Investiga??o do mecanismo de rea??o de Biginelli de derivados cumar?nicos

• Autor(a) principal: Tejero, Tatiane Nicola
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
• Texto Completo: https://tede.ufrrj.br/jspui/handle/jspui/5108
• topic: Rea??o Multicomponente; Rea??o Biginelli; intermedi?rio Knoevenagel; Multicomponent Reaction; Biginelli Reaction; Knoevenagel intermediate; Qu?mica

Multicomponent reactions (MCR) have received great attention in organic synthesis and medicinal chemistry, since they allow the design of new molecules and pharmaceuticals, in special, with great structural complexity and excellent yields. In the Biginelli reaction, the reactants are an aldehyde, a ?-ketoester and urea or thiourea leading to a myriad of dihydropyrimidinones/thiones. From the possible combinations of the reactants, three reaction pathways can be expected: the Knoevenagel pathway, the iminium ion pathway and the enamine pathway, being the second pointed out, from both experimental and theoretical works with common aromatic and aliphatic ?-ketoesters, as the most probable initiation route. However, if a coumarin ?-ketoester derivative is used, the Knovenagel pathway seems to prevail. In order to understand the differences between these reaction pathways, this work has been proposed aiming to the calculations of the possible reaction paths in the coumarin ?-ketoester + benzaldehyde + urea MCR and to the understanding of the contribution of the coumarin nucleus in the ?-ketoester moiety for the changes in the reaction mechanism. Geometry optimizations have been then performed at the Density Functional Theory (DFT) level, adopting the M06-2X, B3LYP and BHandHLYP fuctionals and the 6-31+G(d,p) basis set. From our calculations, the stationary points with lower relative energies belong to the Knoevenagel reaction path. All reaction pathways are initiated with the formation of an ion-dipole pre-barrier complex, stabilized by 8.76 ? 14.84 kcal mol-1 (relative to the isolated protonated reactants). The calculated barrier height for the reaction between the coumarin ?-ketoester and benzaldehyde (which initiates the Knoevenagel channel) is -18.10 kcal mol-1 (relative to the isolated protonated reactants). For the enamine and iminium ion pathways, barrier heights are 6.21 kcal mol-1 and -16.27 kcal mol-1, respectively (the enamine pathway is initiated from the coumarin ?-ketoester and urea reaction and the iminium ion is initiated form the urea and benzaldehyde reaction). Therefore, the barrier height of the first step in the Knoevenagel pathway is ca. 24 and 2 kcal mol-1 lower than the barrier heights of the first step in the enamine and iminium ion pathways, respectively. The reaction product in the Knoevenagel pathway is also the most stabilized (20.44 kcal mol-1 below the isolated protonated reactants, while the products in the enamine and iminium ion pathways are located, with respect the isolated reactants, at 5.85 and -25.04 kcal mol-1, respectively). The second step in all pathways is the dehydration, and barrier heights are 31.12 and 36.13, 28.85 and 31.99 and 32.60 and 36.25 kcal mol-1 (Knoevenagel, enamine and iminium ion, respectively). The final steps concern the addition of the third reactant, and the intermediates and transition states belonging to the Knoevenagel pathway remain the lowest energy structures. Thus, the Knoevenagel pathway is finally attributed as the lowest energy pathway in this complex mechanism for the coumarin ?-ketoester + benzaldehyde + urea MCR. These results satisfactorily compare to the experimental observations and demonstrate that the coumarin nucleus in the ?-ketoester moiety promotes the change of the mechanism initiation from the iminium ion to the Knoevenagel pathway.