Richard H. Holm

Molybdenum-dependent nitrogenases catalyze the transformation of dinitrogen into ammonia under ambient conditions. The active site (FeMo cofactor) is the structurally and electronically complex weak-field metal cluster [MoFe₇S₉C] built of Fe₄S₃ and MoFe₃S₃C portions connected by three sulfur bridges and containing an interstitial carbon atom centered in an Fe₆ trigonal prism. Chemical synthesis of this cluster is a major challenge in biomimetic inorganic chemistry. One synthetic approach of core ligand metathesis has been developed based on the design and synthesis of unprecedented incomplete ([(Tp*)WFe₂S₃Q₃]⁻) and complete ([(Tp*)WFe₃S₃Q₄]²⁻) cubane-type clusters containing bridging halide (Q = halide). These clusters are achieved by template-assisted assembly in the presence of sodium benzophenone ketyl reductant; products are controlled by reaction stoichiometry. Incomplete cubane clusters are subject to a variety of metathesis reactions resulting in substitution of a μ₂-bridging ligand with other bridges such as N₃⁻, MeO⁻, and EtS⁻. Reactions of complete cubanes with Me₃SiN₃ and S₈ undergo a redox metathesis process and lead to core ligand displacement and formation of [(Tp*)WFe₃S₃(μ₃-Q)Cl₃]⁻ (Q = Me₃SiN²⁻, S²⁻). This work affords entry to a wide variety of heteroleptic clusters derivable from incomplete and complete cubanes; examples are provided. Among these is the cluster [(Tp*)WFe₃S₃(μ₃-NSiMe₃)Cl₃]⁻, one of the very few instances of a synthetic Fe–S cluster containing a light atom (C, N, O) in the core, which constitutes a close mimic of the [MoFe₃S₃C] fragment in FeMo cofactor. Superposition of them and comparison of metric information disclose a clear structural relationship [Tp* = tris(3,5-dimethyl-1-pyrazolyl)hydroborate(1−)]. Significance The biosynthesis and mechanism of action of nitrogenase, an enzyme that converts dinitrogen to ammonia under ambient conditions, are problems of prominent significance in metallobiochemistry. Because the active centers of the enzyme are metal–ligand clusters, it is feasible that they are attainable by synthesis and as such are primary goals in the field of biomimetic inorganic chemistry. Here we present a ligand metathesis strategy utilizing the periodic near-identity of molybdenum and tungsten when incorporated into analogous compounds. The approach provides a pathway for constructing heterometal heteroleptic Fe–S clusters of presumed relevance to the active site. Based on cubane-type stereochemistry, clusters have been prepared allowing alterations in structure and ligand binding, and inclusion of a light core atom.

Synthetic iron–sulfur clusters of general formulation [Fe_mS_qL_l]^z with core atoms Fe and S and terminal ligands L constitute a family of molecular clusters with remarkably diverse geometrical and electronic structures. Several structure types are also found in proteins. The large majority of research on these clusters has involved elucidation of physical properties. Here, we direct attention to reactivity in the form of cluster conversions in which the Fe_mS_q cores of reactants are transformed to new structures, usually of different nuclearity, in overall reactions such as self-assembly and fragment condensation and dissociation. An extensive body of core conversions, many of which have not been recognized as such, are presented including those in biological systems. All structural core types are depicted, and all core conversions are diagrammatically summarized. Clusters containing the cubane-type Fe₄S₄ core play a central role in conversion chemistry. The core conversion concept tends to reinforce the description of iron–sulfur cores as modular units subject to various covalent bond interactions that lead to different structures.

Sulfur K-edge X-ray absorption spectroscopy (XAS) and density functional theory (DFT) calculations have been used to determine the electronic structures of two complexes [Mo^IVO(bdt)₂]^2– and [Mo^VIO₂(bdt)₂]^2– (bdt = benzene-1,2-dithiolate(2−)) that relate to the reduced and oxidized forms of sulfite oxidase (SO). These are compared with those of previously studied dimethyl sulfoxide reductase (DMSOr) models. DFT calculations supported by the data are extended to evaluate the reaction coordinate for oxo transfer to a phosphite ester substrate. Three possible transition states are found with the one at lowest energy, stabilized by a P–S interaction, in good agreement with experimental kinetics data. Comparison of both oxo transfer reactions shows that in DMSOr, where the oxo is transferred from the substrate to the metal ion, the oxo transfer induces electron transfer, while in SO, where the oxo transfer is from the metal site to the substrate, the electron transfer initiates oxo transfer. This difference in reactivity is related to the difference in frontier molecular orbitals (FMO) of the metal–oxo and substrate–oxo bonds. Finally, these experimentally related calculations are extended to oxo transfer by sulfite oxidase. The presence of only one dithiolene at the enzyme active site selectively activates the equatorial oxo for transfer, and allows facile structural reorganization during turnover.

The thermodynamics and high-pressure kinetics of the fastest CO ₂ fixation reaction by a metal-bound hydroxide resulted in a clear mechanistic picture and characterization of a very compact five-coordinate transition state.

The planar NNN-pincer complexes [M^II(pyN₂^Me2)(OH)]^1– (M^II = Ni, Cu) fix CO₂ in η¹-OCO₂H complexes; results for the copper system are described. Mn^II, Fe^II, Co^II, and Zn^II behave differently, forming [M^II(pyN₂^Me2)₂]^2– with N₄O₂ coordination. Incorporation of the Ni^II pincer into binucleating macrocycle 2 containing a triamino M^II locus connected by two 1,3-biphenylene groups affords proximal Ni^II and M^II sites for investigation of the synthesis, structure, and reactivity of Ni–X–M bridge units. This ligand structure is taken as a reference for variations in M^II atoms and binding sites and bridges X = OH^– and CN^– to produce additional members of the macrocyclic family with improved properties. Macrocycle 2 with a 22-membered ring is shown to bind M^II = Mn, Fe, and Cu with hydroxo bridges. Introduction of the 4-BuⁱO group (macrocycle 3) improves the solubility of neutral complexes such as those with Ni^II–OH–Cu^II and Ni^II–CN–Fe^II bridges. Syntheses of macrocycle 5 with a 7-Me-[12]aneSN₃ and macrocycle 6 with a 1,8-Me₂-[14]aneN₄ M^II binding site are described together with hydoxo-bridged Ni/Cu and cyano-bridged Ni/Fe complexes. This work was motivated by the presence of a Ni···(HO)–Fe bridge grouping in a reactive state of carbon monoxide dehydrogenase. Attempted decrease in Ni–(OH)–M distances (3.70–3.87 Å) to smaller values observed in the enzyme by use of macrocycle 4 having 1,2-biphenylene connectors led to a mononuclear octahedral Ni^II complex. Bridge structural units are summarized, and the structures of 14 macrocyclic complexes including 8 with bridges are described.

The formation and solution properties, including stability in mixed aqueous–Me₂SO media, have been investigated for an [Fe₄S₄]²⁺ cluster derived from β-cyclodextrin (CD) dithiolate. Clusters of the type [Fe₄S₄(SAr)₄]^2– (Ar = Ph, C₆H₄-3-F) are generated in Me₂SO by redox reactions of [Fe₄S₄(SEt)₄]^2– with 2 equiv of ArSSAr. An analogous reaction with the intramolecular disulfide of 6^A,6^D-(3-NHCOC₆H₄-1-SH)₂-6^A,6^D-dideoxy-β-cyclodextrin (14), whose synthesis is described, affords a completely substituted cluster formulated as [Fe₄S₄{β-CD-(1,3-NHCOC₆H₄S)₂}₂]^2– (15). Ligand binding is indicated by a circular dichroism spectrum and also by UV–visible and isotropically shifted ¹H NMR spectra and redox behavior convincingly similar to [Fe₄S₄(SPh)₄]^2–. One formulation of 15 is a single cluster to which two dithiolates are bound, each in bidentate coordination. With there being no proven precedent for this binding mode, we show that the cluster [Fe₄S₄(S₂-m-xyl)₂]^2– is a single cubane whose m-xylyldithiolate ligands are bound in a bidentate arrangement. This same structure type was proposed for a cluster formulated as [Fe₄S₄{β-CD-(1,3-SC₆H₄S)₂}₂]^2– (16; Kuroda et al. J. Am. Chem. Soc.1988, 110, 4049–4050) and reported to be water-stable. Clusters 15 and 16 are derived from similar ligands differing only in the spacer group between the thiolate binding site and the CD platform. In our search for clusters stable in aqueous or organic–aqueous mixed solvents that are potential candidates for the reconstitution of scaffold proteins implicated in cluster biogenesis, 15 is the most stable cluster that we have thus far encountered under anaerobic conditions in the absence of added ligand.

Syntheses of five types of tungsten–iron–sulfur/selenium clusters, namely, incomplete cubanes, single cubanes, edge-bridged double cubanes (EBDCs), P^N-type clusters, and double-cuboidal clusters, have been devised using the concept of template-assisted assembly. The template reactant is six-coordinate [(Tp*)W^VIS₃]^1– [Tp* = tris(3,5-dimethylpyrazolyl)hydroborate(1−)], which in the assembly systems organizes Fe^2+/3+ and sulfide/selenide into cuboidal [(Tp*)WFe₂S₃] or cubane [(Tp*)WFe₃S₃Q] (Q = S, Se) units. With appropriate terminal iron ligation, these units are capable of independent existence or may be transformed into higher-nuclearity species. Selenide is used as a surrogate for sulfide in cluster assembly in order to determine by X-ray structures the position occupied by an external chalcogenide nucleophile or an internal chalcogenide atom in the product clusters. Specific incorporation of selenide is demonstrated by the formation of [WFe₃S₃Se]^2+/3+ cubane cores. Reductive dimerization of the cubane leads to the EBDC core [W₂Fe₆S₆Se₂]²⁺ containing μ₄-Se sites. Reaction of these species with HSe^– affords the P^N-type cores [W₂Fe₆S₆Se₃]¹⁺, in which selenide occupies μ₆-Se and μ₂-Se sites. The reaction of [(Tp*)WS₃]^1–, FeCl₂, and Na₂Se yields the double-cuboidal [W₂Fe₄S₆Se₃]^2+/0 core with μ₂-Se and μ₄-Se bridges. It is highly probable that in analogous sulfide-only assembly systems, external and internal sulfide reactants occupy corresponding positions in the cluster products. The results further demonstrate the viability of template-assisted cluster synthesis inasmuch as the reduced (Tp*)WS₃ unit is present in all of the clusters. Structures, zero-field Mössbauer data, and redox potentials are presented for each cluster type.

Reaction coordinates for oxo transfer from the substrates Me₃NO, Me₂SO, and Me₃PO to the biologically relevant Mo(IV) bis-dithiolene complex [Mo(OMe)(mdt)₂]⁻ where mdt = 1,2-dimethyl-ethene-1,2-dithiolate(2-), and from Me₂SO to the analogous W(IV) complex, have been calculated using density functional theory. In each case, the reaction first proceeds through a transition state (TS1) to an intermediate with substrate weakly bound, followed by a second transition state (TS2) around which breaking of the substrate X–O bond begins. By analyzing the energetic contributions to each barrier, it is shown that the nature of the substrate and metal determines which transition state controls the rate-determining step of the reaction.