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) (nmp2− = 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 (2ox and 3ox) 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 (NiSODred), suggest that the transition from NiSODred to the five-coordinate oxidized form of NiSOD (NiSODox) may go through a four-coordinate Ni-•S(Cys) (NiSODox-Hisoff) that is stabilized by coordination to Ni(II).

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The complex Na[{Ni(nmp)}SBTA)] (1) (nmp = deprotonated form of N-(2-mercaptoethyl)picolinamide; HSBTA = N,N,N-tris(2-mercaptoethyl)benzene-1,3,5-tricarboxamide, where H = dissociable protons), supported by the thiolate-benzenetricarboxamide scaffold (SBTA), has been synthesized as a trimetallic model of nickel-containing superoxide dismutase (NiSOD). X-ray absorption spectroscopy (XAS) and H NMR measurements on 1 indicate that the Ni centers are square-planar with NS coordination, and Ni-N and Ni-S distances of 1.95 and 2.16 Å, respectively. Additional evidence from IR indicates the presence of H-bonds in 1 from the approximately -200 cm shift in ν from free ligand. The presence of H-bonds allows for speciation that is temperature-, concentration-, and solvent-dependent. In unbuffered water and at low temperature, a dimeric complex (1; λ = 410 nm) that aggregates through intermolecular NH···O═C bonds of BTA units is observed. Dissolution of 1 in pH 7.4 buffer or in unbuffered water at temperatures above 50 °C results in monomeric complex (1; λ = 367 nm) linked through intramolecular NH···S bonds. DFT computations indicate a low energy barrier between 1 and 1 with nearly identical frontier MOs and Ni-ligand metrics. Notably, 1 and 1 exhibit remarkable stability in protic solvents such as MeOH and HO, in stark contrast to monometallic [Ni(nmp)(SR)] complexes. The reactivity of 1 with excess O, HO, and O is species-dependent. IR and UV-vis reveal that 1 in MeOH reacts with excess O to yield an S-bound sulfinate, but does not react with O. In contrast, 1 is stable to O in pH 7.4 buffer, but reacts with O to yield a putative [Ni(nmp)(O)] complex from release of the BTA-thiolate based on EPR.