Searching for mechanisms and noncovalent interactions in liquid-phase enantioseparation

Disclosing mechanisms underlying liquid-phase enantioseparations requires expertise at the interface of analytical,physical, and organic chemistry [P. Peluso, et al. J. Chromatogr. A 2020, 1625, 461303]. 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. On one hand, the enantioseparation process is based on the adsorption phenomenon underlying retention mechanism of analyte enantiomers which compete with solvent molecules onto the chiral selector surface. In this perspective, the overall separation process derives from consecutive single adsorption and desorption steps occurring over the selector surface [P. Peluso & B. Chankvetadze Chem. Rev. 2022, 122, 13235-13400]. On the other hand, shape, geometry, and electron distribution of the three pivotal components of the liquid-phase system, analyte, selector, and mobile phase, in most cases organic compounds, play a key role in the enantiodifferentiation process. Although computational treatment of large multiphase 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 [P. Peluso, et al. Electrophoresis 2019, 40, 1881-1896]. Among the chiral selectors used in enantioseparation science, polysaccharide derivatives and cyclodextrins (CDs) are very popular, which have been successfully used for several decades. High-ordered chiral secondary structures as well as multiple (tunable) recognition sites are the keys to success of polysaccharide carbamate-based chiral selectors in enantioseparation science. Hydrogen bonds, dipole-dipole, and pai-pai interactions are classically considered the most frequent noncovalent interactions underlying enantioselective recognition with these chiral selectors [P. Peluso, et al. J. Chromatogr. A 2020, 1623, 461202; P. Peluso & B. Chankvetadze Anal. Chim. Acta 2021, 1141, 194-205]. Very recently, halogen [P. Peluso, et al. J. Chromatogr. A 2020, 1616, 460788], chalcogen and p-hole bonds [P. Peluso, et al. Molecules 2021, 26, 221] were also identified as interactions working in polysaccharide carbamate-based selectors to promote enantiomer distinction. Even if dispersion (London) forces have been envisaged acting in liquid-phase enantioseparations, focused studies to identify possible contributions of dispersion forces with polysaccharides carbamate-based selectors are practically missing. In CDs, the coexistence of hydrophilic and hydrophobic regions, and the inherent chirality have made these macrocycles versatile selectors for enantioseparation science [P. Peluso & B. Chankvetadze Electrophoresis 2021, 42, 1676-1708]. In this field, computational techniques have become a useful tool to model the dynamics of diastereomeric associate formation, to sample low-energy conformations, to determine enantiomer-CD binding energies, and to profile noncovalent interactions contributing to the stability of CD/enantiomer association. In this lecture, the importance of integrating experimental and computational approaches to study liquid-phase enantioselection will be highlighted, and features and applications of the main computational approaches used in this field will be discussed. Moreover, the most recent results of the Unit of Enantioselective Chromatography and Molecular Recognition at the ICB-CNR of Sassari in modeling enantioselection processes promoted by CD- and polysaccharidebased chiral selectors will be also described.