Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N6-Substituted Adenine

Co-crystal and salt formation of the kinetin analogue N6-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(ox2–) (2) were obtained by solution crystallization, and their X-ray structures are reported along with that of (adeH+)2(mal–)2·ade·2H2O (3) (bzadeH+ = N6-benzyladeninium, adeH+ = adeninium, ade = adenine, mal– = hydrogen maleate, ox2– = oxalate). The hydrogen-bonding motifs in 1–3 are discussed. The salts contain a robust bzadeH+-carboxylate or ade-carboxylate R22(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.