cis-Carboxylate Enhancement of Mn(III)-OH Hydrogen Atom Abstraction through PCET Thermodynamics

Manganese(III)-hydroxo intermediates are proposed as key hydrogen atom abstraction (HAA) species in manganese-dependent enzymes, yet how first-sphere carboxylate ligands control their proton-coupled electron transfer (PCET) thermodynamics remains poorly understood. Here, a cis-(carboxylato)(hydroxo) manganese(III) complex, [Mn^III(TBDAP)(OH)(C₆H₅COO)]⁺ (1), is investigated as a functional model of the manganese lipoxygenase active site. Comparison with an alkoxide analogue, [Mn^III(TBDAP)(OH)(C₆H₅CH₂O)]⁺ (2), reveals a 3000-fold enhancement in HAA reactivity and a large kinetic isotope effect consistent with tunneling-assisted hydrogen transfer. Redox titration experiments and density functional theory (DFT) calculations support a cooperative thermodynamic contribution involving a positive shift in Mn^III/II redox potential and a computationally predicted increase in hydroxo pK_a associated with intramolecular hydrogen bonding, leading to an increased O-H bond dissociation free energy. Para-substituted benzoate derivatives show only modest changes in HAA rates despite electronic perturbations, consistent with possible partial thermodynamic compensation. The results highlight the role of first-sphere ligand environments in regulating metal-hydroxo reactivity through PCET thermodynamics and provide design principles for biological and synthetic oxidation chemistry. A structurally defined cis-carboxylate dramatically enhances the hydrogen atom abstraction reactivity of a Mn(III)-OH complex. A 3000-fold rate acceleration, combined with redox measurements and DFT calculations, reveals cooperative control of PCET thermodynamics and provides insight into how first-sphere carboxylate ligands tune biologically relevant metal-hydroxo intermediates.