Supramolecular structures and tautomerism of carboxylate salts of adenine and pharmaceutically relevant N⁶-substituted adenine

Co-crystal and salt formation of the kinetin analogue N - 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 (adeH⁺)₂(mal^-)₂.ade·2H ₂O (3) (bzadeH⁺ = N⁶-benzyladeninium, adeH ⁺= adeninium, ade = adenine, mal^- = hydrogen maleate, ox² = oxalate. The hydrogen-bonding motifs in - 3 are discussed. The salts contain a robust bzade H-carboxylate or ade-carboxylate R₂ (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.