MECHANISTIC ASPECTS OF HALOGEN BOND-DRIVEN INTERACTIONS IN COMPLEX MOLECULAR ENVIRONMENT

The term halogen bond (XB) describes the intermolecular interaction occurring between a Lewis base and a halogen atom (in particular heavier halogens) which behaves like Lewis acid due to the electropositive sigma-hole. Indeed, the electrophilic nature of halogens is explained by the anisotropic distribution of the electron density around the halogen atoms. In the last decade, XBs occurring in solution have increasingly received attention as a tool to direct molecular recognition processes and underlie protein-ligand binding. Nevertheless, the exploration of solvent effects on XB has begun later compared to solid-state studies, and to date the application of XB in solution is still challenging. Another open issue concerns the application of XB in chiral systems, and only a few chiral molecules having sigma-holes as recognition sites were described recently. In addition, the detection of stereoselective XB-based interactions in solution requires the availability of analytical method characterized by higher sensitivity. In this study, the rational design of new atropisomeric sigma-hole (halogen and chalcogen) bond donors based on the 4,4'-bipyridyl core has been engineered by stereoelectronic activation of the heteroaromatic scaffold. On this basis, a HPLC protocol based on an orthogonal on-column screeninga,b) on polysaccharide-based polymers, as XB acceptors, was developed with the aim to detect stereoselective sigma-hole-driven interactions. Significantly, the HPLC outcomes of 5,5'-dibromo-2,2'-dichloro-3-(arylthio)-4,4'-bipyridines proved that chalcogen bond interactions involving activated sulfur sites as electrophiles can drive enantiodiscrimination processes. As a result of the HPLC study, new structures have been successfully pinpointed for further applications in catalysis and drug design.