Predicting Cocrystallization Based on Heterodimer Energies: The Case of <i>N</i>,<i>N</i>′‑Diphenylureas and Triphenylphosphine Oxide

Diarylureas frequently assemble into structures with one-dimensional H-bonded chain motifs. Herein, we examine the ability of triphenylphosphine oxide (TPPO) to disrupt the H-bonding motif in 14 different <i>meta</i>-substituted <i>N</i>,<i>N</i>′-diphenylureas (mXPU) and form cocrystals; 1:1 mXPU:TPPO cocrystals were obtained in 9 of 14 cases examined (64% success rate). Cocrystals adopt five different lattice types, all of which show unsymmetrical H-bonded [R₂¹(6)] dimers between the urea hydrogens and the phosphine oxygen. Heterodimer (mXPU···TPPO) and homodimer (mXPU···mXPU) interaction energies, Δ<i>E</i>_int, calculated using density functional theory at the B3LYP/6-31G­(d,p) level were used to rationalize the experimental results. A clear trend was observed in which cocrystals were experimentally realized only in cases in which the differences in heterodimer versus homodimer energy, ΔΔ<i>E</i>_int, were greater than ∼5.3–6 kcal/mol. Although calculated interaction energies are a simplified measure of the system thermodynamics, these results suggest that the relative ΔΔ<i>E</i>_int between heterodimers and homodimers is a good predictor of cocrystal formation in this system