Making Benzamide Cocrystals with Benzoic Acids: The Influence of Chemical Structure.

An investigation into the creation of cocrystals of benzamide and substituted benzoic acids was undertaken and four new cocrystals were structurally characterized by single-crystal X-ray diffraction. The attempted cocrystallizations were only successful in those cases where electron-withdrawing functional groups were present as substituents on the benzoic acid. This experimental observation was supported by computational studies, which indicated that in these cases the intermolecular acid···amide interaction between the acid and benzamide was strengthened. A correlation between the interaction energy and the Hammett substitution constant in the applicable cases was displayed. The calculated energy of interaction between benzamide/salicylic acid dimers and benzamide/benzoic acid dimer are the same, yet only benzamide/salicylic acid forms a cocrystal. Lattice energy calculations on the salicylic acid/benzamide crystal structure and hypothetical benzoic acid/benzamide cocrystal structures indicate a difference of approximately 50 kJ mol−1 in energy between these systems, suggesting that the other crystal packing forces are not sufficient to stabilize the benzoic acid/benzamide cocrystal.