Accessing Ni(III)-Thiolate Versus Ni(II)-Thiyl Bonding in a Family of Ni–N₂S₂ Synthetic Models of NiSOD

Superoxide dismutase (SOD) catalyzes the disproportionation of superoxide (O₂^• –) into H₂O₂ and O₂(g) by toggling through different oxidation states of a first-row transition metal ion at its active site. Ni-containing SODs (NiSODs) are a distinct class of this family of metalloenzymes due to the unusual coordination sphere that is comprised of mixed N/S-ligands from peptide-N and cysteine-S donor atoms. A central goal of our research is to understand the factors that govern reactive oxygen species (ROS) stability of the Ni–S­(Cys) bond in NiSOD utilizing a synthetic model approach. In light of the reactivity of metal-coordinated thiolates to ROS, several hypotheses have been proffered and include the coordination of His1-Nδ to the Ni­(II) and Ni­(III) forms of NiSOD, as well as hydrogen bonding or full protonation of a coordinated S­(Cys). In this work, we present NiSOD analogues of the general formula [Ni­(N₂S)­(SR′)]⁻, providing a variable location (SR′ = aryl thiolate) in the N₂S₂ basal plane coordination sphere where we have introduced o-amino and/or electron-withdrawing groups to intercept an oxidized Ni species. The synthesis, structure, and properties of the NiSOD model complexes (Et₄N)­[Ni­(nmp)­(SPh-o-NH₂)] (2), (Et₄N)­[Ni­(nmp)­(SPh-o-NH₂-p-CF₃)] (3), (Et₄N)­[Ni­(nmp)­(SPh-p-NH₂)] (4), and (Et₄N)­[Ni­(nmp)­(SPh-p-CF₃)] (5) (nmp^2– = dianion of N-(2-mercaptoethyl)­picolinamide) are reported. NiSOD model complexes with amino groups positioned ortho to the aryl-S in SR′ (2 and 3) afford oxidized species (2^ox and 3^ox) that are best described as a resonance hybrid between Ni­(III)-SR and Ni­(II)-^•SR based on ultraviolet–visible (UV-vis), magnetic circular dichroism (MCD), and electron paramagnetic resonance (EPR) spectroscopies, as well as density functional theory (DFT) calculations. The results presented here, demonstrating the high percentage of S­(3p) character in the highest occupied molecular orbital (HOMO) of the four-coordinate reduced form of NiSOD (NiSOD_red), suggest that the transition from NiSOD_red to the five-coordinate oxidized form of NiSOD (NiSOD_ox) may go through a four-coordinate Ni-^•S­(Cys) (NiSOD_ox-His_off) that is stabilized by coordination to Ni­(II).