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This perspective aims at illustrating a computational viewpoint on some specific issues concerning structure–activity relationships related to [FeFe]-hydrogenase ([FeFe]-H2ase) biomimicry. Most of the research outlined herein has been addressed by means of density functional theory (DFT) based tools, in some cases in conjunction with experimental techniques. The number of computational, experimental and mixed approach studies on the "hydrogenase models" topic is extraordinarily high. Accordingly, several comprehensive reviews have been published over the last twenty years. Moreover, the number of iron compounds of increasing nuclearity that have been considered as "biomimetic models" of [FeFe]-H2ase has grown exponentially over time. Additionally, the issues regarding some mismatches existing between the natural system and related synthetic analogues, are quite variegated. As a consequence of the countless examples that could be considered as related to "hydrogenase mimicry", the intent of the present contribution is to provide an account of a limited number of recent study cases, in which DFT has been employed to elucidate redox properties, reactivity issues of selected examples of diiron biomimicry. Herein the treated topics have been explicitly chosen to show how DFT has allowed us to rationalize and complement experimental observations, with a special focus on electrocatalysis aspects. Finally, the specific purpose of this perspective is to show how mutually intertwined are the various issues concerning a fascinating branch of biomimetic research. [ABSTRACT FROM AUTHOR]

Catalytic H2 oxidation has been dissected by means of DFT into the key steps common to the Fe2 unit of both the [FeFe]‐hydrogenase cofactor and selected biomimics. The aim was to elucidate the molecular details underlying the very different performances of the two systems. We found that the better enzyme performance is based on a single iron atom that is maintained electron‐poor, favoring H2 binding, although embedded within a highly electron‐rich cofactor, ensuring a facile oxidation of the Fe2–H2 adduct. This is due to 1) CN− coordinating to both iron atoms, due to their amphipathic Lewis acid/base properties, and 2) the 4Fe4S subunit further withdrawing electrons from the Fe2 core. Preserving a moderate electron deficiency at a single iron also helps the cofactor preserve hydride affinity, which favors H2 cleavage. Such valuable characteristics allow the biocatalyst to turnover close to equilibrium conditions. All previous biomimicry has shown, in contrast, the impossibility to properly balance the two apparently contrasting aforementioned requisites, although evident progress has been made by the H2‐ase community. Disclosure of the differences identified could inspire the design of novel biomimics, for instance, reconsidering the use of CN− in the catalyst architecture. Indeed, in the presence of bases normally employed in oxidative catalysis, undesired stable protonation at coordinated CN−, which affects the opposite process (proton reduction), could be overcome. Nature versus biomimicry: Dissecting H2 oxidation by the [FeFe]‐H2ase core in comparison with a series of Fe2S2 models has revealed that CN− ligands and the 4Fe4S subunit are the key to the higher catalytic performance of the enzyme compared with the synthetic compounds. Indeed, cyanides and cubane provide a single electron‐poor iron (which assists H2 binding) embedded within an electron‐rich environment, which in turn ensures a facile subsequent oxidation. [ABSTRACT FROM AUTHOR]

[NiFe]-hydrogenases catalyse the relevant H → 2H + 2e reaction. Aerobic oxidation or anaerobic oxidation of this enzyme yields two inactive states called Ni-A and Ni-B. These states differ for the reactivation kinetics which are slower for Ni-A than Ni-B. While there is a general consensus on the structure of Ni-B, the nature of Ni-A is still controversial. Indeed, several crystallographic structures assigned to the Ni-A state have been proposed, which, however, differ for the nature of the bridging ligand and for the presence of modified cysteine residues. The spectroscopic characterization of Ni-A has been of little help due to small differences of calculated spectroscopic parameters, which does not allow to discriminate among the various forms proposed for Ni-A. Here, we report a DFT investigation on the nature of the Ni-A state, based on systematic explorations of conformational and configurational space relying on accurate energy calculations, and on comparisons of theoretical geometries with the X-ray structures currently available. The results presented in this work show that, among all plausible isomers featuring various protonation patterns and oxygenic ligands, the one corresponding to the crystallographic structure recently reported by Volbeda et al. (J Biol Inorg Chem 20:11-22, 19)-featuring a bridging hydroxide ligand and the sulphur atom of Cys64 oxidized to bridging sulfenate-is the most stable. However, isomers with cysteine residues oxidized to terminal sulfenate are very close in energy, and modifications in the network of H-bond with neighbouring residues may alter the stability order of such species. [ABSTRACT FROM AUTHOR]

Nature is a valuable source of inspiration in the design of catalysts, and various approaches are used to elucidate the mechanism of hydrogenases, the enzymes that oxidize or produce H2. In FeFe hydrogenases, H2 oxidation occurs at the H-cluster, and catalysis involves H2 binding on the vacant coordination site of an iron centre. Here, we show that the reversible oxidative inactivation of this enzyme results from the binding of H2 to coordination positions that are normally blocked by intrinsic CO ligands. This flexibility of the coordination sphere around the reactive iron centre confers on the enzyme the ability to avoid harmful reactions under oxidizing conditions, including exposure to O2. The versatile chemistry of the diiron cluster in the natural system might inspire the design of novel synthetic catalysts for H2 oxidation. [ABSTRACT FROM AUTHOR]

Fe-only hydrogenases are enzymes that catalyze dihydrogen production or oxidation, due to the presence of an unusual Fe6S6 cluster (the so-called H-cluster) in their active site, which is composed of a Fe2S2 subsite, directly involved in catalysis, and a classical Fe4S4 cubane cluster. Here, we present a hybrid quantum mechanical and molecular mechanical (QM/MM) investigation of the Fe-only hydrogenase from Desulfovibrio desulfuricans, in order to unravel key issues regarding the activation of the enzyme from its completely oxidized inactive state (Hoxinact) and the influence of the protein environment on the structural and catalytic properties of the H-cluster. Our results show that the Fe2S2 subcluster in the FeIIFeII redox state-which is experimentally observed for the completely oxidized form of the enzyme-binds a water molecule to one of its metal centers. The computed QM/MM energy values for water binding to the diferrous subsite are in fact over 70 kJ mol-1; however, the affinity toward water decreases by 1 order of magnitude after a one-electron reduction of Hoxinact, thus leading to the release of coordinated water from the H-cluster. The investigation of a catalytic cycle of the Fe-only hydrogenase that implies formation of a terminal hydride ion and a di(thiomethyl)amine (DTMA) molecule acting as an acid/base catalyst indicates that all steps have reasonable reaction energies and that the influence of the protein on the thermodynamic profile of H2 production catalysis is not negligible. QM/MM results show that the interactions between the Fe2S2 subsite and the protein environment could give place to structural rearrangements of the H-cluster functional for catalysis, provided that the bidentate ligand that bridges the iron atoms in the binuclear subsite is actually a DTMA residue. [ABSTRACT FROM AUTHOR]

Density functional theory was used to compare reaction pathways for H2 formation and H+ reduction catalyzed by models of the binuclear cluster found in the active site of [Fe] hydrogenases. Terminal W binding to an FeI-FI form, followed by monoelectron reduction and protonation of the di(thiomethyl)amine ligand, can conveniently lead to H2 formation and release, suggesting that this mechanism could be operative within the enzyme active site. However, a pathway that implies the initial formation of FeII-FeII μ-H species and release of H2 from an FeII-FeI form is characterized by only slightly less favored energy profiles. In both cases, H2 formation becomes less favored when taking into account the competition between CN and amine groups for H+ binding, an observation that can be relevant for the design of novel synthetic catalysts. H2 cleavage can take place on FeII-FeII redox species, in agreement with previous proposals [Fan, H.-J.; Hall, M. B. J. Am. Chem. Soc. 2001, 123, 3828] and, in complexes characterized by terminal CO groups, does not need the involvement of an external base. The step in H2 oxidation characterized by larger energy barriers corresponds to the second W extraction from the cluster, both considering FeII-FeII and FeII-FeIII species. A comparison of the different reaction pathways reveals that H2 formation could involve only FI1-FI, FeII-FeI, and FeII-FeII species, whereas FeIII-FeII species might be relevant in H2 cleavage. [ABSTRACT FROM AUTHOR]

We report a complex with a rare CuII-O-CuII structural motif that is stable at room temperature, which allows its in-depth characterization by a variety of spectroscopic methods. Interest in such compounds is fueled by the recent discovery that a CuII-O-CuII species on the surface of Cu-ZSM-5 is capable of oxidizing methane to methanol, and this in turn ties into mechanistic discussions on the methane oxidation at the dicopper site within the particulate methane monooxygenase. For the synthesis of our Cu2O complex we have developed a novel, neutral ligand system, FurNeu, exhibiting two N-(N',N'-dimethylaminoethyl)(2-pyridylmethyl)amino binding pockets connected by a dibenzofuran spacer. The reaction of FurNeu with CuCl yielded [FurNeu](Cu2(μ-Cl))(CuCl2), 1, demonstrating the geometric potential of the ligand to stabilize Cu-X-Cu moieties. A CuI precursor with weakly coordinating anions was chosen in the next step, namely [Cu(NCCH3)4]OTf, which led to the formation of [FurNeu](Cu(NCCH3))2(OTf)2, 3. Treatment of 3 with O2 or PhIO led to identical green solutions, whose UV-vis spectra were markedly different from the one displayed by [FurNeu](Cu)2(OTf)4, 4, prepared independently from FurNeu and Cu(OTf)2. Further investigations including PhIO consumption experiments, NMR and UV-vis spectroscopy, HR-ESI mass spectrometry, and protonation studies led to the identification of the green product as [FurNeu](Cu2(μ-O))(OTf)2, 5. DOSY NMR spectroscopy confirmed its monomeric character. Over longer periods of time 5 decomposes to give [Cu(picoloyl)2], formed through an oxidative N-dealkylation reaction followed by further oxidation of the ligand. Due to its slow decomposition reaction, all attempts to crystallize 5 failed. However, its structure in solution could be determined by EXAFS analysis in combination with DFT calculations, which revealed a Cu-O-Cu angle that amounts to 105.17°. Moreover, TDDFT calculations helped to rationalize the UV-vis absorptions of 5. The reactivity of complex 5 with 2,4-di-tert-butylphenol, DTBP, was also investigated; the initially formed biphenol product, TBBP, was found to further react in the presence of excessive O2 to yield 2,4,7,9-tetra-tert-butyloxepino[2,3-b]benzofuran, TBOBF, via an intermediate diphenoquinone. It turned out that 5, or its precursor 3, can even be employed as a catalyst for the oxidation of DTBP to TBBP or for the oxidation of TBBP to TBOBF. [ABSTRACT FROM AUTHOR]

• Hierarchical quantum-chemical and hybrid quantum/classical modeling of the MoCu-dependent CO-dehydrogenase. • Smooth energy landscape associated with formation of the key thiocarbonate intermediate unveiled. • Rapid interconversion of several isomers of the CO-enzyme encounter complex supported by theoretical results. • Enzyme inhibition by butyl isocyanide explained based on the computed energy profiles. We present a theoretical investigation providing key insights on a long-standing controversial issue that dominated the debate on carbon monoxide oxidation by Mo Cu CO-dehydrogenases. Previous investigations gravitate around the possible occurrence of a thiocarbonate intermediate, that was repeatedly reported to behave as a thermodynamic sink on the catalytic energy landscape. By using a hierarchy of quantum mechanical and hybrid quantum/classical models of the enzyme, we show that no such energy sink is present on the catalytic energy profile. Consequent perspectives for the definition of a novel mechanistic proposal for the enzyme-catalyzed CO-oxidation are discussed in light of the recent literature. [ABSTRACT FROM AUTHOR]

The redox properties of Ni complexes bound to a new ligand, [DMC-nit]+, where a N-heterocyclic nitrenium group is anchored on a 1,4,8,11-tetraazacyclotetradecane backbone, have been examined using spectroscopic and DFT methods. Ligand-based [(DMC-nit)Ni]2+/+ reduction and metal-based [(DMC-nit)Ni]2+/3+ oxidation processes have been established for the [(DMC-nit)Ni]+/2+/3+ redox series, which represents the first examples of nitrenium nitrogen (Nnit)-bound first-row transition-metal complexes. An unprecedented bent binding mode of Nnit in [(DMC-nit)Ni]2+ is observed, which possibly results from the absence of any Nnit→Ni σ-donation. For the corresponding [(DMC-nit)Ni(F)]2+ complex, σ-donation is dominant, and hence a coplanar arrangement at Nnit is predicted by DFT. The binding of the triazolium ion to Ni enables new chemistry (formate oxidation) that is not observed in a derivative that lacks this functional group. Thus the N-heterocyclic nitrenium ligand is a potentially useful and versatile reagent in transition-metal-based catalysis. [ABSTRACT FROM AUTHOR]