Determining Enantiomer Composition

Scheme 1-3. Determining enantiomer composition with chiral chemical shift reagent 18.

Various chiral derivatizing agents have been reported for the determination of enantiomer compositions. One example is determining the enantiomeric purity of alcohols using 31P NMR.28 As shown in Scheme 1-8, reagent 20 can be readily prepared and conveniently stored in tetrahydrofuran (THF) for long periods. This compound shows excellent activity toward primary, secondary, and tertiary alcohols. To evaluate the utility of compound 20 for determining enantiomer composition, some racemic alcohols were chosen and allowed to react with 20. The diastereomeric pairs of derivative 21 exhibit clear differences in their 31P NMR spectra, and the enantiomer composition of a compound can then be easily measured (Scheme 1-8). 

One of the most powerful methods for determining enantiomer composition is gas or liquid chromatography, as it allows direct separation of the enantiomers of a chiral substance. Early chromatographic methods required the conversion of an enantiomeric mixture to a diastereomeric mixture, followed by analysis of the mixture by either GC or HPLC. A more convenient chromatographic approach for determining enantiomer compositions involves the application of a chiral environment without derivatization of the enantiomer mixture. Such a separation may be achieved using a chiral solvent as the mobile phase, but applications are limited because the method consumes large quantities of costly chiral solvents. The direct separation of enantiomers on a chiral stationary phase has been used extensively for the determination of enantiomer composition. Materials for the chiral stationary phase are commercially available for both GC and HPLC. 

Thus far, we have discussed the nomenclature of different types of chiral systems as well as techniques for determining enantiomer composition. Currently,... 

Figure 3.1 Distribution of (a) methods and (b) CSPs for HPLC for determination of enantiomer composition appeared in Tetrahedron Asymmetry in 2000. Figures represent number of paper counted.

Different methods have been developed for determining the enantiomer compositions of a pair of enantiomers. Some apply measurements of the original molecules, while others use derivatives of the corresponding compounds. 

One of the terms for describing enantiomer composition is optical purity. It refers to the ratio of observed specific rotation to the maximum or absolute specific rotation of a pure enantiomer sample. For any compound for which the optical rotation of its pure enantiomer is known, the ee value may be determined directly from the observed optical rotation. 

NMR spectroscopy cannot normally be used directly for discriminating enantiomers in solution. The NMR signals for most enantiomers are isochronic under achiral conditions. However, NMR techniques can be used for the determination of enantiomer compositions when diastereomeric interactions are introduced to the system. 

Sometimes the enantiomer composition of a compound cannot be directly determined using a chiral CSR. In this case, another compound that can be related to the target compound will be chosen for the determination of enantiomer composition. 

The synthesis of lanthanide chemical shift reagents has been the objective of many groups owing to their effect on NMR spectra simplification. A drawback of the commonly used reagents is their sensitivity to water or acids. Tris(tetraphenylimido diphosphinatojpraseodymium [Pr(tpip)3] has been developed as a CSR for the analysis of carboxylic acids.17 Furthermore, it has been found that dinuclear dicarboxylate complexes can be obtained through reactions with ammonium or potassium salts of carboxylic acids, and these compounds can be used to determine the enantiomer composition of carboxylic acids.18... 

Similarly, Mosher-type amines have been introduced for determining the enantiomer composition of chiral carboxylic acids (Fig. 1-10)27 ... 

Determining the Enantiomer Composition of Chiral Glycols or Cyclic Ketones... 

This chapter has provided a general introduction to stereochemistry, the nomenclature for chiral systems, the determination of enantiomer composition and the determination of absolute configuration. As the focus of this volume is asymmetric synthesis, the coming chapters provide details of the asymmetric syntheses of different chiral molecules. 

S )-Ar- -Butyl-2-(phenylcarbamoyloxy)propionamide (193) was used as chiral solvating agent in the NMR determination of the enantiomer composition of the N-(3,4-dinitrobenzoyl) derivative of amino acid ethyl esters400. 

P. J. van Bladeren, J. M. Sayer, D. E. Ryan, P. E. Thomas, W. Levin, D. M. Jerina, Differential Stereoselectivity of Cytochrome P450b and P450c in the Formation of Naphthalene and Anthracene 1,2-Oxides. The Role of Epoxide Hydrolase in Determining the Enantiomer Composition of the 1,2-Dihydrodiols Formed ,. /. Biol. Chem. 1985, 260, 10226- 10235. 

Taken together, it was demonstrated conclusively that differential expression of PrR isoforms that have distinct selectivities of substrate enantiomers plays a significant role in determining enantiomeric compositions of the product, lariciresinol, in addition to DP [55]. 

Chromatography Basic Protocol 1 Determination of Enantiomer Composition Using Single- Gl.4.1... 

DETERMINATION OF ENANTIOMER COMPOSITION USING SINGLE-DIMENSIONAL HIGH-RESOLUTION GAS CHROMATOGRAPHY... 

DETERMINATION OF ENANTIOMER COMPOSITION USING MULTIDIMENSIONAL GAS CHROMATOGRAPHY (MDGC)... 

Figure 1. Distribution of the methods for the determination of enantiomer composition (a) and items of CSPs used in chiral HPLC (b) appeared in Tetrahedron Asymmetry in 1995-2002.

Stewart T. E., Plummer E. L., McCandless L. L., West J. R. and Silverstein R. M. (1977) Determination of enantiomer composition of several bicyclic ketal insect pheromone components. J. Chem. Ecol. 3, 27 -3. 

The principle of this pulse method and its general equations are easily extended to the case of several components in a mixture. The method was used by Lindholm et al. [24] to determine the quaternary isotherms of the enantiomers of methyl- and ethyl-mandelate on the chiral phase Chiral AGP. One of the serious roadblocks encountered in the use of the pulse tracer method is that the amplitudes of most of the system peaks decrease rapidly when the plateau concentration increases. Since the signal noise increases in the same time, it becomes rapidly impossible to make any accurate measurements of the retention time of these peaks. On the basis of fundamental work by Tondeur et al. [114], the origin of this variation of the relative intensity of the system peaks was explained by Forss n et al. [47], who then derived an effective rule to determine the composition of a perturbation pulse that generates system peaks that are detected easily. The concentrations of the components in the injected perturbation pulse should... 

Successful enantioseparation of individual N -protected amino acids stimulated the development of a rapid method of their simultaneous enantioseparation and quantification in a mixture. A feasibility study on this topic has been recently published by Welsch et al. [69]. The two-dimensional HPLC method involves online coupling of a narrow-bore C18 reverse phase (RP) column in the first dimension (separation of racemic amino acids) to a short enantioselective column based on nonporous 1.5 pm particles modified with t-BuCQD in the second dimension (determination of enantiomer composition). Using narrow-bore column resulted in fast analysis time for example, the mixture of nine racemic N-DNB-protected amino acids was completely analyzed within 16 min. 

The displacement of halogen from phosphonic dihalides with thiols in the presence of an appropriate base leads to 5,S-diesters rather than (9,5-isomers (equation 30 Z = 0)2-7374,375 gych a reaction has been employed in the determination of the enantiomer composition of chiral thiols. The NMR spectra for a series of phosphonodithioates 163 (Z = O, R = Me, Ph, PhCH2) and also for analogous trithiophosphonates 163 (Z = S, R = Me or Ph) in which the group R is derived from a chiral thiol, showed that the best separation of P NMR signals for the diastereoisomeric forms was achieved when R = Me. Displacement reactions which involve the loss of chlorine from R2P(Z)C1 (Z = or Se ). RP(0)(SR )CP and RP(S)(NHR )C1 by thiols in the presence of a tertiary amine base, and many more, are widely exemplified. 

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