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

Abstract

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 4hydroxybenzamide: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••• O 2 N 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.

Systematic Construction of Ternary Cocrystals by Orthogonal and Robust Hydrogen and Halogen Bonds

“…14 The strategy was later shown to be a general one, using different components selected based on the same principles. [15][16][17] A great body of work on the preparation of ternary [18][19][20][21][22] and even quaternary 23,24 co-crystals has been recently reported by Desiraju and co-workers. First, a shapebased approach was devised, where one component in a binary co-crystal can be partially replaced by a third component, 25 in such a way that the molecules participating in (stronger) hydrogen bonding are left in place, while the weakly interacting molecules of the same kind are substituted by similarly shapes ones.…”

2,2,6,6-Tetramethyl-1-oxopiperidinetribromide and two forms of 1-hydroxy-2,2,6,6-tetramethylpiperidinium bromide salt: Syntheses, crystal structures and theoretical calculations

“…This kind of interactions has been studied in ternary cocrystals containing I and Br halogens [49]. In particular, values of Br···O 2 N bonds of 3.269 Å has been reported [49].…”

Quaternary cocrystals: combinatorial synthetic strategies based on long-range synthon Aufbau modules (LSAM)

“…The design of multicomponent molecular crystals is recognized as one of the challenging areas in modern crystal engineering (Aakerö y et al, 2005;Tothadi & Desiraju, 2013;Tothadi et al, 2011;Bolla & Nangia, 2015;Tothadi et al, 2014). Any good synthetic scheme directed towards a higher cocrystal (ternary, quaternary) should ensure its appearance from a solution containing the various solid constituents in high yield, in other words, without two-or single-component byproducts (Dubey & Desiraju, 2014.…”