The complex Na3[{NiII(nmp)}3S3BTAalk)] (1) (nmp2– = deprotonated form of N-(2-mercaptoethyl)picolinamide; H3S3BTAalk = N1,N3,N5-tris(2-mercaptoethyl)benzene-1,3,5-tricarboxamide, where H = dissociable protons), supported by the thiolate-benzenetricarboxamide scaffold (S3BTAalk), has been synthesized as a trimetallic model of nickel-containing superoxide dismutase (NiSOD). X-ray absorption spectroscopy (XAS) and 1H NMR measurements on 1 indicate that the NiII centers are square-planar with N2S2 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–1 shift in νNH 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 (1A; 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 (1M; λ = 367 nm) linked through intramolecular NH···S bonds. DFT computations indicate a low energy barrier between 1A and 1M with nearly identical frontier MOs and Ni–ligand metrics. Notably, 1A and 1M exhibit remarkable stability in protic solvents such as MeOH and H2O, in stark contrast to monometallic [NiII(nmp)(SR)]− complexes. The reactivity of 1 with excess O2, H2O2, and O2•– is species-dependent. IR and UV–vis reveal that 1A in MeOH reacts with excess O2 to yield an S-bound sulfinate, but does not react with O2•–. In contrast, 1M is stable to O2 in pH 7.4 buffer, but reacts with O2•– to yield a putative [NiII(nmp)(O2)]− complex from release of the BTA-thiolate based on EPR.

Ni-containing superoxide dismutase (NiSOD) represents an unusual member of the SOD family due to the presence of oxygen-sensitive Ni–SCys bonds at its active site. Reported in this account is the synthesis and properties of the NiII complex of the N3S2 ligand [N3S2Me2]3– ([N3S2Me2]3– = deprotonated form of 2-((2-mercapto-2-methylpropyl)(pyridin-2-ylmethyl)amino)-N-(2-mercaptoethyl)acetamide), namely Na[Ni(N3S2Me2)] (2), as a NiSOD model that features sterically robust gem-(CH3)2 groups on the thiolate α-C positioned trans to the carboxamide. The crystal structure of 2, coupled with spectroscopic measurements from 1H NMR, X-ray absorption, IR, UV–vis, and mass spectrometry (MS), reveal a planar NiII (S = 0) ion coordinated by only the N2S2 basal donors of the N3S2 ligand. While the structure and spectroscopic properties of 2 resemble those of NiSODred and other models, the asymmetric S ligands open up new reaction paths upon chemical oxidation. One unusual oxidation product is the planar NiII–N3S complex [Ni(Lox)] (5; Lox = 2-(5,5-dimethyl-2-(pyridin-2-yl)thiazolidin-3-yl)-N-(2-mercaptoethyl)acetamide), where two-electron oxidation takes place at the substituted thiolate and py-CH2 carbon to generate a thiazolidine heterocycle. Electrochemical measurements of 2 reveal irreversible events wholly consistent with thiolate redox, which were identified by comparison to the ZnII complex Na[Zn(N3S2Me2)] (3). Although no reaction is observed between 2 and azide, reaction of 2 with superoxide produces multiple products on the basis of UV–vis and MS data, one of which is 5. Density functional theory (DFT) computations suggest that the HOMO in 2 is π* with primary contributions from Ni-dπ/S-pπ orbitals. These contributions can be modulated and biased toward Ni when electron-withdrawing groups are placed on the thiolate α-C. Analysis of the oxidized five-coordinate species 2ox* by DFT reveal a singly occupied spin-up (α) MO that is largely thiolate based, which supports the proposed NiIII-thiolate/NiII-thiyl radical intermediates that ultimately yield 5 and other products.

Metal-nitroxyl (M–HNO/M–NO–) coordination units are found in denitrification enzymes of the global nitrogen cycle, and free HNO exhibits pharmacological properties related to cardiovascular physiology that are distinct from nitric oxide (NO). To elucidate the properties that control the binding and release of coordinated nitroxyl or its anion at these biological metal sites, we synthesized {CoNO}8 (1, 2) and {CoNO}9 (3, 4) complexes that contain diimine–dipyrrolide supporting ligands. Experimental (NMR, IR, MS, EPR, XAS, XRD) and computational data (DFT) support an oxidation state assignment for 3 and 4 of high spin CoII (SCo = 3/2) coordinated to 3NO– (SNO = 1) for Stot = 1/2. As suggested by DFT, upon protonation, a spin transition occurs to generate a putative low spin CoII–1HNO (SCo = Stot = 1/2); the Co–NO bond is ∼0.2 Å longer, more labile, and facilitates the release of HNO. This property was confirmed experimentally through the detection and quantification of N2O (∼70% yield), a byproduct of the established HNO self-reaction (2HNO → N2O + H2O). Additionally, 3 and 4 function as HNO donors in aqueous media at pH 7.4 and react with known HNO targets, such as a water-soluble MnIII-porphyrin ([MnIII(TPPS)]3–; TPPS = meso-tetrakis(4-sulfonatophenyl)porphyrinate) and ferric myoglobin (metMb) to quantitatively yield [Mn(TPPS)(NO)]4– and MbNO, respectively.

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).

The reactivity of free NO (NO+, NO•, and NO–) with thiols (RSH) is relatively well understood, and the oxidation state of the NO moiety generally determines the outcome of the reaction. However, NO/RSH interactions are often mediated at metal centers, and the fate of these species when bound to a first-row transition metal (e.g., Fe, Co) deserves further investigation. Some metal-bound NO moieties (particularly NO+, yielding S-nitrosothiols) have been more thoroughly studied, yet the fate of these species remains highly condition-dependent and, for M–NO–, an unexplored field. Herein, we present an overview of thiol reactions with metal nitrosyls that result in N–O bond activation, ligand substitution on {MNO} fragments, and/or redox chemistry. We also present our results pertaining to the thiol reactivity of nonheme {FeNO}7/8 complexes [Fe(LN4pr)(NO)]−/0 (1 and 2) and the noncorrin {CoNO}8 complex [Co(LN4pr)(NO)] (3), an isoelectronic analogue of the {FeNO}8 complex 1. Among other products, the reaction of 1 with p-ClPhSH affords [Fe2(μ-SPh-p-Cl)2(NO)4]− (anion of 6), a reduced Roussin’s red ester (rRRE), which was characterized by Fourier transform infrared (FTIR), UV–vis, electron paramagnetic resonance (EPR), and X-ray diffraction. Similarly, the reaction of 1 with glutathione in buffer affords the corresponding rRRE, which has also been spectroscopically characterized by EPR and UV–vis. The oxidation states of the metals and nitrosyls both contribute to the complex nature of these interactions, and as such, we discuss the varying product distribution accordingly. These studies shed insight into the products that may form through MNO/RSH interactions that lead to NOx activation and {MNO} redox.

Research on the one-electron reduced analogue of NO, namely nitroxyl (HNO/NO–), has revealed distinguishing properties regarding its utility as a therapeutic. However, the fleeting nature of HNO requires the design of donor molecules. Metal nitrosyl (MNO) complexes could serve as potential HNO donors. The synthesis, spectroscopic/structural characterization, and HNO donor properties of a {CoNO}8 complex in a pyrrole/imine ligand frame are reported. The {CoNO}8 complex [Co(LN4PhCl)(NO)] (1) does not react with established HNO targets such as FeIII hemes or Ph3P. However, in the presence of stoichiometric H+ 1 behaves as an HNO donor. Complex 1 readily reacts with [Fe(TPP)Cl] or Ph3P to afford the {FeNO}7 porphyrin or Ph3P═O/Ph3P═NH, respectively. In the absence of an HNO target, the {Co(NO)2}10 dinitrosyl (3) is the end product. Complex 1 also reacts with O2 to yield the corresponding CoIII-η1-ONO2 (2) nitrato analogue. This report is the first to suggest an HNO donor role for {CoNO}8 with biotargets such as FeIII-porphyrins.

The selective reduction of nitrite (NO2–) to nitric oxide (NO) is a fundamentally important chemical transformation related to environmental remediation of NOx and mammalian blood flow. We report the synthesis and characterization of two nonheme Fe complexes, [Fe(LN4Im)(MeCN)2](BF4)2 (1MeCN) and [Fe(LN4Im)(NO2)2] (2), geared toward understanding the NO2– to NO conversion. Complex 2 represents the first structurally characterized FeII complex with two axial NO2– ligands that functions as a nitrite reduction catalyst.

The EPA has established a maximum contaminant level (MCL) of 10 ppb for arsenic (As) in drinking water requiring sensitive and selective detection methodologies. To tackle this challenge, we have been active in constructing small molecules that react specifically with As3+ to furnish a new fluorescent species (termed a chemodosimeter). We report in this contribution, the synthesis and spectroscopy of two small-molecule fluorescent probes that we term ArsenoFluors (or AFs) as As-specific chemodosimeters. The AFs (AF1 and AF2) incorporate a coumarin fluorescent reporter coupled with an As-reactive benzothiazoline functional group. AFs react with As3+ to yield the highly fluorescent coumarin-6 dye (C6) resulting in a 20–25-fold fluorescence enhancement at λem ∼ 500 nm with detection limits of 0.14–0.23 ppb in tetrahydrofuran (THF) at 298 K. The AFs also react with common environmental As3+ sources such as sodium arsenite in a THF/CHES (N-cyclohexyl-2-aminoethanesulfonic acid) (1:1, pH 9, 298 K) mixture resulting in a modest fluorescence turn-ON (1.5- to 3-fold) due to the quenched nature of coumarin-6 derivatives in high polarity solvents. Bulk analysis of the reaction of the AFs with As3+ revealed that the C6 derivatives and the Schiff-base disulfide of the AFs (SB1 and SB2) are the ultimate end-products of this chemistry with the formation of C6 being the principle photoproduct responsible for the As3+-specific turn-ON. It appears that a likely species that is traversed in the reaction path is an As–hydride–ligand complex that is a putative intermediate in the proposed reaction path.

The biochemical properties of nitroxyl (HNO/NO−) are distinct from nitric oxide (NO). Metal centers, particularly Fe, appear as suitable sites of HNO activity, both for generation and targeting. Furthermore, reduced Fe–NO−/Fe–HNO or {FeNO}8 (Enemark–Feltham notation) species offer unique bonding profiles that are of fundamental importance. Given the unique chemical properties of {FeNO}8 systems, we describe herein the synthesis and properties of {FeNO}7 and {FeNO}8 non-heme complexes containing pyrrole donors that display heme-like properties, namely [Fe(LN4R)(NO)] (R = C6H4 or Ph for 3; and R = 4,5-Cl2C6H2 or PhCl for 4) and K[Fe(LN4R)(NO)] (R = Ph for 5; R = PhCl for 6). X-ray crystallography establishes that the Fe–N–O angle is ~ 155° for 3, which is atypical for low-spin square-pyramidal {FeNO}7 species. Both 3 and 4 display νNO at ~ 1700 cm− 1 in the IR and reversible diffusion-controlled cyclic voltammograms (CVs) (E1/2 = ~− 1.20 V vs. Fc/Fc+ (ferrocene/ferrocenium redox couple) in MeCN) suggesting that the {FeNO}8 compounds 5 and 6 are stable on the CV timescale. Reduction of 3 and 4 with stoichiometric KC8 provided the {FeNO}8 compounds 5 and 6 in near quantitative yield, which were characterized by the shift in νNO to 1667 and ~ 1580 cm− 1, respectively. While the νNO for 6 is consistent with FeNO reduction, the νNO for 5 appears more indicative of ligand-based reduction. Additionally, 5 and 6 engage in HNO-like chemistry in their reactions with ferric porphyrins [FeIII(TPP)X] (TPP = tetraphenylporphyrin; X = Cl−, OTf− (trifluoromethanesulfonate anion or CF3SO3−)) to form [Fe(TPP)NO] in stoichiometric yield via reductive nitrosylation.Isolable {FeNO}8 complexes could be accessed by reduction of their corresponding {FeNO}7 compounds and demonstrate nitroxyl-like reaction behavior.Highlights► {FeNO}7 and {FeNO}8 complexes were synthesized, isolated, and characterized at RT. ► Stability of {FeNO}8 complexes is mediated by the supporting ancillary ligands. ► {FeNO}8 complexes exhibit HNO-like reactivity with Fe(III) porphyrins. ► Fe-coordinated nitroxyl is an effective way to deliver HNO or NO− to ferric hemes.

Nickel-containing superoxide dismutases (NiSODs) represent a novel approach to the detoxification of superoxide in biology and thus contribute to the biodiversity of mechanisms for the removal of reactive oxygen species (ROS). While Ni ions play critical roles in anaerobic microbial redox (hydrogenases and CO dehydrogenase/acetyl coenzyme A synthase), they have never been associated with oxygen metabolism. Several SODs have been characterized from numerous sources and are classified by their catalytic metal as Cu/ZnSOD, MnSOD, or FeSOD. Whereas aqueous solutions of Cu(II), Mn(II), and Fe(II) ions are capable of catalyzing the dismutation of superoxide, solutions of Ni(II) are not. Nonetheless, NiSOD catalyzes the reaction at the diffusion-controlled limit (∼109 M–1 s–1). To do this, nature has created a Ni coordination unit with the appropriate Ni(III/II) redox potential (∼0.090 V vs Ag/AgCl). This potential is achieved by a unique ligand set comprised of residues from the N-terminus of the protein: Cys2 and Cys6 thiolates, the amino terminus and imidazole side chain of His1, and a peptide N-donor from Cys2. Over the past several years, synthetic modeling efforts by several groups have provided insight into understanding the intrinsic properties of this unusual Ni coordination site. Such analogues have revealed information regarding the (i) electrochemical properties that support Ni-based redox, (ii) oxidative protection and/or stability of the coordinated CysS ligands, (iii) probable H+ sources for H2O2 formation, and (iv) nature of the Ni coordination geometry throughout catalysis. This review includes the results and implications of such biomimetic work as it pertains to the structure and function of NiSOD.

Reduced nitrogen oxide ligands such as NO−/HNO or nitroxyl participate in chemistry distinct from nitric oxide (NO). Nitroxyl has been proposed to form at heme centers to generate the Enemark–Feltham designated {FeNO}8 system. The synthesis of a thermally stable {FeNO}8 species namely, [Co(Cp*)2][Fe(LN4)(NO)] (3), housed in a heme-like ligand platform has been achieved by reduction of the corresponding {FeNO}7 complex, [Fe(LN4)(NO)] (1), with decamethylcobaltocene [Co(Cp*)2] in toluene. This complex readily reacts with metMb, resulting in formation of MbNO via reductive nitrosylation by the coordinated HNO/NO−, which can be inhibited with GSH. These results suggest that 3 could serve as a potential HNO therapeutic. Spectroscopic, theoretical, and structural comparisons are made to 1 and the {CoNO}8 complex, [Co(LN4)(NO)] (2), an isoelectronic analogue of 3.

Arsenic contamination is a leading environmental problem. As such, levels of this toxic metalloid must be constantly monitored by reliable and low-cost methodologies. Because the currently accepted upper limit for arsenic in water is 10 ppb, very sensitive and selective detection strategies must be developed. Herein we describe the synthesis and characterization of a fluorescent chemical probe, namely, ArsenoFluor1, which is the first example of a chemosensor for As3+ detection in organic solvents at 298 K. AF1 exhibits a 25-fold fluorescence increase in the presence of As3+ at λem = 496 nm in THF, which is selective for As3+ over other biologically relevant ions (such as Na+, Mg2+, Fe2+, and Zn2+) and displays a sub-ppb detection limit.

We have prepared and characterized a Ni complex with an N3S2 ligand set (1) that represents the first isolable synthetic model of the reduced form of the Ni-SOD (SOD = superoxide dismutase) active site featuring all relevant donor functionality in the proper spatial distribution. As revealed by X-ray crystallography, the axial py-N donor of 1 does not bind NiII in the solid state or in solution like SOD. Oxidation of 1 provides a disulfide-linked dinuclear species, [{Ni(N3S2)}2] (2), which we have isolated and characterized. Moreover, the 1 → 2 conversion is reversible, much like redox cycling in the enzyme.

Nickel superoxide dismutase (Ni–SOD) catalyzes the disproportionation of the superoxide radical to O2 and H2O2 utilizing the Ni(III/II) redox couple. The Ni center in Ni–SOD resides in an unusual coordination environment that is distinct from other SODs. In the reduced state (Ni–SODred), Ni(II) is ligated to a primary amine-N from His1, anionic carboxamido-N/thiolato-S from Cys2, and a second thiolato-S from Cys6 to complete a NiN2S2 square-planar coordination motif. Utilizing the dipeptide N2S2– ligand, H2N-Gly-l-Cys-OMe (GC-OMeH2), an accurate model of the structural and electronic contributions provided by His1 and Cys2 in Ni–SODred, we constructed the dinuclear sulfur-bridged metallosynthon, [Ni2(GC-OMe)2] (1). From 1 we prepared the following monomeric Ni(II)–N2S2 complexes: K[Ni(GC-OMe)(SC6H4-p-Cl)] (2), K[Ni(GC-OMe)(StBu)] (3), K[Ni(GC-OMe)(SC6H4-p-OMe)] (4), and K[Ni(GC-OMe)(SNAc)] (5). The design strategy in utilizing GC-OMe2– is analogous to one which we reported before (see Inorg. Chem.2009, 48, 5620 and Inorg. Chem. 2010, 49, 7080) where Ni–SODred active site mimics can be assembled at will with electronically variant RS– ligands. Discussed herein is our initial account pertaining to the aqueous behavior of isolable, small-molecule Ni–SOD model complexes (non-maquette based). Spectroscopic (FTIR, UV–vis, ESI-MS, XAS) and electrochemical (CV) measurements suggest that 2–5 successfully simulate many of the electronic features of Ni–SODred. Furthermore, the aqueous studies reveal a dynamic behavior with regard to RS– lability and bridging interactions, suggesting a stabilizing role brought about by the protein architecture.

An air-stable eight-coordinate (8C) Mn(II)N8 complex has been synthesized utilizing an N4imidazole/imine ligand. The 8C dodecahedral geometry is structurally robust as the Mn complex is stable to air, NO(g), and potential coordinating anions. The structural, spectroscopic and water relaxivity properties of this complex are reported.

An air-stable eight-coordinate (8C) Mn(II)N8 complex has been synthesized utilizing an N4imidazole/imine ligand. The 8C dodecahedral geometry is structurally robust as the Mn complex is stable to air, NO(g), and potential coordinating anions. The structural, spectroscopic and water relaxivity properties of this complex are reported.

Reduced nitrogen oxide ligands such as NO−/HNO or nitroxyl participate in chemistry distinct from nitric oxide (NO). Nitroxyl has been proposed to form at heme centers to generate the Enemark–Feltham designated {FeNO}8 system. The synthesis of a thermally stable {FeNO}8 species namely, [Co(Cp*)2][Fe(LN4)(NO)] (3), housed in a heme-like ligand platform has been achieved by reduction of the corresponding {FeNO}7 complex, [Fe(LN4)(NO)] (1), with decamethylcobaltocene [Co(Cp*)2] in toluene. This complex readily reacts with metMb, resulting in formation of MbNO via reductive nitrosylation by the coordinated HNO/NO−, which can be inhibited with GSH. These results suggest that 3 could serve as a potential HNO therapeutic. Spectroscopic, theoretical, and structural comparisons are made to 1 and the {CoNO}8 complex, [Co(LN4)(NO)] (2), an isoelectronic analogue of 3.