Mechanistic insights on hydrazones synthesis: a combined theoretical and experimental study†

Hydrazone derivatives of isoniazid have demonstrated potential as anti-tubercular agents. While previous studies have predominantly focused on their biological activity, existing literature lacks both experimental and computational studies on the mechanisms and kinetics of their syntheses. This study aims to address this gap by employing a combined computational and experimental approach to investigate the hydrazone synthesis from isoniazid and isophthalaldehyde through competitive-consecutive reactions. Density functional theory (DFT) calculations were performed to explore the possible reaction pathways and their energy profiles in both the gas phase, and with solvation. Experimental kinetic studies were conducted in a jacketed batch reactor using ethanol/water and dry acetonitrile to support the computational findings by assessing the impact of solvents on reaction dynamics. The computational results indicate that water has a catalytic effect on the reaction, not only by assisting in the rate-limiting step but also by avoiding high-energy isomerizations, required in its absence. Experimental kinetics in dry acetonitrile demonstrated a very slow reaction rate, while the ethanol/water system achieved higher conversion rates in the same amount of time, aligning with the computational findings. Experimentally determined activation energies closely matched the value predicted computationally.