فهرست نشریات علمی دسترسی آزاد ایران

Benzimidazole and its derivatives are widely utilized in medicinal chemistry. Despite their importance, the development of new synthetic methods for benzimidazole and its derivatives has often relied on trial-and-error approaches, largely because of an incomplete understanding of their synthesis pathways, mechanisms, transition states, and intermediates. In this work, we employ density functional theory (DFT) to investigate the electronic structures of reactants, transition states, intermediates, and products involved in benzimidazole synthesis. We calculate the barrier energy for the four elementary steps using the linear synchronous transit/quadratic synchronous transit (LST/QST) approach. Our results reveal that the dehydration steps exhibit lower barrier energies (TS2 = 27.97 and TS4 = 33.45 kcal·mol⁻¹) compared to the steps involving nitrogen attack on the carbon of formic acid to form the N−C bond (TS1 = 41.93 and TS3 = 45.85 kcal·mol⁻¹). In particular, the third elementary step, with a barrier energy of 45.85 kcal·mol⁻¹, emerges as the rate-determining step in benzimidazole synthesis. Further analysis of the three intermediates (I₁, I₂, I₃) with the quantum theory of atoms in molecules (QTAIM) method characterizes intramolecular hydrogen bonding and atomic charge distribution.