Cocrystals of caffeine with formylphenoxyaliphatic acids: Syntheses, structural characterization, and biological activity

Three organic cocrystals namely, caffeine:p-formylphenoxyacetic acid [(caf)(p-fpaa)] (1) caffeine:o-formylphenoxyacetic acid monohydrate [(caf)(o-fpaa)]H2O (2) and caffeine:p-formylphenoxypropionic acid [(caf)(p-fppa)] (3) were synthesized and studied by FT-IR, NMR, and single crystal XRD studies. The crystal system of cocrystal [(caf)(p-fpaa)] (1) is monoclinic with space group P21/n and Z = 16, that of cocrystal [(caf)(o-fpaa)]H2O (2) is triclinic with space group P − 1 and Z = 2, and that of cocrystal [(caf)(p-fppa)] (3) is monoclinic with space group P21/c and Z = 4. The imidazole–carboxylic acid synthon is observed in all the three cocrystals. The intermolecular hydrogen bonds, OH···N and π–π interactions together play a major role in stabilizing the crystal structure of all the three cocrystals. The biological activities of crystals 1–3 were studied.

► Imidazole–carboxylic acid synthon is present in all the three (1–3) cocrystals.
► Cocrystals (1–3) are stabilized by intermolecular H-bonding and π–π interactions.
► Caffeine and the corresponding acid are directly connected in 1 and 3.
► Cocrystal 2 contains a polymeric motif.
► Cocrystals 1–3 have slightly higher DPPH radical scavenging activity than caffeine.