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The electroreductive cross-electrophile coupling which has emerged as a powerful, green and efficient method for constructing challenging C–C bonds has attracted increasing attention from organic chemists.

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.

The Cu(I)-catalyzed [4 + 1] annulation of vinyl indoles and a carbene precursor is a powerful method for constructing cyclopentaindole derivatives. Density functional theory (DFT) calculations were used to elucidate the mechanism and regioselectivity of this reaction. After Cu-assisted indole C3-alkylation, direct 1,5-annulation was favored over the Cu-assisted annulation pathway. Furthermore, the regioselectivity for 1,5-annulation was attributed to the generated five-membered-ring product being more stable than the three-membered-ring product from 1,3-annulation, which was the kinetically favored pathway.

A practical method can be used to assemble four simple molecules into an aromatic system, by which m-alkenyl benzaldehydes can be synthesized with regiospecificity. Moreover, new AIE molecules can be obtained by coupling the products in one pot.

α-Carbonyl cations are the umpolung forms of the synthetically fundamental α-carbonyl carbanions. They are highly reactive yet rarely studied and utilized species and their precursors were rather limited. Herein, we report the generation of α-carbonyl cations from HNTf2-catalyzed alkyne oxidations with pyridine N-oxides and the interception of them via Wagner-Meerwein rearrangement. Broad spectrum of alkynes including aryl alkyne, ynamide, and alkynyl sulfide could be utilized and the migrating priorities of different groups in the Wagner-Meerwein rearrangement step was elucidated. DFT calculations further supported the generation of α-carbonyl cations via the N-O bond cleavage. Another key feature of this methodology was the fragmentation of synthetically inert tert-butyl groups into readily transformable olefin functionalities. The synthetic potential was highlighted by the scale-up reaction and the downstream diversifications including the formal synthesis of nicotlactone B and galbacin.

Dinuclear transition-metal catalysis is a distinctive approach for cross-coupling reactions, but Rh(I)–Rh(III) redox catalysis has rarely been considered. Here, a dinuclear Rh(III)–Rh(III) redox ca...

Bicyclo[1.1.0]butane (BCB) derivatives are versatile coupling partners, and various reaction modes for their activation and transformation have been proposed. In this work, three BCB-activation modes in Rh-catalyzed BCB transformations that construct diastereoselective α-quaternary β-lactones were investigated by density functional theory calculations. Our results show that, compared with C1-C3 insertion and C-C3 oxidative addition, C2-C3 oxidative addition is more favorable. The whole catalytic cycle involves five main steps: C-H activation, oxidative addition, β-C elimination/reductive elimination, Rh walking, and aldehyde insertion/protonation. Independent gradient model, intrinsic reaction coordinate, distortion-interaction energy, and Laplacian electron-density analyses were carried out to investigate the mode of BCB activation. Our calculation also showed that aldehyde-insertion is the diastereoselectivity determining step, which is controlled by the steric effect between the ligand, methyl group, and aldehyde.

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.

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.

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.

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...

Herein, we report a Pd-catalyzed regiospecific cycloaromatization of

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.

In this study, a permanganate/redox mediator system for enhanced transformation of a series of emerging contaminants was evaluated. The presence of various redox mediators (i.e., 1-hydroxybenzotriazole, N-hydroxyphthalimide, violuric acid, syringaldehyde, vanillin, 4-hydroxycoumarin, and p-coumaric acid) accelerated the degradation of bisphenol A (BPA) by Mn(VII). Since 1-hydroxybenzotriazole (HBT) exhibited the highest reactive ability, it was selected to further investigate the reaction mechanisms and quantify the effects of important reaction parameters on Mn(VII)/redox-mediator reactions with BPA and bisphenol AF (BPAF). Interestingly, not only HBT accelerated the degradation of BPA, but also BPA enhanced the decay of HBT. Evidence for the in situ formation of HBT· radicals as the active oxidant responsible for accelerated BPA and BPAF degradation was obtained by radical scavenging experiments and 31P NMR spin trapping techniques. The routes for HBT· radical formation involving Mn(VII) and the electron-transfer pathway from BPA/BPAF to HBT· radicals demonstrate that the Mn(VII)/HBT system was driven by the electron-transfer mechanism. Compared to Mn(VII) alone, the presence of HBT totally inhibited self-coupling of BPA and BPAF and promoted β-scission, hydroxylation, ring opening, and decarboxylation reactions. Moreover, Mn(VII)/HBT is also effective in real waters with the order of river water > wastewater treatment plant (WWTP) effluent > deionized water.

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.

Nickel catalysis has recently emerged as an important addition to the suite of transition metal-catalysed C-H bond functionalization methods. Here we report density functional theory calculations to elucidate the mechanism of Ni(II)-catalysed C–H arylation with a diaryliodonium salt or a phenyliodide. The effect of the choice of oxidant on the order of oxidative addition and C–H bond cleavage is investigated. When the active catalyst is oxidized by the diaryliodonium salt oxidant, C–H bond cleavage occurs to give an alkyl-aryl-Ni(IV) species. Conversely, the relatively weak oxidant phenyliodide leads to an alternative reaction sequence. The active catalyst first undergoes C–H bond cleavage, followed by oxidative addition of the phenyliodide to give a Ni(IV) species. Frontier molecular orbital analysis demonstrates that the reaction sequence of oxidative addition and C–H bond cleavage is determined by the unoccupied Caryl–I bond antibonding orbital level of the oxidant. Nickel-catalysed C-H functionalisation reactions are of increasing importance. Here the mechanism of Ni(II)-catalysed C-H arylation of amides is shown to depend on the nature of the oxidant and in particular the energy of its Caryl-I antibonding orbital.

Permanganate (Mn(VII)) has been widely applied as an oxidant in water treatment plants. However, compared with ozone, Fenton, and other advanced oxidation processes, the reaction rates of some trace organic contaminants (TrOCs) with Mn(VII) are relatively low. Therefore, further studies on the strategies for enhancing the oxidation of organic contaminants by Mn(VII) are valuable. In this work, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), as an electron shuttle, enhanced Mn(VII) oxidation toward various TrOCs (i.e., bisphenol A (BPA), phenol, estrone, sulfisoxazole, etc.). TEMPO sped up the oxidative kinetics of BPA by Mn(VII) greatly, and this enhancement was observed at a wide pH range of 4.0-11.0. The exact mechanism of TEMPO in Mn(VII) oxidation was described briefly as follows: (i) TEMPO was oxidized by Mn(VII) to its oxoammonium cation (TEMPO+) by electron transfer, which was the reactive species responsible for the accelerated degradation of TrOCs and (ii) TEMPO+ could decompose TrOCs rapidly with itself back to TEMPO or TEMPOH (TEMPO hydroxylamine). To further illustrate the interaction between TEMPO and target TrOCs, we explored the transformation pathways of BPA in Mn(VII)/TEMPO oxidation. Compared to Mn(VII) alone, adding TEMPO into the Mn(VII) solution significantly suppressed BPA's self-coupling and promoted hydroxylation, ring-opening, and decarboxylation. Moreover, the Mn(VII)/TEMPO system was promising for the abatement of TrOCs in real waters for humic acid, and ubiquitous cations/anions had no adverse or even beneficial impact on the Mn(VII)/TEMPO system.

Rh-catalyzed C–H bond functionalization can construct the C–heteroatom bonds by selecting substrates that contain heteroatoms. Despite the dominance of Rh-catalyzed C–C bond formation through C–H activation, Rh-catalyzed C–X (X = N, O, halide, B, Si) bond formation reactions through C–H bond functionalization have also been well developed and studied theoretically in detail recently. In this chapter, the theoretical studies of Rh-catalyzed C–H bond activation and C–O bond, C–N bond, C–halide bond, C–B bond, and C–Si bond formation were discussed. This volume provides valuable insight into the mechanism and the origin of the regio- and stereoselectivity for these Rh-catalyzed C–H bond activation reactions.

The density functional theory (DFT) method is the most popular theoretical treatment for the computational investigation of Rh-catalyzed C–H functionalization. In this chapter, the definition of the DFT method and the classification of functionals based on the “Jacob’s ladder” were introduced. The B3LYP functional was discussed in detail because of its comprehensive performance in Rh-catalyzed C–H functionalization. We further introduced the Minnesota series functional, which is one of the best alternative functionals of B3-LYP. Especially, M06-L and M11-L have good performance for energy calculations in Rh-catalyzed C–H functionalization reaction. The popular basis sets and solvent models were then discussed.

C–C bond formation has attracted enormous research interest and lots of synthesis methods were applied to it in recent years. Accordingly, more and more efforts were put into the theoretical study of Rh-catalyzed C–C bond formation through C–H activation because of the complexity of the C–H bond activation reaction itself and its mechanism. In this chapter, the theoretical studies of Rh-catalyzed C–H bond arylation through electrophiles and nucleophile aryl reagents were first discussed. Subsequently, the mechanisms of C–H bond alkylation by using olefins alkynes and diazo compound along with C–H bond alkenylation by using olefins and alkynes were analyzed from theoretical points of view. The mechanisms of C–H bond alkynylation, C–H bond carbonylation, C–H bond annulation with directing group as electrophile, nucleophile, and internal oxidants were further discussed on account of related contributions. Finally, the mechanisms of the outer-sphere C–H activation, sequential C–H activation, and inner-sphere carbene insertion were theoretically considered to provide a whole picture of the C–C bond formation via C–H activation.

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.

This study investigated the impact of pH on the efficiency of ferrate (Fe(VI), K2FeO4) toward fluoroquinolone antibiotics, built kinetic models of Fe(VI) oxidation, and elucidated the involved active species during Fe(VI) oxidation at acidic and alkaline conditions. It was found that the second-order reaction rate constants (kapp, M-1 s-1) of Fe(VI) with three fluoroquinolone antibiotics (i.e., enroxacin, ofloxacin, and norfloxacin) were strongly dependent on pH, and kapp reached its maximum at pH about 6.5. The reactions between HFeO4-/H2FeO4 and neutral/protonated fluoroquinolone antibiotics (X and XH+) were the major ones. Moreover, the reactive species were identified as high-valent iron species, i.e., Fe(VI), Fe(V), and Fe(IV), in alkaline solution, while hydroxyl radicals was generated through Fenton or Fenton-like processes at acidic condition with limited contribution.

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.

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.

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.