Asymmetric Nucleophilic Allylation of α-Chloro Glycinate via Squaramide Anion-Abstraction Catalysis: S1 or S2 Mechanism, or Both?

The nucleophilic substitution mechanism of enantioselective allylation of α-chloro glycinate catalyzed by squaramide organocatalysts was studied using density functional theory. Based on a comprehensive study of S1 and S2 pathways of a catalyst-free reaction, we found that the catalytic reaction slightly favors the S1 mechanism, instead of the previously proposed S2 mechanism. Further investigation of different leaving groups and nucleophiles revealed that this is not limited to the present reaction, and the S1 mechanism might have been generally overlooked. For the squaramide-catalyzed reactions, the S1 mechanism was predicted to be preferred. However, the rate-determining step of the S1 pathway has changed from the chloride-leaving step to the C-C bond-formation step. Therefore, a first-order dependence on both substrates was predicted, in agreement with the observed second-order kinetics. Intriguingly, the lowest-energy enantioselective transition states (TSs) originate from different pathways; -inducing TS corresponds to the S1 pathway, while -inducing TS corresponds to S2. The calculated enantiomeric excesses of two squaramide catalysts agree well with the experimental values. Given the ubiquity of nucleophilic substitution reactions in chemistry and biology, we believe that our finding will inspire more studies that will lead to an improved mechanistic understanding of important chemical reactions, and it may even lead to better catalysts.