Enhanced Crystallinity of Tetrahalopyridyl (THP) Derivatized Compounds

Promoting the formation of ordered crystalline material is a fundamental challenge in the fields of organic synthesis, crystal engineering and wider material science. Traditional approaches typically employ strong, unidirectional intermolecular interactions as the core princi-ples for tecton and synthon design. In contrast, the interactions between complex biomolecules, such as proteins, take advantage of the cooperativity of multiple, weak, polyaxial non-covalent interactions (NCIs), working in concert, to generate strongly associated super-structures. Such design principles have yet to be successfully applied to small molecule crystal engineering. Here we show that the tetra-halopyridyl (THP) unit fulfils these tectonic criteria. Firstly, vast and varied THP based NCIs are identified within the Cambridge Struc-tural Database (CSD). The diversity of NCIs is then validated through manual interrogation of a model library and quantified through quantum topological analyses using Bader’s Atoms In Molecules (QTAIM), non-covalent interactions – reduced density gradient (NCI-RDG) and natural bond orbital (NBO) approaches. Furthermore, the critical importance of F···F interactions is revealed through analysis of 17 pairs of interactions in a diverse library of 12 related scaffolds. The utility of the approach is then shown across a wide variety of substrates including promoting natural product crystallinity and for application in absolute structural determination