Mechanisms and Origins of Stereoselectivity of the NHC-Catalyzed Reaction between β-Bromoenals and Pyrazole-diones: A DFT Study

Density functional theory computations were performed to study the reaction mechanism and origins of stereoselectivity of the reaction between β-bromoenals and a pyrazole-dione catalyzed by a chiral N-heterocyclic carbene (NHC). The catalytic cycle for producing spiropyrazolone-butenolide proceeds via six steps: (1) nucleophilic attack of the NHC on β-bromoenal; (2) 1,2-proton transfer; (3) C-C bond formation; (4) C-Br bond cleavage; (5) deprotonation accompanied by cyclization, and (6) elimination of the NHC. Different from previously proposed cyclization through C-O bond formation that determines the stereochemistry, our results demonstrate the C-C bond forming step is the stereoselectivity-determining step, leading preferentially to the S-configuration spiropyrazolone-butenolide. Additionally, the Brønsted acid (DBU·H⁺) facilitates not only the proton transfer but also the NHC elimination. The calculated barriers for proton transfer without DBU·H⁺ (45.1 kcal/mol) are significantly higher than that with DBU·H⁺ (14.3 kcal/mol). Furthermore, the presence of DBU·H⁺ also decreased the barrier for NHC elimination by 5.8 kcal/mol. NCI and AIM analyses were conducted to reveal the key factors controlling stereoselectivity. These findings provide valuable insights for understanding the mechanism and designing highly selective catalytic reactions in the future.