3-point interaction rule

This separation technique, usually known as chiral ligand exchange chromatography (CLEC), was based on the three-point interaction rule, postulated by Dalgliesh [2] in 1952. 

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... 

A useful concept for chiral separation using a transport or extraction reagent is the three-point binding rule developed for chiral chromatography. The rule states that a minimum of three simultaneous interactions between the chiral stationary phase and one of the enantiomers are necessary to achieve enantioselection, with at least one of these interactions being stereochemically dependent. We describe chiral guanidiniums that apply this rule in the recognition, extraction, or transport separation of amino acids and peptides. 

The three-point attachment rule is largely qualitative and only valid with bimolecular processes (e.g., small Pirkle or ligand-exchange selectors). Another drawback of this model approach is that it cannot be applied to enantiomers with multiple chiral centers. Sundaresan and Abrol [15] proposed a novel chiral recognition model to explain stereoselectivity of substrates with two or three stereo centers requiring a minimum of four or five interaction points. In the same way, Davankov [16] pointed out that much more contact points are realized with chiral cavities of solids. 

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]. 

While the phase rule requires tliree components for an unsymmetrical tricritical point, theory can reduce this requirement to two components with a continuous variation of the interaction parameters. Lindli et al (1984) calculated a phase diagram from the van der Waals equation for binary mixtures and found (in accord with figure A2.5.13 that a tricritical point occurred at sufficiently large values of the parameter (a measure of the difference between the two components). 

The functional form for van der Waals interactions in AMBER is identical with that shown in equation (13) on page 175. The coefficients A. and B.. are computed from the parameters in the file pointed to by the 6-12AtomVDW entry for the parameter set in the Registry or the chem. ini file, usually called nbd.txt(dbf), and optionally with the file pointed to by the 6-12PairVDW entry for the parameter set, usually called npr.txt(dbf). The standard AMBER parameter sets use equations (15) and (16) for the combination rules by setting the 6-12AtomVDWFormat entry to RStarEpsilon. The 1 van der Waals interactions are usually scaled in AMBER to half their nominal value (a scale factor of 0.5 in the Force Field Options dialog box). 

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