Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N-6-Substituted Adenine

Co-crystal and salt formation of the kinetin analogue N-6-benzyladenine with the pharmaceutically acceptable co-crystal and salt formers maleic acid, oxalic acid, glutaric acid, succinic acid, benzoic acid, and fumaric acid has been studied by solid-state and solvent-drop grinding in combination with X-ray powder diffraction. In all cases, salt or co-crystal formation was observed. Single crystals of (bzadeH(+))(mal(-)) (1) and (bzadeH(+))(2)(ox(2-)) (2) were obtained by solution crystallization, and their X-ray structures are reported along with that of (ade(H+))(2)(mal(-))(2).ade center dot 2H(2)O (3) (bzadeH(+) = N-6-benzyladeninium, adeH(+) = adeninium, ade = adenine, mal(-) = hydrogen maleate, ox(2-) = oxalate). The hydrogen-bonding motifs in 1-3 are discussed. The salts contain a robust bzadeH(+)-carboxylate or ade-carboxylate R-2(2)(9) heterosynthon involving the protonated Hoogsteen sites (N6-H, N7-H) of bzadeH(+) and ade. Molecular recognition between the protonated Hoogsteen site and the carboxylate group stabilizes the unusual 7H,9H tautomer of bzadeH(+) in 2 and the noncanonical 7H-adenine tautomer in 3.