Three-point interaction formation

Fig. 22. Principle of chiral receptor—substrate recognition (a) formation of diastereomeric inclusion complexes (b) three-point interaction model.

The first four facets are rotationally equivalent to each other as are the final four. The two sets are related by reflectional symmetry to each other. When a chiral adsorbate, for example, S-lysine, is used, the reflectional symmetry is no longer valid and only rotationally equivalent facets should be formed. This was demonstrated elegantly by Zhao with STM [53], The driving force for facet formation is proposed to be a three-point interaction involving the carboxylate group, the a-amino group, and the amino-terminated side chain. The simultaneous optimization of adsorbate-adsorbate and adsorbate-substrate interactions determines the stereochemistry of the facet. 

This LSR-CSA technique (discussed in detail in ref. 76) has also been appUed to a series of sulfoxides. Nitroarylsulfoxides are also capable of a strong three-point interaction with fluoroalcohols 1, an ability that is responsible for a considerable difference in stability between the solvates. Mixtures of Id and 2,4-dinitrophenyl methyl sulfoxide are red, and the intensity of this color is inversely proportional to temperature, consistent with formation of tt-tt complexes. Crystallization of the racemic sulfoxide from carbon tetrachloride solutions of (/ )- d leaves mother liquor enriched in the (i )-sulfoxide enantiomer, that predicted by the usual solvation model (41), to form the more stable solvate. With this compound it is also apparent that the (/ , iS )-solvate may differ considerably from the predicted conformation, by population of 42. This additional interaction. 

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... 

Figure 10.2. Stereoselective formation of diastereomer association complexes between two enantiomers and a chiral selector according to the three-point interaction model.

Davankov and other researchers made substantial contributions to impart the three-point interaction model with modern interpretation [24-26]. As pointed out by Davankov et al., it is required (but not necessarily sufficient) for the chiral selector to recognize the enantiomers to have at least three configuration-dependent active points, which are different in nature, on both chiral selector and enantiomer molecules. The active points on chiral selector must be complementary to and be able to simultaneously interact with those on enantiomer molecules. It is possible that two of the three required interactions can be repulsive if the third one is strong enough to promote the formation of diastereomeric associates between chiral selector and selectand [25]. Davankov et al. used the left- and right-hand model to vividly demonstrate that with the assistance of achiral surface, two-point or even one-point interaction is sufficient for chiral recognition. They treated these cases as expansion of TPI model rather than contradictions to it and asserted that the model is also applicable to CSPs based on proteins and polysaccharides. In some instances, achiral elements, such as solvent molecules and sorbent surfaces, may also participate in the chiral recognition process [24, 25]. 

The direct separation method of a racemate into its enantiomers is based upon the complex formation between the optical isomers of the solute and a chiral selector, resulting in the formation of labile diastereoisomers [50,53]. These differ in their thermodynamic stability, provided that at least three active points of the selector participate in the interaction with corresponding sites of the solute molecule. The rule of the three-point interaction model is generally valid for enan-tioselective chromatography, with the extension to the rule, starting that one of the required interactions may be mediated by the adsorption of the two components of the interacting pair onto the sorbent surface [50,55], The separation of labile diastereoisomers can be accomplished if the complexes possess different stability constants. The major approaches in the formation of diastereomeric complexes are transition metal ion complexes, ion pairs, and inclusion complexes (diastereomeric complex/salt) (Figure 8.11). In this case, only the chiral purity of the selector influences the resolution [53]. 

The basis of separation in chiral HPLC is the formation of temporary diastereomeric complexes within the chiral stationary phase. This causes enantiomers, which normally exhibit identical partitioning into a non-chiral stationary phase, to partition to a different extent into the stationary phase. In order for separation to occur, the enantiomers must have three points of contact with the stationary phase. This is shown in Figure 12.22, where enantiomer 1 interacts with groups A, B and C. Its mirror image, enantiomer 2, is unable to interact in the same way with more than two of the groups on the chiral stationary phase no matter how it is positioned. 

---