Search

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-β-d-glucose tetraacetate) and TG-RRE, [(μ-S-TG)Fe(NO) 2 ] 2 (TG = 1-thio-β-d-glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2M pro ). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC 50 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.

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-β-d-glucose tetraacetate), was investigated. From the Griess assay and X-band EPR data, decomposition of the product from the histidine-cleaved dimer, [(SGluc)(N His )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.

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 IC 50 ). In contrast, the RRE-DNIC with the biocompatible thioglucose moiety, [(μ-SGlu)Fe(NO) 2 ] 2 (SGlu = 1-thio-β-d-glucose tetraacetate) or SGluRRE, delivered a higher concentration of NO to the cytosol of SMCs with a 10-fold decrease in IC 50 . 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 IC 50 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.

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.

Base metal, molecular catalysts for the fundamental process of conversion of protons and electrons to dihydrogen, remain a substantial synthetic goal related to a sustainable energy future. Here we report a diiron complex with bridging thiolates in the butterfly shape of the 2Fe2S core of the [FeFe]-hydrogenase active site but with nitrosyl rather than carbonyl or cyanide ligands. This binuclear [(NO)Fe(N2S2)Fe(NO)2](+) complex maintains structural integrity in two redox levels; it consists of a (N2S2)Fe(NO) complex (N2S2=N,N'-bis(2-mercaptoethyl)-1,4-diazacycloheptane) that serves as redox active metallodithiolato bidentate ligand to a redox active dinitrosyl iron unit, Fe(NO)2. Experimental and theoretical methods demonstrate the accommodation of redox levels in both components of the complex, each involving electronically versatile nitrosyl ligands. An interplay of orbital mixing between the Fe(NO) and Fe(NO)2 sites and within the iron nitrosyl bonds in each moiety is revealed, accounting for the interactions that facilitate electron uptake, storage and proton reduction.

Dinitrosyliron complexes (DNICs) are organometallic-like compounds of biological significance in that they appear in vivo as products of NO degradation of iron-sulfur clusters; synthetic analogues have potential as NO storage and releasing agents. Their reactivity is expected to depend on ancillary ligands and the redox level of the distinctive Fe(NO)2 unit: paramagnetic {Fe(NO)2}(9), diamagnetic dimerized forms of {Fe(NO)2}(9) and diamagnetic {Fe(NO)2}(10) DNICs (Enemark-Feltham notation). The typical biological ligands cysteine and glutathione themselves are subject to thiolate-disulfide redox processes, which when coupled to DNICs may lead to intricate redox processes involving iron, NO, and RS(-)/RS•. Making use of an N-heterocyclic carbene-stabilized DNIC, (NHC)(RS)Fe(NO)2, we have explored the DNIC-promoted RS(-)/RS• oxidation in the presence of added CO wherein oxidized {Fe(NO)2}(9) is reduced to {Fe(NO)2}(10) through carbon monoxide (CO)/RS• ligand substitution. Kinetic studies indicate a bimolecular process, rate = k [Fe(NO)2](1)[CO](1), and activation parameters derived from kobs dependence on temperature similarly indicate an associative mechanism. This mechanism is further defined by density functional theory computations. Computational results indicate a unique role for the delocalized frontier molecular orbitals of the Fe(NO)2 unit, permitting ligand exchange of RS• and CO through an initial side-on approach of CO to the electron-rich N-Fe-N site, ultimately resulting in a 5-coordinate, 19-electron intermediate with elongated Fe-SR bond and with the NO ligands accommodating the excess charge.

The compounds of this study have yielded to complementary structural, spectroscopic (Mössbauer, EPR/ENDOR, IR), and computational probes that illustrate the fine control of electronic and steric features that are involved in the two structural forms of (μ-SRS)[Fe(CO)2PMe3]2(0,+) complexes. The installation of bridgehead bulk in the -SCH2CR2CH2S- dithiolate (R = Me, Et) model complexes produces 6-membered FeS2C3 cyclohexane-type rings that produce substantial distortions in Fe(I)Fe(I) precursors. Both the innocent (Fc(+)) and the noninnocent or incipient (NO(+)/CO exchange) oxidations result in complexes with inequivalent iron centers in contrast to the Fe(I)Fe(I) derivatives. In the Fe(II)Fe(I) complexes of S = 1/2, there is complete inversion of one square pyramid relative to the other with strong super hyperfine coupling to one PMe3 and weak SHFC to the other. Remarkably, diamagnetic complexes deriving from isoelectronic replacement of CO by NO(+), {(μ-SRS)[Fe(CO)2PMe3] [Fe(CO)(NO)PMe3](+)}, are also rotated and exist in only one isomeric form with the -SCH2CR2CH2S- dithiolates, in contrast to R = H ( Olsen , M. T. ; Bruschi , M. ; De Gioia , L. ; Rauchfuss , T. B. ; Wilson , S. R. J. Am. Chem. Soc. 2008 , 130 , 12021 -12030 ). The results and redox levels determined from the extensive spectroscopic analyses have been corroborated by gas-phase DFT calculations, with the primary spin density either localized on the rotated iron in the case of the S = 1/2 compound, or delocalized over the {Fe(NO)} unit in the S = 0 complex. In the latter case, the nitrosyl has effectively shifted electron density from the Fe(I)Fe(I) bond, repositioning it onto the spin coupled Fe-N-O unit such that steric repulsion is sufficient to induce the rotated structure in the Fe(II)-{Fe(I)((•)NO)}(8) derivatives.

Imidazolate-containing {Fe(NO)(2)}(9) molecular squares have been synthesized by oxidative CO displacement from the reduced Fe(CO)(2)(NO)(2) precursor. The structures of complex 1 [(imidazole)Fe(NO)(2)](4), (Ford, Li, et al.; Chem. Commun.2005, 477-479), 2 [(2-isopropylimidazole)Fe(NO)(2)](4), and 3 [(benzimidazole)Fe(NO)(2)](4), as determined by X-ray diffraction analysis, find precise square planes of irons with imidazolates bridging the edges and nitrosyl ligands capping the irons at the corners. The orientation of the imidazolate ligands in each of the complexes results in variations of the overall structures, and molecular recognition features in the available cavities of 1 and 3. Computational studies show multiple low energy structural isomers and confirm that the isomers found in the crystallographic structures arise from intermolecular interactions. EPR and IR spectroscopic studies and electrochemical results suggest that the tetramers remain intact in solution in the presence of weakly coordinating (THF) and noncoordinating (CH(2)Cl(2)) solvents. Mössbauer spectroscopic data for a set of reference dinitrosyl iron complexes, reduced {Fe(NO)(2)}(10) compounds A ((NHC-iPr)(2)Fe(NO)(2)), and C ((NHC-iPr)(CO)Fe(NO)(2)), and oxidized {Fe(NO)(2)}(9) compounds B ([(NHC-iPr)(2)Fe(NO)(2)][BF(4)]), and D ((NHC-iPr)(SPh)Fe(NO)(2)) (NHC-iPr = 1,3-diisopropylimidazol-2-ylidene) demonstrate distinct differences of the isomer shifts and quadrupole splittings between the oxidized and reduced forms. The reduced compounds have smaller positive isomer shifts as compared to the oxidized compounds ascribed to the greater π-backbonding to the NO ligands. Mössbauer data for the tetrameric complexes 1-3 demonstrate larger isomer shifts, most comparable to compound D; all four complexes contain cationic {Fe(NO)(2)}(9) units bound to one anionic ligand and one neutral ligand. At room temperature, the paramagnetic, S = (1)/(2) per iron, centers are not coupled., (© 2011 American Chemical Society)

The reaction of Fe(CO)(2)(NO)(2) and Ni(N(2)S(2)) (N(2)S(2) = N,N'-Bis(2-mercaptoethyl)-1,4-diazacycloheptane) by a single CO replacement yields [Ni(N(2)S(2))]Fe(NO)(2)(CO), while an excess of Fe(CO)(2)(NO)(2) leads to triply bridging thiolate sulphurs in a cluster of core composition Ni(2)S(4)Fe(3), lacking one Fe(NO)(2) unit to complete the adamantane-like structure. This structural type was earlier identified in a Cu(I)Cl aggregate of M(II)(N(2)S(2)) (M(II) = Ni, Cu), in which complete M(II)(2)S(4)Cu(I)(4) core structures were obtained as the major, and, in the case of Cu(II)(N(2)S(2)), the incomplete Cu(II)(2)S(4)Cu(I)(3) as a minor, product. The full Ni(2)S(4)Fe(4) cluster has not yet been realized for Fe = Fe(NO)(2). Computational analysis of the NiFe-heterobimetallic complex addresses structural issues including a ∠Ni-S-Fe of 90° in the bimetallic complex.

Simple dinuclear iron dithiolates such as (mu-SCH2CH2CH2S)[Fe(CO)3]2, (1) and (mu-SCH2CH2S)[Fe(CO)3]2 (2) are functional models for diiron-hydrogenases, [FeFe]-H2ases, that catalyze the reduction of protons to H2. The mechanism of H2 production with 2 as the catalyst and with both toluenesulfonic (HOTs) and acetic (HOAc) acids as the H+ source in CH3CN solvent has been examined by density functional theory (DFT). Proton dissociation constants (pKa) and electrode reduction potentials (E(o)) are directly computed and compared to the measured pKa of HOTs and HOAc acids and the experimental reduction potentials. Computations show that when the strong acid, HOTs, is used as a proton source the one-electron reduced species 2- can be protonated to form a bridging hydride complex as the most stable structure. Then, this species can be reduced and protonated to form dihydrogen and regenerate 2. This cycle produces H2 via an ECEC process at an applied potential of -1.8 V vs. Fc/Fc+. A second faster process opens for this system when the species produced at the ECEC step above is further reduced and H2 release returns the system to 2- rather than 2, an E[CECE] process. On the other hand, when the weak acid, HOAc, is the proton source a more negative applied reduction potential (-2.2 V vs. Fc/Fc+) is necessary. At this potential two one-electron reductions yield the dianion 2(2-) before the first protonation, which in this case occurs on the thiolate. Subsequent reduction and protonation form dihydrogen and regenerate 2- through an E[ECEC] process.

This study explores the site specificity (sulfur vs the Fe-Fe bond) of oxygenation of diiron (Fe(I)Fe(I) and Fe(II)Fe(II)) organometallics that model the 2-iron subsite in the active site of [FeFe]-hydrogenase: (mu-pdt)[Fe(CO)(2)L][Fe(CO)(2)L'] (L = L' = CO (1); L = PPh(3), L' = CO (2); L = L' = PMe(3) (4)) and (mu-pdt)(mu-H)[Fe(CO)(2)PMe(3)](2) (5). DFT computations find that the Fe-Fe bond in the Fe(I)Fe(I) diiron models is thermodynamically favored to produce the mu-oxo or oxidative addition product, Fe(II)-O-Fe(II); nevertheless, the sulfur-based HOMO-1 accounts for the experimentally observed mono- and bis-O-atom adducts at sulfur, i.e., (mu-pst)[Fe(CO)(2)L][Fe(CO)(2)L'] (pst = -S(CH(2))(3)S(O)-, 1,3-propanesulfenatothiolate; L = L' = CO (1-O); L = PPh(3), L' = CO (2-O); L = L' = PMe(3) (4-O)) and (mu-pds)[Fe(CO)(2)L][Fe(CO)(2)L'] (pds = -(O)S(CH(2))(3)S(O)-, 1,3-propanedisulfenato; L = PPh(3), L' = CO (2-O(2))). The Fe(II)(mu-H)Fe(II) diiron model (5), for which the HOMO is largely of sulfur character, exclusively yields S-oxygenation. The depressing effect of such bridging ligand modification on the dynamic NMR properties arising from rotation of the Fe(CO)(3) correlates with higher barriers to the CO/PMe(3) exchange of (mu-pst)[Fe(CO)(3)](2) as compared to (mu-pdt)[Fe(CO)(3)](2). Five molecular structures are confirmed by X-ray diffraction: 1-O, 2-O, 2-O(2), 4-O, and 6. Deoxygenation with reclamation of the mu-pdt parent complex occurs in a proton/electron-coupled process. The possible biological relevance of oxygenation and deoxygenation studies is discussed.

The immobilization of synthetic analogues of the [FeFe]-hydrogenase, [FeFe]H(2)ase, enzyme active site on polyethyleneglycol-rich polystyrene beads is described. Using the reactivity of the amine termini of the PEG chains with carboxylates incorporated into (mu-SRS)[Fe(CO)(3)](2) or (mu-SR)(2)[Fe(CO)(3)](2) derivative, nu(CO)IR signatures can be used to interrogate the structure and properties of the diiron carbonyl complexes once incorporated into the PEG environment of the polymer beads. Alternatively, the SRS dithiolate was first attached to the resin and the diiron unit assembled via an in situ process on the bead.

A series of asymmetrically disubstituted models of the active site of [FeFe]-hydrogenase, (mu-pdt)[Fe(CO) 2PMe 3][Fe(CO) 2NHC] (pdt = 1,3-propanedithiolate, NHC = IMes, 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene IMes ( 1), IMesMe, 1-methyl,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene ( 2) or IMe, 1,3-bis(methyl)imidazol-2-ylidene ( 3)), have been synthesized and characterized. The one-electron oxidation of these complexes to generate mixed valent models of the H ox state of [FeFe]-hydrogenase, such as the previously reported (mu-pdt)(mu-CO)[Fe(CO) 2PMe 3][Fe(CO)IMes] (+) ( 1 ox ) (Liu, T.; Darensbourg, M. Y. J. Am. Chem. Soc. 2007, 129, 7008-7009) has been examined to explore the steric and electronic effects of different N-atom substituents on the stability and structure of the mixed valent cations. The differences in spectroscopic properties, structures, and relative stabilities of 1 ox , (mu-pdt)[Fe(CO) 2PMe 3][Fe(CO) 2IMesMe] (+) ( 2 ox ), and (mu-pdt)[Fe(CO) 2PMe 3]-[Fe(CO) 2IMe] (+) ( 3 ox ) are discussed in the context of both experimental and theoretical data. Of the three derivatives, only that with greatest steric bulk on the NHC ligand, 1 ox , shows a clear indication of a mu-CO by solution nu(CO) IR and yields to crystallization as a rotated form, commensurate with the two-Fe subsite of H ox. In addition, the reactivity of the complexes with extrinsic CO to form CO adducts and/or exchange with (13)CO is explored by experiment and by using density-functional theory calculations.

Density-functional calculations have been used to examine the electronic structure and bonding in the recently reported complex [(PMe(3))(CO)(2)Fe(mu-pdt)(mu-CO)Fe(CO)(IMes)](+) (1(+), IMes=1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene). This mixed valent Fe(II)Fe(I) complex features a rotated geometry that places a carbonyl ligand in a semi-bridging position, which makes it an accurate model of the S =(1/2) resting state of the [FeFe]-hydrogenase active site. Calculations indicate that the unpaired electron in this complex lies almost entirely on the rotated iron center, implying that this iron remains in the Fe(I) oxidation state, while the unrotated iron has been oxidized to Fe(II). The frontier molecular orbitals in 1(+) are compared with those in the neutral Fe(I)Fe(I) precursor (PMe(3))(CO)(2)Fe(mu-pdt)(mu-CO)Fe(CO)(IMes) at both its optimized geometry (1) and constrained to a rotated geometry (1(rot)). These theoretical results are used to address the role of the bridging CO ligand in 1(+) and to predict reactivity patterns; they are related back to the intricate biological mechanism of [FeFe]-hydrogenase.

Gas-phase density functional theory calculations (B3LYP, double zeta plus polarization basis sets) are used to predict the solution-phase infrared spectra for a series of CO- and CN-containing iron complexes. It is shown that simple linear scaling of the computed C--O and C--N stretching frequencies yields accurate predictions of the the experimentally determined nu(CO) and nu(CN) values for a variety of complexes of different charges and in solvents of varying polarity. As examples of the technique, the resulting correlation is used to assign structures to spectroscopically observed but structurally ambiguous species in two different systems. For the (mu-SCH2CH2CH2S)[Fe(CO)3]2 complex in tetrahydrofuran solution, our calculations show that the initial electrochemical reduction process leads to a simple one-electron reduced product with a structure very similar to the (mu-SCH2CH2CH2S)[Fe(CO)3]2 parent complex. For the iron-iron hydrogenase enzyme active site, our computations show that the absence or presence of a water molecule near the distal iron center (the iron center further from the [4Fe4S] cluster and protein backbone) has very little effect on the predicted infrared spectra.

Owing to the indiscriminate reactivity of the free NO radical, intricate control mechanisms are required for storage, transport and transfer of NO to its various biological targets. Among the proposed storage components are protein-bound thionitrosyls (Rprotein-SNO) and protein-bound dinitrosyl iron complexes. Current knowledge suggests the latter are derived from iron-sulfur cluster degradation in the presence of excess NO. Mobilization of protein-bound NO could involve NO or Fe(NO)2 unit transfer to small serum molecules such as glutathione, free cysteine, or iron-porphyrins. The study reported is of a reaction model which addresses the key steps in NO transfer from a prototypal iron dinitrosyl complex. While the N,N'-bis(2-mercaptoethyl)-N,N'-diazacyclooctane (bme-daco) ligand typically binds in square-planar N2S2 coordination, it also serves as a bidentate dithiolate donor for tetrahedral structures in the preparation of the (H+bme-daco)Fe(NO)2 derivative (Chiang et al., J. Am. Chem. Soc. 126:10867-10874, 2004). The removal of one NO produces the mononitrosyl complex, (bme-daco)Fe(NO), and simplifies studies of NO release mechanisms. We have used heme-type model complexes, Fe or Co porphyrins as NO acceptors, yielding (porphyrin)M(NO), where M is Fe or Co, and monitored reactions by nu(NO) Fourier transform IR spectroscopy. Reaction products were verified by electrospray ionization mass spectrometry. Rudimentary mechanistic studies suggest a role for HNO in the NO release from the dinitrosyl; the mononitrosyl benefits as well from acid catalysis. Other NO uptake complexes such as [(N2S2)Fe]2 [N2S2 is bme-daco or N,N'-bis(2-mercapto-2-methylpropyl)-daco] are shown to form Fe(NO) mononitrosyls with stability and spectroscopic signatures similar to those of the porphyrins.

Simple synthetic di-iron dithiolate complexes provide good models of the composition of the active site of the iron-iron hydrogenase enzymes. However, the formally Fe(I)Fe(I) complexes synthesized to date fail to reproduce the precise orientation of the diatomic ligands about the iron centers that is observed in the molecular structure of the reduced form of the enzyme active site. This structural difference is often used to explain the fact that the synthetic di-iron complexes are generally poor catalysts when compared to the enzyme. Herein, density functional theory computations are used for the rational design of synthetic complexes as structural models of the reduced form of the enzyme active site. These computations suggest several possible synthetic targets. The synthesis of complexes containing five-atom S-to-S linkers of the form S(CH2)2X(CH2)2S (X = CH2, NH, or O) or pendant functionalities attached to the three-carbon framework is one method. Another approach is the synthesis of asymmetrically substituted complexes, in which one iron center has strongly electron donating ligands and the adjacent iron center has strongly electron accepting ligands. The combination of a sterically demanding S-to-S linker and asymmetric substitution of the CO ligands is predicted to be a particularly effective synthetic target.

An N-heterocyclic carbene containing [FeFe]H(2)ase model complex, whose X-ray structure displays an apical carbene, shows an unexpected two-electron reduction to be involved in its electrocatalytic dihydrogen production. Density functional calculations show, in addition to a one-electron Fe-Fe reduction, that the aryl-substituted N-heterocyclic carbene can accept a second electron more readily than the Fe-Fe manifold. The juxtaposition of these two one-electron reductions resembles the [FeFe]H(2)ase active site with an FeFe di-iron unit joined to the electroactive 4Fe4S cluster.

Hydrogen uptake in hydrogenase enzymes can be assayed by H/D exchange reactivity in H(2)/D(2)O or H(2)/D(2)/H(2)O mixtures. Diiron(I) complexes that serve as structural models for the active site of iron hydrogenase are not active in such isotope scrambling but serve as precursors to Fe(II)Fe(II) complexes that are functional models of [Fe]H(2)ase. Using the same experimental protocol as used previously for ((mu-H)(mu-pdt)[Fe(CO)(2)(PMe(3))](2)(+)), 1-H(+) (Zhao et al. J. Am. Chem. Soc. 2001, 123, 9710), we now report the results of studies of ((mu-SMe)(mu-pdt)[Fe(CO)(2)(PMe(3))](2)(+)), 1-SMe(+), toward H/D exchange. The 1-SMe(+) complex can take up H(2) and catalyze the H/D exchange reaction in D(2)/H(2)O mixtures under photolytic, CO-loss conditions. Unlike 1-H(+), it does not catalyze H(2)/D(2) scrambling under anhydrous conditions. The molecular structure of 1-SMe(+) involves an elongated Fe.Fe separation, 3.11 A, relative to 2.58 A in 1-H(+). It is proposed that the strong SMe(-) bridging ligand results in catalytic activity localized on a single Fe(II) center, a scenario that is also a prominent possibility for the enzyme active site. The single requirement is an open site on Fe(II) available for binding of D(2) (or H(2)), followed by deprotonation by the external base H(2)O (or D(2)O).

The article discusses the application of metallodithiolates as ligands to dinitrosyl iron complexes. It mentions that metallodithiolate ligands are used to design heterobimetallic complexes by adduct formation through S-based reactivity. It outlines several strategies to correlating, and reporting complexes.

Owing to the indiscriminate reactivity of the free NO radical, intricate control mechanisms are required for storage, transport and transfer of NO to its various biological targets. Among the proposed storage components are protein-bound thionitrosyls (Rprotein–SNO) and protein-bound dinitrosyl iron complexes. Current knowledge suggests the latter are derived from iron–sulfur cluster degradation in the presence of excess NO. Mobilization of protein-bound NO could involve NO or Fe(NO)2 unit transfer to small serum molecules such as glutathione, free cysteine, or iron-porphyrins. The study reported is of a reaction model which addresses the key steps in NO transfer from a prototypal iron dinitrosyl complex. While the N, N′-bis(2-mercaptoethyl)- N, N′-diazacyclooctane (bme-daco) ligand typically binds in square-planar N2S2 coordination, it also serves as a bidentate dithiolate donor for tetrahedral structures in the preparation of the (H+bme-daco)Fe(NO)2 derivative (Chiang et al., J. Am. Chem. Soc. 126:10867–10874, 2004). The removal of one NO produces the mononitrosyl complex, (bme-daco)Fe(NO), and simplifies studies of NO release mechanisms. We have used heme-type model complexes, Fe or Co porphyrins as NO acceptors, yielding (porphyrin)M(NO), where M is Fe or Co, and monitored reactions by ν(NO) Fourier transform IR spectroscopy. Reaction products were verified by electrospray ionization mass spectrometry. Rudimentary mechanistic studies suggest a role for HNO in the NO release from the dinitrosyl; the mononitrosyl benefits as well from acid catalysis. Other NO uptake complexes such as [(N2S2)Fe]2 [N2S2 is bme-daco or N, N’-bis(2-mercapto-2-methylpropyl)-daco] are shown to form Fe(NO) mononitrosyls with stability and spectroscopic signatures similar to those of the porphyrins. [ABSTRACT FROM AUTHOR]

Abstract: Addition of AgBF4 to (bme-dach)Fe(NO), (bme-dach, N,N′-bis(2-mercapto-ethyl)-1,4-diazacycloheptane) affords a pentametallic C3 paddlewheel complex, {[(bme-dach)Fe(NO)]3Ag2}[BF4]2, resulting from the ability of the thiolate sulfurs of the N2S2 complex to serve as a bidentate bridging ligand to Ag+ ions. Single crystal X-ray analysis reveals the NO ligands coordinated to each Fe are all pointed in the same direction, resulting in a threefold rotation axis and a pseudo-mirror plane bisecting the Ag⋯Ag axis in the asymmetric unit cell. This Ag2 trigonal paddlewheel complex of non-bonded Ag⋯Ag average distance=2.866(3)Ǻ has also been characterized by infrared and UV–vis spectroscopies. The complex shows paramagnetism both in solution (Evans’ method) and in the solid state due to three S=½ {Fe(NO)}7 units. The EPR spectrum shows a single isotropic signal with g =2.024. SQUID analysis confirms this paramagnetism yielding a χT value of 1.17emu-K/mol with the presence of weak ferromagnetic coupling evident at temperatures less than 20K. To our knowledge this is the first example of a paddlewheel complex in which paramagnetism exists within the bridging bidentate ligand “paddles”. [Copyright &y& Elsevier]

Selective synthetic routes to isomeric diiron dithiolate complexes containing the (EtO)2PN(Me)P(OEt)2 (PNP) ligand in an unsymmetrical chelating. role, for example, (μ-pdt)[Fe(CO)3][Fe(CO)(κ²-PNP)] (3) and as a symmetrically bridging ligand in (μ-pdt)(μ-PNP)[Fe(CO)2]2 (4), have been developed. 3 was converted to 4 in 75% yield after extensive reflux in toluene. The reactions of 3 with PMe3 and P(OEt)3 afforded bis-monodentate P-donor complexes (μ-pdt)[Fe(CO)2PR3][Fe(CO)2(PNP)] (PR3 = PMe3, 5; P(OEt)3, 7), respectively, which are formed via an associative PMe3 coordination reaction followed by an intramolecular CO-migration process from the Fe(CO)3 to the Fe(CO)(PNP) unit with concomitant opening of the Fe-PNP chelate ring. The PNP-monodentate complexes 5 and 7 were converted to a trisubstituted diiron complex (μ-pdt)(μ-PNP)[Fe(CO)PR3][Fe(CO)2] (PR3 = PMe3, 6; P(OEt)3, 8) on release of 1 equiv CO when refluxing in toluene. Variable-temperature 31P NMR spectra show that trisubstituted diiron complexes each exist as two configuration isomers in solution. All diiron dithiolate complexes obtained were characterized by MS, IR, NMR spectroscopy, elemental analysis, and X-ray diffraction studies. [ABSTRACT FROM AUTHOR]

Abstract: The flexibility of the coordination sphere in the diiron organometallic is likely an important design component in nature''s electrocatalyst for proton reduction or H2 oxidation, i.e, the active site of [FeFe]hydrogenase. A series of complexes, (μ-SCH2CRR′CH2S)[Fe(CO)3][Fe(CO)2L] with steric bulk incorporated into the μ-S-to-S linker was synthesized and the compounds were analyzed by infrared spectroscopy and cyclic voltammetry [(R/R′=Me/Me, Et/Et, Bu/Et), (L=CO, PPh3, IMes (1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene), and IMe (1,3-dimethylimidazole-2-ylidene))]. While added steric bulk at the bridgehead carbon of the μ-SCH2CR2CH2S produced little change in the ground state structures (X-ray diffraction) and electronic character for the (μ-SRS)[Fe(CO)3]2 complexes, monosubstitution of a CO with L produced distortions consistent with steric interference of the μ-SRS with nearby ligands as compared to the similar (μ-pdt)[Fe(CO)3][Fe(CO)2L] (pdt=S(CH2)3S). Variable temperature NMR studies have shown that the activation barrier for CO site exchange on the sterically bulky complexes decreases in a manner predicted by theory [J.W. Tye, M.B. Hall, M.Y. Darensbourg, Inorg. Chem. 45 (2006) 1552]. [Copyright &y& Elsevier]

Studies the ability of mu-oxo to bridge iron, which is importance in biological systems. Reaction of molecular oxygen with a solution of diiron(II) complex; Abundance of sulfur-rich iron moieties in biology; How differences arise; Topological description of the iron(II) dimers; Physical characteristics of the iron(II) dimers; Methodology and results of the study.