Essential Practical NMR for Organic Chemistry

Essential Practical NMR for Organic Chemistry

A hands-on resource advocating an ordered approach to gathering and interpreting NMR data

The second edition of Essential Practical NMR for Organic Chemistry delivers a pragmatic and accessible text demonstrating an ordered approach to gathering and interpreting NMR data. In this informal guide, you’ll learn to make sense of the high density of NMR information through the authors’ problem-solving strategies and interpretations.

The book also discusses critical aspects of NMR theory, as well as data acquisition and processing strategy. It explains the use of NMR spectroscopy for dealing with problems of small organic molecule structural elucidation and includes a brand-new chapter on Nitrogen-15 NMR. Readers will also find:

• Strategies for preparing a sample, spectrum acquisition, processing, and interpreting your spectrum
• Fulsome discussions of Carbon-13 NMR spectroscopy
• Practical treatments of quantification, safety procedures, and relevant software

An ideal handbook for anyone involved in using NMR to solve structural problems, this latest edition of Essential Practical NMR for Organic Chemistry will be particularly useful for chemists running and looking at their own NMR spectra, as well as those who work in small molecule NMR. It will also earn a place in the libraries of undergraduate and post-graduate organic chemistry students.

The authors have worked in NMR for GlaxoSmithKline R&D for over 40 years each, solving organic chemistry structural problems supporting synthetic and medicinal chemists. This work has required the inference of structural information from complex NMR data as well as the design of experiments to test structural hypotheses. Their breadth of experience includes instrumental, chemical, and informatics approaches to answering those important structural questions.

Contents

Preface xiii

1 Getting Started 1

1.1 The Technique 1

1.2 Instrumentation 2

1.2.1 CW Systems 2

1.2.2 FT Systems 3

1.2.3 Probes 5

1.2.4 Shims 6

1.3 Origin of the Chemical Shift 7

1.4 Origin of ‘Splitting’ 8

1.5 Integration 11

2 Preparing the Sample 13

2.1 How Much Sample Do I Need? 14

2.2 Solvent Selection 15

2.2.1 Deutero Chloroform (CDCl3) 16

2.2.2 Deutero Dimethyl Sulfoxide (DMSO) 16

2.2.3 Deutero Methanol (CD3OD) 17

2.2.4 Deutero Water (D2O) 18

2.2.5 Deutero Benzene (C6D6) 18

2.2.6 Carbon Tetrachloride (CCl4) 18

2.2.7 Trifluoroacetic Acid (CF3COOH) 18

2.2.8 Using Mixed Solvents 19

2.3 Spectrum Referencing (Proton NMR) 19

2.4 Sample Preparation 20

2.4.1 Filtration 21

3 Spectrum Acquisition 25

3.1 Number of Transients 25

3.2 Number of Points 26

3.3 Spectral Width 27

3.4 Acquisition Time 27

3.5 Pulse Width/Pulse Angle 27

3.6 Relaxation Delay 29

3.7 Number of Increments 29

3.8 Non-Uniform Sampling (NUS) 30

3.9 Shimming 30

3.10 Tuning and Matching 32

3.11 Frequency Lock 32

3.11.1 Run Unlocked 32

3.11.2 Internal Lock 32

3.11.3 External Lock 32

3.12 To Spin or Not to Spin? 33

4 Processing 35

4.1 Introduction 35

4.2 Zero-Filling and Linear Prediction 35

4.3 Apodization 36

4.4 Fourier Transformation 37

4.5 Phase Correction 37

4.6 Baseline Correction 40

4.7 Integration 40

4.8 Referencing 40

4.9 Peak Picking 41

5 Interpreting Your Spectrum 43

5.1 Common Solvents and Impurities 46

5.2 Group 1 – Exchangeables and Aldehydes 48

5.3 Group 2 – Aromatic and Heterocyclic Protons 50

5.3.1 Monosubstituted Benzene Rings 52

5.3.2 Multi-substituted Benzene Rings 55

5.3.3 Heterocyclic Ring Systems (Unsaturated) and Polycyclic Aromatic Systems 57

5.4 Group 3 – Double and Triple Bonds 61

5.5 Group 4 – Alkyl Protons 64

6 Delving Deeper 67

6.1 Chiral Centres 67

6.2 Enantiotopic and Diastereotopic Protons 72

6.3 Molecular Anisotropy 73

6.4 Accidental Equivalence 75

6.5 Restricted Rotation 77

6.6 Heteronuclear Coupling 81

6.6.1 Coupling between Protons and 13C 81

6.6.2 Coupling between Protons and 19F 83

6.6.3 Coupling between Protons and 31P 85

6.6.4 Coupling between 1H and Other Heteroatoms 87

6.7 Cyclic Compounds and the Karplus Curve 89

6.8 Salts, Free Bases and Zwitterions 93

6.9 Zwitterionic Compounds Are Worthy of Special Mention 94

7 Further Elucidation Techniques – Part 1 97

7.1 Chemical Techniques 97

7.1.1 Deuteration 97

7.1.2 Basification and Acidification 99

7.1.3 Changing Solvents 99

7.1.4 Trifluoroacetylation 100

7.1.5 Lanthanide Shift Reagents 101

7.1.6 Chiral Resolving Agents 102

8 Further Elucidation Techniques – Part 2 105

8.1 Introduction 105

8.2 Spin-Decoupling (Homonuclear, 1-D) 105

8.3 Correlated Spectroscopy (COSY) 106

8.4 Total Correlation Spectroscopy (TOCSY) 1- and 2-D 110

8.5 The Nuclear Overhauser Effect (NOE) and Associated Techniques 111

9 Carbon-13 NMR Spectroscopy 121

9.1 General Principles and 1-D 13C 121

9.2 2-D Proton–Carbon (Single Bond) Correlated Spectroscopy 124

9.3 2-D Proton–Carbon (Multiple Bond) Correlated Spectroscopy 127

9.4 Piecing It All Together 130

9.5 Choosing the Right Tool 131

10 Nitrogen-15 NMR Spectroscopy 137

10.1 Introduction 137

10.2 Referencing 138

10.3 Using 15N Data 138

10.4 Amines 141

10.4.1 Alkyl 141

10.4.2 Aryl 143

10.5 Conjugated Amines 145

10.6 Amides 145

10.7 Amidines 146

10.8 Azides 147

10.9 Carbamates 147

10.10 Cyanates and Thiocyanates 148

10.11 Diazo Compounds 149

10.12 Formamides 149

10.13 Hydrazines 150

10.14 Hydroxamic Acids 151

10.15 Hydroxylamines 152

10.16 Imides (Alkyl and Aryl) 152

10.17 Imines 152

10.18 Isocyanates and Isothiocyanates 153

10.19 Nitrogen-Bearing Heterocycles 154

10.20 Nitriles 157

10.21 Nitro Compounds 158

10.22 Nitroso and N-Nitroso Compounds 158

10.23 N-Oxides 159

10.24 Oximes 160

10.25 Sulfonamides 161

10.26 Ureas and Thioureas 162

10.27 Other Unusual Compounds 163

10.28 15N Topics 166

10.28.1 1-, 2-, 3- and 4-bond Correlations 166

10.28.2 ‘Through-Space’ Correlations 168

10.28.3 Tautomerism in 15N NMR 169

10.28.4 Restricted Rotation 170

10.28.5 Protonation and Zwitterions 170

11 Some Other Techniques and Nuclei 173

11.1 HPLC-NMR 173

11.2 Flow NMR 174

11.3 Solvent Suppression 175

11.4 MAS (Magic Angle Spinning) NMR 176

11.5 Pure Shift NMR 177

11.6 Other 2-D Techniques 178

11.6.1 INADEQUATE 178

11.6.2 J-Resolved 178

11.6.3 DOSY 178

11.7 3-D Techniques 179

11.8 Fluorine (19F) NMR 180

11.9 Phosphorus (31P) NMR 182

12 Dynamics 183

12.1 Linewidths 187

12.2 Chemical Shifts 187

12.3 Splittings 188

12.4 Relaxation Pathways 188

12.5 Experimental Techniques 188

12.6 In Practice 189

12.7 In Conclusion 191

13 Quantification 193

13.1 Introduction 193

13.2 Different Approaches to Quantification 193

13.2.1 Relative Quantification 193

13.2.2 Absolute Quantification 194

13.2.3 Internal Standards 194

13.2.4 External Standards 195

13.2.5 Electronic Reference (ERETIC) 195

13.2.6 Quantas 196

13.2.7 Eretic2 196

13.3 Things to Watch Out For 197

13.4 Quantification of Other Nuclei 197

13.5 Conclusion 198

14 Safety 199

14.1 Magnetic Fields 199

14.2 Cryogens 201

14.3 Sample-Related Injuries 202

15 Software 203

15.1 Acquisition Software 203

15.2 Processing Software 204

15.3 Prediction and Simulation Software 205

15.3.1 13C Prediction 205

15.3.2 1H Prediction 207

15.3.3 Incremental Approaches 207

15.3.4 HOSE Code Databases 208

15.3.5 Semi-Empirical Approaches 208

15.3.6 Ab Initio Approaches 208

15.3.7 Neural Networks 208

15.5.8 Hybrid Approaches 209

15.5.9 Simulation 209

15.6 Structural Verification Software 209

15.7 Structural Elucidation Software 211

15.8 Summary 212

16 Problems 213

16.1 Questions 213

16.2 Hints 227

16.3 Answers 228

16.4 A Closing Footnote 241

17 Raising Your Game 243

17.1 Spotting the Pitfalls 243

17.2 The Wrong Solvent 244

17.3 Choosing the Right Experiment 245

 Appendix A 261

 Glossary 263

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