Effect of temperature on chromatographic separation driven by enantiomer self-disproportionation

The influence of temperature on the extent of enantiomer self-disproportionation (SDE) and the resulting efficiency of separation of enantiomers by achiral chromatography were examined. The SDE phenomenon is based on the formation of homochiral and heterochiral associates that differ in adsorption behavior. Three chiral components of distinctly different structures and chemical properties were selected for the study: citalopram (CT), methyl p-tolyl sulfoxide (MTSO), and methyl 2-(acetylamino)propanoate (MAAP). The enantiomers of CT formed associates only in the adsorbed phase, whereas MTSO and MAAP were associated in both the liquid and adsorbed phases. The temperature dependence of the association behavior in the liquid phase was determined on the basis of optical rotation measurements, whereas that in the adsorbed phase was determined on the basis of chromatographic elution profiles, which were interpreted using a mechanistic model. For all chiral compounds examined, association in the adsorbed phase had a dominating influence on the extent of SDE. In the case of the enantiomers of MTSO and MAAP, the association process enhanced with increasing temperature, whereas for CT it weakened. The opposite was true for the ratio of the equilibrium constants of the heterochiral and homochiral association, which determined the separation selectivity. This resulted in complex dependences of the separation yield on temperature, which were specific for the chemical structure and the individual concentrations of the enantiomers in their mixtures. It was shown that temperature can be optimized to improve the separation performance.