Differentiation of Chiral Compounds Using NMR Spectroscopy

Thomas J. Wenzel

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9781119323914
• eBook ISBN: 9781119324775
• Edition: 2
• Topic: Physical Sciences
• Subtopic: Spectroscopy & Spectrum Analysis

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.

1
INTRODUCTION

Nuclear magnetic resonance (NMR) spectroscopy is one of the most common methods used to determine enantiopurity and assign the absolute configuration of chiral compounds. The strategy that has been most exploited, as first recognized by Raban and Mislow in 1965 [1], is to use an enantiopure chiral reagent to distinguish a pair of enantiomers through the formation of nonequivalent diastereomeric complexes. With the diastereomeric complexes, the resonances of enantiotopic nuclei become anisochronous and may split into two resonances, one for the (R)‐derivative and one for the (S)‐derivative of the analyte. The area of the two resonances can be used to determine enantiopurity. The enantiopure probe molecule functions as either a chiral derivatizing agent (CDA) or a chiral solvating agent (CSA). Furthermore, the association of an enantiopure compound with a prochiral molecule with nuclei that are enantiotopic by internal comparison (e.g. the methyl groups of 2‐propanol) renders these nuclei nonequivalent such that distinct resonances are often observed in the NMR spectrum. Classifying chiral metal compounds as either CDAs or CSAs is sometimes difficult. What is important is whether the analyte molecule undergoes fast or slow exchange with the metal center. Strategies based on different packing orders for a pair of enantiomers, such as it occurs in liquid crystals or solid‐state systems, have also been used for chiral analysis in NMR spectroscopy.

1.1. CHIRAL DERIVATIZING AGENTS

CDAs form a covalent bond with a reactive moiety of the analyte. Many CDAs are available for the analysis of carboxylic acids, alcohols, and amines, although strategies for preparing derivatives of many other functional groups will be described as well throughout the text. There are two potential concerns with the application of CDAs when determining enantiopurity. One is the possibility of kinetic resolution, which involves a situation where one enantiomer reacts faster with the CDA than the other. If the reagents are not allowed to react for a long enough time, the proportion of the two diastereomers will not be equivalent to the proportion of the two enantiomers in the original mixture. Kinetic resolution is significant when determining enantiopurity, but it is not significant if the CDA is being used to assign the absolute configuration of an enantiopure analyte such as a natural product.

A second concern with CDAs is that no racemization occurs during the derivatization reaction. This can be significant whether it happens to the analyte or the CDA. With some CDAs for which unacceptable levels of racemization did occur, further study was undertaken to develop reaction conditions that minimize or eliminate racemization. When pertinent, these studies are described in the text.

A general understanding is that CDAs used for determining the enantiopurity of an analyte should be 100% enantiopure. A method for using CDAs that are less than 100% enantiopure has been described. The enantiopurity of the reagent must first be accurately measured using an appropriate method. A set of equations is provided in the report to determine the enantiopurity of an unknown from the known purity of the chiral reagent [2].

Many CDAs incorporate moieties, such as aryl rings, that produce specific and predictable perturbations in the chemical shifts of the resonances of the analyte. In such cases, the changes in chemical shifts in the spectrum of an enantiopure analyte in the derivatives with the (R)‐ and (S)‐enantiomers of the CDA can be used to assign absolute configuration. In other situations, moieties on the analyte may cause specific and predictable perturbations of the chemical shifts of resonances of the CDA. If so, these can be used to assign absolute configuration as well.

Another procedure that is often used with CDAs or CSAs is to look for the presence of specific trends in the chemical shifts that correlate with the absolute configuration of the analyte. The assumption is that if the trends are consistent among a series of compounds with known configurations, then they will be consistent for an unknown analyte with a similar structure. Empirical trends such as these have been observed in many situations and are described where appropriate throughout the text.

An alternative, although much less‐used, derivatizing strategy involves a self‐coupling reaction of a chiral molecule. The self‐coupling of two chiral molecules leads to the formation of a mixture of meso (R,S) and threo [(S,S)/(R,R)] derivatives. Assuming these species exhibit distinct resonances in the NMR spectrum, the areas of the different resonances depend on the enantiopurity of the analyte [3]. A recent example is a generalized procedure for determining the enantiopurity of 2‐phenylpropionic acid and other profens. A stereospecific N,N′‐dicyclohexylcarbodiimide coupling produces a statistical mixture of diastereoisomeric chiral ((R,R) and (S,S)) and meso ((R,S) and (S,R)) anhydrides. The ratio of the anhydrides in the ¹H NMR spectrum can be related to the initial enantiopurity. The reaction can be done in an NMR tube in about 2 min. Because the coupling is stereo random, the reaction does not need to go to completion. The method is more accurate for samples with moderate‐to‐high enantiomeric excess than those closer to racemic proportions [4].

1.2. CHIRAL SOLVATING AGENTS

CSAs associate with the analyte through non‐covalent interactions as shown in Eqs 1.1 and 1.2 for the (R) and (S) forms of an analyte (A). This can involve dipole–dipole, ion‐pairing, and π–π interac...

Table of contents

• COVER
• TABLE OF CONTENTS
• PREFACE
• 1 INTRODUCTION
• 2 Aryl‐CONTAINING CARBOXYLIC ACIDS
• 3 OTHER CARBOXYLIC ACID‐BASED REAGENTS
• 4 HYDROXYL‐ AND THIOL‐CONTAINING REAGENTS
• 5 AMINE‐BASED REAGENTS
• 6 MISCELLANEOUS CDAs, CSAs, AND OTHER METHODS OF CHIRAL ANALYSIS
• 7 REAGENTS INCORPORATING PHOSPHORUS, SELENIUM, BORON, AND SILICON ATOMS
• 8 MACROCYCLIC AND RECEPTOR COMPOUNDS AS CHIRAL NMR DIFFERENTIATING AGENTS
• 9 CHIRAL DIFFERENTIATION WITH METAL‐BASED REAGENTS
• 10 CHIRAL NMR DIFFERENTIATION USING ORDERED SYSTEMS
• 11 CLOSING COMMENTS AND FUTURE PROSPECTS
• REFERENCES
• INDEX
• END USER LICENSE AGREEMENT