Mildness in preparative conditions directly affects the otherwise straightforward syntheses outcome of Schiff-base isoniazid derivatives: Aroylhydrazones and their solvolysis-related dihydrazones

Abstract

Aroylhydrazones are versatile compounds with a series of applications, from biological to technological spheres. The simplicity of their preparation allows for a great chemical variability and synthetic manageability. However, the process can be not as straightforward as one would imagine. Some parameters such as specific reactants, the amount of acid employed as catalyst and reaction temperature can have a direct impact on the obtained product. In the present work, we describe two series of novel isoniazid-derived compounds prepared from a pair of different aldehyde precursors, as well as the solvolysis, under harsh synthetic conditions, of the initially formed aroylhydrazones, leading to unexpected dihydrazones. All compounds were unequivocally characterized in solution using 1D and 2D NMR experiments in DMSO‑d6 and, in the solid-state, by other classic techniques. System I is composed by 2-(1H-pyrazol-1-yl)benzaldehyde and its hydrazone derivatives, while system II comprises 2-(4-metoxyphenoxy)benzaldehyde and its related Schiff-base products. The first aldehyde was obtained for the first time via the copper-catalyzed Ullmann C–N coupling between 2-bromobenzaldehyde and pyrazole. Single crystals of its aroylhydrazone and dihydrazone derivatives were isolated and thoroughly characterized, including Hirshfeld surfaces and energy frameworks studies. Finally, we describe an NMR and theoretically-based proposed reaction pathway for the unexpected formation of the dihydrazones involving the solvolysis of the initially formed isonicotinoyl hydrazone followed by attack to a second free aldehyde molecule.