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A computational study was conducted to investigate the mechanism of a new type of C–N bond metathesis reaction, in which a reversible reductive elimination/oxidative addition mode is involved.

Herein, we report the Pd(0)-catalyzed intermolecular asymmetric dearomative [3 + 2] annulation of phenols with vinyl cyclopropanes via in situ generated

Density functional theory calculations have been performed to reveal the chemoselectivity of Rh-catalyzed chiral C-F cleavage and γ-site functionalization. We found that the chemoselectivity is controlled by β-F elimination in methanol solvent, leading to formation of the alkynylic product. In isobutyronitrile solvent, the chemoselectivity is controlled by the allene insertion step, where the fluoroalkenylic product can be observed. The difference can be explained by analysis of the explicit solvent models.

Density functional theory (DFT) calculations have been performed to provide mechanistic insight into the Rh/Cu co-catalyzed multicomponent annulation of indoles, diazo compounds, and α,β-unsaturated esters. Indole can undergo electrophilic attack by a dirhodium–carbene complex to form a cyclopropane intermediate, which is transferred to an enolate by deprotonation. A dimetallic Michael-type addition reaction is proposed by DFT calculation, where the diastereoselectivity is controlled by the interaction energy between the incoming α,β-unsaturated ester and enolate nucleophile. In copper catalysis, an intramolecular oxidation by copper enolate/copper ketonate resonance is revealed, by which copper enolate is partially oxidized to an α-carbonyl radical. Therefore, intramolecular radical addition with the indole moiety achieves annulation with the formation of a C3 radical in dearomatic indole. Oxidative hydrogen atom transfer then gives the aromatic annulation product by using excess copper chloride.

As a C2 synthon, vinylene carbonate has been used instead of acetylene in transition-metal catalyzed-coupling reactions. In this study, the mechanism of the vinylene carbonate activation mode for t...

A three-layer chirality relay model is proposed for Rh(I)-mediated enantioselective siletane activation. A chiral ligand in the back layer controls the position of the alkyne-coordinated metal center in the middle layer, which then provides a chiral environment for the incoming substrate at the front layer. A two-dimensional contour map analysis further clarified this model.

Theoretical calculations were performed to investigate the mechanism and enantioselectivity of cinchonine-thiourea-catalyzed intramolecular hetero-Diels-Alder cycloaddition of ethynylphenol derivatives to afford axial chirality naphthalenylpyran products via a vinylidene ortho-quinone methide (VQM) intermediate. The results show that this transformation occurs through a reaction pathway involving the deprotonation of the naphthol moiety by the quinuclidine base, intramolecular proton transfer in ammonium naphthalenolate, and [4+2] cycloaddition. It is found that the axial chirality of the VQM intermediate is generated by the protonation step, which affects the enantioselectivity of the reaction. The enantioselectivity for the generation of the VQM intermediate is controlled by steric repulsion with the cinchonine framework, which provides an R-axial chirality VQM as the major intermediate. Moreover, the enantioselectivity for the axial chirality of the naphthopyran product is controlled by the cycloaddition step, in which an extra hydrogen bond between the naphthalenol and cinchonine moieties leads to a favorable configuration for the generation of the S-axial chirality naphthopyran product. The calculated enantioselectivity and enantiomeric excesses coincide with experimental observations.

Palladium (Pd)-catalyzed radical oxidative C-H carbonylation of alkanes is a useful method for functionalizing hydrocarbons, but there is still a lack of understanding of the mechanism, which restricts the application of this reaction. In this work, density functional theory (DFT) calculations were carried out to study the mechanism for a Pd-catalyzed radical esterification reaction. Two plausible reaction pathways have been proposed and validated by DFT calculations. The computational results reveal that the generated alkyl radical prefers to add to the carbon monoxide (CO) molecule to form a carbonyl radical before bonding with the Pd species. Radical addition onto Pd followed by CO migratory insertion was unfavorable owing to the high energy barrier of the migratory insertion step. The regioselectivity of the C(sp3 )-H carbonylation was also investigated by DFT. The results show that the regioselectivity is controlled by both the bond dissociation energy of the reacting C-H bond and the stability of the corresponding generated carbon radical. Competitive side reactions also affected the yield and regioselectivity owing to the rapid consumption of the stable radical intermediate.

Density functional theory calculations were performed to study the counterion effect and directing group effect in rhodium mediated concerted metalation deprotonation type C H bond activation of arenes. The use of different carboxylates as counterions results in changes to the activation energies over a narrow range. These changes are mainly attributed to the opposing effects of alkalinity and nucleophilicity of the substituted groups. The effects of directing groups were also considered. By introducing directing groups, the C H bond activation energy is greatly reduced. Our results show that different directing groups have similar effects and activation energies.

While the mechanisms of transition metal-catalyzed coupling reactions have received extensive attention, the extent to which these apply to catalytic Alder-ene-type reactions remains unclear. A novel 1,5-H shift mechanism for a Ru-catalyzed Alder-ene type alkene–alkyne coupling reaction was examined by density functional theory (DFT). This reaction begins with a cyclometallation between alkene and alkyne to form a ruthenacyclopentene. Then, 1,5-H shift generates an olefin coordination intermediate. Sequential ligand exchanges construct the final product and regenerate the active catalyst. Results show that a pathway through a [3 + 2] cyclometallation and 1,5-H shift step is favored over the traditional cycloaddition – β-hydride elimination and reductive elimination route reported previously. The stereoselectivity of the product is also validated and the results show that it is predominately controlled by the energy differences in both the cyclometallation and the 1,5-H shift step. Regioselectivity is mainly controlled by electronic effect and six-membered ring tension.

Nickel-catalyzed C–H bond activation has attracted significant attention for the construction of C–C bond frameworks. We report density functional theory investigations into the mechanism of nickel-catalyzed alkylation of benzamides with alkyl halides. Both the Ni(I)–Ni(III) and Ni(II)–Ni(IV) catalytic cycles were considered. The theoretical study indicated that the most feasible mechanism involved a Ni(II)–Ni(IV) catalytic cycle with four main steps: (i) N–H bond activation and (ii) C–H bond activation through the concerted metalation–deprotonation pathway, (iii) oxidative addition of BuBr to give a high-valent Ni(IV) complex, and (iv) C–C reductive elimination to generate the product and the active catalyst. The rate-determining step of the favored pathway is the oxidative addition, leading to the generation of a Ni(IV) intermediate. In addition, the present study casts light on the role of PPh3, which accelerates the cleavage of N–H bond. Frontier molecular orbital theory and natural population analysis were employed to explain the effect of the phosphine ligand on the structure of the Ni complex.

The trifluoromethyl group (CF3) is a very important functional group. The mechanism of transition metal catalyzed trifluoromethylation has received considerable attention in recent years. In this work, the detailed mechanism of the copper-catalyzed oxytrifluoromethylation of allylamines with CO2 was investigated by density functional theory (DFT) calculations. Differing from the previous Cu(I)–Cu(III) catalytic cycle, the results show that the reaction proceeds through a Cu(I)–Cu(II) catalytic cycle. Deprotonation of allylamines initially occurs with the assistance of a copper catalyst followed by CO2 insertion. In the presence of Togni reagent II, the copper(I) carboxylate species can then be oxidized to the copper(II) dicarboxylate intermediate along with the formation of a free trifluoromethyl radical, which then attacks the alkene moiety to generate the electrophilic addition diradical adduct. The spiro ring is constructed by a carboxylate-delivered radical–radical cross-coupling procedure. In addition, the calculated global electrophilicity shows that the copper(III) intermediate cannot be generated from the combination of the electron deficient copper center and the electrophilic trifluoromethyl radical. Frontier molecular orbital analysis indicates that the Togni reagent II is activated by neutral Cu(I) rather than the cationic Cu(I) species. The origin of the diastereoselectivity can be mainly attributed to the repulsion between the trifluoromethyl group and the carbonyl moiety.

A series of well-defined phosphine-ligated diarylgold(III) complexes cis-[Au(L)(ArF)(Ar′)(Cl)] were prepared, and detailed kinetics of the C(sp2)–C(sp2) reductive elimination from these complexes were studied. The mechanism of the reductive elimination from the complexes cis-[Au(L)(ArF)(Ar′)(Cl)] was further studied by theoretical calculations. The combination of experimental and theoretical results suggests that the biaryl reductive elimination from organogold(III) complexes cis-[Au(L)(ArF)(Ar′)(Cl)] proceeds through a concerted biaryl-forming pathway from the four-coordinated Au(III) metal center. These studies also disclose that the steric hindrance of the phosphine ligands plays a major role in promoting the biaryl-forming reductive elimination from diarylgold(III) complexes cis-[Au(L)(ArF)(Ar′)(Cl)], while electronic properties of these ligands have a much smaller effect. Futhermore, it was found that the complexes with more weakly electron withdrawing aryl ligands undergo reductive elimination more ...

Density functional theory (DFT) calculations were employed to study the mechanism for copper-catalyzed trifluoromethylation of aryl boronic acids by Togni’s reagent. Computational results suggest that the catalytic cycle proceeds with the transmetallation between phenylboronic acid and copper(I) species, which generates a phenylcopper(I) intermediate. Subsequent coordination of Togni’s reagent and the electrophilic substitution of CF3 group to phenyl group finally afford the trifluoromethylation product through a concerted five-membered ring transition state. The transmetallation process with an activation free energy of 21.7 kcal/mol is determined to be the rate-determining step of this reaction. Moreover, the reactivity of alkylboronic acid was also calculated and proven to be unfavorable due to the higher activation free energy of transmetallation process.

Density functional theory method N12 was used to study the mechanism of the [Ir(cod)OH]2/Xyl–MeO–BIPHEP-catalyzed para-selective C–H borylation reaction. The results revealed that the use of a bulky diphosphine ligand such as Xyl–MeO–BIPHEP was unfavorable for the previously proposed iridium(III)/iridium(V) catalytic cycle because it resulted in considerable steric repulsion in the hepta-coordinated iridium(V) intermediate. Inspired by this steric effect, we have proposed a novel iridium(I)-/iridium(III)-based catalytic cycle for this transformation and shown that it can be used to account for the experimental results. The iridium(I)/iridium(III) catalytic cycle induced by this steric effect consists of several steps, including (i) the oxidative addition of the C–H bond of the substrate to an active iridium(I) boryl complex; (ii) the reductive elimination of a C–B bond; (iii) the oxidative addition of B2pin2 to an iridium(I) hydride complex; and (iv) the reductive elimination of a B–H bond. Notably, the c...

DFT calculations are used to reveal the mechanism of Bronsted-base-mediated borylation of propynols. The reaction is predicted to go through a key intermediate of alkenylboronate. Therefore, the possible pathways involve two key steps, borylation and reductive dehydroxylation. The favored pathway for the generation of the alkenylboronate intermediate involves alkoxy exchange, methoxylation, electrophilic substitution, and protonation. Then, the final product is yielded by a second alkoxy exchange, intramolecular nucleophilic attack, β-methoxy elimination, and protonation.

The density functional theory (DFT) method M06-L was used to study the general mechanism of palladium-catalyzed C–S bond formation reactions. Our theoretical calculations revealed that this type of reaction starts with a palladium-assisted metalation–deprotonation step. Oxidative addition of the sulfur source affords a thiolate–palladium(IV) intermediate, and subsequent reductive elimination generates the new C–S bond. A final protonation regenerates the active palladium(II) catalyst and releases the product. Our proposed mechanism could be applied to a series of palladium-catalyzed C–S bond formation reactions used for the construction of dibenzothiophene derivatives. The rate-limiting step of the catalytic cycle is oxidative addition to yield the thiolate–palladium(IV) intermediate. In contrast, formation of a sulfonium intermediate is unfavourable. In addition, the effect of substituents on the rate-determining step was studied with Hammett plots. Our calculations showed that incorporation of electron-withdrawing groups at the 4-position and electron-donating groups at the 15 and 16-positions would promote intramolecular oxidative addition of thioethers to palladium.

Both theoretical and experimental studies were performed to explore the mechanism, regioselectivity, and enantioselectivity of phosphine-catalyzed [3 + 2] annulation between allenoates and acrylate or imine. Using density functional theory computations, we predicted that the enantioselective determining step is the nucleophilic addition of acrylate or imine to the catalyst-activated allenoate. In the key step, we proposed two hydrogen bonding interaction models (intermolecular H-bond model and intramolecular H-bond model). For acrylate substrates, the reaction proceeds via the intramolecular H-bond model and the strong noncovalent interactions between the 2-naphthyl ester moiety lead to the re-face attack pathway being more favorable. For imine substrates, the intermolecular H-bond model operates. In the annulation process, the bulky n-propyl oriented toward a crowded, sterically demanding environment plays a significant role in asymmetric induction. The theoretical calculation results agreed with experimental observations, and these results provide valuable insight into catalyst design and understanding of mechanisms of related reactions.

An in-depth theoretical study of synergistic Cu(II)/Cu(I)-mediated alkyne coupling was performed to reveal the detailed mechanism for C-C bond formation, which proceeded via an unusual dinuclear 1,2-reductive elimination. Because the reactant for dinuclear 1,2-reductive elimination was calculated to be triplet while the products were singlet, the minimum energy crossing point (MECP) was introduced to the Cu/TMEDA/alkyne system to clarify the spin crossing between triplet state and singlet state potential energy surfaces. Computational results suggest that C-H bond cleavage solely catalyzed by the Cu(I) cation is the rate-determining step of this reaction and Cu(II)-mediated dinuclear 1,2-reductive elimination after the MECP is a facile process. These conclusions are in good agreement with our previous experimental results.

In situ X-ray absorption spectroscopy (XAS), infrared (IR) and nuclear magnetic resonance (NMR) techniques were used to identify the structures and reactivity of copper-containing active intermediates in the sp2 C–H bond cleavage reaction of electron-deficient aromatics. An ate-complex [Cu(OtBu)2]Na was found to be able to cleave the C–H bond of benzothiazole (ArH) producing [ArCuI(OtBu)]Na with a rate constant of 3.2 × 10−2 mol−1 L s−1 at −50 °C and with an activation enthalpy of 0.73 kcal mol−1 at room temperature.

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 (S

the 973 Program (2012CB725302);the National Natural Science Foundation of China (21025206;21272180)the Program for Changjiang Scholars and Innovative Research Team in University (IRT1030)

Although zinc catalysis is widely used in organic synthesis, very few studies on the dinuclear zinc mechanism have been reported. Here, a dinuclear zinc pathway is proposed for the Zn(OTf)2 -catalyzed oxidative coupling of aldehydes with terminal alkynes. DFT calculations revealed that the deprotonation of the terminal alkyne would preferentially lead to the formation of a dinuclear zinc intermediate. The nucleophilic addition of this intermediate to an aldehyde, followed by an Oppenauer-type oxidation was investigated theoretically according to the mono- and dinuclear pathways. The formation of a dinuclear zinc intermediate from a mononuclear alkynyl zinc complex was exergonic, favoring the dinuclear zinc pathway. The subsequent protonation and regeneration of the active dinuclear catalyst were also evaluated by DFT calculations. The oxidizabilities of various aldehydes and ketones were evaluated to determine the best oxidant for this step. Trifluoroacetaldehyde was predicted to be a better oxidant for this reaction because its calculated energy barrier for the Oppenauer-type oxidation step was much lower than that of the other carbonyl complexes.

In this study, M11-L was used to evaluate the feasibility of the formation of rhodium(V) species using the rhodium(III)-catalyzed ortho-bromination of arenes as a model reaction. In most cases for these types of reactions, DFT calculations reveal that the bromination step involves a Br transfer from N-bromosuccinimide to the reacting arylrhodium to form a bromonium intermediate, followed by a Br shift to generate a new C−Br bond, which is more favorable than the previously proposed RhIII/RhV catalytic cycle. The rhodium catalyst remains in its +3 oxidation state throughout. The substituent effects of the reacting arene were studied, and computational results showed that the introduction of electron-donating groups on the reacting arene was favorable for this pathway. In contrast, the inclusion of a strong electron-withdrawing group on the aromatic ring would hinder the formation of a bromonium intermediate. Therefore, the RhIII/RhV catalytic cycle is favorable in cases that involve a RhV intermediate, which is generated by oxidative addition with NBS. In this pathway, the C−Br bond is formed by reductive elimination from the RhV intermediate. Additionally, a distortion–interaction analysis model along the reaction pathway was used to explain the directing-group effects. The results showed that the interaction energy controlled the reactivity because of the difference in electronic nature of various directing groups.

Metal-catalyzed transfer hydroformylation is an important way of cleaving C-C bonds and constructing new double bonds. The newly reported density functional theory (DFT) method, M11-L, has been used to clarify the mechanism of the rhodium-catalyzed transfer hydroformylation reported by Dong et al. DFT calculations depict a deformylation and formylation reaction pathway. The deformylation step involves an oxidative addition to the formyl C-H bond, deprotonation with a counterion, decarbonylation, and β-hydride elimination. After olefin exchange, the formylation step takes place via olefin insertion into the Rh-H bond, carbonyl insertion, and a final protonation with the conjugate acid of the counterion. Theoretical calculations indicate that the alkalinity of the counterion is important for this reaction because both deprotonation and protonation occur during the catalytic cycle. A theoretical study into the formyl acceptor shows that the driving force of the reaction is correlated with the stability of the unsaturated bond in the acceptor. Our computational results suggest that alkynes or ring-strained olefins could be used as formyl acceptors in this reaction.

the 973 Program (2012CB725302);the National Natural Science Foundation of China (21025206;21272180)the Program for Changjiang Scholars and Innovative Research Team in University (IRT1030)

The first Ni-catalysed alkene isomerization of allylamides for the synthesis of enamides was demonstrated. Various substituted N-allylamides were found to be suitable substrates for this isomerization. Isotopic labelling experiments showed that it is an intramolecular hydrogen transfer process.