Guide to Fluorine NMR for Organic Chemists

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. a,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. a,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. a,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