Strategies for limiting, or reversing, the degradation of airsensitive, base metal catalysts for the hydrogen evolution/oxidation reaction on contact with adventitious O 2 are guided by nature′s design of hydrogenase active sites. The affinity of oxygen for sulfur and selenium, in [NiFeS]-and [NiFeSe]-H 2 ase, yields oxygenated chalcogens under aerobic conditions, and delays irreversible oxygen damage at the metals by maintaining the NiFe core structures. To identify the controlling features of S-site oxygen uptake, related Ni(μ-E PhX )(μ-S′ N2 )Fe (E = S or Se, Fe = (η 5 -C 5 H 5 )Fe II (CO)) complexes were electronically tuned by the parasubstituent on μ-EPhX (X = CF 3 , Cl, H, OMe, NMe 2 ) and compared in aspects of communication between Ni and Fe. Both single and double O atom uptake at the chalcogens led to the conversion of the four-membered ring core, Ni(μ-E PhX )(μ-S′ N2 )Fe, to a five-membered ring Ni−O−E−Fe−S′, where an O atom inserts between E and Ni. In the E = S, X = NMe 2 case, the two-oxygen uptake complex was isolated and characterized as the sulfinato species with the second O of the O 2 S Ph-NMe2 unit pointing out of the five-membered Ni−O−S− Fe−S′ ring. Qualitative rates of reaction and ratios of oxygen-uptake products correlate with Hammett parameters of the X substituent on E PhX . Density functional theory computational results support the observed remote effects on the NiFe core reactivity; the more electron-rich sulfurs are more O 2 responsive in the S PhX series; the selenium analogues were even more reactive with O 2 . Mass spectral analysis of the sulfinato products using a mixture of 18 O 2 / 16 O 2 suggests a concerted mechanism in O 2 addition. Deoxygenation, by reduction or O atom abstraction reagents, occurs for the 1-O addition complexes, while the 2-O, sulfinato, analogues are inert. The abstraction of oxygen from the 1-O, sulfenato species, is related to oxygen repair in soluble, NAD + -reducing [NiFe]-H 2 ase (

Recent studies have uncovered the therapeutic potential of elesclomol (ES), a copper-ionophore, for copper deficiency disorders. However, we currently do not understand the mechanism by which copper brought into cells as ES–Cu(II) is released and delivered to cuproenzymes present in different subcellular compartments. Here, we have utilized a combination of genetic, biochemical, and cell-biological approaches to demonstrate that intracellular release of copper from ES occurs inside and outside of mitochondria. The mitochondrial matrix reductase, FDX1, catalyzes the reduction of ES–Cu(II) to Cu(I), releasing it into mitochondria where it is bioavailable for the metalation of mitochondrial cuproenzyme— cytochrome c oxidase. Consistently, ES fails to rescue cytochrome c oxidase abundance and activity in copper-deficient cells lacking FDX1. In the absence of FDX1, the ES-dependent increase in cellular copper is attenuated but not abolished. Thus, ES-mediated copper delivery to nonmitochondrial cuproproteins continues even in the absence of FDX1, suggesting alternate mechanism(s) of copper release. Importantly, we demonstrate that this mechanism of copper transport by ES is distinct from other clinically used copper-transporting drugs. Our study uncovers a unique mode of intracellular copper delivery by ES and may further aid in repurposing this anticancer drug for copper deficiency disorders.

With the goal of generating anionic analogues to MN2S2⋅Mn(CO)3Br we introduced metallodithiolate ligands, MN2S22− prepared from the Cys‐X‐Cys biomimetic, ema4− ligand (ema=N,N′‐ethylenebis(mercaptoacetamide); M=NiII, [VIV≡O]2+ and FeIII) to Mn(CO)5Br. An unexpected, remarkably stable dimanganese product, (H2N2(CH2C=O(μ‐S))2)[Mn(CO)3]2 resulted from loss of M originally residing in the N2S24− pocket, replaced by protonation at the amido nitrogens, generating H2ema2−. Accordingly, the ema ligand has switched its coordination mode from an N2S24− cavity holding a single metal, to a binucleating H2ema2− with bridging sulfurs and carboxamide oxygens within Mn‐μ‐S‐CH2‐C‐O, 5‐membered rings. In situ metal‐templating by zinc ions gives quantitative yields of the Mn2 product. By computational studies we compared the conformations of “linear” ema4− to ema4− frozen in the “tight‐loop” around single metals, and to the “looser” fold possible for H2ema2− that is the optimal arrangement for binucleation. XRD molecular structures show extensive H‐bonding at the amido‐nitrogen protons in the solid state.

Occasioned by the discovery of a ligand transfer from M­(N2S2) to MnI in Mn­(CO)5Br, the resulting H2N2S2 ligand-tethered dimanganese complex, (μ4-N,N′-ethylenebis­(mercaptoacetamide))­[Mn2(CO)6], was found to have myriad analogues of the type (μ-S–E)2[Mn2(CO)6], making up an under-studied class containing Mn2S2 rhombs. The attempt to synthesize a nontethered version resulted in a solid-state structure in an anti-conformation. However, a direct comparison of the Fourier-transform infrared spectra of the tethered versus nontethered complexes in combination with theoretical frequency calculation suggested the coexistence of syn- and anti-isomers and their interconversion in solution. Analysis of the syn- versus anti-version of the dimanganese components led to the understanding that whereas the anti-form exists as centrosymmetric RS isomers, the syn-form is restricted by C2 symmetry to be either RR or SS. Molecular scrambling experiments indicated monomeric, pentacoordinate, 16-e– (S–O)­Mn­(CO)3 intermediates with lifetimes sufficiently long to sample R and S monomers. Density functional theory analysis of the mechanistic pathway and a kinetic study corroborated that the proposed isomerization involves the cleavage and reformation of the dimeric structures.

With the goal of generating anionic analogues to MN2S2⋅Mn(CO)3Br we introduced metallodithiolate ligands, MN2S22− prepared from the Cys‐X‐Cys biomimetic, ema4− ligand (ema=N,N′‐ethylenebis(mercaptoacetamide); M=NiII, [VIV≡O]2+ and FeIII) to Mn(CO)5Br. An unexpected, remarkably stable dimanganese product, (H2N2(CH2C=O(μ‐S))2)[Mn(CO)3]2 resulted from loss of M originally residing in the N2S24− pocket, replaced by protonation at the amido nitrogens, generating H2ema2−. Accordingly, the ema ligand has switched its coordination mode from an N2S24− cavity holding a single metal, to a binucleating H2ema2− with bridging sulfurs and carboxamide oxygens within Mn‐μ‐S‐CH2‐C‐O, 5‐membered rings. In situ metal‐templating by zinc ions gives quantitative yields of the Mn2 product. By computational studies we compared the conformations of “linear” ema4− to ema4− frozen in the “tight‐loop” around single metals, and to the “looser” fold possible for H2ema2− that is the optimal arrangement for binucleation. XRD molecular structures show extensive H‐bonding at the amido‐nitrogen protons in the solid state.