Principle of Enantiomer Separation

Enantiomers are molecular entities that exist in mirror image-like, non-superim- 

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T.2.1.2.2. Resolution by Capillary Electrophoresis. Another methodology that has been adapted to analysis of enantiomers is capillary electrophoresisThe principle of electrophoretic separation is differential migration of a charged molecule in a... 

Chiral separation or sorption is another important technique in chirotechnology. In fact, due to the high cost of chiral catalysts, industries generally prefer chiral separation over asymmetric catalysis to obtain optically pure compounds. As in asymmetric heterogeneous catalysis, a chiral selector (a chiral molecule in optically pure form) can be immobilized on a solid support to make a chiral stationary phase (CSP) of use in direct chiral separation. The basic principle of chiral separation is that the chiral selector interacts differently with the enantiomers of a racemic or enantioenriched mixture to form transient diastereoisomeric species of different stability, and this fine distinction leads to the separation of enantiomers during elution. This topic has also produced a huge number of papers and the readers are referred to the previous reviews for more knowledge on this field [70-73]. 

Despite the technical differences and the underlying different fluid dynamics for the two types of systems and their consequences in the process of mixing and separation of the two liquid phases, the principle of chiral separations is the same for the two kinds of colunms the preferential association of one of the enantiomers of the chiral compound considered with the chiral selector (CS) involved in the process. 

Liquid-liquid extraction is a basic process already applied as a large-scale method. Usually, it does not require highly sophisticated devices, being very attractive for the preparative-scale separation of enantiomers. In this case, a chiral selector must be added to one of the liquid phases. This principle is common to some of the separation techniques described previously, such as CCC, CPC or supported-liquid membranes. In all of these, partition of the enantiomers of a mixture takes place thanks to their different affinity for the chiral additive in a given system of solvents. 

Fig. 5-17. Principle of micellar-enhanced ultrafiltration (MEUF). The d-enantiomer of a racemic mixture is preferentially bound to the micelles, which are retained by the membrane. The bulk containing the 1-enantiomer is separated through the membrane [72].

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). In such cases, the peaks may be separated enough to permit the proportions of enantiomers to be determined from their intensities. 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 such as tris[3-trifiuoroacetyl-Lanthanide shift reagents have the property of spreading NMR peaks of compounds with which they can form coordination compounds, for examples, alcohols, carbonyl compounds, amines, and so on. Chiral lanthanide shift reagents shift the peaks of the two enantiomers of many such compounds to different extents. 

An extension of the above principles of morphological modification to racemic mixtures, in which each enantiomer (R or S) crystallizes separately in enantio-morphic crystals (d or l), naturally suggests the possibility of performing by these means a new manual Pasteur-type resolution (Scheme 7), as well as a kinetic resolution (54). 

For the separation of crystalline diastereomeric p,n-pairs, the same principles as for enantiomers are followed. Similar to the chromatographic resolution of enantiomers, the scale may vary significantly, but, in general, the separations of diastereomeric pairs are more reliable. For example, acids and lactones which may be separated via their phenylglycinol amide derivatives by MPLC on silica gel. Some examples with their derivatives and chromatographic method used for separation arc listed in Table 10. 

Based on preliminary results from Helfferich130, further developments by Davankov and co-workers5 131 133 turned the principle of chelation into a powerful chiral chromatographic method by the introduction of chiral-complex-forming synlhetie resins. The technique is based on the reversible chelate complex formation of the chiral selector and the selectand (analyte) molecules with transient metal cations. The technical term is chiral ligand exchange chromatography (CLEC) reliable and complete LC separation of enantiomers of free a-amino acids and other classes of chiral compounds was made as early as 1968 131. 

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