Mechanistic Insights into Amide Hydrogenation via Ru-PNNH Metal-Ligand Cooperation: A DFT Study.

Density functional theory (DFT) calculations were performed to elucidate the detailed mechanism of catalytic amide hydrogenation mediated by a Ru-PNNH complex bearing a tridentate ligand. Three key reactive sites were identified within the catalyst framework: the methylene group on the phosphine side arm (C1), the methylene group on the amine side arm (C4), and the amino group directly coordinated to the Ru center (N1). The catalytic cycle proceeds through three sequential stages: precatalyst activation, deamination, and aldehyde reduction. The deamination step in stage II, with a free energy barrier of 20.1 kcal/mol, is identified as the rate-determining step (RDS) of the overall catalysis. Among the three reactive sites, C4 shows the highest activity, serving as the key center for both the precatalyst activation and the aldehyde reduction stages. The Ru-coordinated amino group is crucial in the deamination stage, especially for C-N bond cleavage. Notably, a cooperative mechanism emerges during the deamination process, where C4 and N1 act in a complementary and alternating manner to drive the key steps. The synergistic interaction exemplifies metal-ligand cooperative catalysis, demonstrating how site-specific reactivity enhances the overall efficiency and selectivity of the transformation.