Chiral molecules recognition mechanism

A number of specialised stationary phases have been developed for the separation of chiral compounds. They are known as chiral stationary phases (CSPs) and consist of chiral molecules, usually bonded to microparticulate silica. The mechanism by which such CSPs discriminate between enantiomers (their chiral recognition, or enantioselectivity) is a matter of some debate, but it is known that a number of competing interactions can be involved. Columns packed with CSPs have recently become available commercially. They are some three to five times more expensive than conventional hplc columns, and some types can be used only with a restricted range of mobile phases. Some examples of CSPs are given below ... 

Several CD derivatives (charged and uncharged) are available which should allow the separation of most chiral molecules with at least one of them. However, due to the complexity of chiral recognition mechanisms, the determination of the best selector based on the analyte structure is challenging. Eurthermore, separations using CDs are influenced by numerous factors, so that no general rule can be applied for the successful resolution of enantiomers. ... 

The chiral recognition mechanisms in NLC and NCE devices are similar to conventional liquid chromatography and capillary electrophoresis with chiral mobile phase additives. It is important to note here that, to date, no chiral stationary phase has been developed in microfluidic devices. As discussed above polysaccharides, cyclodextrins, macrocyclic glycopeptide antibiotics, proteins, crown ethers, ligand exchangers, and Pirkle s type molecules are the most commonly used chiral selectors. These compounds... 

LI Separations in the reversed-phase mode — chiral recognition mechanisms and structural features of selectands. The primary mechanism of interaction between the macrocyclic selectors and the selectands in the reversed-pha.se mode (employing aqueous buffered mobile phases) is (partial) inclusion of hydrophobic molecules or parts of the molecules, such as (substituted) aromatic rings, into the apolar cavity of the CD. It is clear that the dimensions of the CD cavity play a dominant role to facilitate this... 

Fig. 9.16. Simplified schematics illustrating two different molecular recognition mechanisms exemplified for native (i-CD and propranolol. Case A is the polar-organic phase mode where the solvent molecules occupy the cavity and the SA is bound to the outer surface of the CD via polar interactions (hydrogen bonding and/or dipole-dipole interactions) which contribute to chiral recognition in combination with steric interactions. In the reversed-phase mode, the primary binding mechanism is similar to case B SO-SA association may be driven by inclusion type complexation into the hydrophobic cavity of the CD macrocycle (reprinted with permission from Ref. [27. ]).

HPLC-CSPs are based on molecules of known stereochemical composition immobilized on liquid chromatographic supports. Single enantiomorphs, diastereomers, diastereomeric mixtures, and chiral polymers (such as proteins) have been used as the chiral selector. The chiral recognition mechanisms operating on these phases are the result of the formation of temporary diastereomeric complexes between the enantiomeric solute molecules and immobilized chiral selector. The difference in energy between the resulting diastereomeric solute/CSP complexes determines the magnitude of the observed stereoselectivity, whereas the sum total of the interactions between the solute and CSP chiral and achiral, determines the observed retention and efficiency. 

Yoshida et al.86 employed HyperChem and performed MD calculations to verify the recognition mechanism of the MIP they synthesized for the separation of optically active tryptophan methyl ester. The computational modeling proved that the enantiomeric selectivity is conferred by the electrostatic and hydrogen bonding interactions between the functional molecule and the target tryptophan methyl ester along with the chiral space formed on the polymer surface. 

HSA bears structural and functional resemblance to BSA, and HSA-type CSPs [164] also show similar enantioselective binding preferences for acidic and neutral drug molecules, such as 2-aryloxypropanoic acids [165], warfarin [166] and benzodiazepines [167]. The chiral recognition mechanism of HSA has been the subject of a number of investigations [168], which revealed that enantioselective binding occurs primarily at two well-defined hydrophobic sites. Acidic drugs have been shown to bind preferentially to the so-called warfarin-azapropazone (site I) and neutral drugs to the indol-benzodiazepine site (site II). 

Towards a biological target, the potency of two enantiomers can sometimes differ considerably and sometimes be very similar (Table 17.1). Often the activity is concentrated in only one enantiomer. When such a high stereoselectivity arises, it is admitted that the mechanism of action at the molecular level involves a highly specific interaction between the ligand — a chiral molecule — and the recognition site — a chiral environment. It is to be expected that the most active isomer, in terms of affinity, achieves a better steric complementarity to the receptor than the less active one. 

It is because the chiral selector was a relatively simple molecule having naturally its stereoisomer that the chiral recognition mechanism could be fully established in the case of DNB-derivatized amino acid enantiomer separation. Most chiral selectors are very complicated molecules making extremely difficult to predict a priori a chiral recognition mechanism. 

However, the chiral recognition mechanism of the polysaccharide-based CSPs at a molecular level has not yet been completely clarified. In contrast to the small molecule-based CSPs, the understanding of the chiral recognition mechanism of polymer-based CSPs is usually difficult. This is because a variety of interaction sites with different affinities for enantiomers exist in chiral polymer chains, and the... 

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