Three-point interaction model

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

Figure 2.20 Proposed three-point interaction model between Pirkle-type chiral stationary phase and the best orientations of 3-aminobenzo[n]pyrene for maximum interaction. (Adapted from Ref. Ill with permission.)...

Within the solute/CSP complex, chiral recognition is based on the "three-point interaction" model proposed by Dalgliesh (12). According to this mechanism, three interactions occur between the solute and chiral selec-... 

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.

In certain cases, a values of 30 or more have been found, which then correspond to A(AG) values in the range of 2 kcal/mol (8.4 kJ/mol). Generally, such values are obtained owing to very low retention of the first enantiomer eluted. This means that a very enantioselective sorption process is operating in the column, i.e., one of the enantiomers is virtually unbound by the CSP for steric reasons. Such phenomena are not easily explained by the three-point interaction model, but rather indicate the operation of a sort of chiral steric exclusion mechanism, more in line with a steric fit concept involving only one binding interaction. ... 

Fig. 4 The three-point interaction model. Enantiomer (a) presents three groups that match exactly three sites of the selector when its mirror image, Enantiomer (b) can interact with a maximum of two sites of the selector...

The three-point interaction model was useful in the design of some of the earlier chiral stationary phases (CSP). It is still used to rationalize mechanisms for chiral discrimination. It is very important to use it correctly. Figure 5 shows a fancy... 

Fig. 5 Incorrect use of the three-point interaction model seen in [9]. Interaction of methyl-Af-(2-naphthyI)aIaninate with the chiral selector Ai-fS.S-dinitrobenzoyli-f i-leucine n-propylamide. Switching Hydrogen 15 and Group 18 on the selector asymmetric center ( ) would produce the other enantiomeric form. Switching hydrogen 9 and methyl 10 of the leucine asymmetric center ( ) would make the (R)-leucine enantiomer. In both cases, the three interactions mentioned would be similarly possible not allowing for any chiral discrimination...

Historical Development and the Three-Point Interaction Model... 

Abstract There are no particular differences between academic and industrial liquid chromatography chiral separations. In industry, throughput needs and time requirements force for a search for solutions, i.e., enantiomeric fiill separations, without time for additional investigations that could lead to an even better solution. The three-point interaction model is historically recalled and ehallenged. The... 

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 concept of the three-point fit was proposed in 1933 [11]. In this model, stereochemical differences in pharmacological activities were due to the differential binding of enantiomers to a common site on a receptor surface. The three-point interaction model was revisited by Ogston [12]. However, the often-quoted paper is the one from Dalgliesh [13], who invoked a three-point interaction to explain the enantioselective separation of amino acids on cellulose paper. The three-point interaction rule differs from the three-point attachment rule as was pointed out by Davankov [14], who states that the condition for a chiral selector to recognize the enantiomers is that at least three configuration-dependent active points of the selector molecule should interact with three complementary... 

FIGURE 7.1 An illustration of the classical three-point interaction model. Enantiomer 2... 

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]. 

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