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.

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.

From [2Mn2S] Diamond Cores to Butterfly Rhombs: Transformations That Highlight Alternating Peptide Binding Sites.

Thiocarboxamide chelates are known to assemble [2Mn2S] diamond core complexes via µ-S bridges that connect two MnI(CO)3 fragments. These can exist as syn- and anti-isomers and interconvert via 16-electron, monomeric intermediates. Herein, we demonstrate that reduction of such Mn2 derivatives leads to a loss of one thiocarboxamide ligand and a switch of ligand binding mode from an O- to N-donor of the amide group, yielding a dianionic butterfly rhomb with a short Mn0-Mn0 distance, 2.52 Å. Structural and chemical analyses suggest that reduction of the Mn(I) centers is dependent on the protonation state of the amide-H, as total deprotonation followed by reduction does not result in the reduction of the Mn2 core. Partial deprotonation followed by reduction suggests a pathway that involves monomeric Mn(CO)3(S-O) and Mn(CO)3(S-N) intermediates. Ligand modifications to tertiary amides that remove the possibility of amide-H reduction led to complexes that preserve the [2Mn2S] diamond core during chemical reduction. Further comparison with the tethered system, linking the Mn(CO)3(S-O) sites together, suggests that dimer dissociation is necessary for the overall reductive transformation. These results highlight organomanganese carbonyl chemistry to establish illustrations of peptide fragment binding modes in the uptake of low-valent metal carbonyls related to binuclear active sites of biocatalysts.

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.

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.

Interplay of hemilability and redox activity in models of hydrogenase active sites.

The hydrogen evolution reaction, as catalyzed by two electrocatalysts [M(N2S2)·Fe(NO)2]+, [Fe-Fe]+ (M = Fe(NO)) and [Ni-Fe]+ (M = Ni) was investigated by computational chemistry. As nominal models of hydrogenase active sites, these bimetallics feature two kinds of actor ligands: Hemilabile, MN2S2 ligands and redox-active, nitrosyl ligands, whose interplay guides the H2 production mechanism. The requisite base and metal open site are masked in the resting state but revealed within the catalytic cycle by cleavage of the MS-Fe(NO)2 bond from the hemilabile metallodithiolate ligand. Introducing two electrons and two protons to [Ni-Fe]+ produces H2 from coupling a hydride temporarily stored on Fe(NO)2 (Lewis acid) and a proton accommodated on the exposed sulfur of the MN2S2 thiolate (Lewis base). This Lewis acid-base pair is initiated and preserved by disrupting the dative donation through protonation on the thiolate or reduction on the thiolate-bound metal. Either manipulation modulates the electron density of the pair to prevent it from reestablishing the dative bond. The electron-buffering nitrosyl's role is subtler as a bifunctional electron reservoir. With more nitrosyls as in [Fe-Fe]+, accumulated electronic space in the nitrosyls' π*-orbitals makes reductions easier, but redirects the protonation and reduction to sites that postpone the actuation of the hemilability. Additionally, two electrons donated from two nitrosyl-buffered irons, along with two external electrons, reduce two protons into two hydrides, from which reductive elimination generates H2.

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).

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.

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.

Oxygen-Tolerant H2 Production by [FeFe]-H2ase Active Site Mimics Aided by Second Sphere Proton Shuttle.

The instability of [FeFe]-H2ases and their biomimetics toward O2 renders them inefficient to implement in practical H2 generation (HER). Previous investigations on synthetic models as well as natural enzymes proved that reactive oxygen species (ROS) generated on O2 exposure oxidatively degrades the 2Fe subcluster within the H-cluster active site. Recent electrochemical studies, coupled with theoretical investigations on [FeFe]-H2ase suggested that selective O2 reduction to H2O could eliminate the ROS, and hence, tolerance against oxidative degradation could be achieved ( Nat. Chem. 2017, 9, 88-95). We have prepared a series of 2Fe subsite mimics with substituted arenes attached to bridgehead N atoms in the S to S linker, (µ-S2(CH2)2NAr)[Fe(CO)3]2. Structural analyses find the nature of the substituent on the arene offers steric control of the orientation of bridgehead N atoms, affecting their proton uptake and translocation ability. The heterogeneous electrochemical studies of these complexes physiadsorbed on edge plane graphite (EPG) electrode show the onset of HER activity at ∼180 mV overpotential in pH 5.5 water. In addition, bridgehead N-protonation and subsequent H-bonding capability are established to facilitate the O-O bond cleavage resulting in selective O2 reduction to H2O. This allows a synthetic [FeFe]-H2ase model to reduce protons to H2 unabated in the presence of dissolved O2 in water at nearly neutral pH (pH 5.5); i.e., O2-tolerant, stable HER activity is achieved.

Cyanide Docking and Linkage Isomerism in Models for the Artificial [FeFe]-Hydrogenase Maturation Process.

Linkage isomerization of the cyanide on the [2Fe] subsite of the [FeFe]-H2ase active site was reported to occur during the docking of various synthetic diiron complexes onto a carrier protein, apo-HydF, as the initial step for the artificial maturation of the [FeFe]-H2ase enzyme (Berggren et al., Nature, 2013, 499, 66-70). An investigation of our triiron organometallic models (FeFe-CN/NC-Fe') revealed that, once a Fe-CN-Fe connection is formed, high barriers prevent such cyanide linkage isomerization ( Chem. Sci., 2016, 7, 3710-3719). To explore effects of variable oxidation states of the receiver unit, we introduce copper(I/II) fragments, precedented in Holm's models of cytochrome c oxidase to induce cyanide isomerization (Cu-CN/NC-Fe), to the diiron synthetic analogues of [FeFe]-H2ase. For comparison, a zinc variant of the cytochrome c oxidase model is also examined. According to the oxidation state of copper, a cyanide flip was induced during the formation of both Zn-NC-Cu and FeFe-CN-Cu complexes. Density functional theory calculations are used to predict the mechanisms for such linkage isomerization and account for optimal conditions including oxidation states of metals, spin states, and solvation. These results on synthetic paradigms imply a role for oxidation state control of cyanide isomerization during hydrogenase active site assembly.

Structural and Electronic Responses to the Three Redox Levels of Fe(NO)N2 S2 -Fe(NO)2.

The nitrosylated diiron complexes, Fe2 (NO)3 , of this study are interpreted as a mono-nitrosyl Fe(NO) unit, MNIU, within an N2 S2 ligand field that serves as a metallodithiolate ligand to a dinitrosyl iron unit, DNIU. The cationic Fe(NO)N2 S2 ⋅Fe(NO)2 + complex, 1+ , of Enemark-Feltham electronic notation {Fe(NO)}7 -{Fe(NO)2 }9 , is readily obtained via myriad synthetic routes, and shown to be spin coupled and diamagnetic. Its singly and doubly reduced forms, {Fe(NO)}7 -{Fe(NO)2 }10 , 10 , and {Fe(NO)}8 -{Fe(NO)2 }10 , 1- , were isolated and characterized. While structural parameters of the DNIU are largely unaffected by redox levels, the MNIU readily responds; the neutral, S= 1 / 2 , complex, 10 , finds the extra electron density added into the DNIU affects the adjacent MNIU as seen by the decrease its Fe-N-O angle (from 171° to 149°). In contrast, addition of the second electron, now into the MNIU, returns the Fe-N-O angle to 171° in 1- . Compensating shifts in FeMNIU distances from the N2 S2 plane (from 0.518 to 0.551 to 0.851 Å) contribute to the stability of the bimetallic complex. These features are addressed by computational studies which indicate that the MNIU in 1- is a triplet-state {Fe(NO)}8 with strong spin polarization in the more linear FeNO unit. Magnetic susceptibility and parallel mode EPR results are consistent with the triplet state assignment.

Hemilabile Bridging Thiolates as Proton Shuttles in Bioinspired H2 Production Electrocatalysts.

Synthetic analogues and computationally assisted structure-function analyses have been used to explore the features that control proton-electron and proton-hydride coupling in electrocatalysts inspired by the [NiFe]-hydrogenase active site. Of the bimetallic complexes derived from aggregation of the dithiolato complexes MN2S2 (N2S2 = bismercaptoethane diazacycloheptane; M = Ni or Fe(NO)) with (η5-C5H5)Fe(CO)+ (the Fe' component) or (η5-C5H5)Fe(CO)2+, Fe″, which yielded Ni-Fe'+, Fe-Fe'+, Ni-Fe″+, and Fe-Fe″+, respectively, both Ni-Fe'+ and Fe-Fe'+ were determined to be active electrocatalysts for H2 production in the presence of trifluoroacetic acid. Correlations of electrochemical potentials and H2 generation are consistent with calculated parameters in a predicted mechanism that delineates the order of addition of electrons and protons, the role of the redox-active, noninnocent NO ligand in electron uptake, the necessity for Fe'-S bond breaking (or the hemilability of the metallodithiolate ligand), and hydride-proton coupling routes. Although the redox active {Fe(NO)}7 moiety can accept and store an electron and subsequently a proton (forming the relatively unstable Fe-bound HNO), it cannot form a hydride as the NO shields the Fe from protonation. Successful coupling occurs from a hydride on Fe' with a proton on thiolate S and requires a propitious orientation of the H-S bond that places H+ and H- within coupling distance. This orientation and coupling barrier are redox-level dependent. While the Ni-Fe' derivative has vacant sites on both metals for hydride formation, the uptake of the required electron is more energy intensive than that in Fe-Fe' featuring the noninnocent NO ligand. The Fe'-S bond cleavage facilitated by the hemilability of thiolate to produce a terminal thiolate as a proton shuttle is a key feature in both mechanisms. The analogous Fe″-S bond cleavage on Ni-Fe″ leads to degradation.

Synthetic advances inspired by the bioactive dinitrosyl iron unit.

Resulting from biochemical iron-NO interactions, dinitrosyl iron complexes (DNICs) are small organometallic-like molecules, considered to serve as vehicles for NO transport and storage in vivo. Formed by the interaction of NO with cellular iron sulfur clusters or with the cellular labile iron pool, DNICs have been documented to be the largest NO-derived adduct in cells, even surpassing the well-known nitrosothiols (RSNOs). Continuing efforts in biological chemistry are aimed at understanding the movement of DNICs in and out of cells, and their important role in NO-induced iron efflux leading to apoptosis in cells. Intrigued by the integrity of the unique dinitrosyl iron unit (DNIU) and the possibility of roles for it in human physiology or medicinal applications, the understanding of fundamental properties such as ligand effects on its ability to switch between two redox levels has been pursued through biomimetic complexes. Using metallodithiolates and N-heterocyclic carbenes (NHCs) as ligands to Fe(NO)2, the synthesis of a library of novel DNICs, in both the oxidized, {Fe(NO)2}(9), and reduced, {Fe(NO)2}(10), forms (Enemark-Feltham notation), offers opportunity to examine structural, reactivity, and spectroscopic features. The raison d'etre for the MN2S2·Fe(NO)2 synthesis development is for the potential to exploit the ease of accessing two redox levels on two different metal sites, a property presumably required for achieving two electron redox processes in base metals. Hence such molecules may be viewed as synthetic analogues of [NiFe]- or [FeFe]-hydrogenase active sites in nature, both of which use bridging thiolates for connection of the two centers. A particular success was the development of an Fe(NO)N2S2·Fe(NO)2(+/0) redox pair for proton reduction electrocatalysis. Monomeric, reduced NHC-DNICs of the L2Fe(NO)2 type are synthesized via the Fe(CO)2(NO)2 precursor, and oxidized thiolate-containing forms are derived from the dimeric (µ-RS)2[Fe(NO)2]2. Monomeric NHC-DNICs are four coordinate, pseudotetrahedral compounds with planar Fe(NO)2 units in which the slightly bent Fe-NO groups are directed symmetrically inward at both redox levels. They serve as stable analogues of biological histidine binding sites. In agreement with IR data, Mössbauer spectroscopic parameters, and DFT computations, the prototypic NHC-DNICs indicate extensive delocalization of the electron density of iron via π-backbonding. Such π-delocalization presents an unusual reaction path for the one electron process of RS(-)/RSSR interconversion. Comparisons with imidazole-DNICs find NHCs to be the "better" ligands to Fe(NO)2 and prompted investigations in (a) possible relationships between such imidazole- and NHC-containing DNICs, (b) systems that might mimic the reactivity of DNICs with the endogenous gaseotransmitter CO, and (c) mechanistic details of such processes. In a broader context, these studies aim to further describe the behavior of the {Fe(NO)2} unit as a single molecular entity when subjected to various ligand environments and reaction conditions.

Ligand Displacement Reaction Paths in a Diiron Hydrogenase Active Site Model Complex.

The mechanism and energetics of CO, 1-hexene, and 1-hexyne substitution from the complexes (SBenz)2 [Fe2 (CO)6 ] (SBenz=SCH2 Ph) (1-CO), (SBenz)2 [Fe2 (CO)5 (η(2) -1-hexene)] (1-(η(2) -1-hexene)), and (SBenz)2 [Fe2 (CO)5 (η(2) -1-hexyne)] (1-(η(2) -1-hexyne)) were studied by using time-resolved infrared spectroscopy. Exchange of both CO and 1-hexyne by P(OEt)3 and pyridine, respectively, proceeds by a bimolecular mechanism. As similar activation enthalpies are obtained for both reactions, the rate-determining step in both cases is assumed to be the rotation of the Fe(CO)2 L (L=CO or 1-hexyne) unit to accommodate the incoming ligand. The kinetic profile for the displacement of 1-hexene is quite different than that for the alkyne and, in this case, both reaction channels, that is, dissociative (SN 1) and associative (SN 2), were found to be competitive. Because DFT calculations predict similar binding enthalpies of alkene and alkyne to the iron center, the results indicate that the bimolecular pathway in the case of the alkyne is lower in free energy than that of the alkene. In complexes of this type, subtle changes in the departing ligand characteristics and the nature of the mercapto bridge can influence the exchange mechanism, such that more than one reaction pathway is available for ligand substitution. The difference between this and the analogous study of (µ-pdt)[Fe(CO)3 ]2 (pdt=S(CH2 )3 S) underscores the unique characteristics of a three-atom S-S linker in the active site of diiron hydrogenases.

Catalysis and Mechanism of H2 Release from Amine-Boranes by Diiron Complexes.

Studies focused on the dehydrogenation of amine-borane by diiron complexes that serve as well-characterized rudimentary models of the diiron subsite in [FeFe]-hydrogenase are reported. Complexes of formulation (µ-SCH2XCH2S)[Fe(CO)3]2, with X = CH2, CMe2, CEt2, NMe, NtBu, and NPh, 1-CO through 6-CO, respectively, were determined to be photocatalysts for release of H2 gas from a solution of H3B ← NHMe2 (B:A(s)), dissolved in THF. The thermal displacement of the tertiary amine-borane, H3B ← NEt3 (B:A(t)) from photochemically generated (µ-SCH2XCH2S)[Fe(CO)3][Fe(CO)2(µ-H)(BH2-NEt3)], 1-B:A(t) through 6-B:A(t), by P(OEt)3 was monitored by time-resolved FTIR spectroscopy. Rates and activation barriers for this substitution reaction were consistent with a dissociative mechanism for the alkylated bridgehead species 2-CO through 6-CO, and associative or interchange for 1-CO. DFT calculations supported an intermediate [I] for the dissociative process featuring a coordinatively unsaturated diiron complex stabilized by an agostic interaction between the metal center and the C-H bond of an alkyl group on the central bridgehead atom of the SRS linker. The rate of H2 production from the initially formed 1-B:A(s) through 6-B:A(s) complexes was inversely correlated with the lifetime of the analogous 1-B:A(t) through 6-B:A(t) adducts. Possible mechanisms are presented which feature involvement of the pendent nitrogen base as well as a separate mechanism for the all carbon bridgeheads.