Controlling the Reactivity of a Metal-Hydroxo Adduct with a Hydrogen Bond

The enzymes manganese lipoxygenase (MnLOX) and manganese superoxide dismutase (MnSOD) utilize mononuclear Mn centers to effect their catalytic reactions. In the oxidized Mn^III state, the active site of each enzyme contains a hydroxo ligand, and X-ray crystal structures imply a hydrogen bond between this hydroxo ligand and a cis carboxylate ligand. While hydrogen bonding is a common feature of enzyme active sites, the importance of this particular hydroxo-carboxylate interaction is relatively unexplored. In this present study, we examined a pair of Mn^III-hydroxo complexes that differ by a single functional group. One of these complexes, [Mn^III(OH)(PaPy₂N)]⁺, contains a naphthyridinyl moiety capable of forming an intramolecular hydrogen bond with the hydroxo ligand. The second complex, [Mn^III(OH)(PaPy₂Q)]⁺, contains a quinolinyl moiety that does not permit any intramolecular hydrogen bonding. Spectroscopic characterization of these complexes supports a common structure, but with perturbations to [Mn^III(OH)(PaPy₂N)]⁺, consistent with a hydrogen bond. Kinetic studies using a variety of substrates with activated O-H bonds, revealed that [Mn^III(OH)(PaPy₂N)]⁺ is far more reactive than [Mn^III(OH)(PaPy₂Q)]⁺, with rate enhancements of 15-100-fold. A detailed analysis of the thermodynamic contributions to these reactions using DFT computations reveals that the former complex is significantly more basic. This increased basicity counteracts the more negative reduction potential of this complex, leading to a stronger O-H BDFE in the [Mn^II(OH₂)(PaPy₂N)]⁺ product. Thus, the differences in reactivity between [Mn^III(OH)(PaPy₂Q)]⁺ and [Mn^III(OH)(PaPy₂N)]⁺ can be understood on the basis of thermodynamic considerations, which are strongly influenced by the ability of the latter complex to form an intramolecular hydrogen bond.