Integrating experimental and computational approaches to study enantioselective recognition in liquid-phase enantioseparations

Noncovalent interactions play a key role in enantioseparation science, where they are the essential elements of the code by which chiral selector (the agent which discriminates between two enantiomers of a chiral compound) and selectand (each enantiomer which is recognized) interact with each other to result the enantiomer distinction and physical separation [1,2]. Although computational treatment of large multi-phase real-life systems is still in its infancy, in the last few years application of molecular modeling methods and techniques to enantioseparation science have been providing useful information to understand the molecular bases of enantioselective recognition occurring in liquid-phase enantioseparation processes [1-3]. On the other hand, a modern attitude to enantioseparation science needs to be founded on multidisciplinary approaches to disclose the molecular bases of mechanisms controlling selector-selectand affinity and enantioselection, going beyond trial-and-error approaches. In this presentation, advancements and open issues in integrating experimental and computational approaches to inspect chromatographic enantioselection will be described. In particular, features and applications of four computational approaches used in the field of enantioseparation science will be discussed: a) electrostatic potential (V) analysis to investigate in detail the shape of both analyte and selector [4]; b) the Bader- Gatti electron density source function (SF) approach, suitably extended to the V field, to evaluate the atomic contributions to local V [5]; c) molecular dynamics to simulate the binding modes of the enantiomers with the polysaccharide-based selectors [6]; d) time-dependent density functional theory (TD-DFT) calculations to obtain theoretical electronic circular dichroism (ECD) spectra for absolute configuration assignment. [1.] P. Peluso, V. Mamane, R. Dallocchio, A. Dessì, S. Cossu, Noncovalent interactions in high-performance liquid chromatography enantioseparationson polysaccharide-based chiral selectors, J. Chromatogr. A 2020, 1623, 461202. [2.] P. Peluso, B. Chankvetadze, Recognition in the domain of molecular chirality: from noncovalent interactions to separation of enantiomers, Chem. Rev. 2022, 122, 13235-13400. [3.] Peluso, P.; Dessì, A.; Dallocchio, R.; Mamane, V.; Cossu, S. Recent studies of docking and molecular dynamics simulation for liquid- phase enantioseparations, Electrophoresis 2019, 40, 1881-1896. [4.] P. Peluso, B. Chankvetadze, The molecular bases of chiral recognition in 2-(benzylsulfinyl)benzamide enantioseparation. Anal. Chim. Acta 2021, 1141, 194-205. [5.] (a) Gatti, C., SF-ESI codes, 2018, Milano, Italy; (b) P. P e l u - so, A. Dessì, R. Dallocchio, B. Sechi, C. Gatti, B. Chankvetadze, V. Mamane, R. Weiss, P. Pale, E. Aubert, S. Cossu, Enantioseparation of 5,5'-dibromo-2,2'-dichloro-3-selanyl-4,4'-bipyridines on polysaccharide- based chiral stationary phases: exploring chalcogen bonds in liquid-phase chromatography, Molecules 2021, 26, 221. [6.] R. Dallocchio, B. Sechi, A. Dessì, B. Chankvetadze, S. Cossu, V. Mamane, P. Pale, P. Peluso, Enantioseparations of polyhalogenated 4,4'-bipyridines on polysaccharide-based chiral stationary phases and molecular dynamics simulations of selector-selectand interactions, Electrophoresis 2021, 42, 1853-1863.