Mechanochemical Hydrazone Synthesis From Isoniazid and Isophthalaldehyde: Kinetics and Process Optimization of a Competitive-Consecutive Reaction.

Mechanochemistry has emerged a greener and more efficient alternative to solution-based methods for hydrazone synthesis. However, prior studies have predominantly focused on final yields, reaction times, and biological activities, while giving limited attention to reaction kinetics and mixing quality effects, which are essential for process optimization. To address this gap, the present work elucidates the mechanochemical kinetics of hydrazones synthesis from isoniazid and isophthalaldehyde via competitive-consecutive pathways. Although such systems are widely employed in solution to characterize micromixing, no kinetic studies have yet been reported on competitive-consecutive reactions under mechanochemical conditions. In the present study, reactions were conducted in a vibratory ball mill (Pulverisette P0), and the effects of operating parameters on kinetics, yield, selectivity, and mixing quality were systematically assessed. These results were further compared to liquid-phase (EtOH/H2O) and solid-phase syntheses in the presence of a catalytic amount of water. Dry mechanochemical synthesis proceeded with zero-order kinetics, governed by the balance between energy input and mixing, reflecting an intermediate kinetic-mixing regime. Optimized dry grinding enabled faster conversion, further enhanced by catalytic water addition, while reducing environmental impact; however, liquid-phase selectivity remained superior due to more effective mixing.