Insights into the N‐Heterocyclic Carbene (NHC)‐Catalyzed Intramolecular Cyclization of Aldimines: General Mechanism and Role of Catalyst

One of the most challenging questions in the Lewis base organocatalyst field is how to predict the most electrophilic carbon for the complexation of N‐heterocyclic carbene (NHC) and reactant. This study provides a valuable case for this issue. Multiple mechanisms (A, B, C, D, and E) for the intramolecular cyclization of aldimine catalyzed by NHC were investigated by using density functional theory (DFT). The computed results reveal that the NHC energetically prefers attacking the iminyl carbon (AIC mode, which is associated with mechanisms A and C) rather than attacking the olefin carbon (AOC mode, which is associated with mechanisms B and D) or attacking the carbonyl carbon (ACC mode, which is associated with mechanism E) of aldimine. The calculated results based on the different reaction models indicate that mechanism A (AIC mode), which is associated with the formation of the aza‐Breslow intermediate, is the most favorable pathway. For mechanism A, there are five steps: (1) nucleophilic addition of NHC to the iminyl carbon of aldimine; (2) [1,2]‐proton transfer to form an aza‐Breslow intermediate; (3) intramolecular cyclization; (4) the other [1,2]‐proton transfer; and (5) regeneration of NHC. The analyses of reactivity indexes have been applied to explain the chemoselectivity, and the general principles regarding the possible mechanisms would be useful for the rational design of NHC‐catalyzed chemoselective reactions.     

Mechanism and origin of diastereoselectivity of N-heterocyclic carbene-catalyzed cross-benzoin reaction: A DFT study

Herein,the origin of the diastereoselectivity of N-heterocyclic carbene(NHC)-catalyzed cross-benzoin reactions between an a-amino aldehyde and furfural was studied by density functional theory.The computational results showed that the reaction proceeded through four steps:nucleophilic addition of NHC onto furfural,formation of a Breslow intermediate,cross-coupling reaction between Breslow intermediate and a-amino alde hyde,and dissociation of the catalyst.The cross-coupling was identified as the diaste reoselectivity-determining step,with the R-configured product generated preferentially.Noncovalent inte raction(NCI)analysis showed that the C-H…O and C-H…F inte ractions were responsible for determining the diastereoselectivity.     

Understanding the mechanism of the N-heterocyclic carbene-catalyzed ring-expansion of 4-formyl-β-lactams to succinimide derivatives

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed ring-expansion of 4-formyl-β-lactams to succinimides has been studied using DFT methods at the B3LYP/6-31G^∗∗ level. The first step is the nucleophilic attack of NHC to the aldehyde to yield the zwitterionic intermediate, which by a proton-transfer process affords the Breslow intermediate. The lactam N-C breaking bond in this intermediate yields an enol-amidate, which by a keto-enol type equilibrium becomes the ketone form. The subsequent ring-closure achieved by the nucleophilic attack of the amidate to carbonyl carbon allows the formation of the five-membered ring. Finally, elimination of NHC affords the succinimide. Analysis of the nucleophilicity index correctly explains the behaviors of the NHCs and the Breslow intermediates in the umpolung reactivity of aldehydes.     

Understanding the cooperative NHC/LA catalysis for stereoselective annulation reactions with homoenolates. A DFT study

The role of Ti(Oi-Pr)(4) Lewis acid (LA) in the cooperative N-heterocyclic carbene (NHC)/LA catalyzed addition of enals to enones to yield cis-cyclopentenes has been investigated using DFT methods at the B3LYP/6-31G** computational level. Ti(IV) effectively catalyzes the reaction by formation of a complex with cinnamaldehyde 1, which favors the nucleophilic attack of NHC 5 on 1, and the subsequent proton abstraction to yield the extended Ti(IV)-Breslow intermediate 21. The nature of the metal involved in the LA catalyst plays a relevant role due to the more basic character of NHCs than aldehydes. Thus, strong LAs, such as Zn(OTf)(2), prevent the catalytic behavior of NHCs to form a very stable complex. The subsequent formation of a complex between chalcone 2 and the extended Ti(IV)-Breslow intermediate 21 favors the cis stereoselective C-C bond-formation. Analysis of the structures of Ti(IV)-complex precursors for the cis and trans C-C bond-formation steps allows for an explanation of the unexpected cis stereoselectivity.     

A density functional theory study on mechanisms of [4 + 2] annulation of enal with α-methylene cycloalkanone catalyzed by N-heterocyclic carbene

Density functional theory was used to study the reaction mechanisms of the N-heterocyclic carbene (NHC)-catalyzed [4 + 2] annulation reaction between enal and α-methylene cycloalkanone for the formation of tricyclic benzopyran-2-one. The simulations suggest that the energy-favorable catalytic cycle includes five steps: (a) the nucleophilic addition of enal by NHC catalyst; (b) [1, 2]-proton transfer for the formation of Breslow intermediate; (c) [1, 4]-proton transfer for the formation of enolate intermediate; (d) the [4 + 2] cycloaddition process, product formation; and (e) catalyst regeneration. The proton transfer process was particularly designed in two independent ways, the direct proton transfer and the Brønsted acid DBU∙H⁺-mediated proton transfer. Our study reveals that [1, 2]-proton transfer process is the rate-determining step with the accessible energy barrier, which agrees with the experimental observation. Further analysis of the global reaction index confirmed that NHC was primary used as a Lewis base during the reaction processes. The frontier molecular orbital (FMO) analysis indicates that the introduction of the NHC catalyst facilitates the reaction to occur due to the narrower energy gap of FMO.     

N‐Heterocyclic‐Carbene‐Catalyzed Umpolung of Imines

N‐Heterocyclic carbene (NHC) catalysis has been widely used for the umpolung of aldehydes, and recently for the umpolung of Michael acceptors. Described herein is the umpolung of aldimines catalyzed by NHCs, and the reaction likely proceeds via aza‐Breslow intermediates. The NHC‐catalyzed intramolecular cyclization of aldimines bearing a Michael acceptor resulted in the formation of biologically important 2‐(hetero)aryl indole 3‐acetic‐acid derivatives in moderate to good yields. The carbene generated from the bicyclic triazolium salt was found to be efficient for this transformation.     

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‐PCM_MTBE//M06‐2X‐GD3/6‐311++G(2df, 2pd)/IEF‐PCM_MTBE 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.     

Tale of the Breslow intermediate,a central player in N-heterocyclic carbene organocatalysis: then and now

N-Heterocyclic carbenes (NHCs) belong to the popular family of organocatalysts used in a wide range of reactions, including that for the synthesis of complex natural products and biologically active compounds. In their organocatalytic manifestation, NHCs are known to impart umpolung reactivity to aldehydes and ketones, which are then exploited in the generation of homoenolate, acyl anion, and enolate equivalents suitable for a plethora of reactions such as annulation, benzoin, Stetter, Claisen rearrangement, cycloaddition, and C–C and C–H bond functionalization reactions and so on. A common thread that runs through these NHC catalyzed reactions is the proposed involvement of an enaminol, also known as the Breslow intermediate, formed by the nucleophilic addition of an NHC to a carbonyl group of a suitable electrophile. In the emerging years of NHC catalysis, enaminol remained elusive and was largely considered a putative intermediate owing to the difficulties encountered in its isolation and characterization. However, in the last decade, synergistic efforts utilizing an array of computational and experimental techniques have helped in gaining important insights into the formation and characterization of Breslow intermediates. Computational studies have suggested that a direct 1,2-proton transfer within the initial zwitterionic intermediate, generated by the action of an NHC on the carbonyl carbon, is energetically prohibitive and hence the participation of other species capable of promoting an assisted proton transfer is more likely. The proton transfer assisted by additives (such as acids, bases, other species, or even a solvent) was found to ease the kinetics of formation of Breslow intermediates. These important details on the formation, in situ detection, isolation, and characterization of the Breslow intermediate are scattered over a series of reports spanning well over a decade, and we intend to consolidate them in this review and provide a critical assessment of these developments. Given the central role of the Breslow intermediate in organocatalytic reactions, this treatise is expected to serve as a valuable source of knowledge on the same.

Molecular insights on the formation, detection, and even isolation of the Breslow intermediate, which is the most important species in N-heterocyclic carbene (NHC) catalysis, as obtained from experimental and computational studies, are presented.     

Insights into N‐Heterocyclic Carbene‐Catalyzed [4+2] Annulation Reaction of Enals with Nitroalkenes: Mechanisms,Origin of Chemo‐ and Stereoselectivity,and Role of Catalyst

In this paper, density functional theory (DFT) calculations have been employed to investigate the detailed mechanisms, origin of chemo‐ and stereoselectivity, and role of catalyst for the reaction of enals with nitroalkenes catalyzed by N‐heterocyclic carbenes (NHCs). The calculated results disclose that the reaction contains seven steps, that is, the nucleophilic attack on the α, β‐unsaturated aldehyde by NHC, the [1, 2]‐proton transfer for the formation of Breslow intermediate, the β‐protonation for affording enolate intermediate, the nucleophilic addition on the Re/Si face of enolate by the nitroalkenes, the [1, 5] proton transfer, the ring‐closure process, and the regeneration of NHC. The addition on the Re/Si face of enolate is identified to be the stereocontrolling step, in which the chiral centers including α‐carbon of enals and β‐carbon of nitroalkenes are formed. Moreover, the reaction pathway leading to the RR‐configured product has the lowest Gibbs free energy barrier, which is in agreement with the experimental observation. Furthermore, the analyses of electrophilic and nucleophilic Parr functions and global reactivity indices (GRIs) have been performed to explore the origin of chemoselectivity and the role of catalyst. This theoretical work would provide valuable insights for the rational design of more effective organocatalyst for this kind of reactions with high stereoselectivities.     

Elucidation of the reaction mechanisms and diastereoselectivities of phosphine-catalyzed [4 + 2] annulations between allenoates and ketones or aldimines

The phosphine-catalyzed [4 + 2] annulations between allenoates and electron-poor trifluoromethyl ketones or N-tosylbenzaldimine dipolarophiles have been investigated in continuum solvation using density functional theory (DFT) calculations. The detailed reaction mechanisms as well as the high cis-diastereoselectivities of the reactions have been firstly clarified. Our calculated results reveal that the whole catalytic process is presumably initiated with the nucleophilic attack of phosphine catalyst at the allenoate to produce the zwitterionic intermediate , which subsequently undergoes γ-addition to the electron-poor C[double bond, length as m-dash]O (or C[double bond, length as m-dash]N) dipolarophile to form another intermediate . The following [1,3] hydrogen shift of is demonstrated to proceed via two consecutive proton transfer steps without the assistance of protic solvent: the anionic O6 (or N6) of first acts as a base catalyst to abstract a proton from C1 to produce the intermediate , and then the OH (or NH) group can donate the acidic proton to C3 to complete the [1,3] hydrogen shift and generate the intermediate . Finally, the intramolecular Michael-type addition followed by the elimination of catalyst furnishes the final product. High cis-diastereoselectivities are also predicted for both the two reactions, which is in good agreement with the experimental observations. For the reaction of allenoates with trifluoromethyl ketones, the first proton transfer is found to be the diastereoselectivity-determining step. The cumulative effects of the steric repulsion, electrostatic interaction as well as other weak interactions appear to contribute to the relative energies of transition states leading to the diastereomeric products. On the contrary, in the case of N-tosylbenzaldimines, the Michael-type addition is found to be the diastereoselectivity-determining step. Similarly, steric repulsion, as well as electrostatic interaction is also identified to be the dominant factors in controlling the high cis-diastereoselectivity of this reaction.     

Ab initio and density functional theory evidence on the rate-limiting step in the Morita-Baylis-Hillman reaction

The first ab initio and DFT studies on the mechanism of the MBH reaction show that the rate-limiting step involves an intramolecular proton transfer in the zwitterionic intermediate generated by the addition of enolate to electrophile. The activation barrier for the C-C bond-formation is found to be 20.2 kcal/mol lower than the proton-transfer step for the MBH reaction between methyl vinyl ketone and benzaldehyde catalyzed by DABCO.     

Mechanistic insights on N-heterocyclic carbene-catalyzed annulations: the role of base-assisted proton transfers

The density functional theory investigation on the mechanism of NHC-catalyzed cycloannulation reaction of the homoenolate derived from butenal with pentenone is studied. The M06-2X/6-31+G** and B3LYP/6-31+G** levels of theory, including the effect of continuum solvation in dichloromethane and tetrahydrofuran, are employed. Several mechanistic scenarios are examined for each elementary step by identifying the key intermediates and the corresponding transition states interconnecting them on the respective potential energy surfaces. Both assisted and unassisted pathways for important proton transfer steps are considered, respectively, with and without the explicit inclusion of base (DBU) in the corresponding transition states. The barrier for the crucial proton transfer steps involved in the formation of the Breslow intermediate as well as in the subsequent steps is found to be significantly lowered by explicit inclusion of DBU. The energetic comparison between two key pathways, depicted as path A and path B, respectively, leading to cyclopentene and cyclopentanone derivatives, is performed. The major mechanistic bifurcation has been identified as emanating from the site of enolization of the initial zwitterionic intermediate resulting from the addition of a homoenolate equivalent to enone. If the enolization occurs nearer to the NHC moiety, the reaction is likely to proceed through path A, leading to cyclopentene. The enolization away from NHC leads to cyclopentanone product through path B. The computed results are generally in good agreement with the reported experimental results.     

Prediction on the Origin of Selectivities in Base‐controlled Switchable NHC‐catalyzed Transformations

The base‐controlled mechanisms for N‐heterocyclic carbene (NHC)‐catalyzed divergent [3+3] and [3+2] annulation reactions were examined by using the DFT method. The reaction initiates with the complexation of NHC and enal to give the Breslow intermediate, which diverges afterward. Then, the azomethine imine can either react with the Breslow intermediate to give the six‐membered ring product or the β‐carbon protonation occurs for forming the enolate intermediate controlled by different bases. The formed enolate intermediate reacts with azomethine imine to afford the five‐membered ring product. The calculated results show that only the base K₂CO₃ can facilitate the structural transformation between homoenolate and enolate to switch the chemoselectivity; therefore, the [3+3] annulation happens preferentially in the presence of base DBU while the other situation occurs with K₂CO₃ as base. The NCI analysis results reveal that the stereoselectivity is predominately determined by the π???π, C?H???O, and C?H???N interactions. The obtained mechanistic insights should provide valuable clues for the rational design of these kinds of divergent reactions.     

NHC-catalysed benzoin condensation – is it all down to the Breslow intermediate?

The Breslow catalytic cycle describing the benzoin condensation promoted by N-heterocyclic carbenes (NHC) as proposed in the late 1950s has since then been tried by generations of physical organic chemists. Emphasis has been laid on proofing the existence of an enaminol like structure (Breslow intermediate) that explains the observed umpolung of an otherwise electrophilic aldehyde. The present study is not focusing on spectroscopic elucidation of a thiazolydene based Breslow intermediate but rather tries to clarify if this key-intermediate is indeed directly linked with the product side of the overall reaction. The here presented EPR-spectroscopic and computational data provide a fundamentally different view on how the benzoin condensation may proceed: a radical pair could be identified as a second key-intermediate that is derived from the Breslow-intermediate via an SET process. These results highlight the close relationship to the Cannizarro reaction and oxidative transformations of aldehydes under NHC catalysis.     

Palladium-catalyzed synthesis of carbazoles from N-(2-halophenyl)-2,6-diisopropylanilines via C-C cleavage

The synthesis of 1-isopropyl-substituted carbazoles by the palladium-catalyzed dealkylative cyclization of N-(2-halophenyl)-2,6-diisopropylanilines is described. The reaction involves intramolecular C-C bond formation, coupled with the cleavage of a C-X bond and a C-C bond, and is proposed to proceed through the formation of a dearomatized intermediate.     

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.     

Cleavage of a P=P Double Bond Mediated by N-Heterocyclic Carbenes

The reaction of the bulky diphosphenes (Rind)P=P(Rind) ( 1 ; Rind=1,1,3,3,5,5,7,7-octa-R-substituted s-hydrindacen-4-yl) with two molecules of N-heterocyclic carbene (NHC; 1,3,4,5-tetramethylimidazol-2-ylidene) resulted in the quantitative formation of the NHC-bound phosphinidenes NHC→P(Rind) ( 2 ), along with the cleavage of the P=P double bond. The reaction times are dependent on the steric size of the Rind groups (11 days for 2 a (R=Et) and 2 h for 2 b (R=Et, Me) at room temperature). The mechanism for the double bond-breaking is proposed to proceed via the formation of the NHC-coordinated, highly polarized diphospehenes 3 as an intermediate. Approach of a second NHC to 3 induces P−P bond cleavage and P−C bond formation, which proceeds through a transition state with a large negative Gibbs energy change to afford the two molecules of 2 , thus being the rate-determining step of the overall reaction with the activation barriers of 80.4 for 2 a and 29.1 kJ mol⁻¹ for 2 b .     

Rate and Equilibrium Constants for the Addition of N‐Heterocyclic Carbenes into Benzaldehydes: A Remarkable 2‐Substituent Effect

Rate and equilibrium constants for the reaction between N‐aryl triazolium N‐heterocyclic carbene (NHC) precatalysts and substituted benzaldehyde derivatives to form 3‐(hydroxybenzyl)azolium adducts under both catalytic and stoichiometric conditions have been measured. Kinetic analysis and reaction profile fitting of both the forward and reverse reactions, plus onwards reaction to the Breslow intermediate, demonstrate the remarkable effect of the benzaldehyde 2‐substituent in these reactions and provide insight into the chemoselectivity of cross‐benzoin reactions.     

[(NHC)CrCl(μ-Cl)(THF)]_2 and(NHC)_2CrCl_2(NHC=1,3-Diisopropyl-4,5-dimethylimidazole-2-ylidene):Syntheses,Structures,and Polymerization Activities

The preparation of divalent chromium N-heterocyclic carbene(NHC,1,3-diisopropyl4,5-dimethylimidazole-2-ylidene) compounds is reported.The reaction of 1:1 molar ratio of NHC with CrCl2 led to an isolation of [(NHC)CrCl(μ-Cl)(THF)]2(1),while that of 2:1 ratio resulted in the formation of(NHC)2CrCl2(2).1 can be considered as an intermediate in the formation of 2 and further converted into 2 by the addition of another equiv.of NHC.The reaction of 2 with CpNa afforded an ion pair compound [(NHC)2CrCp]+[Cp]-(3),indicating a strong coordination ability of NHC supplanting one of the ionic Cr-Cp bonding.In combination of methylalumoxane(MAO) as cocatalyst 1 and 2 both are active for catalyzing ethylene polymerization.     

(NHC)AuI]-catalyzed formation of conjugated enones and enals: an experimental and computational study

The [(NHC)AuI]-catalyzed (NHC=N-heterocyclic carbene) formation of alpha,beta-unsaturated carbonyl compounds (enones and enals) from propargylic acetates is described. The reactions occur at 60 degrees C in 8 h in the presence of an equimolar mixture of [(NHC)AuCl] and AgSbF6 and produce conjugated enones and enals in high yields. Optimization studies revealed that the reaction is sensitive to the solvent, the NHC, and, to a lesser extent, to the silver salt employed, leading to the use of [(ItBu)AuCl]/AgSbF6 in THF as an efficient catalytic system. This transformation proved to have a broad scope, enabling the stereoselective formation of (E)-enones and -enals with great structural diversity. The effect of substitution at the propargylic and acetylenic positions has been investigated, as well as the effect of aryl substitution on the formation of cinnamyl ketones. The presence or absence of water in the reaction mixture was found to be crucial. From the same phenylpropargyl acetates, anhydrous conditions led to the formation of indene compounds via a tandem [3,3] sigmatropic rearrangement/intramolecular hydroarylation process, whereas simply adding water to the reaction mixture produced enone derivatives cleanly. Several mechanistic hypotheses, including the hydrolysis of an allenol ester intermediate and SN2' addition of water, were examined to gain an insight into this transformation. Mechanistic investigations and computational studies support [(NHC)AuOH], produced in situ from [(NHC)AuSbF6] and H2O, instead of cationic [(NHC)AuSbF6] as the catalytically active species. Based on DFT calculations performed at the B3LYP level of theory, a full catalytic cycle featuring an unprecedented transfer of the OH moiety bound to the gold center to the C[triple chemical bond]C bond leading to the formation of a gold-allenolate is proposed.