Redox-gated thermodynamic trap: design principles for diruthenium paddlewheel metallodrugs exploiting Ru(III)Ru(III)...

The development of highly selective coordination complexes requires a precise understanding of how electronic structure dictates ligand affinity. We employ density functional theory (DFT) and conceptual DFT (cDFT) to elucidate the structural and redox-driven mechanisms of diruthenium paddlewheel complexes. Our analysis reveals a critical electronic-structural switch: the cationic Ru(III)Ru(III) core is paradoxically the softest Lewis acid among all accessible redox states. This finding contravenes simple electrostatic predictions of the Hard and Soft Acids and Bases (HSAB) principle, demonstrating that the significant Ru-Ru bond contraction upon oxidation (from 2.24 Å to 2.19 Å) dominates the electronic structure, creating a highly polarizable Lewis acid center. This unique structural property dictates a pronounced thermodynamic affinity for soft nucleophiles like cysteine (Cys) and selenocysteine (Sec), yielding highly exergonic substitution energies of -33.3 and -26.6 kcal mol^-1, respectively. We characterize this mechanism as a redox-gated thermodynamic trap, where the complex remains in a lower-affinity state until localized oxidation "switches on" the maximally potent Ru(III)Ru(III) form. Detailed frontier molecular orbital analysis confirms that the lowering of the d_z² orbital energy and the availability of empty d_π orbitals in the oxidized state enable superior σ-donation and π-acceptance. These results provide quantitative structural design principles, demonstrating that tuning the equatorial ligands to control oxidation potentials is key to ensuring site-specific activation and irreversible binding to soft biological targets.