The assignment of the absolute configuration by NMR using chiral derivatizing agents : a practical guide / José M. Seco, Emilio Quiñoá, and Ricardo Riguera.

Format:

Book

Author/Creator:

Seco, J. M. (José Manuel), author.

Quiñoá, E. (Emilio), author.

Riguera, R. (Ricardo), author.

Language:

English

Subjects (All):

Nuclear magnetic resonance spectroscopy.

Spectrum analysis.

Nuclear magnetic resonance spectroscopy--Problems, exercises, etc.

Spectrum analysis--Problems, exercises, etc.

Genre:

Problems and exercises.

Physical Description:

xiii, 246 pages : illustrations ; 24 cm

Place of Publication:

New York, NY : Oxford University Press, [2015]

Summary:

Nuclear magnetic resonance spectroscopy (NMR) is a technique that uses the magnetic properties of atomic nuclei to obtain information about the structure and properties of molecules. Proton and Carbon NMR, focusing on 1H and 13C, constitute the most powerful spectroscopic method for structure determination of Organic molecules. Application of this methodology to the assignment of absolute configuration was initiated in the late sixties and now is a well-established method that allows the rapid determination of the absolute configuration of more than one dozen different classes of mono-, bi-, and trifunctional organic compounds. Its simplicity requires the derivatization of the compound with a chiral arylalkoxyacetic acid, and examination of their 1H- and/or 13C-NMR spectra. In The Assignment of the Absolute Configuration by NMR using Chiral Derivatizing Agents: A Practical Guide, Professor Ricardo Riguera and coauthors organize this cutting-edge NMR research, offering a short and usable guide that introduces the reader to the research with a plethora of details and examples. The book briefly explains the theoretical aspects behind this methodology, dedicating most of its space to covering the practical aspects of the assignment, as well as the selection of the most adequate auxiliary reagent and the single or double derivatization, the use of resins etc. Examples and spectra taken from the authors' own experiments are included to illustrate the methodology. Upper-level undergraduates, graduate students, and chemical and pharmaceutical researchers will find this guide useful for their studies. Book jacket.

Contents:

1 The Theoretical Basis for Assignment by NMR 1

1.1 Distinguishing Enantiomers by NMR: The-Use of CDAs 1

1.2 Structural Characteristics of the Auxiliaries and the Substrates 3

1.3 Importance of the Conformation 6

1.4 Importance of the Aromatic Shielding Effect 10

1.5 Use of 13C NMR for Assignment 12

1.6 Simplified Approaches to Assignment by NMR 13

1.6.1 Single-Derivatization Method: Manipulating the Conformational Equilibrium by Temperature 13

1.6.2 Single-Derivatization Method: Manipulating the Conformational Equilibrium by Complexation 14

1.6.3 Single-Derivatization Method Based on Esterification Shifts 16

1.6.4 Mix-and-Shake Method: Assignment Using Resin-Bound CDAs 18

1.7 General Criteria for the Correct Application of the NMR Methodology 18

1.8 Correlation Models for the Assignment of Polyfunctional Compounds 21

1.9 Summary 22

2 Practical Aspects of the Preparation of the Derivatives 27

2.1 Instrumentation, Concentration, Solvent, and Temperature of the NMR Experiment 27

2.2 Source and Preparation of the CDAs 27

2.3 Preparation of the CDA Esters, Thioesters, and Amides 28

2.3.1 Derivatization of Alcohols, Thiols, and Cyanohydrins Using the CDA Acid 28

2.3.2 Derivatization of Amines Using the CDA Acid 28

2.3.3 Preparation of the CDA Acid Chlorides 29

2.3.4 Derivatization of Alcohols, Thiols, and Cyanohydrins Using the CDA Acid Chloride 29

2.4 Resin-Bound CDA Derivatives (Mix-and-Shake Method) 29

2.4.1 Preparation of Resin-Bound CDA Derivatives 30

2.4.2 Preparation of Acid Chloride Resins 30

2.4.3 Preparation of CDA-Resins 31

2.4.4 Determination of the Loading of the CDA-Resins 31

2.4.5 In-Tube Derivatization of Amines 31

2.4.6 In-Tube Derivatization of Primary and Secondary Alcohols, Cyanohydrins, and Secondary Thiols 32

2.4.7 In-Tube Derivatization of Amino Alcohols 34

2.4.8 In-Tube Derivatization of Diols and Triols 35

2.4.9 In-Tube Derivatization for Single-Derivatization Procedures 35

3 Assignment of the Absolute Configuration of Monofunctional Compounds by Double Derivatization 37

3.1 Secondary Alcohols 37

3.1.1 MPA and 9-AM A as CDAs for Secondary Alcohols 37

3.1.2 Example 1: Assignment of the Absolute Configuration of Diacetone D-Glucose Using MPA 39

3.1.3 Example 2: Assignment of the Absolute Configuration of (-)-Isopulegol Using 9-AMA 40

3.1.4 Example 3: Assignment of the Absolute Configuration of (R)-Butan-2-ol Using MPA and ¹³C-NMR 42

3.1.5 Simultaneous Derivatization of the Substrate with the (R)- and (S)-CDAs 43

3.1.6 Example 4: Assignment of the Absolute Configuration of (5)-Butan-2-ol Using a 1:2 Mixture of (R)- and (S)-MPA 44

3.1.7 Example 5: Assignment of the Absolute Configuration of (-)-Menthol Using a 2:1 Mixture of (R)- and (S)-9-AMA and 13C NMR 45

3.1.8 MTPA as the CDA for Secondary Alcohols 47

3.1.9 Example 6: Assignment of the Absolute Configuration of(-)-Borneol Using MTPA 47

3.1.10 Summary 48

3.2 β-Chiral Primary Alcohols 51

3.2.1 Assignment of β-Chiral Primary Alcohols as 9-AMA Esters 51

3.2.2 Example 7: Assignment of the Absolute Configuration of (S)-2-Methylbutan-l-ol Using 9-AMA 52

3.2.3 Absolute Configuration of Primary Alcohols with Polar Groups as 9-AMA Esters 53

3.2.4 Example 8: Assignment of the Absolute Configuration of (S)-2-Chloropropan-l-ol Using 9-AMA 55

3.2.5 Summary 55

3.3 Aldehyde Cyanohydrins 58

3.3.1 Assignment of Aldehyde Cyanohydrins as MPA Esters 58

3.3.2 Example 9: Assignment of the Absolute Configuration of (R)-2-Hydroxy-3-Methylbutanenitrile Using MPA 59

3.3.3 Example 10: Assignment of the Absolute Configuration of (R)-2-Hydroxy-2-(4-Methoxyphenyl)Acetonitrile Using MPA and ¹³C NMR 60

3.3.4 Summary 63

3.4 Ketone Cyanohydrins 63

3.4.1 Assignment of Ketone Cyanohydrins as MPA Esters 65

3.4.2 Example 11: Assignment of the Absolute Configuration of (1R, 2S, 5R)-1-Hydroxy-2-Isopropyl-5-Methylcyclohexanecarbonitrile Using MPA 65

3.4.3 Example 12: Assignment of the Absolute Configuration of (S)-2-Hydroxy-2,4-Dimethylpentanenitrile Using MPA and ¹³C NMR 67

3.4.4 Summary 69

3.5 Secondary Thiols 69

3.5.1 MPA and 2-NTBA Thioesters of Secondary Thiols 69

3.5.2 Example 13: Assignment of the Absolute Configuration of (S)-Butane-2-Thiol Using MPA 71

3.5.3 Example 14: Assignment of the Absolute Configuration of (R)-Ethyl 2-Mercaptopropanoate Using 2-NTBA 72

3.5.4 Example 15: Assignment of the Absolute Configuration of (R)-Ethyl 2-Mercaptopropanoate Using 2-NTBA and ¹³C NMR 73

3.5.5 Summary 76

3.6 α-Chiral Primary Amines 76

3.6.1 BPG as the CDA for α-Chiral Primary Amines 76

3.6.2 Example 16: Assignment of the Absolute Configuration of (-)-Isopinocampheylamine Using BPG 78

3.6.3 Example 17: Assignment of the Absolute Configuration of (S)-Butan-2-Amine Using BPG and 13C NMR 79

3.6.4 MPA as the CDA for α-Chiral Primary Amines 80

3.6.5 Example 18: Assignment of the Absolute Configuration of (-)-Bornylamine Using MPA 82

3.6.6 MTPA as the CDA for α-Chiral Primary Amines 83

3.6.7 Example 19: Assignment of the Absolute Configuration of (-)-Bornylamine Using MTPA 83

3.6.8 Summary 84

3.7 α-Chiral Carboxylic Acids 87

3.7.1 9-AHA Esters of Carboxylic Acids 89

3.7.2 Example 20: Assignment of the Absolute Configuration of (5)-3-(Acetylthio)-2-Methylpropanoic Acid Using 9-AHA 90

3.7.3 Summary 91

4 Assignment of the Absolute Configuration of Monofunctional Compounds by Single Derivatization 93

4.1 Low-Temperature NMR Procedure for Secondary Alcohols 93

4.1.1 Example 21: Assignment of the Absolute Configuration of Diacetone D-Glucose Using (K)-MPA 95

4.1.2 Example 22: Assignment of the Absolute Configuration of (R)-Butan-2-ol Using (S)-MPA 98

4.2 Complexation with Ba²⁺: MPA Esters of Secondary Alcohols 99

4.2.1 Example 23: Assignment of the Absolute Configuration of (R)-Pentan-2-ol Using (S)-MPA 100

4.2.2 Example 24: Assignment of the Absolute Configuration of (.R)-Pentan-2-ol Using (R)-MPA 101

4.3 Complexation with Ba2+: MPA Amides of a-Chiral Primary Amines 102

4.3.1 Example 25: Assignment of the Absolute Configuration of (-)-Isopinocampheylamine Using (R)-MPA 105

4.4 Esterification Shifts 105

4.4.1 Example 26: Assignment of the Absolute Configuration of (1R, 4S)-HydroxycycIopent-2-en-1-yl Acetate as (R)-9-AMA Ester 107

4.4.2 Example 27: Assignment of the Absolute Configuration of (1R, 4S)-Hydroxycyclopent-2-en-l-yl Acetate as (5)-9-AMA Ester 108

4.5 Summary 109

5 Assignment of the Absolute Configuration of Polyfunction al Compounds

5.1 Sec/Sec-1,2- and Sec/Sec-1,n-Diols 111

5.1.1 Double-Derivatization Methods: MPA, 9-AMA, and MTPA 111

5.1.2 Example 28: Assignment of the Absolute Configuration of Heptane-2,3-Diol (Syn) 116

5.1.3 Example 29: Assignment of the Absolute Configuration of Heptane-2,3-Diol (Anti) 118

5.1.4 Example 30: Assignment of the Absolute Configuration of 1,4-Bis-O-(4-Chlorobenzyloxy)-D-Threitol (Syn) Using ¹³C NMR 119

5.1.5 Single-Derivatization Methods: MPA 120

5.1.6 Example 31: Assignment of the Absolute Configuration of a Pure Isomer of 3,4-Dihydroxy-5-Methylhexan-2-One 124

5.1.7 Example 32: Assignment of the Absolute Configuration of Another Isomer of 3,4-Dihydroxy-5-Methylhexan-2-One 124

5.1.8 Summary 125

5.2 Sec/Sec-1,2-Amino Alcohols 127

5.2.1 Double-Derivatization Method: MPA 127

5.2.2 Example 33: Assignment of the Absolute Configuration of 2-Aminopentan-3-ol (Syn) 130

5.2.3 Example 34: Assignment of the Absolute Configuration of Methyl 4-Amino-3-Hydroxy-5-Phenylpentanoate (Anti) 132

5.2.4 Summary 133

5.3 Prim/Sec-1,2-Diols 134

5.3.1 Double-Derivatization Methods: MPA 135

5.3.2 Example 35: Assignment of the Absolute Configuration of (S)-Propane-1,2-Diol Using MPA 138

5.3.3 Double-Derivatization Methods: 9-AMA 140

5.3.4 Example 36: Assignment of the Absolute Configuration of (S)-Propane-1,2-Diol Using 9-AMA 143

5.3.5 Example 37: Assignment of the Absolute Configuration of

(R)-2,3-Dihydroxypropyl Stearate Based Only on the Methylene Hydrogens 144

5.3.6 Example 38: Assignment of the Absolute Configuration of (-R)-l -Phenylethane-1,2-Diol Based Only on the Methylene Hydrogens 145

5.3.7 Single-Derivatization Method: MPA 147

5.3.8 Example 39: Assignment of the Absolute Configuration of (S)-Propane-1,2-Diol 150

5.3.9 Example 40: Assignment of the Absolute Configuration of (R)-Propane-1,2-Diol 152

5.3.10 Summary 154

5.4 Sec/Prim-1,2-Amino Alcohols 155

5.4.1 Double-Derivatization Methods: MPA and the Use of R and Methylene Hydrogens 155

5.4.2 Example 41: Assignment of the Absolute Configuration of (S)-2-Aminopropan-l-ol Based on R and Methylene Hydrogens 157

5.4.3 Double-Derivatization Methods: The Use of OMe and CaH Signals for Assignment 157

5.4.4 Example 42: Assignment of the Absolute Configuration of (S)-2-Aminopropan-1 -ol Using Δδ^RS of OMe and CaH signals 159

5.4.5 Example 43: Assignment of the Absolute Configuration of (S)-2-Aminopropan-l-ol Using the Separation of OMe and CaH Signals 161

5.4.6 Example 44: Assignment of the Absolute Configuration of (S)-2-Amino-3-Methylbutan-l-ol Using the Separation of OMe and CaH Signals 163

5.4.7 Single-Derivatization Method: MPA 165

5.4.8 Example 45: Assignment of the Absolute Configuration of (S)-2-Aminopropan-l-ol by Low-Temperature NMR of a Single Derivative 168

5.4.9 Example 46: Assignment of the Absolute Configuration of (K)-2-Aminopropan-l-ol by Low-Temperature NMR of a Single Derivative 168

5.4.10 Summary 171

5.5 Prim/Sec-1,2-Amino Alcohols 172

5.5.1 Double-Derivatization Methods: MPA and the Use of R and Methylene Hydrogens 173

5.5.2 Double-Derivatization Methods: The Use of OMe and CaH Signals for Assignment 174

5.5.3 Example 47: Assignment of the Absolute Configuration of (S)-l-Aminopropan-2-ol Based on R and Methylene Hydrogens 175

5.5.4 Example 48: Assignment of the Absolute Configuration of (S)-l-Aminopropan-2-ol Using Δδ^RS of OMe and CaH Signals 177

5.5.5 Example 49: Assignment of the Absolute Configuration of (S)-l-Aminopropan-2-ol Using the Separation of the OMe and CaH Signals 178

5.5.6 Example 50: Assignment of the Absolute Configuration of (R)-l-Aminoheptan-2-ol Using the Separation of the OMe and CaH Signals 179

5.5.7 Single-Derivatization Method: MPA 181

5.5.8 Example 51: Assignment of the Absolute Configuration of (S)-l-Aminopropan-2-olby Low-Temperature NMR of a Single Derivative 184

5.5.9 Example 52; Assignment of the Absolute Configuration of (R)-l-Aminopropan-2-ol by Low-Temperature NMR of a Single Derivative 186

5.5.10 Summary 187

5.6 Prim/Sec/Sec-1,2,3-Triols 188

5.6.1 Double-Derivatization Method: MPA 188

5.6.2 Example 53: Assignment of the Absolute Configuration of Hexane-1,2,3-Triol (Syn) 192

5.6.3 Example 54: Assignment of the Absolute Configuration of Hexane-1,2,3-Triol (Anti) 193

5.6.4 Summary 193

6 Exercises 197.

Notes:

Includes bibliographical references and index.

ISBN:

9780199996803

0199996806

OCLC:

920666993