Obtaining Synthon Modularity in Ternary Cocrystals with Hydrogen Bonds and Halogen Bonds

Design of ternary cocrystals based on synthon modularity is described. The strategy is based on the idea of extending synthon modularity in binary cocrystals of 4-hydroxybenzamide:dicarboxylic acids and 4-bromobenzamide:dicarboxylic acids. If a system contains an amide group along with other functional groups, one of which is a carboxylic acid group, the amide associates preferentially with the carboxylic acid group to form an acid–amide heterosynthon. If the amide and the acid groups are in different molecules, a higher multicomponent molecular crystal is obtained. This is a stable pattern that can be used to increase the number of components from two to three in a multicomponent system. Accordingly, noncovalent interactions are controlled in the design of ternary cocrystals in a more predictable manner. If a single component crystal with the amide–amide dimer is considered, modularity is retained even after formation of a binary cocrystal with acid–amide dimers. Similarly, when third component halogen atom containing molecules are introduced into these binary cocrystals, modularity is still retained. Here, we use acid–amide and Br/I···O2N supramolecular synthons to obtain modularity in nine ternary cocrystals. The acid–amide heterosynthon is robust to all the nine cocrystals. Heterosynthons may assist ternary cocrystal formation when there is a high solubility difference between the coformers. For a successful crystal engineering strategy for ternary cocrystals, one must consider the synthon itself and factors like shape and size of the component molecules, as well as the solubilities of the compounds.