Predicting Cocrystallization Based on Heterodimer Energies: The Case of N,N′‑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 meta-substituted N,N′-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, ΔE_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, ΔΔE_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 ΔΔE_int between heterodimers and homodimers is a good predictor of cocrystal formation in this system.