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

Abstract

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.

Unexpected molecular mechanism of trimethylsilyl bromide elimination from 2-(trimethylsilyloxy)-3-bromo-3-methyl-isoxazolidines

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Mechanisms and regioselectivities of DABCO/DMAP‐catalyzed [2+4] annulation reactions of allenoate with α,β‐unsaturated cyclic ketimine: A DFT study

“…In the past decades, density functional theory (DFT) has been extensively used as a powerful method to explore the detailed reaction mechanisms, and predict the regioselectivity as well as chemoselectivities in organocatalytic and biological reactions . It is worth mentioning that the DABCO‐catalyzed [2+4] cycloaddition of ethyl allenoate with arylidenoxindole has been theoretically investigated, but the observed regioselectivity is remarkably different from the reaction in this paper.…”

Theoretical Study on DBU-Catalyzed Insertion of Isatins into Aryl Difluoronitromethyl Ketones: A Case for Predicting Chemoselectivity Using Electrophilic Parr Function

“…All of the theoretical calculations were carried out in the Gaussian 09 suite of programs . All of the stationary points were optimized by DFT method, which has been proved to be a powerful tool for clarifying the detailed reaction mechanisms in enzymes, − transition metals, ,− organocatalysts − ,,,− catalyzed reactions, and other theoretical studies. − All of the species were optimized with M06-2X − density functional and 6-31G­(d, p) basis set in chloroform solvent using the integral equation formalism polarizable continuum model (IEF-PCM). , Harmonic vibrational frequency calculations were performed at the same level of theory as that used for geometry optimizations to provide thermal corrections of Gibbs free energies and to make sure that the local minima had no imaginary frequencies, whereas the saddle points had only one imaginary frequency. Intrinsic reaction coordinates , were calculated to confirm that the transition-state structure connected the correct reactant and product.…”