The curious case of (caffeine)·(benzoic acid): how heteronuclear seeding allowed the formation of an elusive cocrystalElectronic supplementary information (ESI) available: Details regarding computational studies, cocrystal-screening experiments, as well as crystallographic, thermal and spectroscopic analyses. CCDC 898406-898412. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3sc51419f

Cocrystals are modular multicomponent solids with exceptional utility in synthetic chemistry and materials science. A variety of methods exist for the preparation of cocrystals, yet, some promising cocrystal phases have proven to be intractable synthetic targets. We describe a strategy for the synthesis of the pharmaceutically relevant (caffeine)·(benzoic acid) cocrystal ( 1 ), which persistently failed to form using a broad range of established techniques. State-of-the-art crystal structure prediction methods were employed to assess the possible existence of a thermodynamically stable form of 1 , hence to identify appropriate heteronuclear seeds for cocrystallization. Once introduced, the designed heteronuclear seeds facilitated the formation of 1 and, significantly they (or seeds of the product cocrystal) continued to act as long-lasting laboratory "contaminants", which encouraged cocrystal formation even when present at such low levels as to evade detection. The seeding technique described thus enables the synthesis of cocrystals regarded as unobtainable under desired conditions, and potentially signifies a new direction in the field of materials research. Heteronuclear seeding and crystal structure predictions facilitate the formation of the elusive (caffeine)·(benzoic acid) cocrystal.