Estudos mecanísticos de reações de cicloadição e ciclização através de ferramentas experimentais e teóricas
Kawamura, Meire Yasuko
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Part 1: The 1,3-dipolar cycloaddition of nitroolefin and azides have emerged as an important approach for the synthesis of 1,2,3-triazole. We describe the rationalization of the regioselectivity/reactivity trends of this reaction by an experimental and theoretical exploration. DFT calculations revealed 1,5-triazole is favarable, with the rate-limiting cycloaddition step showing high asynchronicity. Kinetic studies corroborated these results, pointing to a second-order velocity law, and 13C kinetic isotopic effect (KIE) at natural abundance with a significant normal effect for the conjugated olefinic centers (1.0216 for C1β-nitro and 1.0158 for C2α-nitro). Distortion/interaction-activation strain (DIAS) and energy decomposition (EDA) analysis disclosed the regioselectivity of this reaction, showing an earlier and less distorted TS for preferred 1,5-triazole compared to 1,4-triazole regioisomer, and the interaction is favored in 1,5-triazole mainly due to on dispersion (Edisp) and electrostatic (Eelec) interactions. Additionally, we explored the mechanistic aspects of the HNO2 elimination elementary step by using quasi-classical dynamics calculations, the calculations indicate a dynamically stepwise mechanism, indicating an existence of a carbocation intermediate. Studies of the reaction between nitro-olefins and sodium azide revealed that Bronstead acid plays a fundamental role for disubstituted nitro-olefins, controlling the reactive species, wherein the path that leads to 1,2,3-NH-triazole is favorable comparing with the path that leads to Michael's adducts. A systematic study has led to the preparation of 1,4-disubstituted 1,2,3- triazoles by the use of a-nitroolefins generated in situ. Part 2: Multicomponent reactions (MCRs) have shown great potential as important tools for the synthetic organic chemistry due to the possibility of diversity and complexity generation in a single step. Among these reactions, the Ugi reaction and its variants are unique strategies that allow the introduction of an amide function in the molecular architecture. Despite the huge advantages offered by these reactions, the lack of stereocontrol is its main limitation. Therefore, this part of the project aimed to evaluate the mechanism of these transformations through theoretical DFT studies of two Ugi reaction variants. It was shown that the diastereoselectivity occurs due to non- covalent interactions, and that due to steric interactions different products were obtained: tetrahydropyridine for R1 = Ph and cyclopentene for R1 = Me substitution.
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