H2 Activation in [FeFe]-Hydrogenase Cofactor Versus Diiron Dithiolate Models: Factors Underlying the Catalytic Success of Nature and Implications for an Improved Biomimicry

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/bas e 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.     

Silicon–Heteroaromatic [FeFe] Hydrogenase Model Complexes: Insight into Protonation,Electrochemical Properties,and Molecular Structures

To learn from Nature how to create an efficient hydrogen‐producing catalyst, much attention has been paid to the investigation of structural and functional biomimics of the active site of [FeFe]‐hydrogenase. To understand their catalytic activities, the μ‐S atoms of the dithiolate bridge have been considered as possible basic sites during the catalytic processes. For this reason, a series of [FeFe]‐H₂ase mimics have been synthesized and characterized. Different [FeFe]‐hydrogenase model complexes containing bulky Si–heteroaromatic systems or fluorene directly attached to the dithiolate moiety as well as their mono‐PPh₃‐substituted derivatives have been prepared and investigated in detail by spectroscopic, electrochemical, X‐ray diffraction, and computational methods. The assembly of the herein reported series of complexes shows that the μ‐S atoms can be a favored basic site in the catalytic process. Small changes in the (hetero)‐aromatic system of the dithiolate moiety are responsible for large differences in their structures. This was elucidated in detail by DFT calculations, which were consistent with the experimental results.     

Toward Functional Type III [Fe]‐Hydrogenase Biomimics for H2 Activation: Insights from Computation

The chemistry of [Fe]‐hydrogenase has attracted significant interest due to its ability to activate molecular hydrogen. The intriguing properties of this enzyme have prompted the synthesis of numerous small molecule mimics aimed at activating H₂. Despite considerable effort, a majority of these compounds remain nonfunctional for hydrogenation reactions. By using a recently synthesized model as an entry point, seven biomimetic complexes have been examined through DFT computations to probe the influence of ligand environment on the ability of a mimic to bind and split H₂. One mimic, featuring a bidentate diphosphine group incorporating an internal nitrogen base, was found to have particularly attractive energetics, prompting a study of the role played by the proton/hydride acceptor necessary to complete the catalytic cycle. Computations revealed an experimentally accessible energetic pathway involving a benzaldehyde proton/hydride acceptor and the most promising catalyst.     

The E2 state of FeMoco: Hydride Formation versus Fe Reduction and a Mechanism for H2 Evolution

The iron-molybdenum cofactor (FeMoco) is responsible for dinitrogen reduction in Mo nitrogenase. Unlike the resting state, E₀, reduced states of FeMoco are much less well characterized. The E₂ state has been proposed to contain a hydride but direct spectroscopic evidence is still lacking. The E₂ state can, however, relax back the E₀ state via a H₂ side-reaction, implying a hydride intermediate prior to H₂ formation. This E₂→E₀ pathway is one of the primary mechanisms for H₂ formation under low-electron flux conditions. In this study we present an exploration of the energy surface of the E₂ state. Utilizing both cluster-continuum and QM/MM calculations, we explore various classes of E₂ models: including terminal hydrides, bridging hydrides with a closed or open sulfide-bridge, as well as models without. Importantly, we find the hemilability of a protonated belt-sulfide to strongly influence the stability of hydrides. Surprisingly, non-hydride models are found to be almost equally favorable as hydride models. While the cluster-continuum calculations suggest multiple possibilities, QM/MM suggests only two models as contenders for the E₂ state. These models feature either i) a bridging hydride between Fe₂ and Fe₆ and an open sulfide-bridge with terminal SH on Fe₆ ( E₂-hyd ) or ii) a double belt-sulfide protonated, reduced cofactor without a hydride ( E₂-nonhyd ). We suggest both models as contenders for the E₂ redox state and further calculate a mechanism for H₂ evolution. The changes in electronic structure of FeMoco during the proposed redox-state cycle, E₀→E₁→E₂→E₀, are discussed.     

[FeFe] Hydrogenase: Protonation of {2Fe3S} Systems and Formation of Super‐reduced Hydride States

The synthesis and crystallographic characterization of a complex possessing a well‐defined {2Fe3S(μ‐H)} core gives access to a paramagnetic bridging hydride with retention of the core geometry. Chemistry of this 35‐electron species within the confines of a thin‐layer FTIR spectro‐electrochemistry cell provides evidence for a unprecedented super‐reduced Fe^I(μ‐H)Fe^I intermediate.     

Ligand Rearrangements at Fe/S Cofactors: Slow Isomerization of a Biomimetic [2Fe‐2S] Cluster

Ligand exchange plays an important role in the biogenesis of Fe/S clusters, most prominently during cluster transfer from a scaffold protein to its target protein. Although in vivo and in vitro studies have provided some insight into this process, the microscopic details of the ligand exchange steps are mostly unknown. In this work, the kinetics of the ligand rearrangement in a biomimetic [2Fe‐2S] cluster with mixed S/N capping ligands have been studied. Two geometrical isomers of the cluster are present in solution, and mechanistic insight into the isomerization process was obtained by variable‐temperature ¹H NMR spectroscopy. Combined experimental and computational results reveal that this is an associative process that involves the coordination of a solvent molecule to one of the ferric ions. The cluster isomerizes at least two orders of magnitude faster in its protonated and mixed‐valent states. These findings may contribute to a deeper understanding of cluster transfer and sensing processes occurring in Fe/S cluster biogenesis.     

Phenalenyl‐Based Organozinc Catalysts for Intramolecular Hydroamination Reactions: A Combined Catalytic,Kinetic, and Mechanistic Investigation of the Catalytic Cycle

Herein, we report the synthesis and characterization of two organozinc complexes that contain symmetrical phenalenyl (PLY)‐based N,N‐ligands. The reactions of phenalenyl‐based ligands with ZnMe₂ led to the formation of organozinc complexes [N(Me),N(Me)‐PLY]ZnMe ( 1 ) and [N(iPr),N(iPr)‐PLY]ZnMe ( 2 ) under the evolution of methane. Both complexes ( 1 and 2 ) were characterized by NMR spectroscopy and elemental analysis. The solid‐state structures of complexes 1 and 2 were determined by single‐crystal X‐ray crystallography. Complexes 1 and 2 were used as catalysts for the intramolecular hydroamination of unactivated primary and secondary aminoalkenes. A combined approach of NMR spectroscopy and DFT calculations was utilized to obtain better insight into the mechanistic features of the zinc‐catalyzed hydroamination reactions. The progress of the catalysis for primary and secondary aminoalkene substrates with catalyst 2 was investigated by detailed kinetic studies, including kinetic isotope effect measurements. These results suggested pseudo‐first‐order kinetics for both primary and secondary aminoalkene activation processes. Eyring and Arrhenius analyses for the cyclization of a model secondary aminoalkene substrate afforded ΔH^≠=11.3 kcal mol^?1, ΔS^≠=?35.75 cal K^?1 mol^?1, and E_a=11.68 kcal mol^?1. Complex 2 exhibited much‐higher catalytic activity than complex 1 under identical reaction conditions. The in situ NMR experiments supported the formation of a catalytically active zinc cation and the DFT calculations showed that more active catalyst 2 generated a more stable cation. The stability of the catalytically active zinc cation was further supported by an in situ recycling procedure, thereby confirming the retention of catalytic activity of compound 2 for successive catalytic cycles. The DFT calculations showed that the preferred pathway for the zinc‐catalyzed hydroamination reactions is alkene activation rather than the alternative amine‐activation pathway. A detailed investigation with DFT methods emphasized that the remarkably higher catalytic efficiency of catalyst 2 originated from its superior stability and the facile formation of its cation compared to that derived from catalyst 1 .     

Electrochemical insights into the mechanisms of proton reduction by [Fe2(CO)6{micro-SCH2N(R)CH2S}] complexes related to the [2Fe](H) subsite of [FeFe]hydrogenase

Electrochemical investigations on a structural analogue of the [2Fe](H) subsite of [FeFe]H(2)ases, namely, [Fe(2)(CO)(6){micro-SCH(2)N(CH(2)CH(2)- OCH(3))CH(2)S}] (1), were conducted in MeCN/NBu(4)PF(6) in the presence of HBF(4)/Et(2)O or HOTs. Two different catalytic proton reduction processes operate, depending on the strength and the concentration of the acid used. The first process, which takes place around -1.2 V for both HBF(4)/Et(2)O and HOTs, is limited by the slow release of H(2) from the product of the {2 H(+)/2 e} pathway, 1-2H. The second catalytic process, which occurs at higher acid concentrations, takes place at different potentials depending on the acid present. We propose that this second mechanism is initiated by protonation of 1-2H when HBF(4)/Et(2)O is used, whereas the reduction of 1-2H is the initial step in the presence of the weaker acid HOTs. The potential of the second process, which occurs around -1.4 V (reduction potential of 1-3H(+)) or around -1.6 V (the reduction potential of 1-2H) is thus dependent on the strength of the available proton source.     

Intramolecular Gas‐Phase Reactions of Synthetic Nonheme Oxoiron(IV) Ions: Proximity and Spin‐State Reactivity Rules

The intramolecular gas‐phase reactivity of four oxoiron(IV) complexes supported by tetradentate N₄ ligands ( L ) has been studied by means of tandem mass spectrometry measurements in which the gas‐phase ions [Fe^IV(O)( L )(OTf)]⁺ (OTf=trifluoromethanesulfonate) and [Fe^IV(O)( L )]²⁺ were isolated and then allowed to fragment by collision‐induced decay (CID). CID fragmentation of cations derived from oxoiron(IV) complexes of 1,4,8,11‐tetramethyl‐1,4,8,11‐tetraazacyclotetradecane (tmc) and N,N′‐bis(2‐pyridylmethyl)‐1,5‐diazacyclooctane ( L ⁸Py₂) afforded the same predominant products irrespective of whether they were hexacoordinate or pentacoordinate. These products resulted from the loss of water by dehydrogenation of ethylene or propylene linkers on the tetradentate ligand. In contrast, CID fragmentation of ions derived from oxoiron(IV) complexes of linear tetradentate ligands N,N′‐bis(2‐pyridylmethyl)‐1,2‐diaminoethane (bpmen) and N,N′‐bis(2‐pyridylmethyl)‐1,3‐diaminopropane (bpmpn) showed predominant oxidative N‐dealkylation for the hexacoordinate [Fe^IV(O)( L )(OTf)]⁺ cations and predominant dehydrogenation of the diaminoethane/propane backbone for the pentacoordinate [Fe^IV(O)( L )]²⁺ cations. DFT calculations on [Fe^IV(O)(bpmen)] ions showed that the experimentally observed preference for oxidative N‐dealkylation versus dehydrogenation of the diaminoethane linker for the hexa‐ and pentacoordinate ions, respectively, is dictated by the proximity of the target C? H bond to the oxoiron(IV) moiety and the reactive spin state. Therefore, there must be a difference in ligand topology between the two ions. More importantly, despite the constraints on the geometries of the TS that prohibit the usual upright σ trajectory and prevent optimal σ_CH–σ* overlap, all the reactions still proceed preferentially on the quintet (S=2) state surface, which increases the number of exchange interactions in the d block of iron and leads thereby to exchange enhanced reactivity (EER). As such, EER is responsible for the dominance of the S=2 reactions for both hexa‐ and pentacoordinate complexes.     

Bioorganometallic Chemistry with IspG and IspH: Structure,Function, and Inhibition of the [Fe4S4] Proteins Involved in Isoprenoid Biosynthesis

Enzymes of the methylerythritol phosphate pathway of isoprenoid biosynthesis are attractive anti‐infective drug targets. The last two enzymes of this pathway, IspG and IspH, are [Fe₄S₄] proteins that are not produced by humans and catalyze 2 H⁺/ 2 e^? reductions with novel mechanisms. In this Review, we summarize recent advances in structural, mechanistic, and inhibitory studies of these two enzymes. In particular, mechanistic proposals involving bioorganometallic intermediates are presented, and compared with other mechanistic possibilities. In addition, inhibitors based on substrate analogues as well as developed by rational design and compound‐library screening, are discussed. The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti‐infective drug design targeting [Fe₄S₄] clusters in proteins.     

Catalytic Potential of Post-Transition Metal Doped Graphene-Based Single-Atom Catalysts for the CO2 Electroreduction Reaction

Catalysts are required to ensure electrochemical reduction of CO₂ to fuels proceeds at industrially acceptable rates and yields. As such, highly active and selective catalysts must be developed. Herein, a density functional theory study of p-block element and noble metal doped graphene-based single-atom catalysts in two defect sites for the electrochemical reduction of CO₂ to CO and HCOOH is systematically undertaken. It is found that on all of the systems considered, the thermodynamic product is HCOOH. Pb/C₃, Pb/N₄ and Sn/C₃ are identified as having the lowest overpotential for HCOOH production while Al/C₃, Al/N₄, Au/C₃ and Ga/C₃ are identified as having the potential to form higher order products due to the strength of binding of adsorbed HCOOH.     

From molecule to bulk material: optical properties of hydrogen-bonded dimers [C12H12N4O2AgPF6]2 and [C28H28N6O3AgPF6]2 depend on the arrangement of the oxime moieties

The dependence of the optical properties of [C(12)H(12)N(4)O(2)AgPF(6)](2) (dimer-1) and [C(28)H(28)N(6)O(3)AgPF(6)](2) (dimer-2) on the arrangement of the oxime moieties in the molecule and in bulk crystals was investigated by means of time-dependent density functional theory. Dimer-1 with simple pyridine oxime ligands and a wavy arrangement has a smaller dipole moment and larger transition energy between the two states, and thus smaller third-order polarizabilities and two-photon absorption cross sections. Dimer-2 with extended pyridine oxime ligands and a ladder arrangement has a larger dipole moment and smaller transition energy between the two states, and thus larger third-order polarizabilities and two-photon absorption cross sections. The lowest energy absorption band is red-shifted for dimer-2 as compared with dimer-1, due to more pronounced pi-pi delocalization interactions and weaker hydrogen bonding in dimer-2. The electronic absorption spectra, frequency-dependent third-order polarizabilities, and two-photon absorption cross sections involve significant contributions from charge transfers from pi/pi* orbitals of the pyridine oxime ligands but no contribution from PF(6) (-) ions or H(2)O molecules in the wavelength range studied for the monomers and dimers of the C(12)H(12)N(4)O(2)AgPF(6) and C(28)H(28)N(6)O(3)AgPF(6) molecules. The third-order susceptibilities and two-photon absorption coefficients of bulk solids were estimated on the basis of the optical properties of the corresponding dimers, and the bulk material constructed from dimer-2 has the larger optical parameters of the two.     

Dissecting the intimate mechanism of cyanation of {2Fe3S} complexes related to the active site of all-iron hydrogenases by DFT analysis of energetics, transition states, intermediates and products in the carbonyl substitution pathway

A bridging carbonyl intermediate with key structural elements of the diiron sub-site of all-iron hydrogenase has been experimentally observed in the CN/CO substitution pathway of the {2Fe3S} carbonyl precursor, [Fe(2)(CO)(5){MeSCH(2)C(Me)(CH(2)S)(2)}]. Herein we have used density functional theory (DFT) to dissect the overall substitution pathway in terms of the energetics and the structures of transition states, intermediates and products. We show that the formation of bridging CO transitions states is explicitly involved in the intimate mechanism of dicyanation. The enhanced rate of monocyanation of {2Fe3S} over the {2Fe2S} species [Fe(2)(CO)(6){CH(2)(CH(2)S)(2)}] is found to rest with the ability of the thioether ligand to both stabilise a mu-CO transition state and act as a good leaving group. In contrast, the second cyanation step of the {2Fe3S} species is kinetically slower than for the {2Fe2S} monocyanide because the Fe2 atom is deactivated by coordination of the electron-donating thioether group. In addition, hindered rotation and the reaction coordinate of the approaching CN(-) group, are other factors which explain reactivity differences in {2Fe2S} and {2Fe3S} systems. The intermediate species formed in the second cyanation step of {2Fe3S} species is a mu-CO species, confirming the structural assignment made on the basis of FT-IR data (S. J. George, Z. Cui, M. Razavet, C. J. Pickett, Chem. Eur. J. 2002, 8, 4037-4046). In support of this we find that computed and experimental IR frequencies of structurally characterised {2Fe3S} species and those of the bridging carbonyl intermediate are in excellent agreement. In a wider context, the study may provide some insight into the reactivity of dinuclear systems in which neighbouring group on-off coordination plays a role in substitution pathways.     

Aerobic Damage to [FeFe]‐Hydrogenases: Activation Barriers for the Chemical Attachment of O2

[FeFe]‐hydrogenases are the best natural hydrogen‐producing enzymes but their biotechnological exploitation is hampered by their extreme oxygen sensitivity. The free energy profile for the chemical attachment of O₂ to the enzyme active site was investigated by using a range‐separated density functional re‐parametrized to reproduce high‐level ab initio data. An activation free‐energy barrier of 13 kcal mol^?1 was obtained for chemical bond formation between the di‐iron active site and O₂, a value in good agreement with experimental inactivation rates. The oxygen binding can be viewed as an inner‐sphere electron‐transfer process that is strongly influenced by Coulombic interactions with the proximal cubane cluster and the protein environment. The implications of these results for future mutation studies with the aim of increasing the oxygen tolerance of this enzyme are discussed.