Abstract

An exploration into the origin of chemoselectivity in the NHC-catalyzed cross-benzoin reaction reveals several key factors governing the preferred pathway. In the first computational study to explore the cross-benzoin reaction, a piperidinonederived triazolium catalyst produces kinetically controlled chemoselectivity. This is supported by 1 H NMR studies as well as a series of crossover experiments. Major contributors include the rapid and preferential formation of an NHC adduct with alkyl aldehydes, a rate-limiting carbon−carbon bond formation step benefiting from a stabilizing π-stacking/π-cation interaction, and steric penalties paid by competing pathways. The energy profile for the analogous pyrrolidinone-derived catalyst was found to be remarkably similar, despite experimental data showing that it is less chemoselective. The chemoselectivity could not be improved through kinetic control; however, equilibrating conditions show substantial preference for the same cross-benzoin product kinetically favored by the piperidinone-derived catalyst.

Introduction

Originally reported in 1832 by Wö hler and Liebig, the benzoin reaction is the coupling of two aldehydes to form an acyloin. The groups of Ukai and Breslow described how thiazolium salts could also catalyze this reaction in the presence of base. Much later, other N-heterocyclic carbene (NHC) catalysts were shown to effect the same transformation. Breslow proposed the currently accepted mechanism, based on analogy to Lapworth’s mechanism for the cyanide-catalyzed benzoin reaction (Scheme 1).

First, deprotonation of the salt (I) generates the active carbene catalyst (II). This nucleophilic species then attacks 1 equiv of aldehyde, generating an intermediate (III) that is rapidly protonated to form a carbene−aldehyde adduct (IV). Deprotonation of this adduct generates a resonance-stabilized zwitterion now referred to as the Breslow intermediate (V). This species is crucial to the reaction, as it induces a reversal of polarity (umpolung), making the previously electrophilic carbonyl carbon nucleophilic. The Breslow intermediate then attacks another 1 equiv of aldehyde and undergoes a proton transfer that is either concerted or stepwise ([V-VI]). Collapse of this species (VI) releases the benzoin (acyloin) product and reintroduces the catalyst into the cycle.