Synthon preferences in cocrystals of cis-carboxamides:carboxylic acids

We study synthon preferences in cocrystals of cis-carboxamides with carboxylic acids using a combination of database analyses, cocrystallisation experiments and theoretical calculations. We classify the cis-carboxamides into three families: primary amides, cyclic amides (lactams) and cyclic imides. Using crystal structure prediction calculations, we sample the phase space of the cocrystals and generate observed as well as non-observed cocrystal structures and synthons in order to compare their relative stability as calculated with the PIXEL method. We conclude our study with a set of rules of synthon preferences derived from our observations and theoretical calculations. Whilst primary amides almost always form heterosynthons with carboxylic acids, cyclic imides seldom crystallise with them and cyclic amides represent a difficult prediction challenge. The study highlights the role played by the side interactions in the stability of the studied synthons.