DFT Study on the Mechanisms and Stereoselectivities of the [4 + 2] Cycloadditions of Enals and Chalcones Catalyzed by N-Heterocyclic Carbene

Abstract

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.

Kooperative Katalyse mit N‐heterocyclischen Carbenen

“…[58] Chen und Huang waren in der Lage,d ie pK a -Werte von Substrat, Katalysator und HFIP fürd ie hoch enantioselektive Addition von 1,3-Dicarbonylverbindungen an Nitroolefine sorgfältig abzustimmen. [63] Sie wiesen nach, dass die Zugabe von Essigsäure entscheidend fürd en Protonentransferschritt ist, der erforderlich ist, um das erweiterte Breslow-Intermediat zu generieren und um den nachfolgenden Protonentransfer zur Protonierung des Homoenolats zu realisieren. [60] Es ist nicht überraschend, dass die bei einer NHC-Reaktion verwendete Base einen starken Einfluss auf den Reaktionsweg haben kann.…”

“…Diese Umwandlung wurde von der Gruppe um Weiund Zhu mittels DFT-Rechnungen ausführlich untersucht. [63] Sie wiesen nach, dass die Zugabe von Essigsäure entscheidend fürd en Protonentransferschritt ist, der erforderlich ist, um das erweiterte Breslow-Intermediat zu generieren und um den nachfolgenden Protonentransfer zur Protonierung des Homoenolats zu realisieren.…”

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

“…1 has been demonstrated to be different from the Stetter reactions818, and the aldehyde-imine aza-benzoin reactions catalyzed by NHC have never been studied in theory, not to mention the competing relationship between them. Besides, our interest in NHC-catalyzed reactions also prompts us to investigate the origin of selectivities for the competing reactions in detail19202122232425262728293031. In the present study, the commonly used DFT theoretical investigation3233343536373839404142 on the reaction between R1 (in which Ar 1  = para chlorphenyl) and R2 (in which Ar 2  = phenyl) catalyzed by NHC depicted in Fig.…”

In Silico Study on Chemical Properties and Reactivity of Enal Derivatives

“…[16][17][18] In view of the ever increasing synthetic importance of enals, we have performed a computational study with the goal to achieve a better understanding of the chemical properties governing the reactivity of these valuable compounds, and with the purpose of contributing to the development of potential new applications for this class of molecules. Protonation reactions were computed as models for enal activation in order to examine the influence of different substituents on the formation and relative stability of the derived oxonium and carbenium intermediates.…”