Activation of inert sp3 β-C–H bonds has attracted widespread attention and been developed with significant progress in recent years, but understanding the mechanism of this kind of reaction continues to be one of the most challenging topics in organic chemistry. In this paper, the possible reaction mechanisms and origin of stereoselectivity in the reaction between saturated carbonyl compounds with enones generating cyclopentenes catalyzed by N-heterocyclic carbene (NHC) have been investigated using density functional theory. The computational results show that the additive DBU plays an important role in NHC-catalyzed C–H activation. Analyses of the natural bond orbital charge and global reaction index indicate that NHC can lower the energy barrier of the entire reaction by activating the α/β-C–H bond rather than by strengthening the nucleophilicity of the reactant as a Lewis base. This is remarkably at variance from previous reports. In addition, the π···π stacking between the phenyl of the enone and the conjugated system of the NHC-bounded enolate intermediate has been found by the analyses of distortion/interaction and atom-in-molecule to be responsible for the stereoselectivity. These results shed light on the detailed reaction mechanism and the significant role of the NHC organocatalyst and offer valuable insights into the rational design of potential catalysts for this kind of highly stereoselective reaction.Keywords: DFT; mechanism; N-heterocyclic carbene; NCI analysis; organocatalysis; saturated carboxylic ester; sp3 β-C−H activation

•Molecular docking predicts groove binding and electrostatic interaction well for the studied copper nucleases.•The DNA binding affinity of copper nucleases influenced by the ligand size, length, functional groups, chelate ring size bound to copper center.•Intercalation modes could be reproduced by “distorted DNA” formed by molecular dynamics simulations.•MM-PBSA approach validated the DNA binding affinity of copper nuclease.In the present work, molecular simulations were performed for the purpose of predicting the binding modes of four types of copper nucleases (a total 33 compounds) with DNA. Our docking results accurately predicted the groove binding and electrostatic interaction for some copper nucleases with B-DNA. The intercalation modes were also reproduced by “gap DNA”. The obtained results demonstrated that the ligand size, length, functional groups and chelate ring size bound to the copper center could influence the binding affinities of copper nucleases. The binding affinities obtained from the docking calculations herein also replicated results found using MM-PBSA approach. The predicted DNA binding modes of copper nucleases with DNA will ultimately help us to better understand the interaction of copper compounds with DNA.

In this study, a density functional theory (DFT) study has been carried out to investigate the mechanisms of Rh(I)-catalyzed carbenoid carbon insertion into a C–C bond reaction between benzocyclobutenol (R1) and diazoester (R2). The calculated results indicate that the reaction proceeds through five stages: deprotonation of R1, cleavage of the C–C bond, carbenoid carbon insertion, intramolecular aldol reaction, and protonation of the alkoxyl-Rh(I) intermediate. We have suggested and studied two possible pathways according to different coordination patterns (including ketone-type and enol-type coordination forms) in the fourth stage and found that the enol-type pathway is favorable, making the coordination mode of the Rh(I) center in the oxa-π-allyl Rh(I) intermediate clear in this reaction system. Moreover, four possible protonation channels have been calculated in the fifth stage, and the computational results show that the H2O-assisted proton transfer channel is the most favorable. The first step of the third stage is rate-determining, and the first steps in stages 3 and 4 play important roles in determining the stereoselectivities. Moreover, the analyses of distortion/interaction, natural bond orbital (NBO), and molecular orbital (MO) have been performed to better understand this title reaction. Furthermore, the pathway corresponding to the RR configurational product is the most favorable path, which is consistent with the experimental result. This work should be helpful for understanding the detailed reaction mechanism and the origin of stereoselectivities of the title reaction and thus could provide valuable insights into rational design of more efficient catalysts for this type of reactions.

The possible reaction mechanisms for a stereoselective carbonyl–ene reaction between trifluoropyruvates and arylpropenes catalyzed by a Lewis acid catalyst (Rh(III)-complex) have been investigated using density functional theory (DFT). Six possible reaction pathways, including four Lewis acid-catalyzed reaction pathways and two non-catalyzed reaction pathways have been studied in this work. The calculated results indicate that the Lewis acid catalyzed reaction pathways are more energetically favorable than the non-catalyzed reaction pathways. For the Lewis acid-catalyzed pathways, there are four steps including complexation of the catalyst with the trifluoropyruvates, C–C bond formation, proton transfer, and decomplexation processes. Our computational outcomes show that the C–C bond formation step is both the rate- and enantioselectivity-determining step, and the reaction pathway leading to the S-configured product is the most favorable pathway among the possible stereoselective pathways. Dication Rh(III)-complexes with different counterions (i.e., OTf−, Cl−, and BF4−) were considered as active catalysts, and the computed results indicate that the stereoselectivity can be improved with the presence of the counterion OTf−. All the calculated outcomes align well with the experimental observations. Moreover, the stereoselectivity associated with the chiral carbon center is attributed to lone pair delocalization and variations in the stronger interaction. Furthermore, analysis of the global reactivity index was also performed to explain the role of the Lewis acid catalyst.

In recent years, the N-protonated chiral oxazaborolidine has been utilized as the Lewis acid catalyst for the asymmetric insertion reaction, which is one of the most challenging topics in current organic chemistry. Nevertheless, the reaction mechanism, stereoselectivity, and regioselectivity of this novel insertion reaction are still unsettled to date. In this present work, the density functional theory (DFT) investigation has been performed to interrogate the mechanisms and stereoselectivities of the formal C–C/H insertion reaction between benzaldehyde and methyl α-benzyl diazoester catalyzed by the N-protonated chiral oxazaborolidine. For the reaction channel to produce the R-configured C–C insertion product as the predominant isomer, the catalytic cycle can be characterized by four steps: (i) the complexation of the aldehyde with catalyst, (ii) addition of the other reactant methyl α-benzyl diazoester, (iii) the removal of nitrogen concerted with the migration of phenyl group or hydrogen, and (iv) the dissociation of catalyst from the products. Our computational results show that the carbon–carbon bond formation step is the stereoselectivity determining step, and the reaction pathways associated with [1, 2]-phenyl group migration occur preferentially to those pathways associated with [1, 2]-hydrogen migration. The pathway leading to the R-configured product is the most favorable pathway among the possible stereoselective pathways. All these calculated outcomes align well with the experimental observations. The novel mechanistic insights should be valuable for understanding this kind of reaction.

The detailed mechanisms and diastereoselectivities of Lewis acid-promoted ketene–alkene [2 + 2] cycloaddition reactions have been studied by density functional theory (DFT). Four possible reaction channels, including two noncatalyzed diastereomeric reaction channels (channels A and B) and two Lewis acid (LA) ethylaluminum dichloride (EtAlCl2) catalyzed diastereomeric reaction channels (channels C and D), have been investigated in this work. The calculated results indicate that channel A (associated with product R-configurational cycloputanone) is more energy favorable than channel B (associated with the other product S-configurational cyclobutanone) under noncatalyzed condition, but channel D leading to S-configurational cyclobutanone is more energy-favorable than channel C, leading to R-configurational cycloputanone under a LA-promoted condition, which is consistent with the experimental results. And Lewis acid can make the energy barrier of ketene–alkene [2 + 2] cycloaddition much lower. In order to explore the role of LA in ketene and C = X (X = O, CH2, and NH) [2 + 2] cycloadditions, we have tracked and compared the interaction modes of frontier molecular orbitals (FMOs) along the intrinsic reaction coordinate (IRC) under the two different conditions. Besides by reducing the energy gap between the FMOs of the reactants, our computational results demonstrate that Lewis acid lowers the energy barrier of the ketene and C = X [2 + 2] cycloadditions by changing the overlap modes of the FMOs, which is remarkably different from the traditional FMO theory. Furthermore, analysis of global reactivity indexes has also been performed to explain the role of LA catalyst in the ketene–alkene [2 + 2] cycloaddition reaction.

The first theoretical investigation using density functional theory (DFT) methods to study the detailed reaction mechanisms of stereoselective [2 + 2 + 2] multimolecular cycloaddition of ketene (two molecules) and carbon disulfide (CS2, one molecule) which is catalyzed by N-heterocyclic carbene (NHC) is presented in this paper. The calculated results indicate that this reaction occurs through four steps: the complexation of NHC with ketene (channel 1a) rather than with CS2 (channel 1b), addition of CS2 (channel 2b) but not dimerization of ketene (channel 2a), formal [4 + 2] cycloaddition with a second molecule of ketene (channel 3a) rather than intramolecular [2 + 2] cycloaddition (channel 3b), and finally regeneration of NHC. The second step is revealed to be the rate-determining step. Moreover, the stereoselectivities associated with the chiral carbon center and the carbon double bond are predicted to be respectively determined in the second and third steps and respectively R and E configurations dominated, which are in good agreement with the experimental results. Furthermore, the possible mechanisms of the identical [2 + 2 + 2] cycloaddition catalyzed by N,N-dimethylpyridin-4-amine (DMAP) have also been investigated to help understand the ring closure mechanism proceeding in the third step.

In the present study, molecular dynamic simulations have been performed to investigate the DNA binding affinities and cleavage activities of a new class of mononuclear copper (p-Cu(BPA) and m-Cu(BPA)) and dinuclear copper–platinum (p-Cu(BPA)-Pt and m-Cu(BPA)-Pt) metallonucleases. The simulated results reveal that the two mononuclear nucleases are noncovalent minor groove DNA binders and the two dinuclear ones tend to be bound to DNA in the major groove by a covalent bond between the platinum center and N7 of the guanine base, which is in agreement with the experimental results. The simulated results show that the binding affinities of the four studied nucleases with DNA are in the order of p-Cu(BPA) < m-Cu(BPA) < p-Cu(BPA)-Pt < m-Cu(BPA)-Pt; the binding affinities are dominated by intermolecular binding modes of nucleases with DNA and the intermolecular hydrogen bonds. The distance probability distributions indicate that the hydrogen atoms of DNA sugar could be abstracted by the four nucleases. Specifically, the dinuclear nucleases abstract hydrogen atoms from the deoxyribose sugar linking to G18 base while mononuclear nuclease abstracts hydrogen atoms from the deoxyribose sugars linking to C15 and C16 bases, suggesting that the dinuclear nucleases improve the sequence-selective cleavage of DNA compared with the mononuclear one. Moreover, the differences in calculated DNA conformational dynamics and groove parameters demonstrate that the extent of DNA conformational distortions induced by dinuclear nucleases is greater than that induced by mononuclear nucleases. This investigation provides detailed information showing that dinuclear nucleases have superior DNA binding affinities and nuclease activities as compared with their mononuclear counterparts.

Density functional theory (DFT) calculations have been performed to provide the first detailed computational study on the mechanism and enantioselectivity for the [4 + 2] cycloaddition reaction of ketenes with N-benzoyldiazenes catalyzed by N-heterocyclic carbenes (NHCs). Two possible mechanisms have been studied: first is the “ketene-first” mechanism (mechanism A), and second is the novel “diazene-first” mechanism (mechanism B). The calculated results reveal that mechanism B is more favorable than mechanism A because it is not only of lower energy barrier but also more consistent with the provided general experimental procedure (Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed.2009, 48, 192–195). The enantioselectivity-determining step is demonstrated to present during the first process of cycloaddition, and the main product configuration is verified to agree with the experimental ee values very well. This study should be of some worth on forecasting how different substituent groups of catalysts and/or reactants affect the enantioselectivity of products. The obtained novel mechanistic insights should be valuable for not only rational design of more efficient NHC catalysts but also understanding the general reaction mechanism of [4 + 2] cycloaddition of ketenes.

Cyclic peptides are exciting novel hosts for chiral and molecular recognition. In this work, the inclusion complexes of cyclic decapeptide (CDP) with the 1-phenyl-1-propanol enantiomers (E-PP) are firstly studied using the density functional theory (DFT) B3LYP method. Our calculated results indicated that S(-)-1-phenyl-1-propanol (S-PP) could form a more stable inclusion complex with CDP than that of R(+)-1-phenyl-1-propanol (R-PP). The obvious differences in binding energy and thermodynamics data suggest that the cyclic decapeptide could differentiate the two enantiomers. Furthermore, molecular dynamics simulation results have supported the conclusions obtained by DFT. The current investigation shows that cyclic peptide is a desirable host molecule for chiral and molecular recognition.

Tungsten peroxo complexes have been widely used in olefin epoxidation, alcohol oxidation, Baeyer–Villiger oxidation and other oxidation reactions, however, there is still not a unanimous viewpoint for the active structure of mononuclear tungsten peroxo complex by now. In this paper, the catalysis of mononuclear tungsten peroxo complexes 0–5 with or without acidic ligands for the green oxidation of cyclohexene to adipic acid in the absence of organic solvent and phase-transfer catalyst has been researched in experiment. Then we have suggested two possible kinds of active structures of mononuclear tungsten peroxo complexes including peroxo ring (nA, n = 0–1) and hydroperoxo (nB, n = 0–1) structures, which have been investigated using density functional theory (DFT). Moreover, the calculations on self-cycle mechanisms involving the two types of active structures of tungsten peroxo complexes with and without oxalic acid ligand have also been carried out at the B3LYP/[LANL2DZ/6-31G(d, p)] level. The highest energy barrier are 26.17 kcal/mol (0A, peroxo ring structure without oxalic acid ligand), 23.91 kcal/mol (1A, peroxo ring structure with oxalic acid ligand), 18.19 kcal/mol (0B, hydroperoxo structure without oxalic acid ligand) and 13.10 kcal/mol (1B, hydroperoxo structure with oxalic acid ligand) in the four potential energy profiles, respectively. The results indicate that both the energy barriers of active structure self-cycle processes with oxalic acid ligands are lower than those without oxalic acid ligands, so the active structures with oxalic acid ligands should be easier to recycle, which is in good agreement with our experimental results. However, due to the higher energy of product than that of the reactant, the energy profile of the self-cycle process of 1B shows that the recycle of 1B could not occur at all in theory. Moreover, the crystal data of peroxo ring structure with oxalic acid ligand could be found in some experimental references. Thus, the viewpoint that the peroxo ring active structure should be the real active structure has been proved in this paper.

The thermal reaction mechanisms of fluorobutanesulfonyl azide with pyrazine under solvent free condition have been studied by density functional theory (DFT) in this paper. Four possible reaction channels including two stepwise channels (channels 1 and 2) and the other two concerted channels (channels 3 and 4) are shown. The calculated results indicate that the stepwise channels (channels 1 and 2) should be easier to occur than the concerted channels (channels 3 and 4), and one of the stepwise channels (channel 1) is the most energy favorable reaction path among all the four possible channels, thus, the main product should be the pyrazinium N-fluorobutanesulfonyl ylide, which is consistent with the experimental result. Moreover, the highest energy barrier of channel 1 is 35.10 kcal/mol at the B3LYP/6-31G (d, p) level (which is 33.97 kcal/mol at the B3LYP/6-311++G (2d, 2p) level), this should be not a very high energy barrier for the experimental temperature (418 K). Furthermore, there are very small differences between the calculated results of two different levels. Therefore, it should be reliable that the stepwise reaction channel is the main reaction path in this reaction.

Recently, N-heterocyclic carbenes (NHCs) have been found to be efficient catalysts for the formal [2 + 2] cycloaddition of aryl(alkyl)ketenes and diazenedicarboxylates to give aza-β-lactams in good enantioselectivity (up to 91% ee) [X.-L. Huang, X.-Y. Chen, S. Ye, J. Org. Chem. 74 (2009) 7585–7587]. However, it is still ambiguous which step is the enantioselectivity-determining step and what the role of NHC catalysts is in this reaction. In this paper, we have suggested a possible mechanism of the title reaction and then theoretically investigated it in detail using density functional theory (DFT). Fully optimized geometries of reactants, products, transition states and intermediates were obtained at the B3LYP/[6-31G (d, p)/LANL2DZ] level of theory, and the results revealed that this reaction had three steps. Our calculated results indicate that the [2 + 2] cycloaddition step is the enantioselectivity-determining step. Moreover, the frontier molecular orbital (FMO) analysis has been carried out to explain why the NHC catalysts can make the [2 + 2] cycloaddition easier to occur, which is mainly due to that the energy gap of FMOs become narrower under the NHC-catalysis condition. Noteworthy, the results of global reactivity indexes analysis are consistent with those of the FMO analysis. Further calculations show that the solvent effect of dichloromethane has no great influence on enantioselectivity of this reaction.Graphical abstractWhy can R1 react with R2 to generate P(R) with a good enantioselectivity under the NHC-catalyzed condition? In this paper, we have investigated the mechanisms of the title reaction using DFT method.Research highlights▶ This study provides a model for predicting the enantioselectivity of the product, which should be helpful in designing other enantioselective catalyst.

Reaction mechanisms of the 6-benzyl-6-azabicyclo[2.2.1]hept-2-ene with benzoyl isocyanate have been investigated using density functional theory (DFT) at the B3LYP/6-31G(d,p) level of theory. The reaction proceeding along six competitive channels includes two categories. That is, two channels are formally [3,3]-sigmatropic rearrangements and four channels are [4+2] cycloadditions. For urea, the formally [3,3]-sigmatropic rearrangement channel and the [4+2] cycloaddition channels are competitive since they have similar barriers. However, the [4+2] cycloaddition channels are energetically favorable pathways to lead to isourea, with the highest barrier of 12.77 kcal/mol. These polar Diels−Alder (P-DA) reactions are controlled by the charge transfer (CT) at the transition states. Moreover, the main products of this reaction include urea and isourea. Furthermore, difference of two new bond lengths at transition states indicate that the [4+2] cycloadditions in this reaction are asynchronous processes, which is in good agreement with the experiment.

The mechanisms of the title reaction have been studied by density functional theory (DFT) and the second order Moller–Pleset (MP2) method. Two possible reaction channels including the non-catalyzed channel (channel 1) and the other catalyzed channel (promoted by Lewis acid ZnCl2, channel 2) are shown. The calculated results indicate that the catalyzed channel is more energy favorable than the non-catalyzed channel, and the energy barrier of channel 2 (31.62 kcal/mol at the B3LYP/6-31G(d,p) level and 30.32 kcal/mol at the MP2/6-311++G(2d,2p) level) is not a high energy barrier for the experimental condition (343 K), thus, we think the Lewis acid ZnCl2 would play an important role in making the title reaction easier to occur, which is in good agreement with the experimental results.

Recently, the first examples of direct vinylation of 1-substituted imidazoles at the 2-position of the imidazole nucleus have been described (J. Org. Chem. 2008, 73, 9155−9157). 1-Substituted imidazoles are C(2)-vinylated with 3-phenyl-2-propynenitrile at room temperature without catalyst and solvent to afford 3-(1-organyl-1H-imidazol-2-yl)-3-phenyl-2-propenenitriles, mainly (ca. 95%) as (Z)-isomers, in 56−88% yield. Nevertheless, the stereoselectivity of vinylation, which has been elusive over the past decades, is still a big problem to explain. In this paper, the reaction mechanisms of stereoselective C(2)-vinylation of 1-methylimidazole with 3-phenyl-2-propynenitrile have been investigated using density functional theory (DFT). The geometries of the reactants, transition states, intermediates, and products were optimized at the B3LYP/6-31G(d,p) level. The calculated results reveal that the reaction contains three processes: formation of zwitterion, proton transfer, and ring rearrangement. Four possible reaction channels are shown, including two (E)-isomer channels and two (Z)-isomer channels. One of the (Z)-isomer channels has the lowest energy barrier among all the four channels, with the highest energy barrier for 83.62 kJ/mol, so it occurs more often than the others at room temperature, which is in good agreement with experiment. Further calculations of solvation effects show that the title reaction can be carried out more smoothly in the gas phase.

A chiral diamide [(2S)-5-oxo-2-(arylamino)carbonylpyrrolidine] has been experimentally employed as an effective chiral catalytic precursor in the borane-mediated asymmetric reduction of prochiral ketones to produce the corresponding secondary alcohols. The mechanism of the reduction has been investigated theoretically by density functional theory, and the results reveal that this reaction is accomplished via four steps. Fully geometry optimized reactants, products, transition states, and intermediates are obtained. The analysis of these results reveals one pathway that is more energetically favorable, and its associated geometries correlate well with the final products of the reaction. Further calculations show that the solvent effect of toluene has no influence on the enantioselectivity of this reduction.

In this study, a density functional theory (DFT) study has been carried out to investigate the mechanisms of Rh(I)-catalyzed carbenoid carbon insertion into a C–C bond reaction between benzocyclobutenol (R1) and diazoester (R2). The calculated results indicate that the reaction proceeds through five stages: deprotonation of R1, cleavage of the C–C bond, carbenoid carbon insertion, intramolecular aldol reaction, and protonation of the alkoxyl-Rh(I) intermediate. We have suggested and studied two possible pathways according to different coordination patterns (including ketone-type and enol-type coordination forms) in the fourth stage and found that the enol-type pathway is favorable, making the coordination mode of the Rh(I) center in the oxa-π-allyl Rh(I) intermediate clear in this reaction system. Moreover, four possible protonation channels have been calculated in the fifth stage, and the computational results show that the H2O-assisted proton transfer channel is the most favorable. The first step of the third stage is rate-determining, and the first steps in stages 3 and 4 play important roles in determining the stereoselectivities. Moreover, the analyses of distortion/interaction, natural bond orbital (NBO), and molecular orbital (MO) have been performed to better understand this title reaction. Furthermore, the pathway corresponding to the RR configurational product is the most favorable path, which is consistent with the experimental result. This work should be helpful for understanding the detailed reaction mechanism and the origin of stereoselectivities of the title reaction and thus could provide valuable insights into rational design of more efficient catalysts for this type of reactions.