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Transition metal cluster complexes, particularly those containing iron and sulfur, are used as catalysts for the biological reduction of inert small molecules such as N2and CO2. The structures of these biological clusters are complicated and the protein backbones around the clusters often play important roles in catalysis, hence reproducing or mimicking the enzymatic functions with synthetic cluster complexes remains a challenge. Appropriate assumptions and hypotheses on the relationships between the structures and functions of biological clusters are needed to develop synthetic molecular catalysts inspired by enzymes. This accountreviews recent studies by the author and his coworkers on iron-containing biomimetic cluster complexes. Cubic Mo-Fe-S clusters supported by bulky cyclopentadienyl ligands on molybdenum were designed and synthesized, and their Fe sites captured and catalytically converted N2under reducing conditions. Iron-hydride clusters, which are relevant to the active species of biological and industrial nitrogen fixation, also served as catalysts for the reduction of N2. Furthermore, various metal-sulfur clusters, ranging from a structural mimic of the complex active site of the N2-reducing enzyme to a simple and cubic [Fe4S4] cluster, were found to catalyze the biologically inaccessible direct conversion of CO2to short-chain hydrocarbons. These studies have demonstrated the potential utility of biomimetic approaches to the catalytic reduction of inert small molecules, through the rational design and synthesis of simple yet appropriate iron-containing cluster complexes.This article addresses recent studies by the author and his coworkers on iron-containing biomimetic cluster complexes, such as the unprecedented catalytic reduction of N2by synthetic metal-sulfur cluster complexes, the synthesis of iron-hydride clusters and their application in the N2-reducing reaction, and the application of synthetic metal-sulfur clusters in the direct conversion of CO2into hydrocarbons.

We have previously shown that cyclopentadienyl (CpR)-supported [Mo3S4] platforms capture and stabilize halides of hetero-metals (M) under reducing conditions to give [Mo3S4M] cubes. Here we report Co and Ni variants with CpXLligands (CpXL= C5Me4SiEt3) and CO binding to the [Mo3S4M] clusters (M = Fe, Co, Ni). Properties of the isolated CO-bound [Mo3S4M] cubes were investigated by X-ray diffraction, IR, and electrochemical analyses. Density functional theory (DFT) calculations were performed for the isolated CO-bound clusters to evaluate M-CO interactions. These analyses constitute foundations to develop bio-mimetic molecular catalysts for the direct conversion of CO and/or CO2into hydrocarbons, which can contribute to the reduction of carbon emissions.Cubic [Mo3S4M]-type clusters (M = Co, Ni) with bulky cyclopentadienyl ligands (CpXL, C5Me4SiEt3) were synthesized. CO binding behaviors of the [Mo3S4M] cubes (M = Fe, Co, Ni) revealed unexpected instability of [CpXL3Mo3S4Fe(CO)]+in comparison with [CpXL3Mo3S4M(CO)]+(M = Co, Ni). Their M-CO interactions were analyzed by DFT calculations.

Nitrogen (N2) fixation by nature, which is a crucial process for the supply of bio-available forms of nitrogen, is performed by nitrogenase. This enzyme uses a unique transition-metal–sulfur–carbon cluster as its active-site co-factor ([(R-homocitrate)MoFe7S9C], FeMoco)1,2, and the sulfur-surrounded iron (Fe) atoms have been postulated to capture and reduce N2(refs. 3–6). Although there are a few examples of synthetic counterparts of the FeMoco, metal–sulfur cluster, which have shown binding of N2(refs. 7–9), the reduction of N2by any synthetic metal–sulfur cluster or by the extracted form of FeMoco10has remained elusive, despite nearly 50 years of research. Here we show that the Fe atoms in our synthetic [Mo3S4Fe] cubes11,12can capture a N2molecule and catalyse N2silylation to form N(SiMe3)3under treatment with excess sodium and trimethylsilyl chloride. These results exemplify the catalytic silylation of N2by a synthetic metal–sulfur cluster and demonstrate the N2-reduction capability of Fe atoms in a sulfur-rich environment, which is reminiscent of the ability of FeMoco to bind and activate N2.

Two different four-electron reductions of dioxygen (O2) on a metal surface are reproduced in homogeneous systems. The reaction of the highly unsaturated (56-electron) tetraruthenium tetrahydride complex 1with O2readily afforded the bis(μ3-oxo) complex 3via a dissociative mechanism that includes large electronic and geometric changes, i.e., a four-electron oxidation of the metal centers and an increase of 8 in the number of valence electrons. In contrast, the tetraruthenium hexahydride complex 2induces a smooth H-atom transfer to the incorporated O2species, and the O–OH bond is cleaved to afford the mono(μ3-oxo) complex 4via an associative mechanism. Density functional theory calculations suggest that the higher degree of unsaturation in the tetrahydride system induces a significant interaction between the tetraruthenium core and the O2moiety, enabling the large changes required for the dissociative mechanism.

The preparation and structural characterization of mononuclear tethered ruthenium(II) complexes of type [(DmpSe)Ru(PR3)]+BArF4–(DmpSe = 2,6-dimesitylphenyl selenolate, ArF= 3,5-bis(trifluoromethyl)phenyl) are described. Unlike relevant known selenolate complexes, the reported family of complexes is cationic with a single monodentate selenolate ligand. The ability of these complexes to engage in cooperative Si–H bond activation at the Ru–Se bond is investigated, and a hydrosilane adduct has been fully characterized by multinuclear NMR spectroscopy and X-ray diffraction. The usefulness of these complexes as catalysts for various ionic dehydrogenative silylation and hydrosilylation reactions is assessed. At all stages, the new complexes are compared with their thiolate homologues [(DmpS)Ru(PR3)]+BArF4–(DmpS = 2,6-dimesitylphenyl thiolate). The differences between the selenolate and thiolate complexes are marginal, but measurable. The larger selenium atom provides more space around the Ru–Se bond than sulfur does for the Ru–S bond, and hence, the selenolate complexes can accommodate sterically more demanding hydrosilanes.

An axially chiral bisphosphine, Fc-Segphos (1), which possesses diferrocenylphosphino-donor moieties, was prepared as a racemate, and its optical resolution was achieved by the use of chiral HPLC. Ligand 1coordinated to a palladium(II) cation in a bidentate fashion to construct a unique chiral environment at the palladium center due to the sterically demanding ferrocenyl groups. Ligand (R)-1was applied in the palladium-catalyzed asymmetric synthesis of axially chiral allenes showing good enantioselectivity of up to 92% ee. In general, (R)-1displayed better enantioselectivity than the parent Segphos in the palladium-catalyzed reaction, and the Pd/(R)-1species showed up to 18% ee enhancement over the (R)-Segphos-derived palladium catalyst.

The incorporation of Rh or Ir into the [Mo3S4] platforms of [CpXL3Mo3S4] or [Cp*3Mo3S4] (CpXL= C5Me4SiEt3, Cp* = C5Me5) led to the formation of cubic [Mo3S4M] clusters, [CpXL3Mo3S4Rh(cod)] (1), [CpXL3Mo3S4Ir(coe)] (2), [Cp*3Mo3S4Rh(coe)] (3), and [Cp*3Mo3S4Ir(coe)] (4) (cod = 1,5-cyclooctadiene, coe = cyclooctene). These clusters were characterized spectroscopically and crystallographically. They catalyzed the C–H borylation of aromatic compounds (benzene, toluene, o-xylene, m-xylene, and p-xylene) in the presence of HBpin (4,4,5,5-tetramethyl-1,3,2-dioxaborolane), yielding the corresponding borylated products. Among these, cluster 3exhibited the highest catalytic activity, while the treatment of cluster 2with excess HBpin generated a millisecond-detectable potential intermediate, [CpXL3Mo3S4Ir(Bpin)]+. Despite the high affinity of Lewis acidic boron toward sulfur, the robust [Mo3S4M] (M = Rh, Ir) cubes protected adequately by Cp ligands have proven effective in borylation chemistry.

Triangular [Mo3S4] clusters are known to serve as platforms to accommodate a metal atom M, furnishing cubic [Mo3S4M] clusters. In this study, three [Mo3S4] clusters supported by η5-cyclopentadienyl (CpR) ligands, [CpR3Mo3S4]+(CpR= C5Me4SiMe3, C5Me4SiEt3, and C5Me4H), were synthesized via half-sandwich molybdenum chlorides CpRMoCl4. In the cyclic voltammogram of the [Mo3S4] cluster having C5Me4H ligands, a weak feature appeared in addition to the [CpR3Mo3S4]0/–redox process, indicating the interaction between [CpR3Mo3S4]−and the [NnBu4] cation of the electrolyte, while such a feature was less significant for the C5Me4SiR3variants. The [Mo3S4] clusters with bulky C5Me4SiR3ligands were successfully applied as platforms to accommodate an Fe atom to furnish cubic [Mo3S4Fe] clusters. On the other hand, the corresponding reactions of the less bulky C5Me4H analogue gave complex mixtures.

The M-cluster is the [(homocitrate)MoFe7S9C] active site of nitrogenase that is derived from an 8Fe core assembled viacoupling and rearrangement of two [Fe4S4] clusters concomitant with the insertion of an interstitial carbon and a ‘ninth sulfur’. Combining synthetic [Fe4S4] clusters with an assembly protein template, here we show that sulfite can give rise to the ninth sulfur that is incorporated in the catalytically important belt region of the cofactor after the radical S-adenosyl-l-methionine-dependent carbide insertion and the concurrent 8Fe-core rearrangement have already taken place. Based on the differential reactivity of the formed cluster species, we also propose a new [Fe8S8C] cluster intermediate, the L*-cluster, which is similar to the [Fe8S9C] L-cluster, but lacks the ninth sulfur from sulfite. This work provides a semi-synthetic tool for protein reconstitution that could be widely applicable for the functional analysis of other FeS systems.

The double Friedel–Crafts acylation of 2,5-dihydro-1-phosphaferrocenes 1was established by the stepwise introduction of two acyl groups and conduction of the second acylation in the absence of extra AlCl3. The reaction was previously reported to be unattainable; however, the careful tuning of the reaction conditions realized the straightforward, operationally simple, and high-yield access to the 2,5-diacylphosphaferrocenes, which have been interesting synthetic targets as potentially useful building blocks. Due to the presence of the competitive two reaction modes, the second Friedel–Crafts acylation on monoacylphosphaferrocene 2provided 2,5-diacylphosphaferrocene 3as a predominant product together with 1′,2-diacylphosphaferrocene 4as a side product. When appropriate acyl sources are chosen in the two acylation steps, two different acyl groups could be introduced in 3and 4.

Asymmetric metathesis dimerization (AMD) reactions of a series of racemic planar-chiral 2-vinylphosphaferrocenes (rac-1) were examined in the presence of a chiral molybdenum-alkylidene precatalyst. The reactions proceeded in a highly enantio- and diastereoselective fashion to realize the efficient kinetic resolution (KR) of the racemic substrates. The AMD/KR reaction of rac-1ashowed excellent diastereoselectivity (chiral-2a/meso-2a= >98/<2) to provide (E)-(S,S)-2aof >99% ee in 38% yield together with unreacted recovered (R)-1aof 63% ee in 58% yield. The selectivity factor (krel) of this reaction was estimated to be 1.5 × 103based on a second-order equation. In all the cases examined, the dimerized products, chiral-2, were obtained in >98% ee even with near 50% conversions (i.e., close to the complete consumption of the more reactive enantiomers in rac-1) thanks to the outstanding enantioselectivity.

Biological nitrogen fixation and H2metabolism are mediated by nitrogenase and hydrogenase, respectively. Their active sites consist of complex transition-metal sulfide/thiolate clusters, which have been long-standing synthetic challenges. This account describes our synthetic approaches toward the active sites of nitrogenase and [NiFe] hydrogenase. A new class of iron–sulfur clusters modeling or structurally analogous to the nitrogenase metallo-clusters, namely P-cluster and FeMo-cofactor, have been synthesized from homogeneous self-assembly reactions of iron(II) amide or mesityl complexes with bulky thiols and elemental sulfur in toluene. A series of thiolate-bridged Fe–Ni complexes modeling the active site of [NiFe] hydrogenase have been synthesized via two ways: One is to use iron(II)–dithiolate complexes carrying CO and CN ligands as precursors to provide the (CO/CN)Fe–Ni complexes. The other way is to split a tetranuclear (CO)3Fe–Ni–Ni–Fe(CO)3complex, which is available from a sequential reaction of [FeBr2(CO)4] with NaStBu and NiBr2(EtOH)4at −40 °C.

Hydrogenases catalyze the reversible oxidation of H2, which is crucial for the anaerobic metabolism of microorganisms. They attract growing interest in connection with H2‐based energy systems. [NiFe] hydrogenase is the most common type among the currently known hydrogenases, and its active site consists of an “organometallic” Fe–Ni complex supported by cysteinyl thiolate ligands. This review presents an overview of the synthesis, properties, and reactions of thiolate‐bridged iron–nickel complexes that model the active site of [NiFe] hydrogenase.

The zirconocene complex [{(C6F5)2B‐(CH2)3‐Cp}(Cp‐PtBu2)ZrCl2] (6; Cp=cyclo‐C5H4) was prepared by hydroboration of [(allyl‐Cp)(Cp‐PtBu2)ZrCl2] (5) with HB(C6F5)2(“Piers’ borane”). It represents a frustrated Lewis pair (FLP) in which both the Lewis acid and the Lewis base were attached at the metallocene framework. Its reaction with 1‐pentyne did not result in the 1,2‐addition of or deprotonation reaction by the FLP, but rather in the 1,1‐carboboration of the triple bond, thereby obtaining a Z/Emixture (1.2:1) of the respective organometallic substituted alkenes 7. The analogous reaction of 1‐pentyne with the phosphorous‐free system [{(C6F5)2B‐(CH2)3‐Cp)}CpZrCl2] (9) gave the respective 1,1‐carboboration products ((Z)‐10/(E)‐10≈1.3:1).

Drug candidates with poor physicochemical properties (such as solubility) tend to have low bioavailability. For example, basic compounds might dissolve under acidic stomach conditions but then precipitate because of a change in pH under the neutral conditions found in the intestines. Therefore, it is essential to prevent precipitation and maintain high drug concentrations in the intestines to improve in vivo plasma exposure. Substances that act as antiprecipitants have been reported as well as bio-relevant media that mimic conditions in the stomach and small intestine. This report describes the development of an antiprecipitant screening system for basic model compounds using 96-well plates and bio-relevant media. Fourteen potential antiprecipitants were screened on one plate, which resulted in the identification of four substances that maintained a supersaturation state. To confirm these results, supersaturation studies were conducted according to the United States Pharmacopeia (USP) II dissolution method, and the results of the newly developed system correlated well with those of the USP II method. This novel system is useful for small-scale formulation screening during early preclinical development. This 96-well plate system will be available for the easily automated system in comparison with the conventional USP II system.

Drug candidates with poor physicochemical properties (such as solubility) tend to have low bioavailability. For example, basic compounds might dissolve under acidic stomach conditions but then precipitate because of a change in pH under the neutral conditions found in the intestines. Therefore, it is essential to prevent precipitation and maintain high drug concentrations in the intestines to improve in vivo plasma exposure. Substances that act as antiprecipitants have been reported as well as bio-relevant media that mimic conditions in the stomach and small intestine. This report describes the development of an antiprecipitant screening system for basic model compounds using 96-well plates and bio-relevant media. Fourteen potential antiprecipitants were screened on one plate, which resulted in the identification of four substances that maintained a supersaturation state. To confirm these results, supersaturation studies were conducted according to the United States Pharmacopeia (USP) II dissolution method, and the results of the newly developed system correlated well with those of the USP II method. This novel system is useful for small-scale formulation screening during early preclinical development. This 96-well plate system will be available for the easily automated system in comparison with the conventional USP II system.

A coordinatively unsaturated iron‐methyl complex having an N‐heterocyclic carbene ligand, [Cp*Fe(LMe)Me] (1; Cp*=η5‐C5Me5, LMe=1,3,4,5‐tetramethyl‐imidazol‐2‐ylidene), is synthesized from the reaction of [Cp*Fe(TMEDA)Cl] (TMEDA=N,N,N′,N′‐tetramethylethylenediamine) with methyllithium and LMe. Complex 1is found to activate the CH bonds of furan, thiophene, and benzene, giving rise to aryl complexes, [Cp*Fe(LMe)(aryl)] (aryl=2‐furyl (2), 2‐thienyl (3), phenyl (4)). The CH bond cleavage reactions are applied to the dehydrogenative coupling of furans or thiophenes with pinacolborane (HBpin) in the presence of tert‐butylethylene and a catalytic amount of 1(10 mol % to HBpin). The borylation of the furan/thiophene or 2‐substituted furans/thiophenes occurs exclusively at the 2‐ or 5‐positions, respectively, whereas that of 3‐substituted furans/thiophenes takes place mainly at the 5‐position and gives a mixture of regioisomers. Treatment of 2with 2 equiv of HBpin results in the quantitative formation of 2‐boryl‐furan and the borohydride complex [Cp*Fe(LMe)(H2Bpin)] (5). Heating a solution of 5in the presence of tert‐butylethylene led to the formation of an alkyl complex [Cp*Fe(LMe)CH2CH2tBu] (6), which was found to cleave the CH bond of furan to produce 2. On the basis of these results, a possible catalytic cycle is proposed.

Treatment of the salt [PPh4]+[Cp*W(S)3]−(6) with allyl bromide gave the neutral complex [Cp*W(S)2S‐CH2‐CHCH2] (7). The product 7was characterized by an X‐ray crystal structure analysis. Complex 7features dynamic NMR spectra that indicate a rapid allyl automerization process. From the analysis of the temperature‐dependent NMR spectra a Gibbs activation energy of ΔG≠(278 K)≈13.7±0.1 kcal mol−1was obtained [ΔH≠≈10.4±0.1 kcal mol−1; ΔS≠≈−11.4 cal mol−1K−1]. The DFT calculation identified an energetically unfavorable four‐membered transition state of the “forbidden” reaction and a favorable six‐membered transition state of the “Cope‐type” allyl rearrangement process at this transition‐metal complex core.

Step‐by‐step: A trinuclear Fe‐Ni‐Fe complex 1was synthesized from the reaction of [Fe(CO)4I2] with Li2[Ni(norbornane‐exo‐2,3‐dithiolate)2]. The CO ligands in 1were transformed into CN−upon treatment with −N(SiMe3)2, and the monocyanide complex 3and the dicyanide complex 4were obtained. Complexes 3and 4were found to react with protonic acids, whereas 1is robust.

Diastereo- and enantioselective kinetic resolution of racemic planar-chiral 1-R-2-vinylferrocenes (rac-1) was attained by the molybdenum-catalyzed asymmetric metathesis dimerization (AMD). Two sequential AMD reactions of rac-1a(R = Br) provided (E)-(S,S)-1,2-di(2-bromoferrocenyl)ethylene in >99% ee, which was converted to (S,S)-1,2-bis[(2-diphenylphosphino)ferrocenyl]ethane (S,S)-5. Planar-chiral bisphosphine (S,S)-5coordinated to a dichloropalladium(II) fragment in a trans-chelating fashion, which was applied as a chiral ligand in the palladium-catalyzed asymmetric allylic alkylation showing enantioselectivity of up to 90% ee.

Coordinatively unsaturated ruthenium complexes with a tethered SDmp (Dmp=2,6‐dimesitylphenyl) ligand, [(DmpS)Ru(PR3)][BArF4] (3 a: R=Et; 3 b: R=Ph; ArF=3,5‐(CF3)2C6H3), were synthesized by the reactions of [{(p‐cymene)RuCl}2(μ‐Cl)2], LiSDmp, phosphines, and NaBArF4. The RuS bonds in 3 aand 3 bwere found to serve as the polarized reactive site in reactions with alkyl halides, diazoalkanes, (p‐tosyliminoiodo)benzene, phenylacetylene, and H2. Alkylation of 3 aand 3 bwith methyl iodide or ethyl bromide occurred instantaneously to give the thioether complexes [(DmpSR′)RuX(PR3)][BArF4] (4 a: R=Et, R′=Me, X=I; 4 b: R=R′=Et, X=Br; 4 c: R=Ph, R′=Me, X=I; 4 d: R=Ph, R′=Et, X=Br). Treatment of 3 awith diazoalkanes N2CHR (R=CO2Et, SiMe3) led to the cycloaddition of carbenes to the RuS bond to form [DmpS(CHR)Ru(PEt3)][BArF4] (5 a: R=CO2Et; 5 b: R=SiMe3), whereas the reaction with (p‐tosyliminoiodo)benzene gave rise to [DmpS{NS(O)(C6H4‐4‐CH3)O}Ru(PEt3)][BArF4] (6), which contains a five‐membered ruthenacycle of RuSNSO. Addition of phenylacetylene to the RuS bond occurred reversibly to produce the vinyl sulfide complexes [DmpS(PhCCH)Ru(PR3)][BArF4] (7 a: R=Et; 7 b: R=Ph). On the other hand, the phenylacetylene at ruthenium slowly isomerized to vinylidene and bridged Ru and S in the products, [DmpS{C(CHPh)}Ru(PR3)][BArF4] (8 a: R=Et; 8 b: R=Ph). Complex 3 acatalyzed the hydrogenation of acetophenone, in which the heterolytic H–H splitting at the Ru–S site is suggested to be involved in the mechanism.

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Model complex: An FeIIcomplex bearing a thiolate, 2‐methoxy‐pyridine, and three facially arranged CO ligands was synthesized as a structural analogue of the active site of a CO‐inhibited form of [Fe] hydrogenase, from the reaction of [FeBr2(CO)4] with NaS{2,6‐(mesityl)2C6H3} and the successive treatment with 2‐methoxy‐pyridine.