Stereoselectivity-determining Step Research Articles

Mechanism and Origin of Stereoselectivity of N-Heterocyclic Carbene (NHC)-Catalyzed Transformation Reaction of Benzaldehyde with o-QDM as Key Intermediate: A DFT Study.

N-heterocyclic carbene (NHC)-bound ortho-quinodimethane, served as a nucleophile, has occupied an important position for constructing various all-carbon or heterocyclic compounds and attracted increasing attention for the functionalization of benzylic carbon of aromatic aldehydes, whereas the mechanistic studies on the generation and transformations of dienolate intermediate are rare. In the present study, the mechanism of activation/transformation of aldehyde catalyzed by NHC was theoretically studied using the density functional theory (DFT) method. Based on the calculations, the nucleophilic addition process is the stereoselectivity-determining step with RS-configured product being generated preferentially. Furthermore, non-covalent index (NCI) and atoms-in-molecules (AIM) analyses have been performed to disclose the origin of stereoselectivity, by which the larger number and stronger weak interactions are the key for stabilizing the low-energy transition state and thus leading to the stereoselectivity inducing.

Mechanisms and origins of stereoselectivity in the NHC-catalyzed oxidative reaction of enals and pyrroles: a density functional theory study.

The mechanism, chemoselectivity and stereoselectivity in the NHC-catalyzed reaction between enals and pyrroles for the synthesis of 5,6-dihydroindolizine were studied using DFT calculations. The cycle for catalytic generation of 5,6-dihydroindolizine proceeds via seven steps: (1) addition of the NHC to enal, (2) formation of a Breslow intermediate through [1,2]-proton transfer, (3) oxidation, (4) Michael addition, (5) [2+2] cycloaddition, (6) liberation of NHCs and (7) decarboxylation. Our results show that the presence of DMAP·H+ lowers the barrier for [1,2]-proton transfer. In addition, NHC·H+ plays a key role in decarboxylation. Michael addition which involves the formation of a new C-C bond was identified to be the chemo- and stereoselectivity-determining step, leading to the experimentally observed 5S,6R-dihydroindolizine. Analysis of the noncovalent interactions revealed that the observed stereoselectivity is attributed to the differential weak interactions (CH⋯π, LP⋯π and CH⋯CH) involved in the transition states during the Michael addition step. The computational results not only rationalize experimental observations but also provide some useful information for the future design of new catalytic processes.

DFT investigation of the mechanism and role of N-heterocyclic carbene (NHC) in constructing asymmetric organosilanes using NHC-catalyzed [4+2] cycloaddition reaction.

Herein, the mechanism and origin of stereoselectivity for the asymmetric [4+2] cycloaddition between (E)-3-(p-tolyl)acrylaldehyde (R1) and phenyl-3-(trimethylsilyl)prop-2-en-1-one (R2) in the presence of an N-heterocyclic carbene (NHC) were theoretically scrutinized. The desirable catalytic cycle is characterized by five steps: (1) the coupling reaction of the NHC catalyst with R1, the formation of the Breslow and enolate intermediates in the second and third steps, (4) the formal [4+2] cycloaddition reaction to form the stereoselective C-C bond, and (5) the regeneration of NHC to obtain asymmetric organosilanes. In the most energetically favorable pathway, the formation of the enolate intermediate exhibits the highest energy barrier of about 19.48 kcal mol-1 (Re-TS2BA) and is the rate-determining step. The [4+2] cycloaddition reaction is the stereoselectivity-determining step forming the chiral C-C bond with RR, RS, SR and SS configurations, among which RS is the most desirable configuration. The origin of stereoselectivity was investigated using distortion energy analysis. The first and fourth steps helped in investigating the effects of electron-donating (Me) and electron-withdrawing (Cl) groups on cinnamaldehyde. Conceptual DFT (CDFT) analysis was carried out to confirm the critical role of the NHC catalyst as a Lewis base during the reaction processes.

Elucidating the mechanism and origin of stereoselectivity in the activation/transformation of an acetic ester catalyzed by an N-heterocyclic carbene.

The activation of an ester by N-heterocyclic carbene (NHC) organocatalysis is an efficient and important approach for generating an NHC-bound enolate intermediate, an important active intermediate in the transformation of carbonyl compounds. Herein, we perform a theoretical study on the NHC-catalyzed activation and transformation reaction of an acetic ester in which the NHC-bound enolate intermediate is a key intermediate. Multiple activation and transformation pathways are proposed and analyzed to identify an energetically favorable pathway. The use of different substrates for the reaction is considered. When a chalcone substrate is used, [4+2] cycloaddition between the enolate intermediate and the chalcone is identified to be both the rate- and stereoselectivity-determining step for the reaction, with the R-configured product being generated as the major isomer. Noncovalent interaction (NCI) and atoms-in-molecules (AIM) analyses are performed to identify the origin of the stereoselectivity of the reaction, and a local reactivity analysis is conducted to explore substrate and catalyst effects on the reaction.

Theoretical study of an N-heterocyclic carbene-catalyzed annulation reaction between an enal and a β-silyl enone: Mechanism and origin of stereoselectivity

In this study, the mechanism and origin of the stereoselectivity of an N-heterocyclic carbene (NHC)-catalyzed transformation reaction between an enal and a β-silyl enone are systematically investigated using density functional theory (DFT) at the M06-2X level. Multiple pathways are proposed and studied to identify the most energetically favorable mechanism for the reaction. The calculation results show that the most energetically favorable pathway comprises the following processes: nucleophilic addition of NHC to the Si-face of the enal to form a zwitterionic intermediate, two sequential CsHCO3-assisted intramolecular proton shifts to produce an enolate intermediate, Michael-type addition of the enolate intermediate to the β-silyl enone, ring closure to construct a six-membered ring intermediate, and the dissociation of NHC to release the final product. The reaction between the enolate intermediate and the β-silyl enone is identified as the stereoselectivity-determining step, preferentially generating an RS-configured product. Subsequent atoms-in-molecules (AIM) and noncovalent interaction (NCI) analyses verify that the main factor for inducing stereoselectivity is the higher number of noncovalent intermolecular interactions in the low-energy transition state.

Mechanisms and origins of stereoselectivity involved in NHC-catalyzed [3 + 3] Annulation of 2-bromoenals and β-ketothioamides: A DFT study

We reported a density functional theory (M06–2X) study of the possible mechanisms operating in a chemo- and stereoselective [3+3] annulation reaction of 2-bromoenal with β-ketothioamide catalyzed by a chiral NHC catalyst. DFT computations suggest the catalytic reaction involves nucleophilic addition, [1,2]-proton transfer, debromination, [1,3]-proton transfer, Michael addition, [1,5]-proton transfer, ring closure and catalyst dissociation, in which Michael addition is the chemo- and stereoselectivity-determining step and provides the SR-configured sipro-piperidinone predominantly. This result is consistent with the stereoselectivity observed in experiment. Nonconvalent interaction (NCI) analysis reveals that the origin of stereoselectivity is the different weak interactions (C–H···π, LP···π and π···π). The computational results should deepen our understanding of NHC catalysis, and may thus contribute to the design of new catalytic systems.

Light-empowered contra-thermodynamic stereochemical editing.

Creating, conserving and modifying the stereochemistry of organic compounds has been the subject of significant research efforts in synthetic chemistry. Most synthetic routes are designed according to the stereoselectivity-determining step. Stereochemical editing is an alternative strategy, wherein the chiral-defining or geometry-defining steps are independent of the construction of the major scaffold or complexity. It enables late-stage alterations of stereochemistry and can generate isomers from a single compound. However, in many instances, stereochemical editing processes are contra-thermodynamic, meaning the transformation is unfavourable. To overcome this barrier, photocatalysis uses photogenerated radical species and introduces thermochemical biases. A range of synthetically valuable contra-thermodynamic stereochemical editing processes have been invented, including deracemization of chiral molecules, positional alkene isomerization and dynamic epimerization of sugars and diols. In this Review, we highlight the fundamental mechanisms of visible-light photocatalysis and the general reactivity modes of the photogenerated radical intermediates towards contra-thermodynamic stereochemical editing processes.

Theoretical investigation on cobalt-catalyzed hydroacylation reaction: Mechanism and origin of stereoselectivity

In the present study, the mechanism of a cobalt-catalyzed hydroacylation reaction between aldehydes and 1,6-enynes and the origin of its stereoselectivity have been systematically investigated using the DFT calculational method. Two possible reaction mechanisms have been investigated: one that starts with oxidative addition of the aldehyde (aldehyde-first) or one that starts with oxidative cyclization of the 1,6-enyne (enyne-first). The computational results show that the aldehyde-first mechanism is energetically more favorable than is the enyne-first mechanism. The aldehyde-first mechanism contains several steps: oxidative addition, acyl migratory insertion, alkene insertion, and reductive elimination. Based on the calculations, the alkene insertion is the stereoselectivity-determining step, generating the S-configured product preferentially. The key to inducing the observed stereoselectivity is the lesser distortion of the structure of the lower-energy transition state that leads to the S-configured product.

Unraveling the mechanism and substituent effects on the N-heterocyclic carbene-catalyzed transformation reaction of enals and imines

An intramolecular hydrogen bond-promoted activation of imines represents a new strategy in annulation reactions catalyzed by N-heterocyclic carbenes (NHCs). In this study, the mechanism and the origin of stereoselectivity in the NHC-catalyzed annulation of enals and imines are suggested and investigated theoretically. The computational results show that the reaction between a Breslow intermediate and an intramolecular hydrogen bond-activated imine is the rate- and stereoselectivity-determining step and results in the preferential generation of RS-configured products. The presence of intramolecular hydrogen bond is crucial for the reaction, because the formation of such bond significantly enhances the electrophilicity of the imine and thus facilitate the reaction. Non-covalent interaction (NCI) analysis shows that the CH•••π, CH•••O, π•••π, and lone pair (LP)•••π interactions contribute significantly to stabilizing the lower-energy transition state, thus inducing to the preferential formation of the RS-configured product.

Origin of Ligand Effects on Stereoinversion in Pd-Catalyzed Synthesis of Tetrasubstituted Olefins.

The mechanism and origin of ligand effects on stereoinversion of Pd-catalyzed synthesis of tetrasubstituted olefins were investigated using DFT calculations and the approach of energy decomposition analysis (EDA). The results reveal that the stereoselectivity-determining steps are different when employing different phosphine ligands. This is mainly due to the steric properties of ligands. With the bulkier Xantphos ligand, the syn/anti-to-Pd 1,2-migrations determine the stereoselectivity. While using the less hindered P(o-tol)3 ligand, the 1,3-migration is the stereoselectivity-determining step. The EDA results demonstrate that Pauli repulsion and polarization are the dominant factors for controlling the stereochemistry in 1,2- and 1,3-migrations, respectively. The origins of differences of Pauli repulsion and polarization between the two stereoselective transition states are further identified.

N-Heterocyclic Carbene-Catalyzed Asymmetric C-O Bond Construction Between Benzoic Acid and o-Phthalaldehyde: Mechanism and Origin of Stereoselectivity.

A computational study was contributed to explore the origin of stereoselectivity of NHC-mediated cyclization reaction between benzoic acid and o-phthalaldehyde for asymmetric construction of phthalidyl ester. The most energetically favorable pathway mainly includes the following steps: (1) nucleophilic attack on carbonyl carbon of o-phthalaldehyde by catalyst NHC, (2) formation of Breslow intermediate, (3) oxidation by DQ, (4) asymmetric formation of dual C-O bonds, and (5) dissociation of catalyst with the product. The C-O bond formation was testified as the stereoselectivity-determining step, the R-configurational pathway is more energetically favorable than the S-configurational one. The non-covalent interaction (NCI) and atom-in-molecule (AIM) analyses were performed to reveal that the O-H ⋅⋅⋅ O and C-H ⋅⋅⋅ O hydrogen-bond interactions are the key factors for controlling the stereoselectivity. The detailed mechanism and origin of stereoselectivity give useful insights for understanding organocatalytic reactions for asymmetric construction of C-O bond.

A computational study on NHC-Catalyzed [3+4] annulation between isatin-derived enal and aurone-derived azadiene: Insights into mechanism and stereoselectivity

Using density functional theory (DFT), a systematic computation has been conducted on the reaction between an enal and an azadiene in the presence of N-heterocyclic carbene (NHC) to explore the catalytic mechanisms and origins of stereoselectivity. Several possible pathways leading to benzofuroazepinone have been investigated. We found that the preferred pathway proceeds via six steps, i.e. (1) the nucleohilic addition wherein the NHC adds to the enal, (2) 1,2- proton transfer allows to form the Breslow intermediate, (3) the carbon−carbon bond formation, (4) 1,3- proton transfer, (5) intramolecular cyclization and (6) catalyst regeneration that eventually leads to the RR-configurational cycloadduct benzofuroazepinone. The DFT results agree well with the experimentally observed stereoselectivity. We also found that HOAc plays a vital role as proton shuttle in proton transfer steps. The 1,3-proton transfer was the stereoselectivity-determining step. Furthermore, we conducted global reactivity index (GRI), distortion/interaction and noncovalent interaction (NCI) analyses to identify the role of the NHC in the reaction as well as the origin of the experimentally observed stereochemistry.

Computational insight into the mechanism and origin of high regioselectivity in the ring-opening cyclization of spirocyclopropanes with stabilized sulfonium ylides by the DFT.

Chromanes with high bioactivity play an important role in nature, and cyclization reactions of cyclopropanes with sulfonium ylides to form chromane skeletons have attracted great attention of scientists. The mechanism as well as origins of regioselectivity and stereoselectivity for the ring-opening/cyclization reactions between cyclohexane-1,3-dione-2-spirocyclopropanes and stabilized sulfonium ylides in CH2Cl2 were investigated by using the density functional theory (DFT) M06-2X/6-311+G(d,p)//M06-2X/6-31G(d,p) method combined with the SMD model. The calculated results revealed that the reaction process involved two key steps: the ring-opening step and the cyclization step, with the former being the rate-determining and stereoselectivity-determining step. The regioselectivity of the ring-opening step of spirocyclopropane indicated that the tertiary carbon was more preferential than the secondary one when sulfonium ylide attacked spirocyclopropane. The theoretical results confirmed that the stereoselectivity of the reaction to form the trans-isomer product is more favorable than the cis-isomer, and the calculated trans/cis ratio is in accordance with the experiment. Moreover, the conceptual density functional theory reactivity indices suggest that the electronic effect controls the regioselectivity. What is more, the stereoselectivity analyzed by weak non-covalent interaction also shows the importance of electronic effect. Graphical Abstract.

Unveiling the Chemo- and Stereoselectivities of NHC-Catalyzed Reactions of an Aliphatic Ester with Aminochalcone.

The possible mechanisms and origin of selectivities in N-heterocyclic carbene (NHC)-catalyzed reactions of an aliphatic ester with aminochalcone were studied using density functional theory. Herein, a general mechanistic map involving various types of possible intermediates was discovered, and the corresponding chemoselective pathways were systematically investigated. Based on the computational results, the most energetically favorable reaction pathway mainly involved in the following processes: formation of a homoenolate intermediate via α/β-H elimination, formal Michael addition of a homoenolate intermediate to aminochalcone, intramolecular aldol-type reaction, and ring closure to form the lactam product. Furthermore, the formal Michael addition process was shown to be the stereoselectivity-determining step, generating the RR-configured product preferentially. The chemoselectivity was successfully predicted by comparing the ω + N index of reacting ability for a nucleophile (N) and electrophile (E). This work would provide a general guideline for predicting chemoselectivity in NHC-catalyzed reactions.

Mechanistic investigation of N-heterocyclic carbene and Na2CO3 cooperatively catalyzed C(sp3)-F bond activation reaction of fluoroenal

The mechanism of N-heterocyclic carbene (NHC)-catalyzed C(sp3)-F bond activation/hetero-Diels-Alder (HDA) cascade reaction between γ-fluoroenal and ketone was theoretically studied. The computed results show that the energy barrier involved in cleavage of the CF bond was greatly lowered in presence of Na2CO3. Moreover, the HDA process between the dienolate and ketone was both the rate- and stereoselectivity-determining step, according to the calculations. Further investigation of the role of the catalyst indicates that the NHC lowers the energy barrier of the cycloaddition step primarily by HOMO activation of the γ-fluoroenal.

A DFT study on the reaction mechanism of enantioselective reduction of ketones with borane catalyzed by a B-methoxy-oxazaborolidine catalyst derived from (–)-β-pinene

Theoretical studies on enantioselective reduction of ketone with borane catalyzed by a B-methoxy-oxazaborolidine catalyst derived from pinene have been performed by means of the density functional theory (DFT) method. All the structures were optimized completely using wB97XD/6-31G(d,p) level and the mechanism of the enantioselective reduction is studied. The formation of the M4s complexes via transition state TS3s was the rate-determining step and the chirality-limiting step for this enantioselective reduction; the dominant reaction is the attack of proton from the Si surface of M3a, which provides the corresponding secondary alcohols in 98% ee. NCI analysis of the four computed transition states associated with stereoselectivity-determining step discloses that TS3a(S) is the stable conformation with respect to TS3a(R), TS3b(S), and TS3b(R). The produced reaction pathway takes place through: M1 → M2a → M3a → M4a(S) → M5a(S) → M6a(S) → M7a(S). The chirality of the reduced product is of S type, which is in agreement with the experiment. Graphical abstract.

Mechanism and stereoselectivity of benzylic C-H hydroxylation by Ru-porphyrin: a computational study.

The mechanism and origin of the stereoselectivity of asymmetric benzylic C-H hydroxylation by Ru-porphyrin were elucidated with density functional theory calculations. The reaction proceeds via a hydrogen-atom abstraction/oxygen-rebound pathway, wherein a high-valent ruthenium-oxo species abstracts a hydrogen atom from ethylbenzene to generate a radical pair intermediate, followed by the oxygen-rebound process to form 1-phenylethanol. The hydrogen-atom abstraction step is the rate- and stereoselectivity-determining step. Based on the mechanistic model, the computed stereoselectivity is in agreement with the experimental observations. Analysis of the distortion/interaction model suggests that stereoselectivity is determined by both the distortion energy of the ethylbenzene and the interaction energy between the ethylbenzene and the chiral Ru-porphyrin. The steric repulsion between the phenyl group of ethylbenzene and the bulky substituent of Ru-porphyrin is the leading cause of chiral induction.

Insight into Isothiourea-Catalyzed Enantioselective Addition of Saturated Esters to Iminium Ions.

The possible mechanisms and origin of the selectivities of isothiourea-catalyzed addition of saturated esters to iminium ions have been investigated by density functional theory. The favorable reaction pathway includes three stages: formation of an ammonium enolate intermediate, enantioselective addition of the ammonium enolate intermediate to the iminium ion, and dissociation of the catalyst to form the product. The enantioselective addition process is the stereoselectivity-determining step, while the chemoselectivity-determining step is included in the formation of the final product. The calculated energy barriers show that the chemoselectivity is thermodynamically controlled, and it depends on the polarities of the products and the nucleophilicities of the N atoms of the enamine reactant moieties of the intermediates. The origin of the stereoselectivity was investigated by non-covalent interaction analysis of the key transition states. Hydrogen bonding interactions were identified as the determining factor for controlling the stereoselectivity. The obtained insight will be valuable for rational design of novel Lewis base organocatalyst-promoted enantioselective addition reactions with special chemoselectivities.

Computational Exploration of Chiral Iron Porphyrin-Catalyzed Asymmetric Hydroxylation of Ethylbenzene Where Stereoselectivity Arises from π-π Stacking Interaction.

The mechanism and origins of stereoselectivity of chiral iron porphyrin-catalyzed asymmetric hydroxylation of ethylbenzene were explored with density functional theory. The hydrogen atom abstraction is the rate- and stereoselectivity-determining step. In good agreement with experimental results, the formation of the (R)-1-phenylethanol product is found to be the most favorable pathway. The transition state of hydrogen atom abstraction which leads to the (S)-1-phenylethanol product is unfavorable by 1.7 kcal/mol compared to the corresponding transition state which leads to the (R)-1-phenylethanol product. Enantioselectivity arises from an attractive π-π stacking interaction between the phenyl group of ethylbenzene substrate and the naphthyl group of the porphyrin ligand.

Insights into N-Heterocyclic Carbene (NHC)-Catalyzed Asymmetric Addition of 2H-Azirine with Aldehyde.

The possible mechanisms and origin of the enantioselectivity of the reaction between 2H-azirine and an aldehyde catalyzed by an N-heterocyclic carbene (NHC) were theoretically studied and predicted at the M06-2X/6-31G(d,p)/IEF-PCMMTBE //M06-2X-GD3/6-311++G(2df, 2pd)/IEF-PCMMTBE level. The most favorable reaction pathway consists of four steps, i.e., complexation of the NHC and the aldehyde, stepwise [1,2]-proton transfer, C-C bond formation coupled with another proton transfer, and recycling of the NHC. The computational results indicate that the stereoselectivity-determining step is also the rate-determining step, which is the third step (i.e., intermolecular addition). The calculated 99 % ee is very close to the experimentally observed value of 96 % ee, demonstrating that the calculations are reliable. Two important roles of the NHC were identified by global reaction index (GRI) analysis and natural population analysis (NPA), that is, realizing the umpolung reactivity of the aldehyde and facilitating the deprotonation of aldehyde. Moreover, the efficiency of different NHC catalysts can be mainly predicted by computing the nucleophilic index of the corresponding Breslow intermediates. Furthermore, distortion/interaction and noncovalent interaction (NCI) analyses revealed that the π⋅⋅⋅π interactions between the NHC and substrates were the key factor in the reaction enantioselectivity.