Quantum chemical insights into reactivity trends of half-sandwich Os(II), Ru(II), Ir(III) and Rh(III) complexes: hydrolysis, cysteine binding, and NADH oxidation from DFT analysis.

Half-sandwich transition-metal complexes of Ru(II), Os(II), Ir(III) and Rh(III) represent versatile scaffolds in inorganic and bioinorganic chemistry due to their tunable coordination environments and potential as redox-active anticancer agents. Yet, a unified theoretical framework describing how metal identity and ancillary ligands jointly regulate their hydrolysis, substitution, and redox behavior remains lacking. In this work, density functional theory (DFT) calculations systematically dissect the mechanistic pathways of representative Ru(II), Os(II), Ir(III) and Rh(III) complexes bearing different bidentate ligands. Three biologically relevant reactions-ligand hydrolysis, cysteine coordination, and NADH oxidation-are explored to reveal how metal-ligand electronic interactions govern reactivity. The hydrolytic activation barriers follow the trend Ru(II) < Os(II) < Rh(III) < Ir(III), with the 4-methylpicolinate-containing Ru(II) complex (Ru3) exhibiting the lowest barrier (18.5 kcal mol), while bipyridine-based species show the highest inertness. All complexes readily bind cysteine associative substitution pathways; notably, the Ir(III)-phpy complex displays an exceptionally low barrier (2.5 kcal mol) due to its strong influence and favorable charge transfer. NADH oxidation proceeds through a two-step hydride transfer mechanism, with 4-methylpicolinate ligands consistently lowering the overall free-energy barrier (Δ), and Ru(II) species exhibiting the highest redox flexibility among the three metals. Collectively, these results establish quantitative structure-reactivity relationships linking metal electrophilicity, ligand field effects, and catalytic adaptability, providing mechanistic insights that guide the rational design of redox-active half-sandwich complexes for biomedical and catalytic applications.