Site specific redox properties in ligand differentiated di-nickel complexes inspired by the acetyl CoA synthase active site.

Bimetallic transition metal complexes with site-specific redox properties offer a versatile platform for understanding electron polarization, intramolecular electron transfer processes, and customizing electronic and magnetic properties that might impact reactivity and catalyst design. Inspired by the dissymmetric nickel sites in the Acetyl CoA Synthase (ACS) Active Site, three new bimetallic Ni(N2S2)-Ni(S2C2R2) complexes based on Ni(N2S2) metalloligand donor synthons, Nid, in mimicry of the nickel site distal to the redox-active iron sulfur cluster of ACS, and nickel dithiolene receiver units, designated as Nip, the nickel proximal to the 4Fe4S cluster, were combined to explore the influence of ligand environment on electronic structure and redox properties of each unit. The combination of synthons gave a matrix of three S-bridged dinickel complexes, characterized by X-ray crystallography, and appropriate spectroscopies. Computational modeling is connected to the electronic characteristics of the nickel donor and receiver units. This study demonstrated the intricacies of identifying sites of electrochemical redox processes, within multi-metallic systems containing non-innocent ligands.

Development of (NO)Fe(N2S2) as a Metallodithiolate Spin Probe Ligand: A Case Study Approach.

ConspectusThe ubiquity of sulfur-metal connections in nature inspires the design of bi- and multimetallic systems in synthetic inorganic chemistry. Common motifs for biocatalysts developed in evolutionary biology include the placement of metals in close proximity with flexible sulfur bridges as well as the presence of π-acidic/delocalizing ligands. This Account will delve into the development of a (NO)Fe(N2S2) metallodithiolate ligand that harnesses these principles. The Fe(NO) unit is the centroid of a N2S2 donor field, which as a whole is capable of serving as a redox-active, bidentate S-donor ligand. Its paramagnetism as well as the ν(NO) vibrational monitor can be exploited in the development of new classes of heterobimetallic complexes. We offer four examples in which the unpaired electron on the {Fe(NO)}7 unit is spin-paired with adjacent paramagnets in proximal and distal positions.First, the exceptional stability of the (NO)Fe(N2S2)-Fe(NO)2 platform, which permits its isolation and structural characterization at three distinct redox levels, is linked to the charge delocalization occurring on both the Fe(NO) and the Fe(NO)2 supports. This accommodates the formation of a rare nonheme {Fe(NO)}8 triplet state, with a linear configuration. A subsequent FeNi complex, featuring redox-active ligands on both metals (NO on iron and dithiolene on nickel), displayed unexpected physical properties. Our research showed good reversibility in two redox processes, allowing isolation in reduced and oxidized forms. Various spectroscopic and crystallographic analyses confirmed these states, and Mössbauer data supported the redox change at the iron site upon reduction. Oxidation of the complex produced a dimeric dication, revealing an intriguing magnetic behavior. The monomer appears as a spin-coupled diradical between {Fe(NO)}7 and the nickel dithiolene monoradical, while dimerization couples the latter radical units via a Ni2S2 rhomb. Magnetic data (SQUID) on the dimer dication found a singlet ground state with a thermally accessible triplet state that is responsible for magnetism. A theoretical model built on an H4 chain explains this unexpected ferromagnetic low-energy triplet state arising from the antiferromagnetic coupling of a four-radical molecular conglomerate. For comparison, two (NO)Fe(N2S2) were connected through diamagnetic group 10 cations producing diradical trimetallic complexes. Antiferromagnetic coupling is observed between {Fe(NO)}7 units, with exchange coupling constants (J) of -3, -23, and -124 cm-1 for NiII, PdII, and PtII, respectively. This trend is explained by the enhanced covalency and polarizability of sulfur-dense metallodithiolate ligands. A central paramagnetic trans-Cr(NO)(MeCN) receiver unit core results in a cissoid structural topology, influenced by the stereoactivity of the lone pair(s) on the sulfur donors. This {Cr(NO)}5 radical bridge, unlike all previous cases, finds the coupling between the distal Fe(NO) radicals to be ferromagnetic (J = 24 cm-1).The stability and predictability of this S = 1/2 moiety and the steric/electronic properties of the bridging thiolate sulfurs suggest it to be a likely candidate for the development of novel molecular (magnetic) compounds and possibly materials. The role of synthetic inorganic chemistry in designing synthons that permit connections of the (NO)Fe(N2S2) metalloligand is highlighted as well as the properties of the heterobi- and polymetallic complexes derived therefrom.

A single carbon atom controls the geometry and reactivity of CoII(N2S2) complexes.

Three- vs. two-carbon N-to-N connectors give rise to monomeric, tetrahedral N2S2Co(II) (µeff = 4.24 BM) or dimeric [(N2S2)Co(II)]2 (diamagnetic) complexes, respectively. Differences in the derivative products of the Lewis acid receivers, W0(CO)3 and W0(CO)4, illustrate nucleophilicity of the thiolate sulfur lone pairs in each case, as well as their structural control.

Bond Trading: Intramolecular Metal and Ligand Exchange within a NO/Ni/Co Complex.

With the goal of generating hetero-redox levels on metals as well as on nitric oxide (NO), metallodithiolate (N2 S2 )CoIII (NO- ), N2 S2 = N,N- dibenzyl-3,7-diazanonane-1,9-dithiolate, is introduced as ligand to a well-characterized labile [Ni0 (NO)+ ] synthon. The reaction between [Ni0 (NO+ )] and [CoIII (NO- )] has led to a remarkable electronic and ligand redistribution to form a heterobimetallic dinitrosyl cobalt [(N2 S2 )NiII ∙Co(NO)2 ]+ complex with formal two electron oxidation state switches concomitant with the nickel extraction or transfer as NiII into the N2 S2 ligand binding site. To date, this is the first reported heterobimetallic cobalt dinitrosyl complex.

Sulfur Lone Pairs Control Topology in Heterotrimetallic Complexes: An Experimental and Theoretical Study.

Heterotrimetallic complexes with (N2S2)M metallodithiolates, M = Ni2+, [Fe(NO)]2+, and [Co(NO)]2+, as bidentate chelating ligands to a central trans-Cr(NO)(MeCN) unit were characterized as the first members of a new class, NiCrNi, FeCrFe, CoCrCo. The complexes exhibit a cisoid structural topology, ascribed to the stereoactivity of the available lone pair(s) on the sulfur donors, resulting in a dispersed, electropositive pocket from the N/N and N/S hydrocarbon linkers wherein the Cr-NO site is housed. Computational studies explored alternative isomers (transoid and inverted cisoid) that suggest a combination of electronic and steric effects govern the geometrical selectivity. Electrostatic potential maps readily display the dominant electronegative potential from the sulfurs which force the NO to the electropositive pocket. The available S lone pairs work in synergy with the π-withdrawing ability of NO to lift Cr out of the S4 plane toward the NO and stabilize the geometry. The metallodithiolate ligands bound to Cr(NO) thus find structural consistency across the three congeners. Although the dinitrosyl [(bme-dach)Co(NO)-Mo(NO)(MeCN)-(bme-dach)Co(MeCN)][PF6]2 (CoMoCo') analogue displays chemical noninnocence and a partial Mo-Co bond toward (N2S2)Co'(NCCH3) in an "asymmetric butterfly" topology [Guerrero-Almaraz P.Inorg. Chem.2021, 60(21 (21), ), 15975-15979], the stability of the {Cr(NO)}5 unit prohibits such bond rearrangement. Magnetism and EPR studies illustrate spin coupling across the sulfur thiolate sulfur bridges.

Correction: Magnetic coupling between Fe(NO) spin probe ligands through diamagnetic NiII, PdII and PtII tetrathiolate bridges.

[This corrects the article DOI: 10.1039/D3SC01546G.].

Magnetic coupling between Fe(NO) spin probe ligands through diamagnetic NiII, PdII and PtII tetrathiolate bridges.

Reaction of the nitrosylated-iron metallodithiolate ligand, paramagnetic (NO)Fe(N2S2), with [M(CH3CN)n][BF4]2 salts (M = NiII, PdII, and PtII; n = 4 or 6) affords di-radical tri-metallic complexes in a stairstep type arrangement ([FeMFe]2+, M = Ni, Pd, and Pt), with the central group 10 metal held in a MS4 square plane. These isostructural compounds have nearly identical ν(NO) stretching values, isomer shifts, and electrochemical properties, but vary in their magnetic properties. Despite the intramolecular Fe⋯Fe distances of ca. 6 Å, antiferromagnetic coupling is observed between {Fe(NO)}7 units as established by magnetic susceptibility, EPR, and DFT studies. The superexchange interaction through the thiolate sulfur and central metal atoms is on the order of NiII < PdII ≪ PtII with exchange coupling constants (J) of -3, -23, and -124 cm-1, consistent with increased covalency of the M-S bonds (3d < 4d < 5d). This trend is reproduced by DFT calculations with molecular orbital analysis providing insight into the origin of the enhancement in the exchange interaction. Specifically, the magnitude of the exchange interaction correlates surprisingly well with the energy difference between the HOMO and HOMO-1 orbitals of the triplet states, which is reflected in the central metal's contribution to these orbitals. These results demonstrate the ability of sulfur-dense metallodithiolate ligands to engender strong magnetic communication by virtue of their enhanced covalency and polarizability.

Chirality-Guided Isomerization of Mn2S2 Diamond Core Complexes: A Mechanistic Study.

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.

Cooperative redox and spin activity from three redox congeners of sulfur-bridged iron nitrosyl and nickel dithiolene complexes.

The synthesis of sulfur-bridged Fe-Ni heterobimetallics was inspired by Nature's strategies to "trick" abundant first row transition metals into enabling 2-electron processes: redox-active ligands (including pendant iron-sulfur clusters) and proximal metals. Our design to have redox-active ligands on each metal, NO on iron and dithiolene on nickel, resulted in the observation of unexpectedly intricate physical properties. The metallodithiolate, (NO)Fe(N2S2), reacts with a labile ligand derivative of [NiII(S2C2Ph2)]0, NiDT, yielding the expected S-bridged neutral adduct, FeNi, containing a doublet {Fe(NO)}7. Good reversibility of two redox events of FeNi led to isolation of reduced and oxidized congeners. Characterization by various spectroscopies and single-crystal X-ray diffraction concluded that reduction of the FeNi parent yielded [FeNi]-, a rare example of a high-spin {Fe(NO)}8, described as linear FeII(NO-). Mössbauer data is diagnostic for the redox change at the {Fe(NO)}7/8 site. Oxidation of FeNi generated the 2[FeNi]+⇌[Fe2Ni2]2+ equilibrium in solution; crystallization yields only the [Fe2Ni2]2+ dimer, isolated as PF6- and BArF- salts. The monomer is a spin-coupled diradical between {Fe(NO)}7 and NiDT+, while dimerization couples the two NiDT+ via a Ni2S2 rhomb. Magnetic susceptibility studies on the dimer found a singlet ground state with a thermally accessible triplet excited state responsible for the magnetism at 300 K (χMT = 0.67 emu·K·mol-1, µeff = 2.31 µB), and detectable by parallel-mode EPR spectroscopy at 20 to 50 K. A theoretical model built on an H4 chain explains this unexpected low energy triplet state arising from a combination of anti- and ferromagnetic coupling of a four-radical molecular conglomerate.

Dinitrosyl iron complexes (DNICs) as inhibitors of the SARS-CoV-2 main protease.

By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB- (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA-RRE, [(µ-S-TGTA)Fe(NO)2]2 (TGTA = 1-thio-ß-d-glucose tetraacetate) and TG-RRE, [(µ-S-TG)Fe(NO)2]2 (TG = 1-thio-ß-d-glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2Mpro). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC50 of 38 ± 2 µM for TGTA-RRE and 33 ± 2 µM for TG-RRE. This study presents a simple computational method for predicting DNIC-protein interactions; the in vitro study is consistent with in silico leads.

Zinc thiotropolone combinations as inhibitors of the SARS-CoV-2 main protease.

Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2Mpro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC50, for SC2Mpro in the 8-34 µM range, the IC50 values are ca. 100 nM for Zn(NO3)2 which are further enhanced in Zn-L combinations (59-97 nM). Isolation of the Zn(L)2 binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2Mpro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-L combinations orient so as to permit dative bonding of Zn(L)+ to basic active site residues.

Linear and Bent Nitric Oxide Ligand Binding in an Asymmetric Butterfly Complex: CoMoCo'.

Two synthetic approaches to install metallodithiolate ligands on molybdenum centers using the synthons [Mo2(CH3CN)10]4+ and (N2S2)Co(NO) [N2S2 = N,N-bis(2-mercaptoethyl)-1,4-diazacycloheptane and NO = nitric oxide], or [Mo(NO)2(CH3CN)4]2+ (CH3CN = acetonitrile) and [(N2S2)Co]2 lead to a bis-nitrosylated, trimetallic dication, CoMoCo'. This unique asymmetric butterfly complex, with S = 1, has a bent NO within the small {Co(NO)}8 wing (denoted as Co), reflecting CoIII(NO-), and is S-bridged to a linear {Mo(NO)}6 diamagnetic unit. The latter is further S-bridged to a pentacoordinate (N2S2)CoIII(CH3CN) donor in the larger wing and is the origin of the two unpaired electrons, denoted as Co'. The asymmetry in Mo-Co distances, 3.33 Šin the Co wing and 2.73 Šin the Co' wing, indicated a Mo-Co' bonding interaction. The transfer of NO from (N2S2)Co(NO) in the former path is needed to cleave the strong quadruple bond in [Mo≣Mo]4+, with the energetic cost compensated for via a one-electron bond between Mo and Co', as indicated by natural bonding orbital analysis.

Self-Assembled Nickel-4 Supramolecular Squares and Assays for HER Electrocatalysts Derived Therefrom.

Solid-state structures find a self-assembled tetrameric nickel cage with carboxylate linkages, [Ni(N2S'O)I(CH3CN)]4 ([Ni-I]40), resulting from sulfur acetylation by sodium iodoacetate of an [NiN2S]22+ dimer in acetonitrile. Various synthetic routes to the tetramer, best described from XRD as a molecular square, were discovered to generate the hexacoordinate nickel units ligated by N2Sthioether, iodide, and two carboxylate oxygens, one of which is the bridge from the adjacent nickel unit in [Ni-I]40. Removal of the four iodides by silver ion precipitation yields an analogous species but with an additional vacant coordination site, [Ni-Solv]+, a cation but with coordinated solvent molecules. This also recrystallizes as the tetramer [Ni-Solv]44+. In solution, dissociation into the (presumed) monomer occurs, with coordinating solvents occupying the vacant site [Ni(N2S'O)I(solv)]0, ([Ni-I]0). Hydrodynamic radii determined from 1H DOSY NMR data suggest that monomeric units are present as well in CD2Cl2. Evans method magnetism values are consistent with triplet spin states in polar solvents; however, in CD2Cl2 solutions no paramagnetism is evident. The abilities of [Ni-I]40 and [Ni-Solv]44+ to serve as sources of electrocatalysts, or precatalysts, for the hydrogen evolution reaction (HER) were explored. Cyclic voltammetry responses and bulk coulometry with gas chromatographic analysis demonstrated that a stronger acid, trifluoroacetic acid, as a proton source resulted in H2 production from both electroprecatalysts; however, electrocatalysis developed primarily from uncharacterized deposits on the electrode. With acetic acid as a proton source, the major contribution to the HER is from homogeneous electrocatalysis. Overpotentials of 490 mV were obtained for both the solution-phase [Ni-I]0 and [Ni-Solv]+. While the electrocatalyst derived from [Ni-Solv]+ has a substantially higher TOF (102 s-1) than [Ni-I]0 (19 s-1), it has a shorter catalytically active lifespan (4 h) in comparison to [Ni-I]0 (>18 h).

Effects of Glutathione and Histidine on NO Release from a Dimeric Dinitrosyl Iron Complex (DNIC).

Rates of NO release from synthetic dinitrosyl iron complexes (DNICs) are shown to be responsive to coordination environments about iron. The effect of biologically relevant cellular components, glutathione and histidine, on the rate of NO release from a dimeric, "Roussin's Red Ester", DNIC with bridging µ-S thioglucose ligands, SGlucRRE or [(µ-SGluc)Fe(NO)2]2 (SGluc = 1-thio-ß-d-glucose tetraacetate), was investigated. From the Griess assay and X-band EPR data, decomposition of the product from the histidine-cleaved dimer, [(SGluc)(NHis)Fe(NO)2], generated Fe(III) and increased the NO release rate in aqueous media when compared to the intact SGlucRRE precursor. In contrast, increasing concentrations of exogenous glutathione generated the stable [(SGluc)(GS)Fe(NO)2]- anion and depressed the rate of NO release. Both of the cleaved, monomeric intermediates were characterized with ESI-MS, EPR, and FT-IR spectroscopies. On the basis of the Griess assay coupled with data from an intracellular fluorometric probe, both the monomeric DNICs and dimeric SGlucRRE diffuse into smooth muscle cells, chosen as appropriate archetypes of vascular relaxation, and release their NO payload. Ultimately, this work provides insight into tuning NO release beyond the design of DNICs, through the incubation with safe, accessible biological molecules.

Synthetic Metallodithiolato Ligands as Pendant Bases in [FeIFeI], [FeI[Fe(NO)]II], and [(µ-H)FeIIFeII] Complexes.

The development of ligands with specific stereo- and electrochemical requirements that are necessary for catalyst design challenges synthetic chemists in academia and industry. The crucial aza-dithiolate linker in the active site of [FeFe]-H2ase has inspired the development of synthetic analogues that utilize ligands which serve as conventional σ donors with pendant base features for H+ binding and delivery. Several MN2S2 complexes (M = Ni2+, [Fe(NO)]2+, [Co(NO)]2+, etc.) utilize these cis-dithiolates to bind low valent metals and also demonstrate the useful property of hemilability, i.e., alternate between bi- and monodentate ligation. Herein, synthetic efforts have led to the isolation and characterization of three heterotrimetallics that employ metallodithiolato ligand binding to di-iron scaffolds in three redox levels, (µ-pdt)[Fe(CO)3]2, (µ-pdt)[Fe(CO)3][(Fe(NO))II(IMe)(CO)]+, and (µ-pdt)(µ-H)[FeII(CO)2(PMe3)]2+ to generate (µ-pdt)[(FeI(CO)3][FeI(CO)2·NiN2S2] (1), (µ-pdt)[FeI(CO)3][(Fe(NO))II(IMe)(CO)]+ (2), and (µ-pdt)(µ-H)[FeII(CO)2(PMe3)][FeII(CO)(PMe3)·NiN2S2]+ (3) complexes (pdt = 1,3-propanedithiolate, IMe = 1,3-dimethylimidazole-2-ylidene, NiN2S2 = [N,N'-bis(2-mercaptidoethyl)-1,4-diazacycloheptane] nickel(II)). These complexes display efficient metallodithiolato binding to the di-iron scaffold with one thiolate-S, which allows the free unbound thiolate to potentially serve as a built-in pendant base to direct proton binding, promoting a possible Fe-H-···+H-S coupling mechanism for the electrocatalytic hydrogen evolution reaction (HER) in the presence of acids. Ligand substitution studies on 1 indicate an associative/dissociative type reaction mechanism for the replacement of the NiN2S2 ligand, providing insight into the Fe-S bond strength.

The roles of chalcogenides in O2 protection of H2ase active sites.

At some point, all HER (Hydrogen Evolution Reaction) catalysts, important in sustainable H2O splitting technology, will encounter O2 and O2-damage. The [NiFeSe]-H2ases and some of the [NiFeS]-H2ases, biocatalysts for reversible H2 production from protons and electrons, are exemplars of oxygen tolerant HER catalysts in nature. In the hydrogenase active sites oxygen damage may be extensive (irreversible) as it is for the [FeFe]-H2ase or moderate (reversible) for the [NiFe]-H2ases. The affinity of oxygen for sulfur, in [NiFeS]-H2ase, and selenium, in [NiFeSe]-H2ase, yielding oxygenated chalcogens results in maintenance of the core NiFe unit, and myriad observable but inactive states, which can be reductively repaired. In contrast, the [FeFe]-H2ase active site has less possibilities for chalcogen-oxygen uptake and a greater chance for O2-attack on iron. Exposure to O2 typically leads to irreversible damage. Despite the evidence of S/Se-oxygenation in the active sites of hydrogenases, there are limited reported synthetic models. This perspective will give an overview of the studies of O2 reactions with the hydrogenases and biomimetics with focus on our recent studies that compare sulfur and selenium containing synthetic analogues of the [NiFe]-H2ase active sites.

Metal-Templated, Tight Loop Conformation of a Cys-X-Cys Biomimetic Assembles a Dimanganese Complex.

With the goal of generating anionic analogues to MN2 S2 ⋅Mn(CO)3 Br we introduced metallodithiolate ligands, MN2 S22- prepared from the Cys-X-Cys biomimetic, ema4- ligand (ema=N,N'-ethylenebis(mercaptoacetamide); M=NiII , [VIV ≡O]2+ and FeIII ) to Mn(CO)5 Br. An unexpected, remarkably stable dimanganese product, (H2 N2 (CH2 C=O(µ-S))2 )[Mn(CO)3 ]2 resulted from loss of M originally residing in the N2 S24- pocket, replaced by protonation at the amido nitrogens, generating H2 ema2- . Accordingly, the ema ligand has switched its coordination mode from an N2 S24- cavity holding a single metal, to a binucleating H2 ema2- 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 H2 ema2- that is the optimal arrangement for binucleation. XRD molecular structures show extensive H-bonding at the amido-nitrogen protons in the solid state.

Controlling O2 Reactivity in Synthetic Analogues of [NiFeS]- and [NiFeSe]-Hydrogenase Active Sites.

Strategies for limiting, or reversing, the degradation of air-sensitive, base metal catalysts for the hydrogen evolution/oxidation reaction on contact with adventitious O2 are guided by nature's design of hydrogenase active sites. The affinity of oxygen for sulfur and selenium, in [NiFeS]- and [NiFeSe]-H2ase, 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-EPhX)(µ-S'N2)Fe (E = S or Se, Fe = (η5-C5H5)FeII(CO)) complexes were electronically tuned by the para-substituent on µ-EPhX (X = CF3, Cl, H, OMe, NMe2) 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-EPhX)(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 = NMe2 case, the two-oxygen uptake complex was isolated and characterized as the sulfinato species with the second O of the O2SPh-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 EPhX. Density functional theory computational results support the observed remote effects on the NiFe core reactivity; the more electron-rich sulfurs are more O2 responsive in the SPhX series; the selenium analogues were even more reactive with O2. Mass spectral analysis of the sulfinato products using a mixture of 18O2/16O2 suggests a concerted mechanism in O2 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]-H2ase (Horch, M.; Lauterbach, L.; et al. J. Am. Chem. Soc. 2015, 137, 2555-2564).

Toward the Optimization of Dinitrosyl Iron Complexes as Therapeutics for Smooth Muscle Cells.

In this study, dinitrosyl iron complexes (DNICs) are shown to deliver nitric oxide (NO) into the cytosol of vascular smooth muscle cells (SMCs), which play a major role in vascular relaxation and contraction. Malfunction of SMCs can lead to hypertension, asthma, and erectile dysfunction, among other disorders. For comparison of the five DNIC derivatives, the following protocols were examined: (a) the Griess assay to detect nitrite (derived from NO conversion) in the absence and presence of SMCs; (b) the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay for cell viability; (c) an immunotoxicity assay to establish if DNICs stimulate immune response; and (d) a fluorometric assay to detect intracellular NO from treatment with DNICs. Dimeric Roussin's red ester (RRE)-type {Fe(NO)2}9 complexes containing phenylthiolate bridges, [(µ-SPh)Fe(NO)2]2 or SPhRRE, were found to deliver NO with the lowest effect on cell toxicity (i.e., highest IC50). In contrast, the RRE-DNIC with the biocompatible thioglucose moiety, [(µ-SGlu)Fe(NO)2]2 (SGlu = 1-thio-ß-d-glucose tetraacetate) or SGluRRE, delivered a higher concentration of NO to the cytosol of SMCs with a 10-fold decrease in IC50. Additionally, monomeric DNICs stabilized by a bulky N-heterocyclic carbene (NHC), namely, 1,3-bis(2,4,6-trimethylphenyl)imidazolidene (IMes), were synthesized and yielded the DNIC complexes SGluNHC, [IMes(SGlu)Fe(NO)2], and SPhNHC, [IMes(SPh)Fe(NO)2]. These oxidized {Fe(NO)2}9 NHC DNICs have an IC50 of ∼7 µM; however, the NHC-based complexes did not transfer NO into the SMC. Per contra, the reduced, mononuclear {Fe(NO)2}10 neocuproine-based DNIC, neoDNIC, depressed the viability of the SMCs, as well as generated an increase of intracellular NO. Regardless of the coordination environment or oxidation state, all DNICs showed a dinitrosyl iron unit (DNIU)-dependent increase in viability. This study demonstrates a structure-function relationship between the DNIU coordination environment and the efficacy of the DNIC treatments.

Proton affinity studies of nickel N2S2 complexes and control of aggregation.

The thiolate ligands of [NiFe]-H2ase enzymes have been implicated as proton-binding sites for the reduction/oxidation of H+/H2. This study examines the ligand effect on reactivity of NiN2S2 complexes with an array of acids in methanol solution. UV-Vis absorption spectroscopy is utilized to observe the transformation from the monomeric species to a trimetallic complex that is formed after proton-induced ligand dissociation. Nickel complexes with a flexible (propyl and ethyl) N to N linker were found to readily form the trimetallic complex with acids as weak as ammonium (pKa = 10.9 in methanol). A more constrained nickel complex with a diazacycloheptane N to N linker required stronger acids such as 2,2-dichloroacetic acid (pKa = 6.38 in methanol) to form the trimetallic complex and featured the formation of an NiN2S2H+ complex with acetic acid (pKa = 9.63 in methanol). The most strained ligand, which featured a diazacyclohexane backbone, readily dissociated from the nickel center upon mixture with acids with pKa ≤ 9.63 and showed no evidence of a trimetallic species with any acid. This research highlights the dramatic differences in reactivity with proton sources that can be imparted by minor alterations to ligand geometry and strain.