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 principles 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 superstructures. Such design principles have yet to be successfully applied to small molecule crystal engineering. Here we show that the tetrahalopyridyl (THP) unit fulfils these tectonic criteria. Firstly, vast and varied THP based NCIs are identified within the Cambridge Structural 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.