Three-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]. 

To facilitate the understanding of chiral recognition at the molecular level, a number of attempts have been made to define minimum criteria in terms of the required intermolecular SO-SA interactions [67-74]. The currently most widely accepted concept is known as the three-point rule [67]. This rule states that for chiral recognition to occur a minimum of three simultaneous interactions between SO and at least one of the enantiomers is required, with at least one of these interactions being stereochemicaUy dependent. This concept is graphically illustrated in Fig. 7.3. 

Confusion often arises due to misinterpretation of the term interaction within the conceptional framework of the three-point rule. It is important to understand that in this particular context interaction refers to intermolecular physical forces and their steric implication rather than to specific spatial relationships between substructure elements in the SO and SA entities. This distinction is crucial as intermolecular forces, depending on their physical nature, may be of single-point or of multi-point quality. For example, forces acting exclusively between specific... 

General discussions of enantioselective recognition are given in a number of reviews.A prevalent concept is the "three-point rule. formulated by Pirkle. as Chiral recognition requires a minimum of three simultaneous interactions between the CSP(/receptor) and at least one of the enantiomers, with one of these interactions being stereochemically dependent. Schematically ... 

Turrently, hydrodynamic interactions between suspended particles cannot be included in a DDFT. However, it is well known that, e.g., the rheology of suspensions cannot be explained without taking these into account. Hydrodynamic interactions in a simple approximation based on Oseen tensors have been included in the Fokker-Planck equation (Eq. 3), and the equivalent of Eq. 4 has been derived and discussed [15, 16]. However, this equation contains three-point and two-point correlations in a form such that the sum rule in Eq. 5 cannot be used. 

Recent experimental results have confirmed the principle of chiral interaction (three-point rule) postulated as early as 19S2 by Dalgliesh (56). Additionally, the results prove that the separation models developed for ligand exchange by high-performance liquid chromatography (16,156,157) are also valid for T1.C the diastereomeric complexes formed with the metal ion (e.g., Cu ) and the chiral adsorbent have different stabilities for the different antipodes, and thus chromatographic separation is achieved. 

Thus, in both the cases (Figures 15.2 and 15.3), H-bond plays a role in the overall stability of the diastereomeric complex except that the site of FI-bond is different. The three-point rule [29] proposed for resolution of enantiomers considers H-bond as one of the important factors along with jv-tt interactions and steric repulsions between the CSP and one of the enantiomeric forms to distinguish between the two enantiomeric forms. In the application of MR the stationary phase is achiral, but the MR being chiral is responsible for diastereomeric formation and the differential interaction of the diastereomers with the ODS causes separation. 

Although the three aspects are not strictly independent, sometimes, from a didactic point of view, and to simplify the synthetic analysis, they may be considered separately. However, their mutual interaction must be allowed for in some further stage of the analysis, in order to introduce the pertinent modifications into the process and to arrive at the simplest possible solution (see Diagram 1.1) this means that the maximum correlation must exist among the different individual synthetic operations, so that each one of them allows, facilitates or simplifies, in some way, all the other ones ("rule of maximum simplicity"). 

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