Bond Cleavage Step Research Articles

Nickel-Catalyzed Direct Arylation of C(sp3)–H Bonds in Aliphatic Amides via Bidentate-Chelation Assistance

The Ni-catalyzed, direct arylation of C(sp(3))-H (methyl and methylene) bonds in aliphatic amides containing an 8-aminoquinoline moiety as a bidentate directing group with aryl halides is described. Deuterium-labeling experiments indicate that the C-H bond cleavage step is fast and reversible. Various nickel complexes including both Ni(II) and Ni(0) show a high catalytic activity. The results of a series of mechanistic experiments indicate that the catalytic reaction does not proceed through a Ni(0)/Ni(II) catalytic cycle, but probably through a Ni(II)/Ni(IV) catalytic cycle.

Mechanism of Rhodium-Catalyzed Carbon–Silicon Bond Cleavage for the Synthesis of Benzosilole Derivatives: A Computational Study

Rhodium-catalyzed carbon-silicon bond cleavage reaction is an efficient approach for the synthesis of silole derivates. The newly reported density functional theory method M11 is employed in order to elucidate how to cleave the inactive C(methyl)-Si bond. The computational results indicate that oxidative addition/reductive elimination pathway is favored over direct transmetallation in the C(methyl)-Si bond cleavage step. Alternatively, 1,4-rhodium-silicon exchange could take place before oxidative addition/reductive elimination. The rate-determining step for both pathways has been targeted on the initial transmetallation of 2-trimethylsilylphenyl boronic acid. The active catalytic species is a monomeric hydroxyrhodium complex, which could be regenerated from the hydrolysis of methylrhodium complex. In addition, theoretical calculations show that the hydrolyses of both aryl and vinyl intermediates are inhibited by intramolecular π-coordinated groups.

Schistosoma mansoni NAD+ catabolizing enzyme: Identification of key residues in catalysis

Schistosoma mansoni NAD+ catabolizing enzyme (SmNACE), a distant homolog of mammalian CD38, shows significant structural and functional analogy to the members of the CD38/ADP-ribosyl cyclase family. The hallmark of SmNACE is the lack of ADP-ribosyl cyclase activity that might be ascribed to subtle changes in its active site. To better characterize the residues of the active site we determined the kinetic parameters of nine mutants encompassing three acidic residues: (i) the putative catalytic residue Glu202 and (ii) two acidic residues within the ‘signature’ region (the conserved Glu124 and the downstream Asp133), (iii) Ser169, a strictly conserved polar residue and (iv) two aromatic residues (His103 and Trp165). We established the very important role of Glu202 and of the hydrophobic domains overwhelmingly in the efficiency of the nicotinamide–ribosyl bond cleavage step. We also demonstrated that in sharp contrast with mammalian CD38, the ‘signature’ Glu124 is as critical as Glu202 for catalysis by the parasite enzyme. The different environments of the two Glu residues in the crystal structure of CD38 and in the homology model of SmNACE could explain such functional discrepancies. Mutagenesis data and 3D structures also indicated the importance of aromatic residues, especially His103, in the stabilization of the reaction intermediate as well as in the selection of its conformation suitable for cyclization to cyclic ADP-ribose. Finally, we showed that inhibition of SmNACE by the natural product cyanidin requires the integrity of Glu202 and Glu124, but not of His103 and Trp165, hence suggesting different recognition modes for substrate and inhibitor.

Co–C Bond Energies in Adenosylcobinamide and Methylcobinamide in the Gas Phase and in Silico

Essential to biological activity of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) is the Co-C bond cleavage step. Hence, we report an accurate determination of the homolytic gas-phase Co-C bond dissociation energies in the related adenosyl- and methylcobinamides (41.5 ± 1.2 and 44.6 ± 0.8 kcal/mol, respectively) utilizing an energy-resolved threshold collision-induced dissociation technique. This approach allows for benchmarking of electronic structure methods separate from (often ill-defined) solvent effects. Adequacy of various density functional theory methods has been tested with respect to the experimentally obtained values.

The key role of a non-active-site residue Met148 on the catalytic efficiency of meta-cleavage product hydrolase BphD

meta-Cleavage product (MCP) hydrolases (EC 3.7.1.9) can catalyze a specific C-C bond fission during the microbial aerobic degradation of aromatics. The previous studies on structure-function relationship of MCP hydrolases mainly focus on the active site residues by site-directed mutagenesis. However, the information about the role of the non-active-site residues is still unclear. In this study, a non-active-site residue Met148 of MCP hydrolase BphD was selected as the mutagenesis site according to the sequence alignments, structure superimpose and the tunnel analysis, which underwent the saturation mutagenesis resulting 19 mutants. The catalytic efficiencies of the mutants on 6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) were all decreased compared with the wild-type one except for the M148D mutant. Especially, the M148P mutant exhibited 290-fold lower k cat/K m than that of the wild-type BphD. Transient kinetic analyses of M148P showed the reciprocal relaxation time corresponded to C-C bond cleavage and product release steps (9.6 s(-1)) was 4.08-fold lower than BphD WT (39.2 s(-1)). Tunnel cluster analysis of BphD WT, M148P and M148W demonstrated that only the bulky Trp148 could block tunnel T2 in the BphD WT, but it exhibited slight effects on the catalytic efficiency (0.94-fold of BphD WT). Therefore, product release was not the main reason for the efficiency decrease of M148P. On the other hand, molecular dynamics simulations on the BphD WT and BphD M148P in complex with HOPDA indicated that the dramatic decrease of the catalytic efficiencies of BphD M148P should be due to the unproductive binding of HOPDA. The study demonstrated the catalytic efficiency of MCP hydrolase can be engineered by modification of non-active site residue.

Do MAO A and MAO B utilize the same mechanism for the C–H bond cleavage step in catalysis? Evidence suggesting differing mechanisms

The detailed molecular mechanism proposed for the MAO-catalyzed oxidation of amines has been controversial with the basic assumption that both MAO A and MAO B follow the same pathway for the C-H bond cleavage step. Using the mechanistic approach of investigation of electronic effects of various benzylamine ring substituents in experiments at pH 9.0, human MAO A exhibits a kinetic behavior characteristic of an H(+) abstraction, while human MAO B exhibits kinetic properties characteristic of a H(-) abstraction. These results lead to the conclusion that the assumption that MAO A and MAO B follow identical mechanisms is incorrect.

Theoretical Study of the Oxidation of Phenolates by the [Cu2O2(N,N′‐di‐tert‐butylethylenediamine)2]2+ Complex

Experiments have shown that the μ-η(2):η(2)-peroxodicopper(II) complex [Cu(2)O(2)(N,N'-di-tert-butylethylenediamine)(2)](2+) rapidly oxidizes 2,4-di-tert-butylphenolate into a mixture of catechol and quinone and that, at the extreme temperature of -120 °C, a bis-μ-oxodicopper(III)-phenolate intermediate, labeled complex A, can be observed. These experimental results suggest a new mechanism of action for the dinuclear copper-containing enzyme tyrosinase, involving an early O-O bond-cleavage step. However, whether phenolate binding occurs before or after the cleavage of the O-O bond has not been possible to answer. In this study, hybrid density functional theory is used to study the synthetic reaction and, based on the calculated free-energy profile, a mechanism is suggested for the entire phenolate-oxidation reaction that agrees with the experimental observations. Most importantly, the calculations show that the very first step in the reaction is the cleavage of the O-O bond in the peroxo complex and that, subsequently, the phenolate substrate coordinates to one of the copper ions in the bis-μ-oxodicopper(III) complex to yield the experimentally characterized phenolate intermediate (A). The oxidation of the phenolate substrate into a quinone then occurs in three steps: 1) C-O bond formation, 2) coupled internal proton and electron transfer, and 3) electron transfer coupled to proton transfer from an external donor (acidic workup, experimentally). The first of these steps is rate limiting for the decay of complex A, with a calculated free-energy barrier of 10.7 kcal mol(-1) and a deuterium kinetic isotope effect of 0.90, which are in good agreement with the experimental values of 11.2 kcal mol(-1) and 0.83(±0.09). The tert-butyl substituents on both the phenol substrate and the copper ligands need to be included in the calculations to give a correct description of the reaction mechanism.

Relationship between supporting electrolyte bulkiness and dissociative electron transfer at catalytic and non-catalytic electrodes

Dissociative electron transfers (DETs) involving aryl halides in the presence of supporting electrolytes with tetraalkylammonium cations TAA+ of different diameters provide a first model case of rationalized relationship between supporting electrolyte bulkiness effect and DET mechanism.In non-catalytic conditions, with the molecule reacting at the OHP, increasingly bulkier TAA+ cations result in increasing double layer (DL) thickness and consequently in increasingly hindered electron tunnelling, and the reduction peak potentials Ep,DET linearly shift in the negative direction with increasing cation diameter dTAA+. The linear variation of Ep,DET with dTAA+ is consistent with the distance dependence of kET for reagents held at fixed distances from the electrode (lnk=lnk0−βx). The ∂Ep,DET/∂dTAA+ slope is not constant in the investigated model series, but linearly increases with decreasing κ parameter, accounting for the heterogeneous ET step becoming increasingly more determining with respect to the following CX bond cleavage step (as a consequence of decreasing stability of the π* orbital corresponding to the radical anion). Thus the β parameter in the electron tunnelling equation appears to be strictly related to the ET activation barrier (in particular, to its relative weight in the overall DET kinetics).On catalytic Ag electrodes, with the molecule reacting at the IHP, the supporting electrolyte effect is assumed to depend on the increasingly smaller effective potential difference available to the molecule, reacting close to the electrode, with increasing double layer thickness. It appears more conspicuous than in non-catalytic conditions, in spite of the less extreme operating potentials, but consistently with the increased relative importance of the ET activation barrier at a catalytic electrode.

Theoretical studies on the common catalytic mechanism of transketolase by using simplified models

Transketolase is a convenient model system to study enzymatic thiamin catalysis. By using density functional theory (DFT) method, the transfer mechanism of a 2-carbon fragment between a donor ketose X5P and an acceptor aldose R5P catalyzed by transketolase has been studied on simplified models. The calculation results indicate that the whole reaction cycle contains several proton transfer processes as well as CC bond formation and cleavage steps. Each CC bond formation or cleavage step is always accompanied by a proton transfer process, which follows a concerted but asynchronous mechanism. The CC bond formation is always prior to the proton transfer, and the CC bond cleavage is always later than proton transfer, suggesting that the CC bond ligation facilitates the proton transfer, and proton transfer promotes the CC bond cleavage. In the first half- and second half-reactions, the energy barriers of CC bond formations are always higher than those of CC bond cleavages. The 4-amino group of cofactor ThDP and histidine residue can act as the proton donor/acceptor during the catalytic reaction.

Water-Dependent Reaction Pathways: An Essential Factor for the Catalysis in HEPD Enzyme

The hydroxyethylphosphonate dioxygenase (HEPD) catalyzes the critical carbon-carbon bond cleavage step in the phosphinothricin (PT) biosynthetic pathway. The experimental research suggests that water molecules play an important role in the catalytic reaction process of HEPD. This work proposes a water involved reaction mechanism where water molecules serve as an oxygen source in the generation of mononuclear nonheme iron oxo complexes. These molecules can take part in the catalytic cycle before the carbon-carbon bond cleavage process. The properties of trapped water molecules are also discussed. Meanwhile, water molecules seem to be responsible for converting the reactive hydroxyl radical group ((-)OH) to the ferric hydroxide (Fe(III)-OH) in a specific way. This converting reaction may prevent the enzyme from damages caused by the hydroxyl radical groups. So, water molecules may serve as biological catalysts just like the work in the heme enzyme P450 StaP. This work could provide a better interpretation on how the intermediates interact with water molecules and a further understanding on the O(18) label experimental evidence in which only a relatively smaller ratio of oxygen atoms in water molecules (∼40%) are incorporated into the final product HMP.

An expeditious route to eight-membered heterocycles by nickel-catalyzed cycloaddition: low-temperature C(sp)2-C(sp)3 bond cleavage.

A cool break: 3-Azetidinone and a variety of diynes undergo a cycloaddition reaction catalyzed by Ni/IPr to give dihydroazocine compounds (see scheme; IPr=1,3-bis(2,6-diisopropylphenyl)imidazolidene). The reaction involves a challenging C(sp)2-C(sp)3 bond cleavage step, yet, surprisingly, proceeds at low temperature.

A novel genetic selection system for PLP-dependent threonine aldolases

Threonine aldolases are versatile pyridoxal-5′-phosphate (PLP)-dependent enzymes key to glycine, serine and threonine metabolism. Because they catalyze the reversible addition of glycine to an aldehyde to give β-hydroxy-α-amino acids, they are also attractive as biotechnological catalysts for the diastereoselective synthesis of many pharmaceutically useful compounds. To study and evolve such enzymes, we have developed a simple selection system based on the simultaneous inactivation of four genes involved in glycine biosynthesis in Escherichia coli. Glycine prototrophy in the deletion strain is restored by expression of a gene encoding an aldolase that converts β-hydroxy-α-amino acids, provided in the medium, to glycine and the corresponding aldehyde. Combinatorial mutagenesis and selection experiments with a previously uncharacterized l-threonine aldolase from Caulobacter crescentus CB15 (Cc-LTA) illustrate the power of this system. The codons for four active site residues, His91, Asp95, Glu96, and Asp176, were simultaneously randomized and active variants selected. The results show that only His91, which π-stacks against the PLP cofactor and probably serves as the catalytic base in the carbon-carbon bond cleavage step, is absolutely required for aldolase activity. In contrast, Asp176, one of the most conserved residues in this enzyme superfamily, can be replaced conservatively by glutamate, albeit with a >5000-fold decrease in efficiency. Though neither Asp95 nor Glu96 is catalytically essential, they appear to modulate substrate binding and His91 activity, respectively. The broad dynamic range of this novel selection system should make it useful for mechanistic investigations and directed evolution of many natural and artificial aldolases.

Analysis of the Palladium-Catalyzed (Aromatic)C–H Bond Metalation–Deprotonation Mechanism Spanning the Entire Spectrum of Arenes

A comprehensive understanding of the C-H bond cleavage step by the concerted metalation-deprotonation (CMD) pathway is important in further development of cross-coupling reactions using different catalysts. Distortion-interaction analysis of the C-H bond cleavage over a wide range of (hetero)aromatics has been performed in an attempt to quantify the various contributions to the CMD transition state (TS). The (hetero)aromatics evaluated were divided in different categories to allow an easier understanding of their reactivity and to quantify activation characteristics of different arene substituents. The CMD pathway to the C-H bond cleavage for different classes of arenes is also presented, including the formation of pre-CMD intermediates and the analysis of bonding interactions in TS structures. The effects of remote C2 substituents on the reactivity of thiophenes were evaluated computationally and were corroborated experimentally with competition studies. We show that nucleophilicity of thiophenes, evaluated by Hammett σ(p) parameters, correlates with each of the distortion-interaction parameters. In the final part of this manuscript, we set the initial equations that can assist in the development of predictive guidelines for the functionalization of C-H bonds catalyzed by transition metal catalysts.

Activation of Anisole by Organoplatinum(II) Complexes: Evidence for Rate-Determining C–H Activation

A study of the basis of selectivity of C–H bond activation of anisole by electrophilic methylplatinum(II) complexes is reported. Anisole reacts with [PtXMe(NN)] in trifluoroethanol solvent to give methane and [PtXAr(NN)], Ar = 2-, 3-, and 4-anisyl, in 90:8:2 ratio when X = HOB(C6F5)3 and NN = (2-C5H4N)2CO (DPK) but not when NN = 2,2′-bipyridine. Similar results are obtained when X = triflate or when NN = (2-C5H4N)2NH. Competition between reaction of anisole and anisole-d8 with [PtXMe(NN)], X = HOB(C6F5)3 and NN = DPK, in trifluoroethanol gave an isotope effect kH/kD = 3.6. Several 4-anisyl complexes, [PtClAr(NN)], [PtAr2(NN)], and [PtMeAr(NN)], NN = DPK, DPA, or bipy, were prepared and reacted with HX [X = Cl, OTf, or HOB(C6F5)3]. Reaction of [PtMeAr(NN)], NN = DPK or bipy, with HX gave a detectable hydride [PtXHMeAr(NN)] when X = Cl, followed by loss of methane to give [PtClAr(NN)], but only [Pt(OTf)Ar(NN)] was detected when X = OTf. Reaction with more HOTf gave anisole and [PtX2(NN)], X = OTf, and no isomerization of the 4-anisyl group to the more favored 2-anisyl group was observed at any stage. The similar reaction of [PtMeAr(NN)] and HOTf in CD3OD/CD2Cl2 gave CHnD4–n (n = 0–4) and mostly 4-MeOC6H4D. It is argued that the anisole C–H bond cleavage step in anisole activation, or the anisyl–H bond forming step in protonolysis, is responsible for the observed selectivity in these reactions.

ChemInform Abstract: Transition Metal Catalyzed Manipulation of Non‐Polar Carbon—Hydrogen Bonds for Synthetic Purpose

AbstractReview: 94 refs.

Carbon–Hydrogen Bond Cleavage Reaction in Four-Coordinate (2,6-Dimethylbenzenethiolato)platinum(II) Complexes. Dramatic Acceleration by Thiolato Hydrogen Acceptor

The (2,6-dimethylbenzenethiolato)platinum(II) complexes PtR(SC6H3Me2-2,6-κ1S)L2 (R = Me, L = PMe3 (1a), PPh3 (1c), L2 = dppe (1d), dppp (1e); R = Et, L = PPh3 (2c); R = CH2CMe3, L = PPh3 (3c)) and Pt(SC6H3Me2-2,6-κ1S)2L2 (L = PMe3 (4a), PEt3 (4b), PPh3 (4c), L2 = dppe (4d), dppp (4e), dppb (4f)) have been prepared. Heating of these compounds results in an internal sp3 C–H bond cleavage reaction, giving the thiaplatinacycle complexes Pt[SC6H3(CH2-2)(Me-6)-κ2S,C]L2 (L = PMe3 (5a), PEt3 (5b), PPh3 (5c), L2 = dppe (5d), dppp (5e), dppb (5f)) in moderate to quantitative yields. The reactions of 1c and 4c proceed via prior dissociation of PPh3, and a concerted mechanism is proposed. Of particular interest is the sp3 C–H bond activation step, whose observed rate constant for 4c is no less than 104-fold faster than that for 1c. The arenethiolato group is expected to enhance the C–H bond cleavage step as a hydrogen acceptor.

2H Kinetic Isotope Effects and pH Dependence of Catalysis as Mechanistic Probes of Rat Monoamine Oxidase A: Comparisons with the Human Enzyme

Monoamine oxidase A (MAO A) is a mitochondrial outer membrane-bound flavoenzyme important in the regulation of serotonin and dopamine levels. Because the rat is extensively used as an animal model in drug studies, it is important to understand how rat MAO A behaves in comparison with the more extensively studied human enzyme. For many reversible inhibitors, rat MAO A exhibits K(i) values similar to those of human MAO A. The pH profile of k(cat) for rat MAO A shows a pK(a) of 8.2 ± 0.1 for the benzylamine ES complex and pK(a) values of 7.5 ± 0.1 and 7.6 ± 0.1 for the ES complexes with p-CF(3)-(1)H- and p-CF(3)-(2)H-benzylamine, respectively. In contrast to the human enzyme, the rat enzyme exhibits a single pK(a) value (8.3 ± 0.1) with k(cat)/K(m) for benzylamine versus pH and pK(a) values of 7.8 ± 0.1 and 8.1 ± 0.2 for the ascending limbs, respectively, of k(cat)/K(m) versus pH profiles for p-CF(3)-(1)H- and p-CF(3)-(2)H-benzylamine and 9.3 ± 0.1 and 9.1 ± 0.2 for the descending limbs, respectively. The oxidation of para-substituted benzylamine substrate analogues by rat MAO A has large deuterium kinetic isotope effects on k(cat) and on k(cat)/K(m). These effects are pH-independent and range from 7 to 14, demonstrating a rate-limiting α-C-H bond cleavage step in catalysis. Quantitative structure-activity correlations of log k(cat) with the electronic substituent parameter (σ) at pH 7.5 and 9.0 show a dominant contribution with positive ρ values (1.2-1.3) and a pH-independent negative contribution from the steric term. Quantitative structure-activity relationship analysis of the binding affinities of the para-substituted benzylamine analogues for rat MAO A shows an increased van der Waals volume (V(w)) increases the affinity of the deprotonated amine for the enzyme. These results demonstrate that rat MAO A exhibits functional properties similar but not identical with those of the human enzyme and provide additional support for C-H bond cleavage via a polar nucleophilic mechanism.

Theoretical study of the mechanism of oxoiron(IV) formation from H2O2 and a nonheme iron(II) complex: O-O cleavage involving proton-coupled electron transfer.

It has recently been shown that the nonheme oxoiron(IV) species supported by the 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane ligand (TMC) can be generated in near-quantitative yield by reacting [Fe(II)(TMC)(OTf)(2)] with a stoichiometric amount of H(2)O(2) in CH(3)CN in the presence of 2,6-lutidine (Li, F.; England, J.; Que, L., Jr. J. Am. Chem. Soc. 2010, 132, 2134-2135). This finding has major implications for O-O bond cleavage events in both Fenton chemistry and nonheme iron enzymes. To understand the mechanism of this process, especially the intimate details of the O-O bond cleavage step, a series of density functional theory (DFT) calculations and analyses have been carried out. Two distinct reaction paths (A and B) were identified. Path A consists of two principal steps: (1) coordination of H(2)O(2) to Fe(II) and (2) a combination of partial homolytic O-O bond cleavage and proton-coupled electron transfer (PCET). The latter combination renders the rate-limiting O-O cleavage effectively a heterolytic process. Path B proceeds via a simultaneous homolytic O-O bond cleavage of H(2)O(2) and Fe-O bond formation. This is followed by H abstraction from the resultant Fe(III)-OH species by an •OH radical. Calculations suggest that path B is plausible in the absence of base. However, once 2,6-lutidine is added to the reacting system, the reaction barrier is lowered and more importantly the mechanistic path switches to path A, where 2,6-lutidine plays an essential role as an acid-base catalyst in a manner similar to how the distal histidine or glutamate residue assists in compound I formation in heme peroxidases. The reaction was found to proceed predominantly on the quintet spin state surface, and a transition to the triplet state, the experimentally known ground state for the TMC-oxoiron(IV) species, occurs in the last stage of the oxoiron(IV) formation process.

ChemInform Abstract: Regioselectivity‐Switchable Hydroarylation of Styrenes.

Cobalt−phosphine and cobalt−carbene catalysts have been developed for the hydroarylation of styrenes via chelation-assisted C−H bond activation, to afford branched and linear addition products, respectively, in a highly regioselective fashion. Deuterium-labeling experiments suggested a mechanism involving reversible C−H bond cleavage and olefin insertion steps and reductive elimination as the rate- and regioselectivity-determining step.

Hydrodeoxygenation pathways catalyzed by MoS 2 and NiMoS active phases: A DFT study

Due to the increasing need for purifying renewable feeds (such as biomass effluents) by means of catalytic hydrotreatment processes, the atomic-scale understanding of the catalytic properties of transition metal sulfide active phases in the presence of oxygenated molecules becomes crucial. Using density functional theory (DFT) calculations, we evaluate the adsorption properties and the hydrodeoxygenation pathways of relevant model O-containing molecules on the M-edge sites of the MoS 2 and NiMoS active phase. We show first that the adsorption energies of methyl propanoate, propanoic acid, propanal, propanol and water are stronger on MoS 2 than on NiMoS. The interaction with the accessible Mo site is directed by the oxygen atom of either the C O group for ester and acid or the OH group for alcohol and water molecules. For propanal, the adsorption mode depends on the nature of the active site: it is found to be bidentate on NiMoS, where the C and O atoms of the carbonyl group simultaneously interact with the dual Ni Mo sites of the M-edge. The investigation into hydrodeoxygenation pathways reveals how the C O hydrogenation and the C O bond cleavage occur on transition metal sulfides. The specific adsorption mode provides a lower activation energy for the hydrogenation of propanal into propanol on NiMoS than on MoS 2. The propanol is further deoxygenated by a nucleophilic substitution mechanism involving a sulfhydryl group and leading to a thiol intermediate before propane formation. The rate-limiting step of the aldehyde HDO process is determined by the C O bond cleavage step for which the activation energy is found smaller for NiMoS than for MoS 2.