Solute-CSP complexes

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. 

A simplified version of this process is presented in Fig, 1. In this example, the two solute/CSP complexes, d-solute-CSP and i-solute-CSP, have different free energies, with the d-soIute-CSP complex being more stable, that is, the one with the lower free energy. As a result, the d isomer will remain on the column longer than the I isomer, and the two enantiomers will be resolved. 

The chiral recognition mechanism can be broken down into parts if one remembers that the parts are interdependent and cannot exist apart from one another. These parts are (1) how the solute/CSP complexes are formed... 

Type /. When the solute/CSP complexes are formed by attractive interactions, hydrogen bonding, ir-ir, dipole stacking, etc., between the solute and CSP... 

Type II. When the primary mechanism for the formation of the solute/CSP complex is through attractive interactions, but inclusion complexes also play an important role... 

Type V. When the CSP is a protein and the solute/CSP complexes are based on combinations of hydrophobic and polar interactions... 

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-... 

This situation has been described by Pirkle et al. (13,14) for a type I CSp (J )-N-(10-undecanoyl)-a-(6,7-dimethyI-l-naphthyl)-isobutyl amine, and fora homologous series of solutes based on dinitrobenzoyl derivatives of 1-phenylalkyl amines. The experimental results indicated that two different interaction mechanisms were responsible for the formation of the solute/CSP complexes. One mechanism was based on dipole-dipole interactions that resulted in diastereomeric complexes where the (R)-solute/CSP complex was more stable, whereas the other was due to hydrogen-bonding interactions and produced a situation where the (S)-solute/CSP complex was more stable. 

Two bonding mechanisms have also been proposed for the stereochemical resolution of enantiomeric amides and anilides on a type I CSP based on (J )-N-(3,5-dinitroben2oyl) phenyl glycine (15-18). Both the mechanisms are based on dipole-dipole interactions between the solute and CSP. The difference arises from the positioriing of the solutes relative to the CSP vrithin the solute/CSP complexes. Pirkle and McCune (15) labeled the two possibilities "head to head" and "head to tail" dipole stacking. 

A limiting factor in the use of these CSPs is the fact that the formation of the solute/CSP complex is dependent on the existence of complimentary interaction sites on the solute. However, this is not a problem with a wide variety of enantiomeric compounds. Type I CSPs have been used to stereochemically resolve alkyl carbinols, aryl-substituted hydantoins, lactams, succinimides, phthalides, sulfoxides, and sulfides (20). 

The authors concluded that an increase in the bulk of the alcohol enhances the ability of the solute enantiomers to displace the modifier from the CSP that stabilizes the diastereomeric solute/CSP complexes. The enhanced stability of the two solute/CSP complexes magnifies the energy differences between them, resulting in an increase in the observed enan-tioselectivity. A similar effect can be produced by lowering the temperature of the chromatographic system (31). 

Although CTA-I has been used to resolve a large number of compounds, the solutes appear to be limited to molecules that contain a phenyl group. This limitation may be due to the fact that it is the phenyl moiety that enters the chiral cavity to form the solute/CSP complex, as postulated by Hesse and Hagel (40), Francotte and Wolf (41) have recently reported the results of a study on the effect on enantioselectivity of pflra-substituents in the aromatic moieties of a series of compounds. They concluded that there are (41)... 

The chiral recognition mechanisms that operate on the cellulosic CSPs have been studied by Wainer and co-workers (49,50). In one study, the chiral recognition of amides on the OB CSP was examined (49), The results indicated that the solute/CSP complexes formed between the OB CSP and the amide solutes were based on attractive hydrogen bonding, ti-tt, and dipole-dipole interactions. Chiral recognition within the solute/CSP complex was due to the differential inclusion (or fit) of the solute into a chiral cavity or ravine on the CSP However, studies with aromatic alcohols... 

The large number of CSP s developed, tested and marketed present somewhat of a problem for how best to categorize them. Wainer has suggested a classification scheme for HPLC CSP s based on the mode of formation of the solute-CSP complex [16]. There are five categories, labeled Type l-V, and molecular modeling has been done on most of these. The categories and modes of association are ... 

Type I. Where solute-CSP complexes are formed by attractive interactions like hydrogen bonding, pi-pi interactions and dipole stacking as represented by Pirkle-like CSPs. 

Wainer [28] has been able to introduce a first simple classification scheme for HPLC CSPs based on the mode of formation of the solute-CSP complexes ... 

Solute-CSP complexes are formed by attractive interactions such as hydrogen-bonding, jv-tt interactions, and dipole stacking (e.g., the Pirkle phase). 

Enantiomeric separation by using CSP is based on the formation of labile (transient) diastereomeric complexes of solute-CSP between the enantiomers and the chiral molecule that is a part of the stationary phase. The five major CSPclasses based on solute-CSP complexes are as follows [51,52,54] ... 

Pirkle phases that form solute-CSP complexes by n electron donor-acceptor mechanism (attractive-repulsive interactions). 

Protein (bovine serum albumin) forms solute-CSP complexes based on hydrophobic and polar interactions. 

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