Insights into N-Heterocyclic Carbene (NHC)-Catalyzed Asymmetric Addition of 2H-Azirine with Aldehyde

The possible mechanisms and origin of the enantioselectivity of the reaction between 2H-azirine and an aldehyde catalyzed by an N-heterocyclic carbene (NHC) were theoretically studied and predicted at the M06-2X/6-31G(d,p)/IEF-PCMMTBE//M06-2X-GD3/6-311++G(2df, 2pd)/IEF-PCMMTBE level. The most favorable reaction pathway consists of four steps, i.e., complexation of the NHC and the aldehyde, stepwise [1,2]-proton transfer, C-C bond formation coupled with another proton transfer, and recycling of the NHC. The computational results indicate that the stereoselectivity-determining step is also the rate-determining step, which is the third step (i.e., intermolecular addition). The calculated 99 % ee is very close to the experimentally observed value of 96 % ee, demonstrating that the calculations are reliable. Two important roles of the NHC were identified by global reaction index (GRI) analysis and natural population analysis (NPA), that is, realizing the umpolung reactivity of the aldehyde and facilitating the deprotonation of aldehyde. Moreover, the efficiency of different NHC catalysts can be mainly predicted by computing the nucleophilic index of the corresponding Breslow intermediates. Furthermore, distortion/interaction and noncovalent interaction (NCI) analyses revealed that the pi ... pi interactions between the NHC and substrates were the key factor in the reaction enantioselectivity.