DFT study on mechanism of the classical Biginelli reaction

The Three‐Component Biginelli Reaction: A Combined Experimental and Theoretical Mechanistic Investigation

“…Recently, Zhou and co-workers reported a short DFT study where they analyzed the iminium mechanism as proposed by Kappe. [52] Figure 5 presents a potential energy surface for the three mechanisms and Figure 6 shows the calculated structures for the lowest energy pathway. Figure 5 shows that the formation of intermediates 11 a and 18 a, through the transition ] via TS1C for the Knoevenagel mechanism (C).…”

Ultrasound‐Assisted Synthesis of Novel Pyrrole Dihydropyrimidinones in Lactic Acid

“…In the past century, multiple mechanisms of the Biginelli reaction have been proposed . Among them, two acid‐catalyzed positive ion mechanisms have attracted much attention.…”

Similarity and Competition between Biginelli and Hantzsch Reactions: an Opportunity for Modern Medicinal Chemistry

“…Readers can find a survey about the chronological advancements of the mechanistic hypothesis in previous, very interest-ing reviews. [8,55] Nowadays, theoretical DFT (density functional theory) [69][70][71] and AFIR (artificial force induced reaction) [72] studies corroborating combined NMR and ESI-MS/MS [73,74] experiments have established that all of these three mechanisms are consistent and possible, even in the same reaction. They all give rise to the same final product, but the prevalence of one of them strictly depends on the catalyst and, less strongly, on the solvent of the reaction.…”

“…They all give rise to the same final product, but the prevalence of one of them strictly depends on the catalyst and, less strongly, on the solvent of the reaction. In particular, the iminium pathway is the most probable mechanism when the Biginelli condensation is catalyzed by both Lewis and Brønsted acids, [64][65][66]69,70] even when such acids are integrated into an ionic liquid medium. [74,75] Moreover, in these conditions the probability of forming an iminium intermediate (9, Figure 3) depends on the formation of an enol tautomer of aromatic aldehydes and, as a consequence, on the presence of protic solvents.…”

“…[68,73] The Knoevenagel pathway is the less probable mechanism, as the energetic barrier for the Knoevenagel intermediate is the highest among all. [69][70][71] It can only be observed in few cases, as for example when the catalytic system is an heteropolyacids in presence of embedded imidazolium based ionic liquid as BMI•PF 3 . [77] Biginelli reactions performed in solvent free or catalyst free conditions can proceed with all the proposed mechanisms, with the prevalence of the iminium mechanism, which passes through the kinetically favored intermediate.…”