Synthesis, tautomeric forms, specific intermolecular interactions, and lipophilicity of methylated 6-hydroxypyridazine-3-carboxylic acid and its 4,5-dihydro analogs

Abstract Effects of methylation for intermolecular interactions and lipophilicity have been studied for a series of methylated 4,5-dihydro-6-hydroxypyridazine-3-carboxylic and 6-hydroxypyridazine-3-carboxylic acids ( 1 and 2 ). In solution they exist in equilibrium of the lactam and lactim tautomers, with the reverse preferences for analogs 1 and 2 , which affect the syntheses of their methylated derivatives. Carboxylic acid 2 preferably crystallizes as a hydrate, built of carboxylate anions and hydronium cations 2 − H 3 O + , hydrogen bonded into catemeric patterns involving both ions. In methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate ( 4A ) the molecules are NH⋯O hydrogen bonded into chains. In both structures 2 − H 3 O + and 4A , there are relatively strong CH⋯O hydrogen bonds, arranging the molecules into sheets. The increased lipophilicity of the methylated derivatives has been correlated with the formation of CH⋯O bonds.