Insights into the Competing Mechanisms and Origin of Enantioselectivity for N-Heterocyclic Carbene-Catalyzed Reaction of Aldehyde with Enamide

Hydroacylation reactions and aza-benzoin reactions have attracted considerable attention from experimental chemists. Recently, Wang et al. reported an interesting reaction of N-heterocyclic carbene (NHC)-catalyzed addition of aldehyde to enamide, in which both hydroacylation and aza-benzoin reactions may be involved. Thus, understanding the competing relationship between them is of great interest. Now, density functional theory (DFT) investigation was performed to elucidate this issue. Our results reveal that enamide can tautomerize to its imine isomer with the assistance of HCO3−. The addition of NHC to aldehydes formed Breslow intermediate, which can go through cross-coupling with enamide via hydroacylation reaction or its imine isomer via aza-benzoin reaction. The aza-benzoin reaction requires relatively lower free energy barrier than the hydroacylation reaction. The more polar characteristic of C=N group in the imine isomers, and the more advantageous stereoelectronic effect in the carbon-carbon bond forming transition states in aza-benzoin pathway were identified to determine that the imine isomer can react with the Breslow intermediate more easily. Furthermore, the origin of enantioselectivities for the reaction was explored and reasonably explained by structural analyses on key transition states. The work should provide valuable insights for rational design of switchable NHC-catalyzed hydroacylation and aza-benzoin reactions with high stereoselectivity.

Scientific RepoRts | 6:38200 | DOI: 10.1038/srep38200 (3) The reaction is highly enantioselective, and it is meaningful to explore the origin of the stereoselectivity and identify the factors that control the stereoselectivity. Due to the difficulty on the structural detection of the intermediates and transition states involved in the rate-and stereoselectivity-determining steps in the experiment, it is highly desirable to perform a theoretical study to obtain the general principle for this kind of organocatalytic reactions.

Results
Our calculated results confirmed that NHC indeed initiate the reaction by nucleophilic attack to the aldehyde substrate yielding the well-known Breslow intermediate, which can then go through a cross-coupling with the other substrate via two competing pathways depicted in Fig. 1 to form the same final products. In the following sections, we will discuss the detailed reaction processes, including the formation of Breslow intermediate, the tautomerization between enamide and the corresponding imine isomer, hydroacylation reactions between Breslow intermediate and enamide, aza-benzoin reaction between Breslow intermediate and imine, the competition of hydroacylation reaction and aza-benzoin reaction, and origin of the enantioselectivity.  Fig. 2, the reaction is initiated by the nucleophilic addition of NHC to 4-chlorobenzaldehyde R1. Noteworthy, R1 has a prechiral center, i.e. C2 atom. Attack from NHC on the Si or Re face of R1 can respectively lead to two stereoselective intermediate M1R or M1S, in which the R/S represents the chirality of C2 atom. The two kinds of stereochemically distinct attack modes have different free energy barriers. According to our calculations, the Si face attack requires the free energy barrier of 9.3 kcal/mol, which is 2.3 kcal/mol lower than that of the Re face attack (Δ G = 11.5 kcal/mol). The produced intermediates M1R and M1S are zwitterions. In the following, zwitterionic intermediates M1R and M1S would go through 1,2-proton transfer to afford the Breslow intermediates M2/M2′, in which C2 has no chirality. Direct 1, 2-proton transfer is impossible because of the strong strain in the three-membered ring transition state. Protic solvents in the reaction system have been demonstrated many times to be able to mediate the proton transfer process in the formation of Breslow intermediates as well as in many other proton transfer processes 11,20,25 . Herein, we proposed that the small amount of HCO 3 − in the reaction system can mediate the proton transfer process. The corresponding transition state TS2R was located 0.4 kcal/mol lower in free energy than TS2S. The newly formed Breslow intermediate M2 produced from TS2R is 7.0 kcal/mol more stable than M2′ generated via TS2S. Structural analyses ( Supplementary Fig. S1) reveal that the advantageous ππ interaction, C-H••• π interaction, C-H••• Cl and C-H••• O hydrogen bond interactions determined that M2 is more stable than M2′. From the free energy profile shown in Fig. 2, it can be concluded that the reaction pathway affording Breslow intermediate M2 is more likely to occur. Therefore, in the following reaction steps, we only considered the reaction processes associated with M2.

Formation of Breslow intermediate. As shown in
The tautomerization between enamide and imine. The reactant enamide R2 can tautomerize to its imine isomer. In the imine configuration, we selected C3= N3 bond as a reference standard. As shown in Fig. 3, if the acyl group and phenyl group are in trans configuration, we denote it as t-R2-imine, while in cis configuration, we denote it as c-R2-imine. Correspondingly, t-R2-imine can tautomerize to t-R2, and c-R2-imine can tautomerize to c-R2. In total, there are four distinctive conformations for R2. In the following, we considered the tautomerization between t-R2 and t-R2-imine, and between c-R2 and c-R2-imine.
Firstly, we considered the bimolecular reaction mechanisms for the tautomerization between t-R2 and t-R2-imine. The bimolecular reaction consists of two reaction processes with the highest activation free energy barrier of 46.4 kcal/mol ( Supplementary Fig. S2), which is so high that it is unlikely for the reaction to happen. In addition, we also considered HCO 3 − -mediated tautomerization mechanism between them. According to the calculated results, HCO 3 − would first abstract the hydrogen from -NH group via transition state t-TS1-HCO 3 − . The free energy barrier for this step was calculated to be 2.

. Followed by the formation of t-M1-HCO 3
− is the hydrogen transfer from H 2 CO 3 to the terminal alkene carbon C4 via transition state t-TS2-HCO 3 − resulting into t-R2-imine. This reaction step requires a free energy barrier of 20.6 kcal/mol, which is significantly lower than that of the bimolecular fashion.
For the cis configuration, we also considered the bimolecular and HCO 3 − -mediated mechanisms. The bimolecular fashion is also a two-step process with activation free energy barrier as high as 48.6 kcal/mol ( Supplementary Fig. S3), while the HCO 3 − -mediated mechanism is a concerted process with activation free energy barrier of only 2.5 kcal/mol. The produced isomer c-R2-imine is 2.0 kcal/mol unstable than c-R2, and the free energy barrier for the reverse reaction is only 0.5 kcal/mol, indicating that this reaction process is highly reversible. Given this reason, we did not take c-R2-imine into consideration in the following reaction processes.
As described on the above, the C= C group in enamides would undergo hydroacylation reactions with the Breslow intermediate, while the C= N group in imines would undergo cross-aza-benzoin reactions with the Breslow intermediate. Based on this, t-R2 and c-R2 would undergo hydroacylation reactions, while t-R2-imine would go through cross-aza-benzoin reactions. In the following, we will discuss these competing reaction pathways in detail.

Hydroacylation reactions between Breslow intermediate and enamide.
Firstly, we take t-R2 into consideration for the hydroacylation reaction with M2. The negatively charged carbon atom C2 in Breslow intermediate M2 would nucleophilic attack on the prechiral center C3 atom of t-R2. Attack to the Re-face of t-R2 via transition state t-TS3S can lead to t-M3S, in which the "S" represents S configuration of C3 atom, while attack to the Si-face of t-R2 via transition state t-TS3R can lead to t-M3R, in which C3 is in R configuration. As shown in Fig. 4, the free energy barrier for t-TS3S with respect to M2 + t-R2 amounts to 23.9 kcal/mol, which is 1.3 kcal/ mol lower than that of t-TS3R (Δ G = 25.2 kcal/mol). Noteworthy, the nucleophilic attack is accompanied by the proton transfer from O2 to C4 atom. In the newly formed intermediates t-M3S and t-M3R, C2-C3 bond is formed and H2 atom is transferred to C4 atom. The bond distances for C2-C3, O2-H2, and H2-C4 in transition states t-TS3S/t-TS3R are 2.73/2.75, 1.36/1.35 and 1.25/1.25 Å, respectively, indicating that proton migration occurs prior to carbon-carbon bond formation. This observation is very different from the previous theoretical study on Stetter reactions 7 . Subsequently, the elimination of NHC from t-M3S and t-M3R via transition states t-TS4S and t-TS4R can produce the final products P1S and P1R, respectively. According to the calculated results, the free energy barriers for this single step are 4.2 and 4.3 kcal/mol for the S and R configurations, respectively. According to the free energy profile shown in Fig. 4, the reaction process leading to product P1S is more energetically favorable than the process leading to P1R, which is in agreement with the experimentally observed results that P1S is the major product.
In addition to t-R2, we also considered c-R2 as a reactant of hydroacylation reaction. There are also two possible stereoselective nucleophilic attack modes, which is corresponding to the attack from the Breslow intermediate M2 on the Re/Si-face of c-R2. The corresponding free energies for the carbon-carbon bond forming transition states c-TS3S and c-TS3R with respect to M2 + t-R2 are 24.8 and 27.6 kcal/mol ( Supplementary Fig. S4), respectively, which are higher than those of t-TS3S (Δ G = 23.9 kcal/mol) and t-TS3R (Δ G = 25.2 kcal/mol). Therefore, it is easier for t-R2 to react with the Breslow intermediate M2 in relative to c-R2. Likewise, proton transfer and carbon-carbon bond formation also take place in the concerted manner although proton transfer occurs first. Finally, the elimination of NHC can produce the final products P1S and P1R, respectively. Interestingly, the reaction process for S configuration also requires lower activation free energies than the R configuration.
Aza-benzoin reaction between Breslow intermediate and imine. As described above, t-R2 can tautomerize to its imine isomer t-R2-imine, which then reacts with Breslow intermediate via aza-benzoin condensation. During this reaction process, C2 atom in Breslow intermediate M2 would nucleophilic attack on C3 atom of t-R2-imine. Attack to the Re-face of t-R2-imine via transition state t-TS3S-b can lead to t-M3S-b, in which C3 is in S configuration. Attack to the Si-face of t-R2 via transition state t-TS3R can lead to t-M3R, in which C3 is in R configuration. In contrast to the hydroacylation reaction for which the terminal alkene carbon abstracts the proton from the hydroxyl group, it is the nitrogen atom in the C= N group that abstracts the proton in the aza-benzoin reaction. As shown in Fig. 5, the free energy barriers for t-TS3S-b and t-TS3R-  to M2 + t-R2 amount to 14.1 and 15.3 kcal/mol, which are significantly lower than those of the hydroacylation reactions. Noteworthy, the nucleophilic attack is accompanied by proton transfer from O2 to N3 atom instead

In the formed intermediates t-M3S-b and t-M3R-b, C2-C3 bond is formed and H2 atom is transferred to N3. Subsequently, the elimination of NHC from t-M3S-b and t-M3R-b via transition states t-TS4S-b and t-TS4R-b
can produce the final products P1S and P1R, respectively. According to the free energy profile, t-TS3S-b is 1.2 kcal/mol lower than that of t-TS3R-b, indicating that the reaction process leading to product P1S is also more energetically favorable than the process leading to P1R.
Pathway Comparison. By now, the reaction pathways for the three possible reactants t-R2, c-R2, and t-R2-imine leading to two enantioselective products have been discussed in detail. An overlay of each reaction pathway leading to the preferred product P1S is depicted in Fig. 6. Nucleophilic attack of NHC to the aryl aldehyde R1 followed by a proton transfer forms Breslow intermediate M2, which can then go through cross-coupling with t-R2 and c-R2 via hydroacylation reactions. As described on the above, the trans configuration of enamide, i.e.

t-R2, can cross transition state t-TS2-HCO 3
− with a potentially high barrier (Δ G = 20.6 kcal/mol) to tautomerize to its imine isomer t-R2-imine, which can also react with the Breslow intermediate M2 via aza-benzoin reaction. As shown in Fig. 6, for the hydroacylation reactions involving t-R2 and c-R2, the carbon-carbon bond formation step has the highest free energy barrier and thus is rate-determining, while for the aza-benzoin reaction pathway involving t-R2-imine, the tautomerization step is rate-determining. Obviously, the aza-benzoin reaction pathways involving t-R2-imine have relative lower free energy barrier with respect to the hydroacylation reactions involving t-R2 and c-R2, indicating that aza-benzoin reaction pathway is very competitive.
To identify why the carbon-carbon bond formation transition state in aza-benzoin reaction has lower free energy barrier relative to the hydroacylation reactions, we first performed NBO charge analyses on t-R2 and t-R2-imine. As shown in Fig. 7a, the NBO charges on C2 of t-R2 and t-R2-imine are 0.14 e and 0.35 e, respectively, indicating that the electrophilicity of C2 in t-R2-imine is stronger than that in t-R2, which facilitates the nucleophilic attack of Breslow intermediate M2 on C2 atom of t-R2-imine. In addition, N2 atom of t-R2-imine is also more negative than C3 atom of t-R2, and the more negative charge on N2 relative to C3 atom should facilitate the proton transfer from the hydroxyl group of Breslow intermediate to N2 atom of t-R2-imine.
In addition to the NBO charge analysis on the reactants, we also compared the structures of two representative key transition states t-TS3S and t-TS3S-b. As indicated on the above, the carbon-carbon bond formation and proton transfer take place through a concerted but asynchronous mechanism in both hydroacylation reaction and aza-benzoin reaction. However, the sequence of the two events is very different. In the hydroacylation reactions, proton migration occurs prior to carbon-carbon bond formation while the sequence is reversed in aza-benzoin reactions. By comparison, the forming C2-C3 bond in t-TS3S and t-TS3S-b is 2.73 and 2.21 Å (shown in Fig. 7b), respectively. The shorter C2-C3 bond distance in t-TS3S-b reveals that the interaction between the two fragments of M2 and t-R2-imine in t-TS3S-b should be stronger than that in t-TS3S. In order to verify this speculation, we also analyzed the second-order perturbative donor-acceptor interactions 43 for the two transition states. Listed in Fig. 7c is the second-order perturbation energy E(2) (kcal/mol) in transition states t-TS3S and t-TS3S-b. As shown, the main stabilization donor-acceptor interactions in transition state t-TS3S come from the charge transfer from the lone pair orbital of O2 atom to the σ * orbital of the forming C4-H2 bond (E n→σ* = 65.5 kcal/mol and E n→σ* = 26.0 kcal/mol) and the charge transfer from the π orbital of C1-C2 bond to the vacant lone pair orbital of C3 atom (E π→n* = 22.7 kcal/mol). By comparison, the main stabilization interactions in t-TS3S-b come from the charge transfer from the lone pair orbital of O2 atom to the σ * orbital of the forming N2-H2 bond with E n→σ* = 316.3 kcal/mol and E n→σ* = 23.8 kcal/mol. Besides, there are some other significant stabilization interactions in t-TS3S-b, like the interaction between N2-H2 σ orbital and the C2-C3 π * orbital with E σ→π* = 47.8 kcal/mol, and the interaction between N2-H2 σ orbital and C9-O1 σ * orbital with E σ→σ* = 45.0 kcal/mol as well as the interaction between C1-N1 π * orbital and the C2-C3 π * orbital with E π→π* = 38.0 kcal/mol. Taken together, the stereoelectronic effect in t-TS3S-b is more favorable than that in t-TS3S.
To sum up, the high polar characteristic of C2= N2 group in t-R2-imine and the more advantageous stereoelectronic effect in t-TS3S-b render the reaction of t-R2-imine with Breslow intermediate M2 more easily. Origin of the enantioselectivity. For both the hydroacylation reactions and the aza-benzoin reactions, the S-configured product is preferentially produced. To explain the observed enantioselectivity, we compared the structures of the enantioselective transition states (shown in Fig. 8).    t-TS3S, t-TS3R, t-TS3S-b and t-TS3R-b. Scientific RepoRts | 6:38200 | DOI: 10.1038/srep38200 determined that t-TS3S has lower free energy relative to t-TS3R . For t-TS3S-b and t-TS3R-b, the N2••• H2 distance in t-TS3S-b is shorter than that in t-TS3R-b, demonstrating that N••• H-O hydrogen bond interaction in t-TS3S-b is stronger than that in t-TS3R-b. Therefore, it is the stronger N•••H-O hydrogen interaction in t-TS3S-b relative to t-TS3R-b that determine the lower energy of t-TS3S-b. On the whole, the more advantageous hydrogen bond interaction and ππ interaction in the favorable carbon-carbon bond formation transition state determine the observed enantioselectivity.

Discussion
The detailed reaction mechanisms as well as the origin of enantioselectivity for the NHC-catalyzed cross-coupling reaction of aldehyde with enamide were investigated. Our calculated results indicate that the NHC catalyst initiate the nucleophilic attack on aldehyde to afford the Breslow intermediate, which can then react with enamide via hydroacylation reaction or its isomer imine via aza-benzoin reaction, preferentially leading to the experimentally observed S-configured product. According to the computational results, the tautomerization step is rate-limiting in aza-benzoin reaction pathway, while for the hydroacylation reactions, the carbon-carbon formation step is rate-determining. NBO analyses reveal that the more polar characteristic of C= N bond in t-R2-imine and advantageous stereoelectronic effect in t-TS3S-b determine that the reaction between M2 and t-R2-imine is more likely to occur. Further structural analyses on the key enantioselective transition states reveal that the hydrogen bond interaction and ππ interaction determine the observed enantioselectivity. This present work can help people understand the details of the competing hydroacylation and aza-benzoin reaction pathways for NHC-catalyzed cross-coupling reactions of aldehydes with enamides, and thus provide valuable mechanistic insights for the rational design on the switchable and novel NHC-catalyzed cross-coupling reactions in future.

Methods
Computational details. The Gaussian 09 44 software was used for all theoretical calculations in the present study. The M06-2X method 45-47 with 6-31 G(d, p) basis set was used for all geometrical optimizations in gas phase. For transition states, the Berny algorithm was employed for both minimizations and optimizations 48 . The corresponding vibrational frequencies were calculated at the same level to identify whether the structure is a transition state or a minimum. It was confirmed that all reactants and intermediates had no imaginary frequencies, and each transition state had only one imaginary frequency. Intrinsic reaction coordinate (IRC) calculations 49,50 , at the same level of theory, were also performed to ensure that the transition states led to the expected reactants and products. Afterwards, the single-point energies in solvent methyl tert-butyl (MTBE) were refined at the M06-2X/6-311+ + G(d, p) level [45][46][47] using IEFPCM solvent model 51,52 . Finally, the Gibbs free energies at the M06-2X/6-311+ + G(d, p) level in the solvent MTBE are used through the whole paper.