sigma-hole bonds: a new tool for high-performance liquid chromatography enantioseparations

Non-covalent interactions play a key role in many areas of science such as crystal engineering, molecular recognition and biology. Recently, various types of the so-called s-hole bonds have been identified and studied as a new family of non-covalent interactions. A s-hole bond (sB) is a non-covalent interaction (RD···A) between a covalently-bonded atom of Groups IV-VII (D, donor), bearing a region with a positive electrostatic potential on unpopulated s* orbitals, and a negative site (A, acceptor). Among these interactions, halogen- and chalcogen-bonds involve atoms of groups VI and VII as donor sites, respectively, and, in the last years, the interest in their fundamentals and applications has been grown rapidly [1]. Moreover, in the last decade, sBs occurring in solution have received attention as a tool to direct molecular recognition processes and underlie protein-ligand binding. However some issues are still open: i) so far, the investigations on sBs have mainly been focused on their description in vacuum and in solid state, whereas the behaviour in solution has received less attention [2]; ii) another open issue concerns the application of sBs in chiral systems, and only few chiral molecules having s-holes as recognition sites were described recently [3]; iii) in particular, the detection of weak stereoselective s-hole-based interactions in solution requires the availability of analytical method characterized by high sensitivity; iv) currently, only four halogen bond-driven enantiodiscrimination processes are known [3]. Recently, we reported the first series of halogen bond-driven enantioseparations observed in High-Performance Liquid Chromatography (HPLC) environment [4]. This result is related to the ability of heavy halogens (iodine and bromine) as halogen bond donor (chiral analyte) to form linear interactions with carbonyl oxygen atoms as halogen bond acceptor (polysaccharide-based support as chiral stationary phase). On this basis, we describe herein the fundamentals of an innovative approach to detect and study weak stereoselective sBs in solution, which is based on: i) the rational design of atropisomeric sB donors based on the 4,4'-bipyridyl core, ii) the application of a HPLC protocol based on an orthogonal on-columnscreening on polysaccharide-based polymers, and iii) DFT calculations and computational simulations to study the involved mechanisms. Significantly, the enantioseparations of fluorinated 3-(arylthio)-4,4'-bipyridines proved that SoooO chalcogen bonds can drive enantiodiscrimination processes in HPLC environment. As a result of the HPLC study, new structures can be successfully pinpointed for further applications in catalysis, molecular recognition and drug design.