Bond Cleavage Step Research Articles

Unraveling the Crucial Role of Single Active Water Molecule in the Oxidative Cleavage of Aliphatic C–C Bond of 2,4′-Dihydroxyacetophenone Catalyzed by 2,4′-Dihydroxyacetophenone Dioxygenase Enzyme: A Quantum Mechanics/Molecular Mechanics Investigation

2,4′-Dihydroxyacetophenone dioxygenase (DAD), a nonheme dioxygenase enzyme, shows exquisite selectivity in the aliphatic C–C bond cleavage of 2,4′-dihydroxyacetophenone (DHAP) in the presence of molecular oxygen (O2). Molecular dynamics simulations revealed the presence of a single water molecule at the active site of the enzyme. This lone water molecule is pivotal for facilitating the oxidative cleavage of the aliphatic C–C bond of 2,4′-DHAP catalyzed by DAD enzyme, as evident from the findings of our hybrid quantum mechanics/molecular mechanics (QM/MM) studies. 2,4′-DHAP is initially deprotonated through a relay proton transfer mechanism with the aid of the active site water molecule. This water molecule also actively participates in the O–O and C–C bond cleavage steps. The activated water molecule acts as catalytic acid–base species. The O–O cleavage step has been predicted to be the rate-determining step with an associated barrier of 20.3 kcal/mol calculated at the uB3LYP-D3/def2-TZVP/OPLS level of th...

Molecular Basis for the Final Oxidative Rearrangement Steps in Chartreusin Biosynthesis.

Oxidative rearrangements play key roles in introducing structural complexity and biological activities of natural products biosynthesized by type II polyketide synthases (PKSs). Chartreusin (1) is a potent antitumor polyketide that contains a unique rearranged pentacyclic aromatic bilactone aglycone derived from a type II PKS. Herein, we report an unprecedented dioxygenase, ChaP, that catalyzes the final α-pyrone ring formation in 1 biosynthesis using flavin-activated oxygen as an oxidant. The X-ray crystal structures of ChaP and two homologues, docking studies, and site-directed mutagenesis provided insights into the molecular basis of the oxidative rearrangement that involves two successive C-C bond cleavage steps followed by lactonization. ChaP is the first example of a dioxygenase that requires a flavin-activated oxygen as a substrate despite lacking flavin binding sites, and represents a new class in the vicinal oxygen chelate enzyme superfamily.

Mechanism investigation for anoin-assisted nickel catalyzed C–F bond functionalization reaction: a DFT study

C–F bond functionalization still faces with great challenges in synthetic chemistry due to the inert nature of C–F bond in organic compounds. Herein, the newly reported DFT method M11-L was used to determine the mechanism of nickel catalyzed C–F/C–H bond cross coupling involving the C–F bond cleavage of flouroarenes and C–H bond functionalization of oxazoles. DFT calculations revealed that fluoride would stabilize the nickel(0) compound to afford an active nickel(0) ate-complex. With the assistance of fluoride, the oxidative addition of C–F bond to nickel(0) ate-complex would yield an active nickel(II) species, which is the rate-determining step in this catalytic cycle. The following C–H bond cleavage step would proceed via a direct deprotonation step under the attack of Bronsted base, to generate diarylnickel(II) species. Finally, reductive elimination step would occur to give the coupling product with regeneration of active nickel(0) ate-complex. In this pathway, we found that the relative free energies of nickel ate-complex species are more stable than commonly assumed neutral-nickel intermediates. This work could provide a new way for the mechanism study of inert C--F bond activation reactions.

Bottom-up Construction of π-Extended Arenes by a Palladium-Catalyzed Annulative Dimerization of o-Iodobiaryl Compounds.

A straightforward method was developed for construction of aromatic compounds with a triphenylene core. The method involves Pd-catalyzed annulative dimerization of o-iodobiaryl compounds by double C-I and C-H bond cleavage steps. Simple reaction conditions are needed, requiring neither a ligand nor an oxidant, and the reaction tolerates a wide range of coupling partners without compromising efficiency or scalability. Significantly, the tetrachloro-substituted synthon, 1,6,11-trichloro-4-(4-chlorophenyl)triphenylene, can be generated and used to prepare a series of fully fused, small graphene nanoribbons by a late-stage arylation with arylboronic acids and a subsequent Scholl reaction. The synthetic strategy enables bottom-up access to extended π-systems in a controlled manner.

Cover Picture: Visible Light Accelerated Vinyl C–H Arylation in Pd‐Catalysis: Application in the Synthesis of ortho Tetra‐substituted Vinylarene Atropisomers (Chin. J. Chem. 1/2018)

The cover picture shows a protocol of a palladium‐catalyzed arylation of vinylarenes with diaryliodonium salts with the assistance of visible light. A palladium‐vinylarene complex may be excited via the visible light irradiation, where the kinetic isotope effect (kH/kD) was around 1.1. However under darkness, the reaction proceeded very slowly, and the kinetic isotope was found as 3.6, indicating the C—H bond cleavage step is the rate‐determining step. This protocol avoided high reaction temperature and enabled us to access a series of ortho tetra‐substituted vinylarene atropisomers with high enantiospecificity. More details are discussed in the article by Gu et al. on page 11–14. image

Mechanism of Rhodium-Catalyzed C-H Functionalization: Advances in Theoretical Investigation.

Transition-metal-catalyzed cross-coupling has emerged as an effective strategy for chemical synthesis. Within this area, direct C-H bond transformation is one of the most efficient and environmentally friendly processes for the construction of new C-C or C-heteroatom bonds. Over the past decades, rhodium-catalyzed C-H functionalization has attracted considerable attention because of the versatility and wide use of rhodium catalysts in chemistry. A series of C-X (X = C, N, or O) bond formation reactions could be realized from corresponding C-H bonds using rhodium catalysts. Various experimental studies on rhodium-catalyzed C-H functionalization reactions have been reported, and in tandem, mechanistic and computational studies have also progressed significantly. Since 2012, our group has performed theoretical studies to reveal the mechanism of rhodium-catalyzed C-H functionalization reactions. We have studied the changes in the oxidation state of rhodium and compared the Rh(I)/Rh(III) catalytic cycle to the Rh(III)/Rh(V) catalytic cycle using density functional theory calculation. The development of advanced computational methods and improvements in computing power make theoretical calculation a powerful tool for the mechanistic study of rhodium chemistry. Computational study is able to not only provide mechanistic insights but also explain the origin of regioselectivity, enantioselectivity, and stereoselectivity in rhodium-catalyzed C-H functionalization reactions. This Account summarizes our computational work on rhodium-catalyzed C-H functionalization reactions. The mechanistic study under discussion is divided into three main parts: C-H bond cleavage step, transformation of the C-Rh bond, and regeneration of the active catalyst. In the C-H bond cleavage step, computational results of four possible mechanisms, including concerted metalation-deprotonation (CMD), oxidative addition (OA), Friedel-Crafts-type electrophilic aromatic substitution (SEAr), and σ-complex assisted metathesis (σ-CAM) are discussed. Subsequent transformation of the C-Rh bond, for example, via insertion of CO, olefin, alkyne, carbene, or nitrene, constructs new C-C or C-heteroatom bonds. For the regeneration of the active catalyst, reductive elimination of a high-valent rhodium complex and protonation of the C-Rh bond are emphasized as potential mechanism candidates. In addition to detailing the reaction pathway, the regioselectivity and diastereoselectivity of rhodium-catalyzed C-H functionalization reactions are also commented upon in this Account. The origin of the selectivity is clarified through theoretical analysis. Furthermore, we summarize and compare the changes in the oxidation state of rhodium along the complete reaction pathway. The work described in this Account demonstrates that rhodium catalysis might proceed via Rh(I)/Rh(III), Rh(II)/Rh(IV), Rh(III)/Rh(V), or non-redox-Rh(III) catalytic cycles.

Silver-Catalyzed Oxidative C(sp3 )-P Bond Formation through C-C and P-H Bond Cleavage.

The silver-catalyzed oxidative C(sp3 )-H/P-H cross-coupling of 1,3-dicarbonyl compounds with H-phosphonates, followed by a chemo- and regioselective C(sp3 )-C(CO) bond-cleavage step, provided heavily functionalized β-ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional-group tolerance, and exclusive selectivity.

Factors Determining the Rate and Selectivity of 4e-/4H+ Electrocatalytic Reduction of Dioxygen by Iron Porphyrin Complexes.

Reactivity as well as selectivity are crucial in the activation and electrocatalytic reduction of molecular oxygen. Recent developments in the understanding of the mechanism of electrocatalytic O2 reduction by iron porphyrin complexes in situ using surface enhanced resonance Raman spectroscopy coupled to rotating disc electrochemistry (SERRS-RDE) in conjunction with H/D isotope effects on electrocatalytic current reveals that the rate of O2 reduction, ∼104 to 105 M-1 s-1 for simple iron porphyrins, is limited by the rate of O-O bond cleavage of an intermediate ferric peroxide species (FeIII-OOH). SERRS-RDE probes the system in operando when it is under steady state such that any intermediate species that has a greater rate of formation relative to its rate of decay, including the rate determining species, would accumulate and can be identified. This technique is particularly well suited to investigate iron porphyrin electrocatalysts as the intense symmetric ligand vibrations allow determination of the oxidation and spin states of the bound iron with high fidelity. The rate of O2 reduction could be tuned up by 3 orders of magnitude by incorporating residues in the catalyst design that can exert "push" or "pull" effects, that is, axial phenolate and thiolate ligands and distal arginine residues. Similarly the rate of O-O bond cleavage can be enhanced by several orders of magnitude upon incorporating a distal Cu site and installing the active site in a hydrophobic protein environment in synthetic models and biosynthetic protein scaffolds. The selectivity, however, is solely determined by the site of protonation of a ferric peroxide (FeIII-OOH) intermediate and can be governed by installing preorganized second sphere residues in the distal pocket. The 4e-/4H+ reduction of O2 entails protonation of the distal oxygen of the FeIII-OOH species, while 2e-/2H+ reduction requires the proximal oxygen to be protonated. Mechanistic investigations of CO2 reduction by iron porphyrins reveal that the rate-determining step is the C-O bond cleavage of a FeII-COOH species analogous to the O-O bond cleavage step of a FeIII-OOH species in O2 reduction. The selectivity, resulting in either CO or HCOOH, is determined by the site of protonation of this species. These similarities suggests that the chemical principles governing the rate and selectivity of reduction of small molecules like O2, CO2, NOx, and SOx may be quite similar in nature.

Mechanistic Studies on Rhodium-Catalyzed Enantioselective Silylation of Aryl C-H Bonds.

Several classes of enantioselective silylations of C-H bonds have been reported recently, but little mechanistic data on these processes are available. We report mechanistic studies on the rhodium-catalyzed, enantioselective silylation of aryl C-H bonds. A rhodium silyl dihydride and a rhodium norbornyl complex were prepared and determined to be interconverting catalyst resting states. Kinetic isotope effects indicated that the C-H bond cleavage step is not rate-determining, but the C-H bond cleavage and C-Si bond-forming steps together influence the enantioselectivity. DFT calculations indicate that the enantioselectivity originates from unfavorable steric interactions between the substrate and the ligand in the transition state leading to the formation of the minor enantiomer.

Electrochemical Reduction of CO2 Catalyzed by Re(pyridine-oxazoline)(CO)3Cl Complexes.

A series of rhenium tricarbonyl complexes coordinated by asymmetric diimine ligands containing a pyridine moiety bound to an oxazoline ring were synthesized, structurally and electrochemically characterized, and screened for CO2 reduction ability. The reported complexes are of the type Re(N-N)(CO)3Cl, with N-N = 2-(pyridin-2-yl)-4,5-dihydrooxazole (1), 5-methyl-2-(pyridin-2-yl)-4,5-dihydrooxazole (2), and 5-phenyl-2-(pyridin-2-yl)-4,5-dihydrooxazole (3). The electrocatalytic reduction of CO2 by these complexes was observed in a variety of solvents and proceeds more quickly in acetonitrile than in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). The analysis of the catalytic cycle for electrochemical CO2 reduction by 1 in acetonitrile using density functional theory (DFT) supports the C-O bond cleavage step being the rate-determining step (RDS) (ΔG⧧ = 27.2 kcal mol-1). The dependency of the turnover frequencies (TOFs) on the donor number (DN) of the solvent also supports that C-O bond cleavage is the rate-determining step. Moreover, the calculations using explicit solvent molecules indicate that the solvent dependence likely arises from a protonation-first mechanism. Unlike other complexes derived from fac-Re(bpy)(CO)3Cl (I; bpy = 2,2'-bipyridine), in which one of the pyridyl moieties in the bpy ligand is replaced by another imine, no catalytic enhancement occurs during the first reduction potential. Remarkably, catalysts 1 and 2 display relative turnover frequencies, (icat/ip)2, up to 7 times larger than that of I.

Mechanistic Insight into the Rh(III)-Catalyzed C-H Activation of 2-Acetyl-1-Arythydrazines in Water.

A mechanistic study of the Cp*RhIII-catalyzed C-H functionalization of 2-acetyl-1-arythydrazines with diazo compounds in water was carried out by using density functional theory calculations. The results reveal that the acetyl-bonded N-H deprotonation is prior to the phenyl C-H activation. The mechanisms from protonation by acetic acid disagree with the proposal by the Wang group. Different from the Rh(III)-catalyzed C-H activation reported by experimental literature, the rate-determining step of the whole catalytic cycle with an overall barrier of 31.7 kcal mol-1 (IV → TS12-P') is the protonation process of hydroxy O rather than the C-H bond cleavage step. The present theoretical study rationalizes the experimental observation at the molecular level.

Nanobelt-arrayed vanadium oxide hierarchical microspheres as catalysts for selective oxidation of 5-hydroxymethylfurfural toward 2,5-diformylfuran

Nanobelt-arrayed vanadium oxide hierarchical microspheres were synthesized to catalyze selective oxidation of 5-hydroxymethylfurfural to 2,5-diformylfuran with the high conversion and selectivity of 93.7% and 95.4%, respectively. This prominent performance can be attributed to the major exposure of (010) facet with highest hydrogen adsorption capability of vanadyl group (VO) sites and the highly oriented morphology for reactant contact and residence time control. Density functional theory calculation of the hydrogen adsorption capabilities on different facets and different chemical environmental sites has been utilized to explain the influence of different facets and lattice oxygen sites on 5-hydroxymethylfurfural oxidation performance based on hydrogen adsorption and αH-C bond cleavage steps. Isotopic studies verified the reaction mechanism and kinetic studies derived the first order reaction rate equation dependent on the 5-hydroxymethylfurfural concentration. These results suggested the crucial roles of (0 1 0) facets and the VO sites in O-H and αH-C bonds cleavage of 5-hydroxymethylfurfural before the reduction product V-OH species further dehydrogenation by molecular oxygen.

Mechanistic Elucidation of Zirconium-Catalyzed Direct Amidation.

The mechanism of the zirconium-catalyzed condensation of carboxylic acids and amines for direct formation of amides was studied using kinetics, NMR spectroscopy, and DFT calculations. The reaction is found to be first order with respect to the catalyst and has a positive rate dependence on amine concentration. A negative rate dependence on carboxylic acid concentration is observed along with S-shaped kinetic profiles under certain conditions, which is consistent with the formation of reversible off-cycle species. Kinetic experiments using reaction progress kinetic analysis protocols demonstrate that inhibition of the catalyst by the amide product can be avoided using a high amine concentration. These insights led to the design of a reaction protocol with improved yields and a decrease in catalyst loading. NMR spectroscopy provides important details of the nature of the zirconium catalyst and serves as the starting point for a theoretical study of the catalytic cycle using DFT calculations. These studies indicate that a dinuclear zirconium species can catalyze the reaction with feasible energy barriers. The amine is proposed to perform a nucleophilic attack at a terminal η2-carboxylate ligand of the zirconium catalyst, followed by a C-O bond cleavage step, with an intermediate proton transfer from nitrogen to oxygen facilitated by an additional equivalent of amine. In addition, the DFT calculations reproduce experimentally observed effects on reaction rate, induced by electronically different substituents on the carboxylic acid.

Access to Enantiopure Triarylmethanes and 1,1-Diarylalkanes by NHC-Catalyzed Acylative Desymmetrization.

We present herein an unprecedented, efficient and enantioselective synthesis of triarylmethanes and 1,1-diarylalkanes through N-heterocyclic carbene-catalyzed acylative desymmetrization of bisphenols. This method utilizes readily available substrates, reagents and a simple procedure to deliver the valuable products in excellent enantiopurity. DFT calculations reveal that the selectivity is governed by the C-C bond cleavage step of the tetrahedral intermediate leading to the ester product. A transition state model featuring a combination of intramolecular hydrogen bond and steric effect is developed to explain the enantioselectivity.

Mechanism of Rh(III)-catalyzed cyclopropanation using N-enoxyphthalimides and alkenes: Insights from DFT calculations

The Rh(III)-catalyzed cyclopropanation reaction using N-enoxyphthalimides and alkenes developed by Rovis group [J. Am. Chem. Soc.2014, 136, 11292−11295] provided an efficient method for the constructions of trans 1,2-disubstituted cyclopropanes in which an elegant control of the diastereoselectivities was achieved. In the current report we aimed at uncovering the mechanism and diastereoselectivity of the reactions using density functional theory (DFT) calculations. By comparing the energies of all possible pathways, we found that a novel mechanism involving a four-membered Rh(V) species is the energetically most favorable one. In this pathway, the four-membered Rh(V) intermediate is formed by sequential CH activation, alkene insertion and NO bond cleavage steps, and the final cyclopropane product is formed via an reductive elimination process. The NO bond cleavage was found to be the diastereoselectivity-determining, which was reproduced well the experimentally observed selectivity. By analyzing using the distortion/interaction model, it was found that the distortion energy plays a main role in determining the diastereoselectivity.

Catalytic C-H oxidations by nonheme mononuclear Fe(II) complexes of two pentadentate ligands: Evidence for an Fe(IV) oxo intermediate

The oxidation reactions of alkanes with hydrogen peroxide and peracids (peracetic acid (PAA) and m-chloroperoxybenzoic acid (mCPBA)) catalysed by two Fe(II) complexes of pentadentate {N5}-donor ligands have been investigated. Kinetic isotope effect experiments and the use of other mechanistic probes have also been performed. While the total yields of oxidized products are similar regardless of oxidant (e.g. 30–39% for oxidation of cyclohexane), the observed alcohol/ketone ratios and kinetic isotope effects differ significantly with different oxidants. Catalytic reactions in H2O2 medium are consistent with the involvement of hydroxyl radicals in the CH bond cleavage step, and resultant low kinetic isotope effect values. On the other hand, catalytic reactions performed using peracid media indicate the involvement of an oxidant different from the hydroxyl radical. For these reactions, the kinetic isotope effect values are relatively high (within a range of 4.2–5.1) and the C3/C2 selectivity parameters in adamantane oxidation are greater than 11, thereby excluding the presence of hydroxyl radicals in the CH bond cleavage step. A low spin Fe(III)-OOH species has been detected in the H2O2-based catalytic system by UV/Vis, mass spectrometry and EPR spectroscopy, while an Fe(IV)-oxo species is postulated to be the active oxidant in the peracid-based catalytic systems. Computational studies on the CH oxidation mechanism reveal that while the hydroxyl radical is mainly responsible for the H-atom abstraction in the H2O2-based catalytic system, it is the Fe(IV)-oxo species that abstracts the H-atom from the substrate in the peracid-based catalytic systems, in agreement with the experimental observations.

Stille coupling via C-N bond cleavage.

Cross-coupling is a fundamental reaction in the synthesis of functional molecules, and has been widely applied, for example, to phenols, anilines, alcohols, amines and their derivatives. Here we report the Ni-catalysed Stille cross-coupling reaction of quaternary ammonium salts via C–N bond cleavage. Aryl/alkyl-trimethylammonium salts [Ar/R–NMe3]+ react smoothly with arylstannanes in 1:1 molar ratio in the presence of a catalytic amount of commercially available Ni(cod)2 and imidazole ligand together with 3.0 equivalents of CsF, affording the corresponding biaryl with broad functional group compatibility. The reaction pathway, including C–N bond cleavage step, is proposed based on the experimental and computational findings, as well as isolation and single-crystal X-ray diffraction analysis of Ni-containing intermediates. This reaction should be widely applicable for transformation of amines/quaternary ammonium salts into multi-aromatics.

Photochemical Reductive C–C Coupling with a Guanidine Electron Donor

The metal‐free photoinduced reductive C–C coupling reactions of a number of substituted benzyl halides (15 examples) with the organic electron‐donor 2,3,5,6‐tetrakis(tetramethylguanidino)pyridine are evaluated. Depending on the substituents at the benzyl group, a C–C coupling product yield in the range 50–95 % is achieved. The photochemical benzyl‐radical formation by homolytic N–C bond cleavage of the initially formed benzyl‐pyridinium salts is the rate‐determining step of these reactions. Electron‐withdrawing as well as ‐donating substituents at the phenyl group increase the reaction rate. Quantum chemical computations did not reveal any correlation between either the enthalpy or Gibbs free energy of the N–C bond cleavage step and the experimentally determined first‐order rate constants. Instead, the structural difference between the excited state generated by irradiation and the electronic ground state of the pyridinium ions could be used to rationalize the differences in the reaction rates.

Isotope-Labeling Studies Support the Electrophilic Compound I Iron Active Species, FeO(3+), for the Carbon-Carbon Bond Cleavage Reaction of the Cholesterol Side-Chain Cleavage Enzyme, Cytochrome P450 11A1.

The enzyme cytochrome P450 11A1 cleaves the C20-C22 carbon-carbon bond of cholesterol to form pregnenolone, the first 21-carbon precursor of all steroid hormones. Various reaction mechanisms are possible for the carbon-carbon bond cleavage step of P450 11A1, and most current proposals involve the oxoferryl active species, Compound I (FeO(3+)). Compound I can either (i) abstract an O-H hydrogen atom or (ii) be attacked by a nucleophilic hydroxy group of its substrate, 20R,22R-dihydroxycholesterol. The mechanism of this carbon-carbon bond cleavage step was tested using (18)O-labeled molecular oxygen and purified P450 11A1. P450 11A1 was incubated with 20R,22R-dihydroxycholesterol in the presence of molecular oxygen ((18)O2), and coupled assays were used to trap the labile (18)O atoms in the enzymatic products (i.e., isocaproaldehyde and pregnenolone). The resulting products were derivatized and the (18)O content was analyzed by high-resolution mass spectrometry. P450 11A1 showed no incorporation of an (18)O atom into either of its carbon-carbon bond cleavage products, pregnenolone and isocaproaldehyde . The positive control experiments established retention of the carbonyl oxygens in the enzymatic products during the trapping and derivatization processes. These results reveal a mechanism involving an electrophilic Compound I species that reacts with nucleophilic hydroxy groups in the 20R,22R-dihydroxycholesterol intermediate of the P450 11A1 reaction to produce the key steroid pregnenolone.

Theoretical Study of Ir-Catalyzed Chemoselective C1–O Reduction of Glucose with Silane

Density functional theory (DFT) calculations have been performed to study the mechanism of Ir(III) pincer complex (POCOP)Ir(H)(acetone)+ (POCOP = 2,6-bis(dibutylphosphinito)phenyl) catalyzed chemoselective C1–O hydrosilylative reduction of glucose. The mechanisms for reduction of the external and internal C1–O (i.e., C1–Oext and C1–Oint) on the C1-MeO-substituted glucose (i.e., 1Me) and C1–Me2EtSiO-substituted glucose (i.e., 1Si) have been investigated. The calculation results show that both mechanisms proceed with the first concerted silyl transfer and the subsequent C1–Oext or C1–Oint bond cleavage and hydride transfer steps. In the hydride transfer step, the Ir-H moiety acts as the hydride source. The C1–O cleavage is the rate-determining step of the overall mechanism. The C1–Oext reduction is more favorable than C1–Oint reduction for the substrate 1Me, while the C1–Oint reduction is more favorable for 1Si. These results are consistent with the recent experimental outcomes. Analyzing the origin of chem...