N-Heterocyclic Carbene (NHC)-Catalyzed sp³ β-C–H Activation of Saturated Carbonyl Compounds: Mechanism, Role of NHC, and Origin of Stereoselectivity

Abstract

Activation of inert sp 3 β-C−H bonds has attracted widespread attention and been developed with significant progress in recent years, but understanding the mechanism of this kind of reaction continues to be one of the most challenging topics in organic chemistry. In this paper, the possible reaction mechanisms and origin of stereoselectivity in the reaction between saturated carbonyl compounds with enones generating cyclopentenes catalyzed by N-heterocyclic carbene (NHC) have been investigated using density functional theory. The computational results show that the additive DBU plays an important role in NHC-catalyzed C−H activation. Analyses of the natural bond orbital charge and global reaction index indicate that NHC can lower the energy barrier of the entire reaction by activating the α/β-C−H bond rather than by strengthening the nucleophilicity of the reactant as a Lewis base. This is remarkably at variance from previous reports. In addition, the π•••π stacking between the phenyl of the enone and the conjugated system of the NHC-bounded enolate intermediate has been found by the analyses of distortion/interaction and atom-in-molecule to be responsible for the stereoselectivity. These results shed light on the detailed reaction mechanism and the significant role of the NHC organocatalyst and offer valuable insights into the rational design of potential catalysts for this kind of highly stereoselective reaction.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…An extensive conformational search for both atropisomers of alcohol 1 revealed that the Trans( re) orientation is strongly favored. This can be attributed to the presence of additional stabilizing non‐covalent interactions compared to the other conformations, as seen by comparing the corresponding NCI plots in Figure b and through a comparative AIM analysis (Figure c) . More precisely, the NCI plots show greater density of favorable non‐covalent interactions (green patches) for Trans( re) compared to its counterpart.…”

Recent Advances on Computational Investigations of N‐Heterocyclic Carbene Catalyzed Cycloaddition/Annulation Reactions: Mechanism and Origin of Selectivities

“…Recently, Sunoj and Wang independently studied the mechanism and stereoselectivity of NHC‐catalyzed β‐C(sp 3 )‐H activation of saturated carbonyl compounds based on the Chi's experimental work using DFT method. As shown in Scheme , according to Wang's computational results, the reaction contains eight steps, including (1) the complexation of 37 and NHC for the formation of an NHC‐bounded intermediate M68 , followed by the dissociation of ArO − , respectively; (2) the deprotonation of α‐C−H in intermediate M69 to form an enolate intermediate M70 ; (3) the β‐C−H deprotonation of enolate M70 affording intermediate M71 via a direct or an A‐assisted (A=DBU, DBU⋅H + , or ArO − ) proton transfer process, (4) attack on the electrophilic α,β‐unsaturated aldehyde 38 by the β‐carbon of the intermediate M71 to form intermediate M72 via transition state TS11 , accompanied by formation of two chiral centers, (5) the intramolecular proton transfer via a seven‐membered ring transition state for the formation of intermediate M73 , (6) the intramolecular aldol reaction to form the five‐membered ring intermediate M74 , (7) the desorption of NHC and the formation of the lactone intermediate M75 , and (8) decarboxylation of the intermediate M75 to form cyclopentene product 39 . The computational results show that the additive DBU plays an important role in NHC‐catalyzed C−H activation.…”

Mechanistic insight on water and substrate catalyzed the synthesis of 3‐(1H‐indol‐3‐yl)‐2‐(4‐methoxybenzyl)isoindolin‐1‐one: Driving by noncovalent interactions

“…To further explore the dominant interactions and disclose the origin of the activation energy difference of the structures of these three key transition states by using non‐covalent interaction (NCI) analysis . NCI was demonstrated to be capable of distinguishing strong attractive interactions (blue regions), weak noncovalent interactions (green regions), and repulsive steric interactions (red regions).…”