The molecular bases of chiral recognition in 2-(benzylsulfinyl)benzamide enantioseparation

Highlights: • Computational approach to understand analytical separations at molecular level. • High enantioseparation of 2-(benzylsulfinyl)benzamide is explored by calculations. • Electrostatic potential analysis is used to unravel enantioseparation mechanism. • Intramolecular hydrogen bond within the analyte impacts enantiodiscrimination. • Conformer transition occurring on selector surface provides very high selectivity. Liquid-phase chromatography on chiral stationary phase is still the most popular and versatile technique to separate enantiomers, which is based on the ability of a chiral selector (CS) to recognize the enantiomers of a chiral compound in a solvating medium. The knowledge of the molecular bases of the enantiodiscrimination process is a basic requirement to approach rationally the enantioseparation task. Indeed, analyte, CS, and mobile phase (MP) being the pivotal components of the chromatographic system, their properties, functions and mutual noncovalent interactions determine the enantioseparation outcome. In the last few decades, focused computational methods and techniques have been integrating experimental data and applying for the comprehension of the enantiorecognition phenomenon at molecular level. In this context, for understanding of molecular mechanisms of chiral recognition in separation of enantiomers, we propose a computational procedure based on conformational and electrostatic potential (V) analysis of both analyte and selector. First, low-energy conformers of the analyte were identified by conformational search, which occurring potentially on the selector surface. Then, local electron charge density of specific molecular regions of the interacting partners were inspected in terms of calculated V. This approach was used to explore at molecular level the enantioseparation mechanism of 2-(benzylsulfinyl)benzamide on cellulose-based CSs. By correlating calculated properties with experimental chromatographic parameters available in the literature, the structural landscape of the analyte and CSs in the enantiodiscrimination event and the differences between potential competing sites were profiled. A conformational transition of analyte structure on the CS surface was found to originate the exceptional enantioseparation of the 2-(benzylsulfinyl)benzamide (α > 100). Importantly, the proposed computational analysis provides a rationale of why and how the analytical separation occurs.