Diastereomers complexes

When a sample is loaded into the capillary, a transient diastereomer complex may be formed between the sample and the selector. The differing mobilities of the diastereomers in the buffer solution in the presence of an electric field is the reason for the separation. The differences of mobility between the diastereomers are the result of different effective charge sensitivities caused by the different spatial orientations of diastereomers or the specific intermolecular interactions between them. 

Figure 2a. P-31 NMR spectra demonstrating formation of the alkyl (11) from the minor diastereomer (Complex 10b) at 220 K sample formed under kinetic control.

The resolution of racemic compounds through the formation of reversible diastereomer complexes is certainly an example of the generation of chirality upon association of an achiral solute (the racemate to be resolved) and a chiral solute (the resolving agent). Such interactions are normally considered solely from the separations point of view [11], and only rarely is CD used to follow the association mechanism. It is evident, however, that the spectroscopic method would be of great value to characterize the associated species. 

In favorable cases, not only structurally related compounds or isomers can be separated, but also enantiomers, when the stability of the diastereomer complexes (CD.G) of the guest (G) is different, i.e. 

Therefore, the most crucial step is the catalytic asymmetric reaction with the substrate. The logarithm of the relative rate is varied from, for example, 0.01 to 100 (Fig. 7-12). Let us examine the case that the one activated diastereomeric complex provides the product in 100% ee (R) and that the other diastereomer provides the opposite enantiomeric product in 50% ee (S). Even when two activated diastereomer complexes are formed in 1 1 ratio, more than 98% ee of the product can be established in the case where the relative rate of the two activated diastereomers is 100 (log rel-act = 2). 

A chiral tris(methimazolyl)borate ligand has been prepared by Bailey et ah60 by the activation of tris(dimethylamino)borane toward reaction with a chiral methimazole (l-(5)-a-methylbenzyl-2-mercaptoimidazolyl) by A-methylimidazole (Fig. 5.12). Its coordination to [RuCl2(p-cymene)]2 provides a single diastereomer complex in which the chirality of the methimazolyl substituents... 

Since enantiomers have identical physical and chemical properties, their separation requires a mechanism that recognizes the difference in their shape. A suitable mechanism for chromatography is provided by the formation of reversible transient diastereomer association complexes with a suitable chiral selector. To achieve a useful separation the association complexes must differ in stability resulting from a sterically controlled preference for the fit of one enantiomer over the other with the chiral selector. In addition, the kinetic properties of the formation/dissociation of the complex must be fast on the chromatographic time scale to minimize band broadening and achieve useful resolution. Enantioselectivity based on the formation of transient diastereomer complexes is commonly rationalized assuming a three-point interaction model [1-4,17,18]. Accordingly, enantioselectivity requires a minimum of three simultaneous interactions between the chiral selector and at least one of the enantiomers, where at least one of these interactions is stereochemically dependent. The points of interactions... 

Common methods for separating enantiomers by formation of transient diastereomer complexes... 

I Diastereomer complexes formed by attractive interactions (e.g. hydrogen bonding, Tt-it, dipole-type interactions) between enantiomers and chiral selector. 

II Primary mechanism of diastereomer complex formation is through attractive interactions (Type I) but inclusion complexes also play a role. 

V Formation of diastereomer complexes by a combination of hydrophobic, electrostatic, and hydrogenbonding interactions with a protein. 

Most enantiomer separations depend, at least in part, on multiple polar interactions between the enantiomers and chiral selector to form diastereomer complexes. These complexes are often too stable for the enantiomers to be eluted by carbon dioxide in the absence of polar modifiers. Optimum resolution is usually observed at low temperatures, frequently subcritical. These conditions typically result in increased peak separations accompanied by increased band broadening. The observed change in resolution depends on which factor is dominant. Mobile phase composition and temperature are the two most important parameters for optimizing resolution in the minimum separation time pressure is often less important as the modified mobile phases are not very compressible. 

A proposed mechanism, shown in Scheme 1, involves a six-member cyclic transition state between the aryl ketone and the active form of the catalyst, 2 [6]. The stable catalyst precursor 1 is transformed to the active catalyst, 2, through the loss of HCl. Treatment with 2-propanol forms ruthenium hydride 3 as a single diastereomer. Complexation of an aryl ketone precedes the hydride transfer step, which results in the reduced product. The mild reaction conditions make this catalyst an excellent candidate for incorporation in an imprinted network. The reported enantiometric excesses (ee s, +90%) serve as a useful benchmark to evaluate the influence of the imprinted polymer on the reduction. To the extent that the ruthenium center is situated in an imprinted cavity, the MIP can influence the approach of the ketone to the metal ion or better accommodate a specific reduction product. 

FIGURE 9.4 Schematic depiction of (A) ideal and (B) nonideal stereochemical arrangements for diastereomeric complex formation between a chiral selector and a pair of enantiomers. Shown in (C) is an aimotated X-ray crystal stmctnre, which shows the optimal alignment of noncovalent forces to initiate diastereomer complex formation between chloro-ferf-bntylcarbamoyl quinine (top) and 5 -(3,5-dinitrobenzoyl)-leucine (bottom) (Reprinted from Reference [87] with permission from the American Chemical Society 2005). 

When the direct separation approach is applied, the CS is added to the BGE solution. The CS and the enantiomers will form diastereomer complexes, which differ in stability constants. One enantiomer will thus interact more strongly with the selector compared with the other, resulting in a separation. Direct chiral separations are applied more frequently than indirect separations because of the above-mentioned drawbacks. Many selectors can be used in direct separations. Therefore, a discussion on the most important selectors took place. For each selector type, a few... 

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