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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
The reason that organic chemists are interested in compounds that contain fluorine is simple. Because of fluorine's steric and polar characteristics, even a single fluorine substituent, placed at a propitious position within a molecule, can have a remarkable effect upon the physical and chemical properties of that molecule. Discussions of the impact of fluorine on physical and chemical properties of compounds have appeared in numerous reviews and monographs.1-13 There are also a number of recent reviews on the subject of fluorine in medicinal, agrochemical, and materials chemistry.14-23
In terms of its steric impact, fluorine is the smallest substituent that can replace a hydrogen in a molecule, other than an isotope of hydrogen. Table 1.1 provides insight into the comparative steric impact of various fluorinated substituents on the equilibrium between axial and equatorial substitution in cyclohexane.24
Table 1.1 Values of A for Some Common Substituents
Fluorine is, of course, the most electronegative atom on the periodic table. sp-Values and F-values (the "pure" field inductive effect) provide indications of the electron-withdrawing influence of substituents, and it can be seen that fluorine itself has the largest F value of an atomic substituent. The values for sP and F for various other fluorinated (and nonfluorinated) substituents provide insight into the relative electron-withdrawing power of fluorinated substituents (Table 1.2).25
Table 1.2 Substituent Effects: sP-Values and F-Values
The strong electronegativity of the fluorinated substituents is reflected in the effect that this group has upon the acidity of alcohols, carboxylic acids, and sulfonic acids, as well as the effect it has on the basicity of amines (Tables 1.3-1.6).1, 26
Table 1.3 Carboxylic Acid Acidity
Table 1.4 Sulfonic Acids
Table 1.5 Alcohol Acidity
Table 1.6 Amine Basicity
Lipophilicity is an important consideration in the design of biologically active compounds because it often controls absorption, transport, or receptor binding; that is, it is a property that can enhance the bioavailability of a compound. The presence of fluorine in a substituent gives rise to enhanced lipophilicity.
For substituents on benzene, lipophilicities are given by values of pX, as measured by the equation in Scheme 1.1, where P values are the octanol/water partition coefficients.
Scheme 1.1
As a measure of the impact of fluorine on a molecule's lipophilicity, the p-value of a CF3 group is 0.88, as compared to 0.56 for a CH3 group.
There is also evidence that single, carbon-bound fluorine substituents, particularly when on an aromatic ring, can exhibit specific polarity influences, including H-bonding, that can strongly influence binding to enzymes.16, 27
These and other insights regarding structure-activity relationships for fluorinated organic compounds allow researchers interested in exploiting the effects of fluorine substitution on bioactivity to more effectively design fluorine-containing bioactive compounds. In the process of the synthesis of such compounds, it is necessary to characterize the fluorine-containing synthetic intermediates and ultimate target compounds. Knowledge of 19F NMR is essential for such characterization.
Over the last decade or so, NMR spectroscopy has emerged as a screening tool to facilitate the drug discovery process, and nowhere has this been more the case than with 19F NMR spectroscopy (more about this in Chapter 2).
Aside from carbon and hydrogen, fluorine-19 is probably the most studied nucleus in NMR. The reasons for this include both the properties of the fluorine nucleus and the importance of molecules containing fluorine. The nucleus 19F has the advantage of 100% natural abundance and a high magnetogyric ratio, about 0.94 times that of 1H. The chemical shift range is very large compared to that of hydrogen, encompassing a range of >350 ppm for organofluorine compounds. Thus, resonances of different fluorine nuclei in a multifluorine-containing compound are usually well separated and the spectra are usually of first order. The nuclear spin quantum number for fluorine is ½ and thus fluorine couples to proximate protons and carbons in a manner similar to hydrogen, and relaxation times are sufficiently long for spin-spin splittings to be resolved. Moreover, long-range spin-spin coupling constants to fluorine can have substantial magnitude, which can be particularly useful in providing extensive connectivity information, especially in 13C NMR spectra.
Although it is of less general importance because of the limited number of phosphorous-containing fluoroorganics, 31P also has a nuclear spin quantum number of ½, its natural abundance is 100%, and it couples strongly to neighboring fluorine. When present, it can therefore have a significant influence on fluorine NMR spectra. 15N also has a nuclear spin quantum number of ½. However, its couplings to fluorine are almost never measured directly because of the very low natural abundance of 15N (0.366%), combined with its small gyromagnetic ratio (-4.314 MHz/T), which is about 1/10th that of 1H. Thus, indirect methods are almost always used to determine both the chemical shifts and any F-N coupling constants.
As hopefully demonstrated by the many examples in this book, a judicious use of fluorine NMR in combination with proton, carbon, phosphorous, and nitrogen NMR can provide unique advantages in the art of structure characterization. This is particularly true when one brings to the task a knowledge of the impact of fluorine substituents on the chemical shifts of and coupling constants to neighboring H, C, P, and N atoms.
Fluorotrichloromethane (CFCl3) has become the accepted, preferred internal reference for the measurement of 19F NMR spectra, and, as such it is assigned a shift of zero. Signals upfield of the CFCl3 peak are assigned negative chemical shift values, whereas those downfield of CFCl3 are assigned positive values for their chemical shifts. When reporting fluorine chemical shifts, it is advised to report them relative to CFCl3.
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