LC-NMR and Other Hyphenated NMR Techniques Overview and Applications

This practical guide provides a basic overview of the pros and cons of NMR spectroscopy as both a hyphenated and non-hyphenated technique. The book begins with a description of basic NMR concepts for the structural elucidation of organic compounds and then details the historical development of NMR and hyphenated NMR in the structural elucidation world, followed by applications of hyphenated NMR as LC-NMR and LC-MS-NMR in industry and academia. It also contains updated information on the latest advancements and applications of LC-NMR in such areas as degradation products, drug metabolism, food analysis, and drug discovery. An essential resource for scientists in industry and academia who work in the areas of organic chemistry, medicinal chemistry, process chemistry, and analytical chemistry.

Preface xi

Abbreviations, Symbols, and Units xv

1. Basic Concepts of NMR Spectroscopy 1

1.1 Introduction / 1

1.2 Basic Knowledge Regarding the Physics of NMR Spectroscopy / 2

1.3 Basic Parameters for NMR Interpretation / 7

1.3.1 Chemical Shift / 8

1.3.2 Spin–Spin Coupling Constants / 13

1.3.3 Spin Systems / 20

1.3.4 Signal Intensities / 21

1.3.5 Bond Correlations / 23

1.3.6 Spatial Correlations / 27

1.3.7 Other Topics / 30

1.4 Conclusions / 35

References / 36

2. Historical Development of NMR and LC-NMR 39

2.1 Introduction / 39

2.2 Historical Development of NMR / 39

2.3 Historical Development of LC-NMR / 46

2.4 Historical Development of Other Analytical Techniques Hyphenated with NMR / 49

2.5 Current Trends / 52

References / 52

3. Basic Technical Aspects and Operation of LC-NMR and LC-MS-NMR 59

3.1 Introduction / 59

3.2 Technical Considerations Regarding LC-NMR / 59

3.2.1 Solvent Compatibility / 60

3.2.2 Solvent Suppression / 61

3.2.3 NMR Flow Cell / 62

3.2.4 LC-NMR Sensitivity / 64

3.3 Technical Considerations Regarding LC-MS-NMR / 65

3.3.1 Deuterated Solvents / 66

3.4 Modes of Operation of LC-NMR / 66

3.4.1 On-Flow Mode / 67

3.4.2 Stop-Flow Mode / 67

3.4.3 Time-Sliced Mode / 77

3.4.4 Loop Collection Mode / 77

3.5 Modes of Operation of LC-MS-NMR / 77

3.5.1 On-Flow Mode / 80

3.5.2 Stop-Flow Mode / 87

3.6 Other Modes of Operation / 87

3.7 Challenging Considerations / 89

3.7.1 Air Bubbles / 89

3.7.2 Carryover with and Without an Autosampler / 90

3.7.3 Sample Solubility and Precipitation / 90

3.7.4 Flow Cell and System Cleaning / 91

3.7.5 Flow Rate and Magnetic Susceptibility / 91

3.7.6 Quantitation / 92

3.8 Conclusions / 92

References / 93

4. Applications of LC-NMR 95

4.1 Introduction / 95

4.2 Applications of LC-NMR / 96

4.2.1 Natural Products / 96

4.2.2 Drug Metabolism / 102

4.2.3 Drug Discovery / 108

4.2.4 Impurity Characterization / 111

4.2.5 Degradation Products / 112

4.2.6 Food Analysis / 115

4.2.7 Polymers / 118

4.2.8 Metabolomics and Metabonomics / 118

4.2.9 Isomers, Tautomers, and Chiral Compounds / 119

4.2.10 Others Areas / 120

4.3 Conclusions and Future Trends / 120

References / 121

5. Applications of LC-MS-NMR 131

5.1 Introduction / 131

5.2 Applications of LC-MS-NMR / 132

5.2.1 Natural Products / 132

5.2.2 Drug Metabolism / 134

5.2.3 Drug Discovery and Development / 135

5.2.4 Metabolomics and Metabonomics / 136

5.2.5 Others Areas / 139

5.3 Conclusions and Future Trends / 139

References / 140

6. Hyphenation of NMR with Other Analytical Separation Techniques 143

6.1 Introduction / 143

6.2 GC-NMR / 144

6.3 GPC-NMR / 144

6.4 SEC-NMR / 145

6.5 SFC-NMR / 146

6.6 SFE-NMR / 147

6.7 CE-NMR / 147

6.8 CEC-NMR / 149

6.9 CZE-NMR / 150

6.10 cITP-NMR / 150

6.11 CapLC-NMR / 152

6.12 SPE-NMR / 154

6.13 SPE-MS-NMR / 159

6.14 Conclusions and Future Trends / 167

References / 168

7. Special Topics and Applications Related to LC-NMR 179

7.1 Introduction / 179

7.2 Off-Line Versus Online NMR for Structural Elucidation / 180

7.2.1 Cases Solved Off-Line / 180

7.2.2 Cases Solved Online / 186

7.3 Analysis of Chiral Molecules by NMR / 188

7.3.1 Classical Approach: Off-Line / 189

7.3.2 Nonclassical Approach: Online / 190

7.4 Monitoring Chemical Reactions In Situ / 190

7.4.1 Classical Approach: Off-Line / 191

7.4.2 Nonclassical Approach: Online / 194

7.5 Analysis of Mixtures Off-Line, Online, and by Other NMR Methodologies / 196

7.5.1 Traditional Analysis of Mixtures by Off-Line HPLC and NMR / 196

7.5.2 Online NMR Analysis of Mixtures / 203

7.5.3 Other NMR Methodologies That Mimic LC-NMR Separation / 208

7.6 Current Trends / 210

References / 211

Index 217