Modern Fluoroorganic Chemistry

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