Optical Purity - Stereochemistry and Conformation - Introduction - March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (2013)

Part I. Introduction

Chapter 4. Stereochemistry and Conformation

4.I. Optical Purity207

An attempt to resolve a racemic mixture by one of the methods described in Section 4.I has given either a pure compound or a new mixture. How can the purity of the two enantiomers obtained be determined? If the (+) isomer is contaminated by, say, 20% of the (−) isomer, how can this be determined? If the value of [α] for the pure material ([α]max) is known, the purity of a sample is easily determined by measuring its rotation. For example, if [α]max is +80° and the resolved (+) enantiomer contains 20% of the (−) isomer, [α] for the sample will be +48°.208 Optical purity is defined as

equation

Assuming a linear relationship between [α] and concentration, which is true for most cases, the optical purity is equal to the percent excess of one enantiomer over the other:209

equation

How is the value of [α]max determined? It is plain that we have two related problems here; namely, what are the optical purities of our two samples and what is the value of [α]max. Finding the properties of one also gives the other. Several methods for solving these problems are known.

One of these methods involves the use of NMR210 (see Sec. 4.E.ii, category 7). If there is a nonracemic mixture of two enantiomers and the proportions constitute an unknown, convert the mixture into a mixture of diastereomers with an optically pure reagent and look at the NMR spectrum of the resulting mixture, for example,

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If the NMR spectrum of the starting mixture is examined, only one peak would be found (split into a doublet by the C–H) for the Me protons, since enantiomers give identical NMR spectra.211 But the two amides are not enantiomers and each Me gives its own doublet. From the intensity of the two peaks, the relative proportions of the two diastereomers (and hence of the original enantiomers) can be determined. Alternatively, the “unsplit” OMe peaks could have been used. This method was satisfactorily used to determine the optical purity of a sample of 1-phenylethylamine (the case shown above),212 as well as other cases, but it is obvious that sometimes corresponding groups in diastereomeric molecules will give NMR signals that are too close together for resolution. In such cases, one may resort to the use of a different optically pure reagent. The 13C NMR can be used in a similar manner.213 It is also possible to use these spectra to determine the absolute configuration of the original enantiomers by comparing the spectra of the diastereomers with those of the original enantiomers.214 From a series of experiments with related compounds of known configurations it can be determined in which direction one or more of the 1H or 13C NMR peaks are shifted by formation of the diastereomer. It is then assumed that the peaks of the enantiomers of unknown configuration will be shifted the same way.

A closely related method does not require conversion of enantiomers to diastereomers, but relies on the fact that (in principle, at least) enantiomers have different NMR spectra in a chiral solvent, or when mixed with a chiral molecule (in which case transient diastereomeric species may form, see Sec. 4.E.ii). In such cases, the peaks may be separated enough to permit the proportions of enantiomers to be determined from their intensities.215 Another variation, which gives better results in many cases, is to use an achiral solvent, but with the addition of a chiral lanthanide shift reagent [e.g., tris[3-trifluoroacetyl-d-camphorato]europium(III)].216 Lanthanide shift reagents have the property of spreading NMR peaks of compounds with which they can form coordination compounds (e.g., alcohols, carbonyl compounds, and amines). Chiral lanthanide shift reagents shift the peaks of the two enantiomers of many such compounds to different extents.

Another method, involving GC,217 is similar in principle to the NMR chiral complex method. A mixture of enantiomers whose purity is to be determined is converted by means of an optically pure reagent into a mixture of two diastereomers. These diastereomers are then separated by GC and the ratios are determined from the peak areas. Once again, the ratio of diastereomers is the same as that of the original enantiomers. High-pressure liquid chromatography has been used in a similar manner and has wider applicability.218 The direct separation of enantiomers by gas or liquid chromatography on a chiral column has also been used to determine optical purity.219

Other methods220 involve isotopic dilution,221 kinetic resolution,222 13C NMR relaxation rates of diastereomeric complexes,223 and circular polarization of luminescence.224