PREFACE xv
1 GENERAL INTRODUCTION 1
1.1. Why Fluorinated Compounds are Interesting? / 1
1.1.1. Steric Size / 1
1.1.2. Polar Effects / 2
1.1.3. Effect of Fluorine Substituents on Acidity and Basicity of Compounds / 2
1.1.4. Effect of Fluorinated Substituents on Lipophilicity of Molecules / 3
1.1.5. Other Effects / 4
1.1.6. Analytical Applications in Biomedicinal Chemistry / 4
1.2. Introduction to Fluorine NMR / 5
1.2.1. Chemical Shifts / 5
1.2.2. Coupling Constants / 7
2 AN OVERVIEW OF FLUORINE NMR 9
2.1. Introduction / 9
2.2. Fluorine Chemical Shifts / 10
2.2.1. Some Aspects of Shielding/Deshielding Effects on Fluorine Chemical Shifts / 11
2.2.2. Solvent Effects on Fluorine Chemical Shifts / 15
2.2.3. Overall Summary of Fluorine Chemical Shift Ranges / 16
2.3. The Effect of Fluorine Substituents on Proton Chemical Shifts / 17
2.4. The Effect of Fluorine Substituents on Carbon Chemical Shifts / 18
2.5. The Effect of Fluorine Substituents on 31P Chemical Shifts / 19
2.6. The Effect of Fluorine Substituents on 15N Chemical Shifts / 20
2.7. Spin-Spin Coupling Constants to Fluorine / 23
2.7.1. Effect of Molecule Chirality on Coupling / 27
2.7.2. Through-Space Coupling / 29
2.7.3. Fluorine-Fluorine Coupling / 32
2.7.4. Coupling Between Fluorine and Hydrogen / 33
2.7.5. Coupling Between Fluorine and Carbon / 35
2.7.6. Coupling Between Fluorine and Phosphorous / 38
2.7.7. Coupling Between Fluorine and Nitrogen / 39
2.8. Second-Order Spectra / 40
2.9. Isotope Effects on Chemical Shifts / 45
2.10. Advanced Topics / 48
2.10.1. Multidimensional 19F NMR / 50
3 THE SINGLE FLUORINE SUBSTITUENT 55
3.1. Introduction / 55
3.1.1. Chemical Shifts - General Considerations / 56
3.1.2. Spin-Spin Coupling Constants - General Considerations / 56
3.2. Saturated Hydrocarbons / 57
3.2.1. Primary Alkyl Fluorides / 57
3.2.2. Secondary Alkyl Fluorides / 61
3.2.3. Tertiary Alkyl Fluorides / 63
3.2.4. Cyclic and Bicyclic Alkyl Fluorides / 66
3.3. Influence of Substituents/Functional Groups / 70
3.3.1. Halogen Substitution / 70
3.3.2. Alcohol, Ether, Epoxide, Ester, Sulfide, Sulfone, Sulfonate, and Sulfonic Acid Groups / 77
3.3.3. Amino, Ammonium, Azide, and Nitro Groups / 80
3.3.4. Phosphorous Compounds / 83
3.3.5. Silanes, Stannanes, and Germanes / 83
3.4. Carbonyl Functional Groups / 84
3.4.1. Aldehydes and Ketones / 85
3.4.2. Carboxylic Acid Derivatives / 86
3.4.3. 1H and 13C NMR Data for Aldehydes, Ketones, and Esters / 86
3.4.4. ß-Ketoesters, Diesters, and Nitroesters / 89
3.5. Nitriles / 89
3.5.1. 1H and 13C NMR Data for Nitriles / 89
3.6. Alkenes with a Single Fluorine Substituent / 90
3.6.1. Hydrocarbon Alkenes / 90
3.6.2. Conjugated Alkenyl Systems / 93
3.6.3. Allylic Alcohols, Ethers, and Halides / 94
3.6.4. Halofluoroalkenes and Fluorovinyl Ethers / 97
3.6.5. Geminal Fluoro, Hetero Alkenes / 98
3.6.6. Multifluoroalkenes / 98
3.6.7. alpha,ß-Unsaturated Carbonyl Compounds / 101
3.7. Acetylenic Fluorine / 104
3.8. Allylic and Propargylic Fluorides / 105
3.8.1. 1H and 13C NMR Data / 106
3.9. Fluoroaromatics / 106
3.9.1. Monofluoroaromatics / 106
3.9.2. Fluoropolycyclic Aromatics: Fluoronaphthalenes / 111
3.9.3. Polyfluoroaromatics / 112
3.10. Fluoromethyl Aromatics / 114
3.11. Fluoroheterocycles / 119
3.11.1. Fluoropyridines, Quinolines, and Isoquinolines / 119
3.11.2. Fluoropyrimidines and Other Fluorine-Substituted Six-Membered Ring Heterocycles / 122
3.11.3. Fluoromethyl Pyridines and Quinolines / 123
3.11.4. Fluoropyrroles and Indoles / 123
3.11.5. Fluoromethyl Pyrroles and Indoles / 125
3.11.6. Fluorofurans and Benzofurans / 125
3.11.7. Fluoromethyl Furans and Benzofurans / 126
3.11.8. Fluorothiophene and Benzothiophene / 127
3.11.9. Fluoromethyl Thiophenes and Benzothiophenes / 128
3.11.10. Fluoroimidazoles and Pyrazoles / 128
3.11.11. Fluoromethyl and Fluoroalkyl Imidazoles, 1H-pyrazoles, Benzimidazoles, 1H-triazoles, Benzotriazoles, and Sydnones / 128
3.12. Other Common Groups with a Single Fluorine Substituent / 129
3.12.1. Acyl Fluorides / 130
3.12.2. Fluoroformates / 131
3.12.3. Sulfinyl and Sulfonyl Fluorides / 131
4 THE CF2 GROUP 133
4.1. Introduction / 133
4.1.1. Chemical Shifts - General Considerations / 134
4.1.2. Spin-Spin coupling Constants - General Considerations / 135
4.2. Saturated Hydrocarbons Containing a CF2 Group / 135
4.2.1. Alkanes Bearing a Primary CF2H Group / 136
4.2.2. Secondary CF2 Groups / 139
4.2.3. Discussion of Coupling Constants Within CF2 Groups / 142
4.2.4. Pertinent 1H Chemical Shift Data / 143
4.2.5. Pertinent 13C NMR Data / 146
4.3. Influence of Substituents/Functional Groups / 148
4.3.1. Halogen Substitution / 148
4.3.2. Alcohol, Ether, Esters, Thioether, and Related Substituents / 152
4.3.3. Epoxides / 155
4.3.4. Sulfoxides, Sulfones, Sulfoximines, and Sulfonic Acids / 156
4.3.5. Multifunctional ß,ß-Difluoro Alcohols / 157
4.3.6. Compounds with Two Different Heteroatom Groups Attached to CF2 Including Chloro- and Bromodifluoromethyl Ethers / 157
4.3.7. Amines, Azides, and Nitro Compounds / 158
4.3.8. Phosphines, Phosphonates, and Phosphonium Compounds / 162
4.3.9. Silanes, Stannanes, and Germanes / 162
4.3.10. Organometallics / 162
4.4. Carbonyl Functional Groups / 164
4.4.1. Aldehydes and Ketones / 164
4.4.2. Carboxylic Acids and Derivatives / 166
4.5. Nitriles / 168
4.5.1. 1H and 13C NMR Spectra of Nitriles / 168
4.6. Amino-, Hydroxyl-, and Keto-Difluorocarboxylic Acid Derivatives / 169
4.7. Sulfonic Acid Derivatives / 170
4.8. Alkenes and Alkynes / 170
4.8.1. Simple Alkenes with Terminal Vinylic CF2 Groups / 170
4.8.2. Conjugated Alkenes with Terminal Vinylic CF2 Group / 172
4.8.3. Cumulated Alkenes with a Terminal CF2 Group / 174
4.8.4. Effect of Vicinal Halogen or Ether Function / 174
4.8.5. Effect of Allylic Substituents / 174
4.8.6. Polyfluoroethylenes / 175
4.8.7. Trifluorovinyl Group / 175
4.8.8. alpha,ß-Unsaturated Carbonyl Systems with a Terminal Vinylic CF2 Group / 176
4.8.9. Allylic and Propargylic CF2 Groups / 177
4.9. Benzenoid Aromatics Bearing a CF2H or CF2R Group / 178
4.9.1. 1H and 13C NMR Data / 179
4.9.2. CF2 Groups with More Distant Aryl Substitutents / 180
4.10. Heteroaromatic CF2 Groups / 180
4.10.1. Pyridines, Quinolones, Phenanthridines, and Acridines / 181
4.10.2. Furans, Benzofurans, Thiophenes, Pyrroles, and Indoles / 181
4.10.3. Pyrimidines / 183
4.10.4. Five-Membered Ring Heterocycles with Two Hetero Atoms: Imidazoles, Benzimidazoles, 1H-pyrazoles, Oxazoles, Isoxazoles, Thiazoles, and Indazoles / 183
4.10.5. Five-Membered Ring Heterocycles with Three or More Heteroatoms: Sydnones, Triazoles, and Benzotriazoles / 183
4.10.6. Various Other Difluoromethyl-Substituted Heterocyclic Systems / 185
5 THE TRIFLUOROMETHYL GROUP 187
5.1. Introduction / 187
5.1.1. NMR Spectra of Compounds Containing the CF3 Group - General Considerations / 187
5.2. Saturated Hydrocarbons Bearing a CF3 Group / 189
5.2.1. Alkanes Bearing a CF3 Group / 189
5.2.2. Cycloalkanes Bearing a CF3 Group / 189
5.2.3. 1H and 13C NMR Data, General Information / 191
5.3. Influence of Substituents and Functional Groups / 193
5.3.1. Impact of Halogens / 193
5.3.2. Ethers, Alcohols, Esters, Sulfides, and Selenides / 195
5.3.3. Sulfones, Sulfoxides, and Sulfoximines / 200
5.3.4. Amines and Nitro Compounds / 200
5.3.5. Trifluoromethyl Imines, Oximes, Hydrazones, Imidoyl Chlorides, Nitrones, Diazo and Diazirine Compounds / 204
5.3.6. Phosphines and Phosphonium Compounds / 205
5.3.7. Organometallics / 205
5.4. Boronic Esters / 207
5.5. Carbonyl Compounds / 207
5.5.1. 1H and 13C NMR Data / 209
5.6. Nitriles / 213
5.6.1. 13C NMR Data for Nitriles / 213
5.7. Bifunctional Compounds / 214
5.8. Sulfonic Acid Derivatives / 214
5.9. Allylic and Propargylic Trifluoromethyl Groups / 214
5.9.1. Allylic Trifluoromethyl Groups / 215
5.9.2. alpha,ß-Unsaturated Carbonyl Compounds / 219
5.9.3. More Heavily Fluorinated Allylics / 222
5.9.4. Propargylic Trifluoromethyl Groups / 222
5.10. Aryl-Bound Trifluoromethyl Groups / 223
5.10.1. Proton and Carbon NMR Data / 224
5.10.2. Multitrifluoromethylated Benzenes / 225
5.11. Heteroaryl-Bound Trifluoromethyl Groups / 228
5.11.1. Pyridines, Quinolines, and Isoquinolines / 228
5.11.2. Pyrimidines and Quinoxalines / 229
5.11.3. Pyrroles and Indoles / 229
5.11.4. Thiophenes and Benzothiophenes / 230
5.11.5. Furans / 230
5.11.6. Imidazoles and Benzimidazoles / 232
5.11.7. Oxazoles, Isoxazoles, Oxazolidines, Thiazoles, 1H-pyrazoles, 1H-indazoles, Benzoxazoles, and Benzothiazoles / 234
5.11.8. Triazoles and Tetrazoles / 235
6 MORE HIGHLY FLUORINATED GROUPS 237
6.1. Introduction / 237
6.2. The 1,1,2- and 1,2,2-Trifluoroethyl Groups / 238
6.3. The 1,1,2,2-Tetrafluoroethyl and
2,2,3,3-Tetrafluoropropyl Groups / 241
6.4. The 1,2,2,2-Tetrafluoroethyl Group / 242
6.5. The Pentafluoroethyl Group / 245
6.5.1. Pentafluoroethyl Carbinols / 248
6.5.2. Pentafluoroethyl Ethers, Sulfides, and Phosphines / 248
6.5.3. Pentafluoroethyl Organometallics / 249
6.6. The 2,2,3,3,3-Pentafluoropropyl Group / 249
6.7. The 1,1,2,3,3,3-Hexafluoropropyl Group / 251
6.8. 1,1,2,2,3,3-Hexafluoropropyl System / 252
6.9. The Hexafluoro-Isopropyl Group / 254
6.10. The Heptafluoro-n-Propyl Group / 255
6.11. The Heptafluoro-iso-Propyl Group / 255
6.12. The Nonafluoro-n-Butyl Group / 255
6.13. The Nonafluoro-iso-Butyl Group / 258
6.14. The Nonafluoro-t-Butyl Group / 258
6.15. Fluorous Groups / 258
6.16. 1-Hydro-Perfluoroalkanes / 259
6.17. Perfluoroalkanes / 260
6.18. Perfluoro-n-Alkyl Halides / 263
6.19. Perfluoroalkyl Amines, Ethers, and Carboxylic Acid Derivatives / 263
6.20. Polyfluoroalkenes / 264
6.20.1. Trifluorovinyl Groups / 264
6.20.2. Perfluoroalkenes / 267
6.21. Polyfluorinated Aromatics / 268
6.21.1. 2,3,5,6-Tetrafluorobenzene Compounds / 268
6.21.2. The Pentafluorophenyl Group / 268
6.22. Polyfluoroheterocyclics / 269
6.22.1. Polyfluoropyridines / 269
6.22.2. Polyfluorofurans / 269
6.22.3. Polyfluorothiophenes / 269
6.22.4. Polyfluoropyrimidines / 271
7 COMPOUNDS AND SUBSTITUENTS WITH FLUORINE DIRECTLY BOUND TO A HETEROATOM 273
7.1. Introduction / 273
7.2. Boron Fluorides / 275
7.3. Fluorosilanes / 275
7.4. Nitrogen Fluorides / 275
7.4.1. Electrophilic Fluorinating Agents / 276
7.5. Phosphorous Fluorides / 277
7.5.1. Phosphorous (III) Fluorides / 277
7.5.2. Phosphorous (V) Fluorides / 277
7.5.3. Phosphorous (V) Oxyfluorides / 280
7.5.4. Cyclophosphazenes / 280
7.6. Oxygen Fluorides (Hypofluorites) / 281
7.7. Sulfur Fluorides / 282
7.7.1. Inorganic Sulfur, Selenium, and Tellurium Fluorides / 282
7.7.2. Diarylsulfur, Selenium, and Tellurium Difluorides / 282
7.7.3. Aryl and Alkyl SF3 Compounds / 283
7.7.4. Dialkylaminosulfur Trifluorides / 283
7.7.5. Hypervalent Sulfur Fluorides / 284
7.7.6. Related Hypervalent Selenium and Tellurium Fluorides / 287
7.7.7. Organic Sulfinyl and Sulfonyl Fluorides / 288
7.8. The Pentafluorosulfanyl (SF5) Group in Organic Chemistry / 289
7.8.1. Saturated Aliphatic Systems / 292
7.8.2. Vinylic SF5 Substituents / 294
7.8.3. Acetylenic SF5 Substituents / 296
7.8.4. Aromatic SF5 Substituents / 297
7.8.5. Heterocyclic SF5 Compounds / 302
7.9. Bromine Trifluoride, Iodine Trifluoride, and Iodine Pentafluoride / 304
7.10. Aryl and Alkyl Halogen Difluorides and Tetrafluorides / 304
7.11. Xenon Fluorides / 305
INDEX 307
