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Differentiation of Chiral Compounds Using NMR Spectroscopy, 2nd Edition

Differentiation of Chiral Compounds Using NMR Spectroscopy, 2nd Edition

Thomas J. Wenzel

ISBN: 978-1-119-32391-4

Jul 2018

608 pages

Description

An updated guide to the most current information available for determining how to use NMR spectroscopy to differentiate chiral compounds 

Differentiation of Chiral Compounds Using NMR Spectroscopy offers a thoroughly revised second edition to the essential volume that puts the focus on the chiral systems that are commercially available and have been widely vetted for use in NMR spectroscopy. The text covers a broad range of reagents that make it possible to determine the enantiomeric purity and assign the absolute configuration of many classes of compounds.

Comprehensive in scope, the text describes the chiral NMR differentiating agents as derivatizing agents, solvating agents, metal-based reagents and liquid crystals and gels, and explains the range and types of compounds for which they can be used for analysis. New to this edition are the most recent findings in the field as well as the development of advanced NMR measurement techniques that allow for the simplification of complex spectra resulting in more readily identified enantiodifferentiation. This important resource:

  • Includes the most recent coverage of a large range of compounds that can be analyzed using chiral NMR reagents
  • Explores the use of chiral NMR reagents and explains their relationship to the stereochemistry of the analyzed molecules
  • Offers the essential information needed to help decide which method is the best NMR method to apply to a class or molecules
  • Contains experimental strategies for using the reagents that are likely to improve the quality of the results

Differentiation of Chiral Compounds Using NMR Spectroscopy is a comprehensive guide designed for investigators planning to use NMR spectroscopy to determine enantiomeric purity or assign the absolute configuration of a compound.

PREFACE xix

ACKNOWLEDGMENTS xxi

1. Introduction 1

1.1 Chiral Derivatizing Agents 1

1.2 Chiral Solvating Agents 2

1.3 NMR Methods to Improve the Quality of Data with CSAs and CDAs 9

1.4 Overview of Chiral Reagents and Methodologies 14

2. Aryl-Containing Carboxylic Acids 19

2.1 Introduction 19

2.2 α-Methoxy-α-Trifluoromethylphenylacetic Acid (Mosher’s Reagent) 22

2.3 α-Methoxy-α-Trifluoromethylphenylacetic Thioacid 35

2.4 α-Methoxyphenylacetic Acid 35

2.5 Mandelic Acid (2-Hydroxy-2-Phenylacetic Acid) 47

2.6 O-Acetyl Mandelic Acid (2-Acetoxy-2-Phenylacetic Acid) 49

2.7 Other O-Derivatized Mandelic Acids 51

2.8 2-Phenylpropionic Acid 52

2.9 2-Phenylselenopropionic Acid 52

2.10 2-Methoxy-2-Phenylpent-3-ynoic Acid 52

2.11 3-Phenylbutanoic Acid/2-Phenylbutanoic Acid 53

2.12 α-Cyano-α-Fluorophenylacetic Acid/α-Cyano-α-Fluoronaphthylacetic Acid/α-Cyano-α-Fluorop-Tolylacetic Acid 54

2.13 N-Boc Phenylglycine (BPG) 56

2.14 1,5-Difuoro-2,4-Dinitrobenzene and Derivatives 57

2.15 2-Fluoro-2-Phenylacetic Acid, 2-Fluoro-2-(1-Naphthyl) Propionic Acid, and 2-Fluoro-2-(2-Naphthyl)Propionic Acid 59

2.16 α-Methoxy-α-(1-Naphthyl)Acetic Acid/α-Methoxy-α-(2-Naphthyl)Acetic Acid 61

2.17 2-tert-Butoxy-2-(2-Naphthyl)Acetic Acid (2-NTBA) 62

2.18 (−)-(R)-(2-Naphthyloxy)Phenylacetic Acid 63

2.19 α-Methoxy-α-Trifluoromethyl-1-Naphthylacetic Acid (MTN(1)A) 63

2.20 Naproxen 64

2.21 2-Methoxy-2-(1-Naphthyl)Propionic Acid (MαNP) 65

2.22 O-Aryl Lactic Acids 70

2.23 α-(2-Anthryl)-α-Methoxyacetic Acid (2-AMA)/α-(9-Anthryl)-α-Methoxyacetic Acid (9-AMA) 72

2.24 Summary 75

3. Other Carboxylic Acid-Based Reagents 79

3.1 Camphanic Acid 79

3.2 Menthoxyacetic Acid 81

3.3 Tetra-tert-Butyltrioxabicyclo[3.3.1-Nonadienedicarboxylic Acid 82

3.4 Di-O-Benzoyl Tartaric Acid/Di-O-p-Toluoyl Tartaric Acid 82

3.5 2-(2,3-Anthracenedicarboximido)Cyclohexane Carboxylic Acid 85

3.6 3β-Acetoxy-Δ5-Etiocholenic Acid 87

3.7 1-Methoxy-2,3-Dihydro-1H-Cyclopenta[a-Naphthalene-1-Carboxylic Acid 88

3.8 1-Fluoroindan-1-Carboxylic Acid 88

3.9 (−)-(R)-2-(2,3,4,5,6-Pentafluorophenoxy)-2-(Phenyl-d5)Acetic Acid 89

3.10 2,2-Diphenyl- and 2,2-Di-2-Naphthalen-2-yl-[1,3-Dioxolane-4, 5-Dicarboxylic Acid 90

3.11 Tetrahydro-1,4-Epoxynaphthalene-1-Carboxylic Acid 90

3.12 2-tert-Butyl-2-Methyl-1,3-Benzodioxole-4-Carboxylic Acid 91

3.13 Benzo[de-Isoquinoline 1,3-Dione Amino Acids 92

3.14 Amino Acids and Derivatives 92

3.15 2-Methylbutyric Acid 96

3.16 Atropisomeric Chiral Carboxylic Acids 96

4. Hydroxyl- and Thiol-Containing Reagents 101

4.1 2,2,2-Trifluorophenylethanol/ 2,2,2-Trifluoro-1-(9-Anthryl)Ethanol 101

4.2 Other Anthryl-Based Reagents 115

4.3 1-Phenylethanol 119

4.4 2-Methoxy-2-Phenylethanol 120

4.5 MethylMandelate 120

4.6 Mandelonitrile121

4.7 Ethyl Mandelate 122

4.8 Aminoindanols 122

4.9 Menthol 123

4.10 trans-Bis(Hydroxydiphenylmethyl)-2,2-Dimethyl-1,

3-Dioxacyclopentane 124

4.11 (S)-Ethyl Lactate 124

4.12 Assignment of Absolute Configuration Using Glycosidation Shifts 125

4.13 2-Butanol and 2-Octanol 131

4.14 Atropisomeric Alcohols 132

4.15 Diol and Dithiol Reagents 137

5. Amine-Based Reagents 141

5.1 Primary Amines 141

5.2 Secondary Amines 154

5.3 Tertiary Amines 158

5.4 Diamine Reagents 159

5.5 Databases Using Amine CSAs 163

6. Miscellaneous CDAs, CSAs, and Other Methods of Chiral Analysis 171

6.1 Amides 172

6.2 Lactams and Lactam-Like Compounds 178

6.3 Aldehydes 184

6.4 Ketones 188

6.5 Anhydrides 189

6.6 Carbonate With (2,6-Dichloro-4-Methoxyphenyl) and (2,4-Dichlorophenyl) Groups 190

6.7 2,2-Dimethoxypropane 190

6.8 Isocyanates and Isothiocyanates 192

6.9 Thioureas 195

6.10 Sulfur-Containing Reagents 198

6.11 Reagents That React at a Chlorine Atom 204

6.12 Polyfunctional Reagents 207

6.13 Micelles 223

6.14 Ionic Liquids 226

6.15 Guanosinemonophosphate (G-Tetrads) 229

6.16 Achiral Reagents for Chiral Analysis: N21,N23-Dibenzyl-5,10,15,20-Tetrakis(3,5-Di-tert-Butyl-4-Oxocyclohexa-2,5-Dienylidene) Porphyrinogen 229

6.17 Assigning Absolute Configuration Using Kinetic Resolution Catalysts 230

6.18 Chiral Analysis Through Isotope Labeling 233

6.19 Self-Induced Diastereomeric Anisochronism: Self-Differentiation of Chiral Compounds 234

6.20 High-Throughput Methods with Chiral NMR Reagents 236

6.21 HPLC–NMR 237

6.22 Database Methods 238

7. Reagents Incorporating Phosphorus, Selenium, Boron, and Silicon Atoms 243

7.1 Phosphorus-Containing Reagents 243

7.2 Selenium-Containing Reagents 282

7.3 Boron-Containing Reagents 285

7.4 Silicon-Containing Reagents 294

8. Macrocyclic and Receptor Compounds as Chiral NMR Differentiating Agents 297

8.1 Cyclodextrins 298

8.2 Crown Ethers 322

8.3 Calixarenes and Resorcinarenes 345

8.4 Receptor Compounds 360

8.5 Cyclosophoraoses: Cyclic-β-d-Glucans 366

8.6 Cryptophane Receptor 367

8.7 1,1′-Binaphthalene-Based Macrocycles and Receptors 369

9. Chiral Differentiation with Metal-Based Reagents 375

9.1 Introduction 375

9.2 Lanthanide Complexes 376

9.3 Transition Metal Complexes 405

10. Chiral NMR Differentiation Using Ordered Systems 441

10.1 Introduction 441

10.2 Chiral Liquid Crystals and Gels 441

10.3 Polymers 477

10.4 Solid-State NMR Spectroscopy 478

11. Closing Comments and Future Prospects 483

11.1 Selection of CSAs and CDAs 483

11.2 Future Prospects 485

REFERENCES 491

INDEX 565