Acid•••Amide Supramolecular Synthon in Cocrystals: From Spectroscopic Detection to Property Engineering

The acid center dot center dot center dot amide dimer heterosynthon in cocrystals of aromatic acids and primary amides is identified by marker peaks in the IR spectra that are characteristic of individual N-H center dot center dot center dot O and O-H center dot center dot center dot O interactions and also of the extended synthon. The O-H center dot center dot center dot O hydrogen bond is crucial to heterodimer formation in contrast to the N-H center dot center dot center dot O bond. A combinatorial study, tuning the chemical nature of acid and amide functionalities, leads to 22 cocrystals out of 36 crystallization attempts. Four quadrants I-IV are defined based on acidity and basicity of the acid and amide components. The strong acid-strong base combination in quadrant I favors the planar acid-amide heterodimer in its eight cocrystals. Quadrant IV with its weak acid-weak base combination is the least favored for the planar heterosynthon and synthon diversity is observed in the eight cocrystals obtained. The strong-weak and weak-strong combinations in quadrants II and III are expectedly ambivalent. This exercise highlights the effect of molecular features on supramolecular behavior. Quadrant I crystals, with their propensity for the planar acid center dot center dot center dot amide heterodimer are suitable for the engineering of crystals that can be sheared. This quadrant favors the formation of elastic crystals too. The overall result is that 57% (4 in 7) of all crystals in this quadrant are deformable, compared with 14% (1 in 7) in the three other quadrants. This work is a complete crystal engineering exercise from synthon identification to a particular desired crystal packing to property selection. One can virtually anticipate the mechanical property of a putative acid center dot center dot center dot amide cocrystal from a knowledge of just the molecular structures of the constituent acid and amide molecules.