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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.

Enynones are powerful synthons for constructing furan derivatives in the presence of transition metal catalysts. Unlike the conventional intramolecular nucleophilic attack with the activation of coinage metals, we propose that enynones undergo an oxidative cyclization process with a Pd(0) species. The full catalytic cycle involves oxidative cyclization, isocyanide insertion, and reductive elimination, which was supported by DFT calculations. Geometric and electronic analyses confirmed the oxidative cyclization process, which proceeds via a Pd(ii) intermediate.

The Ni-catalyzed reaction of ortho-fluoro-substituted aromatic amides with alkynes results in C-F/N-H annulation to give 1(2H)-isoquinolinones. A key to the success of the reaction is the use of KOtBu or even weak base, such as Cs2CO3. The reaction proceeds in the absence of a ligand and under mild reaction conditions (40-60 °C). DFT calculations suggest that the pathway for this Ni-catalyzed C-F/N-H annulation involves N-H deprotonation, oxidative addition of a C-F bond, migratory insertion of an alkyne, and reductive elimination to form 1(2H)-isoquinolinone derivatives.

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.

Cross-coupling reactions have developed into powerful approaches for carbon–carbon bond formation. In this work, a Ni-catalyzed migratory Suzuki–Miyaura cross-coupling featuring high benzylic or allylic selectivity has been developed. With this method, unactivated alkyl electrophiles and aryl or vinyl boronic acids can be efficiently transferred to diarylalkane or allylbenzene derivatives under mild conditions. Importantly, unactivated alkyl chlorides can also be successfully used as the coupling partners. To demonstrate the applicability of this method, we showcase that this strategy can serve as a platform for the synthesis of terminal, partially deuterium-labeled molecules from readily accessible starting materials. Experimental studies suggest that migratory cross-coupling products are generated from Ni(0/II) catalytic cycle. Theoretical calculations indicate that the chain-walking occurs at a neutral nickel complex rather than a cationic one. In addition, the original-site cross-coupling products can be obtained by alternating the ligand, wherein the formation of the products has been rationalized by a radical chain process., Migratory cross-coupling reactions are powerful tools to form bonds at predictable positions. Here the authors report a nickel-catalyzed migratory Suzuki–Miyaura cross-coupling of unactivated alkyl electrophiles with aryl and vinyl boron reagents and provide experimental and computational mechanistic evidence.

Diazo compounds are popular carbenoid precursors that can react with various transition metals to afford carbene species for further transformations. In this study, density functional theory calcul...

Alkaline-earth (Ae) metals have attracted a wealth of interdependent research from synthetic chemists. In Ae-catalyzed organometallic reactions, β-diketiminate is a typical ligand used to stabilize Ae catalysts by forming six-membered rings comprising Ae metals. Herein, studies focusing on the configuration of β-diketiminate-coordinated Ae compounds observed that the C C and C N bonds are homogeneous and unchanged. Furthermore, energetic studies observed that the formation of the Ae-incorporated six-membered rings results in enhanced stability of >20 kcal/mol. The nucleus-independent chemical shifts, anisotropy of the induced current density, and molecular orbital analyses demonstrated the non-aromaticity of the β-diketiminate-coordinated Ae compounds. The improved stability of these compounds can be explained by the delocalization of the π electrons derived from the β-diketiminate moiety.

Computational characterization of the oxidation addition promoted in rhodium-catalyzed cyclopropenone activation and conversion via quinolyl-, pyridyl-, and nitrone-directed C–H activation is presented. Our theoretical studies found that a common catalytic cycle for these reactions starts with Rh(III)-mediated concerted metalation–deprotonation or electrophilic deprotonation to afford the aryl-Rh(III) intermediate. Oxidative addition of cyclopropenone to aryl-Rh(III) then gives a cyclorhoda(V)butanone intermediate, leading to the cleavage of the cyclopropene moiety through a concerted three-membered cyclic transition state. Subsequent reductive elimination of the intermediate generates a target C(aryl)–C(acyl) bond. The final product is produced by further transformations with concomitant regeneration of active Rh(III) catalyst. The previously proposed carbonyl insertion mode for the activation of cyclopropenones is excluded by the density functional theory calculations. The directing group effect in cycl...

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.

The Co2(CO)8-mediated intramolecular Pauson-Khand reaction is an efficient approach for constructing polycyclic skeletons. Recently, some of us reported a series of this type reactions involving sterically-hindered enynes for synthesizing natural products with reasonable reaction rates and yields. However, the reason for the high reactivity of the reaction remains unclear. We employed density functional theory calculations to clarify the mechanism and reactivity for this reaction. In contrast with chain olefin reactants, CO insertion is considered to be the rate-determining step for the overall Pauson-Khand reaction of cyclooctene derivatives. The reduced activation free energy for the alkene insertion step is attributed to: i) the electron-withdrawing group in close proximity to the C C triple bond enhancing the reactivity of the alkyne moiety; ii) lower steric hindrance during alkene insertion when using the cyclooctene derivative. The effect of the substituent on the Co2(CO)8-mediated intramolecular Pauson-Khand reaction was then investigated. Internal alkenes exhibit lower reactivity than terminal alkenes because of the steric hindrance introduced by the substituted group. The cis internal alkene exhibits higher reactivity than the trans internal alkene. An ester group in close proximity to the C C triple bond significantly enhances the reactivity.

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.

The rhodium-catalyzed asymmetric synthesis of dibenzooxasilines developed by Hayashi and co-workers provides an efficient method to construct tetraorganosilicon stereocenters. In the present study, density functional theory (DFT) calculations were performed to investigate the mechanism and enantioselectivity of this reaction. Theoretical calculations indicate that the mechanism involves the initial formation of an aryloxorhodium complex followed by Rh–Si exchange to afford an arylrhodium complex. The favorable oxidative addition/reductive elimination to cleave one Si–C(phenyl) bond from the arylrhodium complex determines the enantioselectivity. The enantioselectivity originates from the silyl moiety extruding from the phenyl ring on the rhodium atom in the reductive elimination transition state.

Phosphoric acid catalysis is a powerful tool for the construction of new C C bonds because of its unique LUMO-lowering activity. Theoretical calculations were employed to investigate phosphoric acid-catalyzed asymmetric conjugate addition of indolizines to α,β-unsaturated ketones. The calculation results showed that this transformation proceeds via a reaction pathway involving nucleophilic addition, deprotonation–aromatization, and tautomerization. The computational results showed that deprotonation–aromatization is the rate-determining step and the enantioselectivity-determining step. The S-configured product was preferentially generated via a pathway starting from the s-cis conjugated ketone, whereas the s-trans isomer led to a side product with the R configuration. Non-covalent interaction analysis showed that the enantioselectivity is mainly caused by bond-rotation strain in the transition states of the deprotonation–aromatization step.

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.

A Ni-catalyzed C−F bond functionalization of unactivated aryl fluorides with oxazoles as coupling partners was developed. Various arylated oxazoles could be obtained in moderate to good yields in the presence of Ni(cod)2/IMes catalytic system. A rapid synthesis of natural product texaline was also demonstrated using this protocol. This transformation could be potentially utilized in regioselective introduction of an oxazole group in late-stage synthetic applications.

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.

Ru-Catalyzed aromatic C-H bond activation and functionalization have emerged as important topics because they have resulted in remarkable progress in organic synthesis. Both experimental and theoretical studies of their mechanisms are important for the design of new synthetic methodologies. In this review, a mechanistic view of the Ru-mediated C-H bond cleavage step is first given to reveal the C-H bond activation modes, including oxidative addition, metathesis and base-assisted deprotonation. In this process, directing groups play an important role in determining the reactivity of the C-H bond. The C-H bond activation generally leads to the formation of a Ru-C bond, which is further functionalized in the subsequent steps. The mechanisms of Ru-catalyzed arylation, alkylation, and alkenylation of arenes are summarized, and these transformations can be categorized into cross-coupling with electrophiles or oxidative coupling with nucleophiles. In addition, the mechanism of ortho-ruthenation-enabled remote C-H bond functionalization is also discussed.

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.

The sequence of C–H bond cleavage, oxidative addition, and reductive elimination is often proposed to account for Rh(III)-catalyzed arene functionalization. Invariably, C–H bond cleavage is the rate-limiting step. In our present work, the sequence of steps in Rh-catalyzed C–H azidation of arenes is theoretically studied by the density functional theory method M11-L. Theoretical calculations indicated that the oxidation of Rh(III) to Rh(V) by PhI(OAc)OTs is a facile process. Subsequent electrophilic deprotonation, which is the rate-determining step, was shown to occur from a Rh(V) intermediate rather than a Rh(III) intermediate. Finally, the C–N3 reductive elimination from a cyclometalated Rh(V) complex could give the azidation product and regenerate the Rh(III) catalyst. Moreover, the natural population analysis (NPA) of the oxidation process clarified that Rh(III) is oxidized to Rh(V) by trivalent iodine.

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 M11 was used to study the mechanism and enantioselectivity of a binaphthophosphepine-catalyzed intramolecular [3 + 2] cycloaddition reaction. The computational results revealed that this reaction proceeds through nucleophilic addition of the phosphine catalyst to the allene, which yields a zwitterionic phosphonium intermediate. The subsequent stepwise [3 + 2] annulation process, which starts with the intramolecular nucleophilic addition of the allenoate moiety to the electron-deficient olefin group, determines the enantioselectivity of the reaction. This step is followed by a ring-closing reaction and water-assisted proton-transfer process to afford the final product with concomitant regeneration of the phosphine catalyst. Theoretical predictions of the enantioselectivity for various phosphine catalysts were consistent with experimental observations, and 2D contour maps played an important role in explaining the origin of the enantioselectivity. Moreover, on the basis of our theoretical study, new binaphthophosphepine catalysts were designed and that are expecting to afford higher enantioselectivity in this cycloaddition reaction.

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.

Terminal alkynes have become one of the most versatile building blocks for C-C bond construction in the past few decades, and they are usually considered to convert to acetylides before further transformations. In this study, a novel direct nucleophilic addition mode for Cu(I)-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones to synthesize chiral allenes is proposed, and it was investigated by density functional theory with the M11-L density functional. Three different reaction pathways were considered and investigated. The computational results show that the proposed reaction pathway, which includes direct nucleophilic attack of protonated acetylene, deprotonation of the vinyl cation, and catalyst regeneration, is the most favorable pathway. Another possible deprotonation-carbenation-insertion pathway is shown to be unfavorable. The direct nucleophilic addition step is the rate- and enantioselectivity-determining step in the catalytic cycle. Noncovalent interaction analysis shows that the steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand is important to control the enantioselectivity. In addition, calculation of a series of chiral bisoxazoline ligands shows that a bulky group on the oxazoline ring is favorable for high enantioselectivity, which agrees with experimental observations. Moreover, copper acetylides are stable, and their generation is a favorable pathway in the absence of chiral bisoxazoline ligands.

Over the past few decades, platinum has attracted remarkable attention and played an important role in promoting construction of C–X (X = C, O, N, B, etc.) bonds in organometallic chemistry. However, understanding the general principle of Pt chemistry is still an urgent task both experimentally and theoretically. Differing from other metals in the same group, such as Ni and Pd, Pt-mediated C–H activation processes mainly involve oxidative addition, σ-complex assisted metathesis, outersphere electrophilic deprotonation, and even carbene Pt complex insertion rather than concerted metalation–deprotonation. In some other catalysis, Pt possesses a strong Lewis acid property to activate a wide range of unsaturated substrates. In this review, the mechanistic principles and recent advancements of various types of Pt-mediated organic molecular activations, including C–H activation, alkyne activation, alkene activation, and allene activation, are systematically summarized from a theoretical viewpoint. These activations generally result in Pt–C bond formation, which can be further transformed for construction of new C–C and C–heteroatom bonds.

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.

Dehydrocoupling of amines and boranes is an efficient method for the formation of N–B bonds; however, the strong B–H bond dissociation energy (BDE) always restricts non-catalytic reaction pathways. Therefore, alkaline-earth-metal (Ae) hydrides are used as catalysts for this type of reaction because of their lower Ae–H bond energy. A theoretical study was performed to study the mechanism of Ae-catalyzed dehydrocoupling reactions. The computational results show that such reactions are initiated from σ-bond metathesis between Ae hydride catalysts and amines to release molecular hydrogen, followed by borane bonding with amino Ae intermediates. Subsequent hydride transfer yields an amino-borane product and, in the process, regenerates the Ae hydride catalyst. Our theoretical calculations revealed that dehydrogenation is the rate-determining step during σ-bond metathesis in the presence of a magnesium hydride catalyst. We predicted that beryllium hydride could not function as a catalyst because the apparent activation free energy is significantly high. Furthermore, we observed that in calcium or strontium hydride-catalyzed reactions, the rate-limiting step changed to the hydride transfer step. Further density functional theory calculations showed that the BDEs of the Ae–H bond controlled the reactivity of the σ-bond metathesis step.

Theoretical calculations have been performed to investigate the mechanism and stereoselectivity of rhodium-catalysed intramolecular [3+2] cycloaddition for construction of a substituted hexahydropentalene complex. A new C-C bond cleavage mechanism, retro-Aldol-type, is proposed and verified for this Rh-catalysed [3+2] cycloaddition reaction.

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.

Density functional theory (DFT) calculation has been used to reveal the mechanism of Pd-catalyzed disilylation of carbene, which is a pathway to construct disilylmethane derivatives. The DFT calculations indicate that the reaction starts with carbenation of a Pd(0) catalyst. Oxidative addition of disilane can then generate a carbene-coordinated disilylpalladium intermediate. Carbene insertion into the Pd–Si bond followed by reductive elimination gives the disilylmethane product and regenerates the Pd(0) catalyst with the formation of two C–Si bonds. The rate-determining step of this reaction is the carbenation step. The computational results show that the phosphine ligand is unfavorable for this type of reaction because of its high dissociation energy. In this type of reaction, a smaller substrate is favorable for the oxidative addition step because the weaker steric repulsion leads to a lower activation free energy of the oxidative addition step. The computational results also reveal that the reactivity of digermane and distannane is higher than that of disilane, which can be attributed to their low bond dissociation energies.

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

Transition metal-catalyzed radical–radical cross-coupling reactions provide innovative methods for C–C and C–heteroatom bond construction. A theoretical study was performed to reveal the mechanism and selectivity of the copper-catalyzed C–N radical–radical cross-coupling reaction. The concerted coupling pathway, in which a C–N bond is formed through the direct nucleophilic addition of a carbon radical to the nitrogen atom of the Cu(II)–N species, is demonstrated to be kinetically unfavorable. The stepwise coupling pathway, which involves the combination of a carbon radical with a Cu(II)–N species before C–N bond formation, is shown to be probable. Both the Mulliken atomic spin density distribution and frontier molecular orbital analysis on the Cu(II)–N intermediate show that the Cu site is more reactive than that of N; thus, the carbon radical preferentially react with the metal center. The chemoselectivity of the cross-coupling is also explained by the differences in electron compatibility of the carbon radical, the nitrogen radical and the Cu(II)–N intermediate. The higher activation free energy for N–N radical–radical homo-coupling is attributed to the mismatch of Cu(II)–N species with the nitrogen radical because the electrophilicity for both is strong.

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.