Computational Mechanistic Study of Brønsted Acid-Catalyzed Unsymmetrical 1,2,4,5-Tetrazines Synthesis

Density functional theory (DFT) calculations were conducted to gain insight into the reaction mechanism of the Brønsted acid-catalyzed unsymmetrical 1,2,4,5-tetrazine synthesis. Various possible reaction pathways were considered, and the most favorable one can be characterized via sequential six steps, including addition of DCM to hydrazine 1 giving complex IM4, N-H bond activation in IM4 mediated by sulfur, AcOH-assisted substitution of 3 with sulfur-activated hydrazine 2, HNO₂-assisted addition of nitrile to intermediate 8, cyclization, and intramolecular elimination leading to the final product 7. Among the six steps, sulfur activation of IM4 N-H bond is found to be the rate-determining step (RDS). The mechanism rationalizes the experimental observation that 2 equiv of sulfur leads to the best yield of product. Furthermore, we disclosed that the Brønsted acid additives (i.e., acetic acid and nitrous acid) served triple roles as catalyst, proton shuttle, and hydrogen bond donor and acceptor in the whole catalysis.