Oxidative Addition of Aryl Electrophiles into a Red-Light-Active Bismuthinidene.

The oxidative addition of aryl electrophiles is a fundamental organometallic reaction widely applied in the field of transition metal chemistry and catalysis. However, the analogous version based on main group elements still remains largely underexplored. Here, we report the ability of a well-defined organobismuth(I) complex to undergo formal oxidative addition with a wide range of aryl electrophiles. The process is facilitated by the reactivity of both the ground and excited states of N,C,N-bismuthinidenes upon absorption of low-energy red light.

Bismuth radical catalysis in the activation and coupling of redox-active electrophiles.

Radical cross-coupling reactions represent a revolutionary tool to make C(sp3)-C and C(sp3)-heteroatom bonds by means of transition metals and photoredox or electrochemical approaches. However, the use of main-group elements to harness this type of reactivity has been little explored. Here we show how a low-valency bismuth complex is able to undergo one-electron oxidative addition with redox-active alkyl-radical precursors, mimicking the behaviour of first-row transition metals. This reactivity paradigm for bismuth gives rise to well-defined oxidative addition complexes, which could be fully characterized in solution and in the solid state. The resulting Bi(III)-C(sp3) intermediates display divergent reactivity patterns depending on the α-substituents of the alkyl fragment. Mechanistic investigations of this reactivity led to the development of a bismuth-catalysed C(sp3)-N cross-coupling reaction that operates under mild conditions and accommodates synthetically relevant NH-heterocycles as coupling partners.

Synthesis and isolation of a triplet bismuthinidene with a quenched magnetic response.

Large spin-orbit coupling (SOC) is an intrinsic property of the heavy elements that directly affects the electronic structures of the compounds. In this work, we report the synthesis and characterization of a monocoordinate bismuthinidene that features a rigid and bulky ligand. All magnetic measurements [superconducting quantum interference device (SQUID), nuclear magnetic resonance (NMR)] point to a diamagnetic compound. However, multiconfigurational quantum chemical calculations predict the ground state of the compound to be dominated (76%) by a spin triplet. The apparent diamagnetism is explained by an extremely large SOC-induced positive zero-field splitting of more than 4500 wavenumbers that leaves the MS = 0 magnetic sublevel thermally isolated in the electronic ground state.

Cleavage of an Aromatic C-C Bond in Ferrocene by Insertion of an Iridium Nitrido Nitrogen Atom.

The intermolecular cleavage of C-C bonds is a rare event. Herein, we report on a late transition-metal terminal nitrido complex, which upon oxidation undergoes insertion of the nitrido nitrogen atom into the aromatic C-C bond of ferrocene. This reaction path was confirmed through 15N and deuterium isotope labeling experiments of the nitrido complex and ferrocenium, respectively. Cyclic voltammetry and UV/vis spectroscopy monitoring of the reaction revealed that oxidation is the initial step, yielding the tentative radical cationic nitrido complex, which is experimentally supported by extended X and Q-band electron paramagnetic resonance (EPR) and ENDOR, UV/vis, vT 1H NMR, and vibrational spectroscopic data. Density functional theory (DFT) and multireference calculations of this highly reactive intermediate revealed an S = 1/2 ground state. The high reactivity can be traced to the increased electrophilicity in the oxidized complex. Based on high-level PNO-UCCSD(T) calculations and UV/vis kinetic measurements, it is proposed that the reaction proceeds by initial electrophilic exo attack of the nitrido nitrogen atom at the cyclopentadienyl ring and consecutive ring expansion to a pyridine ring.

Nickel Meets Aryl Thianthrenium Salts: Ni(I)-Catalyzed Halogenation of Arenes.

Herein, a regioselective, late-stage two-step arene halogenation method is reported. We propose how unusual Ni(I)/(III) catalysis is enabled by a combination of aryl thianthrenium and Ni redox properties that is hitherto unachieved with other (pseudo)halides. The catalyst is accessed in situ from inexpensive NiCl2·6(H2O) and zinc without the need of supporting ligands.

Redox tuning of the H-cluster by second coordination sphere amino acids in the sensory [FeFe] hydrogenase from Thermotoga maritima.

[FeFe] hydrogenases are exceptionally active catalysts for the interconversion of molecular hydrogen with protons and electrons. Their active site, the H-cluster, is composed of a [4Fe-4S] cluster covalently linked to a unique [2Fe] subcluster. These enzymes have been extensively studied to understand how the protein environment tunes the properties of the Fe ions for efficient catalysis. The sensory [FeFe] hydrogenase (HydS) from Thermotoga maritima has low activity and displays a very positive redox potential for the [2Fe] subcluster compared to that of the highly active prototypical enzymes. Using site directed mutagenesis, we investigate how second coordination sphere interactions of the protein environment with the H-cluster in HydS influence the catalytic, spectroscopic and redox properties of the H-cluster. In particular, mutation of the non-conserved serine 267, situated between the [4Fe-4S] and [2Fe] subclusters, to methionine (conserved in prototypical catalytic enzymes) gave a dramatic decrease in activity. Infra-red (IR) spectroelectrochemistry revealed a 50 mV lower redox potential for the [4Fe-4S] subcluster in the S267M variant. We speculate that this serine forms a hydrogen bond to the [4Fe-4S] subcluster, increasing its redox potential. These results demonstrate the importance of the secondary coordination sphere in tuning the catalytic properties of the H-cluster in [FeFe] hydrogenases and reveal a particularly important role for amino acids interacting with the [4Fe-4S] subcluster.

Synthesis, Isolation, and Characterization of Two Cationic Organobismuth(II) Pincer Complexes Relevant in Radical Redox Chemistry.

Herein, we report the synthesis, isolation, and characterization of two cationic organobismuth(II) compounds bearing N,C,N pincer frameworks, which model crucial intermediates in bismuth radical processes. X-ray crystallography uncovered a monomeric Bi(II) structure, while SQUID magnetometry in combination with NMR and EPR spectroscopy provides evidence for a paramagnetic S = 1/2 state. High-resolution multifrequency EPR at the X-, Q-, and W-band enable the precise assignment of the full g- and 209Bi A-tensors. Experimental data and DFT calculations reveal both complexes are metal-centered radicals with little delocalization onto the ligands.

Modulating the frontier orbitals of L(X)Ga-substituted diphosphenes [L(X)GaP]2 (X = Cl, Br) and their facile oxidation to radical cations.

Modulating the electronic structures of main group element compounds is crucial to control their chemical reactivity. Herein we report on the synthesis, frontier orbital modulation, and one-electron oxidation of two L(X)Ga-substituted diphosphenes [L(X)GaP]2 (X = Cl 2a, Br 2b; L = HC[C(Me)N(Ar)]2, Ar = 2,6-i-Pr2C6H3). Photolysis of L(Cl)GaPCO 1 gave [L(Cl)GaP]22a, which reacted with Me3SiBr with halide exchange to [L(Br)GaP]22b. Reactions with MeNHC (MeNHC = 1,3,4,5-tetramethylimidazol-2-ylidene) gave the corresponding carbene-coordinated complexes L(X)GaPP(MeNHC)Ga(X)L (X = Cl 3a, Br 3b). DFT calculations revealed that the carbene coordination modulates the frontier orbitals (i.e. HOMO/LUMO) of diphosphenes 2a and 2b, thereby affecting the reactivity of 3a and 3b. In marked contrast to diphosphenes 2a and 2b, the cyclic voltammograms (CVs) of the carbene-coordinated complexes each show one reversible redox event at E 1/2 = -0.65 V (3a) and -0.36 V (3b), indicating their one-electron oxidation to the corresponding radical cations as was confirmed by reactions of 3a and 3b with the [FeCp2][B(C6F5)4], yielding the radical cations [L(X)GaPP(MeNHC)Ga(X)L]B(C6F5)4 (X = Cl 4a, Br 4b). The unpaired spin in 4a (79%) and 4b (80%) is mainly located at the carbene-uncoordinated phosphorus atoms as was revealed by DFT calculations and furthermore experimentally proven in reactions with n Bu3SnH, yielding the diphosphane cations [L(X)GaPHP(MeNHC)Ga(X)L]B(C6F5)4 (X = Cl 5a, Br 5b). Compounds 2-5 were fully characterized by NMR and IR spectroscopy as well as by single crystal X-ray diffraction (sc-XRD), and compounds 4a and 4b were further studied by EPR spectroscopy, while their bonding nature was investigated by DFT calculations.

Two-component carnitine monooxygenase from Escherichia coli: functional characterization, inhibition and mutagenesis of the molecular interface.

Gut microbial production of trimethylamine (TMA) from l-carnitine is directly linked to cardiovascular disease. TMA formation is facilitated by carnitine monooxygenase, which was proposed as a target for the development of new cardioprotective compounds. Therefore, the molecular understanding of the two-component Rieske-type enzyme from Escherichia coli was intended. The redox cofactors of the reductase YeaX (FMN, plant-type [2Fe-2S] cluster) and of the oxygenase YeaW (Rieske-type [2Fe-2S] and mononuclear [Fe] center) were identified. Compounds meldonium and the garlic-derived molecule allicin were recently shown to suppress microbiota-dependent TMA formation. Based on two independent carnitine monooxygenase activity assays, enzyme inhibition by meldonium or allicin was demonstrated. Subsequently, the molecular interplay of the reductase YeaX and the oxygenase YeaW was addressed. Chimeric carnitine monooxygenase activity was efficiently reconstituted by combining YeaX (or YeaW) with the orthologous oxygenase CntA (or reductase CntB) from Acinetobacter baumannii. Partial conservation of the reductase/oxygenase docking interface was concluded. A structure guided mutagenesis approach was used to further investigate the interaction and electron transfer between YeaX and YeaW. Based on AlphaFold structure predictions, a total of 28 site-directed variants of YeaX and YeaW were kinetically analyzed. Functional relevance of YeaX residues Arg271, Lys313 and Asp320 was concluded. Concerning YeaW, a docking surface centered around residues Arg83, Lys104 and Lys117 was hypothesized. The presented results might contribute to the development of TMA-lowering strategies that could reduce the risk for cardiovascular disease.

Radical Activation of N-H and O-H Bonds at Bismuth(II).

The development of unconventional strategies for the activation of ammonia (NH3) and water (H2O) is of capital importance for the advancement of sustainable chemical strategies. Herein we provide the synthesis and characterization of a radical equilibrium complex based on bismuth featuring an extremely weak Bi-O bond, which permits the in situ generation of reactive Bi(II) species. The ensuing organobismuth(II) engages with various amines and alcohols and exerts an unprecedented effect onto the X-H bond, leading to low BDFEX-H. As a result, radical activation of various N-H and O-H bonds─including ammonia and water─occurs in seconds at room temperature, delivering well-defined Bi(III)-amido and -alkoxy complexes. Moreover, we demonstrate that the resulting Bi(III)-N complexes engage in a unique reactivity pattern with the triad of H+, H-, and H• sources, thus providing alternative pathways for main group chemistry.

Time-Resolved Infrared Spectroscopy Reveals the pH-Independence of the First Electron Transfer Step in the [FeFe] Hydrogenase Catalytic Cycle.

[FeFe] hydrogenases are highly active catalysts for hydrogen conversion. Their active site has two components: a [4Fe-4S] electron relay covalently attached to the H2 binding site and a diiron cluster ligated by CO, CN-, and 2-azapropane-1,3-dithiolate (ADT) ligands. Reduction of the [4Fe-4S] site was proposed to be coupled with protonation of one of its cysteine ligands. Here, we used time-resolved infrared (TRIR) spectroscopy on the [FeFe] hydrogenase from Chlamydomonas reinhardtii (CrHydA1) containing a propane-1,3-dithiolate (PDT) ligand instead of the native ADT ligand. The PDT modification does not affect the electron transfer step to [4Fe-4S]H but prevents the enzyme from proceeding further through the catalytic cycle. We show that the rate of the first electron transfer step is independent of the pH, supporting a simple electron transfer rather than a proton-coupled event. These results have important implications for our understanding of the catalytic mechanism of [FeFe] hydrogenases and highlight the utility of TRIR.

Catalytic synthesis of phenols with nitrous oxide.

The development of catalytic chemical processes that enable the revalorization of nitrous oxide (N2O) is an attractive strategy to alleviate the environmental threat posed by its emissions1-6. Traditionally, N2O has been considered an inert molecule, intractable for organic chemists as an oxidant or O-atom transfer reagent, owing to the harsh conditions required for its activation (>150 °C, 50‒200 bar)7-11. Here we report an insertion of N2O into a Ni‒C bond under mild conditions (room temperature, 1.5-2 bar N2O), thus delivering valuable phenols and releasing benign N2. This fundamentally distinct organometallic C‒O bond-forming step differs from the current strategies based on reductive elimination and enables an alternative catalytic approach for the conversion of aryl halides to phenols. The process was rendered catalytic by means of a bipyridine-based ligands for the Ni centre. The method is robust, mild and highly selective, able to accommodate base-sensitive functionalities as well as permitting phenol synthesis from densely functionalized aryl halides. Although this protocol does not provide a solution to the mitigation of N2O emissions, it represents a reactivity blueprint for the mild revalorization of abundant N2O as an O source.

Vibrational Perturbation of the [FeFe] Hydrogenase H-Cluster Revealed by 13C2H-ADT Labeling.

[FeFe] hydrogenases are highly active catalysts for the interconversion of molecular hydrogen with protons and electrons. Here, we use a combination of isotopic labeling, 57Fe nuclear resonance vibrational spectroscopy (NRVS), and density functional theory (DFT) calculations to observe and characterize the vibrational modes involving motion of the 2-azapropane-1,3-dithiolate (ADT) ligand bridging the two iron sites in the [2Fe]H subcluster. A -13C2H2- ADT labeling in the synthetic diiron precursor of [2Fe]H produced isotope effects observed throughout the NRVS spectrum. The two precursor isotopologues were then used to reconstitute the H-cluster of [FeFe] hydrogenase from Chlamydomonas reinhardtii (CrHydA1), and NRVS was measured on samples poised in the catalytically crucial Hhyd state containing a terminal hydride at the distal Fe site. The 13C2H isotope effects were observed also in the Hhyd spectrum. DFT simulations of the spectra allowed identification of the 57Fe normal modes coupled to the ADT ligand motions. Particularly, a variety of normal modes involve shortening of the distance between the distal Fe-H hydride and ADT N-H bridgehead hydrogen, which may be relevant to the formation of a transition state on the way to H2 formation.

Dialkyl Ether Formation at High-Valent Nickel.

In this article, we investigated the I2-promoted cyclic dialkyl ether formation from 6-membered oxanickelacycles originally reported by Hillhouse. A detailed mechanistic investigation based on spectroscopic and crystallographic analysis revealed that a putative reductive elimination to forge C(sp3)-OC(sp3) using I2 might not be operative. We isolated a paramagnetic bimetallic NiIII intermediate featuring a unique Ni2(OR)2 (OR = alkoxide) diamond-like core complemented by a µ-iodo bridge between the two Ni centers, which remains stable at low temperatures, thus permitting its characterization by NMR, EPR, X-ray, and HRMS. At higher temperatures (>-10 °C), such bimetallic intermediate thermally decomposes to afford large amounts of elimination products together with iodoalkanols. Observation of the latter suggests that a C(sp3)-I bond reductive elimination occurs preferentially to any other challenging C-O bond reductive elimination. Formation of cyclized THF rings is then believed to occur through cyclization of an alcohol/alkoxide to the recently forged C(sp3)-I bond. The results of this article indicate that the use of F+ oxidants permits the challenging C(sp3)-OC(sp3) bond formation at a high-valent nickel center to proceed in good yields while minimizing deleterious elimination reactions. Preliminary investigations suggest the involvement of a high-valent bimetallic NiIII intermediate which rapidly extrudes the C-O bond product at remarkably low temperatures. The new set of conditions permitted the elusive synthesis of diethyl ether through reductive elimination, a remarkable feature currently beyond the scope of Ni.

The Laser-Induced Potential Jump: A Method for Rapid Electron Injection into Oxidoreductase Enzymes.

Oxidoreductase enzymes often perform technologically useful chemical transformations using abundant metal cofactors with high efficiency under ambient conditions. The understanding of the catalytic mechanism of these enzymes is, however, highly dependent on the availability of well-characterized and optimized time-resolved analytical techniques. We have developed an approach for rapidly injecting electrons into a catalytic system using a photoactivated nanomaterial in combination with a range of redox mediators to produce a potential jump in solution, which then initiates turnover via electron transfer (ET) to the catalyst. The ET events at the nanomaterial-mediator-catalyst interfaces are, however, highly sensitive to the experimental conditions such as photon flux, relative concentrations of system components, and pH. Here, we present a systematic optimization of these experimental parameters for a specific catalytic system, namely, [FeFe] hydrogenase from Chlamydomonas reinhardtii (CrHydA1). The developed strategies can, however, be applied in the study of a wide variety of oxidoreductase enzymes. Our potential jump system consists of CdSe/CdS core-shell nanorods as a photosensitizer and a series of substituted bipyridinium salts as mediators with redox potentials in the range from -550 to -670 mV (vs SHE). With these components, we screened the effect of pH, mediator concentration, protein concentration, photosensitizer concentration, and photon flux on steady-state photoreduction and hydrogen production as well as ET and potential jump efficiency. By manipulating these experimental conditions, we show the potential of simple modifications to improve the tunability of the potential jump for application to study oxidoreductases.

Carnitine metabolism in the human gut: characterization of the two-component carnitine monooxygenase CntAB from Acinetobacter baumannii.

Bacterial formation of trimethylamine (TMA) from carnitine in the gut microbiome has been linked to cardiovascular disease. During this process, the two-component carnitine monooxygenase (CntAB) catalyzes the oxygen-dependent cleavage of carnitine to TMA and malic semialdehyde. Individual redox states of the reductase CntB and the catalytic component CntA were investigated based on mutagenesis and electron paramagnetic resonance (EPR) spectroscopic approaches. Protein ligands of the flavin mononucleotide (FMN) and the plant-type [2Fe-2S] cluster of CntB and also of the Rieske-type [2Fe-2S] cluster and the mononuclear [Fe] center of CntA were identified. EPR spectroscopy of variant CntA proteins suggested a hierarchical metallocenter maturation, Rieske [2Fe-2S] followed by the mononuclear [Fe] center. NADH-dependent electron transfer via the redox components of CntB and within the trimeric CntA complex for the activation of molecular oxygen was investigated. EPR experiments indicated that the two electrons from NADH were allocated to the plant-type [2Fe-2S] cluster and to FMN in the form of a flavin semiquinone radical. Single-turnover experiments of this reduced CntB species indicated the translocation of the first electron onto the [Fe] center and the second electron onto the Rieske-type [2Fe-2S] cluster of CntA to finally allow for oxygen activation as a basis for carnitine cleavage. EPR spectroscopic investigation of CntA variants indicated an unusual intermolecular electron transfer between the subunits of the CntA trimer via the "bridging" residue Glu-205. On the basis of these data, a redox catalytic cycle for carnitine monooxygenase was proposed.

Spin Polarization Reveals the Coordination Geometry of the [FeFe] Hydrogenase Active Site in Its CO-Inhibited State.

The active site of [FeFe] hydrogenase features a binuclear iron cofactor Fe2ADT(CO)3(CN)2, where ADT represents the bridging ligand aza-propane-dithiolate. The terminal diatomic ligands all coordinate in a basal configuration, and one CO bridges the two irons leaving an open coordination site at which the hydrogen species and the competitive inhibitor CO bind. Externally supplied CO is expected to coordinate in an apical configuration. However, an alternative configuration has been proposed in which, due to ligand rotation, the CN- bound to the distal Fe becomes apical. Using selective 13C isotope labeling of the CN- and COext ligands in combination with pulsed 13C electron-nuclear-nuclear triple resonance spectroscopy, spin polarization effects are revealed that, according to density functional theory calculations, are consistent with only the "unrotated" apical COext configuration.

Radical C-N Borylation of Aromatic Amines Enabled by a Pyrylium Reagent.

Herein, we report a radical borylation of aromatic amines through a homolytic C(sp2 )-N bond cleavage. This method capitalizes on a simple and mild activation via a pyrylium reagent (Sc Pyry-OTf) thus priming the amino group for reactivity. The combination of terpyridine and a diboron reagent triggers a radical reaction which cleaves the C(sp2 )-N bond and forges a new C(sp2 )-B bond. The unique non-planar structure of the pyridinium intermediate, provides the necessary driving force for the aryl radical formation. The method permits borylation of a wide variety of aromatic amines indistinctively of the electronic environment.

Spectroscopic and biochemical insight into an electron-bifurcating [FeFe] hydrogenase.

The heterotrimeric electron-bifurcating [FeFe] hydrogenase (HydABC) from Thermotoga maritima (Tm) couples the endergonic reduction of protons (H+) by dihydronicotinamide adenine dinucleotide (NADH) (∆G0 ≈ 18 kJ mol-1) to the exergonic reduction of H+ by reduced ferredoxin (Fdred) (∆G0 ≈ - 16 kJ mol-1). The specific mechanism by which HydABC functions is not understood. In the current study, we describe the biochemical and spectroscopic characterization of TmHydABC recombinantly produced in Escherichia coli and artificially maturated with a synthetic diiron cofactor. We found that TmHydABC catalyzed the hydrogen (H2)-dependent reduction of nicotinamide adenine dinucleotide (NAD+) in the presence of oxidized ferredoxin (Fdox) at a rate of ≈17 µmol NADH min-1 mg-1. Our data suggest that only one flavin is present in the enzyme and is not likely to be the site of electron bifurcation. FTIR and EPR spectroscopy, as well as FTIR spectroelectrochemistry, demonstrated that the active site for H2 conversion, the H-cluster, in TmHydABC behaves essentially the same as in prototypical [FeFe] hydrogenases, and is most likely also not the site of electron bifurcation. The implications of these results are discussed with respect to the current hypotheses on the electron bifurcation mechanism of [FeFe] hydrogenases. Overall, the results provide insight into the electron-bifurcating mechanism and present a well-defined system for further investigations of this fascinating class of [FeFe] hydrogenases.