivity ranges of the classes of CH2Cl

CH3

N

N

+

+

N

F 2BF4– Ep,red –0.04 (V vs. SCE)

N

CH3

+

+

F 2CF3SO3– –0.09

+

N F B2F7– –0.34

+

N

N

+

H3C

F F CF3SO3– CF3SO3– –0.37

+

N CH3 F CF3SO3–

–0.47

Ph Ph O S S O N O O F

–0.37

Increasing fluorinating power Scheme 2.94 Reduction peak potentials of different electrophilic fluorination reagents: Ep,red in V relative to the standard calomel electrode (SCE); 1–5 nM in CH3 CN–0.1 M Bu4 N+ BF4 − or CF3 SO3 − [204b].

–0.78

90

2 Introduction of Fluorine

NF-reagent but also that additional modulation of the fluorinating power can be achieved by suitable substitution of the basic structures with electron-donating or -withdrawing groups. Newer QM/MM simulations of the electrophilic fluorination of a malonate coordinated to a titanium center with a simplified Selectfluor™ (F-TEDA) analog [205] throw new light on the electron transfer/fluorine transfer mechanism. During the approach of the electrophilic fluorine towards the carbon nucleophile, an electron is transferred from the nucleophile to Selectfluor, then fluorine is transferred to the nucleophile. Interestingly, the transition state for transfer of the fluorine radical is formed only if a polar solvent (acetonitrile) is used. If the simulation is carried out in vacuo, the reaction stops after the initial electron transfer. In addition to modulation of the general reactivity by choice of substituents with different electron demand, Umemoto and co-workers described a method of increasing the selectivity of the fluorination, particularly for phenols and aromatic urethanes in the ortho-position [199b, 206]. In the reaction of N-fluoropyridinium2-sulfonate, the electrophilic fluorine is supposedly directed by a combination of π···π donor–acceptor interaction and electrostatic (hydrogen) bonding to a specific position (Scheme 2.95). X

O O S N O F H O

OH

+

X +

N F Scheme 2.95 [206].

O

OH

H F

F

SO3–

Directed ortho fluorination of phenols by N-fluoropyridinium-2-sulfonates

A major drawback so far for all NF-reagents is their relatively high molecular weight and their low content of ‘‘active’’ fluorine. For example, for Selectfluor the ratio of active fluorine to the molecular weight is only 5.4%, for NFTh 8.0%, and for NFPy 6.0%. This issue was addressed by the synthesis of more F N

+

F N

+

+

+

N F (BF4–)2

N

(BF4–)2

F

12

11 Scheme 2.96 Electrophilic fluorination reagents with an improved ratio of electrophilic fluorine to molecular weight. The respective ratios are 11 11.2% and 12 theoretically 12.8%, but only one fluorine is reactive, therefore actually only 6.4% ‘‘active’’ fluorine [207, 208].

2.6 ‘‘Electrophilic’’ Fluorination

‘‘compact’’ fluorination reagents [207]. One approach towards this goal was to link two or more pyridinium units to a single molecule (11, commercialized as Synfluor). Another approach, introducing two nitrogen–fluorine bonds to the same diazabicyclooctane (DABCO) system (12) [208], yielded a system with significantly improved fluorination power. Unfortunately, in this system only one fluorine is reactive in fluorination; the other merely modulates its reactivity by means of its positive charge in close vicinity to the reactive center (Scheme 2.96). A similar reactivity-enhancing effect was achieved by use of the N-hydroxy analog (13) of Selectfluor [209], commercialized under the name Accufluor. In addition, a number of other derivatives of the fluorinating agents with up- or down-tuned reactivity are available (Scheme 2.97). The tuning is usually achieved by selection of more or less electronegative substituents on the basic structures DABCO, pyridine, or sulfonimide [210]. +

+

F N

F3C

N OH

13

(BF4–)2

O

O S

O CF 3 S O N F

CH3

H3C

+

N CH3 F BF4– lower

+

N – F BF4 fluorinating power

Cl

+

Cl N F BF4– higher

Scheme 2.97 NF-reagents with up- or down-tuned reactivity.

The range of possible fluorination reactions on electron-rich double bonds, enolates, and enol ethers, with Selectfluor (F-TEDA-BF4 ) as an example, is depicted in Scheme 2.98. Yields from the fluorination of unstabilized carbanions, for example, phenylmagnesium bromide, are usually relatively low, mostly because of competing oxidation side reactions. Although the electrophilic fluorination of aromatic compounds can be achieved by use of a wide range of different NF-reagents (Scheme 2.99), lack of sufficient selectivity in the fluorination and the difficulty of separating the fluoro isomers, because of their very similar boiling points remain a problem. For this reason, electrophilic fluorination of aromatic compounds, either with NF-reagents or with elemental fluorine, is used only in a few special cases. For production-scale synthesis, Halex and Balz–Schiemann chemistry remain unrivaled. Reaction of thioethers with 1 equiv. of NF-reagent results in the formation of α-fluorothioethers via a fluoro-Pummerer rearrangement [215] (Scheme 2.100). With appropriate excesses, α-fluorosulfoxides and -sulfones are obtained [216]. The thiophenyl group can also be used as a subsequently removable directing function for site-selective fluorination of natural products [217].

91

92

2 Introduction of Fluorine

H3C H3C

H3C

H

H H3C H3C

F-TEDA-BF4, CH3CN; r.t. AcO

H3C H3C

H

H

F-TEDA-BF4, CH3CN; r.t.

α:β = 95:5

H OAc

H

95%

AcO

F H

H

OAc

H

O

H

92%

H

H AcO

H3C

OSiMe3

H

H O

α:β = 42:58

F Me3SiO H3C

H3 C H

H

NFPy-OTf, CH2Cl2; r.t.

H3C

O H3C

51%

H Me3SiO

OSiMe3

H F

O

H

98%

F OMe

F-TEDA-BF4, MeOH, CH3CN; r.t.

EtO

ONa OEt

H

CH3

CH3

O

O

O 94%

EtO

F

O OEt

F-TEDA-BF4, THF/DMF; r.t.

MeO

O

N MePhO2S

1. NaH 2. Me2SO4,DMF

PhMgBr

Scheme 2.98 212].

O

NFPy-OTf, CH3CN; reflux

N MePhO2S 61% F-TEDA-BF4, Et2O; r.t.

F

F

N MePhO2S

PhF

Reaction of a variety of substrates with the different NF-reagents [199b, 211,

It was also found that direct selective substitution of aliphatic hydrocarbons via a supposedly electrophilic mechanism can be achieved by use of F-TEDA-BF4 [218]. Depending on the exact reaction conditions, either alkyl fluorides or Ritter-type products are obtained (Scheme 2.101). Relatively short reaction times favor the

2.6 ‘‘Electrophilic’’ Fluorination

93

F OMe + F 45%

OMe Cl2NFPy-BF4, CH3CN; r.t, 3 d

OMe 28%

F 55%

NHCO2Et

F

Cl2NFPy-OTf, (CH2Cl)2; 60 °C,3 d

NHCO2Et

F

F +

NFPy-OTf, (CH2Cl)2; reflux

30%

F 25% O

OH

OH

OH

F

H3C

9%

42%

5%

F

F

H3C

F

+

+

NFPy-OTf, (CH2Cl)2; reflux

F

H17C8O

41%

N

N N

N

Me3NFPy-OTf, CH3CN; r.t.

NH

NH

N N

R = –CH2CH2NHSO2 OC8H17

R

R

Scheme 2.99 Electrophilic fluorination of aromatic compounds [199b, 206, 213, 214].

R

S

R “F+”

R

F + S

R Base

R

R

S F

O

N

AcO S

O

F

O NH

NH AcO

R

SCH2F

Me3NFPy-OTf, CH2Cl2; r.t, 4h

O

R

Further oxidation/ hydrolysis

85%

SMe

O S

52% 1. F-TEDA-BF4, CH3CN, r.t., 15 min 2. NEt3

OMe

AcO O F

N

O

AcO S OMe

Scheme 2.100 α-Fluorination of thioethers with NF-reagents [215–217].

O O R S R F

94

2 Introduction of Fluorine

CH2Cl N +

CH2Cl

F

+

N +

+

N (BF4–)2 F

CH2Cl

+

+

N

+

+

+

(BF4–)2 CH3CN

CH3

O HN

+ HF N

N (BF4–)2 H Very strongly acidic

N

CH3

+

H2O, work-up

CH3

CH3

CH3 83%

50%

OH

2.2 equiv. F-TEDA-BF4; CH3CN; reflux, 16 h

(-)-Menthol

O H3C H3C

aq. NaOH, CH2Cl2; r.t., 16 h

N CH3 H BF4– CH3 N

1 equiv. F-TEDA-BF4, CH3CN; reflux, 24 h

OH H3C H3C

+

NHCOCH3

NHCOCH3

+

97%

F

F

H2O

BF4–

Scheme 2.101 Aliphatic fluorination and Ritter-type reactions of NF-reagents in acetonitrile [218, 219].

formation of the fluorides; longer heating with F-TEDA-BF4 in acetonitrile favors the formation of acetamides, especially in the presence of additional BF3 ·OEt2 as a Lewis acid catalyst [219]. Although enantioselective electrophilic fluorination can be achieved by use of a variety of chiral NF-reagents [220], enantiomeric excesses (ees) are only moderate and far lower than expected for ‘‘real’’ electrophilic addition. It might be speculated that the reason lies in the specific mechanism of electrophilic fluorination in general – the electron transfer which presumably precedes fluorine transfer results in a short-lived radical intermediate which is configurationally unstable and can racemize. Chiral reagents of the first generation are N-fluorosultams, derived either from camphorsultam or from sulfonylcarboximide (Scheme 2.102). Newer approaches make use of derivatives of quinuclidine alkaloids, such as quinine. The quinine derivative is first converted into the fluorination reagent by

2.6 ‘‘Electrophilic’’ Fluorination

95

O O S N F

R′ R′ N F S O OR

H3C 15

14a : R, R′ = H 14b : R = CH3, R′ = H 14c : R = H, R′ = Cl 14d : R = H, R′ = OCH3 O

63% (70% ee)

COOEt

O F COOEt

NaH, (-)–14a

Scheme 2.102 Uncharged chiral electrophilic fluorination reagents of the first generation: N-fluorocamphorsultams (14a–d) [197a] and N-fluorosultam (15) [221].

Selectfluor in a one-pot procedure, and in a second step is reacted with the desired substrate (Scheme 2.103). The ees achieved with this type of reagent are higher than those for the N-fluoroimides, but still below those of other enantioselective reactions. Cl

Cl O

O N

O H

MeO N

+

+

Cl

N + N F 2BF4–

+

N

O

HF

MeO

CH3CN; r.t., 1h

+

+

BF4–

BF4–

N OSiMe3 O

Ph CH3CN; r.t., 2 h

F Ph

Cl

N N

99% 89% ee

Scheme 2.103 Enantioselective electrophilic fluorination of silyl enol ethers by Nfluorodihydroquinine 4-chlorobenzoate. The enantioselective fluorination reagent is generated in situ from F-TEDA-BF4 (Selectfluor™) and dihydroquinine 4-chlorobenzoate [222].

Combination of the dication Selectfluor with a chiral phosphate anion in a phase transfer system results in electrophilic fluorination with good enantioselectivity (Scheme 2.104) [223].

96

2 Introduction of Fluorine

O

N-F+ X– +

*

O

Insoluble

P

O O–

O

M+

*

Soluble

O

O

P

O–

N-F+

Soluble chiral fluorination reagent

MX

i Pr

i Pr H17C8

Cl +

N+ N+

–

N-F X =

F

BF4–

O *

O

P

O

i Pr O O P – + O O M i Pr

+

M =

O–

BF4–

H17C8 iPr

Cl O

F O

95% (97% ee)

NH

O

i Pr Abs

5 mol% catalyst,

O

Cl

N

1.25 equiv. Selectfluor 1.1 equiv. Proton sponge, C6H5F; –20 °C, 24 h

Scheme 2.104 Enantioselective, electrophilic fluorination using a chiral, anionic phasetransfer catalyst [33] [Proton Sponge = 1,8-bis(dimethylamino)naphthalene].

A different approach to enantioselective electrophilic fluorination is the use of chiral auxiliary groups on the substrate; this converts the problem into a diastereoselective fluorination. The ground-breaking work in this field was performed since 1992 by Davis’s group [224], by fluorination of imide enolates modified by Evans’ oxazolidinone chiral auxiliary [225] using N-fluoro-o-benzenedisulfonimide (NFTh) as the electrophilic fluorination agent (Scheme 2.105). O O 1

R

O R3

N R

2

O

80-88% (86-97% de) 1. LDA, THF; –78 °C 2. NFTh, THF; –78 to 0 °C

O

O R3

N F

R1

R2

Scheme 2.105 Synthesis of α-fluorocarbonyl compounds by use of Evans oxazolidinone as chiral auxiliary. R1 = H, Ph; R2 = CH3 , i Pr; R3 = n Bu, t Bu, Bn, Ph [224, 225].

Menthol derivatives are also an inexpensive means of obtaining diastereoselection during electrophilic fluorination [226]. Depending on the size of the substituents at the nucleophilic center, the stereoselectivity not only changes but can be completely inverted (Table 2.2). Yet another example of diastereoselective electrophilic fluorination was observed on the route to fluorinated prostaglandin analogs [227]. In this reaction, the concave

2.6 ‘‘Electrophilic’’ Fluorination Table 2.2

Use of menthol derivatives as chiral auxiliaries [226]. R O Ph

O O

OMe

1. LiN(SiMe3)2, THF; –78 °C 2. Me3NFPy-OTf; –78 °C to r.t.

R F O Ph

F R O

O

O Ph

+

OMe

O O

A

OMe

B

R Me Et Pr CH2 Ph

A:B 3.8:1 1:2 1:2 1:1.6

shape and large size of a tetrahydropyranyl protecting group impedes attack of the fluorinating agent from the concave side of the molecule (Figure 2.7). A newer approach towards the enantioselective electrophilic fluorination of β-ketoesters is based on enolization of the substrate under neutral conditions by coordination to a chiral titanium catalyst [228]. The catalyst, a chiral titanium TADDOLato complex (TADDOL = α,α,α  ,α  -tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5dimethanol) [229, 230], coordinates to the β-ketoester, enolizes it, and thus renders O

O

O

O

F

61%

OTBS THPO

LiN(SiMe3)2,

OTBS

(PhSO2)2NF, THF

THPO KN(SiMe3)2, 70%

ZnCl2, THF/toluene

O O 57 % KN(SiMe3)2, MnBr2,(PhSO2)2NF,

F F OTBS

THPO

THF/toluene

Figure 2.7

Diastereodirection of the fluorination site by neighboring chiral centers [227].

97

98

2 Introduction of Fluorine

it susceptible to electrophilic fluorination (Scheme 2.106). One face of the prochiral enolate substructure is covered by a bulky naphthyl substituent from the TADDOL ligand, impeding electrophilic attack of F-TEDA. + O

O R O Np Np R Np Cl Np O O Ti NCMe MeCN Cl

O

O Np Np O O Ti O MeCN O OR′

Np Np

OR′ CH3

–

–Cl , – MeCN

Cl

O

O S

R

R rac.

O

CH3

R OR′

- H+

F CH3 90% ee

+

O

O Np Np Cl O O Ti O MeCN O OR′

O

Np Np

R

F

O Np Np Cl O O Ti O MeCN O OR´

Naphthyl residue is shielding the enolate Re face

Np Np F-TEDA attacks from Si face

CH3

R

CH3

Scheme 2.106 Asymmetric electrophilic fluorination of β-keto esters, catalyzed by chiral titanium TADDOL complexes. Np = 1-naphthyl, R = Et, R = 2,4,6-(i Pr)3 C6 H2 CH2 [228].

Other methods for enantioselective electrophilic fluorination have been the subject of several review articles [231]. They include, for example, proline derivatives as chiral additive for the fluorination of aliphatic aldehydes [232] and chiral palladium complexes for the enantioselective preparation of fluorinated oxindoles [233, 234]. References 1. Tedder, J.M. (1961) Adv. Fluorine 2. 3. 4. 5. 6. 7.

Chem., 2, 104. Lagow, R.J. and Margrave, J.L. (1979) Prog. Inorg. Chem., 26, 161. Bockem¨uller, W. (1933) Justus Liebigs Ann. Chem., 506, 20. Bigelow, L.A. (1947) Chem. Rev., 40, 51. Fredenhagen, K. and Cadenbach, G. (1934) Chem. Ber., 67, 928. Fukuhara, N. and Bigelow, L.A. (1941) J. Am. Chem. Soc., 63, 788–791. (a) Margrave, J. and Lagow, R.J. (1970) Chem. Eng. News, 63, 40; (b) Persico, D.F., Huang, H.-N., Lagow, R.J., and Clark, L.C. (1985) J. Org. Chem., 50, 5156.

8. Review: Sandford, G. (2003) Tetrahe-

dron, 59, 437–454. 9. Lin, T.-J., Chang, H.-C., and Lagow,

R.J. (1999) J. Org. Chem., 64, 8127–8129. 10. (a) Lebeau, P. and Damiens, A. (1926) C. R. Acad. Sci., 182, 1340; (b) Lebeau, P. and Damiens, A. (1930) C. R. Acad. Sci., 191, 939; (c) Ruff, O. and Keim, R. (1930) Z. Anorg. Chem., 192, 249. 11. (a) Simons, J.H. and Block, L.P. (1937) J. Am. Chem. Soc., 59, 1407; (b) Simons, J.H. and Block, L.P. (1939) J. Am. Chem. Soc., 61, 2962. 12. Stacey, M. and Tatlow, J.C. (1960) Adv. Fluorine Chem., 1, 166.

References 13. Burford, W.B., Fowler, R.D. III,

14.

15.

16. 17.

18.

19. 20. 21.

22.

23.

Hamilton, J.M., Anderson, H.C., Jr., Weber, C.E., and Sweet, R.G. (1947) Ind. Eng. Chem., 39, 319–329. (a) Chambers, R.D., Clark, D.T., Holmes, T.F., Musgrave, W.K.R, and Ritchie, I. (1974) J. Chem. Soc., Perkin Trans. 1, 114; (b) Burdon, J. (1987) J. Fluorine Chem., 35, 15; (c) Burdon, J. and Creasey, J.C., Proctor, L.D., Plevey, R.G., Yeoman, J.R.N (1991) J. Chem. Soc., Perkin Trans. 2, 445. (a) Neretin, I.S., Lyssenko, K.A., Antipin, M.Y., Slovokhotov, Y.L., Boltalina, O.V., Troshin, P.A., Lukonin, A.Y., Sidorov, L.N., and Taylor, R. (2000) Angew. Chem. Int. Ed., 39, 3273–3276; (b) Boltalina, O.V., Markov, V.Y., Taylor, R., and Waugh, M.P. (1996) Chem. Commun., 2549. Rozen, S. and Gal, C. (1987) J. Org. Chem., 52, 2769. (a) Rozen, S., Brand, M. (1986) J. Org. Chem., 51, 3607–3611; (b) Barton, D.H., Lister-James, J., Hesse, R.H., and Pechet, M.M., Rozen, S. (1982) J. Chem. Soc., Perkin Trans. 1, 1105–1110. Schuman, P.D., Tarrant, P., Warner, D.A., and Westmoreland, G. (1971) US Patent 3,954,758; Chem. Abstr., 85, (1976) 123964. Chambers, R.D. and Hutchinson, J. (1998) J. Fluorine Chem., 92, 45–52. Chambers, R.D. and Hutchinson, J. (1998) J. Fluorine Chem., 92, 229–232. (a) Chambers, R.D., Skinner, C.J., Hutchinson, J., and Thomson, J. (1996) J. Chem. Soc., Perkin Trans. 1, 605; (b) Chambers, R.D., Greenhall, M.P., Hutchinson, J., Moillet, J.S., and Thomson, J. (1996) Abstr. Am. Chem. Soc., 211, O11-FLUO. Chambers, R.D. and Spink, R.C.H. (1999) J. Chem. Soc., Chem. Commun., 883–884. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A., Stratmann, R.E., Jr.,, Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C.,

24. 25.

26.

27.

28.

29.

30.

31. 32.

33.

Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., and Pople, J.A. (1998) Gaussian 98, Revision A.6, Gaussian, Inc., Pittsburgh, PA. Fukaya, H. and Morokuma, K. (2003) J. Org. Chem., 68, 8170–8178. Fl¨ukinger, P., L¨uthi, H.P., Portmann, S., and Weber, J. (2002) MOLEKEL 4.2, Swiss Center for Scientific Computing, Manno. (a) Simons, J.H. (1949) J. Electrochem. Soc., 95, 47; (b) Simons, J.H., Francis, H.T., and Hogg, J.A. (1949) J. Electrochem. Soc., 95, 53; (c) Simons, J.H. and Harland, W.J. (1949) J. Electrochem. Soc., 95, 55; (d) Simons, J.H., Pearlson, W.H., Brice, T.J., Wilson, W.A., and Dresdner, R.D. (1949) J. Electrochem. Soc., 95, 59; (e) Simons, J.H., Dresdner, R.D. (1949) J. Electrochem. Soc., 95, 64. Pearlson, W.H. (1986) J. Fluorine Chem., 29, J. H. Simons Memorial Issue. Sartori, P. and Ignatiev, N. (1998) J. Fluorine Chem., 87, 157–162, and references cited therein. Bartlett, N., Chambers, R.D., Roche, A.J., Spink, R.C.H., Chacon, L., and Whalen, J.M. (1996) J. Chem. Soc., Chem. Commun., 1049. Schwetlick, K. (2001) Organikum, 21st edn, Wiley-VCH Verlag GmbH, Weinheim. Pattison, F.L.M. and Norman, J.J. (1959) J. Am. Chem. Soc., 79, 2311. Huheey, J.E. (1988) Anorganische Chemie, Walter de Gruyter, Berlin, p. 72. Garc´ıa Mart´ınez, A., Os´ıo Barcina, J., Rys, A.Z., and Subramanian, L.R. (1992) Tetrahedron Lett., 33, 7787.

99

100

2 Introduction of Fluorine 34. Middleton, W.J. (1974) US Patent 35.

36.

37.

38. 39.

40.

41. 42.

43.

44.

45.

46.

3,940,402; Chem. Abstr., 85, 1976, 6388. Kolomeitsev, A.A., Bissky, G., Kirsch, P., and R¨oschenthaler, G.-V. (2000) J. Fluorine Chem., 103, 159–161. (a) Issleib, K. and Lischewski, M. (1973) Synth. Inorg. Met. Org. Chem., 3, 255–266; (b) Koidan, G.N., Marchenko, A.P., Kudryavtsev, A.A., and Pinchuk, A.M. (1982) J. Gen. Chem. USSR, 52, 1779–1787; (c) Marchenko, A.P., Koidan, G.N., Povolotskii, M.I., and Pinchuk, A.M. (1983) J. Gen. Chem. USSR, 53, 1364–1368. Schwesinger, R., Link, R., Thiele, G., Rotter, H., Honert, D., Limbach, H.-H., and M¨annle, F. (1991) Angew. Chem. Int. Ed. Engl., 30, 1372–1375. Link, R. and Schwesinger, R. (1992) Angew. Chem. Int. Ed. Engl., 31, 850. Henrich, M., Marhold, A., Kolomeitsev, A.A., Kalinovich, N., and R¨oschenthaler, G.-V. (2003) Tetrahedron Lett., 44, 5795–5798. (a) Sun, H. and DiMagno, S.G. (2005) J. Am. Chem. Soc., 127, 2050–2051; (b) Sun, H. and Dimagno, S.G. (2006) Angew. Chem. Int. Ed., 45, 2720–2725. Gordon, D.M. and Danishefsky, S.J. (1990) Carbohydr. Res., 206, 361–366. 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. Maul, J.J., Ostrowski, P.J., Ublacker, G.A., Linclau, B., and Curran, D.P. (1999) Top. Curr. Chem., 206, 79–105. Legros, J., Crousse, B., Bonnet-Delpon, D., Begu´e, J.-P., and Maruta, M. (2002) Tetrahedron, 58, 4067–4070. First synthesis of trifluoroacetic acid: (a) Swarts, F. (1926) Bull. Soc. Chim. Belg., 35, 412; (b) Swarts, F. (1926) Bull. Soc. Chim. Belg., 12, 679; (c) Swarts, F. (1927) Bull. Soc. Chim. Belg., 13, 175. (a) Midgley, T., Henne, A.L., and McNary, R.R. (1931) US Patent 1,833,847; Chem. Abstr., 26, 1932, 9395; (b) Midgley, T., Henne, A.L., and McNary, R.R. (1933) US Patent 1,930,129; Chem. Abstr., 28, 1934, 1142; (c) Midgley, T., Henne, A.L., and McNary, R.R. (1930) Patent GB 359,997; Chem. Abstr., 27, 1933, 2340.

47. (a) Teichmann, M., Descotes, G.,

48. 49.

50. 51. 52. 53.

54.

55. 56.

57. 58.

59. 60. 61.

62.

63.

and Lafont, D. (1993) Synthesis, 889; (b) Goggin, K.D., Lambert, J.F., and Walinsky, S.W. (1994) Synlett, 162; (c) Miethchen, R., Hager, C., and Hein, M. (1997) Synthesis, 159. Review: Yokoyama, M. (2000) Carbohydr. Res., 327, 5–14. Lindhorst, T.K. (2000) Essentials of Carbohydrate Chemistry and Biochemistry, Wiley-VCH Verlag GmbH, Weinheim. Review: Toshima, K. (2000) Carbohydr. Res., 327, 15–26. Kunz, H. and Sanger, W. (1985) Helv. Chim. Acta, 68, 283. Mukaiyama, T., Murai, Y., and Shoda, S. (1981) Chem. Lett., 431. Hashimoto, S., Hayashi, M., and Noyori, R. (1984) Tetrahedron Lett., 25, 1379. (a) Matsumoto, T., Maeta, H., Suzuki, K., and Tsuchihashi, G. (1988) Tetrahedron Lett., 29, 3567; (b) Suzuki, K., Maeta, H., Matsumoto, T., and Tsuchihashi, G. (1988) Tetrahedron Lett., 29, 3571. Ramig, K. (2002) Synthesis, 2627–2631. (a) Olah, G.A., Nojima, M., and Kerekes, I. (1973) Synthesis, 779–780; (b) Olah, G.A., Nojima, M., and Kerekes, I. (1973) Synthesis, 780–783; (c) Olah, G.A., Welsh, J.T., Vankar, Y.D., Nojima, M., Kerekes, I., and Olah, J.A. (1979) J. Org. Chem., 44, 3872–3881. Review: McClinton, M.A. (1995) Aldrichim. Acta, 28, 31–35. Olah, G.A., Li, X.-Y., Wang, Q., and Prakash, G.K.S. (1993) Synthesis, 693–699. Franz, R. (1980) J. Fluorine Chem., 15, 423. Cousseau, J. and Albert, P. (1986) Bull. Soc. Chim. Fr., 910–915. Bucsi, I., T¨or¨ok, B., Iza Marco, A., Rasul, G., Prakash, G.K.S., and Olah, G.A. (2002) J. Am. Chem. Soc., 124, 7728–7736. (a) Kirsch, P. and Tarumi, K. (1998) Angew. Chem. Int. Ed., 37, 484–489; (b) Kirsch, P., Heckmeier, M., and Tarumi, K. (1999) Liq. Cryst ., 26, 449–452. (a) Chehidi, I., Chaabouni, M.M., and Baklouti, A. (1989) Tetrahedron Lett., 30,

References

64. 65.

66.

67.

68.

69. 70.

71. 72. 73. 74.

75.

3167; (b) Hedhli, A. and Baklouti, A. (1994) J. Org. Chem., 59, 3278. Zupan, M. (1977) J. Fluorine Chem., 9, 177–185. (a) Haufe, G., Alvernhe, G., Anker, D., Laurent, A., and Saluzzo, C. (1992) J. Org. Chem., 57, 714; (b) Haufe, G., Alvernhe, G., Anker, D., Laurent, A., and Saluzzo, C. (1988) Tetrahedron Lett., 29, 231. (a) Sauzzo, C., Alvernhe, G., Anker, D., and Haufe, G. (1990) Tetrahedron Lett., 31, 663; (b) Saluzzo, C., Alvernhe, G., Anker, D., and Haufe, G. (1990) Tetrahedron Lett., 31, 2127. York, C., Prakash, G.K.S., and Olah, G.A. (1994) J. Org. Chem., 59, 6493–6494. (a) Giudicelli, M.B., Picq, D., and Veyron, B. (1990) Tetrahedron Lett., 31, 6527; (b) Umezawa, J., Takahashi, O., Furuhashi, K., and Nohira, H. (1993) Tetrahedron: Asymmetry, 4, 2053; (c) Sattler, A. and Haufe, G. (1994) J. Fluorine Chem., 69, 185, and references cited therein. Sulser, U., Widmer, J., and Goeth, H. (1977) Helv. Chim. Acta, 60, 1676. (a) Bonini, C. and Righi, G. (1994) Synthesis, 225; (b) Skupin, R. and Haufe, G. (1998) J. Fluorine Chem., 92, 157–165. Bruns, S. and Haufe, G. (2000) J. Fluorine Chem., 104, 247–254. Review: Brooke, G.M. (1997) J. Fluorine Chem., 86, 1–76. Hewitt, C.D. and Silvester, M.J. (1988) Aldrichim. Acta, 21, 3. Banks, R.E., Smart, B.E., and Tatlow, J.C. (1994) Organofluorine Chemistry: Principles and Commercial Applications, Plenum, New York. (a) Coe, P.L., Patrick, C.R., and Tatlow, J.C. (1960) Tetrahedron, 9, 240; (b) Gething, B., Patrick, C.R., and Tatlow, J.C. (1961) J. Chem. Soc., 1574; (c) Gething, B., Patrick, C.R., and Tatlow, J.C. (1962) J. Chem. Soc., 186; (d) Letchford, B.R., Patrick, C.R., and Tatlow, J.C. (1964) Tetrahedron, 20, 1381; (e) Harrison, D., Stacey, M., Stephens, R., Tatlow, J.C. (1963) Tetrahedron, 19, 1893.

76. (a) Gething, B., Patrick, C.R., Tatlow,

77.

78.

79. 80. 81. 82.

83.

84.

85. 86.

87.

88. 89.

J.C., Banks, R.E., Barbour, A.K., and Tipping, A.E. (1959) Nature, 183, 586; (b) Barbour, A.B. (1969) Chem. Ber., 5, 260. Burdeniuk, J., Siegbahn, P.E.M., and Crabtree, R.H. (1998) New J. Chem., 503. (a) Beck, C.M., Park, Y.J., Crabtree, R.H. (1998) Chem. Commun., 693; (b) Sung, K. and Lagow, R.J. (1998) J. Chem. Soc., Perkin Trans. 1, 637; (c) Kipplinger, J.L. and Richmond, T.G. (1996) J. Am. Chem. Soc., 118, 1805; (d) Burdeniuk, J. and Crabtree, R.H. (1996) J. Am. Chem. Soc., 118, 2525; (e) Burdeniuk, J., Crabtree, R.H. (1998) Organometallics, 17, 1582. Balz, G. and Schiemann, G. (1927) Chem. Ber., 60, 1186. Krackow, M. (1989) EP Patent 330,420; Chem. Abstr., 112, 1990, 35424. Yoneda, N. and Fukuhara, T. (1996) Tetrahedron, 52, 23–36. (a) Christe, K.O. and Pavlath, A.E. (1965) J. Org. Chem., 30, 3170; (b) Christe, K.O. and Pavlath, A.E. (1965) J. Org. Chem., 30, 4104; (c) Christe, K.O. and Pavlath, A.E. (1966) J. Org. Chem., 31, 559. (a) Subramanian, M.A. and Manzer, L.E. (2002) Science, 297, 1665; (b) Subramanian, M.A. (2000) US Patent 6,166,273; Chem. Abstr., 134, 2000, 41972. Reviews: (a) Furuya, T., Kamlet, A.S., and Ritter, T. (2011) Nature, 473, 470–477; (b) Hollingworth, C. and Gouverneur, V. (2012) Chem. Commun., 48, 2929–2942. Patterson, J.C. and Mosley, M.L. (2005) Mol. Imaging Biol., 7, 197–200. (a) Anbarasan, P., Neumann, H., and Beller, M. (2010) Angew. Chem. Int. Ed., 49, 2219–2222; (b) Yamada, S., Gavryushin, A., Knochel, P. (2010) Angew. Chem. Int. Ed., 49, 2215–2218. Tang, P., Furuya, T., and Ritter, T. (2010) J. Am. Chem. Soc., 132, 12150–12154. Furuya, T. and Ritter, T. (2009) Org. Lett., 11, 2860–2863. Fier, P.S. and Hartwig, J.F. (2012) J. Am. Chem. Soc., 134, 10795–10798.

101

102

2 Introduction of Fluorine 90. Grushin, V.V. (2002) Chem. Eur. J., 8, 91.

92.

93.

94.

95. 96. 97.

98. 99.

100.

101.

102.

1006–1014. (a) Hull, K.L., Anani, W.Q., and Sanford, M.S. (2006) J. Am. Chem. Soc., 128, 7134–7135; (b) Furuya, T. and Ritter, T. (2008) J. Am. Chem. Soc., 130, 10060–10061. Fors, B.P., Davis, N.R., and Buchwald, S.L. (2009) J. Am. Chem. Soc., 131, 5766–5768. Lee, E., Kamlet, A.S., Powers, D.C., Neumann, C.N., Boursalian, G.B., Furuya, T., Choi, D.C., Hooker, J.M., and Ritter, T. (2011) Science, 334, 639–642. (a) Clark, J.H., Wails, D., and Bastock, T.W. 1996 Aromatic Fluorination, CRC Press, Boca Raton, FL; (b) Adams, D.J. and Clark, J.H. (1999) Chem. Soc. Rev., 28, 225–231; (c) Sasson, Y., Negussie, S., Royz, M., and Mushkin, N. (1996) J. Chem. Soc., Chem. Commun., 297–298; (d) Christe, K.O., Wilson, W.W., Wilson, R.D., Bau, R., and Feng, J. (1990) J. Am. Chem. Soc., 112, 7619–7625. Fuller, G. (1965) J. Chem. Soc., 6264–6267. Prescott, W. (1978) Chem. Ind. (London), 56. Farnham, W.B., Smart, B.E., Middleton, W.J., Calabrese, J.C., Dixon, D.A. (1985) J. Am. Chem. Soc., 107, 4565–4567, and references cited therein. Paprott, G., Lehmann, S., and Seppelt, K. (1988) Chem. Ber., 121, 727–734. (a) Camaggi, G., Gozzo, F., Cevidalli, G. (1966) J. Chem. Soc., Chem. Commun., 313; (b) Haller, I. (1966) J. Am. Chem. Soc., 88, 2070; (c) Camaggi, G., Gozzo, F. (1969) J. Chem. Soc. C, 489; (d) Review on hexafluorobenzene photochemistry: Lemal, D.M. (2001) Acc. Chem. Res., 34, 662–671. Banks, R.E., Barlow, M.G., Deem, W.R., Haszeldine, R.N., and Taylor, D.R. (1966) J. Chem. Soc. C, 981–984. Filyakova, T.I., Zapevalov, A.Y., Kodess, M.I., Kurykin, M.A., and German, L.S. (1994) Russ. Chem. Bull., 43, 1526–1531. Papprot, G. and Seppelt, K. (1984) J. Am. Chem. Soc., 106, 4060.

103. Laganis, E.D. and Lemal, D.M. (1980)

J. Am. Chem. Soc., 102, 6633. 104. MacNicol, D.D., Mallinson, P.R.,

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

Murphy, A., and Sym, G.J. (1982) Tetrahedron Lett., 40, 4131–4134. Weiss, R., Pomrehn, B., Hampel, F., and Bauer, W. (1995) Angew. Chem. Int. Ed. Engl. Engl., 34, 1319–1321. Chambers, R.D., Seabury, M.J., Williams, D.L.H., and Hughes, N. (1988) J. Chem. Soc., Perkin Trans. 1, 251–254. Platonov, E.V., Haas, A., Schelvis, M., Lieb, M., Dvornikova, K.V., and Osina, O.I. (2002) J. Fluorine Chem., 116, 3–8, and references cited therein. Kobayashi, H., Sonoda, T., Takuma, K., Honda, N., and Nakata, T. (1985) J. Fluorine Chem., 27, 1–22. Kirsch, A. (1993) Tetrakis-, Hexakisund Oktakis(dialkylamino)naphthaline als Elektron-Donor-Verbindungen: Synthese und Eigenschaften PhD thesis, University of Heidelberg. (a) Chambers, R.D., Hall, C.W., Hutchinson, J., and Millar, R.W. (1998) J. Chem. Soc., Perkin Trans. 1, 1705–1713; (b) Chambers, R.D., Hassan, M.A., Hoskin, P.R., Kenwright, A., Richmond, P., and Sandford, G. (2001) J. Fluorine Chem., 111, 135–146; (c) Revesz, L., Di Padova, F.E., Buhl, T., Feifel, R., Gram, H., Hiestand, P., Manning, U., Wolf, R., and Zimmerlin, A.G. (2002) Bioorg. Med. Chem. Lett., 12, 2109–2112. Robertson, D.W., Krushinski, J.H., Fuller, R.W., and Leander, J.D. (1988) J. Med. Chem., 7, 1412–1417. Braun, T., Foxon, S.P., Perutz, R.N., and Walton, P.H. (1999) Angew. Chem. Int. Ed., 38, 3326–3329. B¨ohm, V.P.W., Gst¨ottmayr, C.W.K., Weskamp, T., and Herrmann, W.A. (2001) Angew. Chem. Int. Ed., 40, 3387–3389. (a) Tamao, K., Sumitani, K., and Kumada, M. (1972) J. Am. Chem. Soc., 94, 4374–4376; (b) Corriu, R.J.P and Masse, J.P. (1972) J. Chem. Soc., Chem. Commun., 144.

References 115. Schaub, T., Backes, M., and Radius,

116. 117.

118.

119.

120.

121. 122.

123. 124.

125. 126.

127. 128. 129.

130.

U. (2006) J. Am. Chem. Soc., 128, 15964–15965. Amsharov, K.Y. and Merz, P. (2012) J. Org. Chem., 77, 5445–5448. Allemann, O., Duttwyler, S., Romanato, P., Baldridge, K.K., and Siegel, J.S. (2011) Science, 332, 574–577. (a) Lochmann, L., Posp´ısˇ il, J., and L´ım, D. (1966) Tetrahedron Lett., 7, 257–262; (b) Mongin, F., Maggi, R., and Schlosser, M. (1996) Chimia, 50, 650–652; (c) Schlosser, M. (1988) Pure Appl. Chem., 60, 1627. van Eikema Hommes, N.J.R. and Schleyer, P.v.R. (1992) Angew. Chem. Int. Ed. Engl., 31, 755. (a) Pauluth, D. and Haas, H. (1992) DE Patent 4,219,281; Chem. Abstr., 120, 1994, 269832; (b) Snieckus, V. (1994) Pure Appl. Chem., 66, 2155–2158. Snieckus, V. (1990) Chem. Rev., 90, 879–933, and references cited therein. Coe, P.L., Waring, A.J., and Yarwood, T.D. (1995) J. Chem. Soc., Perkin Trans., 1, 2729–2737. Wittig, G. and Pohmer, L. (1956) Chem. Ber., 89, 1334. (a) Yudin, A.K., Martyn, L.J.P, Pandiaraju, S., Zheng, J., and Lough, A. (2000) Org. Lett., 2, 41–44; (b) Martyn, L.J.P, Pandiaraju, S., and Yudin, A.K. (2000) J. Organomet. Chem., 603, 98–104. Schlosser, M. and Castagnetti, E. (2001) Eur. J. Org. Chem., 3991–3997. (a) Schlosser, M. (2001) Eur. J. Org. Chem., 3975–3984; (b) Schlosser, M. (2005) Angew. Chem. Int. Ed., 44, 376–393. Gschwend, H.W. and Rodriguez, H.R. (1979) Org. React., 26, 1. Kirsch, P., Reiffenrath, V., and Bremer, M. (1999) Synlett, 389–396. Banks, R.E. and Tatlow, J.C. (1986) in Fluorine: The First Hundred Years (1886–1986) (eds R.E. Banks, D.W.A. Sharp, and J.C. Tatlow), Elsevier Sequoia, Lausanne, pp. 227–346. (a) Dumas, J. and P´eligot, E. (1835) Ann. Pharm., 15, 246; (b) Dumas, J. and P´eligot, E. (1836) Ann. Chim. Phys., 61, 193.

131. (a) Fr´emy, E. (1854) Justus Liebigs Ann.

132. 133.

134.

135.

136.

137. 138.

139.

140. 141. 142.

143. 144.

145.

146.

147. 148.

Chem., 92, 246; (b) Fr´emy, E. (1856) Ann. Chim. Phys., 47, 5. Marson, C.M. and Melling, R.C. (1998) Chem. Commun., 1223–1224. Szarek, W.A., Hay, G.W., and Doboszewski, B. (1985) J. Chem. Soc., Chem. Commun., 663–664. Yarovenko, N.N., Raksha, M.A., Shemanina, V.N., and Vasileva, A.S. (1957) J. Gen. Chem. USSR, 27, 2246. Takaoka, A., Iwakiri, H., and Ishikawa, N. (1979) Bull. Chem. Soc. Jpn., 52, 3377–3380. Muneyama, F., Frisque-Hesbain, A.-M., Devos, A., and Ghosez, L. (1989) Tetrahedron Lett., 30, 3077–3080. Ernst, B. and Winkler, T. (1989) Tetrahedron Lett., 30, 3081. Hayashi, H., Sonoda, H., Fukumura, K., and Nagata, T. (2002) Chem. Commun., 1618–1619. Reviews: (a) Wang, C.-L. J. (1985) Org. React., 34, 319–400; (b) Boswell, G.A. Pipka, W.C., Jr., Schribner, R.M., and Tullock, C.W. (1972) Org. React., 21, 1. Nickson, T.E. (1991) J. Fluorine Chem., 55, 169–172. Middleton, W.J. (1975) J. Org. Chem., 40, 574–578. Lal, G.S., Pez, G.P., Pesaresi, R.J., Prozonic, F.M., and Cheng, H. (1999) J. Org. Chem., 64, 7048–7054. Su, T.-L., Klein, R.S., and Fox, J.J. (1982) J. Org. Chem., 47, 1506–1509. Hann, G.L. and Sampson, P. (1989) J. Chem. Soc., Chem. Commun., 1650–1651. (a) Beaulieu, F., Beauregard, L.P., Courchesne, G., Couturier, M., LaFlamme, F., and L’Heureux, A. (2009) Org. Lett., 11, 5050–5053; (b) L’Heureux, A., Beaulieux, F., Bennett, C., Bill, D.R., Clayton, S., LaFlamme, F., Mirmehrabi, M., Tadayon, S., Tovell, D., and Couturier, M. (2010) J. Org. Chem., 75, 3401–3410. Umemoto, T., Singh, R.P., Xu, Y., and Saito, N. (2010) J. Am. Chem. Soc., 132, 18199–18205. Parish, E.J. and Schroepfer, G.J., Jr., (1980) J. Org. Chem., 45, 4034. Ambles, A. and Jacquesy, R. (1976) Tetrahedron Lett., 17, 1083.

103

104

2 Introduction of Fluorine 149. Hayashi, M., Hashimoto, S., and 150. 151.

152.

153.

154. 155.

156.

157.

158. 159.

160. 161.

162.

163.

164.

165.

Noyori, R. (1984) Chem. Lett., 1747. Palme, M. and Vasella, A. (1995) Helv. Chim. Acta, 78, 959. Additional methods are reviewed in: Tozer, M.J. and Herpin, T.F. (1996) Tetrahedron, 52, 8619–8683. Alekseeva, L.A., Belous, V.M., and Yagupolskii, L.M. (1974) J. Org. Chem. USSR, 10, 1063–1068. Kunshenko, B.V., Alekseeva, L.A., and Yagupolskii, L.M. (1974) J. Org. Chem. USSR, 10, 1715. Dmowski, W. (1986) J. Fluorine Chem., 32, 255–282. Kollonitsch, J., Marburg, S., and Perkins, L.M. (1976) J. Org. Chem., 41, 3107–3111. Sondej, S.C. and Katzenellenbogen, J.A. (1986) J. Org. Chem., 51, 3508–3513. Prakash, G.K.S., Hoole, D., Reddy, V.P., and Olah, G.A. (1993) Synlett, 691–693. Kuroboshi, M. and Hiyama, T. (1994) J. Fluorine Chem., 69, 127–128. Chambers, R.D., Sandford, G., Sparrowhawk, M.E., and Atherton, M.J. (1996) J. Chem. Soc., Perkin Trans. 1, 1941–1944. York, C., Prakash, G.K.S., and Olah, G.A. (1996) Tetrahedron, 52, 9–14. (a) Kirsch, P., Bremer, M., Taugerbeck, A., and Wallmichrath, T. (2001) Angew. Chem. Int. Ed., 40, 1480–1484; (b) Kirsch, P. and Taugerbeck, A. (2002) Eur. J. Org. Chem., 3923–3926. Review: Shimizu, M. and Hiyama, T. (2005) Angew. Chem. Int. Ed., 44, 214–231. Eremenko, L.T., Oreshko, G.V., and Fadeev, M.A. (1989) Bull. Acad. Sci. USSR Div. Chem. Sci., 38, 101–104. (a) Yoneda, N. and Fukuhara, T. (2001) Chem. Lett., 222–223; (b) Ayuba, S., Yoneda, N., Fukuhara, T., and Hara, S. (2002) Bull. Chem. Soc. Jpn., 75, 1597–1603. (a) Rozen, S. and Mishani, E. (1993) J. Chem. Soc., Chem. Commun., 1761–1762; (b) Sasson, R., Hagooly, A., and Rozen, S. (2003) Org. Lett., 5, 769–771.

166. Caddick, C., Gazzard, L., Motherwell,

167.

168.

169. 170. 171. 172.

173.

174.

175.

176.

177.

178.

179.

180.

W.B., and Wilkinson, J.A. (1996) Tetrahedron, 52, 149–156. Reddy, V.P., Alleti, R., Perambuduru, M.K., Welz-Biermann, U., Buchholz, H., and Prakash, G.K.S. (2005) Chem. Commun., 654–656. Laurent, E., Marquet, B., Roze, C., and Ventalon, F. (1998) J. Fluorine Chem., 87, 215–220. Ishii, H., Yamada, N., and Fuchigami, T. (2001) Tetrahedron, 57, 9067–9072. Trost, B.M. (1991) Science, 254, 1471–1477. Kuroboshi, M. and Hiyama, T. (1992) Chem. Lett., 827–830. Kuroboshi, M., Suzuki, K., and Hiyama, T. (1992) Tetrahedron Lett., 29, 4173–4176. Ito, Y., Kanie, O., and Ogawa, T. (1996) Angew. Chem. Int. Ed. Engl., 35, 2510–2512. (a) Pearson, R.G. (1963) J. Am. Chem. Soc., 85, 3533–3539; (b) Pearson, R.G. and Songstad, J. (1967) J. Am. Chem. Soc., 89, 1827–1836. Seeberger, P.H. (2003) Chem. Commun., 1115–1121, and references cited therein. D¨obele, M., Wiehn, M.S., and Br¨ase, S. (2011) Angew. Chem. Int. Ed., 50, 11533–11535. Hird, M., Toyne, K.J., Slaney, A.J., Goodby, J.W., and Gray, G.W. (1993) J. Chem. Soc., Perkin Trans. 2, 2337–2349. (a) Kuroboshi, M., Kanie, K., and Hiyama, T. (2001) Adv. Synth. Catal., 343, 235–250; (b) Kanie, K., Tanaka, Y., Suzuki, K., Kuroboshi, M., and Hiyama, T. (2000) Bull. Chem. Soc. Jpn., 73, 471–484; (c) Kanie, K., Takehara, S., and Hiyama, T. (2000) Bull. Chem. Soc. Jpn., 73, 1875–1892. Sevenard, D.V., Kirsch, P., Lork, E., and R¨oschenthaler, G.-V. (2003) Tetrahedron Lett., 44, 5995–5998. (a) Okuyama, T. (1982) Tetrahedron Lett., 23, 2665–2666; (b) Stahl, I. (1985) Chem. Ber., 118, 1798–1808; (c) Klaveness, J. and Undheim, K. (1983) Acta Chem. Scand., Ser. B, 37, 687–691; (d) Klaveness, J., Rise, F., and Undheim, K. (1986) Acta Chem. Scand., Ser. B, 40, 373–380.

References 181. Mayr, H., Henninger, J., and

182.

183. 184.

185. 186.

187.

188. 189. 190. 191.

192. 193.

194.

195.

Siegmund, T. (1996) Res. Chem. Intermed., 22, 821–838. (a) Schaffrath, C., Cobb, S.L., and O’Hagan, D. (2002) Angew. Chem. Int. Ed., 41, 3913–3915; (b) Zhu, X., Robinson, D.A., McEwan, A.R., O’Hagan, D. (2007) J. Am. Chem. Soc., 129, 14597–14604. Fried, J. and Subo, E.F. (1954) J. Am. Chem. Soc., 76, 1455. Reviews: (a) Tius, M.A. (1995) Tetrahedron, 51, 6605–6634; (b) Bardin, V.V., Yagupolskii, Y.L., (1989) in New Fluorinating Agents in Organic Synthesis, (eds L. German, S. Zemskov) Springer, Berlin. Filler, R. (1978) Isr. J. Chem., 17, 71. Eisenberg, M. and DesMarteau, D.D. (1970) Inorg. Nucl. Chem. Lett., 6, 29–34. Tamura, M., Takagi, T., Quan, H., and Sekiya, A. (1999) J. Fluorine Chem., 98, 163–166. Djerassi, C. (1963) Steroid Reactions, Holden Day, San Francisco, CA. Sharts, C.M. and Sheppard, W.A. (1974) Org. React., 21, 125. Rozen, S. (1996) Chem. Rev., 96, 1717–1736. (a) Hebel, D., Lerman, O., and Rozen, S. (1985) J. Fluorine Chem., 30, 141; (b) Appelman, E.H., Mendelsohn, M.H., and Kim, H. (1985) J. Am. Chem. Soc., 107, 6515. Rozen, S. and Menahem, Y. (1980) J. Fluorine Chem., 16, 19. (a) Barton, D.H.R, Godhino, L.S., Hesse, R.H., and Pechet, M.M. (1968) J. Chem. Soc., Chem. Commun., 804; (b) Barton, D.H.R, Danks, L.J., Ganguly, A.K., Hesse, R.H., Tarzia, G., and Pechet, M.M. (1969) J. Chem. Soc., Chem. Commun., 227. Fifolt, M.J., Olczak, R.T., and Mundhenke, R.F. (1985) J. Org. Chem., 50, 4576. (a) Jewett, D.M., Potocki, J.F., and Ehrenkaufer, R.E. (1984) Synth. Commun., 14, 45; (b) Jewett, D.M., Potocki, J.F., and Ehrenkaufer, R.E. (1984) J. Fluorine Chem., 24, 477.

196. Dax, K., Glanzer, B.I., Schulz, G., and

197.

198.

199.

200. 201.

202.

203.

204.

205.

206. 207.

208.

Vyplel, H. (1987) Carbohydr. Res., 162, 13. (a) Differding, E. and Lang, R.W. (1988) Tetrahedron Lett., 29, 6087; (b) Banks, R.E. (1998) J. Fluorine Chem., 87, 1–17, and references cited therein. (a) Davis, F.A. and Han, W. (1991) Tetrahedron Lett., 32, 1631; (b) Davis, F.A., Han, W., and Murphy, C.K. (1995) J. Org. Chem., 60, 4730. (a) Umemoto, T., Kawada, K., and Tomita, K. (1986) Tetrahedron Lett., 27, 4465–4468; (b) Umemoto, T., Fukami, S., Tomizawa, G., Harasawa, K., Kawada, K., and Tomita, K. (1990) J. Am. Chem. Soc., 112, 8563–8575. Banks, R.E. and Williamson, G.E. (1964) Chem. Ind. (London), 1864. Olah, G.A., Hartz, N., Rasul, G., Wang, Q., Prakash, G.K.S., Casanova, J., and Christe, K.O. (1994) J. Am. Chem. Soc., 116, 5671–5673. Reviews: (a) Lal, S.G., Pez, G.P., and Syvret, R.G. (1996) Chem. Rev., 96, 1737; (b) Taylor, S.D., Kotoris, C.C., and Hum, G., Tetrahedron 1999, 55, 12431–12477; (c) Nyffeler, P.T., Dur´on, S.G., Burkart, M.D., Vincent, S.P., and Wong, C.-H. (2004) Angew. Chem. Int. Ed., 44, 192–212. (a) Differding, E. and R¨uegg, G.M. (1991) Tetrahedron Lett., 31, 3815–3818, and references cited therein; (b) Christe, K.O. (1984) J. Fluorine Chem., 25, 269–273; (c) Cartwright, M.M. and Wolf, A.A. (1984) J. Fluorine Chem., 25, 263–267. (a) Differding, E. and Bersier, P.M. (1992) Tetrahedron, 48, 1595–1604; (b) Gilicinski, A.G., Pez, G.P., Syvret, R.G., and Lal, G.S. (1992) J. Fluorine Chem., 59, 157–162. Piana, S., Devillers, I., Togni, A., and Rothlisberger, U. (2002) Angew. Chem. Int. Ed, 41, 979–982. Umemoto, T. and Tomizawa, G. (1995) J. Org. Chem., 60, 6563. Umemoto, T., Nagayoshi, M., Adachi, K., and Tomizawa, G. (1998) J. Org. Chem., 63, 3379. Umemoto, T. and Nagayoshi, M. (1996) Bull. Chem. Soc. Jpn., 69, 2287.

105

106

2 Introduction of Fluorine 209. Stavber, S., Zupan, M., Poss, A.J., and

210. 211. 212.

213.

214. 215. 216. 217. 218.

219.

220.

221.

222.

223.

Shia, G.A. (1995) Tetrahedron Lett., 36, 6769. Resnati, G. and DesMarteau, D.D. (1991) J. Org. Chem., 56, 4925–4929. Umemoto, T., Tomita, K., and Kawada, K. (1990) Org. Synth., 69, 129–143. Taniguchi, N. and Tanaka, A. (1969) JP Patent 08231512; Chem. Abstr., 125, 1996, 328526. Chung, Y., Duerr, B.F., McKelvey, T.A., Nanjappan, P., and Czarnik, A.W. (1989) J. Org. Chem., 54, 1018–1032. Sato, T. (1989) JP Patent 01277236; Chem. Abstr., 113, 1990, 49688. Umemoto, T. and Tomizawa, G. (1990) Bull. Chem. Soc. Jpn., 59, 3625. Lal, G.S. (1993) J. Org. Chem., 58, 2791. Lal, G.S. (1995) Synth. Commun., 25, 725. Chambers, R.D., Kenwright, A.M., Parsons, M., Sandford, G., and Moilliet, J.S. (2002) J. Chem. Soc., Perkin Trans. 1, 2190–2197. Banks, R.E., Lawrence, N.J., Besheesh, M.K., Popplewell, A.L., and Pritchard, R.G. (1996) J. Chem. Soc., Chem. Commun., 1629. Reviews: (a) Davis, F.A., Qi, H., and Sundarababu, G. 1999 Asymmetric fluorination, in Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochallenges and Biomedical Targets, (ed. V.A. Soloshonok) John Wiley & Sons, Inc., New York, pp. 1–32; (b) Resnati, G. (1993) Tetrahedron, 49, 9385. (a) Takeuchi, Y., Suzuki, T., Satoh, A., and Shiragami, T., Shibata, N. (1999) J. Org. Chem., 64, 5708–5711; (b) Kakuda, H., Suzuki, T., Takeuchi, Y., and Shiro, M. (1997) J. Chem. Soc., Chem. Commun., 85. (a) Shibata, N., Suzuki, E., and Takeuchi, Y. (2000) J. Am. Chem. Soc., 122, 10728–10729; (b) for a similar approach: Cahard, D., Audouard, C., Plaquevent, J.-C., Toupet, L., and Roques, N. (2001) Tetrahedron Lett., 42, 1867–1869. Rauniyar, V., Lackner, A.D., Hamilton, G.L., and Toste, F.D. (2011) Science, 334, 1681–1684.

224. (a) Davis, F.A. and Han, W. (1992)

225.

226.

227.

228. 229.

230.

231.

232.

233.

234.

Tetrahedron Lett., 33, 1153; (b) Davis, F.A. and Qi, H. (1996) Tetrahedron Lett., 37, 4345; (c) Davis, F.A., Kasu, P.V.N, Sundarababu, G. and Qi, H. (1997) J. Org. Chem., 62, 7546; (d) Davis, F.A. and Kasu, P.V.N (1998) Tetrahedron Lett., 39, 6135. Evans, D.A., Britton, T.C., Ellman, J.A., and Dorrow, R.L. (1990) J. Am. Chem. Soc., 112, 4011. (a) Ihara, M., Kai, T., Taniguchi, N., and Fukumoto, K. (1990) J. Chem. Soc., Perkin Trans. 1, 2357; (b) Ihara, M., Taniguchi, N., Kai, T., Satoh, K., and Fukumoto, K. (1992) J. Chem. Soc., Perkin Trans. 1, 221. Nakano, N., Makino, M., Morizawa, Y., and Matsumura, Y. (1996) Angew. Chem. Int. Ed. Engl., 35, 1019–1021. Hintermann, L. and Togni, A. (2000) Angew. Chem. Int. Ed., 39, 4359–4362. Review: Seebach, D., Beck, A.K., Heckel, A. (2001) Angew. Chem. Int. Ed., 40, 92–138. Frantz, R., Hintermann, L., Perseghini, M., Broggini, D., and Togni, A. (2003) Org. Lett., 5, 1709–1712. (a) Prakash, G.K.S and Beier, P. (2006) Angew. Chem. Int. Ed., 45, 2172–2174; (b) Pihko, P.M. (2006) Angew. Chem. Int. Ed., 45, 544–547; (c) Brunet, V.A., O’Hagan, D. (2008) Angew. Chem. Int. Ed., 47, 1179–1182. (a) Marigo, M., Fielenbach, D., Braunton, A., Kjœrsgaard, A., and Jørgensen, K.A. (2005) Angew. Chem. Int. Ed., 44, 3703–3706; (b) Steiner, D.D., Mase, N., and Barbas, C.F., III, (2005) Angew. Chem. Int. Ed., 44, 3706–3710. Hamashima, Y., Suzuki, T., Takano, H., Shimura, Y., and Sodeoka, M. (2005) J. Am. Chem. Soc., 127, 10164–10165. (a) Gouverneur, V., (2009) Science, 325, 1630–1631; (b) Watson, D.A., Su, M., Teverovskiy, G., Zhang, Y., Garc´ıa-Fortanet, J., Kinzel, T., and Buchwald, S.L. (2009) Science, 325, 1661–1664.

107

3 Perfluoroalkylation 3.1 Radical Perfluoroalkylation

Whereas haloalkanes are widely used for the electrophilic alkylation of a broad variety of nucleophiles, perfluoroalkyl bromides and iodides do not act analogously as electrophilic perfluoroalkylation reagents (Figure 3.1). For example, the reaction of perfluoroalkyl iodides with aliphatic alcoholates does not yield the expected alkyl perfluoroalkyl ether (analogous to the Williamson ether synthesis) but mostly the hydrofluorocarbon resulting from the reduction of the iodide [1]. In contrast, perfluoroalkyl iodides and bromides have been used as preparatively useful electrophilic iodination and bromination reagents [2]. The reason for this – at first glance – unexpected behavior is inversion of the electrostatic partial charges (compared with, e.g., the corresponding iodoalkanes) by the negative inductive effect of the perfluoroalkyl moiety. Nevertheless, in the presence of some classes of nucleophile, for example, thiolates, resonance-stabilized carbanions, or enamines, the behavior of perfluoroalkyl halides is sometimes puzzling and superficially reminiscent of electrophilic reactivity (Scheme 3.1). This kind of reactivity depends strongly on the solvent, on irradiation with light, or the presence of redox shuttles, for example, methylviologen. A closer look at the optimum reaction conditions and at the by-product spectrum reveals that the observed reactivity can most probably be attributed to a chain reaction involving electrochemically generated and regenerated perfluoroalkyl radicals [5] (Scheme 3.2). In contrast to alkyl radicals, perfluoroalkyl radicals are rather electrophilic in nature. Therefore, the radical pathway sometimes mimics the outcome of a nucleophilic substitution on a perfluoroalkyl bromide or iodide. 3.1.1 Structure, Properties, and Reactivity of Perfluoroalkyl Radicals

Thermodynamically, perfluoroalkyl radicals are not generally more stable or they are even more destabilized than alkyl radicals. Nevertheless, several factors can dramatically stabilize perfluoroalkyl radicals kinetically. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

108

3 Perfluoroalkylation

δ+ δ− R′-l

R—O—R′

RF-l δ− δ+

R—O—RF

R—O−

protonation, fragmentation, addition to electrophiles 85-93%

RF-l

(a)

RF− + Nu-l

RF-l + Nu− δ− δ+

NaOMe, MeOH

RF-H

CH3l

CF3l

(b) Figure 3.1 ((a) The inverted electrophilic reactivity of alkyl halides compared with that of perfluoroalkyl halides. (b) Electrostatic potentials (red, negative; blue, positive partial charges) mapped on the electron isodensity surfaces of CH3 I and CF3 I). The natural

O2N

SNa

SC3F7 + O2N

O2N

F7C3I, DMF;

partial charges of CH3 I are qC = −0.84 e, qH = +0.26 e, qI = +0.07 e, and those of CF3 I are qC = +0.93 e, qF = −0.34 e, qI = 0.09 e [(B3LYP/6–31G*(C,H,F),LANL2DZ(I)//AM1 (AM = active matrix) level of theory] [3, 4].

r.t., 18 h

SS

NO2

(60%)

Scheme 3.1 The reactivity of some oxidizable nucleophiles towards perfluoroalkyl halides suggests an electron transfer-initiated mechanism (P. Kirsch and A. Hahn, 1998, unpublished work).

RF-I [RF-I]·−

RF-I Nu

−

·

Nu

[RF-Nu]·−

RF· I

−

initialization

n-F13C6I + Na+Me2C=NO2−

RF-Nu

−

Nu

propagation

89% hn, DMF; r.t, 3 h

n-F13C6Me2CNO2 + NaI

Scheme 3.2 The mechanism of the perfluoroalkylation of oxidizable nucleophiles (e.g., Nu− = [Me2 CNO2 ]− ) by perfluoroalkyl halides mimics an electrophilic pathway, that is, nucleophilic substitution (SN ) of the halide [6].

3.1 Radical Perfluoroalkylation

Termination of a perfluoroalkyl radical is possible only either (i) by dimerization or (ii) by radical transfer involving either the cleavage of a carbon–carbon bond or of the very stable carbon–fluorine bond. The second option requires relatively high activation energies because of the strengths of the bonds (e.g., the carbon–fluorine bond) that would have to be cleaved. The first option is the most common pathway for termination, especially of primary perfluoroalkyl radicals, which are often used for synthetic purposes. Nevertheless, for secondary and most pronounced for tertiary radicals, very long lifetimes can be observed, because the carbon-centered radical is shielded by a ‘‘protective’’ shell of sterically demanding fluorine atoms. This effectively inhibits dimerization and disproportionation by radical transfer. The best known of these highly persistent perfluoroalkyl radicals are Scherer’s radicals 3 and 4 [7] (Figure 3.2). The radical 3 has a half-life of 1 h at 100 ◦ C for β-scission to the olefin isomers 5 and 6 and trifluoromethyl radicals. This fragmentation can be used as a preparative source of CF3 · radicals – if perfluoroolefins 1 or 2 are heated in the presence of 3, their reaction with the in situ-generated CF3 · yields the even more stable radical 4, which does not react with 100% fluorine gas at 1.3 bar at room temperature even after 300 h. The structure and reactivity of perfluoroalkyl radicals are determined by the complex interplay between the strong σ -acceptor effect and the π-donating effect of fluorine. Whereas the methyl radical is planar, fluorinated methyl radicals are

F CF3 F3C CF3 1 F3C F F CF3 F CF3 F3C CF3 2 F3C F F

100% F2;

r.t.

F CF3 F3C . CF3 F F3C F F CF3 3

1, 90-105° C

F CF3 F3C . CF3 F F3C CF3 F CF3 4

CF3

80-120° C

F

CF3 CF3 CF3 F F + F CF3. + F3C F F3C F F CF3 F CF3 6 5 F3C

Figure 3.2 Synthesis of Scherer’s sterically highly hindered, extremely persistent perfluoroalkyl radicals 3 and 4. The AM1 model shown above indicates the bulky structure of 3 [7].

109

110

3 Perfluoroalkylation

pyramidal [8]. The pyramidalization and inversion barriers increase with increasing fluorination [9]. The calculated inversion barriers are ∼1, 7, and 25 kcal mol−1 for CH2 F· , CHF2 · , and CF3 · , respectively [10]. The reactivity of perfluoroalkyl radicals can be summarized again under the motto ‘‘Think Negative!’’ As a kind of starting point, the absolute electronegativities (as a measure of reactivity) [11] of the methyl and trifluoromethyl radicals do not differ very much. Whereas the nucleophilicity of alkyl radicals increases from primary to tertiary, for their perfluorinated analogs the opposite is observed – their electrophilicity increases from primary to tertiary radicals. 3.1.2 Preparatively Useful Reactions of Perfluoroalkyl Radicals

To make preparative use of perfluoroalkyl radicals, they must first be generated by a method which does not interfere with other functional groups present in the reaction system. Because of their predominantly electrophilic nature, the most important reaction partners for these radicals are either highly polarizable (‘‘soft’’) σ -electron systems (for example, thiolates, selenides, or phosphites) or, preferably, electron-rich π-systems (for example, olefins and some aromatic compounds). The most convenient sources of perfluoroalkyl radicals are perfluoroalkyl halides, from which the corresponding radicals can be generated photochemically or electrochemically [12]. Although electrochemical activation can be achieved either by oxidation or by reduction, for example, of perfluoroalkyl iodides, the most popular method of activation is reduction (Scheme 3.3). The reductive radical generation can also be initiated photochemically via auxiliary radical sources, such as silanes or stannanes. thermal/ photochemical activation

RF-I

Δ or hn

RF+I· H2C=CH2

reductive activation

RF·

RF-I −

e

I

−

RFCH2CH2·

H2C=CH2

Scheme 3.3 iodides.

In(s)

RFCH2CH2I

H2C=CH2

RF·

RF-I activation by radical initiators

RF-I

Δ, 60 °C

In·

InI

Activation mechanisms of radical chain reactions starting from perfluoroalkyl

Other pathways of radical generation involve thermal or photochemical fragmentation of perfluoroacyl peroxides [13] or photochemical fragmentation of perfluoroalkylsulfonyl bromides [14]. The in situ formation of Barton esters from perfluoroacyl chlorides and thiopyridone-N-oxide has also been used as a convenient source of radicals [15] (Scheme 3.4).

3.1 Radical Perfluoroalkylation

RFSO2Br

RFSO2· + Br·

hn

RF ·

− SO2 − Br·

(RFCOO)2

2 RFCOO

Δ or hn

−

N O Na+ + RFCOCl

− 2 CO2

N O RF

2 RF·

N +CO2 + RF ·

hn

S

S O

S

Scheme 3.4 Other commonly used methods for the generation of perfluoroalkyl radicals [13–15]. The activation energy of perfluorodiacyl peroxide fragmentation is ∼24 kcal mol−1 , resulting in a half-life at room temperature of ∼5 h.

As early as the 1940s, Emeleus and Haszeldine [16] discovered that perfluoroalkyl iodides not only are cleaved into perfluoroalkyl radicals by light but also they add readily to a variety of olefins to yield telomers and 1:1 adducts [17]. This kind of radical chain reaction can also be initiated by high temperatures (Scheme 3.5). The addition of perfluoroalkyl iodides to olefins is a very important method for the synthesis I RF-I

Δ or hn − I·

RF·

RF R

ratio = 10 : 1 5:1 1:1 10 : 1

98% hn

CF3CH2CHICH3

n-F7C3-CH2CHICOOEt

CF3(CF2CF2)nI

hn

94% (n=1), 4% (n=2) 81% (n=1) 16% (n=1), 10% (n=2), 5% (n=3), 63% (n>3) mixture with n=10~20

250 °C, 15 h 65%

CF3I +

R

RF·

100% hn, 254 nm, 24 h

62%

n-F15C7I +

R

CF3CH2CH2I(75%) + higher telomers (25%)

CF3I + CH2=CHCH3

CF3I + n CF2=CF2

RF RF-I

CF3I + CH2=CH2 250 ˚C, 48 h

n-F7C3I + CH2=CHCOOEt

·

hn, Hg, 100 h

C7F15

CF3

Scheme 3.5 Photo-initiated and thermally initiated radical additions of perfluoroalkyl iodides and bromides to olefins and aromatic compounds [10].

111

112

3 Perfluoroalkylation

of partially fluorinated alkanes, polymers, oligomers, and their derivatives [18]. The synthesis of some perfluoroalkyl aromatic compounds can also be achieved [19]. Inspired by Kharash’s work on radical addition of CCl4 to olefins [20], the same methodology was applied to perfluoroalkyl halides [12]. It was found that the addition of these compounds to olefins could be achieved with higher selectivity and at lower temperatures in the presence of radical initiators [21] (Scheme 3.6). 91%

n-F13C6I + CH2=CHOAc

AIBN; 80 °C, 1h

n-F13C6-CH2CHIOAc

94%

n-F13C6I + CH2=CH2CHOAc

DBP; 89 °C, 1h

n-F13C6-CH2CH2CHIOAc I

80%

n-F7C3I +

Scheme 3.6

AIBN; 68 °C, 21 h

C3F7 cis:trans = 1:1

Free radical additions of perfluoroalkyl iodides to a variety of olefins [10].

The method of perfluoroalkylation that, especially on the laboratory scale, has many practical advantages, is the reductively initiated radical addition of perfluoroalkyl iodides to olefins (Scheme 3.7). A large variety of reducing agents have been used for the initiation; examples include metals for heterogeneous reactions Cl(CF2)4I + CH2=CHC4H9

n-F13C6I + CH2=CHCH2OAc

85% Fe, DMF; 80 °C, 2 h

Cl(CF2)4-CH2CHIC4H9

95% YbCl3, Zn,

n-F13C6-CH2CHICH2OAc

THF; 50 °C

n-F9C4I + CH2=CHC4H9

90% Na2S2O4, NaHCO3,

n-F9C4-CH2CHIC4H9

H2O, CH3CN; 0 °C,1 h

n-F13C6I + CH2=CHCOOEt

72% bromo(pyridine) cobaloxime(III), Zn; 20 °C

n-F13C6-CH2CH2COOEt

OAc AcO AcO

O

OAc 75-80% RFI, Na2S2O4, NaHCO3, CH3CN,

AcO AcO

O RF OH

H2O; r.t.

RF = Cl(CF2)4, Cl(CF2)6, n-F13C6, n-F17C8

Scheme 3.7

Reductively initiated additions of perfluoroalkyl iodides to olefins [10, 24].

3.1 Radical Perfluoroalkylation

and also low-valence metal salts or dithionites [22] for homogeneous reactions [10]. By use of special reducing agent systems in combination with electron-deficient olefins, the hydroperfluoroalkylation products are obtained in high yields [23]. Reactions with reductively and oxidatively generated [25] perfluoroalkyl radicals have also been successfully used for the perfluoroalkylation of aromatic compounds (Scheme 3.8). For the reductive initiation, the single electron transfer (SET) necessary for formation of the radical anion priming the reaction sequence can be provided either by a reductive reagent (for example, HOCH2 SO2 Na) [26] or by an electron-rich aromatic substrate itself [27]. The oxidatively induced variant permits the perfluoroalkylation of more electron-deficient aromatic substrates, for example, quinoline.

Cl(CF2)4I +

68% HOCH2SO2Na,

N H

(CF2)4Cl

N H

CH3CN, H2O; 60 °C, 5 h

OMe

OMe

OCOC3F7

91%

(n-C3F7CO2)2 +

SET

CH3

CH3

CH3

CH3 C3F7

68%

(n-C3F7CO2)2 +

SET

CH3

CH3 98%

(n-C3F7CO2)2 +

F113; 40 °C, 3h

O

C3F7

O

O

O F3C

NH AcO CF3CO2− +

O

N

O

82%

NH

AcO O

N

O

XeF2; r.t., 3 h

OAc

OAc

(CF2)4Cl +

Cl(CF2)4SO2Na + N

Mn(OAc)3, CH3CN, AcOH, Ac2O

N (CF2)4Cl (23%)

N (32%)

Scheme 3.8 Reductively and oxidatively induced radical perfluoroalkylation of a variety of aromatic and heterocyclic compounds [10].

113

114

3 Perfluoroalkylation

Resonance-stabilized carbanions, for example, enamines [28], are good substrates for SET-induced radical perfluoroalkylation (Scheme 3.9). O CF3 1. CF3I, pentane; r.t., 3 h 2. HCl

N

O CF2Cl

1. CF2BrCl, pentane; r.t., 3 h 2. HCl

Scheme 3.9

Perfluoroalkylation of enamines with perfluoroalkyl iodides [28].

With nonstabilized enolates, the radical reaction does not occur spontaneously but can be effectively initiated by triethylborane. The use of a chiral auxiliary group on the enolate leads to perfluoroalkylation products with reasonably good diastereomeric excesses (Scheme 3.10). O O

O

O CH3 70% (64% de)

N

O

O CH3

N

1. LDA, THF; −78 °C, 1 h 2. CF3I, Et3B;

CF3

−78 to −20 °C, 2h

Li O2

O

Et2BO2· O

O

O I CH3

N

O

Et·

EtI

CF3I

CF3·

O

CF3I Li O

O N

CH3

LiI

Li O

N

H CF3

H CF3 Et3B

O

CH3

O

O · N

CH3

H CF3

Scheme 3.10 Enantioselective perfluoroalkylation [29] using perfluoroalkyl halides with chiral auxiliary groups [30].

3.1 Radical Perfluoroalkylation

115

In 2011, MacMillan’s and Baran’s groups introduced new procedures for unspecific, ‘‘late stage’’ radical trifluoromethylation specifically as tools for combinatorial drug discovery (Schemes 3.11 and 3.12). The electrophilic trifluoromethyl radicals are generated under very mild conditions either photochemically using a ruthenium photocatalyst [31] or by a combination of sodium trifluoromethylsulfinate (Langlois reagent) and tert-butyl hydroperoxide [32].

household light O F3C S

Cl

*Ru(phen)32+ reductant −0.90 V

O SO2, Cl−

−0.18 V CF3SO2Cl·−

. F

SET

Ru(phen)33+ oxidant −0.90 V

F F

Ru(phen)32+ photocatalyst −0.90 V

photoredox catalysis

H R CF3 SET

arene

R

−0.1 V . R

CF3 H

CF3 arene + R

CF3 H

Scheme 3.11 The photocatalytic cycle for Ru(phen)3 2+ -catalyzed radical trifluoromethylation [31] (phen = phenanthroline ligand).

3.1.3 ‘‘Inverse’’ Radical Addition of Alkyl Radicals to Perfluoroolefins

The ‘‘inverse’’ addition of nucleophilic alkyl radicals to electrophilic, highly fluorinated olefins was the subject of a detailed study by Chambers and Sandford’s group [33]. Alkyl radicals can be generated directly from alkanes either with initiators

− H+

116

3 Perfluoroalkylation

O

OH

OH

N

N H

COOH

F

cholesterol-lowering drug Lipitor

CF3-Lipitor 74% yield 1:1:1 mixture of regioisomers

separation by SFC

O F3C N H

OH N

O

OH

OH

N

N H

COOH

OH COOH

CF3

F

F

O N H

F3C

OH N

OH COOH

F

Scheme 3.12 Late-stage trifluoromethylation for the rapid synthesis and screening of various CF3 analogs of Lipitor [31] (SFC = supercritical fluid chromatography).

(such as DBPO, dibenzoyl peroxide) or by γ-irradiation. Via the chain transfer mechanism outlined in Scheme 3.13, they add smoothly to fluoroolefins such as perfluoropropene and pentafluoropropene. Especially for aliphatic systems with primary, secondary, and tertiary hydrogen substituents, reasonably high regioselectivity of the (per)fluoroalkylation can be achieved by appropriate choice of reactant stoichiometry and reaction temperature. In practice, the most important prerequisite for this type of reaction is complete removal of oxygen from the reaction mixture, because oxygen inhibits the radical chain propagation even at very low concentrations.

3.1 Radical Perfluoroalkylation

overall reaction

R3C-H + CF2=CFCF3

initiation

R3C-H

propagation

termination

peroxide, Δ or UV or γ-rays

R3C-CF2CHFCF3 R3C· (+ H·)

· R3C-CF2CFCF3 R3C· + CF2=CFCF3 · R3C-CF2CFCF3 + CF2=CFCF3 · R3C-CF2CFCF3 + R3C-H

R3C-CF2CHFCF3 + R3C·

(a) CF2CHFCF3

CF2CHFCF3 +

CF2CHFCF3 (23%)

CF2=CFCF3

(57%)

(2 equiv.), cat. DTBP; 140 °C

RFH

RFH

RFH

CF2=CFCF3 (1.2 equiv.), cat. DTBP;140 °C

(60%)

CF2=CFCF3 (7 equiv.), cat. DTBP; 140 °C

(b)

(19%)

RFH

RFH

RFH RFH RFH (59%)

RFH

RFH (36%)

Scheme 3.13 Examples of the addition of alkyl radicals to highly fluorinated olefins (RFH = CF2 CHFCF3 ) (b), and the mechanism of the radical chain reaction (a) [33a].

Under the same conditions, radicals are formed not only from saturated hydrocarbons but also even more readily from ethers, in which the radical site is resonance stabilized. Thus, ethers also are readily perfluoroalkylated by fluoroolefins under radical-generation conditions (Scheme 3.14).

-O-CH2-

peroxide, Δ or UV or γ-rays

-O-CH-

+ − -O-CH-

(a) O

O (b)

CF2CHFCF3

CF2 = CFCF3, γ-rays, r.t., 10 d

Scheme 3.14 Resonance stabilization of α-oxaalkyl radicals (a) and radical addition of ethers to highly fluorinated olefins initiated by γ-irradiation (b) [33a].

117

118

3 Perfluoroalkylation

Even easier is the α-fluoroalkylation of alcohols [33b]. The α-hydroxyalkyl radicals are also resonance stabilized. Because of their nucleophilicity, they are highly reactive towards perfluoropropene and have the proper reactivity for the radical chain propagation step (Scheme 3.15). OH

HO CF2CHFCF3 76% CF2=CFCF3 (1.18 equiv.), γ-rays, r.t., 10 d

OH

HO CF2CHFCF3 83%

(cis/trans mixture)

CF2=CFCF3

OH

(2.27 equiv.), DTBP; 140 °C, 24 h

HO CF2CHFCF3

OH 34%

OH

Scheme 3.15

HO CF2CHFCF3

CF2=CFCF3 (2.34 equiv.), DTBP; 140 °C, 24 h

HO CF2CHFCF3

Addition of α-hydroxyalkyl radicals to perfluoropropene [33b].

3.2 Nucleophilic Perfluoroalkylation

Especially for medium-scale synthesis of fine chemicals and pharmaceuticals, a variety of methods for nucleophilic perfluoroalkylation have assumed an important role. For nucleophilic perfluoroalkylation, either perfluoroalkyl carbanions, ‘‘carbanionoid,’’ or perfluoroalkyl metal species must be generated, stabilized, and reacted with suitable electrophiles [34].

3.2.1 Properties, Stability, and Reactivity of Fluorinated Carbanions

Perfluoroalkyl anions can, in principle, be generated by the same methods as ‘‘normal’’ alkyl or aryl anions – either by deprotonation of a suitable CH-acidic precursor by a strong base or by reductive halogen (usually iodine or bromine)–metal exchange (Scheme 3.16). Another method – unique to the ‘‘perfluoro world’’ – is addition of fluoride ions or other anions to perfluoroolefins. All perfluoroalkyl carbanions are stabilized by the negative inductive effect (−Iσ ) of their fluoro substituents. At the same time, α-fluoro carbanions are destabilized

3.2 Nucleophilic Perfluoroalkylation

metallodehalogenation

transmetalation

RFX + RM

RFM + RX

ArFX + RM

ArFM + RX

RFM1 + M2X

RFM2 + M1X

ArFM1

ArFM2 + M1X

+

M2X

RFH + MB

metallodeprotonation

S

ArFH + MB F

F

F

RF

fluoride addition

CF3H + KOt Bu + DMF

ArFM + BH F3CCMFRF

+ MF

(a)

RFM·S + BH

CH3 N OK H3C H CF3 R2C=O "RFM·S"

−tBuOH

(b)

R

R

HO CF3 DMF

S = solvent]. (b) The particularly unstable trifluoromethyl anion can be stabilized by formation of an adduct with a suitable solvent, for example, DMF, which itself acts as a ‘‘CF3 − ’’ source in a haloform-like reaction.

Scheme 3.16 (a) Principal methods for generation of fluorinated carbanions and perfluoroalkyl metal compounds [RF = (per)fluoroalkyl, ArF = (per)fluoroaryl, M = metal, X = halogen, B = base,

by electronic p–π repulsion of the lone electron pairs of the fluorine and at the anionic center (+Iπ effect). This is reflected in the relatively weak acidity of CHF3 in comparison with the other haloforms – the pK a values of the various trihalomethanes are CHF3 30.5, CHCl3 22.4, CHBr3 22.7, and CH4 68–70 [35]. In contrast, for β-fluoro carbanions, negative hyperconjugation [36] has a stabilizing effect. For example, in the perfluoro-tert-butyl anion, the negative charge is not centered completely at the carbon atom, but comparably high partial charges are located on all the β-fluorine atoms [34] (Scheme 3.17).

stabilizing −Iσ (a) stabilizing −Iσ

(b)

F

−

.. :F .... : .. F F: :..

:

−

+Iπ destabilizing

stabilizing

F−

negative hyperconjugation

Scheme 3.17 Effects of stabilizing and destabilizing carbanions: α-fluorocarbanions (a) are stabilized by −Iσ and destabilized by +Iπ effects; β-fluorocarbanions (b) are also stabilized by the −Iσ effect, but additional stabilization is derived from negative hyperconjugation.

119

120

3 Perfluoroalkylation

3.2.2 Perfluoroalkyl Metal Compounds

If the carbanion is not in a ‘‘free’’ state but bound to a metal which is also a ‘‘hard’’ Lewis acid, for example, lithium or magnesium, the potential liberation of the huge lattice energies (e.g., 247 kcal mol−1 for LiF) strongly favors fragmentation of the perfluoroalkyl or perfluoroaryl metal compound (Scheme 3.18). If β-fluorine atoms are available, β-fluoride elimination occurs, leaving a terminal perfluoroolefin. If only α-fluorine is available, such as in CF3 Li (which has never been unambiguously observed), α-fluoride elimination results in the formation of difluorocarbenes. Perfluoroaryllithium species fragment also at low temperatures (typically from −40 to −20 ◦ C, depending on the substitution) in a sometimes violently exothermic reaction, giving the corresponding arynes and lithium fluoride (see also Section 2.4). F

F F

M α-elimination R

R

: + MF F

F F R F F

M β-elimination

R

F

+ MF

F F

F F

M

F

F F

Scheme 3.18 compounds.

F ortho-elimination

+ MF F F

Fragmentation pathways for different types of fluorocarbon metal

As already discussed in Section 2.4, addition of fluoride to perfluoroolefins is very much favored, because conversion of fluorine-substituted sp2 centers into sp3 carbon results in a relief of strain from p–π repulsion. Addition to perfluoropropylene and other perfluoroolefins is highly regioselective – the anion with the largest number of carbon atoms bound to the negatively charged carbon center is always formed. This reactivity can be regarded as the ‘‘negative’’ but analogous version of Markownikov’s rules for the hydrohalogenation of olefins (with protonation of the olefin as the preceding step). The reason for this phenomenon is the additional increase in stabilization of the negative charge by negative hyperconjugation for each newly created adjoining perfluoroalkyl group (Scheme 3.19). Clear experimental evidence of ‘‘negative’’ hyperconjugation was obtained from X-ray structure analysis of the perfluoro-1,3-dimethylcyclobutanide anion [37]. The anionic center and the cyclobutane ring are planar, and the observed bond lengths indicate a strong contribution of negative hyperconjugation. The fact that the same principal structure had been predicted by ab initio computational methods [38] for a model compound (Scheme 3.20) strongly supports the value of this general

3.2 Nucleophilic Perfluoroalkylation

F F F F

F

F F

+ F−

F

FF

F F F

− F

F F F F

CF3

F3C

CF3

F

+ F−

F F

F

F

F

F

F

F

+ F−

>

CF3 − F

F

CF3

F

+ F−

F3C

2 β-fluorines 2 α-fluorines

F

CF3

>>

CF3 − CF3

F

6 β-fluorines (stabilizing) 1 α-fluorine (destabilizing)

F

−

F F

F F

F

F F + F−

> F

CF3 − F

F

F

F − F

Scheme 3.19 The regioselectivity of fluoride addition and the relative stabilities of the carbanions derived from different perfluoroolefins are governed by the number of β-fluorine substituents which can stabilize the negative charge by their combined −Iσ effects and by negative hyperconjugation.

F−

F3C

F F

CF3

F

F F

F

F F

(a)

−0.28

−

F F 0.36

F F

−0.26

F F F

−0.38

(b)

TAS+

−0.29 −0.24

F F

−0.24

−0.36

F F−

F F F F

− CF + Me SiF 3 3

F3C F

(Me2N)3S+ Me3SiF2−

−

F F F

F F

F F F

F F

F F F F

F

F F

F−

F F F

(c) Scheme 3.20 Synthesis and structure of TAS+ [tris(dimethylamino)sulfonium] perfluoro-1,3cyclobutanide (a). Calculated Mulliken partial charges q (e) for a related model anion (b) suggest negative hyperconjugation (c) [38].

121

122

3 Perfluoroalkylation

methodology as a tool for understanding and elucidating the very special reactivity and structure in fluoroorganic chemistry. Not only fluoride ions add readily to perfluoroolefins, but also carbanions themselves. Treatment of perfluoroolefins with catalytic amounts of CsF yields sometimes complex mixtures of various oligomers (the ‘‘negative’’ counterpart of cationic oligomerization; Scheme 3.21). F− −

+F

CF2=CF2

CF3CF2−

CF3CF2CF2CF2−

CF2=CF2

− F−

CF3CF2CF=CF2 F−

F3CF2C

F3C

CF3

− CF2CF3

+ F−

F

CF3CF2−

CF3CF=CF2CF3

F- (S N2′)

CF3 CF2CF3 − trimer F

CF3CF=CF2CF3 dimer −

CF3CF2

F−

F3C

CF3

F3C

CF3

+E isomer F F3CF2C CF2CF3 F3CF2C CF2CF3 tetramer pentamer CF3CF2−

F3CF2C

F− F F

F F3CF2C

C2F5

CF3 F3CF2C CF2CF3

Scheme 3.21

hexamer (major isomer)

Cesium fluoride-catalyzed oligomerization of tetrafluoroethylene [39].

On the other hand, the example of the pentakis(trifluoromethyl)cyclopentadienide anion demonstrates impressively that this type of reaction can also be employed highly selectively to supplant a previous complex multi-step synthesis [40] by a one-pot procedure [41] (Scheme 3.22). Perfluoroalkyl carbanions generated by addition of fluoride to perfluoroolefins can also be used preparatively for the selective introduction of perfluoroalkyl groups by aliphatic [43] or aromatic nucleophilic substitution of suitable substrates. Because for aromatic substrates the nucleofugic leaving group is typically fluoride, the reaction can be performed with a catalytic quantity of fluoride. This catalyst can either be introduced as an inorganic fluoride (CsF) or generated in a preceding electrochemical reaction by reduction–defluorination of the perfluoroolefin itself [44] (Scheme 3.23). Higher homologs of perfluoroalkyllithium compounds are usually generated at very low temperatures (−78 ◦ C or below) in situ and directly reacted with a suitable electrophile, often a carbonyl compound, for example, an aldehyde, ketone [46], or

3.2 Nucleophilic Perfluoroalkylation

+ F−

CF2=CHCF3

CF3

_ F3CCHCF3 + F

CsF, CH3CN; autoclave,100 °C

123

CF3

F3C

F F3 C

F3C

CF3

F3 C

− F−

F

F3 C H F3C CF3

F3 C CF3 F − F F3C F3C H F3C CF3

− H+ F3 C

F3C

CF3

F3C

F

F3C − F3C F3 C F3C

CF3

Scheme 3.22 One-pot synthesis of cesium pentakis(trifluoromethyl)cyclopentadienide by fluoride addition-induced intramolecular cyclization [41]. The ring closure is considered to proceed by an electrocyclic mechanism,

F3C

F3C

CF2CF3 F

CsF

F3C SET

− "CF3+"

− CF CF CF Cs+ 2 2 3

F N

F3 C

F

CF3 F3C CF3

BnBr, sulfolane; 60 °C, 6 d

F

F

CF3 F

F CF2=CFCF3, cat. TDAE

CF3

58%

F3C

F

F

CF3

and final loss of a ‘‘CF3 + ’’ fragment involves a single electron transfer (SET), possibly from the solvent, under the fairly energetic reaction conditions [42].

F3C

F

CF3 F CF3

F3C

CF3

CF3

F3C

−

F3C

− F−

-

F3 C

electrocyclic ring-closure

CF3

N

F

Scheme 3.23 Nucleophilic perfluoroalkylation of aliphatic or aromatic substrates by perfluoroalkyl anions generated by fluoride addition [44, 45] [TDAE = tetrakis(dimethylamino)ethylene].

CF2CF2CF3 CF3

124

3 Perfluoroalkylation

ester [47] (Scheme 3.24). If this carbonyl compound is chiral, reasonable diastereomeric excesses can be obtained [48]. The corresponding trifluoromethyllithium (CF3 Li) is still unknown, because of its immediate α-elimination with difluorocarbene formation. The analogous magnesium (Grignard) species CF3 MgX has been prepared but is too unstable even at very low temperatures to be of any synthetic use.

R

R RF-I +

O R

MeLi·LiBr, Et2O, −78 °C

RF

OH R O

O RF-I + MeO R

(OC)3Cr (S )

O H OMe

Scheme 3.24

72% (>98% de) C2F5Li, Et2O; −40 °C

MeLi·LiBr, Cr Et2O, −78 °C

RF R

CF2CF3 OH H hn OMe

(OC)3Cr (1S,S)

CF2CF3 OH H OMe (R)

Generation and in situ reaction of perfluoroalkyllithium species [48].

Fluorinated aryllithium compounds, on the other hand, are of high synthetic value, as already discussed in Section 2.4. Although the o-fluoroaryllithium species (because they are typically obtained by ortho-metalation) must be handled at temperatures below −40 ◦ C, other fluoroaryllithium and -magnesium compounds can also be prepared at higher temperature, because they cannot undergo spontaneous, explosive ortho-elimination of thermodynamically highly stable metal fluorides to give the corresponding arynes. If the metal is a ‘‘soft’’ Lewis acid, for example, zinc, cadmium, or copper, the corresponding perfluoroalkyl metal compounds are stabilized by the more covalent character of the metal–carbon bond (Scheme 3.25) [49]. The copper(I) compounds, in particular, can be readily isolated, handled, and reacted even at elevated temperatures. The less stable trifluoromethylzinc compounds [50] can be used as a source of nucleophilic trifluoromethyl fragments either in the isolated form or generated in situ by sonication of perfluoroalkyl iodides with zinc in DMF (N,N-dimethylformamide) or THF (tetrahydrofuran). Zinc perfluoroorganyls find application in Barbier-type reactions [51], palladium-catalyzed cross-coupling reactions [52], and hydroperfluoroalkylations of acetylenes and olefins [53] (Scheme 3.26). In contrast, trifluoromethylcopper(I) can be generated and reacted, for example, by thermal decarboxylation of trifluoroacetates in the presence of copper(I) salts at 150 ◦ C, or by reaction of copper powder with perfluoroalkyl iodides. Nevertheless, even for the outwardly stable CF3 Cu there is evidence of

3.2 Nucleophilic Perfluoroalkylation

[CF2XY]· − + M+

CF2XY + M

carbene and metal halide formation

[CF2XY]· −

Y− + CF[2X]· [CF2X]− + M2+

M+ + [CF2X]· [CF2X]−

[:CF2] + X− CO + Me2NCHF2

[:CF2] + Me2NCH=O

fluoride ion formation

[Me2N=CHF]+F−

Me2NCHF2 [:CF2] + [Me2N=CHF]+F− formation of trifluoromethyl [CF3]− + MXY metal species

[CF3]-[Me2N=CHF]+

overall reaction

CF3MX + (CF3)2M + CO + MXY + [Me2N=CHF]+X−

CF3MX or (CF3)2M + Y−

2 CF2XY + 2 M

(a) 80-95%

2 Cd + CF2Br2

DMF

[CF3CdBr + (CF3)2Cd]

(b)

90-100% CuBr; −50 °C to r.t.

[CF3Cu]

Scheme 3.25 (a) Mechanism of the synthesis of trifluoromethylzinc and -cadmium reagents (X, Y = Br, Cl; M = Zn, Cd) and (b) the preparation of trifluoromethylcopper(I) by in situ transmetalation.

R

R RF-I +

O R

RF-I + X

RF-I +

I

Zn, DMF; sonication

RF

Zn, Pd cat., THF; sonication

R

61-74% Zn, CuI, THF; sonication 52-74%

RF-I + CH3

Zn, Cp2TiCl2, THF or DMF; sonication

OH R RF X

RF-CH=CH-R

RF

CH3 CH3

Scheme 3.26 Synthetic use of perfluoroalkylzinc reagents – generated in situ by sonication – for various types of reaction [53].

125

126

3 Perfluoroalkylation

a solvent- and temperature-dependent equilibrium between the trifluoromethylcopper(I) species and a difluorocarbenecopper(I) fluoride complex. This equilibrium can be used for stepwise building of longer chain perfluoroalkylcopper(I) complexes by a difluorocarbene insertion mechanism (Scheme 3.27). The reaction can be blocked if CF3 Cu is stabilized by addition of stoichiometric amounts of HMPA.

CF3Cu

[CF2Cu]+F−

CF3Cu

CF3CF2Cu + CuF

[CF3CFCu]+F− further chain elongation

Scheme 3.27 Elongation of perfluoroalkylcopper(I) compounds by a carbene insertion mechanism [54].

The most common use of perfluoroalkylcopper reagents is cross-coupling with aryl bromides or iodides to give the corresponding perfluoroalkylarenes. A complication, especially for copper-mediated trifluoromethylation, is the concomitant formation of perfluoroethyl derivatives, which are difficult to remove during work-up and purification. The reason for this ubiquitous impurity is the above-mentioned carbene insertion equilibrium; this can sometimes be suppressed by optimization of the solvent [e.g., addition of HMPA (hexamethylphosphoric acid triamide)] and the use of lower reaction temperatures. Especially mild reaction conditions are achieved by using Me3 SiCF3 [2c] as the primary source of the nucleophilic trifluoromethyl group in combination with potassium fluoride and cuprous iodide for the in situ formation of CuCF3 [55] in a mixture of DMF and NMP (N-methylpyrrolidone). The same method (using Me3 SiC2 F5 ) has also been successfully applied to the pentafluoroethylation of aryl iodides (Scheme 3.28). Even higher yields were often achieved using Cu(I)–carbene complexes (Scheme 3.29) [56]. The first truly catalytic trifluoromethylation of an aryl iodide was reported in 2009, using copper(I)–phenanthroline complexes [58]. Here, the reaction is assumed to proceed via generation of a copper(I)–trifluoromethyl complex, followed by oxidative addition of the – preferably electron-poor – aryl iodide to form an arylcopper(III) intermediate [59]. The mechanism of the copper-mediated cross-coupling of iodoarenes and perfluoroalkyl iodides is considered to be similar to that of related reactions involving the interaction of haloarenes with cuprous salts of organic nucleophilic anions (for example, CuCN) [60] (Scheme 3.30). First, a solvated perfluoroalkylcopper(I) complex is formed. This species then coordinates to the iodoarene followed by exchange of ligands [61]. Several electron-transfer steps are probably involved in this process. The efficiency of the reaction depends critically on the solvating power

3.2 Nucleophilic Perfluoroalkylation

CF3

I 75% CF3Cu, DMF, HMPA; 70 °C

NO2

NO2

F

F

F I

F F

F

F

F E:Z = 69:31 I NH2

67%

F

CF3Cu, DMF; −50 °C to r.t, 2-3 h

F

F CF3 F

F

F E:Z = 30:70

53% 1. Cu, C8F17I, DMF; 120 °C 2. t BuONO, CuBr, MeCN, −5 °C to r.t.

F17C8 Br

C8F17

Br F17C8

Br OH OH

OH OH

46% C8F17I, Cu, DMSO; 160 °C F17C8

Br

C8F17

Br O2N

I

O2N

I

I N

Cl

99% (glc) Me3SiCF3, CuI, KF, DMF−NMP(1:1); 80 °C, 24 h 86% Me3SiC2F5, CuI, KF, DMF; 60 °C, 24 h

O2N

CF3

O2N

CF2CF3

CF3

67% Me3SiCF3, CuI,KF, DMF−NMP(1:1); 25 °C, 6 h

N

Cl

Scheme 3.28 Cross-coupling of perfluoroalkylcopper(I) and aryl halides or perfluoroiodoolefins [54, 55, 57]. The CF3 Cu used for the first two reactions was generated by metathesis of trifluoromethylcadmium and copper(I) salts.

of the solvent for the copper(I) complex – DMF, pyridine, and DMSO (dimethyl sulfoxide) give the highest yields. Because the complex is not sensitive to hydrolysis, the reaction also tolerates the presence of free carboxyl, amino, or hydroxy groups. The order of reactivity of the halogens as the aromatic leaving groups is I > Br  Cl.

127

128

3 Perfluoroalkylation

N

N

O O

N

N

Cu

Cu

Me3SiCF3, THF

N

Cu CF3

N

I

91%

MeO DMF, 25 °C

CF3 MeO Scheme 3.29

RF-I

Copper(I)-catalyzed trifluoromethylation of aryl iodides [56].

Cu, solvent L

RFCuL3 + ICuL3 ArI

I CuL2

Ar

ArRF + ICuL3

RF Scheme 3.30 Proposed mechanism for the copper-mediated coupling between perfluoroalkyl iodides and iodoarenes [61].

Instead of aryl iodides, areneboronic acids can also be converted into their corresponding perfluoroalkyl derivatives (Scheme 3.31). Either this reaction is mediated by a Cu(II)–phenanthroline complex together with an oxidant such as atmospheric oxygen, and a perfluoroalkylsilane (e.g., Me3 SiCF3 ) is used as the B(OH)2

Cu(OAc)2, phenanthroline, Me3SiCF3, CsF, O2 (1 atm), 4 A molecular sieves, i-PrCN; r.t.

PhO (a) MeO (b)

CF3

61%

B(OH)2

56%

MeO

PhO

CF2CONEt2

1 equiv. Cu, ICF2CONEt2, DMSO−DMF (5:1); r.t., 12 h, ambient air

Scheme 3.31 Oxidative perfluoroalkylation of boronic acids catalyzed by various copper species: (a) perfluoroalkylsilane donors with a Cu(II) catalyst [62] and (b) perfluoroalkyl iodide donors with a Cu(0) mediator [63]. The oxidant in both cases is atmospheric oxygen.

3.2 Nucleophilic Perfluoroalkylation

perfluoroalkyl donor [62], or the reaction can be conducted with elemental copper(0) and perfluoroalkyl iodide as the perfluoroalkyl donor [63]. All copper-mediated perfluoroalkylations mentioned so far work only with aryl iodides. In contrast, the palladium-catalyzed system presented by Buchwald and co-workers in 2010 extends the scope of catalytic perfluoroalkylations to a variety of aryl chlorides [64]. As for the system used for palladium-catalyzed fluorination (see also Section 2.4.5), the catalyst is a BrettPhos Pd(II) species (Scheme 3.32) [65]. 76%

N Bn

CF3

Cl 3 mol% [(allyl)PdCl]2, 9 mol% BrettPhos,

N Bn

2 equiv. Et3SiCF3, 2 equiv. KF, dioxane; 130 °C, 6-20 h

Scheme 3.32 Palladium-catalyzed trifluoromethylation of aryl chlorides [64].

‘‘Metal-free’’ alternatives to the reductive nucleophilic activation of perfluoroalkyl iodides have been described by Pawelke [66] and Petrov [67]. If perfluoroalkyl iodides are treated at low temperatures with the organic reducing agent TDAE [tetrakis(dimethylamino)ethylene], the resulting ‘‘RF − ’’-like species (presumably a charge-transfer complex RF I···TDAE) can be trapped with a variety of nucleophiles, for example, Me3 SiCl, yielding Ruppert-Prakash reagent Me3 SiCF3 [2c], or carbonyl compounds, yielding the corresponding alcohols (Scheme 3.33).

Me2N

NMe2

RFI + Me2N

NMe2

Me2N

NMe2

Me2N

NMe2

I

55-81% Me3SiCl, diglyme; −30 °C, 2 h

RFSiMe3

RF RF = CF3, C2F5, n-C3F7, i-C3F7, n-C4F9 O

O Cl

56% i-C3F7I, TDAE, glyme; −30 °C, 2 h

SO2Cl

30%

CF3 F CF3 O O S C4F9

n-C4F9I, TDAE, glyme;

O

−30 °C, 2 h

CF3

OH CF3 RF

RFI, TDAE, glyme; −30 °C, 2 h

Scheme 3.33 Nucleophilic perfluoroalkylation by reductive activation of perfluoroalkyl iodides with TDAE [66, 67].

129

130

3 Perfluoroalkylation

Probably the most efficient way to generate CF3 − from the viewpoint of atom economy is deprotonation of inexpensive CHF3 with a strong base [68]. Unfortunately, this route poses two problems. First, the low boiling point of fluoroform (−82.2 ◦ C) creates – at least on the laboratory scale – the practical problem of handling a gas. The second problem is the need to trap and stabilize the trifluoromethyl anion immediately after its generation, to suppress fragmentation. This second complication, in particular, impeded the apparently straightforward preparative use of CHF3 for several years [69]. Persistent work on this challenging subject [70] showed that if DMF is used as solvent in combination with a strong base [KOtBu, KN(SiMe3 )2 , DMSO–KH], CF3 − is trapped by the DMF and the resulting stable hemiaminolate can be used as a reservoir of nucleophilic trifluoromethide anion [71] (Scheme 3.34).

CHF3 + B− +

F3C O−

O H

NMe2 − BH

NMe2

H

F3C OH B−, DMF; −10 °C

Ph

Ph

O Ph

F3C OH

Ph

+ CHF3 (excess)

N(SiMe3)3, cat. Me4NF, DMF

Ph

Ph

F3C OH N(SiMe3)3, cat. Me4NF, cat. DMF, THF

Ph

Ph

Scheme 3.34 Syntheses making use of CHF3 in combination with DMF as a source of nucleophilic ‘‘CF3 − ’’ [68]. The yields for different base systems B− are KOtBu 95%, KN(SiMe3 )2 79% and N(SiMe3 )3 (1.5 equiv.)–Me4 NF (1.5 equiv.) 72%.

This CHF3 –DMF methodology has been extended by the addition of related hemiaminals (readily accessible by reaction of fluoral methylhemiacetal with morpholine or N-benzylpiperazine), which are useful, stable, and inexpensive starting materials for a variety of fluoroorganic compounds [72] (Scheme 3.35). 3.2.3 Perfluoroalkylsilanes

In the last few years, Me3 SiCF3 and its higher perfluoroalkyl homologs have become probably the most popular nucleophilic perfluoroalkylation reagents [73]. Me3 SiCF3 , also called the Ruppert–Prakash reagent, was first synthesized by Ruppert

3.2 Nucleophilic Perfluoroalkylation

F3C OSiMe3 R1 O O

N H

78%

70-95%

CHF3, N(SiMe3)3,

R2 R1R2CO, cat. CsF, DME; 80 °C

cat. Me4NF, THF;

OSiMe3

−10 °C

O

N CF3

O

NH

90% 1. CF3CH(OH)OMe.

70-95%

4Å molecular sieves, THF; r.t. 2. N-TMS-imidazole

RSSR, Bu4N+ (Ph3SiF2)−, glyme; 80 °C, 5 h

R-SCF3

Scheme 3.35 Synthesis of trifluoroacetaldehyde hemiaminal derivatives and their use as nucleophilic trifluoromethylation reagents (TMS = trimethylsilyl) [68].

et al. in 1984 [2c], but its extraordinary value as a nucleophilic trifluoromethylation reagent was later recognized and systematically developed by Prakash and coworkers [74]. The substance class owes its attraction to its stability, ease of its handling (b.p. 54–55 ◦ C for Me3 SiCF3 ), and the versatility of the reactions, which can be achieved highly conveniently. Me3 SiCF3 can be prepared by reaction of CF3 I or CF3 Br with Me3 SiCl in the presence of a variety of reducing agents, for example, P(NMe2 )3 [75], TDAE [66, 67], or aluminum [76]. The synthesis of CF3 Br by electrochemical reduction in the presence of Me3 SiCl has also been reported [77] (Scheme 3.36). CF3Br + P(NMe2)3 + Me3SiCl

CF3SiMe3 + BrClP(NMe2)3 H2O

OP(NMe2)3

(a) [O]

CF3H + PhSSPh

Me3SiCF3 + PhSSPh (b)

KOtBu, DMF

Mg, Me3SiCl,

PhSK + PhSCF3 + PhS(O)CF3 + PhSO2CF3

[O] [O]

DMF

Scheme 3.36 Preparation of trifluoromethyltrimethylsilane (Me3 SiCF3 , Ruppert–Prakash reagent). (a) Ruppert et al.’s original method [2c] leads, after aqueous work-up, to the formation of stoichiometric amounts of the carcinogenic HMPA [OP(NMe2 )3 ]. In

addition, ozone-depleting CF3 Br is used as the starting material. (b) A recent method, with potential for technical scale-up, utilizes the inexpensive CHF3 and depends on a catalytic cycle initiated by diphenyl disulfide [78].

131

132

3 Perfluoroalkylation

Under catalysis by fluoride ions, tert-butylate or other Lewis bases [79], Me3 SiCF3 can transfer ‘‘CF3 − ’’ equivalents in high yields to a large variety of electrophilic substrates. The mechanism of this transfer involves the formation of ‘‘carbanionoid’’ alkoxytrimethyltrifluoromethylsiliconate species, which add their trifluoromethyl moiety to carbonyl groups in a self-activating chain reaction which is initiated by a small amount of fluoride ions (5–10 mol%) [74] (Scheme 3.37). Some of the intermediate siliconate species have been isolated and characterized by either NMR spectroscopy or X-ray crystallography [80, 81]. Remarkably, in contrast with most other organosilicon reagents, the addition reaction cannot be initiated by Lewis acid catalysts. Me3SiCF3

CF3 Me3SiCF3

F−

H3C Si CH3 H3C F

−

− F3C O R R2C=O

Me3SiF

R

CF3

−

H3C Si CH3 H3C F3C O R

R

F3C OSiMe3 R

R

R2C=O

Scheme 3.37 Mechanism of the nucleophilic trifluoromethylation of carbonyl compounds by Me3 SiCF3 [68, 74].

Nucleophilic addition of the trifluoromethyl group to aldehydes, ketones, and other carbonyl compounds [82] leads primarily to the corresponding trimethylsilyl ether; this must subsequently be hydrolyzed to the alcohol. Because typical reaction conditions are very mild, the method is widely applicable, even for sensitive substrates. In contrast with most other methods, fluoride-induced perfluoroalkylation via silicon compounds also works for enolizable carbonyl compounds. With α,β-unsaturated substrates, 1,2-addition directly to the carbonyl group is strongly preferred [73b]. If the oxygen is coordinated to a bulky Lewis acid, for example, aluminum tri[2,6-bis(tert-butyl)phenoxide] (ATPH), the 1,4-addition products are obtained selectively [82f] (Scheme 3.38). Since the original report on the utility of Me3 SiCF3 in 1989 [74], the general method has been widely used for synthesis of trifluoromethylated analogs of a variety of natural products, for example, carbohydrates, nucleotides [83], and steroids (Scheme 3.39). Another recent application of the reagent, in pharmaceutical chemistry, is the trifluoromethylation of the antimalarial compound artemisinin, with the aim of improving the pharmacological profile of the natural compound [85] (Scheme 3.40). Use of chiral fluoride sources [86] at low reaction temperatures opens up – at least in principle – a route to enantioselective nucleophilic trifluoromethylation of prochiral carbonyl compounds (G. K. S. Prakash and A. K. Yudin, 1993, unpublished

3.2 Nucleophilic Perfluoroalkylation

CHO

85%

CF3

1. Me3SiCF3, cat. Bu4NF,

H OH

THF; −20 °C 2. HCl

tBocHN

H H

O O

1. Me3SiCF3, cat. Bu4NF, THF; −20 °C 2. HCl

t BocHN

78%

CF3 H

OH

CF3 OH

1. Me3SiCF3, cat. Bu4NF, THF; −20 °C 2. HCl

CF3 + OH

60%

O

1. Me3SiCF3, cat. Bu4NF, THF; −20 °C 2. HCl

O

90:10 F3C F3C

OH

60% Me3SiCF3, cat. Bu4NF,

OO

Me3SiO O

THF; −20 °C

O

CF3

1. Me3SiCF3, cat. Bu4NF,

O 1. Me3SiCF3, cat. Bu4NF, THF; −20 °C 2. HCl

HO CF3 F 3C OH (cis and trans) O

O 78%

t BuO

Ot Bu O

CF OH 3

THF; −20 °C 2. HCl

1. Me3SiCF3, cat. Bu4NF, THF; −20 °C 2. HCl

HO

OH

F3C OH O

O 30%

O

ATPH, Me3SiCF3, KOtBu, heptane−CH2Cl2;

O

CF3

−78 °C to r.t., 8 h

Scheme 3.38 Reaction of Me3 SiCF3 with a variety of carbonyl compounds. ATPH = aluminum tri[2,6-bis(tert-butyl)phenoxide] [73b, 74, 82].

results), [87] (Scheme 3.41). Enantiomeric excesses obtained so far by this method are, however, only low to moderate. If, instead of the usual polar ether, a nonpolar solvent such as toluene, pentane, or dichloromethane is used as the reaction medium, clean conversion of a large variety (aromatic, aliphatic, nonenolizable, and enolizable) of esters to the corresponding trifluoromethyl ketones can be achieved [88] (Scheme 3.42).

133

134

3 Perfluoroalkylation

O

O O

O

O

O

O

CF3 OH

O

O

98% 1. Me3SiCF3, cat. Et4NF, THF; r.t.

O

O

2. Et4NF (1equiv.)

O

O

70%

O

BzO

Me3SiCF3, Bu4NF,

O

O

O

MeO O

F3C

THF; r.t.

O 49%

O

O O

THF; r.t.

CF3 H3C

H3C H3C

H3C

H H

O

O

OH HO O

MeO O

Me3SiCF3, Bu4NF,

O

O

BzO

H

83%

H

1. Me3SiCF3, cat. Me4NF,

THF; r.t.

H

H

HO F3C

2. 40% aq. HF, CH3CN

H

H

Scheme 3.39 Use of Me3 SiCF3 for the synthesis of carbohydrate analogs and steroids containing a trifluoromethyl group [84].

H H3C

CH3

H H3C

77 %

OO O

1. Me3SiCF3, THF, H 0.1 equiv. Bu4NF·3H2O CH3 2. H2O

O

H 79 % Me3SiCF3, THF, 0.05 equiv. Bu4NF·3H2O

OO O H

O

O H3C

CH3

CH3

CH3

F3C OH 0.2equiv. Bu4NF·3H2O,

OO O O

H2O

H

CH3 F3C OSiMe3

Scheme 3.40 Nucleophilic trifluoromethylation of artemisinin to the β-trimethylsilyl ether as the kinetic primary product and the α-trifluoromethyl hemiketal as the thermodynamic final product after desilylation [85].

3.2 Nucleophilic Perfluoroalkylation

N

HO

F−

+

CF3

H

48% ee

+

(10-20 mol%)

1. Me3SiCF3, toluene; −78 °C 2. HCl

N Ph

Ph O

N

Ph Ph

HO CH3 F3C

CH3

O

N + S

N

Ph

Ph3SnF2−

H

+

F3C H HO

96% (52% ee) 1. Me3SiCF3, Et2O; −78 °C 2. HCl

Ph

(10 mol%) Scheme 3.41 Enantioselective nucleophilic trifluoromethylation of prochiral carbonyl compounds with chiral fluoride sources [87].

O

95%

OMe Me3SiCF3, cat. Bu4NF,

toluene; −78 °C to r.t., 18 h

O

85%

Me3SiCF3, cat. Bu4NF, OMe pentane; −78 °C to r.t., 24 h

CH3(CH2)12COOMe

72% Me3SiCF3, cat. Bu4NF, pentane; −78 °C to r.t., 18 h

O CF3 O CF3 CH3(CH2)12COCF3

70%

COOMe Me3SiCF3, cat. Bu4NF, pentane; −78 °C to r.t., 72 h

COCF3

Scheme 3.42 Preparation of trifluoromethyl ketones from esters with Me3 SiCF3 [88].

Although most carbonyl compounds are sufficiently electrophilic to be reactive towards Me3 SiCF3 , most nitrogen electrophiles have to be activated in some way to make them susceptible towards nucleophilic attack. Nitrosobenzene, the simplest heteroanalogous ‘‘carbonyl’’ compound, smoothly adds Ruppert-Prakash reagent to yield a product which is analogous to the normal carbonyl addition product [89]. Imines, on the other hand, are generally not reactive under the same conditions. They must be activated either by steric strain, for example, the aziridines [90], or by electron-withdrawing substituents at the nitrogen, for example, nitrones [91], or at the electrophilic carbon center [92]. Nonactivated imines might also be reacted

135

136

3 Perfluoroalkylation

with low to moderate yields by use of N-trimethylsilylimidazole as an additional activator [93] (Scheme 3.43).

N

O

CF3 N OSiMe3

quant. Me3SiCF3, cat. Bu4NF, THF; −0 °C

R1

Ph

41-86%

N R2 Me3SiCF3, Nu4NF, THF

Ph

R1

F3 C N R 2 SiMe3 CF3

+ Ar

N − O R3 1

R

Ar N OSiMe3

62-69% Me3SiCF3, KOt Bu, THF; −20 °C

N

2-55%

F3C NHR3

2 1. Me3SiCF3, N-TMS-imidazole,

R

CsF, THF 2. SiO2, 2 M HCl

N F3 C

Ar 48-84%

CF3

Me3SiCF3, CsF,

1

R

2

R

+

F3C NHR3 R1

CF3

F3C NHAr F3C

CF3

THF

Scheme 3.43 Trifluoromethylation of nitrogen electrophiles, imines, and related compounds (TMS = trimethylsilyl) [89–93].

Reversible activation of an imine is achieved by use of the tosyl group, which can be removed after trifluoromethylation to furnish α-trifluoromethylamines [94]. The N-sulfenyl group also leads to sufficient activation of the imino moiety. Thus, via the readily available chiral N-sulfenimines, stereoselective trifluoromethylation is possible with high diastereoselectivity. The resulting sulfenamines can be hydrolyzed and converted to chiral amines carrying a trifluoromethyl group; these are of growing interest as intermediates for pharmaceutical chemistry [95] (Scheme 3.44). A more recent approach to overcome the low reactivity of the Ruppert–Prakash reagent Me3 SiCF3 towards imines is phase-transfer catalysis [96]. By use of a similar synthetic procedure, Me3 SiCF3 can also be employed as a reagent for nucleophilic trifluoromethylation of a variety of sulfur electrophiles (Scheme 3.45). The other way around, Prakash and co-workers demonstrated that trifluoromethyl sulfones can also be used as a source of nucleophilic ‘‘CF3 − ’’ equivalents when they are treated with alcoholates [78].

3.2 Nucleophilic Perfluoroalkylation

H

137

CF3 N

SO2Tol

N H

90%

Me3SiCF3, Bu4N+Ph3SiF2−,

SO2Tol

THF; 0-5 °C

tBu

O S

H N

R

Me3SiCF3, Bu4N+Ph3SiF2−,

tBu

O S

THF; −55 °C

:

O

N H

CF3

R 4 N HCl, MeOH,

+

Cl− H3N

r.t.

CF3 Me Si Me Me F

H R

70-95% (80-99% ee)

CF3

−

N

t Bu

O S

H

H

N

90% Me3SiCF3, Bu4N+Ph3SiF2−,

Ph H

tBu

O S

THF; −25 °C

H NBn2

N

CH2Ph

86% Me3SiCF3, Me4NF,

t Bu

O S

THF; −25 °C 92%

O

CF3 CH2Ph

Ph H

NBn2

N H

CH2Ph 1. 10 equiv. HCl, dioxane, MeOH; 70 °C, 3 h 2. aq. NaHCO3

EtOCOCl, 50% aq. K2CO3,

NBn2

H2N

CH2Ph

dioxane

Pd-C, H2, MeOH–CH2Cl2

2. (Cl3CO)2CO, NEt3, THF

CF3

CF3

O EtO

N H

CF3

1. Pd-C, H2, MeOH–CH2Cl2

60%

CF3 H

CF3

95%

NBn2

N H

EtO

t Bu

O S

CH2Ph

N O

N H

H2N

NH2 CH2Ph

Scheme 3.44 Nucleophilic trifluoromethylation of N-tosylaldimines and chiral sulfinimines [94, 95]. The mechanistic rationalization of the observed stereoselectivity of the addition to chiral sulfinimines is sketched in the box.

R

138

3 Perfluoroalkylation

SO2F

99%

SO2CF3

Me3SiCF3, TASF

O 70% S F Me3SiCF3, TASF NSO2CF3

F Cl

O S Cl

Cl

SCl

PhSSPh

O S CF3 NSO2CF3

F

83% Me3SiCF3, TASF 72% Me3SiCF3, TASF

Cl

O S CF3

Cl

SCF3

25%

SCF3

Me3SiCF3, Bu4NF, THF; 0 °C

H3C

O S

F3C OSiMe3 S CH3 H3C

CH3 Me3SiCF3, cat. Bu4NF, THF

Scheme 3.45

Reaction of Me3 SiCF3 with sulfur electrophiles [97–99].

If equimolar quantities of tetramethylammonium fluoride and a threefold excess of Me3 SiCF3 or its homologs are used, the perfluoroalkyltrimethylsilane acts as an effective source of nucleophilic perfluoroalkyl equivalents for nucleophilic substitution of aliphatic triflates [100] (Scheme 3.46). This method permits the simple synthesis of partially fluorinated alkane structures which are of interest in the chemistry of liquid crystals and other functional materials. CH3(CH2)6OTf

CH3(CH2)6CF3 + CH3(CH2)6F (7%) (81%)

Me3SiCF3, TASF, THF; −10 °C 70%

Me3SiCF3, Me4NF,

H H

glyme; −30 °C to r.t.

OTf

80% Me3SiC2F5, Me4NF, glyme; −30 °C to r.t.

H H

CF3

H H

C2F5

Scheme 3.46 Perfluoroalkylation with Me3 SiCF3 and its homolog Me3 SiC2 F5 by nucleophilic substitution of alkyl triflates (glyme = ethylene glycol dimethyl ether) [100].

A similar method of activation of perfluoroalkylsilanes is used for nucleophilic addition or substitution of trifluoromethyl moieties to obtain electron-deficient fluorinated aromatic compounds [101] (Scheme 3.47).

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

F

F F

N F

F

F

Me3SiCF3, TASF, THF

F3C F3C

N F

F F

F CF3

F

F 3C

F

F

F

F

Me3SiCF3,

F3C

TASF, THF

F CF3 CF3

60% Me3SiCF3, TASF, THF; −30 °C

CF3 F

F3C F3C

F _

CF3 CF3

(Me2N)3S+

CF3

Scheme 3.47 Aromatic nucleophilic substitution and ipso-addition with a variety of ‘‘RF − ’’ sources [101].

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

As already discussed in Section 3.1, perfluoroalkyl halides do not act as effective electrophilic perfluoroalkylation reagents, as might be expected by analogy with the reactivity of alkyl halides. Even if some ‘‘electrophilic’’ perfluoroalkylation reactivity is mimicked with some especially suitable (i.e., easily oxidizable) substrates by an electron transfer-induced radical mechanism, the practical usefulness of this reaction pathway is limited to very few examples. 3.3.1 Properties and Stability of Fluorinated Carbocations

The stability of fluorinated carbocations [102] is determined by a delicate equilibrium between inductive destabilization and mesomeric stabilization of the positive charge. α-Fluoro substituents stabilize the positively charged carbon by π-donation (+R) from their lone electron pairs. The charge, on the other hand, is destabilized by the negative inductive (−Iσ ) effects from α-fluorine. Fluorine substitution in the position β to the positive carbon exerts a strongly destabilizing inductive (−Iσ ) effect only (Scheme 3.48). The strongly stabilizing effect of α-fluorine on carbocations is well demonstrated by the reactivity of exo-difluoromethylenecyclohexane towards triflic acid. Initial protonation of the double bond forms only the cyclohexyldifluoromethyl cation, in contrast with the usually observed high stability of trialkyl carbocations. Molecular modeling [B3LYP/6–31G(d)//B3LYP/6–31G(d) level of theory] indicates stabilization of 3.3 kcal mol−1 in favor of the former cation (P. Kirsch and A. Hahn, 2002,

139

140

3 Perfluoroalkylation +

F

F +

resonance stabilization (+R)

α-fluoro carbocations

F inductive destabilization (-Iσ)

+

F β-fluoro carbocations

Scheme 3.48

inductive destabilization (-Iσ)

+

Stabilizing and destabilizing effects for fluorinated carbocations.

unpublished work). In this case, cation 7 is stabilized by +Iσ effects from the alkyl substituents and some hyperconjugation from the α-C–H bonds. It is, on the other hand, inductively destabilized (−Iσ ) by the two β-fluorines. The cation 8 is stabilized by π-donation (+R) from two α-fluorines, by σ -donation (+Iσ ) from the cyclohexyl group and also by hyperconjugation from one of the α,β-C–C bonds in the cyclohexane. The hyperconjugation is also reflected by the unusually long C–C bond [163 pm; B3LYP/6–31G(d)] (Scheme 3.49).

R F H7C3 F

F H

+

0 °C

H R

Scheme 3.49 The reactivity of exodifluoromethylenecyclohexane derivatives towards triflic acid nicely illustrates the strongly stabilizing effect of α-fluoro substituents on carbocations

F

F quant. (GLC)

+

8

OTf F H

F

7 CF3SO3H, CH2Cl2;

R

H R

F

F OTf F

elongated

(P. Kirsch and A. Hahn, 2002, unpublished work). The elongated C–C bond mirrors the contribution of C–C hyperconjugation to the stabilization of the cation 8.

Because of their strong inductive destabilization, few salts of α- or βfluorocarbenium ions have been isolated and characterized. Despite persistent attempts to isolate salts of the CF3 + cation, this most simple α-fluorocarbenium ion has so far only been the subject of numerous theoretical studies [103]. Recently, the more stable dimethylfluorocarbenium ion, in the form of its hexafluoroarsenate salt (Me2 CF+ AsF6 − ), has been characterized by X-ray crystallography [104]. For β-fluorocarbenium ions also, very few examples have been isolated as their salts and fully characterized; all were additionally stabilized either by bonding to a

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

metal center [105] or by α-substitution with stabilizing heteroatoms such as sulfur [106, 107] (Scheme 3.50). F (CH3)2CF2 + AsF5

O F3C

HF; −196 °C to −50 °C

+

CH3

AsF6− +

O O

H3C

S

66%

F3C

CF3 1. HS(CH2)3SH, CF3SO3H; −10 °C

CF3SO3−

S

2. Ac2O; 0 °C 3. precipitation with Et2O

Scheme 3.50 Representative examples of α- and β-fluorocarbenium salts which have been isolated and fully characterized [104, 107].

Although free trifluoromethyl cation salts have not yet been isolated and characterized, it is possible to generate a mixture of chlorofluoromethyl cations (CFx Cl3 − x + ) in situ from carbon tetrachloride and strong Lewis acids [108]. These systems can be used for electrophilic trihalomethylation of electron-rich aromatic substrates. The remaining chlorine substituents are substituted by fluorine with 70% HF–pyridine (Scheme 3.51).

NH2

NH2

NH2

85% HF, SbF5, CCl4;

CH3

−20 °C, 30 min

CX3 CH3

70% HF-pyr; −78 °C to 0 °C, 18 h

CF3 CH3

CX3 = CCl3, CCl2F, CClF2, CF3 NHAc

NHAc 65% 1. HF, SbF5, CCl4; −20 °C, 30 min 2. 70% HF-pyr; −78 °C to 0 °C, 18 h

H N O

N

CF3

H

50% 1. HF, SbF5, CCl4; −20 °C, 30 min 2. 70% HF-pyr; −78 °C to 0 °C, 18 h

N

F3 C

N

O

Scheme 3.51 Electrophilic trifluoromethylation of activated aromatic substrates by an HF–CCl4 –SbF5 system and subsequent treatment with 70% HF–pyridine [108].

141

142

3 Perfluoroalkylation

3.3.2 Arylperfluoroalkyliodonium Salts

Because of their extremely high group electronegativity (e.g., 3.45 for the CF3 group, compared with only 3.0 for chlorine) [109], perfluoroalkyl groups cannot be expected to be transferred by a truly electrophilic mechanism from their corresponding halides to non-oxidizable nucleophiles. If, on the other hand, the group electronegativity of the leaving group X of a potential perfluoroalkylation reagent RF X is increased until it matches or exceeds this high value for RF , then a process at least similar to electrophilic perfluoroalkylation becomes feasible [110]. This general concept was used by Yagupolskii et al. [111], when they achieved for the first time electrophilic perfluoroalkylation of a variety of nucleophiles using arylperfluoroalkyliodonium chlorides as reagent. Later, the corresponding tetrafluoroborates were reported to be even more reactive [112]. Similar reactivity is observed for the corresponding triflates [also known as FITS (perfluoroalkylphenyliodonium trifluoromethanesulfonate) reagents, perfluoroalkylphenyliodonium trifluoromethanesulfonates] introduced by Umemoto’s group [113] (Scheme 3.52).

n-C8H17-C8F17

58% n-C8H17MgCl, THF; −78 °C, 2 h

C3F7

82% PhCH2MgCl, THF;

RF + I X−

PhSNa, DMF; −30 °C to r.t., 5 h

C3F7

−110 °C, 2 h 35%

C8F17

PhNMe2, DMF;

58% PhCCMgCl, THF; -78 °C, 1 h

C8F17 O

+

(31%)

F17C8O

Na

(7%)

O

O

R

−30 °C to r.t., 5 h

60%

O +

SC3F7

81%

O

NaNO2, DMF;

−

DMF; −55 °C, 3 h

NMe2 C6F13NO2

−30 °C to r.t., 5 h 60% NaNO2, DMF;

C3F7SCN

−30 °C to r.t., 5 h

Scheme 3.52 Examples of the reactivity of arylperfluoroalkyliodonium reagents (reactions on the left, R = H, X = OTf; right, R = CH3 , X = Cl) [110].

Starting materials for the synthesis of all perfluoroalkyliodonium reagents are the perfluoroalkyl iodides, which themselves play a central role as building blocks in fluoroorganic chemistry. The iodides are available either by pyrolysis

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

of the silver salts of perfluoroalkylcarboxylic acids in the presence on iodine [114] or – on a more technical scale – by iodofluorination of tetrafluoroethylene [115] with the iodine–IF5 system [116] and subsequent radical telomerization of tetrafluoroethylene with the resulting intermediate perfluoroalkyl iodides [117] (Scheme 3.53).

R-COCl

RF -COF

Simons ECF

RF -COO−Ag+

I2, Δ

RFI + CO2 + AgI

2. Ag2O

(a) CHCl3

1. H2O

CHF2Cl

HF, SbCl5

CF3CF2=CF2

"IF"

RFI + n CF2=CF2

Δ

CF2=CF2

I2

ICF2CF2I

CF3CFICF3

AIBN, 80 °C

IF5

CF3CF2I

"IF"

RF(CF2CF2)nI (n = 1-5, mainly)

(b) Scheme 3.53 Synthesis of perfluoroalkyl iodides by the Hunsdiecker route (a), based on the electrochemical fluorination of carboxylic acid derivatives (RF = CF3 ∼(CF2 )9 CF3 ), and the industrial telomerization route (b) based on tetrafluoroethylene as the central intermediate.

The perfluoroalkyl iodides are subsequently oxidized to the bis(trifluoroacetates) or to the difluoroiodides, which again are reacted with a suitable arene in an electrophilic substitution. The resulting intermediates are converted into the chlorides or tetrafluoroborates (Yagupolskii’s reagents) or into triflates or hydrogensulfates (Umemoto’s reagents). The covalent or ionic character of the different iodonium salts depends strongly on the electronegativity and nucleofugicity of the counterion X− (Scheme 3.54). According to the 19 F NMR chemical shifts of the α-CF2 group, the ionic character of the iodine–X bond increases for substituents X in the order Cl < OSO2 CH3 < OSO3 H < OTf. Even for the most electronegative triflate group, the I–OTf bond is strongly polarized but not really ionic in nature [113c] (Scheme 3.55). Interestingly, the most basic of the iodonium reagents, aryltrifluoromethyliodonium salts, are still unknown. They cannot be prepared by the methods outlined in Scheme 3.54. The presumed reason for this unexpected fact is the low stability of the carbon–iodine bond of their potential synthetic precursors CF3 IF2 or CF3 IO, compared with their analogs with two or more carbon atoms in the perfluoroalkyl chain [118]. In addition to the arenes, enolates, and other nucleophiles depicted in Scheme 3.52, FITS reagents are also reactive in the perfluoroalkylation of unactivated alkenes, alkadienes [119], and acetylenes [120] (Scheme 3.56). In

143

144

3 Perfluoroalkylation

RF

I

OCOCF3

OCOCF3 RF I

RF I

80% H2O2, (CF3CO)2O; −15 °C to r.t., 2 d

OCOCF3 toluene, CF3COOH; 0 °C, 3 d

CH3

SF4

NaCl, acetone– H2O; 0 °C

RF IF2

RF +

BF3

I BF4− C6H6

RF

RF

I

Cl

IF+ BF4−

CH3 F2n+1Cn

I

OSO3H

62-91% PhX, H2SO4, CF3COOH,

PhX, CF3SO3H,

0° to r.t. (X = H or F)

CF3COOH o r CFCl2CF2Cl, 0 °C to r.t. (X = H or F)

58-95%

X X = H: FITS-n X = F: FITS(F)-n

F2n+1Cn

I

OTf

X X = H: FIS-n X = F: FIS(F)-n Scheme 3.54

RFCF2

Synthesis of a variety of arylperfluoroalkyliodonium salts [110].

δ− δ+ OTf I

Scheme 3.55 For arylperfluoroalkyliodonium reagents – even for the triflates – the iodine–counterion bond is strongly polarized but not completely ionic [113c].

contrast with olefin perfluoroalkylation by means of perfluoroalkyl bromides or iodides (Section 3.1), this reaction does not follow a free radical mechanism but proceeds via cationic intermediates which can be either trapped by addition of nucleophiles or nucleophilic solvents or quenched by β-deprotonation with a base (Scheme 3.57). A mechanism taking either an ionic or a radical path, depending on the solvent, is assumed for the reaction of perfluoroalkyliodonium reagents with acetylenes

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

C8F17

73% FITS-8, pyridine, CH2Cl2; reflux, 30 min

C5H11

71%

C7F15 + H9C4

H9C4

FITS-7, pyridine, CH2Cl2; reflux, 30 min

CH2=CH2

C7F15

(trans : cis 3:1)

50%

MeOCH2CH2C8F17

FITS-8, MeOH, CH2Cl2, Na2CO3; r.t., 1 h 25%

O

FIS-3, methacrylic acid, CH2Cl2, NaHCO3; r.t., 1 h 81%

+

H

1. FITS-8, DMF; r.t., 1 h 2. aqueous work-up 69%

COOH

FITS-8, pyridine, CH2Cl2; r.t., 1 h

OH

FITS-8, pyridine, CH2Cl2; r.t., 1 h

C8F17

O

C8F17

O

O

C8F17 O

O O

TfO−

N

FITS-8, pyridine, CH2Cl2; r.t., 1 h 92%

C3F7

O

O

O

CH2C8F17 (16%)

+

C8F17

O (47%)

Scheme 3.56 Examples of the electrophilic perfluoroalkylation of olefins with FITS reagents [119].

[120], leading to a variety of addition or substitution products (Table 3.1 and Scheme 3.58). Of special importance for the introduction of perfluoroalkyl groups into pharmaceuticals and for the synthesis of perfluoroalkylated analogs of natural products is the reaction of FITS reagents with silyl enol ethers, leading to αperfluoroalkylcarbonyl compounds [121] (Scheme 3.59). Perfluoroalkyliodonium salts are also available as bivalent perfluoroalkylation reagents allowing the introduction of bridging perfluoroalkylene groups between nucleophilic precursors in one synthetic step [122] (Scheme 3.60). The synthesis of FITS reagents poses two principal difficulties: (i) isolation of the FITS reagent from the reaction mixture often requires repeated yieldreducing recrystallization steps and (ii) recovery of the expensive triflic acid

145

146

3 Perfluoroalkylation

(

)n R n = 0, 1

Ph − δ+ δ OTf

RF I

RF

− PhI

FITS

or FIS

(

+

(

)n R

R1

N

OH (

)n

RF

(

)n

O

H2O

OCOR2 RF

OH O

)n R

R

hydride shift (n = 0, R = CH2OCH2CH2OH)

O

(

(R = CH2OCH2CH2OH)

R2

O

R1

R

O RF

+

RF

RF

ring closure; − H+

amide (R CONMe2)

− H+ (R1 = H)

RF

)n

Nu Nu−

2

+

(

)n R

hydride shift (n=0, R = CHR1OH)

RF

RF

− H+

(

)n

R

+

ring closure; − H+

O

RF O Scheme 3.57 [110].

Ionic mechanism of the reaction of FITS and related reagents with olefins

Reaction of phenylacetylene with the FITS-2 reagent in different solvents with or without addition of pyridine as a base [120].

Table 3.1

Solvent

Additive

A

B

C

CH2 Cl2 CH2 Cl2 DMF MeOH HCOOH

Pyridine — — — —

47 15 45 100 4

36 31 0 0 0

4 51 0 0 86

obtained during the synthesis is difficult. A solution to these problems was found in the immobilization of the reagents [123] by means of a solid analog of triflic acid, Nafion-H resin [124] (Scheme 3.61). Highly effective electrophilic trifluoroethylation and 1H,1H-perfluoroalkylation reagents are available by means of a similar iodonium-based concept, either as the

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

R1

RF

R2

Ph − δ+ δ I OTf

+ − PhI

FITS

R1

147

RF

R2 R1

R2

RF

− H+ (R1 = H) Nu−

Nu

−

− PhI OTf ·+

RF

H RF

R2 R1

RF + H· (solvent)

hydride shift (R2 = CHROH)

· R2

R2 1

R

R1

(R1 = H) +

RF R1

R

OH

O RF

− H+

R

RF R1

O

Scheme 3.58 Proposed mechanism for the reaction of perfluoroalkyliodonium reagents with different acetylene derivatives [120].

OSiMe3

O

88%

C8F17

FITS-8, pyridine (1 equiv.), CH2Cl2; reflux, 30 min

OSiMe3 Ph

O

79% FITS-3i, pyridine (1 equiv.), CH2Cl2; reflux, 30 min

F CF3

Ph

OSiMe3

CF3

O C6F13

71% FITS-6, pyridine (1 equiv.), CH3CN; 45 °C, 30 min

CH3

CH3

85%

OSiMe3 FITS-3, pyridine (1 equiv.), CH2Cl2; reflux, 30 min

O C3F7

Scheme 3.59 Perfluoroalkylation of silyl enol ethers with different FITS reagents [121].

triflates [125] or as the more hydrolytically stable triflimides [126]. Because of its resistance to hydrolysis, triflimide 9 can even be employed in aqueous reaction media, rendering it an interesting tool for biochemical applications [126c] (Scheme 3.62).

R2

R2

148

3 Perfluoroalkylation

I(CF2)nI

(CF3COO)2I(CF2)nI(OCOCF3)2

CF3COOOH

benzene, TfOH, CCl2FCClF2; r.t., 3 d

TfO I

(CF2)n

S

S

n = 3: 75% n = 8: 62%

Scheme 3.60

S pyridine; 60 °C, 2 h

(CF2)n I OTf

D-FITS-3 (n = 3): 49% D-FITS-8 (n = 8): 62%

Synthesis and preparative use of perfluoroalkylene FITS reagents [122].

RF-I(OCOCF3)2

Nafion-H, benzene, CF3COOH, (CF3CO)2O; r.t., 4 d

F F

F F x

F F

F

y

O

F3C F

F F

O

SO3 I

z

RF

F F

F F

Scheme 3.61 A Nafion-based polymeric version of FITS facilitates work-up of the reaction mixtures after electrophilic perfluoroalkylation. The effective concentrations of perfluoroalkyl groups of different chain lengths are ∼0.4 mmol g−1 [123].

F3C

OCOCF3 79% I HN(SO2CF3)2, C6H6, OCOCF3 CFC 113

+

I (CF3SO2)2N− 9

CF3 O Ot Bu NH2

CH2Cl2, H2O, NaHCO3; 22 °C, 45 min

O

HN

O OH CF3

77% 6 N HCl; 22 °C, 3-6 h

Scheme 3.62 Example of the synthesis of an aryl 1H,1H-perfluoroalkyliodonium triflimide (9), which is sufficiently hydrolytically stable to trifluoroethylate amino acids electrophilically in an aqueous medium [126].

HN

Ot Bu CF3

The N-trifluoroethyl substructure element has recently gained importance in medicinal chemistry as a means of blocking the oxidative metabolism of pharmaceuticals via the nitrogen site.

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

A recent addition by Togni and co-workers to the toolbox of iodonium-based electrophilic perfluoroalkylation reagents are the compounds depicted in Scheme 3.63 [127]. In contrast to all other FITS reagents, which are available only as longer perfluoroalkyl homologs, they are able to transfer a trifluoromethyl group to all kinds of nucleophiles.

Cl I O

O

CF3 I O

O I O

quant.

Me3SiCF3,

AgOAc

cat. F−; CH3CN 89% KOAc instead of AgOAc and one-pot procedure

CF3 I O

analogous preparation:

O Scheme 3.63 Togni’s trifluoromethylation reagents and their preparation [127].

In combination with a copper(I) catalyst, Togni’s reagents are also able to trifluoromethylate allylsilanes, opening up a convenient access route to a number of useful intermediates [128] (Scheme 3.64). SiMe3 CF3

70% 1.2 equiv.

CF3 I O

O 20 mol% CuCl, MeOH; 70 °C, 2 h Scheme 3.64 Copper-catalyzed electrophilic trifluoromethylation of allylsilanes [128].

3.3.3 Perfluoroalkyl Sulfonium, Selenonium, Telluronium, and Oxonium Salts

A completely different class of electrophilic perfluorination reagents, the trifluoromethyldiarylsulfonium salts, were introduced by Yagupolskii et al. [129] in 1984 (Scheme 3.65).

149

150

Cl

3 Perfluoroalkylation

O S + − CF3 SF3 SbF6

F F S CF3 SbF5

Cl

F Cl

S

+

CF3 SbF6−

OMe NMe2 nucleophile

+ CF3

+

S

OMe

Cl

NMe2

CF3 SbF6− O2N

F3C

NMe2

SNa

OMe

S

+ O2N

SCF3

Cl Scheme 3.65 Synthesis and preparative use of Yagupolskii’s S(trifluoromethyl)diarylsulfonium salts [129].

The first generation of sulfonium-based trifluoromethylation reagent (Scheme 3.65) was very effective for trifluoromethylation of thiolates (e.g., sodium 4-nitrothiophenolate), but they failed to trifluoromethylate electron-rich aromatic substrates such as N,N-dimethylaniline, even at elevated temperatures. Taking the step from an open diarylsulfonium to a cyclic dibenzothiophenium system, Umemoto and Ishihara, in the 1990s, developed a class of reagent with significantly greater trifluoromethylation power [130]. The concept was subsequently extended to trifluoromethyldibenzoselenophenium, -dibenzotellurophenium, and even -dibenzofuranium systems, furnishing a whole range of power-variable electrophilic trifluoromethylation reagents (Schemes 3.66 and 3.67). In 2010, the general concept was extended by Shibata and co-workers towards benzothiophenium systems, which are generated in situ by acid-induced cyclization [131]. Umemoto’s series of reagents is based on leaving groups with different electronegativities. This variation is caused, on the one hand, by the different chalconium centers and, on the other, by mono- or dinitration. The mildest trifluoroalkylating reagents are the telluronium systems, which are able to trifluoromethylate very ‘‘soft’’ and polarizable nucleophiles. The most reactive species is the dibenzofuranium system 11, which has to be generated in situ from a diazonium salt precursor (Scheme 3.68). This system trifluoromethylates even very ‘‘hard’’ nucleophiles, for example, aliphatic alcohols or p-toluenesulfonic acid.

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

MCPBA, CH2Cl2; 0 °C

X CF3

X CF3 O

1. 10% F2–N2, CFCl3;

+

Tf2O, CCl2FCClF2;

−78 °C 2. TfOH; −78 °C to r.t.

X CF3 F

+

X CF3 TfO

r.t., 2 d

10 (X = S) + X CF3SO3− CF3

94% HNO3, X=S

151

Tf2O (1.6 equiv.),

X = S, Se

94% HNO3, Tf2O (3 equiv.); r.t., 2 d

CH3NO2; r.t., 18 h

NO2 + S CF3SO3− CF3

O2N

Scheme 3.66 Synthesis of trifluoromethyldibenzothiophenium and -selenophenium triflates (X = S, Se) and their subsequent nitration [130b]. On the extreme left and the

NO2 + X CF3SO3− CF3

extreme right, the reactive sulfonium intermediates for both synthesis routes are depicted undergoing ring closure by intramolecular electrophilic substitution.

84% +

Te CF3

OTf +

H3C

S

TfO−

Te CF3 H3C S TfO− TfO CH3

+

Te TfO− CF3

− DMSO, − TfOH 76%

CH3

94% HNO3, Tf2O (3 equiv.); r.t., 1 h

Tf2O

O2N

O H3C

S

CH3

+

Te TfO− CF3

Scheme 3.67 Synthesis of trifluoromethyldibenzotellurophenonium-based reagents. Here, the cyclization reaction is initiated by the electrophilic attack of pregenerated sulfonium species on the trifluoromethyltelluride moiety [130b].

Within the different classes of onium reagents, their trifluoromethylating power can be increased stepwise by mono- or dinitration. In the same way as for the FITS reagents, the basic concept for the dibenzothiophenium reagents has been successfully extended to the electrophilic transfer of longer perfluoroalkyl chains [132].

NO2

152

3 Perfluoroalkylation

F3CO

F3CO 70%

NH2

NO+SbF6−, Et2O; −78 °C to 0 °C

+

O SbF6− CF3 11

Δ or hn

N2+ SbF6−

stable at −70 °C

Scheme 3.68 Synthesis of Umemoto’s most reactive trifluoromethylating reagent, the dibenzofuranium system 11, which is generated in situ from the more stable diazonium salt precursor [110, 132].

Umemoto’s reagents are soluble and stable in a variety of polar solvents, for example, DMSO, DMF, acetonitrile, THF, and CH2 Cl2 . A side product of the trifluoromethylation of any nucleophile is the formation of 1 equiv. of dibenzofuran, which is sometimes difficult to separate from the desired reaction product. To facilitate the work-up, zwitterionic dibenzothiopheniumsulfonates were designed. Here, the side product is dibenzothiophenesulfonic acid, which can be conveniently removed from the reaction mixture by extraction with aqueous base [133] (Scheme 3.69).

+

S CF3SO−3 10 CF3 73%

60% SO3-H2SO4; 0 °C to 40 °C, 4 h

+ S CF3

SO−3

Nu−

SO−3

Nu-CF3 + S water soluble

Scheme 3.69 Trifluoromethylation with sulfonated Umemoto’s reagents facilitates work-up of the reaction mixtures [133].

Although most nucleophiles, ranging from very ‘‘soft’’ (e.g., thiolates) to fairly ‘‘hard’’ (e.g., aliphatic alcohols) can be trifluoromethylated by one of Umemoto’s onium reagents with matching reactivity, most early attempts at the synthetically important α-trifluoromethylation of carbonyl compounds via their alkali metal enolates failed (see also Scheme 3.70). These problems arose, presumably, because the reactivity of the enolates was too high, because of the delocalization of the negative charge. It was found that the excess reactivity could be moderated by addition of the enolate to a variety of benzeneboronic esters and other organoboron compounds [134] (Scheme 3.71).

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

CH3

O

O F3C

F3C +

CF3 (26%)

(49%) B

O

−

NH2

(69%)

N

NH2 CF3 +

CF3 CH3

(26%) CF3

(57%)

N H

O K+

O

CF3

N H

O

O

O

153

Me3SiO

NH2

CF3 OH

CF3 (92%) CH3 O

−

O Na

10

H3C CF3 O

CF3 +

+

S

+

CF3

CF3SO3−

NO2

+

O

S CF SO − CF3 3 3

/DMAP

(6%)

(84%) Li

+

11

− O K+

H25C12SNa

Cl

O SbF6− CF3 N

H25C12SCF3 (87%)

TsOH, pyridine

Scheme 3.70

H3C

O S OCF3 O (79%)

Examples of applications of different types of Umemoto’s reagent [132].

Cl

PhCH2CH2OH, 2-chloropyridine

O CF3

Ph3PCF3+CF3SO3− (78%)

Ph3P

+

Se CF3SO3− CF3

CF3 (89%)

OH

OH O2N

(52%)

OCF3 (36%)

+

N SbF − 6 CF3 (53%)

154

3 Perfluoroalkylation

R

−

O M+

R +

too reactive enolate

B R

R

Lewis acid

−

O B R + R M moderately reactive boronate complex

O B

B

13

12 OK

O

O

O 1. boron compound, THF; −78 °C, 1 h 2. 10; −78 °C to 0 °C, 1-2.5 h

OK

CF3 CF3

CF3 + boron compound: none: 0.8% 12: 47% 13: 85%

8% 10% 0%

O 86%

CF3

1. 12, THF; −78 °C, 1 h 2. 10; −78 °C to 0 °C, 2.5 h

Scheme 3.71 α-Trifluoromethylation of carbonyl compounds via boronate complexes of the enolates [134].

Sterically demanding boronic esters can be used to achieve diastereoselective trifluoromethylation of steroid substructures (Scheme 3.72). Chiral boronates act as effective auxiliaries for the enantioselective trifluoromethylation. The mechanism of electrophilic trifluoromethylation with Umemoto’s reagents is considered to proceed via a charge-transfer complex between the onium salt and the nucleophilic substrate. The geometry of this charge-transfer complex finally governs the selectivity of the reaction, for example, the preference for ortho or para trifluoromethylation of aniline. The exact mechanism of the transfer of the trifluoromethyl group from the onium system to the nucleophile remains to be elucidated in detail. Nevertheless, a nucleophilic SN 2 substitution at the CF3 carbon can be ruled out for steric reasons [110], leaving mechanistic alternatives similar to those discussed for electrophilic fluorination or for the reactivity of FITS reagents. In combination with chiral copper complexes, Umemoto’s S-trifluoromethyl dibenzothiophenium reagent has also been used to achieve enantioselective trifluoromethylation of β-dicarbonyl compounds (Scheme 3.73) [135].

3.3 ‘‘Electrophilic’’ Perfluoroalkylation

CH3

B

B

B O CH3

O

O

O H3C

O

O

14 15

16

CH3

CH3

CH3 +

1. boron compound, THF; −78 °C 2. 10; −78 °C to 0 °C or −20 °C to r.t.

KO

CH3 K+ O −B O O

O

O

α CF 3

β

CF3

boron compound: 12: 80% (1:2.5) 14: 51% (1:4)

"CF3+"

steric shielding of the α face

OK

O * 1. optically active boron compound, THF; −78 °C to 0 °C, 1.5 h 2. 10; −78 °C to 0 °C, 3 h

CF3 boron compound: 15: 31% (12% ee) 16: 41% (36% ee)

Scheme 3.72 Stereo- and enantioselective trifluoromethylations using bulky or chiral organoboron auxiliaries [134].

O

O COOtBu

90% (95% ee)

CF3 COOt Bu

10 mol% Cu(OTf)2, 12 mol% ligand*, 1.2 equiv. "CF+3", 4 A molecular sieves, 1.2 equiv. i Pr2NEt; 0 °C

O N NH

+

"CF +3"

S − CF3 BF 4

Ph

ligand*

N

Ph

O

Scheme 3.73 Enantioselective electrophilic trifluoromethylation of β-dicarbonyl compounds using Umemoto’s reagent together with a chiral copper complex [135].

155

156

3 Perfluoroalkylation

3.3.4 Fluorinated Johnson Reagents

Inspired by Johnson’s methylation reagent [136], in 2008 Shibata and co-workers presented a new type of S-CF3 electrophilic trifluoromethylation reagent, which is shelf-stable and easy to handle [137]. Using this reagent, the first example of a vinylogous trifluoromethylation of dicyanoalkylidenes was realized (Scheme 3.74).

O S

O NH S CF3

81%

CF3

NaN3, 25% fuming H2SO4; 70 °C, 3 h

93%

CH3 + O N CH3 S CF3 BF4− Shibata-Johnson reagent

(a)

N

N

N

N 92%

(b)

97% CH3I, K2CO3, THF; reflux, 7 h

CH3 + O N 92% CH3 S CF3 sat. aq. NaBF4, CF3SO3 − MeOH; r.t., 13 h

CF3SO3CH3, neat; r.t., 6 h

O N CH3 S CF3

2.2 equiv. Shibata-Johnson reagent, 2 equiv. P1, CH2Cl2; r.t.

CF3

Scheme 3.74 (a) Synthesis of Shibata’s fluoro-analogous Johnson reagent and (b) its application to the vinylogous trifluoromethylation of dicyanoalkylidenes [136] (P1 = phosphazene base P1 -tBu).

3.4 Difluorocarbene and Fluorinated Cyclopropanes

The reactive species of choice for the synthesis of fluorinated cyclopropane derivatives are fluorinated carbenes [138] (Scheme 3.75). That most extensively used preparatively is difluorocarbene. Despite the negative inductive effect of fluorine, because of its electronegativity, α-fluorinated carbenes are stabilized in their singlet state by π-donation from the fluorine to the carbon. This combination of destabilizing and stabilizing effects renders difluorocarbene a moderately electrophilic species [139].

3.4 Difluorocarbene and Fluorinated Cyclopropanes

F C

F

−

F

F

F

+

F

F

F

:CF2 Scheme 3.75 Despite the resonance stabilization of singlet difluorocarbene by pdonation (+R) (box) from the α-fluorine atom, the carbon atom still has a fairly large positive natural charge qC of +0.84 e (qF = −0.42 e), rendering the species moderately electrophilic (geometry optimization

at the MP2/6–311+G* level of theory, electrostatic potential mapped on electron isodensity surface; blue and red denote positive and negative partial charges, respectively) [3, 4]. Difluorocarbene reacts readily with electron-rich olefins to yield gemdifluorocyclopropanes.

Several strategies are used for the generation of difluorocarbene in situ for synthetic purposes. (i) The fragmentation of tin [140], mercury [141], cadmium or zinc trifluoromethyl [142] compounds works very reliably, but with the need to handle highly toxic (with the exception of zinc) heavy metal derivatives. (ii) A very convenient method is the thermal fragmentation of alkali metal salts of halodifluoroacetic acids [143]. This method has the disadvantage of requiring relatively high reaction temperatures, which might not be compatible with a sensitive substrate for difluorocyclopropanation. A related, milder, variant of this type of reaction is the base- or fluoride-induced fragmentation of derivatives of fluorosulfonyldifluoroacetic acid (e.g., the FSO2 CF2 COOSiMe3 –NaF system) [144], an intermediate from the technical production of Nafion resin. Another, widely used and related fragmentation method is based on the thermolysis of halodifluoromethylphosphonium salts [145]. (iii) The third general method for the generation of difluorocarbene is the reduction of dihalodifluoromethanes by a variety of reducing agents [146]. In addition, difluorocarbene can be generated by thermolysis of a variety of perfluorocarbons [e.g., PTFE (polytetrafluoroethylene ) (Teflon), tetrafluoroethylene, or perfluorocyclopropane] and HCFC (tetrafluoroethylene is technically produced by thermal elimination of hydrochloric acid from CHClF2 via difluorocarbene as an intermediate) [138a] (Scheme 3.76). Difluorocarbene reacts readily with electron-rich olefins, giving the corresponding gem-difluorocyclopropanes, whereas its reactivity towards electron-deficient olefins is much lower [148] (Scheme 3.77). Using the difluorocarbene precursor FSO2 CF2 COOSiMe3 [151], it was possible to difluorocyclopropanate even the relatively electron-deficient n-butyl acrylate in 73%

157

158

3 Perfluoroalkylation

Me3SiCF3/Bu4N+Ph3SiF2+ Me3SiCF3/NaI CF2Br2/Zn/cat. I2 CF2Br2/TiCl4/LiAlH4 CF2Br2/CHBr3/KOH/Bu4N+HSO4−

Me3SnCF3 PhHgCF3 BrCdCF3 BrZnCF3 Δ or I− Δ ClF2CCOONa ClF2COOMe/LiCl/HMPA

F

F

F

F

F

F

F

F F

F

PTFE

FSO2CF2COOSiMe3/NaF [Ph3PCF2Br]+Br−/KF [(Me2N)3PCF2Br]+Br−/KF

Scheme 3.76 Methods commonly used for the in situ generation of singlet difluorocarbene for preparative purposes [138a, 24, 147, 149, 150]. F

H3C

F

91%

CH3 Me3SnCF3;

150 °C, 24 h

H3C

CH3 F F

83% PhHgCF3, NaI, benzene; 80 °C

H3C

OC4H9

H3C

OC4H9

42% ClF2CCOONa;

F

165 °C

F F

H3C H3C

90%

O

CF2Br2, PPh3, KF, glyme,

H3C H3C

F

O

cat. 18-crown-6; r.t.

O

O O OMe F F 92% CF2Br2, PPh3, KF, diglyme, cat. 18-crown-6; r.t.

O OMe

Scheme 3.77 Examples of the difluorocyclopropanation of olefins and acetylenes [141, 143a, 145c,d, 149, 150].

3.4 Difluorocarbene and Fluorinated Cyclopropanes

yield. Unfortunately, this reaction works with only a limited number of electronpoor substrates. Electron-withdrawing carbonyl groups must, therefore, usually be protected as less electronegative ketals during the difluorocyclopropanation step [152] (Scheme 3.78). H3C

H3C O

FSO2CF2COOSiMe3,

O

O

O

65%

17

NaF (0.1 equiv.), diglyme; 122 °C, 1.5 h

F F (COOH)2, dioxane; 110 °C, 6 h

H3C

H3C

O

O

+ (36%) F F 18

F

(15%) 19

H3C 17

path A

+

O H Ph

O

H+

H3C

X

F F +

H3C 17

O OH

path B

+

H+

F

Ph

F F

Ph

F path A: X = CH2CH2OH

− X+

path B: X = H

H3C

O

Ph

F F − HF

19 Scheme 3.78 Difluorocyclopropanation of ketal-protected carbonyl compounds and subsequent deprotection can overcome the low reactivity of electron-deficient olefins towards difluorocarbene. The creation of

carbocationic centers adjacent to the difluorocyclopropane ring during acidic hydrolysis often leads to ring-opening and rearrangement products (19) [152].

Probably the mildest and most convenient access to difluorocarbene is via the fluoride- or iodide-induced fragmentation of the Ruppert–Prakash reagent Me3 SiCF3 [147]. It allows the difluorocyclopropanation of olefins between room temperature and 65 ◦ C, and of acetylenes at temperatures around 110 ◦ C.

159

160

3 Perfluoroalkylation

In an elegant reaction sequence, difluorocyclopropanation has been used as the initial step for subsequent [3,3]-sigmatropic rearrangement, leading finally to difluoroheptatrienes [148], which are not readily accessible by other means (Scheme 3.79). F

F

F F F F

.

.

C4H9 t1/2 = 25.6 h at 298 K Scheme 3.79 Synthesis of a fluorinated natural product analog via sigmatropic rearrangement of a divinyl gem-difluorocyclopropane [148].

A mechanistically completely different method for obtaining difluorocyclopropenes (Scheme 3.80) does not depend on addition of difluoromethylene [153]. The reaction is initiated by addition of the sterically demanding tert-butyl group to the acetylene carbon adjacent to the trifluoromethyl group. The resulting vinyllithium species has very close contact between lithium and one fluorine atom of the trifluoromethyl group, facilitating extrusion of lithium fluoride. As for many other examples, here also the driving force of the reaction is the formation of lithium fluoride with its high lattice energy. H Ph3Si

CMe3 +

H Ph3Si

CF3

CF3 F

CF3 Li

t BuLi, Et2O;

Ph3Si

r.t., 20 h

+ CMe3 F F

Ph3Si

F F CMe3

Ph3Si CMe3 (80% of product mixture) Scheme 3.80 Addition of sterically demanding tert-butyllithium to trifluoromethylacetylene derivatives leads to difluorocyclopropenes [153]. The driving force of the cyclization reaction is energetically favorable extrusion of lithium fluoride from the vinyllithium intermediate.

References 1. Howell, J.L., Muzzi, B.J., Rider, N.L.,

Aly, E.M., and Abuelmagd, M.K. (1995) J. Fluorine Chem., 72, 61. 2. (a) Banus, J., Emeleus, H.J., and Haszeldine, R.N. (1951) J. Chem. Soc.,

60; (b) Miller, W.T., Jr., Bergman, E., and Fainberg, A. (1957) J. Am. Chem. Soc., 79, 4159; (c) Ruppert, I., Schlich, K., and Volbach, W. (1984) Tetrahedron Lett., 25, 2159; (d) Benefice, S.,

References

3.

4.

5. 6. 7.

8. 9.

Blancou, H., and Commeyras, A. (1984) Tetrahedron, 40, 1541; (e) Blancou, H. and Commeyras, A. (1982) J. Fluorine Chem., 20, 255; (f) Chen, Q.Y. and Yang, Z.Y. (1985) J. Fluorine Chem., 28, 399; (g) Huang, W. and Zhang, H. (1990) J. Fluorine Chem., 50, 133; (h) Meinert, H., Knoblich, A., Mader, J., and Brune, H. (1992) J. Fluorine Chem., 59, 379. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A., Jr., Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., and Pople, J.A. (1998) Gaussian 98, Revision A.6, Gaussian, Inc., Pittsburgh, PA. Fl¨ukinger, P., L¨uthi, H.P., Portmann, S., and Weber, J. (2002) MOLEKEL 4.2, Swiss Center for Scientific Computing, Manno. Feiring, A.E. (1984) J. Fluorine Chem., 24, 191–203. Feiring, A.E. (1983) J. Org. Chem., 48, 347–354. Scherer, K.V., Ono, T., Jr., Yamanouchi, K., Fernandez, R., and Henderson, P. (1985) J. Am. Chem. Soc., 107, 718–719. Fessenden, R.W. and Schuler, R.H. (1965) J. Chem. Phys., 43, 2704–2718. Bernardi, F., Cherry, W., Shaik, S., and Epiotis, N.D. (1978) J. Am. Chem. Soc., 100, 1352–1356.

10. For a review on the structure of vari-

11.

12. 13.

14. 15. 16. 17. 18.

19.

20.

21.

22.

23.

24.

ous kinds of fluorinated radicals, see: Dolbier, W.R. Jr. (1996) Chem. Rev., 96, 1557–1584. (a) Pearson, R.G. (1989) J. Org. Chem., 54, 1423–1430; (b) Pearson, R.G. (1988) J. Am. Chem. Soc., 110, 7684–7690. Brace, N.O. (1999) J. Fluorine Chem., 93, 1–25. (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., 25, 245–263. Huang, W.-Y. (1992) J. Fluorine Chem., 58, 1–8. Barton, D.H.R., Lacher, B., and Zard, S.Z. (1986) Tetrahedron, 42, 2325–2328. Emeleus, H.J. and Haszeldine, R.N. (1949) J. Chem. Soc., 2948–2952. Haszeldine, R.N. (1949) J. Chem. Soc., 2856–2861. (a) Sosnovsky, G. (1964) Free Radical Reactions in Preparative Organic Chemistry, Macmillan, New York; (b) Jeanneaux, F., Le Blanc, M., Vambon, A., and Guion, J. (1974) J. Fluorine Chem., 4, 261–270; (c) Haszeldine, R.N., J. Chem. Soc. 1953, 3761–3768; (d) Qiu, Z.-M. and Burton, D.J. (1995) J. Org. Chem., 60, 3465–3472. (a) Tiers, G.V.D. (1960) J. Am. Chem. Soc., 82, 5513; (b) Cowell, A.B. and Tamborski, C. (1981) J. Fluorine Chem., 17, 345–356. (a) Kharash, M.S., Jensen, E.V., and Urry, W.H. (1947) J. Am. Chem. Soc., 69, 1100–1105; (b) Kharash, M.S., Reinmuth, O., and Urry, W.H. (1947) J. Am. Chem. Soc., 69, 1105–1110. (a) Tarrant, P. and Lovelace, A.M. (1954) J. Am. Chem. Soc., 76, 3466–3468; (b) Tarrant, P. and Lovelace, A.M. (1955) J. Am. Chem. Soc., 77, 2783–2787. Huang, X.-T., Long, Z.-Y., and Chen, Q.-Y. (2001) J. Fluorine Chem, 111, 107–113. (a) Hu, C.-M. and Qiu, Y.-L. (1991) Tetrahedron Lett., 32, 4001–4002; (b) Hu, C.-M. and Qiu, Y.-L. (1992) J. Org. Chem., 57, 3339–3342. Huang, W.-Y. and Xie, Y. (1991) Chin. J. Chem., 9, 351–359.

161

162

3 Perfluoroalkylation 25. (a) Tanabe, Y., Matsuo, N., and Ohno,

26. 27.

28.

29.

30.

31. 32.

33.

34. 35. 36.

N. (1988) J. Org. Chem., 53, 4582–4585; (b) Huang, W.-Y., Liu, J.-T., and Li, J. (1995) J. Fluorine Chem., 71, 51–54. Huang, B.-N. and Liu, J.-T. (1993) J. Fluorine Chem., 64, 37–46. (a) Zhao, C.-X., El-Taliawi, G.M., and Walling, C. (1983) J. Org. Chem., 48, 4908–4910; (b) Sawada, H., Yoshida, M., Hauii, H., Aoshima, K., and Kobayashi, M. (1986) Bull. Chem. Soc. Jpn., 59, 215–219. Cantacuzene, D., Wakselman, C., and Dorme, R. (1977) J. Chem. Soc., Perkin Trans. 1, 1365–1371. (a) Iseki, K., Nagai, T., and Kobayashi, Y. (1993) Tetrahedron Lett., 34, 2169; (b) Iseki, K., Nagai, T., and Kobayashi, Y. (1994) Tetrahedron: Asymmetry, 5, 974; (c) Takeyama, Y., Ichinose, Y., Oshima, K., and Utimoto, K. (1989) Tetrahedron Lett., 30, 3159; (d) Miura, K., Takeyama, Y., Oshima, K., and Utimoto, K. (1991) Bull. Chem. Soc. Jpn., 64, 1542. Evans, D.A., Ennis, M.D., and Mathre, D.J. (1982) J. Am. Chem. Soc., 104, 1737. Nagib, D.A. and MacMillan, D.W.C. (2011) Nature, 480, 224–228. Ji, Y., Brueckl, T., Baxter, R.D., Fujiwara, Y., Seiple, I.B., Su, S., Blackmond, D.G., and Baran, P.S. (2011) Proc. Natl. Acad. Sci. U. S. A., 108, 14411–14415. (a) Chambers, R.D., Fuss, R.W., Spink, R.C.H., Greenhall, M.P., Kenwright, A.M., Batsanov, A.S., and Howard, J.A.K. (2000) J. Chem. Soc., Perkin Trans. 1, 1623–1638; (b) Chambers, R.D., Diter, P., Dunn, S.N., Farren, C., Sandford, G., Batsanov, A.S., and Howard, J.A.K. (2000) J. Chem. Soc., Perkin Trans. 1, 1639–1649. Review: Farnham, W.B. (1996) Chem. Rev., 96, 1633–1640. Schlosser, M. (1998) Angew. Chem. Int. Ed., 37, 1496–1513. (a) Roberts, J.D., Hammond, G.S., and Cram, D.J. (1957) Annu. Rev. Phys. Chem., 8, 299–330; (b) Holtz, D. (1971) Prog. Phys. Org. Chem., 8, 1.

37. Farnham, W.B., Dixon, D.A., and

38.

39. 40. 41.

42.

43.

44.

45.

46.

47.

48. 49.

50.

Calabrese, J.C. (1988) J. Am. Chem. Soc., 110, 2607. (a) Dixon, D.A. (1986) J. Phys. Chem., 90, 2038; (b) Dixon, D.A., Fukunaga, T., and Smart, B.E. (1986) J. Am. Chem. Soc., 108, 1585; (c) Dixon, D.A., Smart, B.E., and Fukunaga, T. (1986) Chem. Phys. Lett., 125, 447; (d) Dixon, D.A., Fukunaga, T., and Smart, B.E. (1986) J. Am. Chem. Soc., 108, 4027. Graham, D.P. (1966) J. Org. Chem., 31, 955. Langanis, E.D. and Lemal, D.M. (1980) J. Am. Chem. Soc., 102, 6633. Chambers, R.D., Mullins, S.J., Roche, A.J., and Vaughan, J.F.S. (1995) J. Chem. Soc., Chem. Commun., 841. Chambers, R.D., Gray, W.K., Vaughan, J.F.S., Korn, S.R., Medebielle, M., Batsanov, A.S., Lehmann, C.W., and Howard, J.A.K. (1997) J. Chem. Soc., Perkin Trans. 1, 135–145. Chambers, R.D., Magron, C., and Sandford, G. (1999) J. Chem. Soc., Perkin Trans. 1, 283–290. Chambers, R.D., Gray, W.K., and Korn, S.R. (1995) Tetrahedron, 51, 13167–13176. Makarov, K.N., Gervits, L.L., and Knunyants, I.L. (1977) J. Fluorine Chem., 10, 157–158. (a) Gassmann, P.G. and O’Reilly, N.J. (1985) Tetrahedron Lett., 26, 5243; (b) Solladie-Cavallo, A. and Suffert, J. (1985) Synthesis, 659; (c) Suzuki, H., Shiraishi, Y., Shimokawa, K., and Uno, H. (1988) Chem. Lett., 127; (d) Uno, H., Shiraisi, Y., and Suzuki, H. (1989) Bull. Chem. Soc. Jpn., 62, 2636; (e) Rong, G. and Keese, R. (1990) Tetrahedron Lett., 31, 5617. Uno, H., Shiraishi, Y., Shimokawa, K., and Suzuki, H. (1987) Chem. Lett., 1153. Solladie-Cavallo, A. and Suffert, J. (1897) Tetrahedron Lett., 1984, 25. Review: Tomashenko, O.A. and Grushin, V.V. (2011) Chem. Rev., 111, 4475–4521. Naumann, D., Tyrra, W., Kock, B., Rudolph, W., and Wilkes, B. (1994) J. Fluorine Chem., 67, 91–93.

References 51. (a) Kitazume, T. and Ishikawa, N.

52. 53. 54. 55.

56.

57.

58. 59.

60.

61. 62.

63. 64.

(1985) J. Am. Chem. Soc., 109, 5186; (b) Kitazume, T. and Ishikawa, N. (1981) Chem. Lett., 1679. Kitazume, T. and Ishikawa, N. (1982) Chem. Lett., 137. Kitazume, T. and Ishikawa, N. (1982) Chem. Lett, 1453. Wiemers, D.M. and Burton, D.J. (1986) J. Am. Chem. Soc., 108, 832–834. (a) Urata, H. and Fuchikami, T. (1991) Tetrahedron Lett., 32, 91–94; (b) Cottet, F. and Schlosser, M. (2002) Eur. J. Chem., 327–330. Bubinina, G.G., Furutachi, H., and Vicic, D.A. (2008) J. Am. Chem. Soc., 130, 8600–8601. (a) Burton, D.J. (1992) in Organometallics in Synthetic Organofluorine Chemistry in Synthetic Fluorine Chemistry (G.A. Olah, R.D. Chambers, and G.K.S. Prakash, eds.), John Wiley & Sons, Inc., New York, pp. 205–226; (b) Schneider, S. and Bannwarth, W. (2000) Angew. Chem. Int. Ed., 39, 4142–4145; (c) Tian, Y. and Shan, K.S. (2000) Tetrahedron Lett., 41, 8813–8816. Oishi, M., Kondo, H., and Amii, H. (2009) Chem. Commun., 1909–1911. (a) Monnier, F. and Taillefer, M. (2009) Angew. Chem. Int. Ed., 48, 6954–6971; (b) Altman, R.A., Hyde, A.M., Huang, X., and Buchwald, S.L. (2008) J. Am. Chem. Soc., 130, 9613–9620; (c) Tye, J.W., Weng, Z., Johns, A.M., Incarvito, C.D., and Hartwig, J.F. (2008) J. Am. Chem. Soc., 130, 9971–9983; (d) Huffman, L.M. and Stahl, S.S. (2008) J. Am. Chem. Soc., 130, 9196–9197. (a) Bacon, R.G.R. and Hill, H.A.O. (1965) Q. Rev. Chem. Soc., 19, 95; (b) Stephens, R.D. and Castro, C.E. (1963) J. Org. Chem., 28, 3313. McLoughlin, V.C.R. and Trower, J. (1969) Tetrahedron, 25, 5921–5940. Sebecal, T.D., Parsons, A.T., and Buchwald, S.L. (2011) J. Org. Chem., 76, 1174–1176. Qi, Q., Shen, Q., and Lu, L. (2012) J. Am. Chem. Soc., 134, 6548–6551. Cho, E.J., Senecal, T.D., Kinzel, T., Zhang, Y., Watson, D.A., and Buchwald, S.L. (2010) Science, 328, 1679–1681.

65. Fors, B.P., Davis, N.R., and Buchwald,

66. 67. 68. 69.

70.

71.

72.

73.

74.

75.

76. 77.

78.

S.L. (2009) J. Am. Chem. Soc., 131, 5766–5768. Pawelke, G. (1989) J. Fluorine Chem., 42, 429. Petrov, V.A. (2001) Tetrahedron Lett., 42, 3267–3269. Langlois, B.R. and Billard, T. (2003) Synthesis, 185–194. Shono, T., Ishifune, M., Okada, T., and Kashimura, S. (1991) J. Org. Chem., 56, 2. (a) Barhdadi, R., Troupel, M., and P´erichon, J. (1998) J. Chem. Soc., Chem. Commun., 1251; (b) Foll´eas, B., Marek, I., Normant, J.F., and Saint-Jalmes, L. (1998) Tetrahedron Lett., 39, 2973; (c) Foll´eas, B., Marek, I., Normant, J.F., and Saint-Jalmes, L. (2000) Tetrahedron, 56, 275; (d) Russell, J. and Roques, N. (1998) Tetrahedron, 54, 13771. (a) Large, S., Roques, N., and Langlois, B.R. (2000) J. Org. Chem., 65, 8848; (b) Roques, N., Russell, J., Langlois, B., Saint-Jalmes, L., and Large, S. (1998) WO Patent 98/22435; Chem. Abstr., 129, (1998) 40975. (a) Billard, T., Bruns, S., and Langlois, B.R. (2000) Org. Lett., 2, 2101; (b) Billard, T., Langlois, B.R., and Blond, G. (2000) Tetrahedron Lett., 41, 8777; (c) Blond, G., Billard, T., and Langlois, B.R. (2001) Tetrahedron Lett., 42, 2473. Reviews: (a) Lamberth, C. (1996) J. Prakt. Chem., 338, 586–587; (b) Prakash, G.K.S. and Yudin, A.K. (1997) Chem. Rev., 97, 757–786; (c) Singh, R.P. and Shreeve, J.M. (2000) Tetrahedron, 56, 7613; (d) Prakash, G.K.S. and Mandal, M. (2001) J. Fluorine Chem., 112, 123–131. Prakash, G.K.S., Krishnamurti, R., and Olah, G.A. (1989) J. Am. Chem. Soc., 111, 393–395. Ramaiah, P., Krishnamurti, R., and Prakash, G.K.S. (1995) Org. Synth., 72, 232. Grobe, J. and Hegge, J. (1995) Synlett, 641. Prakash, G.K.S., Deffieux, D., Yudin, A.K., and Olah, G.A. (1994) Synlett, 1057. (a) Prakash, G.K.S., Hu, J., and Olah, G.A. (2003) J. Org. Chem., 68,

163

164

3 Perfluoroalkylation

79.

80.

81.

82.

83. 84.

85.

4457–4463; (b) Prakash, G.K.S., Hu, J., and Olah, G.A. (2003) Org. Lett., 5, 3253–3256; (c) Prakash, G.K.S., Hu, J., Mathew, T., and Olah, G.A. (2003) Angew. Chem. Int. Ed., 42, 5216–5219. Fuchikami, T. and Hagiwara, T. (1995) JP Patent 07-118188; Chem. Abstr., 1995, 123, 198413. Corriu, R.J. and Colin, Y.J. (1989) in Chemistry of Organosilicon Compounds, Vol. 2 (eds S. Patai and Z. Rappoport), John Wiley & Sons, Ltd., Chichester, p. 1241. Kolomeitsev, A.A., Medebielle, M., Kirsch, P., Lork, E., and R¨oschenthaler, G.-V. (2000) J. Chem. Soc., Perkin Trans. 1, 2183–2185. (a) Krishnamurti, R., Bellew, D.R., and Prakash, G.K.S. (1991) J. Org. Chem., 56, 984; (b) Skiles, J.W., Fuchs, V., Miao, C., Sorcek, R., Grozinger, K.G., Mauldin, S.C., Vitous, J., Mui, P.W., Jacober, S., Chow, G., Matteo, M., Skoog, M., Weldon, S.M., Possanza, G., Keirns, J., Letts, G., and Rosenthal, A.S. (1992) J. Med. Chem., 35, 641; (c) Quast, H., Becker, C., Witzel, M., Peters, E.-M., Peters, K., and von Schnering, H.G. (1996) Liebigs Ann., 985; (d) Broicher, V. and Geffken, D. (1990) Z. Naturforsch., 45b, 401; (e) Broicher, V. and Geffken, D. (1989) Tetrahedron Lett., 30, 5243; (f) Sevenard, D.V.., Sosnovskikh, V.Y.., Kolomeitsev, A.A., K¨onigsmann, M.H., and R¨oschenthaler, G.-V. (2003) Tetrahedron Lett., 44, 7623–7627. Plantier-Royon, R. and Portella, C. (2000) Carbohydr. Res., 327, 119–146. (a) Munier, P., Picq, D., and Anker, D. (1993) Tetrahedron Lett., 34, 8241–8244; (b) Munier, P., Giudicelli, M.-B., Picq, D., and Anker, D. (1996) J. Carbohydr. Chem., 15, 739–762; (c) Johnson, C.R., Bhumralkar, D.R., and De Clercq, E. (1995) Nucleosides Nucleotides, 14, 185–194; (d) Kozikowski, A.P., Ognyanov, V.I., Fauq, A.H., Wilcox, R.A., and Nahorski, S.R. (1994) J. Chem. Soc., Chem. Commun., 599–600; (e) Wang, Z. and Ruan, B. (1994) J. Fluorine Chem., 69, 1. Grellepois, F., Chorki, F., Crousse, B., Our´evitch, M., Bonnet-Delpon, D., and

86. 87.

88.

89. 90. 91.

92. 93.

94. 95.

96.

97.

98. 99.

B´egu´e, J.-P. (2002) J. Org. Chem., 67, 1253–1260. Review: Ooi, T. and Maruoka, K. (2004) Acc. Chem. Res., 37, 526–533. (a) Iseki, K., Nagai, T., and Kobayashi, Y. (1994) Tetrahedron Lett., 35, 3137; (b) Iseki, K. and Kobayashi, Y. (1995) Rev. Heteroat. Chem., 12, 211; (c) Kuroki, Y. and Iseki, K. (1999) Tetrahedron Lett., 40, 8231–8234. Wiedemann, J., Heiner, T., Mloston, G., Prakash, G.K.S., and Olah, G.A. (1998) Angew. Chem. Int. Ed., 37, 820–821. McClinton, M.A. and McClinton, D.A. (1992) Tetrahedron, 48, 6555–6666. F´elix, C.P., Khatimi, N., and Laurent, A. (1994) Tetrahedron Lett., 35, 3303. (a) Nelson, D.W., Easley, R.A., and Pintea, B.N.V. (1999) Tetrahedron Lett., 40, 25; (b) Nelson, D.W., Owens, J., and Hiraldo, D. (2001) J. Org. Chem., 66, 2572. Petrov, V.A. (2000) Tetrahedron Lett., 41, 6959. Blazejewski, J.-C., Anselmi, E., and Wilmshurst, M. (1999) Tetrahedron Lett., 40, 5475–5478. Prakash, G.K.S., Mandal, M., and Olah, G.A. (2001) Synlett, 77–78. (a) Prakash, G.K.S., Mandal, M., and Olah, G.A. (2001) Angew. Chem., 113, 609–610; (b) Prakash, G.K.S., Mandal, M., and Olah, G.A. (2001) Org. Lett., 3, 2847–2850; (c) Prakash, G.K.S. and Mandal, M. (2002) J. Am. Chem. Soc., 124, 6538–6539. Bernardi, L., Indrigo, E., Pollicino, S., and Ricci, A. (2012) Chem. Commun., 48, 1428–1430. (a) Kolomeitsev, A.A., Movchun, V.N., Kondratenko, N.V., and Yagupolskii, Y.L. (1990) Synthesis, 1151; (b) Movchun, V.N., Kolomeitsev, A.A., and Yagupolskii, Y.L. (1995) J. Fluorine Chem., 70, 255; (c) Garlyauskajte, R.Y., Sereda, S.V., and Yagupolskii, L.M. (1994) Tetrahedron Lett., 50, 6891. Billard, T. and Langlois, B.R. (1996) Tetrahedron Lett., 37, 6865–6868. Patel, N.R. and Kirchmeier, R.L. (1992) Inorg. Chem., 31, 2537.

References 100. Sevenard, D., Kirsch, P., R¨ oschenthaler,

101.

102. 103.

104.

105.

106.

107.

G.-V., Movchun, V., and Kolomeitsev, A. (2001) Synlett, 379–382. (a) Bardin, V.V., Kolomeitsev, A.A., Furin, G.G.., and Yagupolskii, Y.L. (1990) Izv. Akad. Nauk. SSSR, Ser. Khim., 1693–1694; (1991) Chem. Abstr., 115, 279503; (b) Kolomeitsev, A.A., Movchun, V.A., and Yagupolskii, Y.L. (1992) Tetrahedron Lett., 33, 6191–6192. Review: Krespan, C.G. and Petrov, V.A. (1996) Chem. Rev., 96, 3269–3301. (a) Frenking, G., Fau, S., Marchand, C.M., and Gr¨utzmacher, H. (1997) J. Am. Chem. Soc., 119, 6648; (b) Christe, K.O., Hoge, B., Boatz, J.A., Prakash, G.K.S., Olah, G.A., and Sheehy, J.A. (1999) Inorg. Chem., 38, 3132. Christe, K.O., Zhang, X., Bau, R., Hegge, J., Olah, G.A., Prakash, G.K.S., and Sheehy, J.A. (2000) J. Am. Chem. Soc., 122, 481–487. (a) Kondratenko, M.A., Mal´ezieux, B., Gruselle, M., Bonnet-Delpon, D., and B´egu´e, J.-P. (1995) J. Organomet. Chem., 487, C15–C17; (b) Gruselle, M., Mal´ezieux, B., Andr´es, R., Amouri, H., Vaissermann, J., and Melikyan, G.G. (2000) Eur. J. Inorg. Chem., 359–368; (c) Amouri, H., B´egu´e, J.P., Chennoufi, A., Bonnet-Delpon, D., Gruselle, M., and Mal´ezieux, B. (2000) Org. Lett., 2, 807–809. (a) Olah, G.A., Pittman, C.U., Jr., Waack, R., and Doran, M. (1966) J. Am. Chem. Soc., 88, 1488–1499; (b) Olah, G.A. and Pittman, C.U., Jr., (1966) J. Am. Chem. Soc., 88, 3310–3317; (c) S¨urig, T., Gr¨utzmacher, H.-F., B´egu´e, J.P., and Bonnet-Delpon, D. (1993) Org. Mass Spectrom., 28, 254–261; (d) Olah, G.A., Burrichter, A., Rasul, G., Yudin, A.K., and Prakash, G.K.S. (1996) J. Org. Chem., 61, 1934–1939; (e) Laali, K.K., Tanaka, M., and Hollerstein, S. (1997) J. Org. Chem., 62, 7752–7757; (f) Karpov, V.M., Mezhenkova, T.V., Platonov, V.E., and Sinyakov, V.R. (2001) J. Fluorine Chem., 107, 53–57. Sevenard, D.V., Kirsch, P., Lork, E., and R¨oschenthaler, G.-V. (2003) Tetrahedron Lett., 44, 5995–5998.

108. (a) Debarge, S., Violeau, B., Bendaoud,

109. 110.

111.

112.

113.

114. 115. 116.

N., Jouannetaud, M.-P., and Jacquesy, J.-C. (2003) Tetrahedron Lett., 44, 1747–1750; (b) Debarge, S., Kassou, K., Carreyre, H., Violeau, B., Jouannetaud, M.-P., and Jacqesy, J.-C. (2004) Tetrahedron Lett., 45, 21–23. Huheey, J.E. (1965) J. Phys. Chem., 69, 3284. Reviews: (a) Umemoto, T. (1996) Chem. Rev., 96, 1757–1777; (b) Shibata, N., Matsnev, A., and Cahard, D. (2010) Beilstein J. Org. Chem., 6 (65) (doi: 10.3762/bjoc.6.65). Yagupolskii, L.M., Maletina, I.I., Kondratenko, N.V., and Orda, V.V. (1978) Synthesis, 835. (a) Yagupolskii, L.M., Mironova, A.A., Maletina, I.I., and Orda, V.V. (1980) Zh. Org. Khim., 16, 232; (b) Yagupolskii, L.M. (1987) J. Fluorine Chem., 36, 1; (c) Miranova, A.A., Orda, V.V., Maletina, I.I., and Yagupolskii, L.M. (1989) J. Org. Chem. USSR, 25, 597. (a) Umemoto, T. (1980) DE Patent 3021226; Chem. Abstr., 94, (1981) 208509; (b) Umemoto, T., Kuriu, Y., Shuyama, H., Miyano, O., and Nakayama, S.-I. (1982) J. Fluorine Chem., 20, 695; (c) Umemoto, T., Kuriu, Y., Shuyama, H., Miyano, O., and Nakayama, S.-I. (1986) J. Fluorine Chem., 31, 37; (d) Umemoto, T. (1983) Yuki Gosei Kagaku Kyokaishi, 41, 251–265; (1983) Chem. Abstr., 98, 214835. Haszeldine, R.N. (1951) J. Chem. Soc. (London), 584–587. Hamilton, J.M., Jr., (1963) Adv. Fluorine Chem., 3, 147. (a) Coffman, D.D., Raasch, M.S., Rigby, G.W., Barrick, P.L., and Hanford, W.E. (1949) J. Org. Chem., 747–753; (b) Emeleus, H. and Haszeldine, R.N. (1949) J. Chem. Soc. (London), 2948; (c) Brace, N.O. (1962) US Patent 3,016,407; Chem. Abstr., 1962, 57, 55746; (d) Simons, J.H. and Brice, T.J. (1953) US Patent 2,614,131; Chem. Abstr., 47, (1953) 8770; (e) Haszeldine, R.N. and Leedham, K. (1953) J. Chem. Soc. (London), 1548; (f) Parsons, R.E.

165

166

3 Perfluoroalkylation

117.

118.

119.

120. 121.

122. 123. 124. 125.

126.

(1966) US Patent 3,283,020; Chem. Abstr., 66, (1967) 65059; (g) Parsons, R.E. (1964) US Patent 3,132,185; Chem. Abstr., 61, (1964) 10993; (h) Hauptschein, M. and Braid, M. (1961) J. Am. Chem. Soc., 83, 2383; (i) Chambers, R.D., Musgrave, W.K.R., and Savory, J. (1961) J. Proc. Chem. Soc., 113; (j) Chambers, R.D., Musgrave, W.K.R., and Savory, J. (1961) J. Chem. Soc. (London), 3779. (a) Parsons, R.E. (1965) FR Patent 1,385,682; Chem. Abstr., 62, (1965) 73830; (b) Parsons, R.E. (1966) US Patent 3,234,294; Chem. Abstr., 62, (1965) 73830; (c) Hauptschein, M. (1961) US Patent 3,006,973; Chem. Abstr., 56, (1962) 31072; (d) Haszeldine, R.N. (1949) J. Chem. Soc. (London), 2856; (e) Haszeldine, R.N. (1953) J. Chem. Soc. (London), 3761. (a) Naumann, D. and Baumanns, J. (1976) J. Fluorine Chem., 8, 177; (b) Baumanns, J., Deneken, L., Naumann, D., and Schmeisser, M. (1973) J. Fluorine Chem./1974, 3, 323; (c) Naumann, D., Deneken, L., and Renk, E. (1975) J. Fluorine Chem., 5, 509. Umemoto, T., Kuriu, Y., and Nakayama, S. (1982) Tetrahedron Lett., 23, 1169. Umemoto, T., Kuriu, Y., and Miyano, O. (1982) Tetrahedron Lett., 23, 3579. Umemoto, T., Kuriu, Y., Nakayama, S., and Miyano, O. (1982) Tetrahedron Lett., 23, 1471. Umemoto, T. and Nakamura, T. (1984) Chem. Lett., 983. Umemoto, T. (1984) Chem. Lett., 25, 81. Kasp, J., Montgomery, D.D., and Olah, G.A. (1978) J. Org. Chem., 43, 3147. (a) Umemoto, T. and Gotoh, Y. (1985) J. Fluorine Chem., 28, 235; (b) Umemoto, T. and Gotoh, Y. (1986) J. Fluorine Chem., 31, 231; (c) Umemoto, T. and Gotoh, Y. (1987) Bull. Chem. Soc. Jpn., 60, 3307; (d) Umemoto, T. and Gotoh, Y. (1987) Bull. Chem. Soc. Jpn., 60, 3823–3825. (a) Bravo, P., Montanari, V., Resnati, G., and DesMarteau, D.D. (1994) J. Org. Chem., 59, 6093–6094; (b) DesMarteau, D.D. and Montanari, V.

127.

128.

129.

130.

131.

132.

133. 134. 135.

136.

(1998) J. Chem. Soc., Chem. Commun., 2241; (c) DesMarteau, D.D. and Montanari, V. (2001) J. Fluorine Chem., 109, 19–23. (a) Eisenberger, P., Gischig, S., and Togni, A. (2006) Chem. Eur. J., 12, 2579–2586; (b) Kieltsch, I., Eisenberger, P., and Togni, A. (2007) Angew. Chem. Int. Ed., 46, 754–757; (c) Eisenberger, P., Kieltsch, I., Armanino, N., and Togni, A. (2008) Chem. Commun., 1575–1577; (d) Niedermann, K., Fr¨uh, N., Vinogradova, E., Wien, M.S., and Togni, A. (2011) Angew. Chem. Int. Ed., 50, 1059–1063; (e) Mej´ıa, E. and Togni, A. (2012) ACS Catal., 2, 521–527. (a) Shimizu, R., Egami, H., Hamashima, Y., and Sodeoka, M. (2012) Angew. Chem. Int. Ed., 51, 4577–4580; (b) Mizuta, S., Galicia-L´opez, O., Engle, K.M., Verhoog, S., Wheelhouse, K., Rassias, G., and Gouverneur, V. (2012) Chem. Eur. J., 18, 8583–8587. (a) Yagupolskii, L.M., Kondratenko, N.V., and Timofeeva, G.N. (1984) J. Org. Chem. USSR, 20, 103; (b) simplified synthesis: Magnier, E., Blazejewski, J.-C., Tordeux, M., and Wakselman, C. (2006) Angew. Chem. Int. Ed., 45, 1279–1282. (a) Umemoto, T. and Ishihara, S. (1990) Tetrahedron Lett., 31, 3579; (b) Umemoto, T. and Ishihara, S. (1993) J. Am. Chem. Soc., 115, 2156; (c) Umemoto, T. and Ishihara, S. (1998) J. Fluorine Chem., 92, 181–187. Matsnev, A., Noritake, S., Nomura, Y., Tokunaga, E., Nakamura, S., and Shibata, N. (2010) Angew. Chem. Int. Ed., 49, 572–576. Umemoto, T. (1997) MEC Reagent Brochure, DAIKIN Fine Chemicals Research Center, Tokyo. Umemoto, T., Ishihara, S., and Adachi, K. (1995) J. Fluorine Chem., 74, 77–82. Umemoto, T. and Adachi, K. (1994) J. Org. Chem., 59, 5692–5699. Deng, Q.-H., Wadepohl, H., and Gade, L.H. (2012) J. Am. Chem. Soc., 134, 10769–10772. (a) Johnson, C.R., Janiga, E.R., and Haake, M. (1968) J. Am. Chem. Soc.,

References

137.

138.

139.

140.

141.

142.

143.

90, 3890–3891; (b) Johnson, C.R., Haake, M., and Schroeck, C.W. (1970) J. Am. Chem. Soc., 92, 6594–6598; (c) Johnson, C.R. and Janiga, E.R. (1973) J. Am. Chem. Soc., 95, 7692–7700; (d) Johnson, A.W. (1966) Ylide Chemistry, Academic Press, New York; (e) Trost, B.M. and Melvin, L.S., Jr., (1975) Sulfur Ylides: Emerging Synthetic Intermediates, Academic Press, New York. Noritake, S., Shibata, N., Nakamura, S., and Toru, T. (2008) Eur. J. Org. Chem., 3465–3468. (a) Brahms, D.L.S. and Dailey, W.P. (1996) Chem. Rev., 96, 1585–1632, and references cited therein; (b) Gerstenberger, M.R.C. and Haas, A. (1981) Angew. Chem. Int. Ed. Engl., 20, 647–667; (c) Tozer, M.J. and Herpin, T.F. (1996) Tetrahedron, 26, 8619–8683. (a) Dixon, D.A. (1986) J. Phys. Chem., 90, 54–56; (b) Carter, E.A. and Goddard, W.A. III (1988) J. Chem. Phys., 88, 1752–1763. Seyferth, D., Dentouzos, H., Zuzki, R., and Muy, J.Y.-P. (1967) J. Org. Chem., 32, 2980. (a) Seyferth, D., Hopper, S.P., and Darragh, K.V. (1969) J. Am. Chem. Soc., 91, 6536–6537; (b) Seyferth, D., Hopper, S.P., and Murphy, J. (1972) J. Organomet. Chem., 46, 201; (c) Seyferth, D. and Hopper, S.P. (1972) J. Org. Chem., 37, 4070–4075. Naumann, D., M¨ockel, R., and Tyrra, W. (1994) Angew. Chem. Int. Ed. Engl., 33, 323–325. (a) Birchall, J.M., Cross, G.W., and Haszeldine, R.N. (1960) Proc. Chem. Soc., 81; (b) Burton, D.J. and Wheaton, G.A. (1976) J. Fluorine Chem., 8, 97; (c) Burton, D.J. and Wheaton, G.A. (1978) J. Org. Chem., 43, 2643.

144. (a) Chen, Q.-Y. and Wu, S.-W. (1989) J.

145.

146.

147.

148. 149.

150. 151.

152. 153.

Org. Chem., 54, 3023; (b) Chen, Q.-Y. and Wu, S.-W. (1989) J. Chem. Soc., Chem. Commun., 705. (a) Burton, D.J. and Naae, P.G. (1973) J. Am. Chem. Soc., 95, 8467; (b) Bessard, Y., M¨uller, U., and Schlosser, M. (1990) Tetrahedron, 46, 5213; (c) Bessard, Y. and Schlosser, M. (1990) Tetrahedron, 46, 5222–5229; (d) Bessard, Y. and Schlosser, M. (1991) Tetrahedron, 47, 7323–7328. (a) Dolbier, W.R., Jr., and Burkholder, C.R. (1990) J. Org. Chem., 55, 589; (b) Dolbier, W.R., Jr., Wojtowicz, H., and Burkholder, C.R. (1990) J. Org. Chem., 55, 5420; (c) Balcerzak, P. and Jonczyk, A. (1994) J. Chem. Res. (S), 200; (d) Crabb´e, P., Cervantes, A., Cruz, A., Galeazzi, E., Iriate, J., and Verlarde, E. (1973) J. Am. Chem. Soc., 95, 6655. Wang, F., Luo, T., Hu, J., Wang, Y., Krishnan, H.S., Jog, P.V., Ganesh, S.K., Prakash, G.K.S., and Olah, G.A. (2011) Angew. Chem. Int. Ed., 50, 7153–7157. Erbes, V.P. and Boland, W. (1992) Helv. Chim. Acta, 75, 766–772. (a) Cullen, W.R. and Waldman, M.C. (1969) Can. J. Chem., 47, 3093–3098; (b) Cullen, W.R. and Waldman, M.C. (1971) J. Fluorine Chem., 1, 151. Seyferth, D. and Hopper, S.P. (1971) J. Organomet. Chem., 26, C62–C64. Tian, F., Kruger, V.K., Bautista, O., Duan, J.-X., Li, A.-R., Dolbier, W.R., and Chen, Q.-Y., Jr., (2000) Org. Lett., 2, 563–564. Xu, W. and Chen, Q.-Y. (2003) Org. Biomol. Chem., 1, 1151–1156. Brisdon, A.K., Crossley, I.R., Flower, K.R., Pritchard, R.G., and Warren, J.E. (2003) Angew. Chem. Int. Ed., 42, 2399–2401.

167

169

4 Selected Fluorinated Structures and Reaction Types 4.1 Difluoromethylation and Halodifluoromethylation

Compounds carrying a difluoromethoxy group as a substituent play an important role in pharmaceutical chemistry [1] and in liquid crystals for display applications [2]. Although most of these substances have an aromatic difluoromethoxy group, aliphatic difluoromethyl ethers also have important applications, for example, as anesthetics [3]. Aromatic difluoromethyl ethers are conveniently synthesized by reaction of phenolates with CHClF2 [4]. Although this is superficially similar to simple nucleophilic substitution of chlorine by the phenolate, the conversion in fact proceeds via difluorocarbene as the reactive, electrophilic species [5] (Scheme 4.1). Analogous difluoromethylation products are also obtained from other nucleophiles [6]. The difluoromethylation of aliphatic alcohols is also possible, in principle, but the resulting difluoro ethers often tend to undergo acid-catalyzed hydrolysis to the corresponding formates. They are only stable if the corresponding alcohol is sufficiently acidic, that is, if it carries electron-withdrawing substituents. ODifluoromethylated carbohydrates have been reported [7]. In contrast, some highly fluorinated alkyl difluoromethyl ethers can be synthesized under fairly drastic conditions (Scheme 4.2), and because of their extreme stability they can be used as inhalation anesthetics [3, 8]. Another, related type of reaction is the halodifluoromethylation of nucleophiles by dihalodifluoromethanes (e.g., CF2 Br2 ) [9]. This reaction is always initiated by a single electron transfer from the nucleophile to the CF2 XY species (X and Y denote halogens other than fluorine). The subsequent fate of the resulting radical ion pair depends on the ability of the nucleophile to form a stabilized radical, and also on the choice of solvent [10]. For phenoxides [4a, 5, 11] and thiophenoxides [4c, 11a], a reaction pathway via difluorocarbene is usually preferred whereas enamines and ynamines are halodifluoromethylated by a radical chain mechanism (see also Section 3.1) [12] (Scheme 4.3).

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

170

4 Selected Fluorinated Structures and Reaction Types

CHClF2

Nu–

[CClF2]–

Base; − H+

[NuCF2]–

− Cl–

:CF2

NuCF2H

+ H+

OCHF2

OH 65% CHClF2, aq. NaOH, dioxane; 70 °C

N

N CHClF2, aq. K2CO3

O

N H

N

H2N

OH

OCHF2 N (58%)

Scheme 4.1

N CF2Br

1. KOtBu, DMF 2. CF2Br2; r.t., 48 h

Na,NH3

SNa 56% OH KOtBu, CHClF2,

H2 N

MeOH

O

O

O

Electrophilic difluoromethylation of O-, N-, and S-nucleophiles [4a,b, 6].

O O

Cl

OCHF2

O

59%

O O

ZnBrCF3⋅2CH3CN, Zn, molecular sieves 3Å, CH2Cl2; r.t., 6-8 h

Cl

F H

O

α-phenylethylamine; crystallization

HO

O O

F H

CF3

Cl H

HF2CO

1. HgO 2. CHF2Br

Cl

HOOCCF2O

Cl

84%

HF2CO

SF4, HF

O

O O

O

77%

Scheme 4.2

SCHF2 OH

H2N

O

OH

HO

O N (9%) CHF2

N

85%

N H S S OH H2N

N +

H

F F 39%

KOH, diethylene glycol; 210-230 °C

H O

F

HF2CO

CF3

Cl H

Synthesis of aliphatic difluoromethyl ethers [3, 7a, 8].

F

4.1 Difluoromethylation and Halodifluoromethylation

Nu– + YCF2X SET

[Nu·YCF2X·–]

Carbene mediated NuY + mechanism NuCF2Y

Nu· +

CF2X–

NuCF2X

CF2X–

YCF2X·–

X–

YCF2X

Radical mediated mechanism

YCF2X·–

Y–

YCF2X :CF2

NuCF2–

NuCF2X·–

Nu–

XCF2·

Nu–

Scheme 4.3 The different possible mechanistic pathways for the halodifluorination of different substrates [9, 10].

Bromodifluoromethylation of C-nucleophiles which are not resonance stabilized is considered to proceed via the carbene mechanism (Scheme 4.4). A typical by-product of this reaction is the brominated nucleophile [13]. Br

CF2Br THPO (52%) +

THPO

THPO CF2ClBr, THF; −80 °C

76%

(25%)

NaI, acetone; reflux, 2 h

CF2I THPO OTBDMS

62% Li

THF; −15 °C

F F THPO

OTBDMS

Scheme 4.4 Synthetic steps toward gem-difluoromethylene analogs of arachidonic acid via bromodifluoromethylation of C-nucleophiles [13].

171

172

4 Selected Fluorinated Structures and Reaction Types

The initial reduction step does not necessarily rely on the nucleophilic substrate as the reducing agent. It can also be induced by addition of catalytic amounts of copper as an auxiliary reducing agent [14] (Scheme 4.5). The whole reaction sequence follows supposedly an SRN 1 mechanism [15]. Me2N

Me2N

75%

N

53%

Me2N

–

+ Br N CF2Br

Cat. Cu, CF2Br2, CH3CN; r.t., 1 h

Me2N +

N

1. Me3SiCl, PhCN; − 20 °C 2. Me3SiOTf; r.t.

+

TDAE

N

CF2–

TfO– CF2SiMe3

Scheme 4.5 Bromodifluorination of N-nucleophiles [4-(N,N-dimethylamino)pyridine (DMAP)] under the action of electrocatalysis by copper and subsequent reduction by TDAE [tetrakis(dimethylamino)ethylene] to a nitrogen ylide, which is formally an adduct of DMAP, to difluorocarbene [6a, 16].

An N-tosyl-S-difluoromethyl-S-phenylsulfoximine reagent was developed by Hu and co-workers in order to achieve clean difluoromethylation of a variety of S-, N-, and C-nucleophiles [17].

4.2 The Perfluoroalkoxy Group

Perfluoroalkoxy groups and, especially, the trifluoromethoxy group, are commonly used as structural elements in pharmaceuticals (Section 9) and organic materials

OMe

OCCl3

OCF3 82% HF; 120-160 °C, 40-50 bar, 3 h

Cl2

Cl

Cl

Cl

OCF3

OH 35-70%

X

HF, CCl4; 100-150 °C, autogeneous pressure, 8 h

X

Scheme 4.6 Technical syntheses of trifluoromethoxyarenes via the trichloromethoxy derivative or directly from the phenol [19] (X denotes 3- or 4-NO2 , 4-Cl, 2,4-Cl2 , 3-CF3 , 4-NH2 , 2-F, 4-OH).

4.2 The Perfluoroalkoxy Group

(Section 8) [18]. Aromatic and aliphatic perfluoroalkoxy groups are conveniently accessible via fluorodesulfuration chemistry (see also Section 2.5.4). Nevertheless, the technically important trifluoromethoxy arenes, in particular, are produced on a larger scale by a different method, based on chlorine–fluorine exchange with hydrofluoric acid [19] (Scheme 4.6). The fluorination of perfluoroacyloxyarenes with sulfur tetrafluoride to give the corresponding perfluoroalkoxyarenes affords access to a larger structural variety [20]. For less sensitive structures, this method can also be extended to the synthesis of alkyl perfluoroalkyl ethers [21] (Scheme 4.7).

O

O F

SF4, HF; 100–175 °C, 8 h

CF3

O O

SF4, HF; 100–175 °C, 8 h

O

O2N

OC2F5

61%

(CF2)2CF3

O

OCF3

57%

O(CF2)3CF3

30% SF4, HF; 100–175 °C, 8 h O2N

O F

O

O

F O

54% SF4, HF; 100–175 °C, 8 h

F3CO

OCF3

Scheme 4.7 Synthesis of aromatic and aliphatic perfluoroalkyl ethers via the fluorination of the corresponding perfluoroalkanoates with SF4 [20a, 21a].

Even though perfluoroalkoxide anions are usually poor nucleophiles, they can be used for nucleophilic perfluoroalkoxylation of some aliphatic substrates [22]. The perfluoroalkoxide anion is stable in the presence of relatively large cations, for example, K+ , Rb+ , Cs+ [23], tris(dimethylamino)sulfonium (TAS+ ) [24], 1,1,2,2,6,6hexamethylpiperidinium (pip+ ) [25], and hexamethylguanidinium HMG+ ) [26] cations. Trifluoromethoxide salts can also be conveniently generated by reaction of naked fluoride with an organic cation with trifluoromethyl triflate (Scheme 4.8) [27]. Under the conditions of most nucleophilic exchange reactions, the anion exists in equilibrium with perfluorocarboxylic acid fluoride and a fluoride anion [28]. Nucleophilic perfluoroalkoxylation, therefore, always competes with fluorination.

173

174

4 Selected Fluorinated Structures and Reaction Types

O + F–

RF

RFCF2O–

F

NMe2 S+ Me2N NMe2 Me3SiF2–

88%

TAS+ CF3O–

COF2, THF; –75 °C to r.t.

N N+

N 98%

N

Me3SiF2–

N+

N+

CF3SO2OCF3, CH3CN; –30 to 20 °C

pip+ (CF3)2FO–

(CF3)2CO, C3H7CN; r.t.

OCF3

OTf O BnO

OBn

TAS+ CF3O–, CH2Cl2; r.t., 2.5 h

O

OMe

O

BnO

OBn

BnO

OMs

KF, cat. CsF, diglyme; 85–105 °C, 8–14 h

RF F F RF

OBn OBn (18%)

OBn (76%)

MsO

OMe

+

O +

F O

OMe

OBn

RF

CF3O–

pip+ CF3CF2O–

CF3COF, CH3CN; r.t.

F–

RF

N

O O

RF = F: 14% RF = CF3: 46%

Scheme 4.8 Generation of perfluoroalkoxide anions and their use to generate aliphatic perfluoroalkyl ethers by nucleophilic substitution of a suitable leaving group [TAS+ = tris(dimethylamino)sulfonium; pip+ = 1,1,2,2,6,6-hexamethylpiperidinium] [22, 24, 25, 27, 28b].

The trifluoromethoxy group can also be introduced into aromatic systems using a silver-mediated, oxidative process [29]. TAS+ CF3 O− is used as an OCF3 donor. The aromatic acceptor is either an arylstannane or a boronic acid. Analogously to the silver-mediated fluorination of arylstannanes [30], the mechanism is considered to proceed via Ag(I) species which are oxidized to Ag(II) by the electrophilic fluorination reagent F-TEDA-PF6 (Schemes 4.9 and 4.10; see also Section 2.4.5).

4.2 The Perfluoroalkoxy Group

OCF3

SnBu3 R

175

R

2.0 equiv. TAS+CF3O–, 1.2 equiv. F-TEDA-PF6, 2.0 equiv. AgPF6, 2.0 equiv. NaHCO3,

THF–acetone (1:3); 2-4 h, –30 °C

OCF3

COOMe NHBoc

F3CO

(88%)

(92%) F3CO

F3CO NBoc

H

O

N

(72%) HO (59%)

OMe O

Scheme 4.9 Silver-mediated oxidative trifluoromethoxylation of arylstannanes [29]. The yields are given in parentheses.

OCF3

B(OH)2 R

R

Agl·AgI 1. 1.0 equiv. NaOH, MeOH; 15 min, 23 °C

R

2.0 equiv. TAS+CF3O–, 1.2 equiv. F-TEDA-PF6, 2.0 equiv. NaHCO3,

2. 2.0 equiv. AgPF6, 30 min, 0 °C

OCF3

(72%)

THF–acetone (1:3); 2-4 h, –30 °C

CF3O

OCF3

MeO2C

OCF3

NBoc (76%)

(64%)

(65%) Me

Scheme 4.10 Silver-mediated oxidative trifluoromethoxylation of areneboronic acids [29]. The yields are given in parentheses.

176

4 Selected Fluorinated Structures and Reaction Types

4.3 The Perfluoroalkylthio Group and Sulfur-Based Super-Electron-Withdrawing Groups

The trifluoromethylthio group is a widely used structural motif in agrochemicals, because it induces an exceptionally high lipophilicity (π p = +1.44) [31]. Its analogs with sulfur in higher oxidation states, for example, the trifluoromethylsulfonyl group and fluorinated sulfimide- and sulfoximide-based structures, are among the strongest known electron-withdrawing substituents. All these sulfur-based structures are very resistant to acidic hydrolysis. The trifluoromethylthio group can be generated either from the corresponding thiols [32], rhodanides [33], or disulfides, or by reaction of nucleophilic [34] or electrophilic SCF3 transfer reagents with suitable arene or olefin substrates [35, 36] (Schemes 4.11 and 4.12). CS2 + 3 AgF

CH3CN; -Ag2S

Me3SiCF3

Me3SiC2F5 (a)

CS2

(b)

Cl2

ClSCCl3

AgSCF3

Me4NF, S8, glyme; −20 °C Me4NF, S8, glyme; −20 °C 76%

48% HBr; 5−10 °C, 18 h

CuBr; -AgBr

CuSCF3

Me4N + SCF3–

Me4N + SC2F5–

BrSCCl3

68% NaF, sulfolane; 160 °C

F3CSSCF3 Cl2

F3CSCl

Scheme 4.11 Syntheses of the most important nucleophilic (a) and electrophilic (b) perfluoroalkylthio transfer reagents [34a,b, 37].

With the development of suitable ligand systems since 2010 [43], the palladiumcatalyzed trifluoromethylthiolation of aryl halides under mild conditions has also become possible (Scheme 4.13) [44]. Organic perfluoroalkylthio derivatives can be oxidized to the sulfoxides [45] and sulfones [35a, 40] by a variety of methods (Scheme 4.14). Compared with nonfluorinated thioethers, the SRF derivatives are less susceptible to oxidation. Therefore, more energetic reaction conditions must be chosen. An alternative route to aromatic trifluoromethylsulfonyl and sulfinyl compounds is based on the nucleophilic trifluoromethylation of sulfonyl or sulfinyl halides with Me3 SiCF3 [46] (Scheme 4.15). One entrance into the chemistry of sulfimide-based functional groups is electrophilic activation of the corresponding sulfoxides with triflic anhydride and

4.3 The Perfluoroalkylthio Group and Sulfur-Based Super-Electron-Withdrawing Groups

SMe

SCF3

SCCl3

Cl2

HF

SCF3

SK 62% CF3Br, DMF; 2.7 bar, r.t., 3 h

SH

SC4F9

83%

1. NaH, DMF; r.t., 2 h 2. F9C4I; r.t., 18 h

Cl

I

O2N O

O2N

80%

Cl N

SCF3

80% CF3SCu, DMF; 120 °C, 2.5 h

O 2N

Cl

O2N

Cl2CS, KF, CH3CN; −15 °C to r.t.

N

O2N

N

14%

SCl

SCF3

Me3SiCF3, Bu4N+F −,

O

N

O2N

SCF3

THF; 0 °C 96%

(C8H17S)2

C8H17SCF3

Me3SiCF3, Bu4N+F −, THF; 0 °C

S O

N

F3CS

OMe

O

56%

OMe

Me3SiCF3, Bu4N+F −,

O

O

BnBr

THF; −25 °C, 1 h

95% TDAE2+(SCF3−)2,

O

O

BnSCF3

CH3CN–DMF 10:1; 0 °C to r.t., 30 min

SCF3 F3CSSCF3

Me2N B(OH)2 PhO

Me2N SCF3

91%

3.0 equiv. S8, 5 equiv. Me3SiCF3, 0.1 equiv. CuSCN, 0.2 equiv. phenanthroline, 3.0 equiv. K3PO4, 2.0 equiv. Ag2CO3, molecular

PhO

sieve (4A), DMF; 24 h, r.t.

Scheme 4.12 Syntheses of different perfluoroalkylthioarenes [33a, 34c, 35c, 36, 38–42].

177

178

4 Selected Fluorinated Structures and Reaction Types

SCF3

Br R

R 1.5 mol% [(cod)Pd(CH2TMS)2], 1.75 mol% BrettPhos, 1.3 equiv. PhEt3NI, 1.3 equiv. AgSCF3, toluene; 2 h, 80 °C

SCF3

SCF3 O

(98%)

(93%)a

N

SCF3

(> 99%)

NHPh SCF3

O

CN

F3CS S (96%)c

b

(94%)

O Me

O2N

(96%)

SCF3 d

Scheme 4.13 Palladium-catalyzed formation of ArSCF3 using AgSCF3 as trifluoromethylthiolate source [44]. a 2.0 mol% Pd, 2.2 mol% BrettPhos; b 3.0 mol% Pd, 3.3 mol% BrettPhos; c 1.5 mol% Pd, 1.65 mol% BrettPhos; d 3.0 mol% Pd, 3.0 mol% BrettPhos.

SCF3

43%

30% H2O2, HOAc;

Cl

50 °C, 5 h

SC4F9

reflux, 24 h

CF3

Cl O O S C4F9

87%

CrO3, HOAc;

Cl

O S

Cl

SCF3

SO2CF3 80%

F3CS

SCF3

CrO3, HOAc; reflux, 20 h

F3CSO2

SO2CF3

Scheme 4.14 Synthesis of perfluoroalkylsulfinyl (SORF ) and perfluoroalkylsulfonyl (SO2 RF ) derivatives [35a, 40, 45].

4.4 The Pentafluorosulfanyl Group and Related Structures

179

SO2CF3

SO2F 99% Me3SiCF3, cat. TASF, hexane; r.t.

O

S

Cl

O

S

CF3

53% Me3SiCF3, cat. TASF, THF; −25 °C

Scheme 4.15 Conversion of sulfonyl and sulfinyl halides to the corresponding trifluoromethyl sulfones and sulfoxides by nucleophilic trifluoromethylation [46].

subsequent reaction of the resulting sulfonium salts with trifluoromethanesulfonamide [47] (Scheme 4.16). The other entrance is oxidative imination of a sulfoxide, then trifluoromethanesulfonylation of the resulting imidosulfone [48]. O S

CF3 Tf2O, CH2Cl2; r.t.

Cl 73%

NSO2CF3 S CF3

70% CF3SO2NH2, CH2Cl2; r.t., 12 h

Cl

24% oleum, NaN3; 0 °C to 70 °C

O CF3 S NH Cl

Cl

OTf + S CF3 TfO−

50%

O CF3 S NSO2CF3

1. NaH, Et2O Cl 2. Tf2O, CH2Cl2; −10 °C to reflux, 3 h

Scheme 4.16 Syntheses of some sulfur imide-based super-electron-withdrawing substituents via the sulfoxides [46b–48].

A third method is based on oxidative amination of diaryl disulfides with N,N-dichlorotrifluoromethanesulfonamide, leading to imidosulfinyl chlorides (Scheme 4.17).

4.4 The Pentafluorosulfanyl Group and Related Structures

Another sulfur-based, strongly polar functional group is the λ6 -pentafluorosulfanyl group [50]. Within a few years after the initial synthesis and characterization of a variety of aromatic [51] and aliphatic [52] SF5 derivatives at the beginning of the 1960s, interest in this unusual group vanished almost completely, with very few exceptions [53], partly because of inconvenient synthetic access to this class of substance and partly because of unfounded prejudice regarding the hydrolytic stability of the pentafluorosulfanyl group.

180

4 Selected Fluorinated Structures and Reaction Types O S

Cl

O Cl S NSO2CF3

95-99% F3CSO2NCl2, CH2Cl2; r.t., 15-20 min

Cl

Cl 98%

AgF, CH3CN; r.t., 30 min

O F S NSO2CF3 Cl O F S NSO2CF3

F

F

70%

O CF3 S NSO2CF3

Me3SiCF3, cat. TASF, THF; −20 °C to r.t., 1 h

Cl S

S

Cl 95-99% F3CSO2NCl2, CH2Cl2; r.t., 2-3 h

NSO2CF3 S Cl

95-99%

Cl

F3CSO2NCl2, CH2Cl2; r.t., 15-20 min

Cl

NSO2CF3 60-80% S Cl SbF3, cat. F3CSO2NCl2; NSO2CF3 70 °C, 2-3 min

Cl

NSO2CF3 S F NSO2CF3

Scheme 4.17 Syntheses of some sulfur imide-based super-electron-withdrawing substituents via oxidation by N,N-dichlorotrifluoromethanesulfonamide [46b, 49].

The exploration of this functional group was resumed when, towards the end of the 1990s, the first commercial quantities of o- and m-nitropentafluorosulfanylbenzene became available from a direct fluorination process [54]. Because of its strong polarity and high lipophilicity, the pentafluorosulfanyl group is an interesting structural motif not only for the design of bioactive compounds [55] but also for organic functional materials, for example, polymers [53b–d] and liquid crystals [56]. The first practicable synthesis of aromatic pentafluorosulfuranyl derivatives was introduced by Sheppard in 1960 [51a, 57]. It was based on the stepwise oxidative fluorination of diaryl disulfides with AgF2 , via the trifluorosulfanylarenes [58], to the corresponding pentafluorosulfanyl compounds [51b]. This early synthesis suffered from relatively low yields and sometimes bad reproducibility. Then Thrasher and co-workers [53b–d, 59] found that the autoclave material used by Sheppard, copper, acts as a catalyst in the conversion. Copper and some other metals are considered to facilitate the fluorination reaction via formation of metal thiolate intermediates. The first breakthrough in the commercialization of pentafluorosulfanyl arenes came in 1996 with the introduction of a new, very reliable synthetic procedure based on direct fluorination of bis(nitrophenyl) disulfides [54c]. This sudden, convenient access to larger quantities of this class of substance triggered renewed interest in the exploration of the chemical properties of SF5 compounds, especially their

4.4 The Pentafluorosulfanyl Group and Related Structures

hydrolytic stability. A more recent breakthrough in 2008 provided a synthetic access to the SF5 group, which no longer requires elemental fluorine [60]: an aromatic disulfide is oxidized by chlorine in the presence of a fluoride source, yielding a chlorotetrafluorosulfanyl derivative [61]. The remaining chlorine is exchanged by a Lewis acidic fluoride, such as zinc fluoride or HF (Scheme 4.18). SF5

~2% S2F10, CFCl3; 180°C, 10 h

F

F

NO2

18%

S S O2N

SF5

AgF2, CFC-113, copper sheet as catalyst; 60°C, 2 h, then 125−130°C, 3 h

F

O2N

16% 1. AgF2, CFC-113; 80°C, copper autoclave 2. 120°C O2N

S NO2

S

Cl2, KF, CH3CN; 0°C, 3 h

41% 88%

10% F2-N2, CH3CN;

O2N

SF5

24 h, −7.6 to −4.5°C

O2N

SF4Cl

89% ZnF2; 120°C, 2 h

Scheme 4.18 Different syntheses of pentafluorosulfanylarenes [51b,d, 54c,d, 59, 60]. The commercial process for the synthesis of m- and p-nitropentafluorosulfanylbenzene is based on either direct or chlorine-mediated fluorination of the corresponding disulfides.

It has been known since Sheppard’s original work [51b] that the hydrolytic stability of aromatic pentafluorosulfanyl groups equals or exceeds that of trifluoromethyl groups (Scheme 4.19); this is considered sufficiently stable for ubiquitous use as a structural motif in medicinal chemistry. Aromatic SF5 derivatives tolerate attack by strong Brønstedt acids and bases, and they are stable under the conditions used for different nickel-, palladium-, or platinum-catalyzed hydrogenation reactions, or carbon–carbon coupling reactions [56, 62]. Like their trifluoromethyl analogs, they are sensitive towards strong Lewis acids [63]. The real Achilles’ heel of the SF5 group, which distinguishes it from the trifluoromethyl function, is its susceptibility to reduction by some organometallic reagents. Sheppard observed that p-bromopentafluorosulfanylbenzene (1) could not be converted directly into the Grignard compound with magnesium metal, but only under the catalytic action of methylmagnesium iodide [51b]. Attempts to lithiate the bromoarene 1 with n-butyllithium in tetrahydrofuran (THF) at −78 ◦ C

181

182

4 Selected Fluorinated Structures and Reaction Types

SF5

OH 1. t BuLi, Et2O; −70 °C 58%

H2SO4, NaNO2;

2. B(OMe)3; −70 to −20 °C 3. HOAc, H2SO4, 30% H2O2;

80 °C

SF5

−20 to 35 °C, 1 h

SF5

1

Quant. H2, 5% Pd-C,

NO2 H11C5

THF; 1 bar, r.t.

SF5

NH2

SF5

SF5

46%

55%

1. HBr, NaNO2; −5 °C

1. Mg, MeI, Et2O

2. CuBr; r.t. to 80 °C

Br

2. CO2

33% 1. tBuLi, Et2O; −70 °C

4-H11C5PhCCH, cat. Pd(PPh3)4, pyrrolidine; r.t, 18 h

H7C3

SF5

COOH

76%

2. N-formylpiperidine; −40 °C to r.t.

23% 4-H7C3PhB(OH)2, cat.Pd(PPh3)4, toluene, 2 N NaOH; r.t, 2 d

SF5

nBuLi, THF; −78 °C

S + F5S F5S

(4%)

SF5

SF5

CHO

(6%)

Scheme 4.19 Examples of conversions of 4-nitropentafluorosulfanylbenzene demonstrate the stability of the aromatic pentafluorosulfanyl group, which is comparable to that of the trifluoromethyl function [51b, 56a]. The Achilles’ heel of the SF5 group is its susceptibility to reduction by some organometallic species, for example, n-butyllithium in THF.

4.4 The Pentafluorosulfanyl Group and Related Structures

also resulted merely in the immediate formation of a variety of reduction products. When, on the other hand, tert-butyllithium in diethyl ether at −78 ◦ C was used instead, the compound was cleanly lithiated and could be used for many different transformations [56a]. Sheppard was unable to convert o-nitrophenylsulfur trifluoride into the corresponding SF5 derivative in the same manner as for the m- and p-nitrophenyl derivatives. He explained this as a consequence of the bulkiness of the pentafluorosulfanyl group, which interacts sterically with the ortho-nitro function [51b], and even speculated that ortho-substituted pentafluorosulfanylbenzenes in general are unstable. However, during the last decade, it has been shown repeatedly that ortho-fluorinated aromatic disulfides can be fluorinated by AgF2 or elemental fluorine to the o-fluoropentafluorosulfanylarene [59]. Moreover, the ortho-fluorine can be replaced by a variety of nucleophiles without any evidence that the resulting substitution products are in any way susceptible to hydrolysis (Scheme 4.20). O O S

OEt SF5

SF5

O2N 49%

N

O2N

O2N

Fe, EtOH, HCl; reflux

SF5

44%

SF5

p-NO2PhSNa,

O2N

F5S S

SF5

44%

NO2

EtOC(S)SK, EtOH; reflux

F

H2N

46% EtOH; reflux

O2N 78%

120 °C

S

F piperidine, EtOH; reflux

KMnO4, HOAc;

60%

EtOH,KOH; reflux

64%

SF5

NO2

NO2 SF5

1. NaNO2, 48% HBr 2. CuBr

O2N

F SF5 Br

Scheme 4.20 Conversions of 1-fluoro-4-nitro-2-pentafluorosulfanylbenzene into other functionalized derivatives demonstrate the hydrolytic stability of the pentafluorosulfanyl group even in the presence of bulky ortho-substituents [59].

Electronically, the SF5 group can be regarded as a ‘‘super-trifluoromethyl’’ group. It has inductive and resonance effects [64] (σ I = 0.55, σ R = 0.11) which are

183

184

4 Selected Fluorinated Structures and Reaction Types

analogous to, but significantly stronger than, those of CF3 (σ I = 0.39, σ R = 0.12) [51c]. The electronegativity of the SF5 group is 3.62 [65], compared with 3.45 for CF3 [66]. A particularly attractive property in the design of functional organic materials, for example, liquid crystals, is the strong dipole moment which can be achieved by use of the SF5 group. For example, the dipole moment of pentafluorosulfanylbenzene (PhSF5 ) is 3.44 D (25 ◦ C) [51c] compared with only 2.6 D for benzotrifluoride (PhCF3 ) [67]. Since the 1950s, perfluoroaliphatic SF5 compounds have been made by a variety of methods, including fluorination with cobalt trifluoride and direct and electrochemical fluorination [50a]. Selective introduction of a pentafluorosulfanyl group into more complex aliphatic compounds, on the other hand, still remains a challenge. Most syntheses of aliphatic pentafluorosulfanyl derivatives are based on radical addition of SF5 X (X = Cl, Br) to olefins (Scheme 4.21). The general reactivity of SF5 X is very similar to that of perfluoroalkyl iodides and bromides and the stability of the resulting adducts is comparable to that of their perfluoroalkyl analogs [52, 68]. The radical addition of SF5 Br to olefins was found to become more controllable by use of catalytic amounts of triethylborane [69]. Since access to SF5 Cl and SF5 Br remains difficult, the chemistry and the physicochemical properties of aliphatic and olefinic SF5 has been explored to a limited extent [68c, 70]. Arenes bridged by a tetrafluorosulfanyl group are accessible by the same principal method as pentafluorosulfanyl compounds [71a] (Scheme 4.22). Direct fluorination of the corresponding diaryl sulfides with 10% fluorine in nitrogen yields mixtures of the cis and trans isomers. The aromatic moieties must be deactivated, by electron-withdrawing substituents, against the attack by fluorine. Because diaryl trifluorosulfuranonium cations (2) are resonance-stabilized, the cis isomer can be easily isomerized into the thermodynamically more stable trans isomer by the action of a catalytic amount of a fluorophilic Lewis acid. A similar method has been applied to the synthesis of arenes carrying the trans-SF4 CF3 group, which was intended as a highly polar but also highly hydrophobic terminal group for liquid crystals [71b] (Scheme 4.23). The pentafluorosulfanyloxy group can be regarded as a sulfur-based analog of the trifluoromethoxy group. Aromatic pentafluorosulfanyloxy compounds are highly stable towards hydrolysis, similarly to their pentafluorosulfuranyl analogs, because of kinetic stabilization by the five fluorine atoms shielding the central sulfur against nucleophilic attack. The substance class is accessible by high-temperature reaction between arenes and bis(pentafluorosulfanyl) peroxide (F5 SOOSF5 ) [72], a thermally stable compound (b.p. 49 ◦ C) [73] (Scheme 4.24). Because access to F5 SOOSF5 is difficult, after the initial publication in 1962 this chemistry has, unfortunately, not been explored further. Physicochemical studies on ppentafluorosulfanyloxybenzoic acid (pK a = 5.04; for comparison, benzoic acid 5.68 and p-nitrobenzoic acid 4.55) showed that the p-OSF5 group has a relatively large σ para value of +0.44 (for comparison, p-F +0.062, p-COOEt +0.45), indicating a strong inductive electron-withdrawing (−I) effect.

4.4 The Pentafluorosulfanyl Group and Related Structures

F5S

OMe

40% SF5Cl + H

H

35%

KOH, MeOH; 25 − 61 °C Cl

F5S

K2CO3, acetone; 35 °C, 12 h

Zn, diglyme; 140 °C

Br

19%

F5S

Cl

Br2; hn, r.t., 13 h 90%

Cl

F5S

Br

92%

F5S

160 − 170 °C

∼ 56%

185

UV irradiation

Br

SF5

H

F5S

SF5

F5S

SF5

88% KOH, MeOH; 65% 25 − 60 °C

Co2 (CO)8

SF5

OMe F5S 85% F5S

CH2N2, Et2O; 0−5 °C

F5S + N N H 60:40

50%

2,3-Dimethylbutadiene; 120−140 °C

F5S

F5S

NH N

CH3 CH3

Chloranil, p-xylene; reflux SF5

SF5 16% SF5Cl; r.t.,18 h

H H7C3 H

Scheme 4.21

85% SF5Br, BEt3 (0.15 equiv.), n-heptane; −40 − −20 °C, 2 h

CH3 CH3

Cl

79%

KOH, H2O, EtOH; 75 °C, 15 min H H7C3 H

Br

74% SF5 KOH powder, n-heptane; 35°C, 18 h

Examples of syntheses of some nonaromatic pentafluorosulfanyl derivatives [52, 68].

H H7C3 H

SF5

186

4 Selected Fluorinated Structures and Reaction Types

F F O2N

O2N

S

F

F

80% 10% F2–N2, CH3CN,

NO2

S

NaF; 5 °C

cis:trans 85:15

NO2

F F O2N

S

87%

catalytic isomerization: 1. BF3·OEt2 (0.1 equiv.), CH2Cl2; r.t., 1 h 2. Me3SiOMe; r.t., 10 min

NO2

F

F F O2N

+

S

NO2

F F 2 Scheme 4.22 Synthesis of isomeric bis(4-nitrophenyl)tetrafluorosulfanes and subsequent catalytic isomerization to the energetically preferred trans isomer [71].

4.4 The Pentafluorosulfanyl Group and Related Structures

O2N

SCF3

F F

50%

+

87%

F CF3

48%

F F

O2N

Cat. Raney Ni, H2, THF

F

S

O2N

10% F2−N2, CH3CN; 0 °C

SF4CF3

H2N

187

S

CF3

F F

AlCl3(0.8 equiv.), CH2Cl2; −10 °C,0 min

(cis/trans 85:15)

1. 47% HBr, NaNO2; 0−5 °C 52% 2. CuBr; 85°C

Br

F F

14%

SF4CF3

S

C3H7

F F

B(OH)2

C3H7 cat. Pd(PPh3)4, THF, borate buffer PH 9; 85 °C

Scheme 4.23 The synthesis of trans-trifluoromethyltetrafluorosulfuranylarenes [71b] and subsequent reactions. Analogously to the case of 2 (Scheme 4.22), the AlCl3 -catalyzed isomerization is considered to proceed via the equilibration of a trifluoromethyltrifluorosulfuranonium cation. OSF5

OSF5 X = CH3

88%

F5SOOSF5, CFCl3;

H2SO4, HOAc, Ac2O,

90 °C, 10 h

CrO3; 0-10 °C

CH3

COOH

OSF5 X = Cl

+

F5SOOSF5; 150 °C, 15 h

X

Cl

10:1

OSF5 Cl OSF5

OSF5 50%

X = H: 50% F5SOOSF5;

H2SO4, cat.I2;

150 °C, 15 h

110-115 °C, 7 h HOAc, H2SO4, HNO3; 80 °C, 3 h

OSF5

OSF5

SO3H 64%

H2SO4, HNO3; 50 °C, 1 h

OSF5 NO2

Ac2O, HCl, Zn

HN

CH3

NO2

SO3H

O

Scheme 4.24 Synthesis of a variety of pentafluorosulfanyloxybenzene derivatives [73].

CF3

188

4 Selected Fluorinated Structures and Reaction Types

References 1. McCarthy, J. (2000) Utility of fluorine

2. 3.

4.

5. 6.

7.

8.

9. 10.

11.

in biologically active molecules. Tutorial, Division of Fluorine Chemistry, 219th National Meeting of the American Chemical Society, San Francisco, March 26, 2000. Kirsch, P. and Bremer, M. (2000) Angew. Chem. Int. Ed., 39, 4216–4235. K. Ramig and D.F. Halpern (1999) in Enantiocontrolled Synthesis of FluoroOrganic Compounds: Stereochemical Challenges and Biomedical Targets (ed. V.A. Soloshonok), John Wiley & Sons, Inc., New York, pp. 454–468. (a) Miller, T.G. and Thanassi, J.W. (1960) J. Org. Chem., 25, 2009–2012; (b) Shen, T.Y., Lucas, S., and Sarett, L.H. (1961) Tetrahedron Lett., 2, 43–47; (c) Suda, M. and Hino, C. (1981) Tetrahedron Lett., 22, 1997; (d) Morimota, K., Makino, K., and Sakata, G. (1992) J. Fluorine Chem., 59, 417. Hine, J. and Porter, J.J. (1957) J. Am. Chem. Soc., 79, 5493–5496. (a) Bissky, G., Staninets, V.I., Kolomeitsev, A.A., and R¨oschenthaler, G.-V. (2001) Synlett, 374–378; (b) Tsushima, T., Ishikawa, S., and Fujita, Y. (1990) Tetrahedron Lett., 31, 3017. (a) Miethchen, R., Hein, M., Naumann, D., and Tyrra, W. (1995) Liebigs Ann., 1717–1719; (b) Tyrra, W. and Naumann, D. (1996) J. Prakt. Chem., 338, 283–286. Huang, C.G., Rozov, L.A., Halpern, D.F., and Vernice, G.G. (1993) J. Org. Chem., 58, 7382–7387. Tozer, M.J. and Herpin, T.F. (1996) Tetrahedron, 52, 8619–8683. Rico, I., Cantacuzene, D., and Wakselman, C. (1983) J. Org. Chem., 48, 1979. (a) Rico, I. and Wakselman, C. (1981) Tetrahedron Lett., 22, 323; (b) Fuss, A. and Koch, V. (1990) Synthesis, 604; (c) Fuss, A. and Koch, V. (1990) Synthesis, 681; (d) Kolycheva, M.T., Gerus, I.I., Yagupolskii, Y.L., Galushko, S.V., and Kukhar, V.P. (1991) Zh. Org. Khim., 27, 781.

12. Rico, I., Cantacuzene, D., and

13.

14.

15. 16.

17. 18.

19.

20.

21.

22. 23. 24.

25. 26.

27.

28.

Wakselman, C. (1981) Tetrahedron Lett., 22, 3405. Kwok, P.-Y., Muellner, F.W., Chen, C.-K., and Fried, J. (1987) J. Am. Chem. Soc., 109, 3684–3692. Kolomeitsev, A., Schoth, R.-M., Lork, E., and R¨oschenthaler, G.-V. (1996) Chem. Commun., 335–336. Wakselman, C. (1992) J. Fluorine Chem., 59, 367. Bissky, G., R¨oschenthaler, G.-V., Lork, E., Barten, J., M´edebielle, M., Staninets, V., and Kolomeitsev, A.A. (2001) J. Fluorine Chem., 109, 173–181. Zhang, W., Wang, F., and Hu, J. (2009) Org. Lett., 11, 2109–2112. Leroux, F.R., Manteau, B., Vors, J.-P., and Pazenok, S. (2008) Beilstein J. Org. Chem., 4 (13), doi: 10.3762/bjoc.4.13. (a) Farbwerke Hoechst, AG (1957) GB Patent 765,527; (1957) Chem. Abstr., 51, 81705; (b) Feiring, E.A. (1979) J. Org. Chem., 44, 2907. (a) Sheppard, W.A. (1964) J. Org. Chem., 29, 1–11; (b) Alekseeva, L.A., Belous, V.M., and Yagupolskii, L.M. (1974) J. Org. Chem. USSR, 10, 1063–1068. (a) Sheppard, W.A. (1964) J. Org. Chem., 29, 11–15; (b) Hasek, W.R., Smith, W.C., and Engelhardt, V.A. (1960) J. Am. Chem. Soc., 82, 543–551. Trainor, G.L. (1985) J. Carbohydr. Chem., 4, 545–563. Redwood, M.E. and Willis, C.J. (1965) Can. J. Chem., 43, 1893. Farnham, W.B., Smart, B.E., Middleton, W.J., Calabrese, J.C., and Dixon, D.A. (1985) J. Am. Chem. Soc., 107, 4565–4567. Zhang, X. and Seppelt, K. (1997) Inorg. Chem., 36, 5689–5693. Kolomeitsev, A.A., Bissky, G., Barten, J., Kalinovich, N., Lork, E., and R¨oschenthaler, G.-V. (2002) Inorg. Chem., 41, 6118–6124. Kolomeitsev, A.A., Vorobyev, M., and Gillandt, H. (2008) Tetrahedron Lett., 49, 449–454. (a) Chambers, R.D. 1973 Fluorine in Organic Chemistry, John Wiley & Sons,

References

29.

30.

31.

32.

33.

34.

35.

36.

Inc., New York, pp. 224–228, and references cited therein; (b) Schwertfeger, W. and Siegemund, G. (1980) Angew. Chem. Int. Ed. Engl., 19, 126. Huang, C., Liang, T., Harada, S., Lee, E., and Ritter, T. (2011) J. Am. Chem. Soc., 133, 13308–13310. Tang, P., Furuya, T., and Ritter, T. (2010) J. Am. Chem. Soc., 132, 12150–12154. (a) Fujita, T., Iwasa, J., and Hansch, C. (1964) J. Am. Chem. Soc., 86, 5175; (b) Hansch, C., Muir, R.M., Fujita, T., Maloney, P.P., Geiger, F., and Streich, M. (1963) J. Am. Chem. Soc., 85, 2817. (a) Haszeldine, R.N., Rigby, R.B., and Tipping, A.E. (1972) J. Chem. Soc., Perkin Trans. 1, 2180; (b) Still, I.W.J (1991) Phosphorus Sulfur Silicon Relat. Elem., 58, 129. (a) Bouchu, M.-N., Large, S., Steng, M., Langlois, B., and Praly, J.-P. (1998) Carbohydr. Res., 314, 37–45; (b) Russell, J. and Roques, N. (1998) Tetrahedron, 54, 13771–13782. (a) Clark, J.H., Jones, C.W., Kybett, A.P., and McClinton, M.A. (1990) J. Fluorine Chem., 48, 249–253; (b) Kirsch, P., R¨oschenthaler, G.-V., Bissky, G., and Kolomeitsev, A. (2001) DE Patent 10254597; (2003) Chem. Abstr., 139, 68948; (c) Kolomeitsev, A., Medebielle, M., Kirsch, P., Lork, E., and R¨oschenthaler, G.-V. (2000) J. Chem. Soc., Perkin Trans. 1, 2183–2185; (d) Tyrra, W., Naumann, D., Hoge, B., and Yagupolskii, Y.L. (2003) J. Fluorine Chem., 119, 101–107. (a) Yagupolskii, L.M., Kondratenko, N.V., and Sambur, V.P. (1975) Synthesis, 721–723; (b) Remy, D.C., Rittle, K.E., Hunt, C.A., and Friedman, M.B. (1976) J. Org. Chem., 41, 1644–1646; (c) Kondratenko, N.V., Kolomeitsev, A.A., Popov, V.I., and Yagupolskii, L.M. (1985) Synthesis, 667–669; (d) Clark, J.H., Jones, C.W., Kybett, A.P., McClinton, M.A., Miller, J.M., Bishop, D., and Blade, R.J. (1990) J. Fluorine Chem., 48, 249–255. Chen, C., Xie, Y., Chu, L., Wang, R.W., Zhang, X., and Qing, F.-L. (2012) Angew. Chem. Int. Ed., 51, 2492–2495.

37. (a) Dear, R.E. and Gilbert, E.E. (1972)

38. 39. 40.

41. 42.

43.

44.

45.

46.

47.

48.

49.

Synthesis, 310; (b) Lehms, I., Kaden, R., Oese, W., Mross, D., Kochmann, W., and Ziegenhagen, D. (1990) DD Patent 274820; (1990) Chem. Abstr., 113, 114647. Review: Neugebauer, T. (2000) GIT Labor Fachz., (9), 1057–1060. Wakselman, C. and Tordeux, M. (1985) J. Org. Chem., 50, 4047–4051. Joglekar, B., Miyake, T., Kawase, R., Shibata, K., Muramatsu, H., and Matsui, M. (1995) J. Fluorine Chem., 74, 123–126. Billard, T. and Langlois, B.R. (1996) Tetrahedron Lett., 37, 6865–6868. Andreades, S., Harris, J.F., and Sheppard, W.A. Jr., (1964) J. Org. Chem., 29, 898–900. (a) Fors, B.P., Davis, N.R., and Buchwald, S.L. (2009) J. Am. Chem. Soc., 131, 5766–5768; (b) Watson, D.A., Su, M., Teverovskiy, G., Zhang, Y., Garc´ıa-Fortanet, J., Kinzel, T., and Buchwald, S.L. (2009) Science, 325, 1661–1664. Teverovskiy, G., Surry, D.S., and Buchwald, S.L. (2011) Angew. Chem. Int. Ed., 50, 7312–7314. Yagupolskii, L.M., Kondratenko, N.V., and Temofeeva, G.N. (1984) J. Org. Chem. USSR, 20, 103–106. (a) Kolomeitsev, A.A., Movchun, V.N., Kondratenko, N.V., and Yagupolski, Y.L. (1990) Synthesis, 1151–1152; (b) Garlyauskajte, R.Y., Sereda, S.V., and Yagupolskii, L.M. (1994) Tetrahedron, 50, 6891–6906; (c) Movchun, V.N., Kolomeitsev, A.A., and Yagupolskii, Y.L. (1995) J. Fluorine Chem., 70, 255–257. Kondratenko, N.V., Popov, V.I., Timofeeva, G.N., Ignatiev, N.V., and Yagupolskii, L.M. (1985) J. Org. Chem. USSR, 21, 2367–2371. Kondratenko, N.V., Popov, V.I., Radchenko, O.A., Ignatiev, N.V., and Yagupolskii, L.M. (1987) J. Org. Chem. USSR, 23, 1542–1547. Yagupolskii, L.M., Garlyauskajte, R.Y., and Kondratenko, N.V. (1992) Synthesis, 749–750.

189

190

4 Selected Fluorinated Structures and Reaction Types 50. Recent reviews: (a) Lentz, D. and

51.

52.

53.

54.

Seppelt, K. (1999) in Chemistry of Hypervalent Compounds, Chapter 10 (ed. K. Akiba,), John Wiley & Sons, Inc., New York, p. 295; (b) Winter, R. and Gard, G.L. 1994 in Inorganic Fluorine Chemistry: Towards the 21st Century, ACS Symposium Series, Vol. 555 (eds. J.S. Thrasher, S.H. Strauss), American Chemical Society, Washington, DC pp. 128–147. (a) Sheppard, W.A. (1960) J. Am. Chem. Soc., 82, 4751–4752; (b) Sheppard, W.A. (1962) J. Am. Chem. Soc., 84, 3064–3071; (c) Sheppard, W.A. (1962) J. Am. Chem. Soc., 84, 3072–3076; (d) Roberts, H.L. (1962) J. Chem. Soc., 3183–3185. (a) Hoover, F.W. and Coffman, D.D. (1964) J. Org. Chem., 29, 3567–3570; (b) Case, J.R., Ray, N.H., and Roberts, H.L. (1961) J. Chem. Soc., 2066–2070. (a) Raasch, M.S. (1963) US Patent 3,073,861; (1963) Chem. Abstr., 58, 81271; (b) Jesih, A., Sypyagin, A.M., Chen, L.F., Hong, W.D., and Thrasher, J.S. (1993) Polym. Prepr. Am. Chem. Soc. Div. Polym. Chem., 34 (1), 385; (c) Clair, A.K.S., Clair T.L.S., and Thrasher, J.S. (1992) US Patent 5,220,070; (1992) Chem. Abstr., 117, 70558; (d) Williams, A.G. and Foster, N.R. (1994) WO Patent 94/22817; (1995) Chem. Abstr., 122, 58831. (a) Chambers, R.D., Greenhall, M.P., Hutchinson, J., Moilliet, J.S., and Thomson, J. (1996) in Abstracts of Papers, Proceedings of the 211th National Meeting of the American Chemical Society, New Orleans, LA, March 24–26, 1996, American Chemical Society, Washington, DC, FLUO 11; (b) Greenhall, M.P. (1997) Presented at the 15th International Symposium on Fluorine Chemistry, Vancouver, Canada, August 2–7, 1997, presentation FRx C-2; (c) Bowden, R.D., Greenhall, M.P., Moillet, J.S., and Thomson, J. (1997) (F2 Chemicals), WO Patent 97/05106; (1997) Chem. Abstr., 126, 199340; (d) Bowden, R.D., Greenhall, M.P., Moillet, J.S., and Thomson, J. (1997) (F2 Chemicals), US Patent 5,741,935; (1997) Chem. Abstr., 126, 199340.

55. (a) Stinson, S.C. (1996) Chem. Eng.

56.

57. 58. 59.

60.

61. 62.

63. 64.

65.

66. 67. 68.

News, 74 (29), 35; (b) Stinson, S.C. (2000) Chem. Eng. News, 78 (28), 63. (a) Kirsch, P., Bremer, M., Heckmeier, M., and Tarumi, K. (1999) Angew. Chem. Int. Ed., 38, 1989–1992; (b) Kirsch, P., Bremer, M., Taugerbeck, A., and Wallmichrath, T. (2001) Angew. Chem. Int. Ed., 40, 1480–1484; (c) Kirsch, P., Bremer, M., Heckmeier, M., and Tarumi, K. (2000) Mol. Cryst. Liq. Cryst., 346, 29–33. Sharts, C.M. (1998) J. Fluorine Chem., 90, 197–199. Sheppard, W.A. (1962) J. Am. Chem. Soc., 84, 3058–3063. (a) Sipyagin, A.S., Bateman, C.P., Tan, Y.-T., and Thrasher, J.S. (2001) J. Fluorine Chem., 112, 287–295, and references cited therein; (b) Kirsch, P. and Hahn, A. (2005) Eur. J. Org. Chem., 3095–3100. (a) Umemoto, T. (2008) (IM&T Research, Inc.), WO Patent 2010/014665; (b) Umemoto, T., Garrick, L.M., and Saito, N. (2012) Beilstein J. Org. Chem., 8, 461–471. Umemoto, T. and Singh, R.P. (2012) J. Fluorine Chem., 140, 17–27. Bowden, R.D., Comina, P.J., Greenhall, M.P., Kariuki, B.M., Loveday, A., and Philp, D. (2000) Tetrahedron, 56, 3399. Kleemann, G. and Seppelt, K. (1981) Angew. Chem. Int. Ed. Engl., 20, 1037. (a) Taft, R.W. and Lewis, I.C. Jr., (1959) J. Am. Chem. Soc., 81, 5343; (b) Taft, R.W. Jr., (1960) J. Phys. Chem. 64, 1805. Castro, V., Boyer, J.L., Canselier, J.P., Terjeson, R.J., Mohtasham, J., Peyton, D.H., and Gard, G.L. (1990) Magn. Reson. Chem., 28, 998. Huheey, J.E. (1965) J. Phys. Chem., 69, 3284. Roberts, J.D., Webb, R.L., and McElhill, E.A. (1950) J. Am. Chem. Soc., 72, 408. (a) Wessel, J., Hartl, H., and Seppelt, K. (1986) Chem. Ber., 119, 453; (b) Henkel, T., Klauck, A., and Seppelt, K. (1995) J. Organomet. Chem., 501, 1; (c) Kirsch, P., Binder, J., Lork, E., and R¨oschenthaler, G.-V. 2006 J. Fluorine Chem. 127, 610–619; (d) Winter,

References R.W. and Gard, G.L. (2004) J. Fluorine Chem., 125, 549–552; (e) Sergeeva, T.A. and Dolbier, W.R. (2004) Org. Lett., 6, 2417–2419. 69. A¨ıt-Mohand, S. and Dolbier, W.R. Jr., (2002) Org. Lett., 4, 3013–3015. 70. Examples: (a) Lim, D.S., Ngo, S.C., Lal, S.G., Minnich, K.E., and Welch, J.T. (2008) Tetrahedron Lett., 49, 5662–5663; (b) Welch, J.T. (2007) WO Patent 2008/101212; (c) Ponomarenko, M.V., Kalinovich, N., Serguchev, Y.A., Bremer, M., and R¨oschenthaler, G.-V. (2012) J. Fluorine Chem., 135, 68–74.

71. (a) Kirsch, P., Bremer, M., Kirsch, A.,

and Osterodt, J. (1999) J. Am. Chem. Soc., 121, 11277–11280; (b) Kirsch, P. and Hahn, A. (2006) Eur. J. Org. Chem., 1125–1131. 72. (a) Harvey, R.B. and Bauer, S.H. (1954) J. Am. Chem. Soc., 76, 859–864; (b) Roberts, H.L. (1960) J. Chem. Soc., 2774–2775. 73. (a) Case, J.R., Price, R., Ray, N.H., Roberts, H.L., and Wright, J. (1962) J. Chem. Soc., 2107–2110; (b) Case, J.R. and Roberts, H.L. (1963) UK Patent 928,412; (1963) Chem. Abstr., 59, 68933.

191

193

5 The Chemistry of Highly Fluorinated Olefins

Fluorinated olefins are particularly useful and versatile, both as synthons and in materials science [1]. This chapter gives examples of the chemistry of these compounds, but does not claim to be even close to completeness. The aim is merely to introduce the synthetic opportunities and potential applications of these structurally interesting compounds.

5.1 Fluorinated Polymethines

The chemistry of fluorinated olefins is dominated by nucleophilic addition and substitution reactions (Section 2.4.7). Depending on the acidity or basicity of the reaction medium, after a primary addition step the resulting anion is either quenched by protonation or by β-elimination of fluoride (Scheme 5.1).

F

F

F

− F Nu

F

F

−F

F

F

Nu

F

Basic medium

−

−

Nu F

F

F

F

F

F

Nu NuH Nu−

H

Neutral medium

Scheme 5.1 Different pathways for reaction of tetrafluoroethylene with nucleophiles.

On reaction with basic nucleophiles, for example, organometallic species or alcoholates, substitution products are obtained [2]. With only mildly basic to neutral nucleophiles, such as phenolate–phenol mixtures, on the other hand, addition products predominate [3] (Scheme 5.2).

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

194

5 The Chemistry of Highly Fluorinated Olefins 93%

F

F

F

F

EtOCF2CF2H

NaOEt, EtOH; 50 °C, 8 h

F

F

EtO

F

53% NaOEt, dioxane; 40 °C, 120 h

ONa

H11C5 +

OH

H11C5

EtOH, HFP; 50 °C

H11C5

F

O F

F

H CF3

(1:1)

ONa

H11C5

EtOH, HFP; 50 °C

H11C5

O

F

F

CF3

Scheme 5.2 Use of perfluoropropene for the fluoroalkylation or fluoroalkenylation of alcohols and phenols (HFP = hexafluoropropene) [2, 3], and P. Kirsch, E. Poetsch, and R. Sander, 1995, unpublished work.

This kind of chemistry is not limited to tetrafluoroethylene and it can be extended to systems with a lower fluorine content on the one hand [4], and to conjugated polyfluoromethine compounds on the other [5, 6] (Scheme 5.3). F

F F F

CN

33% NaCN, CH3CN,

F

cat. H2O; 90 °C, 3 h 80%

1. 10% aq. KOH; 90 °C, 40 min 2. H2SO4

F COOH F

Scheme 5.3 Synthesis of α,β-difluorocinnamonitriles [4] and subsequent hydrolysis to the isomeric α,β-difluorocinnamic acids.

Use of chlorotrifluoroethylene as a central scaffold allows the stepwise synthesis of, for example, α,β-difluorocinnamic acids, by nucleophilic substitution by an aryl Grignard species, followed by organometallic activation of the chlorine and subsequent quenching with a suitable electrophile (Scheme 5.4). The initial nucleophilic substitution step with Grignard or organolithium nucleophiles often takes several hours at room temperature for completion [7]. When catalytic quantities of CuI are added the reaction is complete after only a few minutes at −70 ◦ C (P. Kirsch,

5.1 Fluorinated Polymethines

195

A. Hahn, and A. Ruhl, 2001, unpublished work). The reason for this dramatic acceleration of the rate of reaction is, presumably, formation of diaryl cuprate species which act as very ‘‘soft’’ and more reactive nucleophiles, in contrast with the ‘‘hard’’ organolithium or magnesium nucleophiles. F Br MeO

Cl

78% 1. Mg, Et2O 2. CF2 = CFCl;

F

MeO

−30 °C to reflux, 4 h

1. n-BuLi, THF, Et2O, 25%

pentane; −100 °C to −85 °C 2. CO2 3. HCl

F COOH F

MeO

F Br O H11C5

Cl

1. n -BuLi, THF; −70 °C 2. CuI (0.15 equiv.) 3. CF2 = CFCl;

F

O

82%

O

O

H11C5

E/Z mixture

1. n-BuLi, THF, Et2O,

−90 to −70 °C, 1 h 76%

pentane; −100 °C to −85 °C 2. CO2 3. HCl

F F COOH

O H11C5

O

Scheme 5.4 Synthesis of substituted α,β-difluorocinnamic acids [7, 8].

Many methods are used for preparation of fluoroolefin precursors [9]. One of these strategies is based on Wittig-like metathesis reactions between carbonyl compounds and α-fluoroalkylphosphoranes [10] (Scheme 5.5). F

56% CF2Br2, PPh3, Zn, DMAc;

CHO

F

0 °C to 100 °C, 1 h

52% (E/Z = 3:2)

91% (E:Z=13:1)

SBAH, benzene; reflux, 3 h

F

CHFI2, PPh3, Zn (Cu), triglyme; 0 °C to 100 °C, 1 h

Scheme 5.5 Synthesis of fluoro- and difluoroolefins by metathesis of carbonyl compounds with fluoroalkylphosphoranes [SBAH = sodium bis(methoxyethoxy)aluminum hydride] [10d].

Another principal method is the fluorovinylation of suitable precursors by transition metal-catalyzed carbon–carbon coupling reactions [11]. Activated fluorovinyl

196

5 The Chemistry of Highly Fluorinated Olefins

species can be conveniently generated in situ from commonly used hydrofluorocarbons, for example, HFC-134a [12] (Scheme 5.6). Fluorinated vinyl zinc halides are often used for the coupling reactions, but other activated species, for example, stannanes [13] or boronates [14], have also been applied successfully. F

F F

s-BuLi, THF, Et2O;

F

−110 °C

Li

CF3CFHLi

n-BuLi, Et2O; −78 °C

N

2. cat. Pd (PPh3)4; −5 °C

N

CF3CFH2

F

50% 1. ZnCl2; −100 °C

F

I

CF2 = CFH

− LiF

n-BuLi, Et2O; −78 °C

CF2 = CFLi 1. ZnBr2; −78 °C 2. 1, 4-diiodobenzene, cat. Pd (PPh3)4, DMF;

83%

70 °C, 6 h

F F

F F

F F

Scheme 5.6 Examples of the coupling of fluorinated vinyl species to other building blocks via transition metal catalysis [11e, 12, 15]. F 33%

F

H3C

F

F

F

Cl

1. n-BuLi, THF, Et2O, H3C hexane; −100 °C 2. F F F F

F

F

F

F

−100 °C to −25 °C

F

F

F

F

F

Cl

F

22% 1. n-BuLi, THF, Et2O, hexane; −100 °C 2.

F F

F

F

F

F

F F

F F −80 °C to −70 °C, 3 h

Scheme 5.7 Homologation of fluorinated polyenes by nucleophilic replacement of fluorine by lithium organyls [6, 17].

5.1 Fluorinated Polymethines

Another method for homologation of conjugated fluorinated polyenes is based on nucleophilic replacement of fluoride from fluoroolefins [6, 16] (Scheme 5.7). The ease of structural modification of fluorinated olefins makes them an interesting structural scaffold for design of functional materials such as liquid crystals [8, 18, 19], compounds for nonlinear optics (NLO) [20], and media for holographic data storage [21] (Scheme 5.8).

F F

O

F

F

F

F

O F

F

F

(a) F

F Li

S

F

F F

F

S F

F

F

F

F Li

F

F

Li

S

F

F

S

S S F

(b)

F

F

F

F F F F F F F

F F

F F

F F Li

F

S S

Et Et

S

Et hn

hn ′

colorless

F F F F

F F blue (c)

Et S

Et

S

Scheme 5.8 Examples of the use of fluoroolefins as liquid crystals (top) [8, 19], NLO compounds (middle) [20], and photochromic materials for holographic data storage (bottom) [21].

197

198

5 The Chemistry of Highly Fluorinated Olefins

5.2 Fluorinated Enol Ethers as Synthetic Building Blocks

Difluoroenol ethers are synthetically equivalent to nucleophilic gemdifluoromethylene building blocks [22] which can be derivatized in their α-positions by a wide range of structures [23]. Similarly to their nonfluorinated analogs, they react with a variety of different electrophiles or radicals [24] and afford particularly convenient access to fluorinated analogs of natural products and other bioactive compounds. Compounds carrying a trifluoroacetyl group, for example, trifluoromethyl ketones and esters of trifluoroacetic acid, can be converted into the corresponding trimethylsilyl difluoroenol ethers [25] or into trimethylsilyldifluoroacetic acid esters [26] by reduction with magnesium metal in the presence of Me3 SiCl (Scheme 5.9). These readily accessible species are synthetically very useful as nucleophilic difluoromethylene equivalents. The same type of chemistry [27] can also be extended to trifluoromethylimines [28].

OSiMe3

O R

F3C

Mg (2 equiv.), Me3SiCl (4 equiv.),

F

THF or DMF; 0 °C, 30 min

O F3 C

R = aryl: 82−98% R = alkyl: 56−62%

R F

O

55-66%

Me3SiF2C

OAr Mg (8 equiv.), Me3SiCl (16 equiv.),

OAr

DMF; 0 °C, 3 h

N F3 C

Me3Si

Ar R

Mg (2 equiv.), Me3SiCl (4 equiv.), THF or DMF; 0 °C, 30 min

N F3 C Scheme 5.9

F

N

Ar R = aryl: 63−99% R = H: 70% R = COOEt: 63%

R F Me3Si

Ar Cl Mg (2 equiv.), Me3SiCl (4 equiv.), THF or DMF; 0 °C, 30 min

F

N

Ar SiMe3

F

Magnesium metal-promoted activation of trifluoroacetyl groups [25–28].

Trimethylsilyl difluoroenol ethers and their imine analogs react with a variety of different electrophiles [27] (Schemes 5.10 and 5.11). They have been used, for example, for the synthesis of fluorinated amino acids [28] and antimalarials [29]. Difluoromethyl ketones can also be reduced by magnesium to the corresponding fluoroenol ethers [30]. Thus, by application of one or two sequential reduction– desilylation steps, trifluoromethyl ketones can be converted into difluoromethyl and

5.2 Fluorinated Enol Ethers as Synthetic Building Blocks CHO

OSiMe3

OH O

F

71%

+

F

F F

TiCl4, CH2Cl2; −78 °C

OMe 86%

OMe Me3Si F

HN MeO

MeOH, CSA; r.t.

COOEt

F F

OMe

N COOEt

N

F

S

66%

COOEt

F F

PhSCl, CH2Cl2; −78 °C

83%

NaBH4, EtOH

OMe N S

COOEt

F F

Scheme 5.10 Examples of reactions with silyl difluoroenolates and difluoroenamines (CSA = camphorsulfonic acid) [25, 28].

H H H3C

H3C

CH3

OO O

66%

OO O H F CH3

O OAc

H CH3 O

O

OSiMe3

F F

Ph

F cat. SnCl4, CH2Cl2; −78 °C

H H H3C

CH3

H3C

CH3 97%

OO O

OO O O

H F O CH3 OHC F

OSiMe3

CH3

HO

Ph

H CH3 F F

O

cat. BF3·OEt2, CH2Cl2; −30 °C

Scheme 5.11 Synthesis of a difluoromethylene ketone-derivatized artemisinine by use of a difluoroenol silyl ether [29].

199

200

5 The Chemistry of Highly Fluorinated Olefins

fluoromethyl ketones (Scheme 5.12). Deuterodesilylation instead of the usual protodesilylation allows convenient access to deuterated analogs of these compounds. Me3SiO

O

F

Mg, Me3SiCl, THF;

S

O

F

CF3

CF2H

92% 3 M HCl

S

0 °C, 2 h

S O

O CF3

CF2D

88% 1. Mg, Me3SiCl, THF; 0 °C, 1 h 2. Bu4NF, D2O, THF

CF3 O

33%

CF2H

1.Mg, Me3SiCl, DMF; 0 °C, 2 h 2. 3 M HCl

O 35%

1. Mg, Me3SiCl, DMF; 0 °C, 2 h 2. 3 M HCl

CFH2 O

Scheme 5.12 Synthesis of fluoromethyl and difluoromethyl ketones by stepwise reduction of trifluoromethyl ketones with magnesium [30]. This method also allows the simple preparation of deuterated analogs.

Trimethylsilyl enol ethers can be thermally dimerized to the corresponding silylprotected tetrafluorocyclobutanediols [31]. If these intermediates are desilylated by use of tetrabutylammonium fluoride (TBAF), the resulting trans-diol is stable whereas the cis-diol undergoes clean conversion to the 2,2,3,3-tetrafluorobutane-1, OSiMe3

F

F

89%

F

110 °C, 6 h [2+2] cycloaddition

F Ph Me3SiO

F Bu4NF, THF; Ph OSiMe3 −80 °C, 2 h

F

F

F

F

F

F

F

Ph HO

Ph OH

+ Ph HO

Ph OH

F

F

F

F

Ph HO 63%

.

.

Ph OH

air oxidation

O F F F F

Scheme 5.13

F

F

O

Thermal dimerization of difluoroenolates and subsequent reactions [31].

5.2 Fluorinated Enol Ethers as Synthetic Building Blocks

4-dione (Scheme 5.13). Ring opening is assumed to proceed via a diradical which is oxidized by ambient air to the diketone. Reaction of trifluoromethyl vinyl ketones with magnesium–Me3 SiCl leads to a difluoro analog of Danishefsky’s diene (1) [32] (Scheme 5.14), which is a useful building block for the synthesis of fluorinated heterocycles [33]. Another inexpensive and readily accessible precursor to difluoroenol ethers is trifluoroethanol. Several O-substituted derivatives of trifluoroethanol have been O

O

O 80−90%

F3C

O

CF3 pyridine, H C = CHOC H ; 2 4 9

F3C

OC4H9

−10 °C to r.t., 16 h

OSiMe3

85%

F

Mg, Me3SiCl, DMF; 50 °C, 3 min

OC4H9 1

F

O

CHO

F F

64%

O

1. 1, ZnBr2, CH2Cl2; 0 °C, 2 h 2. cat. CF3COOH, CCl4; r.t., 5 min

O

F F

60%

N

1, ZnI2, CH3CN;

N

−20 °C, 4 h O F

MeO

52%

N

MeO

1, ZnI2, CH3CN;

OMe

N

−20 °C, 4 h

OMe O

CHO

F F

40% (92% ee) 1, Ti(OiPr)4, CH2Cl2; r.t, 16 h

O

*

OH OH (R)-BINOL

Scheme 5.14 Synthesis and preparative use of 1 as a fluorinated analog [27, 33] of Danishefsky’s diene [32].

201

202

5 The Chemistry of Highly Fluorinated Olefins

1. NaH, THF; 0 °C 2. MEM-Cl

F3C

O

OMEM

OH

F LDA (2 equiv., reverse addition), THF; −78 °C, 30 min

F3C

O Li O

F 2

NEt2 ODEC 1. NaH, THF; 0 °C 2. DEC-Cl

F

CHO

F

LDA (2 equiv., reverse addition), THF; −78 °C, 20 min

F3 C

MEMO F

90%

2

O

F

CH2 = CHCH2Br,

NaOH, Bu4N+HSO4−

F

MEMO

F F

55%

F -

O

MEMO

F LDA, THF; −78 °C to −30 °C

3

MEMO F

91%

OH

O Li

O

[2,3]-Wittig rearrangement

OH OH F F

OH O 65%

78%

SOCl2, MeOH; 0 °C

O

Ti (OiPr)4 (0.6 equiv.),

F F

OH

64%

F CH2Cl2; −78 °C OCONEt2 2. NEt3

−78 °C

O F 62%

F

Li

THF; −78 °C

F

1. DMSO, (COCl)2,

26, BF3·OEt2, THF;

O

O

52%

F

OH

O

Grubbs I catalyst (5 mol%), CH2Cl2; reflux, 24 h

F OCONEt2

F OCONEt2

OCONEt2

F

xylene; 155 °C

O

O

Scheme 5.15 Preparation of two different 1-lithio-2,2-difluoroenolates [34] (2 and 3) (box), and examples of their preparative use (MEM = 2-methoxyethoxymethyl; DEC = N,Ndiethylcarbamoyl) [35].

5.2 Fluorinated Enol Ethers as Synthetic Building Blocks

203

converted into 1-lithio 2,2-difluoroenolates by elimination of hydrogen fluoride and subsequent metalation with lithium diisopropylamide (LDA) [34]. These building blocks have the advantage that they are bivalent two-carbon units which can either be reacted sequentially with two different electrophiles or reacted first with an electrophile and then in an electrocyclic reaction (Scheme 5.15). Difluoroenol ethers are also available from esters and lactones by a Wittig-like reaction with CF2 Br2 –P(NMe2 )3 in the presence of a reducing agent [36, 37] (Scheme 5.16). H H

H

42%

O

H7C3

O

O

H7 C3

CF2Br2, P(NMe2)3, THF–dioxane 10:1; 0 °C to r.t.,18 h

F

H F F

O

Me3SiO Me3SiO

O

OSiMe3 OSiMe3

O

Me3SiO

69% CF2Br2, P(NMe2)3, Zn, THF; –20 °C to reflux, 18 h

Me3SiO

TBDMSO

TBDMSO O

O

O O

F

OSiMe3 OSiMe3 F

O

56%

F

CF2Br2, P(NMe2)3, Zn, THF; –20 °C to reflux, 2 h

O

O

Scheme 5.16 Synthesis of difluoroenol ethers from esters and lactones [36, 37].

Difluoroester enolates are available by reduction of halodifluoroacetates with zinc metal [38]. Although the reaction of O-trimethylsilyl difluoroester enolates with carbonyl compounds leads to the same reaction products as the analogous Reformatsky reaction [39] (Scheme 5.17), use of chiral catalysts results in additions with much greater enantioselectivity [40] (Scheme 5.18). F F

F F O BnO

OBn OBn

HO

64% BrCF2COOEt, Zn dust, THF; 60 °C

COOEt

BnO

HO +

OBn

71%

BnO

OBn OBn

OBn 1. MCPBA, CH2Cl2 2. CSA

OH

F F O

BnO

COOEt

COOEt OBn

OBn Scheme 5.17 Example of the synthesis of gem-difluorinated carbohydrate analogs via a Reformatsky reaction with ethyl bromodifluoroacetate [39c].

204

5 The Chemistry of Highly Fluorinated Olefins

12%

BrCF2COOEt

Mg, Me3SiCl, cat. (CH2Br)2, THF; 40 °C

F

OSiMe3

F

OEt

CH3 O (20 mol%)

1. NaOH, THF, H2O 2. Recrystallization

H19C9

OEt

H19C9 F F

O N B H Ts H19C8CHO, EtNO2; −78 °C to 0 °C

OH O

80%

OH O

93% (92% ee)

ONa 1. 4-MeOPhNH2, Bop-Cl, F F

OMe

OH O

>99% ee

H19C9

i Pr2EtN, CH2Cl2

N F F H

2. Recrystallization

MeO

MeO 99%

91% (98% ee)

O N

DEAD, PPh3, THF; r.t, 40 min

F H19C9

NH O

1. NaOH, THF, H2O 2. H2SO4, MeOH; reflux

F

OMe

H19C9

F F

Scheme 5.18 Examples of the use of halodifluoroacetates for generation of O-trimethylsilyl difluoroester enolates (DEAD = diethyl azodicarboxylate) [38a, 40].

A type of building block with similar reactivity is obtained by elimination of HF from aminals [41] or hemiaminals [42] of trifluoroacetaldehyde [43] (Scheme 5.19). OH O NMe2 F 3C NMe2

n-BuLi, Et2O; r.t., 8-10 h

F

NMe2

72%

F

NMe2

PhCHO, Et2O; 3-5 h

NMe2 F F

(a) OMe F 3C

N

OMe F n-BuLi, THF;

NBn –78 °C to 10 °C

N F

NBn 70%

PhCOCl, Me3SiOTf, THF; 10 °C to r.t., 18 h

CHO O

MeO Me3SiOTf; 10 °C to r.t.,18 h

O N

F F

NBn

OH O

(b)

MeO

X F F X = OMe: 65% X = NR2: 25%

Scheme 5.19 Examples of the preparative use of difluoroketene aminals (a) [41] and hemiaminals (b) [43].

References

References 1. (a) Chambers, R.D. (1997) Organofluo-

2.

3.

4.

5.

6.

7.

8.

9.

10.

rine Chemistry: Fluorinated Alkenes and Reactive Intermediates, Topics in Current Chemistry, Vol. 192, Springer, Heidelberg; (b) Chambers, R.D. (1997) Organofluorine Chemistry: Techniques and Synthons, Topics in Current Chemistry, Vol. 193, Springer, Heidelberg. Okuhara, K., Baba, H., and Kojima, R. (1962) Bull. Chem. Soc. Jpn., 35, 532–535. (a) Coffman, D.D., Raasch, M.S., Rigby, G.W., Barrick, P.L., and Hanford, W.E. (1949) J. Am. Chem. Soc., 71, 747–753; (b) Miller, W.T. Jr., Fager, E.W., and Griswold, P.H. (1948) J. Am. Chem. Soc., 70, 431; (c) Hanford, W.E. and Rigby, G.W. (1946) US Patent 2,409,274; (1947) Chem. Abstr., 41, 4798. Sevastyan, A.P., Khranovskii, V.A., Fialkov, Y.A., and Yagupolskii, L.M. (1974) J. Org. Chem. USSR, 10, 417–418. Review: Kremlev, M.M. and Yagupolskii, L.M. (1998) J. Fluorine Chem., 91, 109–123. Shtarev, A.B., Kremlev, M.M., and Chv´atal, Z. (1997) J. Org. Chem., 62, 3040–3045. Yagupolskii, L.M., Kremlev, M.M., Khranovskii, V.A., and Fialkov, Y.A. (1976) J. Org. Chem. USSR, 12, 1365–1366. Kirsch, P., Hirschmann, H., and Krause, J. (1998) DE Patent 19906254; (1999) Chem. Abstr., 131, 221337. (a) Burton, D.J., Yang, Z.-Y., and Qiu, W. (1996) Chem. Rev., 96, 1641; (b) van Steenis, J.H. and van der Gen, A. (2002) J. Chem. Soc., Perkin Trans. 1, 2117–2133. (a) Fuqua, S.A., Duncan, W.G., and Silverstein, R.M. (1965) J. Org. Chem., 30, 1027–1029; (b) Fuqua, S.A., Duncan, W.G., and Silverstein, R.M. (1965) J. Org. Chem., 30, 2543–2545; (c) Herkes, F.E. and Burton, D.J. (1967) J. Org. Chem., 32, 1311–1318; (d) Hayashi, S., Nakai, T., Ishikawa, N., Burton, D.J., Naae, D.G., and Kesling, H.S. (1979) Chem. Lett., 983–986.

11. (a) Burton, D.J. (1992) in Organometallics

12.

13.

14.

15. 16.

17.

18.

19.

20.

in Synthetic Organofluorine Chemistry in Synthetic Fluorine Chemistry (eds G.A. Olah, R.D. Chambers, and G.K.S. Prakash), John Wiley & Sons, Inc., New York, pp. 205–226; (b) Heinze, P.L. and Burton, D.J. (1988) J. Org. Chem., 53, 2714–2720; (c) Morken, P.A. and Burton, D.J. (1993) J. Org. Chem., 58, 1167–1172; (d) Davis, C.R. and Burton, D.J. (1996) Tetrahedron Lett., 37, 7237–7240; (e) Nguyen, B.V. and Burton, D.J. (1997) J. Org. Chem., 62, 7758–7764. Burdon, J., Coe, P.L., Haslock, I.B., and Powell, R.L. (1996) Chem. Commun., 49–50. (a) Sorokina, R.S., Rybakova, L.F., Kalinovskii, I.O., and Beletskaya, I.P. (1985) Bull. Acad. Sci. USSR Div. Chem. Sci., 34, 1506–1509; (b) Sorokina, R.S., Rybakova, L.F., Kalinovskii, I.O., Chernoplekova, V.A., and Beletskaya, I.P. (1982) J. Org. Chem. USSR, 18, 2180. (a) Frohn, H.-J., Adonin, N.Y., Bardin, V.V., and Starichenko, V.F. (2002) J. Fluorine Chem., 117, 115–120; (b) Frohn, H.-J., Adonin, N.Y., Bardin, V.V., and Starichenko, V.F. (2002) Tetrahedron Lett., 43, 8111–8114. Jiang, X.-K., Ji, G.-Z., and Wang, D.Z.-R. (1996) J. Fluorine Chem., 79, 173–17. Yagupolskii, L.M., Kremlev, M.M., Fialkov, Y.A., Khranovskii, V.A., and Yurchenko, V.M. (1976) J. Org. Chem. USSR, 12, 1565. Yagupolskii, L.M., Kremlev, M.M., Fialkov, Y.A., Khranovskii, V.A., and Yurchenko, V.M. (1977) J. Org. Chem. USSR, 13, 1438–1439. Moklyachuk, L.I., Kornilov, M.Y., Fialkov, Y.A., Kremlev, M.M., and Yagupolskii, L.M. (1990) J. Org. Chem. USSR, 26, 1324–1329. Kirsch, P., Krause, J., Hirschmann, H., and Yagupolskii, L.M. (2001) DE Patent 10102630; (2001) Chem. Abstr., 135, 325345. Shtarev, A.B. and Chv´atal, Z. (1997) J. Org. Chem., 62, 5608–5614.

205

206

5 The Chemistry of Highly Fluorinated Olefins 21. Kobatake, S., Shibata, K., Uchida, K.,

22.

23. 24. 25.

26. 27. 28.

29.

30. 31.

32.

33.

34.

35.

and Irie, M. (2000) J. Am. Chem. Soc., 122, 12135–12141. Reviews: (a) Tozer, M.J. and Herpin, T.F. (1996) Tetrahedron, 52, 8619–8683; (b) Percy, J.M. (1997) Top. Curr. Chem., 193, 131–195. Shi, G.-Q. and Cai, W.-L. (1996) Synlett, 371–372. Okano, T., Nakajima, A., and Eguchi, S. (2001) Synlett, 1449–1451. Amii, H., Kobayashi, T., Hatamoto, Y., and Uneyama, K. (1999) Chem. Commun., 1323–1324. Amii, H., Kobayashi, T., and Uneyama, K. (2000) Synthesis, (14) 2001–2003. Uneyama, K. and Amii, H. (2002) J. Fluorine Chem., 114, 127–131. (a) Mae, M., Amii, H., and Uneyama, K. (2000) Tetrahedron. Lett., 41, 7893–7896; (b) Suzuki, A., Mae, M., Amii, H., and Uneyama, K. (2004) J. Org. Chem., 69, 5132–5134. Chorki, F., Grellepois, F., Crousse, B., Our´evitch, M., Bonnet-Delpon, D., and B´egu´e, J.-P. (2001) J. Org. Chem., 66, 7858–7863. Prakash, G.K.S., Hu, J., and Olah, G.A. (2001) J. Fluorine Chem., 112, 357–362. Kobayashi, S., Yamamoto, Y., Amii, H., and Uneyama, K. (2000) Chem. Lett., 1366. (a) Danishefsky, S. (1981) Acc. Chem. Res., 14, 400; (b) Danishefsky, S.J., DeNinno, M.P. (1987) Angew. Chem. Int. Ed. Engl., 26, 15; (c) Danishefsky, S. (1989) Chemtracts Org. Chem., 2, 273. Amii, H., Kobayashi, T., Terasawa, H., and Uneyama, K. (2001) Org. Lett., 3, 3103–3105. (a) Patel, S.T., Percy, J.M., and Wilkes, R.D. (1995) Tetrahedron, 51, 9201–9216; (b) Howarth, J.A., Owton, W.M., Percy, J.M., and Rock, M.H. (1995) Tetrahedron, 51, 10289–10302. (a) 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; (b) Dimartino, G., Gelbrich, T., Hursthouse, M.B., Light, M.E., Percy, J.M., and Spencer, N.S. (1999) Chem. Commun., 2535–2536.

36. Houlton, J.S., Motherwell, W.B., Ros,

37. 38.

39.

40.

41.

42.

43.

B.C., Tozer, M.J., Williams, D.J., and Slawin, A.M.Z. (1993) Tetrahedron, 49, 8087–8106. Kirsch, P. and Poetsch, E. (1998) Adv. Mater., 10, 602–606. (a) Kitagawa, O., Taguchi, T., and Kobayashi, Y. (1988) Tetrahedron Lett., 29, 1803–1806; (b) Taguchi, T., Kitagawa, O., Suda, Y., Ohkawa, S., Hashimoto, A., Iitaka, Y., and Kobayashi, Y. (1988) Tetrahedron Lett., 29, 5291–5294; (c) Burton, D.J. and Easdon, J.C. (1988) J. Fluorine Chem., 38, 125–129; (d) Kitagawa, O., Hashimoto, A., Kobayashi, Y., and Taguchi, T. (1990) Chem. Lett., 1307–1310. (a) Hallinan, E.A. and Fried, J. (1984) Tetrahedron Lett., 25, 2301; (b) Braun, M., Vonderhagen, A., and Waldm¨uller, D. (1995) Liebigs Ann., 1447–1450; (c) Marcotte, S., D’Hooge, F., Ramadas, S., Feasson, C., Pannecoucke, X., and Quirion, J.-C. (2001) Tetrahedron Lett., 42, 5879–5882. (a) Iseki, K., Kuroki, Y., Asada, D., and Kobayashi, Y. (1997) Tetrahedron Lett., 38, 1447–1448; (b) Iseki, K., Kuroki, Y., Asada, D., Takahashi, M., Kishimoto, S., and Kobayashi, Y. (1997) Tetrahedron, 53, 10271–10280. (a) Xu, Y., Dolbier, W.R. Jr., and Rong, X.X. (1997) J. Org. Chem., 62, 1576–1577; (b) Ding, Y., Wang, J., Abboud, K.A., Xu, Y., Dolbier, W.R. Jr., and Richards, N.G.J. (2001) J. Org. Chem., 66, 6381–6388. (a) Billard, T., Langlois, B.R., and Blond, G. (2000) Tetrahedron Lett., 41, 8777–8780; (b) Billard, T., Langlois, B.R., and Blond, G. (2001) Eur. J. Org. Chem., 1467–1471; (c) Blond, G., Billard, T., and Langlois, B.R. (2001) Tetrahedron Lett., 42, 2473–2475; (d) Blond, G., Billard, T., and Langlois, B.R. (2001) J. Org. Chem., 66, 4826–4830; (e) Billard, T. and Langlois, B.R. (2002) J. Org. Chem., 67, 997–1000. Blond, G., Billard, T., and Langlois, B.R. (2002) Chem. Eur. J., 8, 2917–2922.

207

Part II Fluorous Chemistry

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

209

6 Fluorous Chemistry

In most chemical syntheses, the work-up procedure after the reaction itself is the most tedious and time-consuming step. Side products, excess reagents, and solvents must be removed. If an expensive catalyst is used, there is a strong incentive to recover and recycle it. In addition to economic aspects, especially in the design of large-scale industrial processes, ecological considerations, for example, resource-saving use of reagents and solvents, have gained increasing importance. The unique properties of highly fluorinated and perfluorinated (‘‘fluorous’’) solvents and reagents open up several routes to a solution of these problems and to a sustainable ‘‘green’’ chemistry [1–6]. These properties include their very temperature-dependent miscibility with typical hydrocarbons, their nontoxicity, and their extreme chemical inertness.

6.1 Fluorous Biphase Catalysis

Most perfluoroaliphatic solvents are not miscible with hydrocarbon solvents at room temperature. At elevated temperatures, however, a homogeneous system is formed, which separates again on cooling. This strongly temperature-dependent and reversible miscibility gap is well demonstrated by the phase diagram of the perfluoro(methylcyclohexane)/benzene system depicted in Figure 6.1. Reagents with very high fluorine contents (>60% fluorine by weight) tend to dissolve well in fluorous solvents. In a biphasic fluorocarbon–hydrocarbon system they have a strong preference for the fluorous phase. Thus, by simple temperature cycling, such a solvent system can be reversibly switched between a biphasic and a homogeneous state. In the biphasic state, fluorous reagents are exclusively present in the perfluorocarbon phase and can be separated from reaction mixture by simple means. The effects of ‘‘fluorous’’ solvents and reagents have been utilized since the beginning of the 1990s. The first practical applications were the immobilization and recovery of expensive or toxic catalysts [8] and the use of chemically inert fluorocarbons to stabilize reactive intermediates [9] (Scheme 6.1). Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

6 Fluorous Chemistry 100 90 80

1-phase region

70

Temperature T (°C)

210

60 50 40 30 2-phase region

20 10 0 0

0.1

0.2

0.3

0.4 0.5 0.6 0.7 Molar fraction x (benzene)

0.8

0.9

1

Figure 6.1 Phase diagram of the perfluoro(methylcyclohexane)/benzene system (x denotes the molar fraction of benzene; The line marks the critical temperature T c above which complete miscibility occurs [4, 7].

O

CF3

F F F

Ni O

O

CH3

n

F CF3

CF3

1

F CF3 O

O Ni

2

Ni(COD)2

F3 C F

F F

F

F F

O

F CF3 CH3

O n F CF3

O

CsF, diglyme

F F F

F CF3

F

F F

F

F

F F F

F n

MeOH

F3C F F

F F CF3 O

F F F CF3 3

O

F CF3 OMe n

F CF3

O

O

F

acetone

F CF3

O

O

O

O

F

F

F F

O F3C F F

F F F

Scheme 6.1 Catalysts for olefin dimerization – standard nickel catalyst (1) and its fluorous analog (2) (n = 3–5). In a Hostinert 216 (3)–toluene biphasic system, the catalyst stays in the fluorous phase [10] whereas the product dissolves preferentially in toluene [9].

6.1 Fluorous Biphase Catalysis

gas phase

gas phase

organic phase toluene + olefin + Ph(CO)2(acac)

organic phase toluene + aldehyde

fluorous phase C6F11CF3 + P[(CH2)2(CF2)5CF3]3

fluorous phase C6F11CF3 + catalyst

recycling

product separation

gas phase

CO, H2, 12 bar, 100 °C

cooling

homogeneous phase RCH=CH2 catalyst

P[(CH2)2(CF2)5CF3]3 + Rh(CO)2(acac)

H2, CO

Figure 6.2 Principle of the Union Carbide hydroformylation process [12]. The reactants, precatalyst, and fluorous ligand in a fluorocarbon–hydrocarbon system are heated under carbon monoxide and hydrogen

RCH2CH2CHO

HRh(CO){P[(CH2)2(CF2)5CF3]3}2

pressure to allow the catalyzed reaction in a homogeneous phase. On cooling, the system separates and the expensive catalyst can be separated and re-used with the fluorous phase.

The real breakthrough in the fluorous biphase concept [11] came in 1994, when Horv´ath and R´abai described a novel catalytic hydroformylation process based on a fluorous solvent in combination with a fluorous catalyst [12] (Figure 6.2). The solvent system was perfluoro(methylcyclohexane)–toluene, and a fluorous rhodium catalyst was constituted in situ from Rh(CO)2 (acac) and a phosphane ligand containing long perfluoroalkyl chains (often referred to as ‘‘ponytails’’). The two-phase system is heated to 100 ◦ C, under pressure, with the olefin, carbon monoxide, and hydrogen, forming a homogeneous phase in which hydroformylation occurs. On cooling, the product separates with the organic phase as the upper layer and the catalyst retained in the fluorous phase (lower layer). For the next cycle, new toluene and olefin are added and the procedure is repeated with only negligible leaching of the expensive rhodium catalyst into the organic product phase. Several factors must be taken into account in the design of the fluorous phosphane ligand [13] (Scheme 6.2). (1) The fluorine content of the ligand should be >60% of the molecular weight. (2) To shield the phosphorus center from the inductive effects of the perfluoroalkyl groups (‘‘ponytails’’), an isolating alkylene segment (CH2 )n has to be inserted. (3) If the fluorous chain (CF2 )m CF3 is too long, the solubility of the ligand in the organic and fluorous phases will be too low. Because the

211

212

6 Fluorous Chemistry

P[(CH2)n(CF2)mCF3]3

"isolation" against inductive effect of perfluoroalkyl chain

"anchor" for selective solubility in fluorous phase

fluorous "ponytail"

PH3 + CH2=CH(CF2)5CF3

26% AIBN; 100 °C, 2 h

P[(CH2)2(CF2)5CF3] Rh(CO)2(acac), quant. 2.74 MPa CO–H2 (1:1), C6F11CF3; 80 °C, 2 h

HRh(CO){P[(CH2)2(CF2)5CF3]3}2

Scheme 6.2 Design and synthesis of the fluorous phosphane ligands and the catalyst for fluorous biphasic hydroformylation [13].

ethylene bridge (n = 2) has been identified as the optimum isolating group, the best compromise between fluorophilicity and general solubility is the perfluorohexyl chain (m = 5). The temperature-dependent miscibility of fluorous biphasic systems [4] can be predicted by use of the Hildebrand–Scatchard or regular solution theory [7, 14]. According to this theory, the critical temperature (T c ), above which the two liquids of a biphasic system mix in all ratios is close to the phase-separation temperature of a biphasic system consisting of equal volumes of each phase:   K v1 + v2 Tc = 4R  2 K = δ1 − δ2

(6.1) (6.2)

where R is the universal gas constant and vi the molar volume. The variable K (J m−3 ) is a measure of the interaction energy between unlike molecules relative to that between similar molecules. The weaker the interaction between two unlike molecules, the higher is the value of K. Large values of K correspond to a high critical temperature T c , that is, to low miscibility of the biphasic system.

6.1 Fluorous Biphase Catalysis

 δi =

Hiv vi

(6.3)

The Hildebrand parameter δ i (MPa0.5 ) of a solvent is defined by Eq. (6.3) as a function of the enthalpy of vaporization (Hi v and the molar volume (vi ). From Eqs. (6.1) and (6.2), it can be calculated that two liquids are miscible at room temperature when |δ 1 − δ 2 | is less than about 7 MPa0.5 for an average molar volume of 100 ml. The Hildebrand parameters, δ i , are very low for typical fluorous solvents (ranging from 12.1 for perfluorohexane to 12.7 for perfluorotributylamine), intermediate for organic solvents (n-hexane 14.9, toluene 18.2, dichloromethane 19.8, acetonitrile 24.3), and high for hydrophilic solvents (methanol 29.7, ethylene glycol 34.9, water 48.0). Of special usefulness for fluorous biphasic separations are organic solvents with a Hildebrand parameter of ∼18 MPa0.5 , because these result in phase separation at room temperature. Supercritical carbon dioxide (scCO2 ) with a pressure-dependent δ-value between fluorous and organic solvents [δ(scCO2 ) = 18.2 MPa0.5 × ρ sc /ρ liq ] dissolves many fluorous compounds in sufficient concentrations to be useful as a ‘‘green’’ reaction medium [15]. A similar quantitative theory allowing the prediction of the fluorophilicity fi (a substance is considered fluorophilic if fi > 0) or the fluorous partition coefficients Pi for fluorous reagents [16] is, unfortunately, not available.    c C F CF fi = lnPi = ln i  6 11 3  ; T = 298 K (6.4) ci C6 H5 CH3 Nevertheless, for the general design of fluorous compounds, some rules have been derived by combination of empirical and computational methods [quantitative structure–activity relationships (QSARs), neural network simulation] [17]. These rules are illustrated by the data in Table 6.1 and can be summarized as follows: • Rule 1: The fluorine content must be at least 60% by molecular weight. • Rule 2: The longer the fluorous ponytail, the higher is the partition coefficient and the lower is the absolute solubility in both phases. On the other hand, an increase in the proportion of ‘‘anti-fluorous’’ (fluorophobic) [19, 20] domains in the molecule increases the absolute solubility in the organic phase. • Rule 3: Increasing the number of fluorous ponytails leads to an increase in the partition coefficient while retaining acceptable solubility in the fluorous phase [21]. • Rule 4: The number of ‘‘anti-fluorous’’ functional groups capable of attractive intermolecular interactions, via electrostatic forces, hydrogen bonds, or dispersion interactions, must be minimized [22]. An example of such an ‘‘anti-fluorous’’ effect is the low fluorophilicity of hexafluorobenzene (12) and pentafluorobenzene (13), despite their high relative fluorine contents. Both compounds can participate in specific electrostatic interactions with electron-rich hydrocarbons, for example, the toluene component of the biphasic test mixture.

213

214

6 Fluorous Chemistry Partition coefficients (Pi ) at T = 24 ◦ C in the perfluoro(methylcyclohexane)– toluene system, fluorophilicity parameters (fi ), and fluorine content (fluorine as a percentage of molecular weight) of a variety of fluorinated and non-fluorinated compounds.

Table 6.1

(CH2)12H

(CF2)8F 5

4

(CF2)8F (CF2)8F

(CF2)8F (CF2)8F 7

6

8

(CF2)8F

(CF2)8F (CF2)10F (CF2)10F

(CF2)6F (CF2)6F 10

9

(CF2)8F (CF2)8F 11 (CF2)8F H

F F F

F

F

F

F

F 12 Compound 4 5 6 7 8 9 10 11 12 13

Pi 0.10 0.98 10.36 9.75 10.24 2.80 37.46 >3000 0.39 0.29

Data modified or calculated from Ref. [18].

F F F 13 fi −2.31 −0.02 2.34 2.28 2.33 1.03 3.62 >8 −0.94 −1.24

Fluorine content (%) 0 60 64 64 64 62 67 66 61 57

6.1 Fluorous Biphase Catalysis

215

The effect of structure (linear or branched, incorporation of heteroatoms, etc.) and conformational flexibility or rigidity of the fluorous ponytail on the partition coefficients has not yet been studied in detail. After publication of details of the biphasic catalytic hydroformylation system in 1994, many applications of the same concept were found. A variety of fluorous triarylphosphane ligands were synthesized to permit recycling of precious transition metal catalysts [15b, 23] (Scheme 6.3). I

F17C8

53%

NH2

1. Cu, C8F17I, DMF; 120 °C

Br

2. tBuONO, CuBr, MeCN; −5 °C to RT

RF RF = C8F17 25%

1. tBuLi, THF; −78 °C 2. PCl3; −78 °C to r.t.

P RF

RF Br

RF = CH2CH2C8F17

F17C8CH2CH2

46%

61%

Br 1. Mg, Et2O; r.t

Br

Na2[PdCl4], Et2O; r.t, sonication

2. F17C8CH2CH2I, [Cu(COD)Cl], THF; −5 °C to r.t.

((RFPh)3P)2PdCl2 fluorous catalyst

14: 94% 15: 98%

MeOOC + Br

O

SnBu3 catalyst, C6F11CF3,

14: RF = C8F17 15: RF = (CH2)2(CF2)8F

MeOOC O

DMF, LiCl; 80 °C

Scheme 6.3 An example of the synthesis of a fluorous phosphane ligand and one of the variety of reactions catalyzed by fluorous transition metal complexes [23g].

Because of their high solubility in scCO2 , similar fluorous catalyst systems have also been successfully used for the enantioselective hydroformylation of olefins in this environmentally benign reaction medium [24] (Scheme 6.4). Fluorous chiral binaphthol ligands have been used for the enantioselective addition of diethylzinc to aldehydes in a biphasic system [25] (Scheme 6.5). Lanthanoid salts with noncoordinating anions carrying long perfluoroalkyl chains, Yb[C(SO2 C8 F17 )3 ]3 (19) and Sc[C(SO2 C8 F17 )3 ]3 (20), have been successfully used as Lewis catalysts for O-acylations and Friedel–Crafts, Diels–Alder, and Mukayama aldol reactions in fluorous biphasic media [26] (Scheme 6.6).

216

6 Fluorous Chemistry

CHO CHO *

+

cat. HRh(CO)2(16), CO–H2 (60 bar), scCO2 (d = 0.6 g·ml−1); 60 °C

93% 92% ee, (R)

NEt2 P

RF

MgBr

Br

7%

RF -I, CuCl

Br

conc. HCl

1. n-BuLi 2. PCl2 (NEt2)

OTf OTf

OH OH Tf2O

O H P

RF

RF

RF

O

17 RF

OTf P

17, Pd(OAc)2, dppb, NEt(i Pr)2

RF RF

O

LiOH, H2O, THF

OH

OH SiHCl3, NEt3

P

P RF

RF RF

RF

O

O P Cl O NEt3

O

P

O 16

P RF RF

Scheme 6.4 Synthesis of the chiral fluorous (R,S)-3-H2 F6 -Binaphos (16) ligand for the rhodium-catalyzed enantioselective hydroformylation of olefins in supercritical carbon dioxide (scCO2 ) [24] [RF = (CH2 )2 (CF2 )6 F].

6.1 Fluorous Biphase Catalysis

217

OH

O H

70−80% (55−60% ee)

+ Et2Zn

Et

(S )-18 (20 mol%), Ti(OiPr)4, perfluoro(methyldecalin)– hexane; 45 °C, 1 h

(a)

C8F17

Br

Br Br OH OH

F17C8

98%

OH OH

Br2; −78 °C

OH OH

46% C8F17I, Cu, DMSO; 160 °C

Br

F17C8 C8F17

Br

Br C8F17

81%

F17C8

O O O

(+)-(S)-camphorsulfonyl chloride (CsoCl)

SO2

O SO2Cl

SO2 O

F17C8 C8F17

C8F17

C8F17 F17C8

F17C8 less polar

OCso OCso

OH OH

85% NaOH

F17C8

F17C8 C8F17 chromatography

(S)-18

C8F17

C8F17 F17C8

F17C8 OCso OCso

more polar

OH OH

82% NaOH

F17C8

F17C8 (b)

C8F17

C8F17

(R)-18

Scheme 6.5 Enantioselective carbon–carbon bond formation in a fluorous biphasic system (a), and synthesis of the fluorous 1,1 -bis(2-naphthol) (BINOL) catalyst (18) (b) (Cso = camphorsulfonyl) [25].

C8F17

218

6 Fluorous Chemistry

19: Yb[C(SO2C8F17)3]3 20: Sc[C(SO2C8F17)3]3 96-98%

OH

OAc

Ac2O, 19 or 20 (1 mol%), C6F11CF3–toluene; 30 °C, 20 min 91%

+

20 (5 mol%), C6F11CF3–(CH2Cl)2;

O

O

35 °C, 8 h

O 87%

MeO

Ac2O, 20 (10 mol%), C6F11CF3–(CH2Cl)2;

MeO

70 °C, 6 h

CHO

OSiMe3 + OMe

84%

OSiMe3 COOMe

19 or 20 (1 mol%), C6F11CF3–toluene; 40 °C,15 min

Scheme 6.6 Reactions in fluorous biphasic media catalyzed by fluorous lanthanoid-based Lewis acids [26].

In these reactions, the fluorous medium avoids deactivation of the Lewis acid by solvent coordination. The catalyst can also be recycled and reused. Disadvantages of this ‘‘classic’’ fluorous biphase catalysis are the high price and the high global warming potential of the perfluoroalkane solvent, even if it can be reused several times. Gladysz and co-workers reported a system making use of the extreme temperature dependence of the solubility of fluorous trialkylphosphanes in organic solvents [27] (Figure 6.3). For example, the solubility of the fluorous phosphane P[(CH2 )2 (CF2 )8 F] (21) in octane is 150-fold higher at 100 ◦ C than at 20 ◦ C. After catalyzing the addition of an alcohol to methyl propiolate in a simple hydrocarbon solvent, the phosphane catalyst can be nearly quantitatively removed from the reaction mixture simply by cooling to −30 ◦ C and decanting from the waxy solid. An even more convenient way to separate fluorous catalysts from organic reaction mixtures is to use fluorous affinity in the solid state [28]. The fluorous phosphine ligand used, for example, in a Morita–Baylis–Hillman reaction, can be removed by adsorption on poly(tetrafluoroethylene) (PTFE, Teflon), either as Teflon tape or Gore-Rastex fibers, and coprecipitation together with them [29] (Scheme 6.7). For typical fluorous biphase catalysis, the most important aspect is the simple recycling and re-use of the catalyst. Fluorous solvents have one special

6.1 Fluorous Biphase Catalysis

O

82% (1st cycle), 75% (5th cycle)

O

O

BnO

P[(CH2)2(CF2)8F]3 (21)(10 mol%),

O

BnOH, octane; 65 °C, 8 h

COOMe

O O BnOH

65 °C

BnO

homogeneous octane solution

−30 °C octane

octane

decant product solution

fluorous catalyst (10 mol%) recycle catalyst

Figure 6.3 Catalysis with a fluorous phosphane catalyst (21) in a homogeneous hydrocarbon solvent. Because of the very different solubility of 21 in hot and cold octane, the catalyst can be quantitatively precipitated from the reaction mixture simply by cooling to −30 ◦ C (the lower scheme was re-drawn from Ref. [27]).

OH

O

O

O 10 mol% P((CH2)3C8F17)3; CH3CN, 60-64 °C

H

addition of catalystloaded PTFE to solution of starting material

physisorption of fluorous phosphine or PTFE at −30 °C

decanting of product solution

Scheme 6.7 The fluorous phosphine catalyst for a Morita–Baylis–Hill reaction can be fully recovered by adsorption to PTFE, most effectively as high surface area Gore-RastexTM fibers [29].

advantage over hydrocarbon solvents, however: their very high oxygen-dissolving capacity, combined with their extreme resistance to oxidative decomposition, makes perfluorocarbons in combination with fluorous catalysts the optimum choice for oxidation reactions. Thus, the biomimetic oxidation of olefins with molecular oxygen and 2-methylpropanal as a co-reductand has been achieved with

219

220

6 Fluorous Chemistry

a fluorous cobalt porphyrin catalyst (22) [30], and also even without catalyst [31] (Scheme 6.8).

C8F17

F17C8

95%

F17C8

N

C8F17

N Co

N

O

22 (0.1 mol%), O2, Me2CHCHO, C6F13CF3; r.t., 5 h

N C8F17

F17C8

O

O2, Me3CHO,

22

solvent; 25 °C, 4 h

C8F17

F17C8

no solvent: 0% FC-75 : 95%

Scheme 6.8 Catalyzed and uncatalyzed biomimetic oxidations in fluorous solvents (FC-75 consists mainly of perfluoro n-butyltetrahydrofuran, b.p. 102 ◦ C, commercially available from 3M) [30, 31].

Similar results have been obtained with manganese, cobalt, and copper complexes of fluorous aza-crown ethers (23 and 24) [32] (Scheme 6.9).

F17C8

C8F17

N

N

23

N

OH

C8F17 RFO

O

N

N

N

N

O

RFO 24

RFO

O

O

cat. Mn-, Co-,Cumacrocycle, O2,

O +

tBuOOH, C6F14

RFO

RFO = −CF _ 3)CF2)q(OCF2)pOCF3, _ 2(OCF(CF q = 3.38; p = 0.11 Scheme 6.9 Oxidation of cyclohexene with molecular oxygen catalyzed by transition metal complexes of fluorous macrocycles (23 and 24) in perfluorohexane as solvent [32].

A variety of different substrates can also be oxidized by molecular oxygen in the presence of fluorous ruthenium or nickel β-diketonates in fluorous solvents [33] (Scheme 6.10).

6.1 Fluorous Biphase Catalysis

F15C7

OMe

+

O

O

O

O

80%

H3C

C7F15 NaOMe, Et O; 2

C7F15

F15C7

0 °C, 12 h, then r.t., 48%

62%

−

F15C7 K+ F15C7

F15C7

O

O

Ru O 3

O

Ni F15C7

25

2

26

O

O 72%

TIPSO

NiCl2, NaOAc

81%

RuCl3, EtOH, KHCO3

H

TIPSO

OH

3 mol% 25, O2 (1 atm), toluene–perfluorodecalin; 64 °C, 12 h

O Ph

S

91%

Ph

3 mol% 25, O2 (1 atm),

Ph

S

Ph

1.6 equiv. Me2CHCHO, toluene–C8F15Br; 60 °C,10-16 h

Ph

S

83%

Et

3 mol% 25, O2 (1 atm),

O O S Ph Et

5 equiv. Me2CHCHO, toluene–C8F15Br; 85%

O

5 mol% 26, O2 (1 atm), 1.5-2 equiv. Me2CHCHO, toluene–C8F15Br; 50 °C, 12 h

Scheme 6.10 Oxidations with molecular oxygen, catalyzed by fluorous ruthenium and nickel β-diketonates (25 and 26) [33].

221

222

6 Fluorous Chemistry

Similar, fluorous palladium β-diketonate complexes (27) have been employed for Wacker oxidation of olefins to the corresponding ketones in a biphasic system [34] (Scheme 6.11). O 54-95%

R

R

t BuOOH (1.5-3.5 equiv.), 27 (5 mol%), benzene–C8F17Br

CH3

F15C7

O O Pd O

F15C7

Ph

73%

Ph

Ph

Ph

t BuOOH (1.5 equiv.), 27 (5 mol%), benzene–C8F17Br;

2

56 °C

27 Ph

59%

COOEt

Ph

t BuOOH (1.5 equiv.), 27 (5 mol%), benzene–C8F17Br;

COOEt O

56 °C

Scheme 6.11 system [34].

Wacker oxidation of olefins with a fluorous Pd(II) catalyst (27) in a biphasic

Another industrially important oxidation reaction, the Baeyer–Villiger oxidation [35] of ketones to esters by 35% aqueous hydrogen peroxide, can also be advantageously conducted in a fluorous biphasic medium [36]. When the recyclable fluorous Lewis acidic tin(IV) complex 28 is used as catalyst, very high selectivity of conversion of ketones to the corresponding esters or lactones is achieved (Scheme 6.12). Sn[N(SO2C8F17)2]4 28 O

O 96% conversion (99% selectivity)

O

28 (1 mol%), CF3C6F11–(CH2Cl)2 1:1, 35% aq. H2O2; 50 °C, 1 h

O

O

94% conversion (99% selectivity)

O

28 (1 mol%), CF3C6F11–(CH2Cl)2 1:1, 35% aq. H2O2; 50 °C, 2 h

O H3C

67% conversion (99% selectivity) 28 (3 mol%), CF3C6F11–(CH2Cl)2 1:1, 35% aq. H2O2; 50 °C, 5 h

O H3C

O

Scheme 6.12 Baeyer–Villiger oxidation of ketones to the corresponding lactones. The oxidations were conducted in a fluorous biphasic medium in the presence of the fluorous tin(IV) complex 28 as Lewis acid catalyst. The selectivity is defined as the ratio of the quantity of lactone formed to that of ketone used [36].

6.1 Fluorous Biphase Catalysis

223

The use of fluorous chiral manganese salen (Jacobsen–Katsuki) catalysts (29 and 30) [37] in combination with different oxidants allows the enantioselective epoxidation of olefins [38] in high yields and with moderate to high enantiomeric excess (Scheme 6.13).

H

H N

N Mn O ClO

F17C8

29: 83% (92% ee) 30: 77% (90% ee)

C8F17

C8F17 F17C8 Ph

catalyst, D-100, O2 (1 atm); r.t., 2-3 h

29

Ph 29: 70% (10% ee) 30: 73% (13% ee)

N

N Mn O ClO

F17C8

catalyst, D-100, O2 (1 atm); r.t., 8 h

C8F17 30

C8F17 F17C8 (a)

COOH I

OH I

COOMe 65% 1. Me2SO4, K2CO3, acetone; reflux 2. C8F17I, Cu, DMF;

F17C8

OMe C8F17

125 °C

52% 1. LiAlH4, Et2O; 0 °C 2. aq. NaOCl, KBr (10 mol%), TEMPO, PhCF3; 5 °C 3. BBr3, CH2Cl2; −78 °C to r.t.

CHO F17C8

OH C8F17

(b)

O

1. EtOH; reflux R R H H H 2N NH2 2. Mn(OAc)2·4H2O

29: R = −(CH2)4− 30: R = Ph

Scheme 6.13 Enantioselective epoxidation of olefins with fluorous Jacobsen–Katsuki catalysts 29 and 30 (a) [38a], and the synthesis of these catalysts (b) (D-100 consists mainly of n-perfluorooctane, b.p. 100 ◦ C, and is commercially available from Ausimont).

Because of the inertness of perfluorohexane and of 5,10,15,20-tetrakis (perfluoropropyl)porphyrin (31) as sensitizer, the photocatalytic oxidation of allyl alcohols and cyclohexene with singlet oxygen (1 O2 ) can be achieved with negligible degradation of the porphyrin catalyst [39] (Scheme 6.14). In perfluorohexane, singlet oxygen has the relatively long lifetime of ∼100 ms whereas the lifetime in

O

224

6 Fluorous Chemistry OH

OH 57%

H13C6

CH3 sensitizer, O , CCl ; 2 4

H13C6

hn, 0 °C, 22.5 h

OOH OOH

96 % sensitizer, O2, C6F14–CD3CN; hn, 0 °C, 48 h

C3F7

sensitizer:

NH

N C3F7

F7C3 N

HN

C3F7

31

Scheme 6.14 Photosensitized oxidation of allylic alcohols and cyclohexene with singlet oxygen (1 O2 ) in the presence of a fluorous porphyrin sensitizer (31) [39a].

acetonitrile is only 54.4 μs [40]. In contrast, if ‘‘nonfluorous’’ tetraphenylporphyrin is used instead of its fluorous analog, the catalyst is rapidly destroyed by oxidation.

References 1. Horv´ath, I.T. (1998) Acc. Chem. Res., 31, 2. 3. 4.

5.

6.

7. 8.

641–650. Fish, R.H. (1999) Chem. Eur. J., 5, 1677–1680. Hope, E.G. and Stuart, A.M. (1999) J. Fluorine Chem., 100, 75–83. de Wolf, E., van Koten, G., and Deelman, B.-J. (1999) Chem. Soc. Rev., 28, 37–41. Cavazzini, M., Montanari, F., Pozzi, G., and Quici, S. (1999) J. Fluorine Chem., 94, 183–193. Boswell, P.G., Lugert, E.C., R´abai, J., Amin, E.A., and B¨uhlmann, P. (2005) J. Am. Chem. Soc., 127, 16976–16984. Lo Nostro, P. (1995) Adv. Colloid Interface Sci., 56, 245. (a) Vogt, M. (1991) Zur Anwendung perfluorierter Polyether bei der Immobilisierung homogener Katalysatoren. PhD thesis, RWTH Aachen; (b) Keim, W., Vogt, M., Wasserscheid, P., and Driessen-H¨olscher, B. (1999) J. Mol. Catal. A: Chem., 139, 171–175.

9. Zhu, D.-W. (1993) Synthesis, 953–954. 10. Marchioni, G., Ajroldi, G., and Pezzin,

11. 12. 13.

14. 15.

G. (1996) Structure–Property Relationships in Perfluoropolyethers: A Family of Polymeric Oils, Comprehensive Polymer Science, 2nd Suppl. (eds G. Allen, S.L. and Aggarwal, S. Russo), Pergamon Press, Oxford, pp. 347–388. Horv´ath, I.T. (1998) Acc. Chem. Res., 31, 641–650. Horv´ath, I.T. and R´abai, J. (1994) Science, 266, 72–75. Horv´ath, I.T., Kiss, G., Cook, R.A., Bond, J.E., Stevens, P.A., R´abai, J., and Mozeleski, E.J. (1998) J. Am. Chem. Soc., 120, 3133–3143. Scott, R.L. (1958) J. Phys. Chem., 62, 136, and references cited therein. (a) Leitner, W. (2002) Acc. Chem. Res., ` G. and Leitner, 35, 746–756; (b) Francio, W. (1999) Chem. Commun., 1663–1664; (c) Koch, D. and Leitner, W. (1998) J. Am. Chem. Soc., 120, 13398; (d) Cooper, A.I., Londono, J.D., Wignall,

References

16.

17.

18.

19.

20.

21.

22.

23.

G., McClain, J.B., Samulski, E.T., Lin, J.S., Dobrynin, A., Rubinstein, M., Burke, A.L.C., Fr´echet, J.M.J., and DeSimone, J.M. (1997) Nature, 389, 368–371. (a) Kiss, L.E., Rab´ai, J., Varga, L., K¨ovesdi, I. (1998) Synlett, 1243; (b) Szl´avik, Z., T´ark´anyi, G., Tarczay, G., ´ and R´abai, J. (1999) J. G¨om¨ory, A., Fluorine Chem., 98, 83. Kiss, L.E., K¨ovesdi, I., and Rab´ai, J. (2001) J. Fluorine Chem., 108, 95–109. Rocaboy, C., Rutherford, D., Bennett, B.L., and Gladysz, J.A. (2000) J. Phys. Org. Chem., 13, 596–603. Alvey, L.J., Rutherford, D., Juliette, J.J.J., and Gladysz, J.A. (1998) J. Org. Chem., 63, 6302. Curran, D.P., Hadida, S., Kim, S.-Y., and Luo, Z. (1999) J. Am. Chem. Soc., 121, 6607. Richter, B., de Wolf, E., van Koten, G., and Deelman, B.-J. (2000) J. Org. Chem., 65, 3885. (a) Giddings, J.C. (1991) Unified Separation Science, John Wiley & Sons, Inc., New York, pp. 16–36; (b) Hildebrand, J.H. and Scott, R.L. (1964) The Solubility of Nonelectrolytes, 3rd edn., Dover, New York. (a) Bhattacharyya, P., Gudmundsen, D., Hope, E.G., Kemmitt, R.D.W., Paige, D.R., and Stuart, A.M. (1997) J. Chem. Soc., Perkin Trans. 1, 3609–3612; (b) Kling, R., Sinou, D., Pozzi, G., Choplin, A., Quignard, F., Busch, S., Kainz, S., Koch, D., and Leitner, W. (1998) Tetrahedron Lett., 39, 9439–9442; (c) Mathivet, T., Monflier, E., Castanet, Y., Mortreux, A., and Couturier, J.-L. (1998) Tetrahedron Lett., 39, 9411–9414; (d) Sinou, D., Pozzi, G., Hope, E.G., and Stuart, A.M. (1999) Tetrahedron Lett., 40, 849–852; (e) Mathivet, T., Monflier, E., Castanet, Y., Mortreux, A., and Couturier, J.-L. (1999) Tetrahedron Lett., 40, 3885–3888; (f) Bhattacharyya, P., Croxtall, B., Fawcett, J., Fawcett, J., Gudmunsen, D., Hope, E.G., Kemmitt, R.D.W., Paige, D.R., Russell, D.R., Stuart, A.M., and Wood, D.R.W. (2000) J. Fluorine Chem., 101, 247–255; (g)

24.

25. 26.

27.

28.

29. 30. 31.

32.

33.

34.

35. 36.

37.

38.

Schneider, S. and Bannwarth, W. (2000) Angew. Chem. Int. Ed., 39, 4142–4145. ` G., Wittmann, K., and Leitner, Francio, W. (2001) J. Organomet. Chem., 621, 130–142. Tian, Y. and Chan, K.S. (2000) Tetrahedron Lett., 41, 8813–8816. Mikami, K., Mikami, Y., Matsumoto, Y., Nishikido, J., Yamamoto, F., and Nakajima, H. (2001) Tetrahedron Lett., 42, 289–292. Wende, M., Meier, R., and Gladysz, J.A. (2001) J. Am. Chem. Soc., 123, 11490–11491. Baker, R.J., Colavita, P.E., Murphy, D., Platts, J.A., and Wallis, J.D. (2012) J. Phys. Chem. A, 116, 1435–1444. Seidel, F.O. and Gladysz, J.A. (2008) Adv. Synth. Catal., 350, 2443–2449. Pozzi, G., Montanari, F., and Quici, S. (1997) Chem. Commun., 69–70. Pozzi, G., Montanari, F., and Rispens, M.T. (1997) Synth. Commun., 27, 447–452. (a) Vincent, J.-M., Rabion, A., Yachandra, V.K., and Fish, R.H. (1997) Angew. Chem. Int. Ed. Engl., 36, 2346–2348; (b) Pozzi, G., Cavazzini, M., Quici, S., and Fontana, S. (1997) Tetrahedron Lett., 38, 7605–7608. Klement, I., L¨utjens, H., and Knochel, P. (1997) Angew. Chem. Int. Ed. Engl., 36, 1454–1456. Betzemeier, B., Lhermitte, F., and Knochel, P. (1998) Tetrahedron Lett., 39, 6667–6670. cf. Renz, M. and Meunier, B. (1999) Eur. J. Org. Chem., 54, 737–750. Hao, X., Yamazaki, O., Yoshida, A., and Nishikido, J. (2003) Tetrahedron Lett., 44, 4977–4980. (a) Jacobsen, E.N. (1993) in Catalytic Asymmetric Synthesis (ed. I. Ojima), Wiley-VCH Verlag GmbH, Weinheim, p. 159; (b) Katsuki, T. (1996) J. Mol. Catal., 113, 87, and references cited therein. (a) Pozzi, G., Cinato, F., Montanari, F., and Quici, S. (1998) Chem. Commun., 877–878; (b) Cavazzini, M., Manfredi, A., Montanari, F., Quici, S., and Pozzi, G. (2000) Chem. Commun., 2171–2172.

225

226

6 Fluorous Chemistry 39. (a) DiMagno, S.G., Dussault, P.H.,

and Schultz, J.A. (1996) J. Am. Chem. Soc., 118, 5312–5313; (b) for a similar reaction, see: Chambers, R.D., and

Sandford, G. (1996) Synth. Commun., 26, 1861–1866. 40. Ogilby, P.R. and Foote, C.S. (1983) J. Am. Chem. Soc., 105, 3423–3430.

227

7 Fluorous Synthesis and Combinatorial Chemistry 7.1 Fluorous Synthesis

Fluorous solvents and biphasic systems have advantages not only for catalytic processes but also for classic organic synthesis. Since the mid-1990s, several synthetic procedures have been published that make use of fluorous reagents which facilitate either work-up or recycling, particularly of toxic compounds. One of the first examples, combining both of these advantages, was the introduction of fluorous tin halides [1] and hydrides [2] by Curran et al. [3] (Scheme 7.1). Fluorous tin halides can be reduced to the corresponding hydrides, which are the reagents of choice for radical hydrodehalogenations. After the reaction, the reagent used, again a fluorous tin halide, can be recovered readily by extraction with a perfluorocarbon solvent. C6F13CH2CH2MgI

86% PhSnCl3, Et2O

(C6F13CH2CH2)3SnPh

93–98%

(C6F13CH2CH2)3SnBr 1

(C6F13CH2CH2)3SnH 2

LiAlH4, Et2O

C10F21I

98% Br2, Et2O

73% 2, AIBN (5 mol%), PFMC; 80 °C, 2 h

C10F21H 90% CH2Cl2

Br Ph

2, AIBN (5 mol%), BTF; 80 °C, 2 h

95% PFMC

1 Ph

Ph

Ph

72%

Br

1. 2 (10 mol%), BTF–tBuOH, NaCNBH3, AIBN (5 mol%) 2. triphasic work-up (H2O–BTF–PFMC)

Scheme 7.1 Examples of radical reductions by the fluorous tin hydride reagent 2. The reagent can be removed from the reaction mixture by organic–fluorous liquid–liquid extraction [2a, 3]. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

228

7 Fluorous Synthesis and Combinatorial Chemistry

The fluorous tin halides are also of use as precursors for the trialkylstannyl activating group which is required for the Stille coupling [4]. Here a trialkylstannylarene (typically tributylstannyl) is cross-coupled with a bromoarene in the presence of a palladium catalyst. The major obstacle to large-scale application of the Stille reaction is the toxicity of the auxiliary organotin reagents. If a fluorous version of the trialkylstannyl residue is used instead, the organotin by-products can be easily recovered by means of a reaction work-up with an organic–aqueous–fluorous threephase extraction procedure [1a,d] (Scheme 7.2). Purification of the biaryl reaction (C6F13CH2CH2)3SnBr

OMe

74% p-MeO-PhMgBr

(C6F13CH2CH2)3Sn 90%

OMe

CH2Cl2 1. PhI, PdCl2(PPh3)2 (2 mol%), LiCl, DMF–THF (1:1); 80 °C, 22 h 2. 3-phase work-up (H2O–CH2Cl2–FC-72)

99%

(C6F13CH2CH2)3SnCl

FC-72

Scheme 7.2 Stille coupling with a fluorous trialkyltinarene component [1a]. Three-phase work-up permits convenient removal (and possible subsequent recycling) of toxic organotin side products (FC-72 consists mostly of isomers of C6 F14 , b.p. 56 ◦ C, and is commercially available from 3M). aq. NH4Cl

R

Et3NH+Cl− R

OH (excess)

CH2Cl2

1. (C6F13CH2CH2)3SiCl (2), NEt3, THF 2. 3-phase extraction (aq. NH4Cl–CH2Cl2–FC-72)

OH (for recycling) R OSi(CH2CH2C6F13)3

FC-72

1. R1-CNO (excess, generated in situ) 2. 3-phase extraction (H2O–CH2Cl2–FC-72) CH2Cl2

FC-72

R1

N O R

organic OSi(CH2CH2C6F13)3 side-products

H2O

inorganic side-products

1. HF-pyr, Et2O 2. 3-phase extraction (aq. NH4Cl–CH2Cl2–FC-72) FC-72

fluorous side-products

32–73%

R1

CH2Cl2

N O R OH

aq. NH4Cl

inorganic side-products

Scheme 7.3 Simplification of product purification after 1,3-dipolar cycloaddition by use of fluorous silyl protecting groups (R = H, CH3 ; R1 = CH3 , C3 H7 , Ph) [5]. The nitrile oxide (R1 CNO) is generated in situ by either the Huisgen or the Mukaiyama method [6].

7.1 Fluorous Synthesis

product is also significantly simplified by this procedure, because separation of organotin compounds from other substances is notoriously difficult. Fluorous trialkylsilyl protecting groups have also been used to simplify the purification of complex reaction mixtures [5] (Scheme 7.3). Separation of the reaction products can be achieved by means of a simple three-phase extraction (aqueous–organic–fluorous) instead of the usual chromatography. In this respect, the concept of using fluorous protecting groups has some parallels with the solid-phase-supported chemistry, which also was primarily developed to simplify multiple work-up operations. Another example of the advantages of fluorous markers for facilitating product purification is multi-component reactions such as the Ugi [7] or Biginelli reaction [8] (Scheme 7.4). Fluorous tagging of one component and use of the other components in large excess drives the reaction to completion and allows the separation of the desired fluorous condensation product from side products and remaining other reagents by simple two- or three-phase liquid–liquid extractions [5]. In the final reaction step, the fluorous silyl group is removed by treatment with O (C10F21CH2CH2)3Si

O

OH 84%

NC

CHO

1. CF3CH2OH; 90 °C 2. 2-phase extraction (benzene–FC-72) 3. Bu4NF

NH2

H N

N O

(purity >95% by GLC) O O (C10F21CH2CH2)3Si O O

NH2 N H CHO

O

OEt (10 equiv.)

(10 equiv.) 1. cat. HCl, THF–BTF (2:1); 50 °C, 3 d 2. 3-phase extraction (H2O–benzene–FC-72) 3. Bu4NF

60%

O O

H N

N O COOEt

Scheme 7.4 Fluorous variants of the Ugi (a) and Biginelli multi-component reactions (b) allow the purification of the primary fluorous condensation products (not shown) by simple two- or three-phase extraction, followed by ‘‘traceless’’ cleavage of the fluorous silyl tag with TBAF [5].

229

7 Fluorous Synthesis and Combinatorial Chemistry

230

tetrabutylammonium fluoride (TBAF). The product is thus obtained in high purity, requiring no chromatographic purification of any of the intermediates. Formation of glycosidic linkages can be achieved by a variety of different methods [9]. In principle, for most of these methods the yield of the glycosidation product can be optimized by using a large excess of either the glycosyl donor or the acceptor component. Nevertheless, this approach is not often chosen, because (C6F13CH2CH2)3SiBr

95% 1. p-MePhMgBr,

(C6F13CH2CH2)3Si

CH3

THF 2. 2-phase extraction (CH3CN–FC-72)

3: "BnFBr"

75%

1. NBS, cat. AIBN, CCl4; reflux 2. silica gel flash chromatography

(C6F13CH2CH2)3Si

CH2Br

O

HO HO

OH 1. NaH, DMF 2. BnFBr (3), cat. Bu4NI, BTF 3. 3-phase extraction (H2O–CH2Cl2–FC-72) 4. silica gel chromatography

51%

O

O

(recycling) O

O

O O

(10 equiv.)

O O

O

+

BnFO BnFO

O MeOH

OH BnFO

OH

O TsOH, C6H5CF3 85% FC-72

BnFO

O

O

O

BnFO BnFO

O O

O O

H2, Pd(OH)2, FC-72 FC-72

BnFH (recycling)

MeOH

HO

O

HO

O

O

O

O OH

O

O

Scheme 7.5 Synthesis (box) and use of a fluorous benzyl protecting group [BnF = (C6 F13 CH2 CH2 )3 SiPhCH2 ] in carbohydrate chemistry [10a]. The BnF protecting group permits the use and subsequent clean separation of excess glycosyl acceptor for a glycal-based glycosylation procedure [11].

7.1 Fluorous Synthesis

of the resulting separation problems or the difficult accessibility of the excess component. Again, the use of fluorous auxiliary groups offers an elegant solution to this dilemma. Because carbohydrate chemistry is highly dependent on protecting group methodology, the use of modified fluorous protecting groups, for example, a fluorous benzyl group, allows the simple separation and purification of the desired glycosylation product, and the fluorous protecting reagent 3 can even be recycled for repeated use [10] (Scheme 7.5). O C8F17

N

HO

C8F17 O 4: "HOBfp"

Ph O O O HO OH

HO O

Ph O O

OH O OTr

1. HCl, AcOEt–EtOC4F9; 0 °C, 2 h 2. 2-phase extraction (toluene–FC-72)

O

1. HOBfp (4), DCC, DMAP, CH2Cl2; r.t., 3 h 2. 2-phase extraction (toluene–FC-72)

HO OH O BfpO O BfpO OBfp

HO OBz O BfpO O BfpO OBfp

BfpO

OBfp

O BfpO O OBfp

O OTr

O

OBfp O OH

O

1. BzCl, NEt3, CH2Cl2–EtOC4F9; −20 °C, 7 h 2. 2-phase extraction (MeOH–FC-72)

OBfp O OBz

O

BnO OBn O BnO BnO O

CCl3 NH

BnO OBn O BnO BnO O OBz O BfpO O BfpO OBfp

1. Me3SiOTf, 4Å molecular sieves, Et2O–EtOC4F9; 0 °C, 20 min 2. 2-phase extraction (MeOH–FC-72)

OBfp O OBz

O

34% (over 5 steps)

1. NaOMe, Et2O–MeOH; r.t., 1 h 2. silica gel chromatography

BnO OBn O BnO BnO O OH O HO O HO OH

OH O OH

O

Scheme 7.6 Synthesis of a precursor of the trisaccharide moiety of globotriaosylceramide (Gb3) [10b] using a fluorous acyl protecting group (Bfp) (EtOC4 F9 is commercially available from 3M under the brand name Novec HFE-7200).

231

232

7 Fluorous Synthesis and Combinatorial Chemistry

A related strategy was used for the synthesis of a more complex carbohydrate, the trisaccharide moiety of globotriaosylceramide (Gb3) [10b] (Scheme 7.6). In this reaction, an acyl-based fluorous protecting group was used to facilitate the intermediate purification steps in a similar way as can be achieved by solid-phase carbohydrate chemistry [12].

7.2 Separation on Fluorous Stationary Phases

To make effective use of fluorous biphasic systems, the fluorous phase may also be a stationary phase. Fluorous compounds or compounds carrying fluorous ‘‘ponytails’’ have high affinity for ‘‘fluorous reversed-phase’’ silica gel [1c, 13] which has been modified by means of a fluorous silane [14]. This effect has been used fluorophilic solvent

fluorophobic solvent O F O F fluorous silica gel

fluorous (F) and organic (O) components

F

F

fluorous silica gel

fluorous silica gel

O

F

O

F

elution with two different solvents

C6F13 group of tin

Before SPE

CHO +

Sn(CH2CH2CH2C6F13)3

F3C

(1 equiv.)

alcohol CF3

After SPE RCHO CF3

(2 equiv.) 1. SnCl4, THF; −78 °C to r.t. 2. FSPE

alcohol CF3

OH

F3C

−50 −50

−100 −100

−150 −150

Figure 7.1 The principle of fluorous solid-phase extraction (FSPE). Allylation of 4-trifluoromethylbenzaldehyde with a fluorous allyltin reagent and subsequent work-up of the reaction mixture by FSPE. The 19 F NMR spectra of the reaction mixture before and after FSPE purification are also shown. Figure modified from Ref. [16], courtesy of Georg Thieme Verlag.

7.3 Fluorous Concepts in Combinatorial Chemistry

to achieve convenient isolation and purification of a variety of compounds with high fluorine contents, first by simple solid-phase extraction (SPE) [15] and later by chromatography with a mobile phase based on a fluorophilicity gradient [16]. In fluorous solid-phase extraction (FSPE; Figure 7.1), a reaction mixture containing organic and fluorous components is placed on a fluorous silica gel column in a ‘‘fluorophobic’’ solvent, for example, acetonitrile, methanol, or a methanol–water mixture. Then, with a fluorophobic mobile phase, first the organic compounds are eluted while the fluorous compounds remain adsorbed by the solid phase. In the second step, a ‘‘fluorophilic’’ solvent such as tetrahydrofuran (THF), diethyl ether, or benzotrifluoride (BTF) is used to elute the fluorous compounds. If, instead of two-solvent FSPE, a gradient leading from a fluorophobic solvent to a fluorophilic solvent is used, real chromatography becomes possible on fluorous reversed-phase silica gel (FRPSG) (Figure 7.2). Although ‘‘ordinary’’ organic compounds cannot be separated by fluorous chromatography, for substances with perfluoroalkyl substituents of different lengths very efficient separations can be achieved. Within the same class of substance, elution occurs in order of the fluorine content of the analyte. This rule cannot be generalized, however, because other factors such as polarity and structural features also have a significant effect on retention times [17].

7.3 Fluorous Concepts in Combinatorial Chemistry

Fluorous chromatography is a simple means of separating different perfluoroalkyl homologs of structurally similar compounds and a unique opportunity for combinatorial chemistry. RF = C3F7 C5F11 3.3 min 6.7

O RF 30 min 100% MeOH

0 min 80% MeOH 20% H2O

RF = C7H15 C4F9 2.6 min 4.6

C6F13 9.7

C7F15 13.5

C8F17 17.7

C9F19 22.0

N N O

5

C10F21 26.0

Figure 7.2 Separation of a mixture of amides (5) carrying different perfluoroalkanoyl substituents on a Fluofix 120E column. A gradient from 80:20 MeOH–H2 O (highly fluorophobic) to MeOH (slightly fluorophilic) was used as mobile phase. Figure modified from Ref. [16], courtesy of Georg Thieme Verlag.

233

234

7 Fluorous Synthesis and Combinatorial Chemistry tag and mix 1

S . . . Sn

F

F 1S 1...F nS n Fn

detag

demix

1

n substrates

m synthetic steps

F 1-P 1

F 1S 1...F nS n

. . fluorous . silica gel F n-P n n products

P1 . . . Pn

Figure 7.3 Schematic representation of the principle of fluorous mixture synthesis [17, 20]. With this scheme, m × n reaction steps can be performed in parallel by means of m synthetic steps plus n tagging and n detagging procedures.

One of several different approaches [18] to the preparation of larger compound libraries for medicinal chemistry or materials science is parallel mixture synthesis in solution. Here, a library of m somehow ‘‘labeled,’’ structurally similar, starting materials (S) is mixed, and then subjected to a number (n) of synthetic steps. So far, this approach has proved highly economical and time saving – m × n reaction steps have been condensed into only n, in addition to the initial m labeling procedures. The problem starts with the demixing of the labeled products. For ‘‘conventional’’ labels (such as fluorophors) in combination with standard or reversed-phase chromatography, the retention times of the products depend mostly on their polarity and on sometimes subtle differences between their molecular structures. Therefore, even if all products can be separated, considerable efforts must subsequently be made to correlate the isolated fractions with the desired structures within the library. Because of these difficulties, for conventional solution-phase mixture syntheses the problem has often been circumvented by directly subjecting ‘‘organized’’ mixtures to biological assays in a so-called deconvolution process [19]. The combination of fluorous synthesis with fluorous chromatography offers an elegant solution to this labeling problem (Figure 7.3). If the starting library (Sn ) is tagged with different fluorous labels (Fn ) of different lengths, after mixing and conducting the series of synthetic conversions, demixing of the labeled product library (Fn –Pn ) can be conveniently achieved by fluorous chromatography. As an additional advantage, for smaller libraries the identity of the isolated labeled compounds can be derived from the order of elution, which is far more strongly related to the length of the fluorous alkyl label than to other structural characteristics. This concept of fluorous mixture synthesis has been used and extended for the preparation of compound libraries of interest in medicinal chemistry [17, 20–22]. The introduction of additional substituent groups in combination with the discriminating perfluoroalkyl labels during the synthetic sequence allows the convenient preparation and subsequent separation of relatively large libraries. For the library of 100 mappicine derivatives outlined in Scheme 7.7, 300 reactions would be required for the conventional, sequential approach. By application of fluorous mixture synthesis this was condensed into 26 steps. In addition, four tagging and 100 detagging operations are required to obtain the full, unprotected 100-member library from unprotected starting materials.

7.3 Fluorous Concepts in Combinatorial Chemistry

O

OMe CH3

N Me3Si

R1 6

CH3

HN 1. ICl, CH2Cl2, CCl4 2. BBr3, CHCl3

R1

I 7

OSi(iPr)2CH2CH2RF

1 mixture of 4 compounds

O R2

CH3

N

R2

R1

I Br

8

NaH, LiCl, DMF

OSi(iPr)2CH2CH2RF 1 mixture of 4 compounds

OSi(i Pr)2CH2CH2RF

5 mixtures of 4 compounds each

5 propargyl halides

R2 R3

O N

R3

N 9

NC

Me3SnSnMe3; sunlamp irradiation

5 isonitriles

CH3 R1

RFCH2CH2(iPr)2SiO · 25 mixtures of 4 compounds each · 99/100 products formed · 87/99 could be isolated in pure form by preparative demixing

Scheme 7.7 Fluorous mixture synthesis of 100 mappicine analogs [20]. The coding scheme for the substituents RF , R1 , R2 , and R3 is: R1 , RF = Pr, C4 F9 ; Et, C6 F13 ; iPr, C8 F7 ; CH2 CH2 C6 H11 , C10 F21 ; R2 = H, Me, Et, C5 H11 , Si(iPr)Me2 ; R3 = H, F, Me, OMe, CF3 . The mixture of 6 (four compounds) was converted into four compounds of 7, which were split and reacted with five propargyl bromides.

The resulting five mixtures [each containing four different propargylamines (8)] were split and reacted with five isonitriles, giving five mixtures containing 20 different tagged, racemic mappicines (9), each. Demixing was achieved on a preparative Fluofix 120E column with the gradient 0–30 min from 80% MeOH–H2 O to 100% MeOH and 30–40 min from 100% MeOH to 90% MeOH–10% THF.

A similar approach of ‘‘fluorous quasi-racemic synthesis’’ [20] was used to synthesize both enantiomers of mappicine at the same time in a ‘‘coded’’ mixture. The pyridine derivative 10 was split, and the carbonyl group was reduced enantioselectively by (+)- and (−)-DIP-Cl (β-chlorodiisopinocampheylborane), respectively. The resulting enantiomerically pure alcohols were subsequently derivatized – the R-enantiomer with BrSi(iPr)2 CH2 CH2 C6 F13 to yield (R)-(11) and the S-enantiomer with BrSi(iPr)2 CH2 CH2 C8 F17 to yield the quasi-enantiomer (S)-(12). The mixture of the two quasi-enantiomers was then subjected to the reaction sequence, leading to the fluorous mappicines (R)-(13) and (S)-(14). These were separated by fluorous chromatography and deprotected to yield the two mappicine enantiomers (Scheme 7.8).

235

7 Fluorous Synthesis and Combinatorial Chemistry

236

OMe 80% (>98% ee)

OMe CH3

N

CH3

N

1. (+)-DIP 2. BrSi(iPr)2CH2CH2C6F13,

Me3Si (R )-11 OSi(iPr)2CH2CH2C6F13

imidazole, DMF

OMe

Me3Si

10

O

CH3

N

80% (>98% ee) 1. (-)-DIP 2. BrSi(iPr)2CH2CH2C8F17,

Me3Si (S)-12 OSi(iPr)2CH2CH2C8F17

imidazole, DMF

mixing of both quasi-enantiomers

O

OMe N

CH3

Me3Si OSi(i Pr)2CH2CH2RF

CH3

HN

48% 1. ICl, CH2Cl2, CCl4 2. BBr3, C HCl3

I OSi(iPr)2CH2CH2RF

O 61%

Br

NaH, LiCl, DMF

N

CH3

I RFCH2CH2(i Pr)2SiO

O

67%

N

PhNC, Me3SnSnMe3; sunlamp irradiation

N

CH3

RFCH2CH2(iPr)2SiO demixing by fluorous chromatography

O

O

N

N

N

CH3

CH3

C8F17CH2CH2(iPr)2SiO

C6F13CH2CH2(iPr)2SiO (R )-13

N

detagging

(S )-14

O

O

N N

N CH3

(R )-mappicine HO

N

CH3

(S)-mappicine HO

Scheme 7.8 ‘‘Fluorous quasi-racemic synthesis’’ of both enantiomers of mappicine [20]. (DIP = diisopinocampheylborane; RF is either C6 F13 or C8 F17 ).

7.3 Fluorous Concepts in Combinatorial Chemistry

237

A recent example of the parallel synthesis of different quinazoline-2,4-dione derivatives (15) demonstrates how to combine the advantages of fluorous synthesis with those of solid-phase chemistry without using expensive perfluorinated solvents [22] (Scheme 7.9). First, a fluorous benzyl alcohol (16) is adsorbed on FRPSG. Then, in a sequence of splits and reactions, the linker group, which remains bound to the FRPSG by fluorophilic interactions, is converted into a library of differently substituted carboxamidourethanes (17). These are cyclized and the liberated quinazoline-2,4-diones (15) are eluted from the support with the fluorophobic solvents water and CH3 CN–H2 O (4:1), leaving the fluorous benzyl alcohol adsorbed by the fluorous phase to be reused in another reaction cycle.

O N

R1 N R2

15

R3 RF

O

RF

OH Si 16

RF cyclization: NEt3, DMF

RF

O CCl3

Cl

RF

activated charcoal,

R1

THF

O

O RF RF

N R2

O Si

17

RF O

RF RF

N H

RF

R3

O Si

RF RF

RF R

R3NH2

R1

RF HN

1

R2

O

TBTU, EtN(i Pr)2, THF

RF RF

O Si

N R2

EtN(iPr)2, THF

O

OH

RF RF

RF

fluorous reversed-phase silica gel Scheme 7.9 Fluorous synthesis of a library of substituted quinazoline-2,4-diones (15) [22]. The key to this approach is a fluorous benzyloxycarbonyl group on which the target molecules are stepwise constructed and which keeps the different synthetic intermediates bound to fluorous reversed-phase silica

Cl

gel (FRPSG) during the purification cycles. The structural diversity of the target compound library (15) is introduced by the different anthranilic acid derivatives and primary amines (in boxes) [TBTU = O-(benzotriazol1-yl)-N,N,N ,N -tetramethyluronium tetrafluoroborate].

O

OH

238

7 Fluorous Synthesis and Combinatorial Chemistry

In the last few years, fluorous combinatorial chemistry has been extended and augmented by other fluorous techniques developed by analogy with established methods in solid-phase-supported synthesis. Use of fluorous condensation reagents for the Mitsunobu reaction [23] allows the easy removal of all condensation reagents except the coupled starting materials after the reaction [24] (Scheme 7.10). O C6F13CH2CH2OH

C6F13

O

C6F13

N

N

N

N2H4HCl, NEt3

C6F13 18: FTPP (X = no substituent) 19: FTPPO (X = O)

C6F13CH2CH2O

N N H H

OCH2CH2C6F13

20: FDCEH O

C6F13CH2CH2O

N N OCH2CH2C6F13 21: FDEAD

Br2, pyridine

COOH + EtOH + FTPP + FDEAD 21 18 NO2

1. react in THF 2. FSPE fluorous: Et2O

92%

COOEt

O2N

FTPPO

(19) + FDCEH (20)

NO2 SiO2, flash chromatography less polar

80%

F

DCEH (20)

100%

Br2

F

DEAD (21)

Scheme 7.10 The Mitsunobu reaction with fluorous condensation reagents [24] allows the simple purification of the reaction product and recycling of the reagents F TPP (18) and F DEAD (21).

N

O

O

O2N

organic: MeOH–H2O (80:20)

N

N

O P X

O

86%

more polar

F

TPPO (19)

94%

AlH3

F

TPP (18)

(F TPP = fluorous triphenylphosphine; F TPPO = fluorous triphenylphosphine oxide; F DEAD = fluorous diethyl diazodicarboxylate; F DCEH = fluorous dicarboxyethoxyhydrazine).

7.3 Fluorous Concepts in Combinatorial Chemistry

A fluorous variant of the Swern [25] and Corey–Kim oxidations [26] permits handling of stoichiometric quantities of malodorous dimethyl sulfide to be avoided [27] (Scheme 7.11). Fluorous scavengers facilitate the removal of excess reagents from complex reaction mixtures [28] (Scheme 7.12). Thus, the fluorous anhydrides 24 and

I

RF

NaBH4, MeSSMe, EtOH, THF; 0 °C to r.t.

71% (2 steps)

S

RF

RF

30% H2O2, MeOH,

F

O S

F DMSO 23a: RF = C4F9 23b: RF = C6F13

DMS hexane; r.t., 1 h 22a: RF = C4F9 22b: RF = C6F13

Swern oxidation FC-72

OH

22a

91% toluene

Corey-Kim oxidation

FDMSO

30% H2O2

23a

OTBDMS CHO

F

1. DMSO (23a), (COCl)2, CH2Cl2; −30 °C 2. EtN(iPr)2; −30 °C to r.t. 3. 2-phase extraction (tolueneFC-72)

Br

88%

FDMS

OTBDMS

Br

73%

FDMS

FC-72

22b

F

1. DMS (22b), NCS, toluene; −25 °C, 2 h 2. NEt3 3. 2-phase extraction (tolueneFC-72)

HO

78% toluene

O

Scheme 7.11 Fluorous variants of the Swern and Corey–Kim oxidations of alcohols to the corresponding aldehydes or ketones [27] (F DMS = fluorous dimethyl sulfide, F DMSO = fluorous dimethyl sulfoxide).

C8F17

N O

O

O

excess R1R2NH

24

R1

C8F17

N H N R2

O

removable by FSPE

O C8F17

NCO excess R1R2NH

C8F17

25 C8F17

C8F17 26

SH excess ArCOCH Br 2

N H

R1 N removable by FSPE R2 Ar

S O

removable by FSPE

Scheme 7.12 Examples of fluorous scavengers enabling simple removal of excess reagents from complex reaction mixtures [28].

239

240

7 Fluorous Synthesis and Combinatorial Chemistry

CH2Cl2

O RF

N H

N H

RF

CH2Cl2 C6F13

COOH

C6F14 O RF

N H

HN N H

C6F14

RF

RF

O

H

RF N H

O

O C6F13

Scheme 7.13 ‘‘Lightly’’ fluorous N,N -dialkylurea (RF = C6 F13 ) has a relatively low partition coefficient of 30:70 in a C6 F14 –CH2 Cl2 biphasic system. After addition of perfluoroheptanoic acid, the partition coefficient of the resulting hydrogen-bonded complex is 99:1, and the urea is completely removed from the organic into the fluorous phase [29].

CH3

Cl N

N

N

1. C8F17CH2CH2SH, EtN(iPr)2, THF, DMF

Cl

CH3

RFS N Cl

2. flash chromatography on silica gel

85%

N

91%

N

OxoneTM, acetone, H2O; 60 °C, 12 h

first nucleophile, e.g., N

H N

N

F3C

1. EtN(iPr)2, K2CO3, DMF;

O O S

CH3

RFS

N

CH3

RF

N N

N N

F3C

F3C

80 °C, 12 h 2. purification by FSPE

O CH3

N 96% second nucleophile, e.g., O

NH

1. EtN(iPr)2, DMF; 80 °C, 10 h 2. purification adsorption of product on acidic ion exchange resin and subsequent FSPE

N N

N N

F3C

Scheme 7.14 Example of the use of fluorous ‘‘catch and release’’ tags [30b] (RF = CH2 CH2 C8 F17 ).

7.3 Fluorous Concepts in Combinatorial Chemistry

isocyanates 25 allow the removal of excess amine reagents. Several custom-tailored fluorous scavengers with complementary reactivity are available for the removal of other reactive species. Fluorous scavengers do not necessarily need to form a covalent bond with the species that they have to remove into the fluorous phase. For example, ‘‘lightly’’ fluorous N,N  -dialkylureas can bind to perfluorocarboxylic acids by hydrogen bonding [29]. Although the urea is partly dissolved in the organic phase, the resulting complex has a significantly increased fluorophilicity and is found exclusively in the fluorous phase (Scheme 7.13). By analogy with similar concepts in use in solid-phase combinatorial chemistry, several examples of fluorous ‘‘catch and release’’ tags have been described by Zhang and co-workers [30] (Scheme 7.14). These functionalities first act as a fluorophilic auxiliary during a multi-step synthesis and simplify purification of the intermediates. In the last reaction step, the tag is replaced by another reactive agent, thus releasing the target compound while simultaneously permitting a further increase in the molecular diversity of combinatorial libraries. Fluorous tagging has not only been used for the synthesis and organization of compound libraries. Similar labeling techniques have been adopted in proteomics [31]. Proteins are protease-digested into smaller peptide fragments. Into a particularly activated subset of this peptide library fluorous tags are introduced, for example, as thiols. The tagged and non-tagged peptides are separated and concentrated by FSPE and subsequently analyzed by mass spectrometry (Figure 7.4). F

Protein

Proteolysis

Selective introduction of fluorous tag

Wash

Elute

Non-tagged Fluorous-tagged peptides peptides

MS

MS

Figure 7.4 Fluorous proteomics is based on the isolation on concentration of a subset of particularly activated peptides in a complex library. Reproduced with permission from Ref. [31].

241

242

7 Fluorous Synthesis and Combinatorial Chemistry

References 1. (a) Curran, D.P. and Hoshino, M.

2.

3.

4.

5.

6.

7. 8.

9.

(1996) J. Org. Chem., 61, 6480–6481; (b) Larhed, M., Hoshino, M., Hadida, S., Curran, D.P., and Hallberg, A. (1997) J. Org. Chem., 62, 5583; (c) Curran, D.P., Hadida, S., and He, M. (1997) J. Org. Chem., 62, 6714–6715; (d) Hoshino, M., Degenkolb, P., and Curran, D.P. (1997) J. Org. Chem., 62, 8341; (e) Spetseris, N., Hadida, S., Curran, D.P., and Meyer, T.Y. (1998) Organometallics, 17, 1458; (f) Curran, D.P. and Luo, Z. (1998) Med. Chem. Res., 8, 261; (g) Curran, D.P., Luo, Z., and Degenkolb, P. (1998) Bioorg. Med. Chem. Lett., 8, 2403; (h) Ryu, I., Niguma, T., Minakata, S., Komatsu, M., Luo, Z., and Curran, D.P. (1999) Tetrahedron Lett., 40, 2367–2370. (a) Curran, D.P. and Hadida, S. (1996) J. Am. Chem. Soc., 118, 2531–2532; (b) Horner, J.H., Martinez, F.N., Newcomb, M., Hadida, S., and Curran, D.P. (1997) Tetrahedron Lett., 38, 2783; (c) Hadida, S., Super, M., Beckman, E.J., and Curran, D.P. (1997) J. Am. Chem. Soc., 119, 7406; (d) Ryu, I., Niguma, T., Minakata, S., Komatsu, M., Hadida, S., and Curran, D.P. (1997) Tetrahedron Lett., 38, 7883. Review: Curran, D.P., Hadida, S., Kim, S.-Y., and Luo, Z. (1999) J. Am. Chem. Soc., 121, 6607–6615. (a) Milstein, D. and Stille, J.K. (1978) J. Am. Chem. Soc., 100, 3636–3638; (b) Stille, J.K. (1986) Angew. Chem. Int. Ed. Engl., 25, 508–523; (c) Mitchell, T.N. (1992) Synthesis, 803–815. Studer, A., Hadida, S., Ferritto, R., Kim, S.-Y., Jeger, P., Wipf, P., and Curran, D.P. (1997) Science, 275, 823–826. Caramella, P. and Gr¨unanger, P. (1984) 1,3-Dipolar Cycloaddition Chemistry, Vol. 1, Wiley–Interscience, New York, pp. 291–392. Ugi, I. (1982) Angew. Chem. Int. Ed. Engl., 21, 810. (a) Biginelli, P. (1893) Gazz. Chim. Ital., 23, 360–416; (b) Kappe, C.O. (1993) Tetrahedron, 49, 6937–6963. Lindhorst, T.K. (2000) Essentials of Carbohydrate Chemistry and Biochemistry, Wiley–VCH Verlag GmbH, Weinheim.

10. (a) Curran, D.P., Ferritto, R., and

11.

12.

13.

14. 15.

16. 17. 18.

Hua, Y. (1998) Tetrahedron Lett., 39, 4937–4940; (b) Miura, T. and Inazu, T. (2003) Tetrahedron Lett., 44, 1819–1821. (a) Danishefsky, S.J. and Bilodeau, M.T. (1996) Angew. Chem. Int. Ed. Engl., 35, 1380; (b) Boons, G.J. (1996) Tetrahedron, 52, 1095; (c) Toshima, K. and Tatsuta, K. (1993) Chem. Rev., 93, 1503. (a) Plante, O.J., Palmacci, E.R., and Seeberger, P.H. (2001) Science, 291, 1523; (b) Ando, H., Manabe, S., Nakahara, Y., and Ito, Y. (2001) J. Am. Chem. Soc., 113, 3848. (a) Berendsen, G.E. and Galan, L.D. (1978) J. Liq. Chromatogr., 1, 403; (b) Berendsen, G.E., Pikaart, K.A., Galan, L.D., and Olieman, C. (1990) Anal. Chem. 1980, 52; (c) Billiet, H.A.H, Schoenmakers, P.J., and de Galan, L. (1981) J. Chromatogr., 218, 443; (d) Sadek, P.C. and Carr, P.W. (1984) J. Chromatogr., 288, 25; (e) Kainz, S., Luo, Z., Curran, D.P., and Leitner, W. (1998) Synthesis, 1425–1427. Curran, D.P. (1999) Med. Res. Rev., 19, 432–438. (a) Gayo, L.M. and Suto, M.J. (1997) Tetrahedron Lett., 38, 513; (b) Siegel, M.G., Hahn, P.J., Dressman, B.A., Fritz, J.E., Grunwell, J.R., and Kaldor, S.W. (1997) Tetrahedron Lett., 38, 3357; (c) Flynn, D.L., Crich, J.Z., Devraj, R.V., Hockerman, S.L., Parlow, J.J., South, M.S., and Woodard, S. (1997) J. Am. Chem. Soc., 119, 4874. Curran, D.P. (2001) Synlett, 1488–1496, and references cited therein. Curran, D.P. and Oderaotoshi, Y. (2001) Tetrahedron, 57, 5243–5253. (a) Balkenhohl, F., von dem B¨ussche-Hunnefeld, C., Lansky, A., and Zechel, C. (1996) Angew. Chem. Int. Ed. Engl., 35, 2289; (b) Lam, K.S., Lebl, M., and Krchnak, V. (1997) Chem. Rev., 87, 411; (c) Furk, A. (1996) in Combinatorial Peptide and Nonpetide Libraries (ed. G. Jung), Wiley-VCH Verlag GmbH, Weinheim, pp. 111–137; (d) Nicolaou, K.C., Xiao, X.Y., Parandoosh, Z., Senyei, A., and Nova, M.P. (1995) Angew. Chem. Int. Ed. Engl., 34, 2289.

References 19. (a) An, H. and Cook, P.D. (2000) Chem.

20.

21. 22.

23.

24.

Rev., 100, 3311; (b) Houghten, R.A., Pinilla, C., Appel, J.R., Blondelle, S.E., Dollery, C.T., Eicheler, J., Nefzi, A., and Ostresh, J.M. (1999) J. Med. Chem., 42, 3743; (c) Carell, T., Wintner, E.A., Sutherland, A.J., Rebek, J. Jr., Dunayevskiy, Y.M., and Vouros, P. (1995) Chem. Biol., 2, 171; (d) Boger, D.L., Chai, W.Y., and Jin, Q. (1998) J. Am. Chem. Soc., 120, 7220. Luo, Z., Zhang, Q., Oderaotoshi, Y., and Curran, D.P. (2001) Science, 291, 1766–1769. Zhang, W. (2003) Tetrahedron, 49, 4475–4489. Schwinn, D., Glatz, H., and Bannwarth, W. (2003) Helv. Chim. Acta, 86, 188–195. (a) Mitsunobu, O. (1991) in Comprehensive Organic Synthesis, vol. 6 (eds. B.M. Trost, and I. Fleming), Pergamon Press, Oxford, pp. 1, 65; (b) Hughes, D.L. (1992) Org. React. (N. Y.), 42, 335; (c) Hughes, D.L. (1996) Org. Prep. Proced. Int., 28, 127. Dandapani, S. and Curran, D.P. (2002) Tetrahedron, 58, 3855–3864.

25. (a) Review: Mancuso, A.J. and Swern,

26. 27. 28.

29.

30.

31.

D. (1981) Synthesis, 165; (b) Mancuso, A.J., Huang, S.-L., and Swern, D. (1978) J. Org. Chem., 43, 2480; (c) Tidwell, T.T. (1990) Org. React., 39, 297; (d) Tidwell, T.T. (1990) Synthesis, 857. Corey, E.J. and Kim, C.U. (1972) J. Am. Chem. Soc., 94, 7586. Crich, D. and Neelamkavil, S. (2002) Tetrahedron, 58, 3865–3870. (a) Zhang, W., Chen, C., and Nagashima, T. (2003) Tetrahedron Lett., 44, 2065–2068; (b) Zhang, W., Curran, D.P., and Chen, C. (2002) Tetrahedron, 58, 3871–3875; (c) Lindsley, C.W., Zhao, Z., and Leister, W. (2002) Tetrahedron Lett., 43, 4225–4228. Palomo, C., Aizpurua, J.M., Loinaz, I., Fernandez-Berridi, M.J., and Irusta, L. (2001) Org. Lett., 3, 2361–2364. (a) Zhang, W. (2003) Org. Lett., 5, 1011; (b) Chen, C. and Zhang, W. (2003) Org. Lett., 5, 1015–1017. Brittain, S.M., Ficarro, S.B., Brock, A., and Peters, E.C. (2005) Nat. Biotechnol., 23, 463–468.

243

245

Part III Applications of Organofluorine Compounds

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

247

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

The first and economically most significant class of organofluorine compounds produced on a technical scale were the various chlorofluorocarbons (CFCs (Table 8.1) [1]. Initially they were used as refrigerants in cooling and air conditioning equipment. Later they also found wide application as propellants for aerosol cans and foaming agents in the production of heat-insulating polymer formulations. The unique usefulness of CFCs was recognized for the first time in 1928 by T. Midgley at Frigidaire Corporation [2, 3]. The special properties which made this substance class so attractive for many applications were their high volatility and their lack of chemical reactivity, which rendered them non-toxic and non-flammable. The first domestic refrigerator containing a CFC appeared in 1933. At the peak of their industrial use CFC were produced on a scale of approximately 1 million tons per year. The economically most important of these so-called ‘‘Freons’’ (in Germany ‘‘Frigens’’) were Freon 11 (CFCl3 ), Freon 12 (CF2 Cl2 ), Freon 113 (CF2 ClCFCl2 ), and Freon 114 (CF2 ClCF2 Cl) and the hydrochlorofluorocarbon (HCFC) Freon 22 (HCFC-22, CHF2 Cl). The numbering system used for CFC and HCFC is based on a three-digit number. The last digit denotes the number of fluorine atoms, the second last the number of hydrogen atoms minus one, and the first digit the number of carbon atoms minus one (for methane derivatives this digit is zero and is therefore omitted). All remaining atoms are assumed to be chlorine [4]. Bromofluorocarbons such as CF3 Br and CF2 Br2 , the so-called ‘‘Halons,’’ have been widely used until recently as fire-extinguishing chemicals. For Halons, a different five-digit coding scheme is used. Here, the five digits stand for the number of C, F, Cl, Br, and I atoms – in that order. Accordingly, Halon 1211 corresponds to CF2 ClBr. Halons are particularly useful as fire-extinguishing chemicals because they are non-toxic and non-flammable. The homolytic carbon–bromine bond dissociation energy (64.3 kcal mol−1 ) is low enough to start at relatively moderate temperatures, drawing heat from a fire as a result of its endothermicity. Since the Montreal Protocol in 1987, the use of ozone-depleting CFCs and related compounds has been severely restricted, and they are currently being phased out. Because these compounds have such unique properties and are almost irreplaceable for many applications, much effort has been devoted to finding non-ozone-depleting replacements with significantly shorter atmospheric lifetimes (Scheme 8.1). Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

248

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds Properties and technical applications of some (hydro)halofluorocarbons [1].

Table 8.1

Boiling point (◦ C)

Compound HFC-23 (CHF3 ) CFC-13 (CClF3 ) HFC-22 (CHClF2 )

−81 −82 −41

CFC-12 (CCl2 F2 )

−30

CFC-11 (CCl3 F)

−24

Halon 1211 (CBrClF2 ) Halon 2402 (CBrF2 CBrF2 ) CFC-113 (CCl2 FCClF2 )

−4 −47 −48

HFC-134a (CF3 CH2 F)

−27

Applications Azeotrope with CFC-13 in biomedical freezers See above Room air conditioning, supermarket freezers, industrial refrigeration, Japanese domestic refrigerators; tetrafluoroethylene feedstock; polystyrene foam blowing Domestic refrigeration, automobile air conditioning, supermarket fresh food stores, industrial air conditioning, hot climate air conditioning; medical aerosols Water chiller air conditioning systems; polyurethane foam blowing; medical aerosols Fire extinguishers Fire extinguishers Train switch gear coolant; solvent; chlorotrifluoroethene feedstock Domestic refrigeration, automobile air conditioning, supermarket fresh food stores, hot climate air conditioning; insulating foam blowing; metered dose inhalers; solvent for flavor and fragrance extraction

Cl + 3 HF Cl

Cl

CF3CH2Cl + HF

Cl2 Cl

Cl

Cl

Cl

CF3CH2Cl + 2 HCl

chromia catalyst

CF3CH2F + HCl

chromia catalyst

CCl2FCCl2F

isomerization

CF3CCl3 HF

+ HF

Cl2

CClF2CClF2

+

CF3CCl2F hydrogenolysis

isomerization

CF3CHF2 + CF3CHClF

H7C3COF

electrochemical fluorination

F7C3COF

KF

hydrogenolysis

F9C4O–K+

CF3CH2F

R2SO4 (R = CH3, C2H5)

F9C4OR

Scheme 8.1 Typical technical syntheses of some (hydro)halofluorocarbons and fluorinated ethers as non-ozone-depleting CFC replacements [1].

8.1 Polymers and Lubricants

Most of these alternatives are hydrofluorocarbons (HFCs) and fluorinated ethers, for example, E143a (CF3 OCH3 ), E134 (CHF2 OCHF2 ), and E125 (CF3 OCHF2 ) for use as refrigerants and foam blowing applications and C4 F9 OCH3 and C4 F9 OC2 H5 as replacements for the solvent CFC-113 (CCl2 FCClF2 ). The main synthetic route to CFCs, HCFCs, and Halons is Swarts fluorination. Technically this is often achieved by reaction of a chlorinated or brominated precursor with anhydrous hydrofluoric acid in the presence of a solid Lewis acid catalyst, for example, chromia. Other important reactions are Lewis acid-catalyzed halogen isomerization and hydrogenolysis of chlorine or bromine.

8.1 Polymers and Lubricants

Fluoropolymers are still one of the largest scale applications of fluoro-organic compounds [5]. This field began with the serendipitous discovery of polytetrafluoroethylene (PTFE) (Teflon) by R. J. Plunkett at DuPont in 1938 (Figure 8.1). When he cut open a cylinder of tetrafluoroethylene when it mysteriously lost its pressure but kept its weight, he found a white powder with most unusual properties, making it the most widely used fluoropolymer. PTFE is extremely chemically stable against a variety of the most aggressive reagents, for example, elemental fluorine, uranium hexafluoride, molten alkali metal hydroxides, and hot mineral acids. As a structural material it retains its function from near absolute zero to 260 ◦ C. In addition it has, like the perfluoroalkanes, very low surface energy, leading to unusually advantageous low friction and antistick properties. One of the first popular applications of PTFE was as a lining for anti-stick frying pans. More recently, very thin fibers produced by fibrillation of a stretched PTFE sheet have found use in special performance garments under the

Figure 8.1 R. J. Plunkett (right) with a cut cylinder of polymerized tetrafluoroethylene. Courtesy of the Hagley Museum and Library, Wilmington, DE, USA.

249

250

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

brand name Gore-Tex. Gore-Tex garments protect the wearer against liquid water while being permeable to water vapor from perspiration. Low molecular mass PTFE (3000–50 000 Da), obtained by polymerization in the presence of a chain-transfer reagent such as methylcyclohexane, or by γ-irradiation of high molecular mass PTFE, is used as a highly effective lubricant which is extremely resistant to chemical degradation [6] (Scheme 8.2). CHClF2

:CF2 + HCl

750–850 °C

F

F

F

CF3

F

F :CF2

F

F

side reaction

K2S2O8, emulsion in water

-(CF2CF2)n-

Scheme 8.2 Technical synthesis of tetrafluoroethylene by thermal fragmentation of CHClF2 . In a side reaction, difluorocarbene is inserted into a carbon–fluorine bond of tetrafluoroethylene to give perfluoropropene. Radical polymerization in aqueous emulsion at 10–70 bar is initiated by per oxides, and the polymer is obtained as a powder.

During the Manhattan Project, directed towards the construction of the first nuclear weapons [7], a strong need arose for materials, lubricants, and cooling fluids resistant to attack by the extremely aggressive uranium hexafluoride (UF6 ) (Scheme 8.3). U 3O 8

H2

UO2

HF; 550 °C

UF4

F2; 250 °C

UF6 gaseous diffusion

235UF 6

235

U (0.6%)

238UF

6

238

U (99.4%)

Scheme 8.3 Synthesis of the volatile uranium compound UF6 , which is used for the separation of 0.6% 235 U from the major isotope 238 U by gaseous diffusion. Only 235 U can be used for nuclear weapons because – in contrast with 238 U – it is fissible in a fast neutroninitiated chain reaction [7].

The volatile UF6 (sublimation at 65 ◦ C) was, and remains, the key material for separation of 0.6% 235 U from the major uranium isotope 238 U (Figure 8.2). The reactivity of UF6 is comparable to that of elemental fluorine, and it oxidizes most metals immediately and reacts violently with conventional organic materials. When

8.1 Polymers and Lubricants

U.S.Army air force Hiroshima (60%) A new dimension . . . E, August 20, 1945

(a)

(b)

Figure 8.2 (a) The K-25 facility in Oak Ridge, TN, where uranium isotopes were separated by gaseous diffusion of UF6 . (b) The atomic bomb which destroyed Hiroshima on 6 August 1945 was based on 235 U from this facility. Courtesy of the Manhattan Project Heritage Preservation Association [8].

the first large-scale separation of the uranium isotopes was achieved in a gaseous diffusion plant in 1943, PTFE seals in combination with compressed nickel powder diffusion barriers played a crucial role in this success. After the explosion of the first atomic bomb based on 235 U over Hiroshima on 6 August 1945, the atomic weapons programs in the West and the Eastern Bloc became one of the dominant forces driving the development of industrial fluorine chemistry. In addition to its many highly desirable properties, PTFE also has some major disadvantages. First, because of its very high melt viscosity, it cannot be processed by extrusion like other polymers. It must be formed into blocks by sintering PTFE powder under pressure (100–400 bar, 365–385 ◦ C). These blocks are subsequently cut mechanically into their final shape. For chemical labware made from PTFE by this method, a resulting major disadvantage is the opaqueness of the vessels. Another problem with the labware is the extremely low thermal conductivity of PTFE. This cost-intensive procedure is similar to the processing of some highmelting metals or ceramics. Melt-processable varieties of PTFE were subsequently obtained by copolymerization with 5% perfluoropropene, which disrupts the high crystallinity of PTFE. A second problem is the tendency of PTFE to creep under applied pressure, which limits the mechanical stability of PTFE devices. This can be overcome to some extent by blending PTFE with filler materials, such as glass or carbon. Also, the otherwise highly advantageous anti-stick properties of PTFE cause problems during the manufacture of devices – usually, the material cannot be attached to metal surfaces; no conventional adhesives stick to it. For the PTFE coating of frying pans, a layer of specially treated aluminum is used to connect the metal to the anti-stick layer. Polymers with elastomeric properties have been obtained since the 1960s by copolymerization of tetrafluoroethylene with trifluorovinyl ethers such as

251

252

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

poly(heptafluoropropyl trifluorovinyl ether) (PPVE). These so-called secondgeneration fluoropolymers combine high thermal and chemical resistance with elasticity and are used for coatings, seals, and other parts which can be produced by conventional extrusion and molding processes. An early alternative to PTFE was polychlorotrifluoroethylene (PCTFE), which was invented in 1941 by W. T. Miller at Cornell University (Scheme 8.4). In contrast with PTFE, this material can be extruded at 250–300 ◦ C. Depending on molecular mass, PCTFE has applications as a thermoplastic or a lubricant. F CF2ClCFCl2

Zn

F

F Cl radical polymerization in solution (CFCl3), initiated by (Cl3CCOO)2

–(CF2CFCl)n–

Scheme 8.4

Synthesis of polychlorotrifluoroethylene (PCTFE).

Another widely used fluoropolymer with highly advantageous properties is polydifluoroethylene or poly(vinylidene difluoride) (PVDF) (Scheme 8.5). In terms of quantities produced, PVDF is second only to PTFE, because it can be processed not only into dimensionally stable mechanical components but also into transparent films with very good light transmittance. This and its high UV resistance make it very suitable as a cover for solar collectors (as a flexible and low-weight glass replacement) and as a component for the formulation of high-performance paints and other coatings. Cl Cl

F F + 2 HF

Lewis acid catalyst (antimony halide)

Cl

CH3

+ HCl

Δ

F F

Scheme 8.5

+ HCl

Synthesis of the PVDF monomer 1,1-difluoroethylene.

PVDF is not solely of interest as a structural material. Oriented films have piezoelectric properties which are used for highly sensitive microphones, acoustic transducers, and military applications. More recent applications are sonic wavedriven nanogenerators [9] or ferroelectric, nonvolatile electronic memories [10]. The piezoelectric characteristics of PVDF can be even improved by copolymerization with small quantities of other monomers which enhance its elastomeric properties. The interesting dielectric properties of PVDF can be explained by its pattern of fluorination. In the stretched polymer with its zigzag conformation, all gem-difluoromethylene groups are oriented to one side, perpendicular to the

8.1 Polymers and Lubricants

μ F F F F F F

F F

F F

F

F

F F F F F F

Figure 8.3 Piezoelectric poly(vinylidene difluoride) (PVDF) and its non-piezoelectric isomer, poly(ethylene-co-tetrafluoroethylene) (ETFE) [11].

polymer backbone. Because of this alignment, the dipole moments of the carbon–fluorine bonds are additive; they also couple with the dipoles of neighboring polymer strands (Figure 8.3). In contrast, the isomeric poly(ethylene-cotetrafluoroethylene) (ETFE) cannot adopt such a polar conformation because each local dipole moment is compensated by the adjacent gem-difluoromethylene group pointing in the opposite direction. Other types of perfluorinated polymer include ether structures. The monomers of these materials, third-generation fluoropolymers, are trifluoroenol ethers and cyclic difluoroendiol ethers. Perfluoropolyethers (PFAs) are readily processable and, because of their transparency, they are often used for chemical apparatus if aggressive reagents are involved. Another application of PFAs is as sample vessels for ion analysis (Scheme 8.6).

CF2CF2

n

CF2CF

m

OC3F7

CF2CF2

F

F

O

O

n

m

F3C CF3 Scheme 8.6 Examples of perfluorinated polyethers: PFA (a) is used for labware in analytical chemistry, Teflon AF (b) has special applications in the manufacture of electronic circuits.

Perfluoroether oligomers are used as the structural basis for most fluorinated lubricants [6] (Scheme 8.7). These materials have, like perfluoroalkanes, very low surface energies and friction coefficients [12] but do not usually have better lubricant characteristics than their hydrocarbon analogs. Their advantage compared with those much cheaper (typically by a factor of 50) compounds is their extreme resistance toward chemical degradation (especially oxidation to carboxylic acids), their extremely low vapor pressure, and their non-miscibility with organic solvents. PFAs have therefore become the lubricants of choice for vacuum pumps used to evacuate microchip plasma etching chambers, in which corrosive gases, for example, hydrogen fluoride or silicon tetrafluoride, are generated. Their very low vapor pressure, which, at a given viscosity, is much lower than for analogous hydrocarbon lubricants, renders PFAs the ideal lubricant for mechanical devices used in spacecraft. For example, during the Giotto mission to Halley’s comet in 1985, some critical mechanical components moving perpetually in the high vacuum of space were lubricated with PFAs.

253

254

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

F F

F3C

[O]

F–

F

F

F

F3C

F

F2

O

F F

F F

F

F3C

O 2, h n

F

F

F 3C

F F 1. Δ 2. F2

O

O

F F

F–

F F F 3C

Scheme 8.7

O

F F

O

F F

F F

F F

F F

F F F F O

O

F F

O

O

F

F

F2

F m

O

F

F

O

CF3

m

F

F

n

F F

O

F F

F

F + CH2O

O

O

F F

n

F CF3

F F O

F CF3 O

F F

F

CF3

F CF3

F F

F3C

F CF3

F F

F F F

+ F

F

n

F F

n

F

F

O

F F

F CF3 O

F F F3C

O

F CF3 O

F F

O

F3C

F

n

F F

F F n

CF3

F F

Syntheses of typical perfluorinated polyether lubricants [5].

Perfluorinated polyethers have also gained importance as actively functional materials. Ionic polymer membranes (e.g., DuPont’s Nafion) based on sulfonic acid-derivatized PFAs have been used for nearly 30 years as ion-conducting membranes in chloralkali electrolysis cells, replacing the large amounts of toxic mercury used until then in the classic Castner–Kellner cells (Scheme 8.8). One of the earliest applications of Nafion was as a membrane in the hydrogen–oxygen fuel cells which powered the Apollo spacecraft carrying the first astronauts to the Moon.

F

F F F CF3 O

F F

F CF3

O

F F O

SO2F

F F F F

Scheme 8.8 Nafion is produced by copolymerization of a fluorosulfonylated trifluoroenol ether with tetrafluoroethylene, then hydrolysis to the sulfonic acid.

Nafion can be regarded as a polymeric analog of trifluoromethanesulfonic acid and was therefore the first solid superacid.

8.1 Polymers and Lubricants

Towards the end of the 1990s, the electronics industry was planning on achieving the transition from 248 nm (KrF excimer laser) to 193 nm (ArF excimer laser) technology for photolithographic patterning processes for mass production in electronic circuitry. The next step, then in preparation, was down to 157 nm (F2 laser) [13]. Nowadays (2012), patterns with 45 nm resolution are standard, and resolutions down to 22 nm are in development to be achieved. The 157 nm technology was to be firmly based on inorganic and organic fluorine chemistry; the best known optical material for lithographic lenses in this short wavelength range is calcium fluoride (CaF2 ). A major challenge was the design of photoresists which are highly transparent in the 157 nm region [14]. In the photolithographic process, the complex patterns on a chip are obtained by passing light of a given wavelength through a mask containing the pattern on to a wafer substrate which is covered with a thin layer of a photoresist. In a ‘‘positive’’ working resist, the incident light causes chemical transformations in the illuminated areas which render them more soluble than the untreated photoresist. After irradiation, the exposed parts of the photoresist can be washed away with a suitable solvent. The wafer with the patterned photoresist layer is now subjected to an ion-etching process, which selectively ablates the uncovered areas of the wafer substrate. After removal of the remaining photoresist, the pattern of the mask has been transferred to the wafer. A complex sequence of several of these patterning processes is used to mass produce all kinds of electronic integrated circuits. Modern optics allows the reduction of the dimensions of the patterned structures to approximately half the wavelength of the illuminating light source. Photoresists have to meet, among others (for a more detailed discussion see Ref. [14]), the following requirements at least: (i) they need functionality for image formation and subsequent selective dissolution; (ii) the transparency at the imaging wavelength must be high enough to permit complete penetration through the photoresist layer; (iii) the non-illuminated photoresist remaining after dissolution must be resistant to the etching process. Current photoresists cannot be used for 157 nm technology, mainly because their transmittance at 157 nm is too low. Although materials with aromatic substructures are fairly useful for the 248 nm process, only purely aliphatic polymers are employed in the current 193 nm technology. For an illuminating wavelength of 157 nm, even the absorptivity of most aliphatic compounds is too high. Therefore, only partially fluorinated polymers with absorption characteristics carefully optimized by experiment [15] and molecular modeling [16] can be used. The ‘‘solubility switch’’ after illumination is usually achieved by addition of a photo-activatable superacid (e.g., a diaryliodonium hexafluoroantimonate) [17], which typically cleaves an acid-labile tert-butyl ester in the polymer (Scheme 8.9).

255

256

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds CF2CF2

OtBu O solubility switch

O F3C HO CF3

insoluble

CH2CH

illumination at 157 nm, photo-generated superacid

CF2CF2

soluble

CH2CH O

O +

F3C HO CF3

OH CH3 CH3

Scheme 8.9 Candidate for a 157 nm photoresist [14]. The perfluoroisopropanol moiety enhances transparency and general solubility. The tert-butyl ester group serves as the acidlabile solubility switch which can be activated by photo-generated superacid.

8.2 Applications in the Electronics Industry

In addition to polymers, there are many other applications of low molecular mass fluorochemicals in the electronics industry. Some typical applications of perfluoroalkanes and ethers are listed in Table 8.2. An important field of application of fluorinated gases such as CF4 , CClF3 , CHF3 , and C2 F6 is the plasma-etching process during fabrication of microchips [18, 19]. Like all chemicals involved in semiconductor manufacturing processes, the etching gases must be extremely pure, to avoid changing the carefully adjusted electronic characteristics of the semiconductors. Table 8.2

Applications of perfluorinated fluids in electronics manufacturing processes [18].

Application

Properties exploited

Fluid type

Shock testing of microchips

Inertness towards encapsulating resins, wide liquid range Thermal stability, inertness towards encapsulating resins Inertness towards resins, good heat-transfer properties Very high sensitivity electroncapture detectors toward CFCs Non-flammability

Perfluorinated cyclic ethers

Vapor-phase soldering of printed circuit boards Cooling supercomputers Tracer for gas emissions Solvent mixtures with alcohols and hydrocarbons to replace CFC-113 for cleaning microchips

Perfluorophenanthrene Perfluorocarbons Perfluorocyclohexanes Perfluorocarbons

8.2 Applications in the Electronics Industry

A problem with the first generation of liquid etching agents was the inability to etch straight, perpendicular walls into silicon wafers. Because of their surface tension, their etching rate depends strongly on the exact geometric environment and on the nature of the adjoining contact surfaces. In the anisotropic plasma etching process, in contrast, straight features can be obtained by exposing the masked wafer to a plasma created by electrical discharges in a perfluorocarbon atmosphere, because the etching rate is highly dependent on the direction relative to the crystallographic lattice axes of the substrate (Figure 8.4). This plasma contains, among a variety of charged species, excited fluorine atoms which can ablate, for example, silicon as volatile silicon tetrafluoride (SiF4 ). For the very small features achievable by 193 and 157 nm photolithography, especially, plasma etching has become indispensable. For the production of micro-mechanical devices, etching paths parallel to the wafer substrate surface are often required. Bromine trifluoride (BrF3 ) is used for this special kind of anisotropic etching. Because of the extreme reactivity of this compound, electrical excitation and plasma formation are not necessary. A typical microchip manufacturing process also contains several chemical vapor deposition (CVD) steps, to apply different functional layers to the silicon wafer substrate. These layers of metal (e.g., tungsten) or dielectrics (SiO2 , Si2 N3 , various doped oxides, silicon oxynitride) are deposited from reactive, gaseous, chemical precursors, for example, SiH4 , tetraethoxysilane, or tungsten hexafluoride (WF6 ). After each of these deposition steps, the residues from the CVD chemicals must be removed from the internal surface of the vacuum chamber. Historically, this was done by taking the chamber off-line and cleaning manually with wet chemicals. Because this downtime was expensive in terms of the high cost of extremely capital intensive wafer fabrication facilities (FAB), deposition chambers are nowadays cleaned by means of a plasma of different fluorochemicals. In the same way as for plasma etching, the active species in this ‘‘dry’’ chamber-cleaning process [20] are excited fluorine atoms which carry the residues away as volatile fluorides. Typical chamber-cleaning gases are NF3 [21] and, more recently, the less hazardous C2 F6 , C3 F8 , and CF4 –O2 and C2 F6 –O2 mixtures [22].

Wet isotropic etch

Mask

Mask

Layer to be etched Substrate Plasma anisotropic etch

Figure 8.4 Comparison of the anisotropic etching process with liquid and gaseous (plasma) etching agents.

257

258

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

Beyond this more basic use for the production of silicon-based electronics, some custom-tailored fluorochemicals have also been under investigation as functional media in NMR-based quantum computing [23].

8.3 Fluorinated Dyes

One of the earliest industrial applications of fluoro-organic chemicals was as dyes. The electron-withdrawing effect of fluorine and, in particular, the trifluoromethyl group can be used to tune the electronic levels and thus the color. In addition, fluorine-containing dyes show excellent color fastness [24, 25]. Most of the industrially relevant fluorinated dyes are azo compounds, but also anthraquinone dyes were commercialized in the 1930s by IG Farben in Germany. For example (Scheme 8.10), the coupling product 1 of Fast Scarlet VD as the diazonium component and Naphthol AS was used as the red dye of the Nazi swastika flag [24]. Indanthrene Blue CLB (2) was part of the German airforce uniform color (‘‘Flieger Gray’’) [26].

Cl OH CF3 N

O

F3C N

F9C4 OH H N

1

N

S

N

O

O

N

N

3

S N

HN 2

N

F9C4SO2 O

CF3

OH N

N 4

Scheme 8.10 Examples of the first commercially relevant fluorinated dyes (1 and 2) [24] and of dyes for nonlinear optics (3 and 4).

The reason for the enhanced color fastness of dyes containing a trifluoromethyl group is mainly their improved resistance towards photochemical oxidation [27]. However, perfluoroalkyl groups (3) and perfluoroalkylsulfonyl groups (4) are also used to obtain a high hyperpolarizability in intramolecular push–pull chromophoric systems for nonlinear optics [28]. Additional benefits of perfluoroalkyl substituents are increased lipophilicity and improved solubility in organic solvents [29]. As another class of fluorine-containing dyes, polymethine cyanines and azomethines have found their way into practical applications, for example, as sensitizers for photographic films [30, 31]. Using the wide range of substituent effects by fluorine and fluorinated functional groups, substitution of the aromatic moieties can be used to adjust the absorption maximum (Table 8.3).

8.3 Fluorinated Dyes Influence of various fluorine-containing substituents X on the benzothiazole moieties of 5a–i on the absorption characteristics [30].

Table 8.3

S

S

X

+

BF4−

N

X N

5a-i X

λmax (nm)

Δλmax (nm)

H F CF3 C(CF3 )3 OCF3 N(CF3 )2 SO2 CF3 SO2 C3 F7 SO2 C(CF3 )3

498 502 501 504 502 502 522 525 528

0 +4 +3 +6 +4 +4 +24 +27 +29

Compound 5a 5b 5c 5d 5e 5f 5g 5h 5i

SH

F

S

2 O

NHCH3

F F

O

Cl

S

+

Cl

6c N

N R BF4–

R

NEt3 S 2 N –

BF4

CH2F

+

BF4–

CH3

N+ CH3

BF4–

N F

R

F

6d

R

Cl

+

BF4– CH2F

F

S

F

S N

N+

F

S

BF4–

S

S HC(OEt)3

S

N+ R

N F

F

6e

R

CH3

Scheme 8.11 Synthesis of fluorinated trimethine cyanine dyes [30].

An even larger effect on the absorption characteristics is exerted by simple fluorine substituents on the polymethine chain, strongly depending on their position (Scheme 8.11). The examples 6 in Table 8.4 show that fluorination in the α- and γ-positions of the trimethine cyanine chain has a bathochromic effect, whereas β-fluorination causes a hypsochromic shift.

259

260

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds Influence of the position of fluorination within the trimethine cyanine chain on the absorption maximum λmax , compared with the reference 6a with X1 = X2 = X3 = H [30].

Table 8.4

X2

S

S

+

N R

N X1

X3

BF4−

R

6a-e Compound 6a 6b 6c 6d 6e

R

X1

X2

X3

λmax (nm)

Δλmax (nm)

C2 H5 CH3 CH3 CH3 CH3

H F H F F

H H F H F

H H H F F

558 567 522 592 578

0 +9 −36 +34 +20

8.4 Liquid Crystals for Active Matrix Liquid Crystal Displays 8.4.1 Calamitic Liquid Crystals: a Short Introduction

As early as 1888, the Austrian botanist F. Reinitzer [32] found that cholesteryl benzoate, if heated above its melting point, 146.6 ◦ C, formed a milky, iridescent fluid with some of the typical characteristics of a liquid and some of a crystal [33]. On further heating above 180.6 ◦ C a clear melt was obtained. On cooling, the effect was found to be reversible. The subsequently so-called ‘‘mesophase’’ combines its fluidity with some typical anisotropic properties of the solid, crystalline state, for example, birefringence. In the years that followed, this phenomenon became the subject of intensive study [34, 35] and it was found that many compounds with rod-like molecular geometry formed ‘‘liquid crystalline’’ phases [36]. The structurally most simple of these calamitic mesophases is the nematic phase. The nematic mesophase can be understood as a one-dimensionally ordered elastic fluid in which the molecules are orientationally ordered but in which there is no long-range positional ordering of the molecules. The rod-like molecules tend to align parallel to each other with their long axes all pointing roughly in the same direction [37] (Figure 8.5). In addition to the nematic phase, some substances form smectic mesophases in which the molecules are ordered in a layer structure underlying the directional order. The geometries of the different types of smectic phase are defined by the tilt orientational ordering of the long axes of the molecules relative to the layer planes.

8.4 Liquid Crystals for Active Matrix Liquid Crystal Displays

Translational order is lost

Molecules are able to rotate

Molecules in fixed positions unable to rotate T1

T3

Soft diffuse layers

T2

The crystal state long range order

261

The soft smectic crystal state long range translational order rotational disorder

The smectic mesophase layer ordering T4

^

n Director

Molecules free to rotate and tumble

Layer order lost

T5

The isotropic liquid a disordered structure

The nematic mesophase orientationally ordered

Figure 8.5 Schematic representation of phase transitions in calamitic (rod-like) liquid crystals [37].

8.4.2 Functioning of Active Matrix LCDs

After Reinitzer’s discovery, nearly 80 years were to pass until the first successful attempts to use liquid crystals in the design of electrically switchable displays. The first prototypes of liquid crystal displays (LCDs), reported by the Radio Corporation of America (RCA) in the 1960s [38], were based on the dynamic scattering mode (DSM). This mode is based on a cell containing a uniformly oriented nematic liquid crystal layer which is doped with a conducting salt. If a voltage is applied, migrating ions cause director fluctuations in the normally transparent layer, resulting in scattering of light. A DSM display suffers from slow response times and rapid electrochemical degradation; this limits its lifetime and its commercial attractiveness. In addition to these inherent problems, the liquid crystalline material used for this application was derived either from aromatic azomethines (7), which are highly sensitive to hydrolysis, or from azoxy compounds (8) [39], which suffer from photochemical lability (Scheme 8.12). The broad application of LCDs became feasible as a result of two, nearly simultaneous, groundbreaking innovations – the invention of the twisted nematic (TN) cell by Schadt and Helfrich [40] in 1971 and the discovery of the cyanobiphenyls (9) by Gray and co-workers [41] in the early 1970s. A further decisive development

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

R1

R1

N R2

7

H7C3

CN

8

R2

CN

9

10

H CN

H7C3

O N N

H7C3

H

CN

O H7C3 O 12

11

Scheme 8.12 Examples of liquid crystals of the first (7 and 8) and second (9–12) generation (R = alkyl).

on the materials side was the cyanophenylcyclohexanes (PCHs) (10), reported in 1977 by Eidenschink et al. [42]. By making use of the melting point depression of mixtures of alkyl homologs of these and structurally similar substance classes (11 and 12) [43], it finally became possible to provide nematic materials for TN displays with a broad operating temperature range and almost unlimited lifetime (Scheme 8.12). In a liquid crystal cell based on the TN mode, a homogeneously aligned layer of a nematic liquid crystalline material with positive dielectric anisotropy (ε), helically twisted by 90◦ , is placed in an indium tin oxide (ITO)-lined glass cell between crossed polarizers (Figure 8.6). The orientation of the liquid crystal is achieved by means of an alignment layer of directionally rubbed polyimide within the cell [44]. To ensure homogeneous handedness of the helical structure and thus to avoid the formation of domains in the display, a small amount (up to 0.1%) of a chiral dopant is added to the liquid crystal material [45]. In the off-state the incoming light Off

1.0 Transmission

262

T = 90%

0.8 0.6

Gray scale

0.4 0.2 On

0.0 Off (a)

On

V90

0 (b)

1

2 3 Voltage/V

4

5

Figure 8.6 Working principle of a twisted nematic (TN) cell in the ‘‘normally white’’ configuration (a), and the change of transmission with increasing applied voltage (b). In the cell configuration sketched above the threshold voltage (V th ) for the electro-optical response corresponds to approximately V 90 for 90% of maximum transmission.

8.4 Liquid Crystals for Active Matrix Liquid Crystal Displays

is polarized and the plane of polarization of the light passing through the liquid crystal layer is rotated by 90◦ and thus able to exit the second polarizer. If a voltage is applied, the liquid crystal helix is deformed and the incident light cannot pass the crossed polarizers. Thus, in the off-state the cell, which is illuminated from the back, appears white; in the on-state it is black. A gray scale can be achieved by applying a voltage between the threshold voltage (V th ) and the saturation voltage. The first TN-LCDs were simple, directly addressed segment displays as still used, for example, for wrist watches. When attempts were made to increase the information content of the displays by time-sequential addressing in rows and lines (multiplexing), the limits of the TN cell were soon met. At higher multiplex ratios [46], contrast loss occurred, because of ever shorter addressing times. The development of the super-twisted nematic (STN) cell in 1984 [47] pushed the practicable limit to higher multiplex ratios, but it did not lead to a general solution of the problem. Even by the end of the 1960s, the first commercial LCDs still based on the DSM had faced the same principal problem of addressability at higher multiplex ratios. As a solution, the use of an ‘‘active matrix’’ of a thin film transistor (TFT) in combination with a voltage holding capacitor for each pixel was proposed [48] (Figure 8.7). In the long term, the DSM mode itself did not prove feasible, but the general idea of active matrix addressing was intensively re-evaluated during the 1980s for TN displays, to allow precise control of the applied voltage, and thus the optical transmission, for each pixel separately. Full color capability is achieved by dividing each pixel into three sub-pixels, in combination with color filters for the three basic colors [49]. These efforts resulted in the first prototype of a 3 in (7.5 cm diagonal) TFT display presented by Sharp in 1986. Because the manufacturing process of the TFT arrays is highly complex and expensive in terms of financial investment and human resources, the larger scale production of active matrix (AM)-LCDs for use in notebook computers only started in 1989 [50].

Polarizer

Color Opposing filters electrodes

Glass

TFT

Black matrix

Spacers Liquid crystal

Polyimide layer x-Electrode y-Electrode

(a)

TFT pixel electrode (drain)

Glass

Pixel

(b)

Backlight

TFTs

Figure 8.7 Set-up of a typical active matrix LCD: ‘‘Exploded’’ view of 12 pixels (a) and cross-section of three sub-pixels in the basic colors (b) (PI = polyimide, TFT = thin film transistor). The spacers are used to adjust the cell gap to typically 3–6 μm.

263

264

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

The major drawback of the first AM-LCD was the strong dependence of the contrast on the viewing angle, resulting in gray-scale inversion and color shift when looking at the display from other than an approximately perpendicular direction. This problem was solved for the ‘‘classic’’ TN-TFT design by using birefringent compensation films, sometimes in combination with multi-domain technology [51]. In recent years, technological diversification has been targeted at further improvement of the performance of active matrix-addressed LCDS. The in-plane-switching (IPS) and fringe-field-switching (FFS) modes [52], the multi-domain vertical alignment (MVA) LCD mode [53], and the technically related Advanced Super-V (ASV) mode [54] have succeeded in increasing the viewing angle to 170◦ , in reducing the switching time to less than 10 ms, and in dramatically improving the contrast ratio for the newest generation of LCD TV. Currently, innovation in LCD technology is driven predominantly by smartphones, tablet PCs and LCD TV applications, which require displays able to show high-quality moving pictures. The time span between two video frames at a rate of 25 per second (PAL standard) is 16.7 ms. This means that for a video-compatible LCD, a switching time significantly below about 15 ms has become an absolute necessity. 8.4.2.1 The Physical Properties of Nematic Liquid Crystals For each particular application and for each display mode, a nematic material with custom-tailored physical properties [55] is required. The most application-relevant of these properties are the temperature range of the nematic phase (i.e., the temperature range between the melting point and the clearing temperature T NI ), the dielectric anisotropy ε, the birefringence n, the rotational viscosity γ 1 , and the elastic constants K 1 , K 2 , and K 3 . Although the dielectric and optical anisotropies ε and n are properties of the condensed nematic phase, they can be related to the physical properties of single molecules. This is of great importance for the targeted, rational design of liquid crystalline materials. To respond to an applied electric field, the liquid crystal must exhibit dielectric anisotropy (ε = ε || − ε ⊥ ), defined as the difference between the dielectric constant ˆ of the nematic phase. The relationship parallel and perpendicular to the director (n) between ε on a supramolecular level and the physical characteristics of the single molecules is described by the Maier–Meier equation:    μ2  NhF 1 − 3cos2 β S (8.1) α − F ε = ε0 2kB T

where kB denotes the Boltzmann constant, S the Saupe orientational order parameter of the nematic phase, F the reaction field factor, where F = 1/(1 − fα) and f = ε − 1/2πε 0 a3 (2ε + 1), and h the cavity factor, where h=3ε/(2ε + 1). For ε, the macroscopic dielectric constant is used [56]. The dielectric anisotropy is proportional to the square of the molecular dipole moment, μ, and is a function of the orientation of this dipole relative to the nematic direction, described by the angle β. For the practical design of calamitic liquid

8.4 Liquid Crystals for Active Matrix Liquid Crystal Displays

crystals, the director (ˆn) is usually approximated by the orientation of the long axis of n0 long molecular axis (β = 0◦ ), it has the greatest effect on the dielectric anisotropy of the material. If the dipole moment is perpendicular to the long axis (β = 90◦ ), ε becomes negative. In between, at the magic angle β = 54.7◦ , ε passes through a minimum determined by the very small value of the anisotropy of the polarizability (α). The dielectric anisotropy is the decisive factor affecting the threshold voltage V th of the electro-optical response and consequently also the operating voltage of the driving circuitry of an LCD. The birefringence (n = ne − n0 = n|| − n⊥ ) of a nematic liquid crystal is correlated with the anisotropy of the molecular polarizability [α = α || − α ⊥ = α xx − (α yy + α zz )/2], with the xx-axis corresponding to the long molecular axis [57]:

2 n −1 n2e − 1 N 2α S = ; 02 α + n2 + 2 3ε0 3 n +2

N n2 + 2n2o α S = ; n2 = e α− 3ε0 3 3

(8.2)

The switching time τ of a TN cell depends mostly on the rotational viscosity γ 1 , which can be influenced by molecular design, and on the elastic splay constant K 1 ; the correlation of K 1 with molecular structure remains elusive. Owing to the clear correlation between molecular properties which can be calculated by computational methods and the physical properties of the nematic phase, the dielectric anisotropy (ε) and the birefringence (n) can be predicted with reasonable accuracy by molecular modeling [58]. On the other hand, the viscoelastic terms γ 1 and K 1 , K 2 , K 3 are currently not really predictable, even though some recent results based on neural networks [35b], Monte Carlo simulations [59], and molecular mechanics approaches [60] give rise to some careful optimism (Figures 8.8 and 8.9). The relationship between the physical properties of liquid crystalline materials and LCD performance is summarized in Table 8.5. A prerequisite for the experimental determination of the anisotropic electrooptical properties (ε, n) is the occurrence of a nematic phase with a defined order parameter S [36]. As single substances, many commercially used ‘‘liquid crystalline’’

η1

η2

η3

γ1

Figure 8.8 The corresponding shear and rotational flow profiles for the anisotropic Miesowicz viscosity terms η1 , η2 , and η3 [61], and the rotational viscosity γ 1 , relative to an isolated liquid crystal molecule. In the design of TN LCDs, γ 1 is of predominant importance, because it is proportional to the switching time of the display [62].

265

266

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

Equilibrium configuration

Splay

Twist

Bend

Figure 8.9 Elastic deformations of calamitic, rod-like liquid crystals in the nematic phase. The corresponding elastic elasticity constants are K 1 (splay), K 2 (twist), and K 3 (bend). K 1 has the largest influence on the threshold voltage, V th , of TN cells [55f]. Relationship between the physical properties of nematic liquid crystals and the corresponding application-relevant display properties.

Table 8.5

Liquid crystal

Display properties

Nematic phase range Dielectric anisotropy (ε)

Operating temperature range (typically −30 to 90 ◦ C) Operating voltage and maximum achievable integration density (miniaturization) of the driving circuits; large impact on manufacturing costs Cell gap (typically 3–6 μm) Switching time (τ on + τ off ), below 16.7 ms for video applications Operating voltage for display panel

Birefringence (n) Rotational viscosity (γ 1 ) Elastic constants (K 1 , K 2 , K 3 )

materials have either no mesophase or a smectic phase only. As components of nematic basic mixtures, on the other hand, they behave like typical liquid crystals, contributing with their molecular anisotropies to the overall anisotropy of the mixture. To obtain for all potentially interesting substances a uniform and comparable set of characterization properties for application-oriented evaluation, so-called ‘‘virtual’’ properties are used. These are derived by extrapolation of the properties of a defined solution of the material of interest in a standardized nematic host mixture. The change of the order parameter induced by addition of the analyte is taken into account for the extrapolation procedure [63a]. Usually, the values for ε, n, and γ 1 are measured by this procedure. In addition, for the characterization profile a ‘‘virtual’’ clearing point (T NI ) is also cited. With currently existing liquid crystalline single materials, simultaneous optimization of all these properties for one specific application cannot be achieved. Therefore, commercial liquid crystals are typically mixtures of 5–15 substances. Usually, these complex mixtures are based on different alkyl homologs of the same basic structure [64] (Figure 8.10). In addition to these properties, another set of application-relevant properties is used to characterize the ‘‘reliability’’ of a liquid crystalline single substance or a

8.4 Liquid Crystals for Active Matrix Liquid Crystal Displays

Temperature

Temperature

Isotropic

Nematic

Solid

0.0

0.25 0.5 0.75 Fraction of one component

1.0

Figure 8.10 Typical phase diagram of a binary mixture of nematic liquid crystals. By use of ‘‘eutectic blocks’’ of structurally similar compounds (e.g., alkyl homologs), the nematic phase range is extended to lower temperatures [64].

mixture. The different LCD manufacturers define these properties differently, but usually they are centered around the chemical long-term stability under thermal, oxidative, and photochemical stress, the specific resistivity, and the voltage-holding ratio (VHR) [65]. The voltage holding ratio is defined as the ratio of voltage applied to a pixel at the end and at the beginning of a given time span. If the specific resistivity or the VHR of a liquid crystal too low, this results in visible flicker or contrast loss of the display. The reliability of the liquid crystal therefore has a decisive impact on the production yield and costs for the LCD manufacturer (Table 8.6). 8.4.3 Why Fluorinated Liquid Crystals?

Fluorochemicals, in general, have the disadvantage of relatively high price and, often, synthetic access is challenging. Nevertheless, most liquid crystalline single materials nowadays in use for AM-LCD technology contain fluorine, either as part of a polar group or within the mesogenic core structure [63] (Scheme 8.13). There are many good reasons to make use of the unique properties of fluorinated substructures for the design of liquid crystals and these far outweigh the economic and synthetic disadvantages. 8.4.3.1 Improved Mesophase Behavior by Lateral Fluorination Some of the reasons for the preference for fluorinated liquid crystals date back to the beginnings of LCD technology; others have gained paramount importance since the introduction of AM-LCD in 1989. Lateral fluorination of aromatic substructures in the mesogenic core structure of liquid crystals often results in significant broadening of the nematic phase range, a decrease in the melting point, and improved solubility. A less welcome side-effect of lateral fluorination is a decrease in the clearing temperature compared with the nonfluorinated analog. Clearing point depression as a result of lateral fluorination was observed as early as the 1950s by Gray and coworkers [66]; more beneficial

267

268

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds The most important active matrix (AM) LCD technologies and requirements for the corresponding liquid crystalline materials.

Table 8.6

Technology

Applications

Material requirements

Characteristics

Standard AM-LCDs (5 V/4 V driver)

PC monitors, notebook PCs, flat-panel TVs

ε ≈ 4–8 n ≈ 0.085–0.10 T NI ≈ 80–120 ◦ C

Well-established technology; use of birefringent compensation films for improvement of dependence of contrast on viewing angle

AM-LCDs with low threshold voltage (3.3 V/2.5 V driver)

Notebook PCs, personal digital assistants (PDAs), viewfinder for digital cameras

ε ≈ 10–12 n ≈ 0.085–0.10 T NI ≈ 70–80 ◦ C

Cheaper and more compact driving circuitry required than for standard AM-LCDs; low power consumption; better miniaturization achievable; material very sensitive to ionic impurities

Reflective/ transflective AM-LCDs

Video games (‘‘Gameboy’’), sub-notebook PCs, PDAs

ε ≈ 4–8 n ≈ 0.06–0.08 T NI ≈ 80–90 ◦ C

Requires no backlight and only one polarizer, therefore reduction of power consumption by 70–90%; high brightness and contrast difficult to achieve

In-plane switching (IPS), fringe field switching (FFS)

PC monitors, flat panel TVs, touchpanels for smartphones and tablet PCs

ε ≈ 10–12 n ≈ 0.075–0.09 T NI ≈ 70–85 ◦ C

Very wide viewing angle and brilliant picture

Multi-domain vertical alignment (MVA), advanced super view (ASV), patterned vertical alignment (PVA)

PC monitors, flat panel TVs

ε ≈ −3 to −5 n ≈ 0.08–0.09 T NI ≈ 70–80 ◦ C

Very wide viewing angle and brilliant picture; high contrast; fast switching (kT), charge carriers are captured and immobilized in these so-called trap states. The charge carrier mobility is directly related to the hopping probability, which can be described by the Marcus equation [90]:

 2  2 λ + G0 1 2π   HAB exp − (8.3) ket =  4λkb T 4πλkb T The rate constant of the electron transfer ket is determined by the transfer integral |HAB |, the energy difference between relaxed initial and final state (G◦ ), and the reorganization energy λ. The exponential term implies that the transfer rate increases initially with increasing −G◦ . When −G◦ becomes equal to the reorganization energy λ, a maximum is reached. Further increase of −G◦ results in a decreased reaction rate. This effect is called the Marcus inverted region. However, for the electron transfer between identical molecules, as in the case of a typical organic semiconductor, G◦ equals zero, leaving only the reorganization energy term λ. The Marcus theory suggests two different ways to increase the electron transfer rate ket and the efficiency of the hopping process in an organic semiconductor: 1) Optimization of the transfer integral |HAB |. The pair of individual molecules must have a significant electronic overlap between the donating orbital of the electron donor and the receiving orbital of the acceptor. The transfer integral describes the probability of the electron transfer between the two molecules. It

8.5 Fluorine in Organic Electronics

283

depends in a very sensitive manner on the distance between π systems, on the degree of overlap, and on their relative orientation [91]. 2) Minimization of the reorganization energy λ. In order to minimize the relaxation term λ, the changes in geometry of between neutral state and the radical cation (p-type) or radical anion (n-type) should be as small as possible. In a real device, where electrons or holes are injected through the source and drain electrodes, depending on the type of semiconductor (p or n), the energies of the valence band (HOMO in an organic crystal) and the conduction band (LUMO in an organic crystal) must match the work function of the contact materials. Otherwise, there will be an energetic barrier impeding the charge injection. Fluorination can address several of these issues: Fluorine and fluorinated substituents generally lower the HOMO and LUMO energy levels through their inductive (−Iσ ) effect. Aromatic fluorination has as an additional +Mπ effect, Table 8.17 Effects of aromatic (72–75) and aliphatic (76 and 77) perfluorination on redox potentials and HOMO–LUMO gaps [93–95].

S

S

S

S

S

72 F

F

F

F

F

F F

F

F

F

F

F

F

F

F

F

F

F

S S F

74 R

F

S S

F

F

F

S

F F

S

73

S F

F

75

S

S S

S S

S

R

76: R = C6H13 77: R = C6F13

Compound

Ered (V) Eox (V) ΔV red1-ox1 (V) HOMO–LUMO gap (eV)c

Pentacene (72) Perfluoropentacene (73) Sexithiophene (74)

−1.87a −1.13a −2.31a

−1.86a −2.05a Dihexylsexithiophene (76) −1.78b −2.01b Diperfluorohexylsexithiophene (77) −1.42b −1.65b Perfluorosexithiophene (75)

0.22a 0.79a 0.41a 0.63a 0.95a

2.09 1.92 2.72

2.21c 2.02 —

2.81

—

0.87b 1.09b 1.06b 1.22b

2.65

2.61

2.48

2.64

Differential pulse voltammetry (DPV), vs. Fc/Fc+ . Cyclic voltammetry (CV) in tetrahydrofuran (THF), vs. Fc/Fc+ . c Calculated at the B3LYP/6–31G(d) level of theory.

a b

F

284

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

which may influence not only the absolute HOMO and LUMO energies but also the band gap [92]. This means (Table 8.17) that the same basic structure, for example, sexithiophene (Scheme 8.14) or pentacene (Scheme 8.15), can be converted by addition of fluorine or perfluoroalkyl groups from a p-type to an n-type semiconductor. Lowering the orbital energies in general also increases device stability, because an electrode material for electron injection with a lower work function can be used. For example, air-sensitive calcium may be replaced by more stable aluminum. Also, the photochemical stability is enhanced. Perfluoroalkyl groups tend to aggregate within crystal structures, often stabilizing the semiconductor against degradation by oxygen or water. Br

F

Br

F

F

F

79%

Me3Si

SiMe3

S

Me3Si

SiMe3

S

Br

NBS, AcOH; 80 °C

SiMe3

S 78 F

F 86%

F

Br2, CH2Cl2; reflux

F

78

1. n-BuLi, THF

Bu3Sn

2. Bu3SnCl; –78 °C

S 79

80 F

F

1. 2 equiv. n-BuLi, THF 2. (PhSO2)2NF

F

SnBu3 78, cat. PdCl2(PPh3)2,

S

DMF; 80 °C

F

F

F

S S

S F

R

S F

R = SiMe3 R = Br

50%

F

S

F

81

3. Bu3SnCl; –78 °C

F

F

62%

85%

79

Br

SiMe3

S

F

F

Br

62%

78, cat. PdCl2(PPh3)2, DMF; 80 °C

NBS, AcOH; 80 °C 74%

R

F

R = SiMe3 R = Br 50%

NBS, AcOH; 80 °C 57%

F

F

F

S

F

F

F

F

S

S

S

S

S

F

Cu, DMF; 120 °C

F

Scheme 8.14

F

F

F

75

F

F

Synthesis of perfluorosexithiophene (75) [93].

Aromatic fluorination can also act as a tool to influence the relative orientation in addition to the interplanar distance of π systems [96], thus modifying the transfer integral via frontier orbital overlap (Scheme 8.16 and Figure 8.15). Highly fluorinated sections of an extended π system tend to ‘‘stick’’ to a more electronrich section by the quadrupolar interaction already discussed in Section 1.4.1. Such partial aromatic fluorination not only influences the molecular orientation,

8.5 Fluorine in Organic Electronics

F

OH

O

AlCl3, NaCl; 200 °C

F 82

F

O

OH

OH

Sn, HCl, HOAc; reflux

F

85% 82, AlCl3, NaCl; 280 °C

F F

95%

O

F

O

OH

F

F

O

OH

F

OH

O

SF4, HF; 150 °C

F

F F

OH

O

OH

F

F

F F F F F F

F F

F F

F F F F F F

F

Sn; 280 °C

F F

F

F

F

F

F

F

65%

OH

F

F

40%

OH

F

71%

O + F

O

F

F

F F

F F

F

F

F

F

73 Scheme 8.15 Synthesis of perfluoropentacene (73) [94].

F

F

F

S F

S

F 84

F

F

F

S

S F

F 85

S

S

F

F

F

F

F

F F

F

83

F

F

S S

F

F

F

F

F

F

S

S 86

Scheme 8.16 Examples of different fluorination concepts resulting in n-type or ambipolar semiconductors [99].

285

286

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

(a)

(b)

Figure 8.15 Complementary electrostatic potentials (a) (red denotes negative and blue positive partial charges between −0.021 e and 0.030 e) of different parts of 85 induce tight, antiparallel stacking in the crystal (b). Charge transport occurs along the stack axes.

but in many cases also lowers the interplanar or aromatic edge–edge distances, thus significantly increasing the transfer integral. Often, fluorination switches the supramolecular organization from a herringbone arrangement to untilted π-stacks, which is favorable to electron transfer (85 and 86) [97]. Similar concepts have also been applied to polymeric organic semiconductors. Alternating electron-rich and electron-poor segments lead not only to a smaller band gap, but also to closer stacking, to a higher crystalline order and subsequently to higher charge carrier mobilities [98]. For small aromatic molecules, this approach normally leads to linear, onedimensional π-stacks with antiparallel arrangement of the arenes [97]. This limits the main channel of charge carrier mobility to only one dimension, rendering the charge transport highly vulnerable against structural defects. A better, more isotropic charge carrier mobility can be achieved by a brickwork-like, twodimensional arrangement of the aromatic building blocks [100]. This has been realized in practice by introducing bulky substituents into the middle of the aromatic moiety (Scheme 8.17). SiEt3

F S

S F

S F

F S

F ...S interactions S

SiEt3 87

F

F S

F ...F interactions

Scheme 8.17 The crystal structure of the dithienoanthracene derivative 87 is controlled by the steric repulsion between the bulky triethylsilylethinyl substituents preventing cofacial stacking. Laterally, the structure is stabilized by directed sulfur-fluorine and, presumably, fluorine–fluorine interactions.

8.5 Fluorine in Organic Electronics

Aromatic fluorination not only influences π-stacking by interplanar interactions [101] – more subtly, weak bonds between electronegative fluorine and electropositive hydrogen [102], halogens [103], or sulfur [100] also shape the crystal structure by weak electrostatic interactions between the edges of the arenes (Scheme 8.17). Another example of crystal design utilizing aryl–perfluoroaryl stacking in order to optimize charge carrier transport is shown in Scheme 8.18 [104]. Here, the molecules are attached to each other by the intermolecular interaction of a perfluorophenyl with a phenyl moiety.

Br

Br 57%

+

PhB(OH)2, cat. Pd2(dba)3, DPE-phos, 2 M aq. K2CO3,

Br

toluene-EtOH; 95 °C, 4.5 h

F F

F

H

H

cat. Pd(OAc)2, S-phos, K2CO3,

F

HH

H

pentafluorobenzene,

F

F

H

78%

F

F

F

F

i PrOAc; 80 °C, 43 h

F

F

F

F

F

88

HH

H

H

H H

Scheme 8.18 Synthesis and crystal packing (box) of 88. The distance between the phenyl and pentafluorophenyl planes is 337 pm and the highlighted F···H distances are 240 pm.

One possible, practical application of OTFTs containing fluorinated materials is exemplified by the design of an inverter, printed on a banknote [105] as a possible anti-counterfeiting security measure. The material used as the n-channel is octafluorocopperphthalocyanine [106]. A major advantage of fluorinated organic semiconductors is their often significantly enhanced chemical and photochemical stability [100]. Apart from modifying

287

288

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

the crystal structure or the electronic properties, fluorinated structural elements have been used also for the modulation of the solubility and facilitation of synthesis and purification of organic semiconductors (Scheme 8.19; see also Section 7.2) [107]. Si(iPr)3

C6F13 F13C6 R F13C6

R + anti isomer (12%)

C6F13

xylenes; 145 °C, 4 d, after homogenization

F13C6 C6F13

Si(iPr)3 TBAF, THF; −78 °C to r.t.

quant.

(74%) R = Si(i Pr)3 R =H I

Me3Si

[Pd(PPh3)2Cl2], CuI, toluene−diisopropylamine

98%

C6F13 F13C6 TBAF, THF; −78 °C to r.t.

92%

R = SiMe3 R R=H

cat. Pd(PPh3)4, CuI, R perfluoro(methylcyclohexane)toluene−diisopropylamine I (3:5:1); 85 °C, 4 d

R

R

I

F13C6 C6F13

R

C6F13

F13C6

n

R

X: R = C6F13 F13C6 X: R = OC14H27

C6F13

Scheme 8.19 Fluorous biphase synthesis of poly(p-phenylenethynylene) derivatives: on heating, the polymerization occurs in a single phase. After cooling, the fluorous phase

separates. Depending on the substituent R, the polymer is soluble either in the organic phase (R = OC14 H27 ) or in the fluorous phase (R = C6 F13 ) [107].

The fluorophilic effect of perfluoroalkyl side chains has been used to induce spontaneous phase segregation (Figure 8.16), creating a fluorous monolayer of about 3 nm on the surface of the polymeric, liquid crystalline p-type semiconductor [poly(3-dodecylthiophene) (P3DT)] [108]. In a bulk heterojunction OPV cell, the

8.5 Fluorine in Organic Electronics

F

F

F

F F

F

F

F F F F F F

S

F

F

F

F

F F F F F F

F F F F F F

F

F F F F F F F

F F F F F F F

F F F F F F F

F F F F F

Perfluorinated, polar hydrophobic surface layer

S S

S

S

S S

S

Hydrocarbon-based, nonpolar smectic liquid crystalline bulk

Figure 8.16 Hemifluorinated side chains segregate to the polymer surface and create a dipolar layer with very low surface energy on top of the nonfluorinated bulk material.

fluorous layer performs two functions: it reduces the surface energy of the P3DT bulk phase, and it forms a local dipole moment, shifting the ionization energy by up to +1.8 eV. Thus, it forms a buffer layer between the p- and n-type semiconductor phases, preventing unfavorable charge recombination. SAMs are often used to form a dipolar film on the metal electrodes (typically gold, silver, or copper) in order to adjust their work function to the HOMO or LUMO levels of the organic semiconductor (Figure 8.17). This match is required to avoid an energetic barrier for the charge injection [109]. An additional function, particularly of fluorinated SAMs, is the modification of the surface energy of electrodes or the dielectric (in bottom gate TFTs), which influences the morphology of the semiconductor with which it is in direct contact. The highest charge carrier concentration in an OFET is mainly confined to a semiconductor layer of about 2 nm in direct contact with the dielectric. Therefore, influencing the morphology in this contact region often enhances the performance of the OFET dramatically [110]. Also for the dielectric of an OFET, fluorination can offer some advantages. (i) Most fluoropolymers have a very low dielectric constant, which in general helps to obtain high field induced charge carrier mobilities, particularly in amorphous organic semiconductors [111]. (ii) Their low surface energy often allows the morphology of the adjoining semiconductor layer to be controlled over a relatively

289

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

+

−

+

− LUMO

LUMO

F FF FF F

E

290

F

s s

Metal

F FF FF F

Metal

HOMO HOMO (a) F F

F F

F

F

F

F

F

F F

F F

F F

F F F

F

F SH

F

SH

F F F

SH (b)

SH

Figure 8.17 Using a dipolar SAM, the work function of a gold or silver electrode can be shifted by up to ±0.8 eV, depending on the direction and magnitude of the surface dipole moment (a). In addition, the SAM influences the morphology of the organic semiconductor with which it is in direct contact (b).

large distance, which can be extremely beneficial to charge carrier mobility and OFET performance. (iii) Fluoropolymers, such as CYTOP (Scheme 8.20) [112], are soluble in perfluorinated solvents (see also Section 6.1), whereas typical organic semiconductors dissolve only in hydrocarbon-based solvents. This ‘‘orthogonal solubility’’ facilitates the printing of multi-layer structures, avoiding any functional layer being dissolved or contaminated by printing the subsequent layer on top of it. F F

F F

O

F F

F F

F F

n

Scheme 8.20 Structure of the perfluorinated dielectric CYTOP.

8.5.2 Organic Light-Emitting Diodes (OLEDs)

Also OLED technology is more and more dependent on fluorinated functional materials. In the most basic case, an OLED consists of a thin layer of an organic

8.5 Fluorine in Organic Electronics

semiconductor into which electrons and holes are injected by opposite electrodes. In the area where electrons and holes meet, excitons are formed and decay with light emission. In reality, the setup of an OLED is not that simple, and the device consists of several layers of functional materials, each optimized for its specific purpose (Figure 8.18). For example, there are separate hole and electron transport layers in addition to special emitters which are embedded in a matrix facilitating exciton diffusion and charge recombination. As for OFETs, printable and solution-processable OLED systems are expected to reduce manufacturing cost dramatically. Owing to the complex multi-layer structure of an OLED, it is important to protect one functional layer from the solvent used for processing the subsequent layer. One approach to address this issue is the use of materials which can be cross-linked after printing and thus made insoluble [113]. There are several types of reactive groups used for cross-linkable materials (such as styrenes and oxetanes), but especially the trifluorovinyloxy group offers some advantage, being compatible with a large variety of synthetic conditions (Scheme 8.21). Moreover, polymerization does not require an initiator which would contaminate the functional layer, but can be induced thermally [114]. Another application of fluorinated materials for OLEDs are so-called triplet emitters. According to spin statistics, only 25% of the recombining electron–hole pairs end up as singlet excitons, and 75% as triplet excitons [115]. For most organic compounds, emission from an excited triplet state comprises a ‘‘forbidden’’ transition, which means that 75% of the excited states cannot enter a radiative pathway. However, some complexes of heavy metals (Ir, Pt) show strong spin–orbit

Seal Metal cathode Electron transport layer Emissive layer

− +

Hole injection layer Anode Substrate Figure 8.18 Typical OLED stack on a glass or plastic substrate with an indium tin oxide (ITO) anode. The hole injection layer is a p-type semiconductor, the emissive layer a matrix material doped with a suitable emitter compound, and the electron transport

layer an n-type semiconductor. The cathode is a very thin, transparent layer of a metal (Al, Ba) with a low work function. In order to protect the stack from degradation by water or oxygen, it has to be encapsulated with a sealing material.

291

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

292

n

m

F

O O

O

RO

O

F F + F F

F

F

F

F 225 °C,

F

RO

OR 1 h

OR F

F

O O

O

H9C4 N

F

O

F

F

O

F

F

F

O

N

F F F O

N N N

O

C4H9

N

O

H9C4 O O N

N

F O F

O

F

F

O Si O

C4H9

N

O

F

F

F

F F

C4H9

N

H9C4 Scheme 8.21 Cross-linking by thermal dimerization of trifluorovinyloxy functions (box). Examples of cross-linkable hole conductors [114].

coupling and are therefore able to emit light from a triplet state [116]. In particular for blue triplet emitters, fluorinated iridium and platinum complexes are used (Scheme 8.22) [117].

References F

F

F F

F N N

F

N N

Ir

CH3 O

Ir

O N

F

O CH3

F

F

Pt N

N

F

O

F

F

Scheme 8.22 Examples of fluorinated Ir- and Pt-based triplet emitters for OLEDs [117].

References 1. Powell, R.L. (2000) Applications: Poly-

2.

3.

4.

5.

6.

7.

mers, in Houben–Weyl: Organo-Fluorine Compounds, Vol. (eds B. Baasner, H. Hagemann, and J.C. Tatlow), Georg Thieme, Stuttgart, pp. 59–69. (a) Midgley, T.and Henne, A.L. (1930) Ind. Eng. Chem., 22, 542; (b) Midgley, T. (1937) Ind. Eng. Chem., 29, 239. Review on CFCs: Barbour, A.K., Belf, L.J., andBuxton, M.W. (1963) Adv. Fluorine Chem., 3, 181. For more details on fluorocarbon nomenclature, see: Banks, R.E. (2000) Nomenclature, in Houben–Weyl: Organo-Fluorine Compounds, Vol. E 10a (eds B. Baasner, H. Hagemann, and J.C. Tatlow), Georg Thieme, Stuttgart, pp. 12–17. Powell, R.L. (2000) Applications: polymers, in Houben–Weyl: Organo-Fluorine Compounds, Vol. E 10a (B. Baasner, H. Hagemann, and J.C. Tatlow), Georg Thieme, Stuttgart, pp. 76–78. (a) Sianesi, D., Marchionni, G., De Pasquale, R.J. (1994) in Organofluorine Chemistry, Principles and Commercial Applications (eds R.E. Banks, B.E. Smart, and J.C. Tatlow), Plenum Press, New York, p. 431; (b) Ohsaka, Y. (1994) in Organofluorine Chemistry, Principles and Commercial Applications (eds R.E. Banks, B.E. Smart, J.C. Tatlow), Plenum, New York, p. 463. (a) Goldwhite, H. (1986) in Fluorine: the First Hundred Years (1886–1986) (R.E. Banks, D.W.A. Sharp, J.C. Tatlow), Elsevier Sequoia, Lausanne, pp. 109–132; (b) Rhodes, R. (1986) The Making of the Atomic Bomb, Simon and Schuster, New York; (c) Morel, B., and Duperret,

8.

9.

10.

11.

12.

13.

14.

B. (2009) J. Fluorine Chem. 130, 7–10; (d) Kraus, F. (2008) Nachr. Chem., 56, 1236–1240. Manhattan Project Heritage Preservation Association (2012) Preserving, Exhibiting, Interpreting and Teaching the History of the Manhattan Project, http://www.childrenofthemanhattan project.org (accessed 28 September 2012). Cha, S.N., Kim, S.M., Kim, H.J., Ku, J.Y., Sohn, J.I., Park, Y.J., Song, B.G., Jung, M.H., Lee, E.K., Choi, B.L., Park, J.J., Wang, Z.L., Kim, J.M., and Kim, K. (2011) Nano Lett. , 11, 5142–5147. Naber, R. C. G., Asadi, K., Blom, P.W.M., Leeuw de, D.M., Boer de, B. (2010) Adv. Mater., 22, 933–946. Smart, B.E. (1994) in Characteristics of C–F Systems in Organofluorine Chemistry: Principles and Commercial Applications (eds R.E. Banks, B.E. Smart,and J.C. Tatlow), Plenum Press, New York pp. 57–88. Caporiccio, G. (1986) in Fluorine: the First Hundred Years (1886–1986) (eds R.E. Banks, D.W.A. Sharp, and J.C. Tatlow), Elsevier Sequoia, Lausanne p. 314. Rothschild, M., Bloomstein, T.M., Fedynyshyn, T.H., Liberman, V., Mowers, W., Sinta, R., Switkes, M., Grenville, A., and Orvek, K. (2003) J. Fluorine Chem., 122, 3–10. Feiring, A.E., Crawford, M.K., Farnham, W.B., Feldman, J., French, R.H., Leffew, K.W., Petrov, V.A., Schadt, F.L., Wheland III,, R.C., Zumsteg, F.C., J. Fluorine Chem. 2003, 122, 11–16.

293

294

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds 15. (a) Feiring, A.E. and Feldman, J. (2000)

16.

17.

18.

19.

20. 21.

22. 23.

24. 25.

26.

WO Patent 2000/17712; (2000) Chem. Abstr., 132, 258158; (b) Feiring, A.E. and Feldman, J. (2000) WO Patent 2000/67072; (2000) Chem. Abstr., 133, 357252; (c) Crawford, M.K., Farnham, W.B., Feiring, A.E., Feldman, J., French, R.H., Leffew, K.W., Petrov, V.A., Schadt, F.L. Zumsteg F.C. III, (2002) J. Photopolym. Sci. Technol., 15, 677–687. (a) Waterland, R.L., Dobbs, K.D., Rinehart, A.M., Feiring, A.E., Wheland, R.C., Smart, B.E. (2003) J. Fluorine Chem., 122, 37–46; (b) Zhan, C.-G., Dixon, D.A., Matsuzawa, N.N., Ishitani, A., Uda, T. (2003) J. Fluorine Chem., 122, 27–35. (a) Houlihan, F.M., Nalamusu, O., and Reichmanis, E., (2003) J. Fluorine Chem., 122, 47–55; (b) Desmarteau, D.D., Pennington, W.T., Montanari, V., and Thomas, B.H. (2003) J. Fluorine Chem., 122, 57–61. Powell, R.L. (2003) in Applications: Polymers in Houben–Weyl: Organo-Fluorine Compounds, Vol. E 10a (eds B. Baasner, H. Hagemann, J.C. Tatlow), Georg Thieme, Stuttgart, pp. 79–83. Woytek, A.J. (1986) in Fluorine: the First Hundred Years (1886–1986) (eds R.E. Banks, D.W.A. Sharp, and J.C. Tatlow), Elsevier Sequoia, Lausanne, p. 331. Allgood, C.C. (2003) J. Fluorine Chem., 122, 105–112. Benzing, D.W., Benzing, J.C., Boren, A.D., and Tang, C.C. (1986) US Patent 4,657,616; (1987) Chem. Abstr., 106, 111827. Allgood, C. (1998) Adv. Mater., 10, 1239–1242. VanderSypen, L.M.K., Steffen, M., Breyta, G., Yannoi, C.S., Sherwood, M.H., and Chuang, I.L. (2001) Nature, 414, 883–887. Review: Adams, D.A.W. (1951) J. Soc. Dyers Colourists, 223–235. Dickey, J.B., Towne, E.B., Bloom, M.S., Taylor, G.J., Mill, H.M., Corbitt, R.A., McCall, M.A., Moore, W.H., and Hedberg, D.G., (1953) Ind. Eng. Chem., 45, 1730–1734. Hendricks, J.O. (1953) Ind. Eng. Chem., 45, 99–105.

27. Matsui, M. (2006) Fluorine-containing

28.

29. 30.

31. 32. 33.

34.

35.

36.

37.

38.

dyes, in Functional Dyes (eds S.H. Kim), Elsevier, Amsterdam, pp. 257–266. (a) Matsui, M., Marui, Y., Kushida, M., Funabiki, K., Muramatsu, H., Shibata, K., Hirota, K., Hosoda, M., and Tai, K. (1998) Dyes Pigments, 38, 57; (b) Matsui, M., Kawase, R., Funabiki, K., Muramatsu, H., Shibata, K., Ishigure, Y., Hirota, K., Hosoda, M., and Tai, K. (1997) Bull. Chem. Soc. Jpn., 70, 3153. Matsui, M. (1999) J. Fluorine Chem., 96, 65–69. Review: Yagupol’skii, L.M., Il’chenko, A.Y., Gandel’sman, L.Z. (1983) Russ. Chem. Rev. 1983, 52, 993–1009; (1983) Usp. Khim., 52, 1732–1759. Kremlev, M.M., Yagupolskii, L.M. (1998) J. Fluorine Chem., 91, 109–123. Reinitzer, F. (1888) Monatsh. Chem., 9, 421. Lehmann, O. (1904) Fl¨ussige Kristalle, sowie Plastizit¨at von Kristallen im Allgemeinen, Molekulare Umlagerungen und Aggregatzustands¨anderungen, Engelmann, Leipzig. Dunmur, D.A., and Sluckin, T. (2011) Soap, Science and Flat-Screen TV – A History of Liquid Crystals, Oxford University Press, Oxford . (a) Demus, D., Demus, H., and Zaschke, H. (1974) Fl¨ussige Kristalle in Tabellen, VEB Deutscher Verlag f¨ur Grundstoffindustrie, Leipzig; (b) Vill, V. (1998) LiqCryst 3.1 – Databases of Liquid Crystalline Compounds, LCI Publisher, Hamburg. (a) Gennes de, P.G., and Prost, J., 1993 The Physics of Liquid Crystals, Oxford University Press, London ; (b) Jeu de, W.H. (1980) Physical Properties of Liquid Crystalline Materials, Gordon and Breach, New York. Demus, D., Goodby, J., Gray, G.W., Spiess, H.-W., Vill, V. (eds) (1998) Handbook of Liquid Crystals, Wiley-VCH Verlag GmbH, Weinheim. (a) Williams, R. (1963) J. Chem. Phys., 39, 384; (b) Williams, R. (1962) US Patent 3,322,485; (1968) Chem. Abstr., 68, 34254; (c) Heilmeier, G., Zanoni, L.A., and Barton, and L.A. (1968) Appl. Phys. Lett., 13, 46.

References 39. Kelker, H., and Scheurle, B.

40. 41.

42.

43.

44. 45.

46.

47.

48.

(1969) Angew. Chem. Int. Ed. Engl., 8, 884–885. Schadt, M., Helfrich, W. (1971) Appl. Phys. Lett., 18, 127. (a) Gray, G.W. and Harrison, K.J. (1972) GB Patent 1,433,130; Chem. Abstr., 81, (1974) 96988; (b) Gray, G.W., Harrison, K.J., and Nash, J.A. (1973) Electron. Lett., 9, 130. Eidenschink, R., Erdmann, D., Krause, J., and Pohl, L. (1977) Angew. Chem. Int. Ed. Engl., 16, 100. (a) Demus, D., Deutscher, H.-J., Kuschel, F., and Schubert, H. (1975) DE Patent 2,429,093; (1977) Chem. Abstr., 89, 129118; (b) Eidenschink, R., Erdmann, D., Krause, J., and Pohl, L. (1978) Angew. Chem. Int. Ed. Engl., 17, 133; (c) Eidenschink, R., Haas, G., R¨omer, M., and Scheuble, B.S. (1984) Angew. Chem. Int. Ed. Engl., 23, 147. Cognard, J. (1982) Mol. Cryst. Liq. Cryst. Suppl. Ser., Suppl. 1, 1–75. (a) Solladi´e, G., and Zimmermann, R.G. (1984) Angew. Chem. Int. Ed. Engl., 23, 348–362; (b) Pauluth, D., and W¨achtler, A.E.F. (1997) Synthesis and application of chiral liquid crystals, in Chirality in Industry II (eds A.N. Collins, G.N. Sheldrake, and J. Crosby), John Wiley & Sons, Ltd., Chichester, pp. 264–285. (a) Hirschmann, H. and Reiffenrath, V. (1998) Applications: TN, STN displays, in Handbook of Liquid Crystals (eds D. Demus, J. Goodby, G.W. Gray, H.-W. Spiess, and V. Vill), Wiley-VCH Verlag GmbH, Weinheim, 199–229; (b) Scheuble, B.S. (1989) Kontakte (Darmstadt), (1), 34–48; (c) Alt, P.M., and Pleshko, P. (1974) IEEE Trans. Electron. Devices, ED-21, 146–155. Scheffer, T.J., Nehring, J., Kaufmann, M., Amstutz, H., Heimgartner, D., and Eglin, P. (1985) SID Dig. Tech. Pap., 16, 120–123. (a) Lechner, B.J. (1971) Proc. IEEE, 59, 1566; (b) Brody, T.P., Asars, J.A., and Dixon, G.D. (1973) IEEE Trans. Electron. Devices, ED-20, 995; (c) Baraff, D.R., Long, J.R., MacLaurin, B.K., Miner, C.K., and Streater, R.W. (1981)

49. 50.

51.

52.

53. 54.

55.

IEEE Trans. Electron. Devices, ED-28, 736–739; (d) Kobayashi, S., Hori, H., and Tanaka, Y. (1997) Active matrix liquid crystal displays, in Handbook of Liquid Crystal Research (eds P.J. Collins, J.S. Patel), Oxford University Press, New York and Oxford, 415–444. Working Knowledge (1997) Sci. Am., (11), 87. (a) Finkenzeller, U. (1990) Spektrum Wiss. (8), 55–62; (b) Pauluth, D., and Geelhaar, T. (1997) Nachr. Chem. Tech. Lab., 45, 9–15. (a) Yang, K.H. (1991) Int. Dev. Res. Cent. Techn. Rep. IDRC, 68; (b) Iimura, Y., Kobayashi, S., Sugiyama, T., Toko, Y., Hashimoto, T., and Katoh, K. (1994) SID Dig. Tech. Pap., 915; (c) Sugiyama, T., Toko, Y., Hashimoto, T., Kato, K., Iimura, Y., Kobayashi, S. (1994) SID Dig. Tech. Pap., 919; (d) Schadt, M., Seiberle, H., Schuster, A., Kelly, S.M. (1995) Jpn. J. Appl. Phys., 34, 764. (a) Kiefer, R., Weber, B., Winscheid, F., and Baur, G. (1992) Proceedings of the 12th International Display Research Conference (Society of Information Display and the Institute of Television Engineers of Japan) (Hiroshima, Japan), p. 547; (b) Oh-e, M. and Kondo, K. (1997) Liq. Cryst., 22, 379–390, and references cited therein; (c) Lee, S.H., Lee, S.L. and Kim, H.Y. (1998) Appl. Phys. Lett., 73, 2881; (d) Yu, I.H., Song, I.S., Lee, J.Y., and Lee, S.H (2006) J. Phys. D: Appl. Phys., 39, 2367; (e) Lim, Y.J., Lee, M.-H., Lee, G.-D., Jang, W.-G., and Lee, S.H. (2007) J. Phys. D: Appl. Phys., 40, 2759. Takeda, A. (1999) EKISHO J. Jpn. Liq. Cryst. Soc., 3, 117–123. Sharp Corporation (2012) Electronics Components, http://sharpworld.com/products/device/lcd/asv.html (accessed 28 September 2012). (a) Maier, W., and Saupe, A. (1959) Z. Naturforsch., 14A, 882; (b) Maier, W., Saupe, A. (1960) Z. Naturforsch., 15A, 287; (c) Marcelja, S. (1974) J. Chem. Phys., 60, 3599; (d) Ypma, J.G.J., Vertogen, G., and Koster, H.T. (1976) Mol. Cryst. Liq. Cryst., 37, 57; (e) Jeu

295

296

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds

56.

57. 58.

59.

60. 61. 62.

63.

64. 65.

de, W.H., van der Veen, J. (1977) Mol. Cryst. Liq. Cryst., 40, 1; (f) Finkenzeller, U. (1988) Kontakte (Darmstadt), (2), 7–14. (a) Maier, W., Meier, G. (1961) Z. Naturforsch., 16a, 262–267; (b) Demus, D., Pelzl, G. (1982) Z. Chem., 21, 1; (c) Michl, J., Thulstrup, E.W. (1995) Spectroscopy with Polarized Light: Solute Alignment by Photoselection, in Liquid Crystals, Polymers, and Membranes, Wiley-VCH Verlag GmbH, Weinheim, pp. 171–221; (d) Maier, W., and Saupe, A., Z. Naturforsch. A 1959, 14, 882; (e) Maier, W., and Saupe, A. (1960) Z. Naturforsch. A, 15, 287. Vuks, M.F. (1966) Opt. Spectrosc., 20, 361. (a) Bremer, M. and Tarumi, K. (1993) Adv. Mater, 5, 842–848; (b) Klasen, M., Bremer, M., G¨otz, A., Manabe, A., Naemura, S., and Tarumi, K. (1998) Jpn. J. Appl. Phys., 37, L945–L948. (a) Wilson, M.R. (1998) Theory of the liquid crystalline state: molecular modelling, in Handbook of Liquid Crystals, Vol. 1 (eds D. Demus, J. Goodby, G.W. Gray, H.-W. Spiess, V. Vill), WileyVCH Verlag GmbH, Weinheim, p. 72; (b) Bates, M.A. and Luckhurst, G.R. (1999) Computer simulation of liquid crystal phases formed by Gay–Berne mesogens, in Liquid Crystals I (ed D.M.P. Mingos), Springer, Heidelberg, p. 65. Kuwajima, S., Manabe, A. (2000) Chem. Phys. Lett., 332, 105–109; Miesowicz, M. (1946) Nature, 158, 27. (a) Ericksen, J.L. (1961) Trans. Soc. Rheol., 5, 23; (b) Leslie, F.M. (1968) Arch. Rat. Mech. Anal., 28, 265; (c) Raviol, A., Stille, W., and Strobl, G. (1995) J. Chem. Phys., 103, 3788–3794. Reviews: (a) Kirsch, P. and Bremer, M. (2000) Angew. Chem. Int. Ed., 39, 4216–4235; (b) Kirsch, P., Reiffenrath, V., Bremer, M. (1999) Synlett, 389–396. Eidenschink, R. (1979) Kontakte (Darmstadt) (1), 15–18. (a) Sasaki, A., Uchida, T., and Miyagami, S. (1986) Japan Display ’86, p. 62; (b) Schadt, M. (1992) Displays, 13, 11; (c) Nakazono, Y., Ichinose, H., Sawada, A., Naemura, S., Bremer, M.,

66.

67. 68.

69.

70.

71. 72. 73.

74.

75.

and Tarumi, K. (1997) IDRC ’97 Digest, p. 65; (d) Nagata, S., Takeda, E., Nanno, Y., Kawaguchi, T., Mino, Y., Otsuka, A., and Ishihara, S. (1989) Proceedings of SID ’89 Digest, p. 242; (e) Naemura, S., Nakazono, Y., Ichinose, H., Sawada, A., B¨ohm, E., Bremer, M., and Tarumi, K. (1997) Proceedings of SID ’97 Digest, p. 199; (f) Fukuoka, N., Okamoto, M., Yamamoto, Y., Hasegawa, M., Tanaka, Y., Hatoh, H., and Mukai, K. (1994) AM LCD ’94, p. 216. (a) Gray, G.W., and Jones, B. (1954) J. Chem. Soc., 2556; (b) Gray, G.W. and Worrall, B.M. (1959) J. Chem. Soc. 1545. Byron, D.J., Lacey, D., Wilson, R.. (1981) Mol. Cryst. Liq. Cryst, 73, 273. (a) Dubois, J., Zann, A., Beguin, A. (1977) Mol. Cryst. Liq. Cryst , 42, 138; (b) Gray, G.W., Hogg, C., and Lacey, D. (1981) Mol. Cryst. Liq. Cryst., 67, 1; (c) Gray, G.W. and Kelly, S.M. (1981) Mol. Cryst. Liq. Cryst., 75, 109. Balkwill, P., Bishop, D., Pearson, A., and Sage, I. (1985) Mol. Cryst. Liq. Cryst., 123, 1–13. (a) Fearon, J.., Gray, G.W., Fill, A.D., and Toyne, K.J. (1985) Mol. Cryst. Liq. Cryst., 124, 89–103. Osman, M.A. (1985) Mol. Cryst. Liq. Cryst., 128, 45–63. Bremer, M., Naemura, S., Tarumi, K. (1998) Jpn. J. Appl. Phys., 37, L88–L90. (a) Wavefunction Inc. (1998) Spartan 5.0, Wavefunction, Irvine, CA; (b) Fl¨ukinger, P., L¨uthi, H.P., Portmann, S., and Weber, J. (2002) MOLEKEL 4.2, Swiss Center for Scientific Computing, Manno. (a) Bartmann, E., Poetsch, E., Finkenzeller, U., and Rieger, B. (1990) DE Patent 4,015,681; Chem. Abstr., 116, (1991) 185190]; (b) Kirsch, P., Bremer, M., Huber, F., Lannert, H., Ruhl, A., Lieb, M., Wallmichrath, and T. (2001) J. Am. Chem. Soc., 123, 5414–5417. (a) Bartmann, E. (1996) Adv. Mater., 8, 570–573; (b) Kirsch, P., Bremer, M., Taugerbeck, A., Wallmichrath, T. (2001) Angew. Chem. Int. Ed., 40, 1480–1484; (c) Kirsch, P., and

References

76.

77.

78.

79.

80.

Bremer, M. (2010) ChemPhysChem, 11, 357–360. Kirsch, P., Huber, F., Lenges, M., Taugerbeck, A. (2001) J. Fluorine Chem., 112, 69–72. Kirsch, P., Binder, W., Hahn, A., J¨ahrling, K., Lenges, M., Lietzau, L., Maillard, D., Meyer, V., Poetsch, E., Ruhl, A., Unger, G., and Fr¨ohlich, R. (2008) Eur. J. Org. Chem., 3479–3487. (a) Weinhold, F. and Carpenter, J.E. (1988) The Structure of Small Molecules and Ions, Plenum Press, New York, p. 227; (b) Reed, A.E., Curtiss, L.A., and Weinhold, F. (1988) Chem. Rev., 88, 899–926; (c) Reed, A.E., Weinstock, R.B., and Weinhold, F. (1985) J. Chem. Phys., 83, 735–747; (d) Reed, A.E. and Weinhold, F. (1983) J. Chem. Phys., 78, 1736; (e) Reed, A.E., Weinhold, F. (1983) J. Chem. Phys., 78, 4066; (f) Poster, J.P., Weinhold, F. (1980) J. Am. Chem. Soc., 102, 7211; (g) Carpenter, J.E., Weinhold, F. (1988) J. Mol. Struct. (THEOCHEM), 169, 41. (a) Rabolt, J.F., Russell, T.P., Twieg, R.J. (1984) Macromolecules, 17, 2786–2794; (b) Mahler, W., Guillon, D., Skoulios, A. (1985) Mol. Cryst. Liq. Cryst. Lett., 2, 111–119. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A. Jr.,, Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., and Pople, J.A. (1998) Gaussian 98,

81.

82.

83. 84.

85. 86.

87. 88. 89.

90. 91.

92.

Revision A.6, Gaussian, Inc., Pittsburgh, PA. (a) Overview: Hiyama, T., Organofluorine Compounds: Chemistry and Applications, Springer, Berlin, pp. 202–211; (b) Meyer, R.B., Liebert, L., Strazelecki, L., Keller, P. (1975) J. Phys. (Paris), 36, L69; (c) Chandani, A.D.L., Gorecka, E., Ouchi, Y., Takezoe, H., Fukuda, A., Jpn. J. Appl. Phys. 1989, 28, L1265; (d) Clark, N.A., Handschy, M.A., Lagerwall, S.T., Appl. Phys. Lett. 1980, 36, 899; (e) Coleman, D.A., Fernsler, J., Chattham, N., Nakata, M., Takanishi, Y., K¨orblova, E., Link, D.., Shao, R.-F., Jang, W.G., Maclennan, J.E., Mondainn-Monval, O., Boyer, C., Weissflog, W., Pelzl, G., Chien, L.-C., Zasadzinski, J., Watanabe, J., Walba, D.M., Takezoe, H., and Clark, N.A. (2003) Science, 301, 1204–1211. Review: Hertel, D., M¨uller, C.D., Meerholz, K. (2005) Chem. Unserer Zeit, 39, 336–347. OPV Review: Facchetti, A. (2011) Chem. Mater., 23, 733–758. (a) OFET Review: Bao, Z., and Locklin, J. (2007) Organic Field-Effect Transistors, Optical Science and Engineering Series, CRC Press, Boca Raton, FL; (b) Hasegawa, T. and Takeya, J. (2009) Sci. Technol. Adv. Mater., 10, 024314. Tang, M.L., Bao, Z. (2011) Chem. Mater., 23, 446–455. Ma, H., Yip, H.-L., Huang, F., Jen, A.K.-Y. (2010) Adv. Funct. Mater., 20, 1371–1388. Lilienfeld, J.E. (1926) US Patent 1,745,175. Heil, O. (1934) GB Patent 439,457. Coropceanu, V., Cornil, J., Silva Filho da, D.A., Olivier, Y., Silbey, R., and Bredas, J.-L. (2007) Chem. Rev., 107, 926–952. Nobel Lecture: Marcus, R.A. (1993) Angew. Chem., 105, 1161–1172. Feng, X., Marcon, V., Pisula, W., Hansen, M.R., Kirkpatrick, J., Grozema, F., Andrienko, D., Kremer, K., M¨ullen, K. (2009) Nat. Mater., 8, 421–426. Medina, B.M., Beljonne, D., Egelhaaf, H.-J., Gierschner, J. (2007) J. Chem. Phys., 126, 111101.

297

298

8 Halofluorocarbons, Hydrofluorocarbons, and Related Compounds 93. Sakamoto, Y., Komatsu, S., and Suzuki,

94.

95.

96.

97. 98.

99.

100.

101.

102. 103.

104.

105.

106. 107. 108.

T. (2001) J. Am. Chem. Soc., 123, 4643–4644. Sakamoto, Y., Suzuki, T., and Kobayashi, M., Gao, Y., Fukai, Y., Inoue, Y., Sato, F., Tokito, S. (2004) J. Am. Chem. Soc., 126, 8138–8140. Facchetti, A., Yoon, M.-H., Stern, C.L., Hutchinson, G.R., Ratner, M.A., Marks, T.J. (2004) J. Am. Chem. Soc., 126, 13480–13501. Reichenb¨acher, K., S¨uss, H.I., and Hulliger, J. (2005) Chem. Soc. Rev., 34, 22–30. Cho, D.M., Parkin, S.R., and Watson, M.D. (2005) Org. Lett., 7, 1067–1068. Tsao, H.N., Cho, D., Andreasen, J.W., Rouhanipour, A., Breiby, D.W., Pisula, W., M¨ullen, K. (2009) Adv. Mater., 21, 209. (a) Newman, C.R., Frisbie, C.D., Silva Filho, D.A. da, Br´edas, J.-L., Ewbank, P.C., Mann, K.R. (2004) Chem. Mater., 16, 4436–4451; (b) Usta, H., Facchetti, A., Marks, T.J. (2011) Acc. Chem. Res., 44, 501–510. Subramanian, S., Park, S.K., Parkin, S.R., Podzorov, V., Jackson, T.N., Anthony, J.E. (2008) J. Am. Chem. Soc., 130, 2706–2707. Berger, R., Resnati, G., Metrangelo, P., Weber, E., and Hulliger, J. (2011) Chem. Soc. Rev., 40, 3496–3508. Ganguly, P., and Desiraju, G.R. (2010) Cryst. Eng. Commun., 12, 817–833. Metrangolo, P., Resnati, G., Pilati, T., Liantonio, R., and Meyer, F. (2007) J. Polym. Sci. A: Polym. Chem., 45, 1–15. Okamoto, T., Nakahara, K., Saeki, A., Seki, S., Oh, J.H., Akkerman, H.B., Bao, Z., and Matsuo, Y. (2011) Chem. Mater., 23, 1646–1649. Zschieschang, U., Yamamoto, T., Takimiya, K., Kuwabara, H., Ikeda, M., Sekitani, T., Someya, T., and Klauk, H. (2010) Adv. Mater., 23, 654–658. Ling, M.M., Bao, Z. (2006) Org. Electron., 7, 568. Lim, J., Swager, T.M. (2010) Angew. Chem. Int. Ed., 49, 7486–7488. Geng, Y., Wei, Q., Hashimoto, K., Tajima, K. (2011) Chem. Mater., 23, 4257–4263.

109. (a) Ishii, H., Sugiyama, K., Ito, E.,

110.

111.

112.

113.

114.

115.

116.

117.

Seki, K. (1999) Adv. Mater., 11, 605–625; (b) Boer de, B., Hadipour, A., Mandoc, M.M., Woudenbergh van, T., Blom, P.W.M. (2005) Adv. Mater, 17, 621–625. Gundlach, D.J., Royer, J.E., Park, S.K., Subramanian, S., Jurchescu, O.D., Hamadani, B.H., Moad, A.J., Kline, R.J., Teague, L.C., Kirillov, O., Richter, C.A., Kushmerick, J.G., Richter, L.J., Parkin, S.R., Jackson, T.N., Anthony, J.E. (2008) Nat. Mater., 7, 216–221. Veres, J., Ogier, S., Lloyd, G., Leeuw de, D. (2004) Chem. Mater., 16, 4543–4555. AGC Asahi Glass Co. (2012) CYTOP, http://www.agc.com/english/chemicals/ shinsei/cytop/about.html (accessed 28 September 2012). Ma, H., Yip, H.-L., Huang, F., and Jen, A.K.-Y. (2010) Adv. Mater., 20, 1371–1388. (a) Huang, F., Cheng, Y.J., Zhang, Y., Liu, M.S., Jen, A.K.-Y. (2008) J. Mater. Chem., 18, 4495–4508; (b) Ji, J., Narayan-Sarathy, S., Neilson, R.H., Oxley, J.D., Babb, D.A., Rondan, N.G., and Smith Jr.,, D.W. (1998) Organometallics, 17, 783–785. Segal, M., Baldo, M.A., Holmes, R.J., Forrest, S.R., Soos, Z.G. (2003) Phys. Rev. B, 68, 075211. Yersin, H., and Finkenzeller, W.J. (2008) Triplet emitters for organic light–emitting diodes: basic properties, in Highly Efficient OLEDs with Phosphorescent Materials (ed H. Yersin), WileyVCH Verlag GmbH, Weinheim, 1–97. (a) Kamatani, J., Okada, S., Tsuboyama, A., Takiguchi, T., and Miura, S. (Canon) (2000) WO Patent 2002045466; (2002) Chem. Abstr., 137, 26192; (b) Petrov, V.A., Wang, Y., and Grushin, V. (DuPont), (2000) WO Patent 2002002714; (2002) Chem. Abstr., 136, 93307; (c) Endo, A., and Adachi, C. (2009) Chem. Phys. Lett., 483, 224–226; (c) Tian, N., Lenkeit, D., Pelz, S., Fischer, L.H., Escudero, D., Schiewek, R., Klink, D., Schmitz, O.J., Gonz´alez, L., Sch¨aferling, M., and Holder, E. (2010) Eur. J. Inorg. Chem., 4875–4885.

299

9 Pharmaceuticals and Other Biomedical Applications

In 2009, amongst the 200 best-selling drugs, 31 (16%) contained fluorine. At the head of this list is atorvastatin (Lipitor, US$13.3 billion sales), and the next best-selling fluorinated drug fluticasone (Seretide, US$8.1 billion) is ranked fourth [1]. There are many very different but highly specific reasons to make use of fluorinated substructures in medicinal chemistry [2]. Depending on the field of application, the strategies used to utilize effectively the unique properties of fluorine are quite diverse (Scheme 9.1). The action of most ‘‘normal’’ pharmaceuticals [3] is based on highly specific interactions with target structures in the organism and sometimes also on specific metabolic conversions. In these compounds, the degree of fluorination is usually fairly low, and a few fluorine substituents or fluorinated groups only are selectively introduced into the active structure, each with a specific purpose [4]. There is also, in contrast, a fundamentally different type of application, including inhalation anesthetics [5], X-ray and ultrasound contrast agents [6], blood replacements, and respiratory fluids. Here, the active compound does not participate in any biochemical conversions. With the possible exception of inhalation anesthetics, its action is based on a rather unspecific physical effect. Such compounds are often applied in extremely large doses (tens of grams per treatment) and they are designed such that, ideally, they leave the organism through the lungs or skin. Such compounds are highly fluorinated or even perfluorinated, to achieve total chemical inertness.

9.1 Why Fluorinated Pharmaceuticals?

The similarity in size makes fluorine an obvious candidate to replace hydrogen, often without significant disruption of the molecular geometry and shape [7]. Because fluorine is so strongly electronegative, however, it has a dramatic effect on the electronic properties of the basic compound. On a molecular level this allows modulation of the lipophilicity profile, of electrostatic interactions with the target structure, and inhibition of some metabolic pathways [8]. At the physiological level, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

300

9 Pharmaceuticals and Other Biomedical Applications

F Cl O

CH3

N

OH OH O

N H

Cl

F2HCO

F3C

O Roflumilast

ONa

O N

N N

SO2NH2

Celebrex

Cerivastatin OH

O

+

O

OH

COOH

F N

F

N F

NH2MeCl−

N

HN

O Ezetimibe

Fluoxetine hydrochloride

F

HO

F3C Cl

O O

N H Efavirenz

O

Ciprofloxacin

NH2 N

N

F O HO F Gemcitabine

Scheme 9.1 Examples of fluorine-containing pharmaceuticals: steroids (fluticasone), nonsteroidal anti-inflammatory drugs [roflumilast and Celebrex (celecoxib)], modulators of cholesterol metabolism (cerivastatin and ezetimibe), antidepressants (fluoxetine), antibiotics (ciprofloxacin), and antivirals (efavirenz and gemcitabine) [2].

better bioavailability, increased selectivity for the target organs, and – in general – a far lower effective dose than for analogous nonfluorinated pharmaceuticals can be achieved. A unique mechanism-based mode of action (‘‘suicide inhibition’’) for some fluoropharmaceuticals involves direct chemical reaction of a fluorinated substructure with the target protein.

9.2 Lipophilicity and Substituent Effects

Every substituent has a particular steric and electronic influence on its main scaffolding structure. These substituent effects can be condensed into a set of physicochemical terms. The most important of these translate the steric interaction of the substituent with its immediate environment [9], its interaction with different types of solvent system (the lipophilicity logP or π describes the distribution in an n-octanol–water system) [10], and its electronic influence

9.2 Lipophilicity and Substituent Effects

on the reactivity (σ ) of the basic structure into the quantitative language of thermodynamics. Substituent effects usually have a large impact on the biological activity of organic compounds. Lipophilicity (π) decisively affects the resorption of pharmaceuticals, their ability to reach their target organs, and their final distribution in the different compartments of the living organism. For example, drugs targeting the central nervous system, such as antidepressants, must have specific lipophilicity to be able to pass the blood–brain barrier. The Hammett constant, σ , can describe the influence of a functional group on the acidity or basicity of a neighboring site, as already discussed in Section 1.4.2. It determines the distribution of partial charges over the surface of a biologically active molecule, modulating its binding behavior towards a target structure. In addition, substituent properties can be used systematically to find quantitative structure–activity relationships (QSARs) during lead optimization in structures of pharmaceutical interest [11, 12]. The physicochemical effects of fluorine-containing substituents are among the most extreme (Table 9.1). Thus, the SCF3 group is, despite its relatively high polarity (σ p = +0.48), one of the most lipophilic functions (π p = +1.44), far exceeding that of fluorine (σ p = +0.06) and chlorine (σ p = +0.23). Also, the SF5 group has Comparison of Hammett constants (180 ◦ C, decomp. correct elemental analysis. A.1.4 Isomerization to trans-4

The isomeric mixture (trans–cis-4, 15:85) (60 g, 0.17 mol) was suspended in dry CH2 Cl2 (1.8 l) and treated at room temperature with BF3 ·Et2 O (2.61 ml, 17 mmol) for 60 min. After addition of MeOSiMe3 (6 ml, 44 mmol), the suspension was stirred for a further 30 min and then evaporated to dryness. The crude product was recrystallized twice from acetonitrile. Yield: 52 g (87%) trans-4, pale yellow needles [3]; m.p. 249 ◦ C, decomp.; 1 H NMR (300 MHz, DMSO-d6 (dimethyl sulfoxide), 303 K): δ = 8.31 (d, 4H, J = 12 Hz), 8.42 (d, 4H, J = 12 Hz); 19 F NMR (280 MHz, CDCl3 , 303 K): δ = 48.1 (s); MS (EI): m/z 352 [M+ ], 333 [M+ – F], 192 [O2 NPhSF2 + ], 146 [PhSF2 + ], 141 [O2 NPhF+ ], 111 [OPhF+ ], 95 (100%) [PhF+ ].

A.2 Hydrofluorination and Halofluorination A.2.1 General Remarks

When handling 70% HF–pyridine, skin contact and inhalation of fumes must be avoided. Experiments should be conducted under a well-ventilated hood and protective goggles and gloves should be used. Competent medical care must be

353

354

Appendix A Typical Synthetic Procedures

sought immediately even after apparently minor contamination. After skin contact, as a first-aid measure, immediate and thorough rinsing with water and subsequent treatment with calcium gluconate gel are recommended [4]. Triethylamine tris(hydrofluoride) is less corrosive than 70% HF–pyridine but the same safety precautions must be applied. In contrast with 70% HF–pyridine, NEt3 ·3HF does not attack borosilicate glassware. A.2.2 Synthesis of the Liquid Crystal 6

In a PTFE flask, a solution of 5 (100 g, 0.36 mol) in CH2 Cl2 (200 ml) was treated with 70% HF–pyridine (36.3 ml, 1.45 mol) and stirred at room temperature for 18 h. The mixture was poured on to ice (300 g) and extracted with CH2 Cl2 (3 × 100 ml). The combined organic extracts were washed until neutral with saturated aqueous NaHCO3 and dried over MgSO4 . After addition of pyridine (1% v/v), the solution was evaporated to dryness, yielding 98 g of crude hydrofluorination product. The crude product was filtered over silica gel (n-heptane–pyridine, 99:1) and crystallized from the same solvent at −20 ◦ C to furnish 6 (38.4 g, 36% [5]) (Scheme A.3); mesophase sequence 1) : C 52 SB 109 I; 1 H NMR (500 MHz, CDCl3 , 303 K): δ = 0.85–1.56 (m, 34H), 1.70–1.75 (m, 2H), 1.86–1.92 (mc, 1H); 19 F NMR (280 MHz, CDCl3 , 303 K): δ = −160.4 (mc); MS (EI): m/z 276 (M+ – HF). 36%

H11C5

70% HF-pyr, CH2Cl2;

5

Scheme A.3

r.t., 18 h

H H11C5

F C3H7

H 6

Hydrofluorination of olefins [5].

A.2.3 Synthesis of 8

A magnetically stirred mixture of α-methylstyrene (7) (7.1 g, 60 mmol), NEt3 ·3HF (14.7 ml, 90 mmol), and CH2 Cl2 (60 ml) in a 250 ml, single-necked, round-bottomed flask was treated with N-bromosuccinimide (NBS) (11.8 g, 66 mmol) at 0 ◦ C. After 15 min, the bath was removed and stirring was continued at room temperature for 5 h. The reaction mixture was poured into ice–water (1000 ml), made slightly basic with aqueous 28% ammonia, and extracted with dichloromethane (4 × 150 ml). The combined extracts were washed with 0.1 N HCl (2 × 150 ml) and 5% NaHCO3 solution (2 × 150 ml) and then dried over MgSO4 . After removal of the solvent by rotary evaporation, the crude product was distilled to give the product 8 [6] (Scheme A.4): 11.6 g (89%); b.p. 50–52 ◦ C/0.15 mmHg; nD 20 1.5370. 1) C = crystalline; SB = smectic B; N = nematic; I = isotropic. The transition temperatures are cited in degrees celsius.

A.3 Electrophilic Fluorination with F-TEDA–BF4 (Selectfluor) Scheme A.4 [6].

Br F

Bromofluorination of olefins

89% NBS, NEt3·3HF, CH2Cl2; 0 °C to r.t.

7

8

A.3 Electrophilic Fluorination with F-TEDA–BF4 (Selectfluor) A.3.1 Synthesis of the Fluorosteroid 11

A solution of 3β-acetoxyandrosterone (9) (0.5 g, 1.52 mmol) in isopropenyl acetate (5.0 ml) was heated at 80 ◦ C for 24 h under N2 . The reaction was cooled and quenched by addition of 200 μl of triethylamine. The solvent was removed by distillation in vacuo (0.1 mmHg), and the residue (10) was dissolved in acetonitrile (25 ml). F-TEDA–BF4 (N-fluoro-N  -chloromethyldiazoniabicyclooctane bis(tetrafluoroborate)) (537 mg, 1.52 mmol) was added and the reaction was monitored by thin-layer chromatography (TLC) (ethyl acetate–hexane, 1:4). After 2 h, the solution was poured into ethyl acetate (25 ml), washed with water (3 × 25 ml), dried (MgSO4 ), filtered, and evaporated in vacuo. Flash chromatography of the residue on silica gel (ethyl acetate–hexane, 1:4) afforded 474 mg (90%) of 3β-acetoxy-16fluoroandrostrone (11) (α:β ≈ 94:6), which had spectroscopic properties consistent with those reported in the literature [7] (Scheme A.5). H3 C H3C

H

H3C H3 C

H H

AcO

O

H

OAc

9

CH3 80 °C, 24 h

H3 C 90% F-TEDA-BF4, CH3CN; r.t., 2 h

H

H

H

10

H3C

O

H H

AcO

H H

AcO

OAc

F H

11

Scheme A.5 Electrophilic fluorination of steroids [8].

A.3.2 Synthesis of Diethyl Fluorophenylmalonate (13)

A solution of diethyl phenylmalonate (12) (1 mmol) in tetrahydrofuran (THF) (50 ml) was added to an oil-free suspension of NaH (40 mg of 60%, 24 mg, 1 mmol)

355

356

Appendix A Typical Synthetic Procedures

COOEt COOEt

94% 1. NaH, THF; 0 °C to r.t., 1 h 2. F-TEDA-BF4, DMF; r.t., 30 min

12 Scheme A.6

COOEt F

COOEt

13

Electrophilic fluorination of malonates [8].

in THF (5.0 ml) under N2 at 0 ◦ C. The solution was stirred at 0 ◦ C for 30 min and then at room temperature for 1 h. The sodium salt was diluted with N,Ndimethylformamide (DMF) (2.0 ml) and F-TEDA–BF4 (354 mg) was added. After being stirred for 30 min at room temperature, the mixture was poured into Et2 O, washed with 5% H2 SO4 (10 ml) and saturated NaHCO3 (10 ml), dried (MgSO4 ), filtered, and evaporated in vacuo. Purification by flash chromatography on silica gel afforded the pure product 13 (94%) [9] (Scheme A.6).

A.4 Fluorinations with DAST and BAST (Deoxofluor) A.4.1 General Remarks

Because DAST (diethylaminosulfur trifluoride) and BAST (bis(2-methoxyethyl) aminosulfur trifluoride; commercialized as Deoxofluor) hydrolyze readily, giving HF, similar precautions must be taken to those for handling hydrofluoric acid and its amine complexes [4]. Because neat DAST tends to explode if heated above 40–50 ◦ C, safety screens are recommended if DAST is heated. For reactions or more inert substrates, requiring higher temperatures, BAST (Deoxofluor) was developed as a safer alternative, because it decomposes on heating only slowly and without detonation [10]. In the fluorination reactions described in Sections A.4.2 and A.4.3, BAST may be replaced by DAST with similar results. A.4.2 General Procedure for Fluorination of Alcohols

The alcohol (10 mmol) in dry CH2 Cl2 (3.0 ml) was added at −78 ◦ C [for benzyl alcohol (14)] or at room temperature [for protected glucose (16)], under N2 , to a solution of BAST (2.43 g, 11 mmol) in CH2 Cl2 (2.0 ml) in a 50 ml, three-necked flask equipped with an N2 inlet tube, septum, and magnetic stirring bar. The reaction was monitored by GC–MS for disappearance of the starting material. On completion, the solution was poured into saturated aqueous NaHCO3 (25 ml) and after CO2 evolution had ceased it was extracted into CH2 Cl2 (3 × 15 ml), dried (Na2 SO4 ), filtered, and evaporated in vacuo. Flash chromatography on silica gel

A.4 Fluorinations with DAST and BAST (Deoxofluor)

F

OH 96% BAST, CH2Cl2; −78 °C, 3 h

14 BnO

O

BnO

OH

15

98%

OBn

BnO

BAST, CH2Cl2;

OBn 16

O

BnO

r.t., 30 min

F

α:β = 28:72

OBn OBn 17

Scheme A.7 Fluorination of alcohols with BAST (Deoxofluor) [10].

in hexanes–ethyl acetate afforded the pure products: benzyl fluoride (15) (1.05 g, 96%) and fluoroglucoside (17) (5.32 g, 98%, α:β = 28:72) [10] (Scheme A.7). A.4.3 General Procedure for Fluorination of Aldehydes and Ketones

A solution of the aldehyde (18) or ketone (20) (10 mmol) in CH2 Cl2 (3.0 ml), in a 25 ml PTFE bottle equipped with an N2 inlet tube and stirring bar, was treated with a solution of BAST (3.76 g, 17 mmol) in CH2 Cl2 (2.0 ml) at room temperature. Ethanol (92 mg, 116 μl, 2 mmol) was added (for in situ generation of catalytic quantities of HF) and the mixture was stirred at room temperature. The progress of the reaction was monitored by GC–MS. On completion, the solution was poured into saturated NaHCO3 and after CO2 evolution had ceased it was extracted into CH2 Cl2 (3 × 15 ml), dried (Na2 SO4 ), filtered, and evaporated in vacuo. Flash chromatography on silica gel in hexanes–Et2 O afforded the pure products benzal fluoride (19) (1.22 g, 95%) and 1,1-difluoro-4-tert-butylcyclohexane (21) (1.50 g, 85%) [10] (Scheme A.8). CHF2

CHO 95% 18

BAST, HF (20 mol%), CH2Cl2; r.t.

O

19 F F

85% BAST, HF (20 mol%), CH2Cl2; r.t.

20

21

Scheme A.8 Fluorination of aldehydes and ketones with BAST (Deoxofluor) [10].

357

358

Appendix A Typical Synthetic Procedures

A.5 Fluorination of a Carboxylic Acid with Sulfur Tetrafluoride A.5.1 General Remarks

Sulfur tetrafluoride is a hazardous and highly toxic gas [4], in some respects comparable to phosgene [11]. For reactions with SF4 with or without HF, autoclaves made from Hastelloy C with Monel 400 piping and valves are recommended [12]. When handling SF4 , sufficient ventilation must be provided and protective goggles and gloves should be worn. On autoclave depressurization, excess SF4 and HF should be scrubbed with potassium hydroxide solution. A.5.2 Synthesis of 4-Bromo-2-(trifluoromethyl)thiazole (23)

A 300 ml autoclave was charged with acid (22) (0.1 mol), evacuated, cooled to −60 ◦ C, and subsequently charged with HF (30 g) and SF4 (33 g, 0.3 mol). The reaction mixture was heated at 40 ◦ C for 20 h with stirring at 400–600 rpm. The volatile compounds were then vented and the reaction solution was diluted with diethyl ether (100 ml). The organic solution was stored over NaF as a precaution and was later washed with water (1 × 200 ml) and 10% NaOH (1 × 200 ml), and distilled to give 18.4 g (76%) of pure 23 [13] (Scheme A.9); b.p. 101–105 ◦ C/150 mmHg; 1 H NMR (CDCl3 ): δ = 7.46 (s, 1H); 19 F NMR (CDCl3 ): δ = −66.5. S

COOH N

Br 22

S

76% SF4, HF; 40 °C, 20 h

Br

CF3

N 23

Scheme A.9 Conversion of a carboxyl group to a trifluoromethyl group by sulfur tetrafluoride [13].

A.6 Generation of a Trifluoromethoxy Group by Oxidative Fluorodesulfuration of a Xanthogenate A.6.1 Synthesis of the Liquid Crystal 25

To a suspension of NBS (5.0 mmol) and CH2 Cl2 (2.5 ml) in an oven-dried polypropylene round-bottomed tube equipped with a rubber septum and a PTFE-coated magnetic stirring bar were added dropwise pyridine (0.46 ml) and, subsequently, 70% HF–pyridine (1.0 ml, 40 mmol HF) at −42 ◦ C (cooled by means of a CCl4 –dryice bath) under an argon atmosphere. The resulting mixture was stirred at room temperature for 5 min and then cooled to 0 ◦ C. A solution of the xanthogenate (24)

A.7 Oxidative Alkoxydifluorodesulfuration of Dithianylium Salts H O

H11C5 H 24

S

40% NBS, pyridine, SMe 70% HF-pyr, CH2Cl2; 0 °C, 1 h

H OCF3

H11C5 H 25

Scheme A.10 Synthesis of trifluoromethyl ethers from xanthogenates [14].

(1.0 mmol) in CH2 Cl2 (1.5 ml) was added dropwise to the suspension at 0 ◦ C to give a dark-red mixture. This was stirred at 0 ◦ C for 1 h, diluted carefully with Et2 O (5.0 ml), and quenched with ice-cold buffer solution (pH 10; NaHCO3 , NaHSO3 , and NaOH). The pH of the mixture was adjusted to 10 by careful addition of ice-cold 10% aqueous NaOH solution and extracted with Et2 O; the aqueous phase was extracted with Et2 O three times. The combined organic phase was washed with brine, dried over MgSO4 , filtered, and concentrated under reduced pressure. Flash column chromatography (silica gel; cyclohexane) afforded 40% trifluoromethyl ether 25 [14]; m.p. 30.8–31.1 ◦ C; b.p. 160 ◦ C/0.4 mmHg; RF = 0.91 (silica gel; hexane); 1 H NMR (200 MHz, CDCl3 ): δ = 0.75–1.92 (m, 19H), 0.87 (t, J = 7 Hz, 3H), 2.00–2.28 (m, 4H), 4.07 (tt, J = 5 Hz, J = 11 Hz, 1H); 19 F NMR (188 MHz, CDCl3 ): δ = −58.0 (s, 3F) (Scheme A.10).

A.7 Oxidative Alkoxydifluorodesulfuration of Dithianylium Salts A.7.1 Dithianylium Triflate (27)

To a suspension of 26 (250 g, 0.89 mol) in a mixture of toluene (250 ml) and isooctane (250 ml), 1,3-propanedithiol (125 g, 1.16 mol) was added. The milky suspension was heated to 50 ◦ C and trifluoromethanesulfonic acid (173 g, 1.16 mol) was added within 30 min (slightly exothermic). The resulting solution was heated to 102–104 ◦ C and reaction water (28 ml) was removed azeotropically within 4 h. The solution was cooled to 90 ◦ C and methyl tert-butyl ether (1000 ml) was added within 45 min at 90–70 ◦ C. The suspension was cooled to 0 ◦ C and filtered under a dry nitrogen atmosphere. The crystals were washed with methyl tert-butyl ether (4 × 250 ml) and dried in vacuo to yield 27 (402 g, 90%) as pinkish crystals. The purity was estimated by 1 H NMR spectroscopy to be about 95%, sufficient for further reactions [15]. Slow decomposition starting from 90 to 100 ◦ C; 1 H NMR (250 MHz, CDCl3 , 303 K): δ = 1.35–0.75 (m, 21H), 2.03–1.60 (m, 4H), 2.17 (d, J = 10 Hz, 2H), 2.60–2.45 (m, 2H), 3.15–2.95 (m, 2H), 3.75 (t, J = 5 Hz, 4H); 13 C NMR (60 MHz, CDCl3 , 303 K): δ = 14.5, 17.3, 23.1, 27.1, 29.5, 30.3, 32.5, 33.8, 35.5, 37.7, 38.1, 42.3, 43.2, 53.5, 57.2, 121.1 (q, CF3 SO3 − ), 203.4 (–S–C=S+ –); MS (EI): m/z (%) = 352 [M+ –CF3 SO3 H] (100).

359

360

Appendix A Typical Synthetic Procedures

A.7.2 Synthesis of 28 from the Dithianylium Salt 27

A solution of 3,4,5-trifluorophenol (10 g, 68 mmol) in a mixture of triethylamine (7.33 g, 72 mmol) and CH2 Cl2 (90 ml) was cooled to −70 ◦ C and a solution of 27 (30.9 g, 62 mmol) in CH2 Cl2 (85 ml) was added within 45 min at the same temperature. After stirring for 1 h, NEt3 ·3HF (50 ml, 310 mmol) was added over 5 min. Then, over a period of 1 h, a solution of bromine (49.5 g, 310 mmol) in CH2 Cl2 (20 g) was added at −70 ◦ C. The mixture was stirred for a further 1 h at −70 ◦ C and then left to warm to 0 ◦ C. The solution was poured into a mixture of 32% aqueous NaOH (107 g) and ice (200 g). The pH was adjusted to 5–8 by addition of about 28 g of 32% aqueous NaOH. The aqueous layer was extracted with CH2 Cl2 (50 ml) and the combined organic extracts were filtered through Celite (2.5 g), washed with water, and evaporated to dryness. The residue was dissolved in n-heptane (60 ml), stirred for 30 min with silica gel (5.0 g), filtered, and evaporated to dryness. The crude product was chromatographed with n-heptane on silica gel to yield 22.8 g (84%) of 28 as a nematic oil which slowly crystallized (purity 99.2%, verified by GLC and HPLC) [15]. Further purification was accomplished by recrystallization from n-heptane at −20 ◦ C (purity >99.9%; GLC and HPLC); mesophase sequence 1) 1 : C 59 N 112.1 I; 1 H NMR (250 MHz, CDCl3 , 303 K): δ = 1.38–0.80 (m, 27H), 2.08–1.65 (m, 4H), 6.82 (mc, 2H, ar-2,6-H); 19 F NMR (280 MHz, CDCl3 , 303 K): δ = −79.3 (d, J = 8.4 Hz, 2F, CF 2 O), −133.8 (mc, 2F, ar-3,5-F), −165.3 (mc, 1F, ar-4-F); MS (EI): m/z (%) = 432 [M+ ] (25), 284 [M+ – F3 PhOH] (50). A.7.3 Synthesis of 28 from the Ketenedithioketal 29

To a solution of 29 [16] (1.00 g, 2.84 mmol) in CH2 Cl2 (15 ml), trifluoromethanesulfonic acid (0.25 ml, 2.84 mmol) was added dropwise at 0 ◦ C. The cooling bath was removed and the mixture was stirred for 30 min at room temperature. It was then cooled to −70 ◦ C and solutions of 90% 3,4,5-trifluorophenol in toluene (0.70 g, 4.25 mmol) and triethylamine (0.71 ml, 5.10 mmol) in CH2 Cl2 (3.0 ml) were added. After stirring for 1 h at −70 ◦ C, NEt3 ·3HF (2.29 ml, 14.2 mmol) was added. After 5 min, a suspension of 1,3-dibromo-5,5-dimethylhydantoin (DBH) (4.05 g, 14.2 mmol) in CH2 Cl2 (15 ml) was added in portions over 30 min. After stirring for an additional 60 min, the mixture was left to warm to −20 ◦ C and then poured into ice-cold 1 N aqueous NaOH (50 ml). The organic layer was separated and the aqueous layer was extracted with CH2 Cl2 (3 × 30 ml). The combined organic extracts were stirred for 15 min with Celite (5.0 g), filtered, washed with brine (2 × 30 ml), dried (Na2 SO4 ), and evaporated to dryness. The residue was dissolved in n-hexane and filtered through a short silica gel column (Scheme A.11). Yield: 1.14 g (93%) of 28, containing 96.9% trans,trans and 2.2% trans,cis isomer (GLC). 1) C = crystalline; SB = smectic B; N = nematic; I = isotropic. The transition temperatures are cited in degrees celsius.

A.8 Electrophilic Trifluoromethylation with Umemoto’s Reagents

H COOH

H11C5 H 26

361

H

90%

S

+

H11C5

HS(CH2)3SH, CF3SO3H,

H 27

toluene-i-octane 1:1; reflux, azeotropic removal of H2O

S CF3SO3−

1. 3,4,5-trifluorophenol, NEt3, CH2Cl2; −78 °C 2. NEt3·3HF; −78 °C

84%

3. Br2, CH2Cl2; −78 °C to r.t.

F

H H11C5 H

F

F

O

F

28 S H11C5 S 29

93% 1. CF3SO3H, CH2Cl2; 0 °C to r.t., 30 min 2. 3,4,5-trifluorophenol, NEt3, CH2Cl2; −70 °C 3. NEt3·3HF; −70 °C 4. DBH, CH2Cl2; −70 °C to −20 °C

Scheme A.11 Synthesis of α,α-difluoro ethers via dithianylium salts [15].

Further purification to >99.8% (GLC) of trans,trans-28 [15] was accomplished by crystallization from n-heptane at −20 ◦ C.

A.8 Electrophilic Trifluoromethylation with Umemoto’s Reagents A.8.1 Trifluoromethylation of the Trimethylsilyldienol Ether 30

Under an argon atmosphere, S-(trifluoromethyl)dibenzothiophenium triflate (31) (1.0 mmol) was added to a stirred solution of 30 (1.0 mmol) and pyridine (1.0 mmol) in DMF (6 ml). The mixture was heated at 100 ◦ C for 18 h, then subjected to aqueous work-up by the usual methods [17], yielding a mixture of α- and β-32 (69%; α:β 3.6:1) as an oil; IR (neat): 1681 cm−1 (C=O); MS (EI): m/z 232 [M+ ] (Scheme A.12). α-32: 1 H NMR (CDCl3 ): δ = 1.26 (s, 3H), 2.25–2.20 (m, 1H), 2.50 (ddd, J = 16.8 Hz, J = 12.6 Hz, J = 6.3 Hz, 1H), 3.05 (m, 1H), 6.01 (m, 1H); 19 F NMR (CDCl3 ): δ = −68.38 (dd, J = 8.2 Hz, J = 2.2 Hz). β-32: 1 H NMR (CDCl3 ): δ = 1.29 (s, 3H), 2.20–2.15 (m, 1H), 2.65 (ddd, 1H, J = 17.8 Hz, J = 15.0 Hz, J = 5.1 Hz), 3.05 (m, 1H), 5.89 (s, 1H); 19 F NMR (CDCl3 ): δ = −66.44 (d, J = 11.5 Hz).

F

362

Appendix A Typical Synthetic Procedures

CH3

CH3 69%

O

Me3SiO

30

32 S

+

CF3

CF3SO3−

CF3

α/β 3.6:1

31 pyridine (1 equiv.), DMF; 100 °C, 18 h Scheme A.12

Electrophilic trifluoromethylation with Umemoto’s reagent [17].

A.9 Nucleophilic Trifluoromethylation with Me3 SiCF3 A.9.1 Nucleophilic Trifluoromethylation of Ketone 33

A mixture of 33 (10 mmol), Me3 SiCF3 (12 mmol), and THF (25 ml) cooled to 0 ◦ C in an ice-bath was treated with tetrabutylammonium fluoride (20 mg). Instantaneously a yellow color developed with initial evolution of fluorotrimethylsilane. The mixture was then brought to ambient temperature and stirred. After 1 h, the intermediate trimethylsilyl ether 34 was hydrolyzed by addition of 1 N HCl and stirring for 1 h. (For some carbonyl compounds, for example benzophenone, acidic hydrolysis of the intermediate trimethylsilyl ethers is difficult. For these, fluoride-induced hydrolysis in a cesium fluoride–methanol system under reflux is often more successful.) Isolation of 35 [18] was achieved by aqueous work-up by the usual methods (Scheme A.13). Yield 77%, m.p. 59–61 ◦ C, b.p. 72–73 ◦ C/40 mmHg; 19 F NMR: δ = −86.0 (s); MS (EI): m/z (%) = 168 [M+ ] (0.1), 83 (100). O

F3C OH

F3C OSiMe3 77% Me3SiCF3, THF,

33

cat. Bu4NF; 0 °C

1N HCl; r.t., 1 h

34

35

to r.t., 1 h

Scheme A.13

Nucleophilic trifluoromethylation of ketones [18].

A.10 Transition Metal-Mediated Aromatic Perfluoroalkylation A.10.1 Copper-Mediated Trifluoromethylation of 36 Using Silane Reagents

A mixture of 36 (0.5 mmol), Et3 SiCF3 (0.6 mmol), CuI (0.75 mmol), KF (0.6 mmol), and DMF–NMP (N-methylpyrrolidone) (1:1) (1 ml) was heated in a sealed Pyrex

A.10 Transition Metal-Mediated Aromatic Perfluoroalkylation

tube at 80 ◦ C for 24 h. After cooling, the tube was opened with the usual safety precautions and the contents were subjected to an aqueous work-up. Compound 37 was obtained in 99% yield with minimal contamination by its pentafluoroethyl analog [19]. Similar results can be achieved by use of Me3 SiCF3 (Ruppert–Prakash reagent) [20]. When Me3 SiC2 F5 or Me3 Si-n-C3 F7 is used instead (in DMF at 60 ◦ C for 24 h), the pentafluoroethyl (40) or perfluoropropylarenes (38) are obtained in reasonable to good yields [19] (Scheme A.14). O2N

99%

I

Et3SF3, CuI, KF,

O2N

DMF-NMP(1:1); 80 °C, 24 h

36

41% Me3Si-n-C3F7, CuI,

37

O2N

KF, DMF; 60 °C, 24 h

I

CF3

C3F7 38

68%

C2F5

Me3SiC2F5, CuI, KF, DMF; 60 °C, 24 h

39

40

Scheme A.14 Copper-mediated perfluoroalkylation of iodoarenes by perfluoroalkylsilane reagents [19].

A.10.2 Palladium-Mediated Trifluoromethylation of Aryl Chloride 41

In a nitrogen-filled glovebox, an oven-dried resealable test-tube equipped with a magnetic stirring bar was charged with KF (116 mg, 2.0 mmol) and 41 (292 mg, 1.0 mmol). A premixed solution of [(allyl)PdCl]2 (11.0 mg, 0.03 mmol), BrettPhos (48.3 mg, 0.09 mmol), and Et3 SiCF3 (376 μl, 2.0 mmol) in dioxane (3.3 ml) was added. After sealing the tube with a screw-cap, it was removed from the glovebox and placed in a preheated oil-bath at 130 ◦ C under vigorous stirring. After 6 h, the tube was taken out of the oil-bath and allowed to cool to room temperature. The reaction mixture was diluted with diethyl ether, filtered through a plug of silica gel to remove all solids, concentrated in vacuo, and purified via a Biotage SP4 (silica-packed 25 g snap cartridge) to furnish 42 as a colorless solid in 72% yield (235 mg) [21]; m.p. 115–116 ◦ C; 1 H NMR (400 MHz, CDCl3 ): δ = 8.09 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.43–7.36 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.24–7.11 (m, 4H), 7.01 (dd, J = 7.7, J = 1.5 Hz, 2H), 5.42 (s, 2H); 13 C NMR (101 MHz, CDCl3 ): δ = 141.8, 140.0, 136.7, 129.1, 127.9, 127.9 (q, J = 31.9 Hz), 127.4, 126.5, 125.8 (q, J = 1.2 Hz), 125.1 (q, J = 272.2 Hz), 122.3, 121.2, 120.9, 120.2, 116.2 (q, J = 3.6 Hz), 109.6, 106.3 (q, J = 4.2 Hz), 46.9; 19 F NMR (282

363

364

Appendix A Typical Synthetic Procedures

MHz, CDCl3 ): δ = −61.1; anal. calcd. for C20 H14 F3 N: C 73.84, H 4.34%; found: C 73.86, H 4.31% (Scheme A.15).

72%

N

N

Cl KF, cat. [(allyl)PdCl]2, cat. BrettPhos,

CF3

Et3SiCF3, dioxane; 130 °C, 6 h

42

41 Scheme A.15

Palladium-mediated trifluoromethylation of aryl chlorides [21].

A.11 Copper-Mediated Introduction of the Trifluoromethylthio Group A.11.1 Preparation of Trifluoromethylthio Copper Reagent 43

Silver fluoride (15 g, 0.12 mol), carbon disulfide (15 ml), and acetonitrile (100 ml) were placed in a three-necked 250 ml flask fitted with an overhead stirrer and condenser. The mixture was stirred for 14 h at 80 ◦ C (oil-bath), then the condenser’s position was altered to allow the removal of any remaining carbon disulfide by distillation. Copper(I) bromide (5.69 g, 40 mmol) was then added and the mixture was left stirring for a further 1 h. The black precipitate formed was removed by filtration and the acetonitrile was removed under reduced pressure to yield 43 as a white–gray solid (6.6 g, 98%) [22] (19 F NMR spectroscopy showed this to be mainly CuCSF3 with slight contamination by HF2 − species) (Scheme A.16). 3 AgF + CS2

CH3CN; 80 °C, 14 h

AgSCF3 + Ag2S 98%

CuBr; 80 °C, 1 h

CuSCF3 + AgBr 43

Scheme A.16 Preparation of trifluoromethylthio copper(I) reagent [22].

A.11.2 Reaction of CuSCF3 with 4-Iodoanisole (44)

Trifluoromethylthio copper(I) (43) (0.47 g, 2 mmol), 4-iodoanisole (44) (1.55 g, 10 mmol), and NMP (10 ml) were placed in a 25 ml round-bottomed flask and heated at 150 ◦ C for 18 h. The resulting black solution was left to cool. Water was then added and the organic products were extracted twice into diethyl ether. The ether extracts were combined and washed three times with water. The ether was removed by rotary evaporation to yield 0.21 g of product 45 (45%) [22]; 19 F NMR (CDCl3 ): δ = −44.4 (s); MS (EI): m/z (%) 208 [M+ ] (60), 139 (100) (Scheme A.17).

A.12 Substitution Reactions on Fluoroolefins and Fluoroarenes

MeO

I 44

45% CuSCF3 (43), NMP;

MeO

150 °C, 18 h

SCF3 45

Scheme A.17 Introduction of the trifluoromethylthio group using CuSCF3 [22].

A.12 Substitution Reactions on Fluoroolefins and Fluoroarenes A.12.1 Preparation of α,β-Difluoro-β-chlorostyrenes (47)

A sample of chlorotrifluoroethylene (23.3 g, 200 mmol) was condensed at −30 ◦ C into a solution of p-anisylmagnesium bromide [prepared from 46 (23.5 g, 126 mmol) with magnesium in THF by the usual methods] (126 mmol) in THF (150 ml). The solution was stirred for 1.5 h at −30 ◦ C and then boiled for 4 h with a reflux condenser packed with dry-ice. The mixture was filtered and the filtrate was treated with hydrochloric acid and ice, extracted with diethyl ether, washed with water and 5% Na2 CO3 , and dried. Yield: 24 g (78%) of 47 [23] as an isomeric mixture with a cis:trans ratio of about 1:3 (JFF ≈ 9–12 Hz for the cis and 126–127 Hz for the trans isomer); b.p. 115–116 ◦ C/15 mmHg; nD 25 1.5399. A.12.2 Preparation of α, β-Difluorocinnamic Acid (48)

A solution of styrene (47) (4.1 g, 20 mmol) in a mixture of THF (9 ml), diethyl ether (5 ml), and pentane (5 ml) was cooled to −100 ◦ C and a 1 M solution of n-butyllithium in diethyl ether (20 ml), cooled to −90 to −100 ◦ C, added during 30 min. The mixture was stirred for 1 h at −85 to −90 ◦ C and poured on to a mixture of diethyl ether and dry-ice. The acid was extracted from the ether with 10% Na2 CO3 and the soda extracts were washed with diethyl ether, filtered, and acidified with 15% HCl. The product was removed by filtration, washed with water, dried, and recrystallized from benzene (Scheme A.18). Yield: 1.1 g (25%) of 48 [23]; m.p. 185–187 ◦ C. A.12.3 ortho-Metalation of 1,2-Difluorobenzene (49) with LDA

n-Butyllithium in hexane (32.5 ml, 52 mmol) was added in portions to dry diisopropylamine (7.3 ml) in dry THF at 0 ◦ C under nitrogen [24] (Scheme A.19). The mixture was stirred at 0 ◦ C for 15 min, then cooled to −78 ◦ C. 1,2-Difluorobenzene (49) (5.3 ml, 52 mmol) was added in portions to this mixture. After being stirred for 30 min, acetone (4 × 5 ml) was added and the mixture was left to warm to room temperature. (Caution: Lithiated o-fluoroarene intermediates should never be allowed to warm to above −40 to −30 ◦ C! The compounds tend to eliminate LiF in a highly exothermic and often violent reaction.) The product was poured into 1

365

366

Appendix A Typical Synthetic Procedures

MeO

I 46

F

78%

MeO

1. Mg, THF 2. CF2=CFCl; −30 °C (1.5 h),

Cl 47

then reflux (4 h)

F

1. n-BuLi, THF, Et2O, 25%

pentane; −100 °C 2. CO2; −90 °C

F MeO COOH 48 Scheme A.18

F

Synthesis of α,β-difluorocinnamic acids [23].

M HCl (200 ml) and extracted with diethyl ether (100 ml); the ether solution was washed with water (200 ml) and dried (MgSO4 ). The solvent was removed by rotary evaporation and the crude yellow product was distilled under reduced pressure and subsequently further purified by column chromatography (silica gel; CH2 Cl2 ) to give 50 as a colorless oil (6.9 g, 74%) [24]; b.p. 80–82 ◦ C/5.0 mmHg; MS (EI): m/z 172 [M+ ], 157 [M+ –CH3 ]. F

F F

49

F

74% 1. LDA, THF; −78 °C 2. acetone; −78 °C to r.t.

Scheme A.19

50

OH

Derivatization of 1,2-difluorobenzene via ortho-metalation [24].

A.13 Reactions with Difluoroenolates A.13.1 Preparation of the Trimethylsilyl Difluoroenol Ether 52

A mixture of Me3 SiCl (2.6 g, 24 mmol) and Mg (290 mg, 12 mmol) in freshly distilled THF (24 ml) was cooled to 0 ◦ C under an argon atmosphere and trifluoroacetophenone (51) (1.04 g, 6.0 mmol) was added dropwise; the mixture was then stirred for an additional 20 min. After evaporation of most of the THF, hexane (20 ml) was added to the residue and the resulting salt was filtered and the filtrate was concentrated to give 1.21 g (about 88%) of crude 52 (purity, determined by GLC, >95%) [25].

References

A.13.2 Addition of 52 to Carbonyl Compounds

A solution of crude 52 (1.21 g, 0.53 mmol) and benzaldehyde (1.27 g, 12 mmol) in CH2 Cl2 (10 ml) was cooled to −78 ◦ C and a solution of TiCl4 (6 mmol) in CH2 Cl2 (10 ml) was added dropwise. The reaction mixture was then quenched with aqueous NH4 Cl and the organic layer was washed with brine and dried over MgSO4 . Purification of the product by chromatography [silica gel; hexane–ethyl acetate (5:1)] provided 53 (1.18 g, 71% based on 51) as a colorless oil [25] (Scheme A.20). OSiMe3 F

O CF3

88% (crude)

F

Mg, Me3SiCl, THF; 0 °C, 20 min

51

52 71%

O

PhCHO, TiCl4, CH2Cl2; −78 °C

OH

F F 53 Scheme A.20 Reaction of trimethylsilyl difluoroenol ethers with aldehydes [25].

References 1. Heckmann, J. (1989) Dr¨ agerheft,

2. 3.

4. 5. 6.

7.

8.

341, 6 (edited by Kali-Chemie, Werk Wimpfen, Bad Wimpfen, Germany). Chambers, R.D. and Hutchinson, J. (1998) J. Fluorine Chem., 92, 45–52. Kirsch, P., Bremer, M., Kirsch, A., and Osterodt, J. (1999) J. Am. Chem. Soc., 121, 11277–11280. Peters, D. and Miethchen, R. (1996) J. Fluorine Chem., 79, 161–165. Kirsch, P. and Tarumi, K. (1998) Angew. Chem. Int. Ed., 37, 484–489. Haufe, G., Alvernhe, G., Laurent, A., Emet, T., Goj, O., Kr¨oger, S., and Sattler, A. (1998) Org. Synth., 76, 159–168. Banks, R.E., Mohialdin-Khaffaf, S.N., Lal, G.S., Sharif, I., and Syvret, R.G. (1992) J. Chem. Soc., Chem. Commun., 595. Lal, G.S. (1993) J. Org. Chem., 58, 2791–2796.

9. Umemoto, T., Fukami, S., Tomizawa,

10.

11. 12. 13. 14.

15.

16.

G., Harasawa, K., Kawada, K., and Tomita, K. (1990) J. Am. Chem. Soc., 112, 8563. Lal, G.S., Pez, G.P., Pesaresi, R.J., Prozonic, F.M., and Cheng, H. (1999) J. Org. Chem., 64, 7048–7054. Smith, W.C. (1962) Angew. Chem., 74, 742–751. Nickson, T.E. (1991) J. Fluorine Chem., 55, 169–172. Nickson, T.E. (1991) J. Fluorine Chem., 55, 173–177. Kanie, K., Takehara, S., and Hiyama, T. (2000) Bull. Chem. Soc. Jpn., 73, 1875–1892. Kirsch, P., Bremer, M., Taugerbeck, A., and Wallmichrath, T. (2001) Angew. Chem. Int. Ed., 40, 1480–1484. The ketenedithioketal 29 is synthesized in analogy with Ager, D. J. (1990) Org. React., 38, 1–223.

367

368

Appendix A Typical Synthetic Procedures 17. Umemoto, T. and Ishihara, S. (1993) J. 18.

19. 20. 21.

Am. Chem. Soc., 115, 2156–2164. Prakash, G.K.S., Krishnamurti, R., and Olah, G.A. (1989) J. Am. Chem. Soc., 111, 393–395. Urata, H. and Fuchikami, T. (1991) Tetrahedron Lett., 32, 91–94. Ruppert, I., Schlich, K., and Volbach, W. (1984) Tetrahedron Lett., 25, 2195. Cho, E.J., Senecal, T.D., Kinzel, T., Zhang, Y., Watson, D.A., and Buchwald, S.L. (2010) Science, 328, 1679–1681.

22. Clark, J.H., Jones, C.W., Kybett, A.P.,

and McClinton, M.A. (1990) J. Fluorine Chem., 48, 249–253. 23. Yagupolskii, L.M., Kremlev, M.M., Khranovskii, V.A., and Fialkov, Y.A. (1976) J. Org. Chem. USSR, 12, 1365–1366. 24. Coe, P.L., Waring, A.J., and Yarwood, T.D. (1995) J. Chem. Soc., Perkin Trans. 1, 2729–2737. 25. Amii, H., Kobayashi, T., Hatamoto, Y., and Uneyama, K. (1999) Chem. Commun., 1323–1324.

369

Appendix B Index of Synthetic Conversions

Group

Starting material; method

Page

Ar–F

Ar–H; direct fluorination Ar–H; electrophilic fluorination Ar–H; oxidative fluorination Ar–B(OH)2 ; palladium catalysis Ar–NH2 ; Balz–Schiemann reaction Ar–OH; fluoroformate method Ar–SnBu3 ; silver catalysis Ar–OTf; palladium catalysis Ar–X; nucleophilic substitution (Halex) Perfluorocycloalkanes; reductive defluorination– aromatization gem Difluorocyclopropanes Olefin; difluorocarbene precursor C–C(O)–R ; CF2 Br2 , P(NMe2 )3 R2 C=CF2 Ar–I; CF2 =CFZn, catalyst R–CF=CF2 R–Metal; CF2 =CF2 BrF2 CCOOEt; Zn, carbonyl compound R–CF2 C(O)–R R(OSiMe3 )C=CF2 ; cyclodimerization R(OSiMe3 )C=CF2 ; R –COX Dithianylium salt; oxidative fluorodesulfuration R–CF2 N3 in the presence of azide R–CF2 OOR Dithianylium salt; oxidative fluorodesulfuration in the presence of R –OOH R–CF2 O–R Dithianylium salt; oxidative fluorodesulfuration in the presence of R –OH Ketenedithioketal; protonation, followed by oxidative fluorodesulfuration in the presence of R –OH

33 88, 91, 93 50 52, 54 48 49 50 53 52 47 156ff. 195, 203 196 193, 195, 197 203 200 199 85 85 83ff. 84

(continued overleaf)

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

370

Appendix B Index of Synthetic Conversions

(continued) Group

Starting material; method

Page

R–CF2 –R

Dithianes, dithiolanes: oxidative fluorodesulfuration R–C(O)–R ; difluoroenol ether RC(O)R ; SF4 , DAST RC(S)R ; oxidative fluorodesulfuration R–C(NX)–R ; Me3 SiCF3 , F− R–C(O)–R ; CF3 H, base R–C(O)–R ; Me3 SiRF , fluoride R–C(O)–R ; RF I, TDAE R–C(O)–R ; RF Li R–C(O)–R ; RF ZnX R–COOR ; RF I, MeLi R–COCl; RF I, TDAE R–COOR ; Me3 SiRF , TBAF Acetylenes; NO+ BF4 − /HF–amine complex Enol ethers and enolates; electrophilic fluorination Epoxides; ring opening with HF–amine complex Olefins; direct fluorination Olefins; halofluorination Olefins; hydrofluorination R–COOH; XeF2 R–H; CoF3 process R–H; direct fluorination R–H; electrochemical fluorination (ECF) R–H; electrophilic fluorination R–H; high oxidation state transition metal fluorides R–OH; aHF or HF-pyridine R–OH; one-step activation-substitution (SF4 , DAST, FAR reagents, α-fluoroenamine reagents, DMI, FluoleadTM , XtalFluorTM ) R–Sar oxidative fluorodesulfuration R–X; Lewis acid-assisted nucleophilic substitution R–X; nucleophilic substitution DMAP; CF2 Br2 Imidazole; CF2 Br2 R–CHO; XeF2 R–OH; CHClF2 , base R–OH; difluorocarbene source Ar–OH; CCl4 , HF RF C(O)F + R–X; nucleophilic replacement in the presence of F− R–OCORF ; SF4 R–OCSSMe; oxidative fluorodesulfuration R–OH; 2-perfluoroalkyl-1,3-dithianylium triflate, oxidative fluorodesulfuration R–OH; perfluoroolefin under neutral conditions

79ff. 198ff. 74ff. 81ff. 138–139 132 133ff. 131 126 127 126 131 137 45 92 45–46 32 43ff. 43ff. 30 30 29, 31 34 95 31 73–74 67ff.

R–C(NHX)RF –R R–C(OH)RF –R

R–C(O)RF

R–F

R2 N–RF R–OCHF2

R–ORF

81 39ff. 36ff., 55ff. 174 172 86 171ff. 171ff. 174 176 75 81 83 194

Appendix B Index of Synthetic Conversions

371

(continued) Group

R(OR )=CF2 R–OSF5 R–RF

R–SCF3 (NSO2 CF3 ) R–SF5

R–SF4 CF3 R–SF4 –R R–S(NSO2 CF3 )2 F R–SO2 RF R–S(O)RF

Starting material; method

Page

R–OH; Umemoto’s O-trifluoromethyl dibenzofuramium reagent Ar–SnBu3 ; TAS+ OCF3 − , AgPF6 , F-TEDA–PF6 R–C(O)CF3 ; Mg, Me3 SiCl R–C(O)OR ; CF2 Br2 , P(NMe2 )3 , Zn Ar–H; F5 SOOSF5 Ar–F; Me3 SiCF3 , F− Ar–Cl; Et3 SiCF3 , palladium catalyst Ar–H; CCl4 –HF–SbF5 70% HF-pyridine Ar–I; RF –copper reagent Ar–H; RF I, high temperature Ar–H; Umemoto’s reagent, FITS reagent, Togni’s reagent Ar–H; TfCl, Ru(phen)3 2+ catalyst, light Ar–H; CF3 SO2 Na, t-BuOOH Ar–B(OH)2 ; Me3 SiCF3 , copper catalyst, O2 Enamine; radical addition of RF I or RF Br Enamine; Umemoto’s reagent, FITS reagent, Togni’s reagent Enolate; radical addition of RF I or RF Br Enolate; Umemoto’s reagent, FITS reagent, Togni’s reagent Perfluoroolefin + F− + RX; generation of perfluoroalkyl anion and subsequent nucleophilic replacement of X R–CH=CH2 ; radical addition of RF I or RF Br R–CH=CH2 ; FITS reagent, Togni’s reagent, Shibata–Johnson reagent R–COOH; SF4 R–C(O)RF ; SF4 , DAST R–C(S)SMe; oxidative fluorodesulfuration R–H; ‘‘inverse’’ radical addition of perfluoroolefins R–X; nucleophilic perfluoroalkylation by Me3 SiRF R–S(O)RF ; Tf2 O, followed by RF SO2 NH2 Ar–H; S2 F10 Ar–SS–Ar; AgF2 (Cu) Ar–SS–Ar; direct fluorination Ar–SS–Ar; Cl2 , KF, ZnF2 Ar–SCF3 ; direct fluorination Ar–S–Ar; direct fluorination R–SS–R; RF SO2 NCl2 , followed by SbF3 R–SO2 X (X = Cl, F); Me3 SiRF , F− R–SRF ; oxidation R–S(O)Cl; Me3 SiRF , F− R–SRF ; oxidation

151ff. 175, 177 197ff. 203 188 141 131 144 126ff. 115 143ff., 151ff. 117 117 130 116 143ff., 151ff. 114 143ff., 151ff. 125

112ff. 147, 155, 156 76 74 81 119 140 181 182 182 182 188 187 182 182 140, 181 180 181 180 (continued overleaf)

372

Appendix B Index of Synthetic Conversions

(continued) Group

Starting material; method

Page

R–S(O)RF (NSO2 CF3 )

R–S(O)F(NSO2 CF3 ); Me3 SiRF , F− R–S(O)RF ; NaN3 –oleum, followed by RF SO2 Cl Ar–H; CF3 SCl Ar–I; CuSCF3 reagent Ar–Br; AgSCF3 , palladium catalyst Ar–B(OH)2 ; Me3 SiCF3 , S8 , Ag2 CO3 , CuSCN, phenanthroline R–SCl; Me3 SiRF , F− R–SCN; Me3 SiRF , F− R–SH; perfluoroolefin under neutral conditions R–SH; RF I, base R–SH; Umemoto’s reagent, FITS, Togni’s reagent R–SS–R; Me3 SiRF , F− R–X; nucleophilic replacement by RF S− Q+

182 181 179 179 180 179 140 179 20 110 143ff., 151ff. 140, 179 179

R–SRF

373

Index

a

c

Accufluor 91 acetyl hypofluorite 87 agricultural chemistry 336–340 alcohol fluorination procedure 358–359 aldehydes and keynotes fluorination procedure 359 alkali metal fluorides 36 alkylphosphonates 318 alternating toxicity 19 amine–hydrogen fluoride reagents 73–74 Anh–Eisenstein effect 307–308 anhydrous hydrofluoric acid (aHF) 4 anomeric effect 306 anthraquinone dyes 258 anti-fluorous effect 213 areneboronic acids 128 aromatic fluorination 283–287 aromatic nucleophilic substitution 59–62 aryl iodide 51, 126 aryloxyphenoxypropionates 336 arylstannanes 51 azomethines 258

calamitic liquid crystals 260 carbon–fluorine bond activation, by transition metals 63 carbonyl conversion, into gem-difluoromethylene 74–77 carboxyl groups conversion, into trifluoromethyl groups 77–78 carboxylic acid fluorination with sulfur tetrafluoride 360 – 4-bromo-2-(trifluoromethyl)thiazole synthesis 360 Castner–Kellner cells 254 chemical properties 13–15 chemical vapor deposition (CVD) 257 chlorofluorocarbon (CFC) 2, 18, 40, 247 – and ozone depletion 15–17 chlorotrifluoroethylene 194 cis effect 307–308 cobalt trifluoride process 28–31 collagen 308–309 combinatorial chemistry, fluorous 233 Contergan (thalidomide) 316 contrast media and medical diagnostics 335–336 copper-mediated introduction of trifluoromethylthio group 366 – CuSCF3 reaction 4-iodoanisole 366 – trifluoromethylthio copper reagent 43 preparation 366 copper-mediated trifluoromethylation 364–365 CuSCF3 reaction 4-iodoanisole 366 cyanobiphenyls 261 cyanophenylcyclohexane 262 cytochrome P450 enzyme 310 CYTOP 290

b Balz–Schiemann reaction 47–48, 264 BAST fluorinations, see DAST and BAST fluorinations 358 benzoylureas 340 bioisosteric mimicking 316–323 birefringence 260, 264, 265 blood substitutes and respiratory fluids 334–335 BrettPhos ligands 52 bridge structures, fluorinated 275–279 bromine trifluoride (BrF3 ) 257 bromofluorocarbons 247

Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Second Edition. Peer Kirsch. © 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.

374

Index

d density functional theory (DFT) 13 Deoxo-Fluor™ 72 diazabicyclooctane (DABCO) 91 diblock compounds 279 dielectric anisotropy 264–265, 270, 277 N, N-diethylamino sulfur trifluoride (DAST) 71–73, 76, 77 – and BAST fluorinations 358 – – alcohol fluorination procedure 358–359 – – aldehydes and keynotes fluorination procedure 359 diethyl fluorophenyl malonate synthesis 357–358 difluoro analog 317 α,α-difluoroalkylamine reagents 68 difluorocarbene and fluorinated cyclopropanes 156–160 difluoroenolates reactions 368 – trimethylsilyl difluoroenol ether preparation 368 difluoroenol ethers 198, 203 difluoroester enolates 203 difluoromethane difluoromethylation and haldodifluoromethylation 169–172 – pentafluorosulfanyl group and related structures 179–184 – perfluoroalkoxy group 172–174 – perfluoroalkylthio group and sulfur-based super-electron-withdrawing groups 176–179 difluorooxymethylene bridge 277–278 α,β-difluoro cinnamic acid 367 α,β-difluoro-β-chlorostyrenes preparation 367 2,2-difluoro-1,3-dimethylimidazolidine (DFI) 71 dithianylium salts 83–84 – oxidative alkoxydifluorodesulfuration 361 – – dithianylium triflate 361 dithianylium triflate 361 dithioesters 82 dithioorthoester 84 dyes, fluorinated 258–259 dynamic scattering mode (DSM) 261, 263

e ecological impact 15–18 eflornithine 328 electrochemical fluorination (ECF) 34–35 electronics industry 256–258

electrophiles 43–44 electrophilically activated arylation, by fluoroarenes 63 electrophilic fluorination 85–98 – with F–TEDA–BF4 (Selectfluor) – – diethyl fluorophenyl malonate synthesis 357–358 – – fluosteroid 11 synthesis, A 357 electrophilic perfluoroalkylation 139 – arylperfluoroalkyliodonium salts 142–149 – fluorinated Johnson reagents 156 – properties and stability of fluorinated carbocations 139–141 – sulfonium, selenonium, telluronium, and oxonium salts 149–154 electrophilic trifluoromethylation, with U memento’s reagents 363 – trimethylsilyldienol ether 30 trifluoromethylation 363 enol ethers, as synthetic building blocks 198–204 estrogen synthase

f Fast Scarlet VD 258 field effect transistor (FET) 281 Finklestein exchange 36 Flumetralin 388 FluoLead™ 73–76 fluorapatite 3 fluorine 5–7 – electrochemical fluorination (ECF) 34–35 – electrophilic fluorination 85–98 – fluoroaromatic compounds – – aromatic nucleophilic substitution 59–62 – – Balz–Schiemann reaction 47–48 – – carbon–fluorine bond activation by transition metals 63 – – fluoroaromatic compounds activation by ortho-metalation 64–67 – – fluoroformate process 49 α-fluoroalkylation, of alcohols 118 α-fluoroenamine reagent 68–71, 77 ω-fluoro fatty acids 19 5-fluorouracil 326 – – halex process 55 – – orthogonal reactivity of perfluoroaromatic and perfluoroolefinic systems 55–58 – – reductive aromatization 47 – – special fluorine effect 58–59 – – synthesis 46–47

Index – – transition metal-catalyzed aromatic fluorination 49–52 – functional group transformations – – carbonyl conversion into gem-difluoromethylene 74–77 – – carboxyl groups conversion into trifluoromethyl groups 77–78 – – hydroxy groups conversion into fluoro groups 67–74 – – oxidative fluorodesulfuration 78–84 – nucleophilic fluorination 36 – – amine–hydrogen fluoride and ether–hydrogen fluoride reagents 42 – – Finklestein exchange 36 – – general fluorine effect 41 – – hydrofluorination, halofluorination, and epoxide ring opening 43–46 – – Lewis acid-assisted fluorination 39–41 – – naked fluoride 36–38 – perfluorination and selective direct fluorination 27–34 fluorine-18 (18 F) 329–330 fluoroacetic acid 19 fluoroaromatic compounds – aromatic nucleophilic substitution 59–62 – Balz–Schiemann reaction 47–48 – carbon–fluorine bond activation by transition metals 63 – fluoroaromatic compounds activation by ortho-metalation 64–67 – fluoroformate process 49 – halex process 55 – orthogonal reactivity of perfluoroaromatic and perfluoroolefinic systems 55–58 – reductive aromatization 47 – special fluorine effect 58–59 – synthesis 46–47 – transition metal-catalyzed aromatic fluorination 49–52 fluorochemicals, analysis of 20–21 fluoroformate process 49 fluoroneplanocin A 326–327 fluoronorepinephrine (F-NE) 303 fluoroolefins and fluoroarenes, substitution reactions on 367 – α,β-difluoro cinnamic acid 367 – α,β-difluoro-β-chlorostyrenes preparation 367 – ortho-metalation of 1,2-difluorobenzene, with LDA 367–368 fluoropolymers 249 fluorosurfactants 19–20 fluorous chemistry 209 – biphase catalysis 209–224

fluorous reversed-phase silica gel (FRPSG) 233, 237 fluorous solid-phase extraction (FSPE) 233, 241 fluosteroid 11 synthesis 357 fluourous synthesis 227–232 flutolanil 340 Freons 247 fungicides 338–340

g gauche effect 303, 306–308, 310, 314 general fluorine effect 41 global warming potential (GWF) 17 glycosyl fluorides 40 Gore-Tex 250 greenhouse effect 17–18

h Halex process 55 halofluorocarbons 333 Halons 247 halothane 333 Hammett constant 301 herbicides 336–338 hydrochlorofluorocarbon (HFC) 247 hydrofluoric acid 3–5, 42 hydrofluorination and halofluorination 355–356 – and epoxide ring opening 43–46 hydrofluoroolefin (HFO) 17 hydrogen bonding and electrostatic interactions 303–305 hydroxy groups, conversion into fluoro groups 67–74 hypofluorites 86–87

i IG Farben 258 imines 135–136 Indanthrene Blue CLB indium tin oxide (ITO) inhalation anesthetics insecticides 340 iodides, perfluoroalkyl iodoarenes 126

258 262 333–334 126, 129

k ketenedithioketal 362–363 Krebs cycle 308

375

376

Index

l lateral fluorination, improved mesophase behavior by 267–269 Lewis acid-assisted fluorination 39–41 lipophilicity and substituent effects 300–302 liquid crystals, for active matrix liquid crystal displays 260, 279–280 – calamitic liquid crystals 260 – functioning 261–264 – – nematic liquid crystals physical properties 264–267 – reasons 267 – – fluorinated bridge structures 275–279 – – fluorinated polar groups 269–274 – – improved mesophase behavior by lateral fluorination 267–269 – – improved reliability 274–275

m Maier–Meier equation 264 Manhattan Project 2, 250 Marcus equation 282 Marcus inverted region 282 Marcus theory 282–283 Me3 SiCF3 (Ruppert–Prakash reagent) 126, 130–138 mesophase 260, 275 metabolic stabilization and modulation of reaction centers 310–316 metal fluorides 38 methoxyflurane 334 microreactors 33 Montreal Protocol 2, 17 morpholino sulfur trifluoride (MOST) 72

n Nafion 254 naked fluoride 36–38 Naphthol AS 258 n-type semiconductors 281 nematic liquid crystals, physical properties of 264–267 nematic mesophase 260 neural network simulation 213 NF-reagents 88–98 NIH shift 310 nitrosobenzene 135 NMR spectroscopy 20–21 nucleophilic fluorination 36 – amine–hydrogen fluoride and ether–hydrogen fluoride reagents 42 – Finklestein exchange 36 – general fluorine effect 41

– hydrofluorination, halofluorination, and epoxide ring opening 43–46 – Lewis acid-assisted fluorination 39–41 – naked fluoride 36–38 nucleophilic perfluoroalkylation 118 – perfluoroalkyl metal compounds 120–130 – perfluoroalkysilanes 130–138 – properties, stability, and reactivity of fluorinated carbanions 118–119 nucleophilic trifluoromethylation, with Me3 SiCF3 364 ketone

o octafluorocopperphthalocyanine 287 Olah’s reagent 42 olefins 193 – fluorinated enol ethers as synthetic building blocks 198–204 – fluorinated polymethines 193–197 organic electronics, fluorine in 281 – organic field effect transistors (OFETs) 281–290 – organic light-emitting diodes (OLED) 290–292 organic field effect transistors (OFETs) 281–290 organic light-emitting diodes (OLED) 290–292 organic thin-film transistor (OTFT) 281, 287 organofluorine chemistry 325 organohydrogen chemistry 325 orthogonal glycosidic activation 81–82 orthogonal reactivity, of perfluoroaromatic and perfluoroolefinic systems 55–58 orthogonal solubility 290 ortho-metalation of 1,2-difluorobenzene, with LDA 367–368 oxidative fluorodesulfuration 78–84 ozone depletion, by CFCs 15–17

p palladium complex 51–52 palladium-mediated trifluoromethylation, of aryl chloride 365–366 peptides 323 pentafluorosulfanyl group and related structures 179–184 pentafluorosulfanylarenes 318 perchloryl fluoride (FClO3 ) 86 perfluorinated bridge 278–279

Index perfluorination and selective direct fluorination 27–34 perfluoroalkane 1 perfluoroalkoxy group 172–174 perfluoroalkylation 107 – difluorocarbene and fluorinated cyclopropanes 156–160 – electrophilic 139 – – arylperfluoroalkyliodonium salts 142–149 – – fluorinated Johnson reagents 156 – – properties and stability of fluorinated carbocations 139–141 – nucleophilic 118 – – perfluoroalkyl metal compounds 120–130 – – perfluoroalkysilanes 130–138 – – properties, stability, and reactivity of fluorinated carbanions 118–119 – radical 107 – – alkyl radicals inverse radical addition to perfluoroolefins 115–118 – – structure, properties, and reactivity 107 perfluoroalkyl groups 258 perfluoroalkylsulfonyl groups 258 perfluoroalkylthio group and sulfur-based super-electron-withdrawing groups 176–179 perfluorocarbon (PFC) 7–11, 14–15, 18, 328–336 perfluoroether oligomers 253 perfluoroisobutene 19 perfluoro-n-octyl bromide (PFOB) 335 perfluorooctanoic acid 19 perfluorooctyl carboxylates 19 perfluorooctylsulfonic acid (PFOS) 19 perfluoropolyether (PFA) 253–254, 353 pharmaceuticals 299–300 – agricultural chemistry 336–340 – bioisosteric mimicking 316–323 – blood substitutes and respiratory fluids 334–335 – contrast media and medical diagnostics 335–336 – hydrogen bonding and electrostatic interactions 303–305 – inhalation anesthetics 333–334 – lipophilicity and substituent effects 300–302 – mechanism-based suicide inhibition 325–329 – metabolic stabilization and modulation of reaction centers 310–316

– radiopharmaceuticals 329–332 – stereoelectronic effects and conformation 306–310 photoresists 255 physical properties 7–13 physiological properties 18–20 plasma-etching process 256–257 polar groups, fluorinated 269–275 polar hydrophobicity 322 poly(3-dodecylthiophene) (P3DT) 288 polychlorotrifluoroethylene (PCTFE) 252 polycyclic aromatic hydrocarbon (PAH) 63 poly(ethylene-co-tetrafluoroethylene) (ETFE) 253 poly(heptafluoropropyl trifluorovinyl ether) (PPVE) 252 polymers and lubricants 249–255 polymethine cyanines 258 polymethines, fluorinated 193–197 polytetrafluoroethylene (PTFE) 3, 10, 14, 19, 218, 249–251 poly(vinylidene difluoride) (PVDF) 252–253 ponytails 211, 232 positron emission tomography (PET) 330–331 pseudo-bases 305 pseudohalogen 317 p-type semiconductors purine nucleoside phosphorylase (PNP) 314 pyrethroids 340 pyridine 42 pyridyloxyacetic acid derivatives 338

q quantitative structure–activity relationship (QSAR) 213, 301

r radical perfluoroalkylation 107 – alkyl radicals inverse radical addition to perfluoroolefins 115–118 – preparatively useful radicals 110–115 – structure, properties, and reactivity 107–110 radiopharmaceuticals 329–332 reductive aromatization 47

s scavengers, fluorous 239–241 Selectfluor™ 90, 91, 95

377

378

Index selective direct fluorination 353 – bis (4-nitrophenyl) tetra fluorosulfurane synthesis 354–355 – diethyl malonate fluorination to diethyl fluoromalonate 354 – isomerization to trans-4 355 self-assembled monolayers (SAMs) 289 silver catalysis 51 Simons electrochemical fluorination process 35 single electron transfer (SET) 113–114 smectic mesophase 260 special fluorine effect 58–59 specific resistivity 267 spin statistics 291 stationary phases, fluorous 232–233 stereoelectronic effects and conformation 306–310 substituent effects, see lipophilicity and substituent effects suicide inhibition, mechanism-based 325–329 sulfonylureas 338 sulfur tetrafluoride (SF4 ) 71, 74–76, 78 superfluorinated material (SFM) 270, 275 super-twisted nematic (STN) 263 Swarts fluorination 249 synthetic procedures 353 – carboxylic acid fluorination with sulfur tetrafluoride 360 – – 4-bromo-2-(trifluoromethyl)thiazole synthesis 360 – copper-mediated introduction of trifluoromethylthio group 366 – – CuSCF3 reaction 4-iodoanisole 366 – – trifluoromethylthio copper reagent 43 preparation 366 – DAST and BAST fluorinations 358 – – alcohol fluorination procedure 358–359 – – aldehydes and keynotes fluorination procedure 359 – difluoroenolates reactions 368 – – trimethylsilyl difluoroenol ether 52 preparation 368 – dithianylium salts oxidative alkoxydifluorodesulfuration 361 – – dithianylium triflate 361 – electrophilic fluorination with F-TEDA–BF4 (Selectfluor) – – diethyl fluorophenyl malonate synthesis 357–358 – – fluosteroid 11 synthesis 357 – electrophilic trifluoromethylation with U memento’s reagents 363

– – trimethylsilyldienol ether 30 trifluoromethylation 363 – hydrofluorination and halofluorination 355–356 – nucleophilic trifluoromethylation with Me3 SiCF3 – selective direct fluorination 353 – – bis (4-nitrophenyl) tetra fluorosulfurane synthesis 354–355 – – diethyl malonate fluorination to diethyl fluoromalonate 354 – – isomerization to trans-4 355 – substitution reactions on fluoroolefins and fluoroarenes 367 – – α,β-difluoro cinnamic acid 367 – – α,β-difluoro-β-chlorostyrenes preparation 367 – – ortho-metalation of 1,2-difluorobenzene with LDA 367–368 – transition metal-mediated aromatic perfluoroalkylation 364 – trifluoromethoxy group generation, by oxidative fluorodesulfuration of xanthogenate 360

t tagging, fluorous 241 tetrabutylammonium fluoride (TBAF) 38, 200, 230 tetrafluoroethylene bridge 275–278 tetrahydrofuran (THF) 27, 357–358 tetrakis(dimethylamino)ethylene (TDAE) 129 thalidomide 315, 316 thin film transistor (TFT) 263 transition metal-catalyzed aromatic fluorination 49–52 transition metal-mediated aromatic perfluoroalkylation 364 – palladium-mediated trifluoromethylation, of aryl chloride 130–132 triflates (FITS) 142, 143, 145 trifluoromethoxide salts 173–174, 176 trifluoromethoxy group 174, 176 trifluoromethylcopper(I) 124 trifluoromethylthio copper reagent 43 preparation 366 trifluoromethylthio group trifluoromethylzinc compounds 124 trifluralin 338 trimethylsilyldienol ether 30 trifluoromethylation 363 trimethylsilyl difluoroenol ethers 198, 368 trimethylsilyl enol ethers 200

Index triplet emitters 291–292 twisted nematic (TN) 261–263, 265 two-step activation and fluorination 68

u ultrasound imaging 336 U memento’s reagents 363 uranium hexafluoride (UF6 ) 250

v voltage-holding ratio (VHR) 267, 275

x xanthogenate oxidative fluorodesulfuration, trifluoromethoxy group generation by 360 xenon difluororide 85 XtalFluor™ 73

379