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Decades of biophysical study on the hydrogenase (H2ase) enzymes have yielded sufficient information to guide the synthesis of analogues of their active sites. Three families of enzymes serve as inspiration for this work: the [FeFe]-, [NiFe]-, and [Fe]-H2ases, all of which feature iron centers bound to both CO and thiolate. Artificial H2ases effect the oxidation of H2 of H2 and the reverse reaction, the reduction of protons. These reactions occur via the intermediacy of metal hydrides. The inclusion of amine bases within the catalysts is an important design feature that is emulated in related bioinspired catalysts. Continuing challenges are the low reactivity of H2 towards biomimetic H2ases.
Hydrogenases (H2ases) are enzymes that catalyze the interconversion of protons and electrons with H2. They exist in a variety of bacterial and archaeal organisms where they dispose of reducing equivalents as gaseous H2 (a waste product!) or oxidize H2 in processes that are coupled to the reduction of an oxidant such as sulfate. Otherwise, H2 is inert in most biological contexts. The ability of evolutionarily primitive organisms to efficiently process H2 reflects the reducing environment assumed for early Earth. The biochemistry underpinning such organisms is potentially relevant to a variety of technologies that use hydrogen, either directly (e.g., hydrogenations of alkenes) or indirectly (e.g., conversion of nitrogen into ammonia using natural gas). New technologies could, in principle, be based on the active sites of the H2ases, which has encouraged efforts to replicate their behavior in vitro. Furthermore, a mechanistic understanding of these enzymatic processes could underpin therapies for certain bacterial infections.
Hydrogen is a potential energy vector for the future. New production, storage, and utilization technologies are needed to enable this “hydrogen economy.” Study of artificial H2ases could contribute solutions to all of these activities. Hydrogen is currently produced from hydrocarbons by steam reforming. The process is estimated to be 60–85% energy-efficient and uses Ni catalysts. Carbon-neutral routes to H2 mainly rely on the decomposition of water. High temperature electrolysis is even more efficient than steam reforming but is not competitive because of the high price of electricity. Ultimately, H2-producing electrolyzers are likely to be powered by solar energy.
Artificial H2ases are metal complexes that exhibit at least some of the catalytic properties of the enzymes. Their design is informed by structural biology. Targeted properties for artificial H2ases include that they be (i) inexpensive, (ii) efficient (i.e., operate at low overpotentials and rates of thousands of moles of H2 produced per mole of catalyst per second), and (iii) rugged. Enthusiasm for catalysts derived from “easth-abundant metals” (e.g., Fe, Ni, possibly Co) is high, but it should be noted that iron- and cobalt-based catalysts have often been displaced in favor of expensive platinum-metal catalysts. Artificial H2ases derived from nonprecious metals remains the primary focus. In Nature, there are three classes of H2ase, each designated by the metal content of their active sites: [FeFe], [NiFe], and [Fe].
“H2ases cleave H2 heterolytically, which means that H2 is cleaved into H− and H+;H− isbound to the metal, and H+ is bound to a base or released to the solvent. In contrast, low-valent platinum metals typically excel at homolytic activation (“oxidative addition”) of H2, in which H2 is reduced into two equivlents of metal bound H− while the metal is oxidized. (Figure 1). H− binds to metals in two main ways: (i) as a “terminal hydride” (i.e. M-H) or (ii) as a “bridging hydride” (i.e. M-H-M). [FeFe]-H2ases operate via terminal hydrides, and the [NiFe]-H2ases feature -hydrides (“mu;-hydrides”). It is likely that -hydrides arise via transient terminal hydrides. Metal hydrides can be oxidized by two electrons, whereupon the H− ligand is converted to H+. Heterolytic activation is ideal for the hydrogenation of polar substrates, as is practiced by the [Fe]-H2ase, and for the extraction of electrons for chemical work, as is practiced by the other two H2ases. Heterolytic activation is an essential step in H2-based fuel cells utilizing first row metals.
The [FeFe] H2ases utilize two key states in the catalytic cycle, an oxidized state (Hox) that is poised to convert H2 to protons (as required for an H2-based fuel cell), and a reduced state (Hred) that is poised to convert protons to H2 (as required for energy storage). Artificial [FeFe]-H2ases have the formulae Fe2[(SCH2)2X](CO)6-xLx where L is a Lewis basic ligand, often organophosphines (R3P); Nature employs CN- and an 4Fe-4S cluster for L (Figure 2), but artificial [FeFe]-H2ases almost always dispense with such complicating ligands. The dithiolate can be varied from −SCH2CH2S− to − SCH2XCH2S−, where X = CH2, O, or the biomimetic NR′ (R′ = H, alkyl, aryl). For the design of artificial H2ases, the amine-functionality not only assists with proton shuttling (see below), but provides a convenient site for attachment of other groups such as photosensitizers. The redox potentials of catalysts can be adjusted by variations in the ligands.
It is clear that protonation of many artificial [FeFe]-H2ases occurs at a single Fe center,[17–19] as foretold by biophysical studies. It is tempting to speculate that catalysis via “terminal protonation” is evolutionarily advantaged. Relative to protonation of the Fe-Fe bond, the reorganizational energy associated with proton transfer at one metal may be smaller and the protonation/deprotonation rates would be correspondingly higher. Additional advantages to terminal hydrides are that they reduce at milder potentials and are adjacent to the dithiolate cofactor (see below). The majority of artificial [FeFe]-H2ases feature hydrides that bridge the two Fe centers, the so-called -hydrides. In terms of structure, μ-hydrides appear more relevant to the [NiFe]-H2ases, not the [FeFe]-H2ases where the bridging site is occupied by a CO ligand. Despite their abiological stereochemistry, some diiron μ-hydrides are excellent catalysts for H2 evolution.
Most [FeFe]-inspired artificial H2ases require additional energy beyond the thermodynamic minimum, thus they operate at large overpotentials (>500 mV). High overpotentials are often manifested by the requirement that H2 evolution only occurs with strong acids. Protonations can be very slow with weaker acids, e.g. those with pKa’s close to neutral pH, resulting in low catalytic rates.[22,23] Terminal protonation of [FeFe] models requires that the diiron center distort to a ‘rotated’ form that is primed for protonation. Adopting this rotated form has been calculated to require up to 10 kcal/mol, which may also contribute to the overpotential. Recent work shows that both steric bulk and electronic asymmetry can lower the barriers to rotation.
In artificial H2ases, the amine has recently been shown to strongly influence the rates of proton transfer to and from the diiron center. Weak acids are slow to protonate typical substituted metal centers, but complexes of the type Fe2((SCH2)2NH)(CO)2(PR3)4 readily catalyze H2 evolution even from weak acids via intermediacy of Fe(II)Fe(II) hydrides (Figure 3). Similarly, with suitable bases, such amine-complemented-hydrides readily deprotonate. The ease of these acid-base reactions is attributable to the low barriers associated with protonation at amines and the easy proton relay from the amine to the nearby Fe(I). The amine relay strategy promises also to be applicable to catalysts that operate via μ-hydrides.
Models for the Hox state have been prepared simply by oxidizing diiron(I) complexes,[16,29] These mixed valence models fail to react readily with H2. One clue into their flawed design is that these models bind CO only weakly, whereas the enzyme is strongly inhibited by CO. The H2-binding site appears to be Fe(I) but models and theory show that H2 prefers Fe(II) (ferrous). The binding of H2 could conceivably be coupled to oxidation at Fe (reader does not know what distal/proximal mean in the enzyme) to the Fe(II) via proton-coupled electron transfer (PCET). This analysis suggests more elaborate designs for the next-generation artificial [FeFe]-H2ases.
With the ultimate goal of obtaining H2 from water or possibly other renewable materials, much work has focused on photocatalytic ensembles containing mimics of the [FeFe]-H2ase active site. Relevant parameters include the redox properties and robustness of the diiron center and the sensitizer.[33–35] Hydrogen has recently been obtained with hundreds of turnovers by irradiation (455–850 nm) of solutions containing ascorbate, Ru(bipy)32+, and the catalyst Fe2(S2C6H2Cl2)(CO)6. H2 evolution occurs at the diiron center which is reduced by Ru(bipy)3+, which in turn is generated by ascorbate reduction of the photoexcited dication *Ru(bipy)32+. Thus, while the source of the reducing equivalents differs from the usual electrochemical experiments, the overall chemistry of the diiron hydrides remains the same as in thermal reactions. This area is poised for rapid growth with a focus on robustness, rates, photon energies, and the source of the reducing equivalents.
Artificial H2ases based on the active site of the [NiFe] H2ases are obvious targets because this enzyme is widespread and has been characterized crystallographically to high precision.[37,38] As for the [FeFe]-H2ases, only a few states are catalytically relevant. Advanced structural models feature ferrous cyanide centers bound to nickel(II) dithiolates. The compound [(CO)3Fe( μ-S2C3H6)( μ-H)Ni(dppe)]BF4 is a unique hydride-containing model. This salt catalyzes the evolution of H2 from acetonitrile solutions of trifluoroacetic acid (pKa = 12.65, E°(H+/H2) = −1.36 vs NHE) at −1.83 V vs NHE. The overpotential of ~450 mV is competitive with most artificial [FeFe]-H2ases. The mechanism of proton reduction catalysis is partially clarified by the fact that the hydride complex itself is unreactive toward protons; it must first be reduced (Figure 4).
The reverse reaction, hydrogen oxidation by Ni-Fe thiolates, has not yet been achieved. Solutions to this challenge can be expected with the development of unsaturated models with biologically relevant oxidation states, i.e. Ni(II)Fe(II) and Ni(III)Fe(II).
The third H2ase is the [Fe]-H2ase, also called Hmd (H2-forming methylene- tetrahydromethanopterin dehydrogenase). Because Hmd contains only a single metal and no redox-cofactors, it is an unusual platform for the activation of H2. Hmd-inspired artificial H2ases however pose challenging targets since the carbocationic substrate participates in the H2 activation process. Artificial H2ases inspired by Hmd are just appearing.[42,43] As with the other artificial H2ases, phosphine ligands are useful as illustrated by the most advanced model, which features a phosphine-stabilized Fe-acyl thiolate carbonyl center. Both the structural biology and literature precedents suggest that the pyridone group is mechanistically important (Scheme 1), but such modules have not yet been installed into catalytic systems.
Many artificial H2ases are inspired by biology but bear little structural similarity to the active sites of the enzymes. DuBois et al. in particular have pioneered the development of artificial H2ases using “PNP” ligands wherein ordinary bidentate diphosphine ligands are complemented by non-coordinating amine bases. Catalysis by Ni-PNP complexes is sharply accelerated relative to complexes of ordinary diphosphines. The reactions of [Ni(PNP)2]2+ complexes are facilitated because they require two components (i.e. complex + H+ or H2) vs. three-component processes (i.e. complex + H2/H+ + base). Complexes of diaminodiphosphines (P2N2’s, Scheme 2) are even more active, producing H2 at 350 s−1, about 50% of the enzymatic rate. The high activity of the P2N2-Ni systems is attributed to their structure, which position amines near the H2− binding site on Ni(II). These Ni-PNP systems have now been interfaced with conducting carbon nanotubes to give efficient, low-overpotential catalysts for both the production and oxidation of H2.
The excitement over artificial H2ases has revived interest in the ability of cobaloximes to catalyze H2 evolution. Modified cobaloximes are excellent electrocatalysts in terms of high rates and low overpotentials. These catalysts are structurally austere: the metal carries a single hydride with sparse adjacent functionality. They owe their activity to the ability of the imino ligands (RC=NR′) to stabilize the metal in several oxidation states, a property reminiscent of the corrinoid ligand in vitamin B12-dependent enzymes. Mechanisms for H2 evolution remain slightly mysterious since metal hydride intermediates are not observed. Kinetic analyses indicate that this family of artificial H2ases operate, at least in part, via bimetallic mechanisms, i.e., 2 LxM-H 2 LxM + H2. The dioxime platform is particularly amenable to optimization leading to rugged catalysts with both cobalt and nickel.
Study of artificial H2ases is motivated by topical interest in energy-related catalysis, but, equally importantly, progress has been underpinned by a multiyear investment in the fundamental coordination chemistry of H2. Relative to the enzymes, the great advantage offered by artificial H2ases derives from the fact that their properties (redox potentials, solubility, basicity) can be manipulated with some degree of predictability. Furthermore, such complexes can often be prepared on multigram scale (Figure 5).
Certain trends can be anticipated. Most obviously, the active sites of all H2ases feature Fe-SR-CO centers. A wide range of Fe-S-CO compounds await analysis. Such approaches will also be relevant to the design of rugged catalyst as required for practical photocatalysis.
Most artificial H2ases exhibit only weak affinities for H2, thus limiting prospects for oxidation of hydrogen and related applications. The recently popularlarized concept of “frustrated Lewis pairs” provides guidance on this issue. Within this paradigm, a Lewis acid (usually a cationic metal center) and Lewis base are constrained within close proximity but are prevented from combining, as illustrated by complexes of the PNP and azadithiolate ligands.
The authors acknowledge support from the U.S. Department of Energy, Office of Basic Energy Sciences and the U.S. National Institutes of Health.
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