Switching between Inner- and Outer-Sphere PCET Mechanisms of Small-Molecule Activation: Superoxide Dismutation and Oxygen/Superoxide Reduction Reactivity Deriving from the Same Manganese Complex

Readily exchangeable water molecules
are commonly found in the
active sites of oxidoreductases, yet the overwhelming majority of
studies on small-molecule mimics of these enzymes entirely ignores
the contribution of water to the reactivity. Studies of how these
enzymes can continue to function in spite of the presence of highly
oxidizing species are likewise limited. The mononuclear MnII complex with the potentially hexadentate ligand N-(2-hydroxy-5-methylbenzyl)-N,N′,N′-tris­(2-pyridinylmethyl)-1,2-ethanediamine
(LOH) was previously found to act as both a H2O2-responsive MRI contrast agent and a mimic of superoxide
dismutase (SOD). Here, we studied this complex in aqueous solutions
at different pH values in order to determine its (i) acid–base
equilibria, (ii) coordination equilibria, (iii) substitution lability
and operative mechanisms for water exchange, (iv) redox behavior and
ability to participate in proton-coupled electron transfer (PCET)
reactions, (v) SOD activity and reductive activity toward both oxygen
and superoxide, and (vi) mechanism for its transformation into the
binuclear MnII complex with (H)OL–LOH and its hydroxylated derivatives. The conclusions drawn
from potentiometric titrations, low-temperature mass spectrometry,
temperature- and pressure-dependent 17O NMR spectroscopy,
electrochemistry, stopped-flow kinetic analyses, and EPR measurements
were supported by the structural characterization and quantum chemical
analysis of proposed intermediate species. These comprehensive studies
enabled us to determine how transiently bound water molecules impact
the rate and mechanism of SOD catalysis. Metal-bound water molecules
facilitate the PCET necessary for outer-sphere SOD activity. The absence
of the water ligand, conversely, enables the inner-sphere reduction
of both superoxide and dioxygen. The LOH complex maintains
its SOD activity in the presence of •OH and MnIV-oxo species by channeling these oxidants toward the synthesis
of a functionally equivalent binuclear MnII species.