Chiral solvating agents CSAs

When a chiral solute dissolves in a chiral solvent then a stereochemical interaction must be involved. The expense of using a chiral material as a bulk solvent for NMR determination of enantiomeric purity is rarely justified. A solvating agent is added in between 1 to 10 mole equivalents to a solution of the solute enantiomers in an achiral bulk 

The magnitude of the chemical shift non-equivalence is generally smaller when using CSAs in comparison with CDAs. Non-polar achiral solvents maximise the anisochronicity between the diastereomeric complexes while polar solvents effectively exclude formation of these complexes with the CSA and hence reduce A6 to zero. 

The most commonly used CSAs are a series of 1-aryl-2,2-2-trifluoroethanols (15). It is generally accepted that for induction of chemical shift non-equivalence each solvation complex must feature a minimum of three interactions. Two interactions are necessary 

Distinct NMR resonances were first observed for the enantiomers of 2,2,2-trifluoro-l-phenylethanol in the presence of (/ )-phenylethylamine. With (/ )-2-naphthylethylamine the magnitude of the non-equivalence was increased. A systematic study of a series of aryl alcohols in the presence of amines showed a consistent correlation between the sense of non-equivalence and the absolute configuration of the alcohol. From the simple solvation models proposed, the reciprocality of the CSA approach is evident, i.e. if chiral A can be used to assay racemic B then chiral B can be used to assay racemic A. With this in mind 1 -(9-anthryl)-2,2,2-trifluoroethanol (15a) was developed as a CSA for chiral amines. It is also effective with alcohols, lactones, a-amino acid esters, a-hydroxy acid esters and sulphoxides and is the most widely used chiral solvating agent. Other more specific solvating agents have been developed. Kagan has developed A -(3,5-dinitrobenzoyl)-l-phenylethylamine,forexample, as a CSA specifically for the assay of chiral sulphoxides prepared from sulphides by a modified Sharpless oxidation (section 6.3.2). 

The solvation models proposed by Pirkle are clearly an oversimplification in many cases. For example, with methyl isopropyl sulphoxide in the presence of 1 -(9-anthryl)-2,2,2-trifluoroethanol, A6 continues to increase after one equivalent of the solvating agent has been added and reaches a maximum with three equivalents of CSA. 

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There are three types of chiral auxiliary that are used chiral derivatizing agents (CDAs), chiral lanthanide shift reagents (CLSRs) and chiral solvating agents (CSAs)75. Chiral derivatizing agents (CDAs), such as the enantiomers of o -methoxy-o -(trifluoromethyl)phenylacetic acid (MTPA, 83)76, require the separate formation of discrete... 

Related to the NMR use of CLSRs is the application of chiral solvating agents (CSAs), so-called because the first report of the determination of enantiomeric excess by NMR was that of a partially racemic sample of 2,2,2-trifluro-l-phenylethanol (98),... 

Barretta and coworkers63 reported a direct determination of the enantiomeric purity of chiral trisubstituted allenes by using permethylated cyclodextrin as a chiral solvating agent. They found that the heptakis ft-cyclodextrin TRIMEB discussed above can be successfully used as a chiral solvating agent (CSA) for the NMR determination of the enantiomeric purity of trisubstituted allenes llOa-f. An accurate analysis of the experimental conditions (molar ratio aliene/TRIMEB, temperature and solvent) required to optimize the enantioseparation has been carried out. The XH NMR spectra of TRIMEB, allenes llOa-f, and the mixtures TRIMEB/allene have been recorded at 300 MHz in CD3OD as solvent. 

In the case of the direct method , NMR spectra of enantiomers are recorded in the presence of a nonracemic chiral solvating agent (CSA, Pirkle s method)78, or after addition of a paramagnetic chiral (nonracemic) lanthanide shift reagent (LSK) to the solution of the sample. 

In 1965, the determination of the enantiomeric purity (ee) by NMR spectroscopy using a chiral solvating agent (CSA)69- 73 was first postulated17 and demonstrated experimentally by Pirkle in 1967. An example is the nonequivalence of the proton and fluorine resonances of racemic 2,2,2-trifluoro-l-phenylethanol in the presence of optically active 1-phenylethanamine78 or l-(l-naphthyl)ethanamineS3 (Figure 5). 

Because snsnXioseparation proved to be impossible for DIBOA and DIMBOA attempts to accomplish at least an cnantiodifferentiation by means of the chiral solvating agent (CSA) NMR technique have been undertaken because NMR is based upon a rapid measuring and differentiation process in comparison to the chromatographic separation processes. The NMR discrimination of enantiomeric cyclic hemiacetals and methyl acetals was not described yet. On principle, a pair of... 

Firstly, one can use a "chiral solvating agent (CSA) in which one relies on diastereomeric interactions, or complexations, to give a chemical shift difference for the two enantiomers. The method was first used to demon- 01... 

In the last decades, NMR has evolved as one of the methods used for the determination of chiral species. Among recent examples, chiral hexacoordinated phosphate anion, [bis(tetrachlorobenzenediolato)mono ([l,r]binaphtalenyl-2,2 -diolato)phosphate], (d,i )-BINPHAT (52), as its tetrabutylammonium salt, has found widespread use as a very efficient NMR chiral solvating agent (CSA) for quaternary ammonium cations (quats) derived from a Troger base (53) (Figure 5). ... 

Chiral solvating agents (CSA) form diastereo-isomeric. solvation complexes with solute enantiomers via rapidly reversible equilibria in competition with the bulk solvent. 

Three types of chiral auxiliary are widely used. Chiral derivatising agents (CDAs)[ l form diastereomers while chiral solvating agents (CSAs)t l and chiral lanthanide shift reagents (CLSRs)t l form diastereomeric complexes in situ with the substrate enantiomers. 

Chiral solvating agents function by two possible mechanisms Equations [1] and [2] represent the association of a pair of enantiomers with a chiral solvating agent (CSA), in which and X5 denote the association constants for the R and S enantiomers... 

The second approach, the so-called direct method, consists of the direct determination of enantiomers immersed in a chiral environment. A diversity of techniques has been used to determine enantiomeric composition in samples. Polarimetry, NMR using chiral solvating agents (CSAs), or the different chromatographic and related techniques are the most popular. Polarimetry is still broadly applied in organic chemistry laboratories at least as a semiquantitative method. The general, easy-to-perform, and nondestructive characteristics of polarimetry are properties that justify its use. However, limitations such as the need to know the specific optical rotation for the compound of interest, the inherent low sensitivity, and the possible inaccuracies related to the presence of impurities or to the low specific rotation of certain compounds cannot be overlooked. 

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