Links between through-bond interactions and assembly structure in simple piperidones

3,5-Disubstituted piperidones provide an opportunity to explore donor–acceptor through-bond interactions in the context of molecular and supramolecular structure. The crystal structure of cis-3,5-dibenzyl-1-phenylpiperidin-4-one 3 is disordered and the lattice accommodates a 3 : 1 ratio of the N-Ph equatorial (3-eq) and N-Ph axial (3-ax) epimers, based on refined values of occupancy factors. The fortuitous result allows a side-by-side comparison of the two configurations with respect to their donor–acceptor through-bond interactions. The energy difference between 3-ax and 3-eq (ΔE_ax–eq) has been evaluated in the gas phase using extensive first principles calculations, and for many levels of theory this difference parallels the experimentally-observed configurational ratio in the solid state (where the epimers share nearly identical packing environments). The calculations further show a difference in the through-bond stabilization for 3-ax and 3-eq, with larger contributions for 3-ax. Natural bond order (NBO) analysis quantifies the delocalization of the donor nitrogen lone pair into the adjacent carbon–carbon bonds and carbonyl acceptor for the 3-ax epimer. The work concludes that molecular-level structural perturbations that arise from or otherwise influence through-bond donor–acceptor interactions have consequences on solid-state and supramolecular assembly structure.