Mechanistic Insights into Superoxide Dismutation Driven by Dinuclear Manganese Complexes: The Role of the Mn₂-Core

The dinuclear Mn₂(II,II)L₂-core (HL = 2-{[[di(2-pyridyl)methyl](methyl)amino]-methyl}phenol) has been recently reported to be the most active dual superoxide dismutase (SOD) and catalase (CAT) functional analogue, enabling cascade detoxification of the superoxide radical anion. Here, we investigated the mechanism of catalytic O₂^•– decomposition by two stereoisomers with the Mn₂(II,II)L₂-core, Mn₂L₂Ac and Mn₂L₂, in order to (i) precisely determine the catalytic SOD activity of the complexes, (ii) characterize the key intermediates involved in the dismutation process, and (iii) discriminate between single- and di-Mn center catalysis in relation to the configuration of the Mn₂-core. The conclusions drawn from low-temperature mass spectrometry, stopped-flow kinetics, cyclic voltammetry, water exchange ¹⁷O nuclear magnetic resonance (NMR), and electron paramagnetic resonance (EPR) analyses were supported by the structural characterization and quantum chemical analysis of the proposed reaction intermediates. This study allows us to determine k_cat for Mn₂L₂Ac and Mn₂L₂ (4.6 × 10⁷ and 2.2 × 10⁷ M^–1 s^–1, respectively, in 3-(N-morpholino)propanesulfonic acid (MOPS) at pH = 7.4) and detect the key intermediates involved in the catalytic cycle driven by these Mn₂-SOD mimics, highlighting the formation of a side-on η²–Mn₂(III,II)–peroxo, as an initial intermediate. The effects of the Mn₂(II,II)-core configuration on the SOD activity were discussed.