Isomers, Conformers, and Cocrystal Stoichiometry: Insights from the Crystal Energy Landscapes of Caffeine with the Hydroxybenzoic Acids

Caffeine cocrystallizes with each of the monohydroxybenzoic acids (2-, 3-, and 4-hydroxybenzoic acid (HBA)) but with very different behavior. (1) The computed crystal energy landscapes for 1:1 systems of caffeine with 2HBA, two conformers of 3HBA, and 4HBA, presented in this paper, help rationalize this diversity. The known cocrystal structures of caffeine/2HBA and caffeine/3HBA are found and calculated to be stable relative to their separate components. The instability of any possible cocrystal between caffeine and the more stable conformer of 3HBA, relative to the experimental structure, is confirmed, as is the ability of caffeine and 4HBA to form cocrystals. Comparison of all the energy landscapes, and in particular the distributions of different hydrogen bonding motifs, provides a rationalization of the variation in crystallization behavior between the isomers and conformers in this superficially similar homologous series. In particular, an explanation is suggested for the formation of three-independent-molecule cocrystals in the case of 4HBA but not 2- or 3HBA.