The possible mechanisms of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed chemoselective insertion of N-methyl isatin into aryl difluoronitromethyl ketone to synthesize 3,3-disubstituted and 2,2-disubstituted oxindoles have been studied in this work. As revealed by calculated results, the reaction occurs via two competing paths, including α and β carbonyl paths, and each path contains five steps, that is, nucleophilic addition of DBU to ketone, C–C bond cleavage affording difluoromethylnitrate anion and phenylcarbonyl–DBU cation, nucleophilic addition of difluoromethylnitrate anion to carbonyl carbon of N-methyl isatin, acyl transfer process, and dissociation of DBU and product. The computational results suggest that nucleophilic additions on different carbonyl carbons of N-methyl isatin via α and β carbonyl paths would lead to different products in the third step, and β carbonyl path associated with the main product 3,3-disubstituted oxindole is more energetically favorable, which is consistent with the experimental observations. Noteworthy, electrophilic Parr function can be successfully applied for exactly predicting the activity of reaction site and reasonably explaining the chemoselectivity. In addition, the distortion/interaction and noncovalent interaction analyses show that much more hydrogen bond interactions should be responsible for the lower energy of the transition state associated with β carbonyl path. The obtained insights would be valuable for the rational design of efficient organocatalysts for this kind of reactions with high selectivities.Topics: Carbonyl compounds (organic); Catalysts; Chemical potential; Conformation; Electronic properties; Electronic structure; Free energy; Insertion reaction; Insertion reaction; Molecular structure; Reaction mechanism; Reaction rate theory;

The N-heterocyclic carbene (NHC)-catalyzed γ-C–H deprotonation/functionalization of α,β-unsaturated esters with hydrazones leading to the δ-lactams has been theoretically investigated by using density functional theory. Three possible reaction mechanisms including Mechanism A, for which the NHC catalyst serves as a nucleophilic catalyst to attack on the carbonyl carbon atom to initiate the reaction, Mechanism B, in which NHC triggers the reaction through the hydrogen bond, and Mechanism C, which is the direct deprotonation/functionalization process without the presence of NHC, have been suggested and studied in detail. The most favorable Mechanism A was identified to proceed through the following processes: nucleophilic attack on the carbonyl carbon of the ester by NHC, γ-deprotonation, formal [4 + 2] cycloaddition of dienolate with hydrazone, and regeneration of NHC. Multiple possible deprotonation pathways were explored, and the additive base such as K2CO3 would significantly lower the energy barrier. The formal [4 + 2] cycloaddition step is the stereoselectivity-determining step, and R-configured rather than S-configured product was preferentially generated. In addition, the C–H···O, C–H···N, LP···π, and C–H···π interactions have been identified in the most energetically favorable transition state involved in the stereoselectivity-determining step. The additional analysis indicates that NHC strengthens the acidity and electrophilicity to promote the deprotonation, indicating this is not a simple NHC-catalyzed umpolung carbonyl reaction. The mechanistic insights and the significant role of NHC obtained in this study should provide valuable insights for understanding the organocatalytic γ-C(sp3)–H bond functionalization reaction.

In this work, the reaction mechanism, stereoselectivity, and chemoselectivity of oxidative α-fluorination of aliphatic aldehydes enabled by N-heterocyclic carbene catalysts have been investigated using a density functional theory (DFT) method. The computed outcomes reveal that the whole reaction includes several processes, i.e., formation of the Breslow intermediate, oxidative deprotonation to give the cation intermediate, deprotonation of the α-C(sp3)–H bond, α-fluorination, esterification by CyOH affording the α-fluoroester, and dissociation of the catalyst and the final product. According to the computational results, the fluorination process was identified to be the stereoselectivity-determining step. The addition on the different prochiral faces of the enolate intermediate results in the formation of a stereoselective fluorinated intermediate and the chiral center assigned to the α-carbon emerges during the fluorination process. Non-covalent interaction (NCI) analysis revealed the presence of relatively stronger non-covalent interactions (i.e. π–π stacking), which leads to the predominant position of the S-configurational reaction pathway. Moreover, the competing reaction pathways affording the by-products of aliphatic ester and difluorinated ester were calculated to be kinetically unfavorable. Furthermore, global reactivity index (GRI) analysis shows that NHC promotes the reaction by enhancing the nucleophilicity of the enolate intermediate and the electrophilicity of the monofluorinated intermediate. The obtained theoretical insights would be useful for rational design of the fluorination of aliphatic aldehydes with high selectivity under organocatalysis.

A systematically theoretical study has been carried out to understand the mechanism and chemoselectivity of N-heterocyclic carbene (NHC)-catalyzed fluorination reaction of alkynals using density functional theory calculations. The calculated results reveal that the reaction contains several steps, i.e., formation of the actual catalyst NHC, the nucleophilic attack of NHC on the carbonyl carbon atom of a formyl group, the formation of Breslow intermediate, the removal of methyl carbonate group to afford cumulative allenol intermediate, C–F bond formation coupled with generation of (SO2Ph)2N− anion, esterification accompanied with formation of (SO2Ph)2NH, and dissociation of NHC from product. For the formation of Breslow intermediate via the [1,2]-proton transfer process, apart from the direct proton transfer mechanism, the H2O- and EtOH-mediated proton transfer mechanisms were also investigated, and the free energy barriers for the crucial proton transfer steps can be significantly lowered by explicit inclusion of the protic media EtOH. Furthermore, multiple analyses have also been performed to explore the roles of catalysts and origin of chemoselectivity. Noteworthily, the in situ formed Brønsted base (BB) (SO2Ph)2N− anion was found to play an indispensable role in the esterification process, indicating that the reaction undergoes NHC-BB cooperatively catalytic mechanism, which is remarkably different from the direct esterification pathway proposed in the experimental references. This theoretical work provides a case on the exploration of the dual catalysis in NHC chemistry, which is valuable for rational design on newly cooperative organocatalysis in future.

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

The mechanisms and chemo- and stereo-selectivities of PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles leading to functionalized pyrrolidines (5-endo-trig cyclization, Mechanism A) and their competing reaction leading to another kind of pyrrolidine (5-exo-trig cyclization, Mechanism B) have been investigated using density functional theory (DFT). Multiple possible reaction pathways associated with four different isomers (RR, SR, RS, and SS) for Mechanism A, and two isomers (R and S) for Mechanism B have been studied. The calculated results indicate that the Gibbs free energy barriers of Mechanism A are remarkably lower than those of Mechanism B, and the reaction pathway leading to the RS-configured product has the lowest Gibbs free energy barrier, which is in agreement with the experiments. A C–H⋯π interaction has been identified to be responsible for the favorability of RS isomers by non-covalent interaction (NCI) analysis. Moreover, global reaction indexes (GRIs) and NBO analyses confirm that PBu3 acts as a Lewis base to strengthen the nucleophilicity of the reaction active site. The mechanistic insights gained in the present study should be valuable for the rational design of effective organocatalysts for this kind of reaction with high chemo- and stereo-selectivities.

A comprehensive density functional theory (DFT) investigation has been performed to interrogate the mechanisms and stereoselectivities of the Csp2–Csp3 single bond activation of cyclobutenones and their [4+2] cycloaddition reaction with imines via N-heterocyclic carbene (NHC) organocatalysis. According to our calculated results, the fundamental reaction pathway contains four steps: nucleophilic addition of NHC to cyclobutenone, C–C bond cleavage for the formation of an enolate intermediate, [4+2] cycloaddition of the enolate intermediate with isatin imine, and the elimination of the NHC catalyst. In addition, the calculated results also reveal that the second reaction step is the rate-determining step, whereas the third step is the regio- and stereo-selectivity determining step. For the regio- and stereo-selectivity determining step, all four possible attack modes were considered. The addition of the CN bond in isatin imine to the dienolate intermediate is more energy favorable than the addition of the CO bond to a dienolate intermediate. Moreover, the Re face addition of the CN bond in isatin imine to the Re face of the dienolate intermediate leading to the SS configuration N-containing product was demonstrated to be most energy favorable, which is mainly due to the stronger second-order perturbation energy value in the corresponding transition state. Furthermore, by tracking the frontier molecular orbital (FMO) changes in the rate-determining C–C bond cleavage step, we found that the reaction obeys the conservation principle of molecular orbital symmetry. We believe that the present work would provide valuable insights into this kind of reaction.

A theoretical investigation has been performed to interrogate the mechanism and stereoselectivities of aminomethylation reaction of α,β-unsaturated aldehyde with N,O-acetal, which is initiated by N-heterocyclic carbene and Brønsted acid (BA). The calculated results disclose that the reaction contains several steps, i.e., formation of the actual catalysts NHC and Brønsted acid Et3N·H+ coupled with activation of C–O bond of N,O-acetal, nucleophilic attack of NHC on α,β-unsaturated aldehyde, formation of Breslow intermediate, β-protonation for the formation of enolate intermediate, nucleophilic addition on the Re/Si face to enolate by the activated iminium cation, esterification coupled with regeneration of Et3N·H+, and dissociation of NHC from product. Addition on the prochiral face of enolate should be the stereocontrolling step, in which the chiral α-carbon is formed. Furthermore, NBO, GRI, and FMO analyses have been performed to explore the roles of catalysts and origin of stereoselectivity. Surprisingly, the added Brønsted base (BB) Et3N plays an indispensable role in the esterification process, indicating the reaction proceeds under NHC-BA/BB multicatalysis rather than NHC-BA dual catalysis proposed in the experiment. This theoretical work provides a case on the exploration of the special roles of the multicatalysts in NHC chemistry, which is valuable for rational design on new cooperative organocatalysis.

Cobalt-mediated C–H functionalization has been the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions (such as the cobalt-catalyzed C–H oxidation) are poorly understood. In this paper, possible mechanisms including single electron transfer (SET) and the concerted metalation–deprotonation (CMD) pathways of the CoII/CoIII-catalyzed alkoxylation of C(sp2)–H bonds have been investigated for the first time using the DFT method. CoII(OAc)2 has been employed as an efficient catalyst in our previous experimental study, but the calculated results unexpectedly indicated that the intermolecular SET pathway with CoIII as the actual catalyst might be the most favorable pathway. To support this theoretical prediction, we have explored a series of Cp*CoIII(CO)I2 catalyzed C(sp2)–H bond alkoxylations, extending the application of cobalt-catalyzed functionalization of C–H bonds. Furthermore, kinetic isotope effect (KIE) data, electron paramagnetic resonance (EPR) data, and TEMPO inhibition experiments also support the SET mechanism in both the Co-catalyzed alkoxylation reactions. Thus, this work should support an understanding of the possible mechanisms of the CoII/CoIII-catalyzed C(sp2)–H functionalization, and also provide an example of the rational design of novel catalytic reactions guided by theoretical calculations.

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.

•The direct C–H functionalization of quinoline N-oxide by H-phosphonate is studied in theory.•All the structures are optimized at the B3LYP(SMD, xylene)/6-31G(d, p) level.•All the structures are optimized at the M06-2X(SMD, xylene)/6-31G(d, p) level.•The novel mechanism provides insights on rational design of the phosphonation.In this paper, a density functional theory (DFT) study has been carried out to theoretically investigate the mechanisms of direct regioselective phosphonation of heteroaryl N-oxides (A) with H-phosphonates (B1) under metal- and external oxidant-free conditions. The calculated results indicate that the reaction proceeds through two stages including nucleophilic addition of H-phosphonate to heteroaryl N-oxide (A) and the dehydration. Starting from the reactant B1 or its tautomer B2, two possible pathways have been suggested and studied in the first stage. Moreover, three possible channels including B1-assisted dehydration, B2-assisted dehydration, and direct dehydration have been investigated and compared in the second stage. Based on the computational results, we can conclude that both pathways associated with B1 and B2 are possible to occur under the experimental condition, and the B1/B2-assisted dehydration would have lower barriers than the direct dehydration. This work should be helpful for understanding the detailed mechanism of the title reaction, and thus provide valuable insights into rational design on the effective method/condition for this kind of reaction.

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.

Lewis base N-heterocyclic carbene (NHC)-catalyzed annulation is the subject of extensive interest in synthetic chemistry, but the reaction mechanisms, especially the unexpected chemoselectivity of some of these reactions, are poorly understood. In this work, a systematic theoretical calculation has been performed on NHC-catalyzed annulation between allenals and chalcone. Multiple possible reaction pathways (A–E) leading to three different products have been characterized. The calculated results reveal that NHC is more likely to initiate the reaction by nucleophilic attack on the center carbon atom of the allene group but not the carbonyl carbon atom in allenals leading to the Breslow intermediate, which is remarkably different from the other NHC-catalyzed annulations of unsaturated aldehydes with chalcones. The computed energy profiles demonstrate that the most energetically favorable pathway (A) results in polysubstituted pyranyl aldehydes, which reasonably explains the observed chemoselectivity in the experiment. The observed chemoselectivity is demonstrated to be thermodynamically but not kinetically controlled, and the stability of the Breslow intermediate is the key for the possibility of homoenolate pathway D and enolate pathway E. This work can improve our understanding of the multiple competing pathways for NHC-catalyzed annulation reactions of unsaturated aldehydes with chalcones and provide valuable insights for predicting the chemoselectivity for this kind of reaction.

In this paper, two possible mechanisms (mechanisms A and B) on the stereoselective [2 + 2] cycloaddition of aryl(alkyl)ketenes and electron-deficient benzaldehydes catalyzed by N-heterocyclic carbenes (NHCs) have been investigated using density functional theory (DFT). Our calculated results indicate that the favorable mechanism (mechanism A) includes three processes: the first step is the nucleophilic attack on the arylalkylketene by the NHC catalyst to form an intermediate, the second step is the [2 + 2] cycloaddition of the intermediate and benzaldehyde for the formation of a β-lactone, and the last step is the dissociation of the NHC catalyst and the β-lactone. Notably, the [2 + 2] cycloaddition, in which two chiral centers associated with four configurations (SS, RR, SR and RS) are formed, is demonstrated to be both the rate- and stereoselectivity-determining step. Moreover, the reaction pathway associated with the SR configuration is the most favorable pathway and leads to the main product, which is in good agreement with the experimental results. Furthermore, the analysis of global and local reactivity indexes has been performed to explain the role of the NHC catalyst in the [2 + 2] cycloaddition reaction. Therefore, this study will be of great use for the rational design of more efficient catalysts for this kind of cycloaddition.

Reaction mechanisms of the N-heterocyclic carbene (NHC)-catalyzed dimerization of methyl methacrylate were studied using density functional theory (DFT) at the M05-2X/6-31G(d,p) level of theory. Four possible reaction channels (A, B, C, and D) have been investigated in this work. Particularly, we proposed a novel reaction pathway, where the proton transfers are assisted by a different molecule. The calculated results indicate that the channels B and D are more energetically favourable channels. The obtained results suggest that the E-isomer product is the main product, which is in agreement with the experimental results. Further calculations and analyses of global and local reactivity indices reveal the role of the NHC catalysts in the title reaction. The mechanistic insights gained are valuable for not only rational design of more efficient NHC catalysts but also for understanding the similar reaction mechanism.

The possible reaction mechanisms of stereoselective [4 + 2] cycloaddition of enals and chalcones catalyzed by N-heterocyclic carbene (NHC) have been investigated using density functional theory (DFT). The calculated results indicate that the most favorable reaction channel occurs through five steps. The first step is the nucleophilic attack on the enal by NHC. Then, there are two consecutive acid (AcOH)-assisted proton-transfer steps. Subsequently, the fourth step is the [4 + 2] cycloaddition process associated with the formation of two chiral centers, followed by dissociation of NHC and product. Our computational results demonstrate that the [4 + 2] cycloaddition is the rate-determining and stereoselectivity-determining step. The energy barrier for the SS configurational channel (17.62 kcal/mol) is the lowest one, indicating the SS configurational product should be the main product, which is in agreement with experiment. Moreover, the role of NHC catalyst in the [4 + 2] cycloaddition of enal and chalcone was explored by the analysis of global reactivity indexes. This work should be helpful for realizing the significant roles of catalyst NHC and the additive AcOH and thus provide valuable insights on the rational design of potential catalyst for this kind of reactions.

The inclusion complexes of two modified cyclic decapeptides with 1-phenyl-1-propanol (PP) enantiomers were first studied using the density functional theory B3LYP method. Our calculated results indicated that modified cyclic decapeptide (CM-CDP and DA-CDP) could form stable inclusion complexes. Significantly, based on the structural characteristics and hydrogen bond analyses, we found that the primary driving force of inclusion complex formation is a cooperative work of hydrogen bonds, steric effect, and electronic interactions, which facilitates the enhancement of binding affinity of the PP enantiomers with CM-CDP and DA-CDP. The current study shows that modified cyclic decapeptide is a desirable host molecule for chiral and molecular recognition.

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.

The mechanisms and chemo- and stereo-selectivities of PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles leading to functionalized pyrrolidines (5-endo-trig cyclization, Mechanism A) and their competing reaction leading to another kind of pyrrolidine (5-exo-trig cyclization, Mechanism B) have been investigated using density functional theory (DFT). Multiple possible reaction pathways associated with four different isomers (RR, SR, RS, and SS) for Mechanism A, and two isomers (R and S) for Mechanism B have been studied. The calculated results indicate that the Gibbs free energy barriers of Mechanism A are remarkably lower than those of Mechanism B, and the reaction pathway leading to the RS-configured product has the lowest Gibbs free energy barrier, which is in agreement with the experiments. A C–H⋯π interaction has been identified to be responsible for the favorability of RS isomers by non-covalent interaction (NCI) analysis. Moreover, global reaction indexes (GRIs) and NBO analyses confirm that PBu3 acts as a Lewis base to strengthen the nucleophilicity of the reaction active site. The mechanistic insights gained in the present study should be valuable for the rational design of effective organocatalysts for this kind of reaction with high chemo- and stereo-selectivities.

A comprehensive density functional theory (DFT) investigation has been performed to interrogate the mechanisms and stereoselectivities of the Csp2–Csp3 single bond activation of cyclobutenones and their [4+2] cycloaddition reaction with imines via N-heterocyclic carbene (NHC) organocatalysis. According to our calculated results, the fundamental reaction pathway contains four steps: nucleophilic addition of NHC to cyclobutenone, C–C bond cleavage for the formation of an enolate intermediate, [4+2] cycloaddition of the enolate intermediate with isatin imine, and the elimination of the NHC catalyst. In addition, the calculated results also reveal that the second reaction step is the rate-determining step, whereas the third step is the regio- and stereo-selectivity determining step. For the regio- and stereo-selectivity determining step, all four possible attack modes were considered. The addition of the CN bond in isatin imine to the dienolate intermediate is more energy favorable than the addition of the CO bond to a dienolate intermediate. Moreover, the Re face addition of the CN bond in isatin imine to the Re face of the dienolate intermediate leading to the SS configuration N-containing product was demonstrated to be most energy favorable, which is mainly due to the stronger second-order perturbation energy value in the corresponding transition state. Furthermore, by tracking the frontier molecular orbital (FMO) changes in the rate-determining C–C bond cleavage step, we found that the reaction obeys the conservation principle of molecular orbital symmetry. We believe that the present work would provide valuable insights into this kind of reaction.

Cobalt-mediated C–H functionalization has been the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions (such as the cobalt-catalyzed C–H oxidation) are poorly understood. In this paper, possible mechanisms including single electron transfer (SET) and the concerted metalation–deprotonation (CMD) pathways of the CoII/CoIII-catalyzed alkoxylation of C(sp2)–H bonds have been investigated for the first time using the DFT method. CoII(OAc)2 has been employed as an efficient catalyst in our previous experimental study, but the calculated results unexpectedly indicated that the intermolecular SET pathway with CoIII as the actual catalyst might be the most favorable pathway. To support this theoretical prediction, we have explored a series of Cp*CoIII(CO)I2 catalyzed C(sp2)–H bond alkoxylations, extending the application of cobalt-catalyzed functionalization of C–H bonds. Furthermore, kinetic isotope effect (KIE) data, electron paramagnetic resonance (EPR) data, and TEMPO inhibition experiments also support the SET mechanism in both the Co-catalyzed alkoxylation reactions. Thus, this work should support an understanding of the possible mechanisms of the CoII/CoIII-catalyzed C(sp2)–H functionalization, and also provide an example of the rational design of novel catalytic reactions guided by theoretical calculations.

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.

Reaction mechanisms of the N-heterocyclic carbene (NHC)-catalyzed dimerization of methyl methacrylate were studied using density functional theory (DFT) at the M05-2X/6-31G(d,p) level of theory. Four possible reaction channels (A, B, C, and D) have been investigated in this work. Particularly, we proposed a novel reaction pathway, where the proton transfers are assisted by a different molecule. The calculated results indicate that the channels B and D are more energetically favourable channels. The obtained results suggest that the E-isomer product is the main product, which is in agreement with the experimental results. Further calculations and analyses of global and local reactivity indices reveal the role of the NHC catalysts in the title reaction. The mechanistic insights gained are valuable for not only rational design of more efficient NHC catalysts but also for understanding the similar reaction mechanism.

In this paper, two possible mechanisms (mechanisms A and B) on the stereoselective [2 + 2] cycloaddition of aryl(alkyl)ketenes and electron-deficient benzaldehydes catalyzed by N-heterocyclic carbenes (NHCs) have been investigated using density functional theory (DFT). Our calculated results indicate that the favorable mechanism (mechanism A) includes three processes: the first step is the nucleophilic attack on the arylalkylketene by the NHC catalyst to form an intermediate, the second step is the [2 + 2] cycloaddition of the intermediate and benzaldehyde for the formation of a β-lactone, and the last step is the dissociation of the NHC catalyst and the β-lactone. Notably, the [2 + 2] cycloaddition, in which two chiral centers associated with four configurations (SS, RR, SR and RS) are formed, is demonstrated to be both the rate- and stereoselectivity-determining step. Moreover, the reaction pathway associated with the SR configuration is the most favorable pathway and leads to the main product, which is in good agreement with the experimental results. Furthermore, the analysis of global and local reactivity indexes has been performed to explain the role of the NHC catalyst in the [2 + 2] cycloaddition reaction. Therefore, this study will be of great use for the rational design of more efficient catalysts for this kind of cycloaddition.