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Theoretical study of the mechanism of cycloaddition (3 + 2) reactions involving enolates and azides

Grant number: 18/01211-9
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2018
Effective date (End): February 29, 2020
Field of knowledge:Physical Sciences and Mathematics - Chemistry - Organic Chemistry
Acordo de Cooperação: GlaxoSmithKline
Principal Investigator:Arlene Gonçalves Corrêa
Grantee:Attilio Chiavegatti Neto
Host Institution: Centro de Ciências Exatas e de Tecnologia (CCET). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated research grant:14/50249-8 - Green chemistry: sustainable synthetic methods employing benign solvents, safer reagents, and bio-renewable feedstock, AP.PCPE


The optimization of already established synthetic routes, either by reducing the number of stages or by the development of new reactions, is fundamental in organic synthesis. The use of efficient processes facilitates the access to new drugs and molecules of high added value for biological applications and in the most diverse industries. The association of 1,2,3-triazole nuclei as candidates for drugs and industrial products is increasing in the literature and the synthesis of this class of compounds is the object of study of this work. Nowadays, it is possible to associate with experimental investigation the computational studies in organic reactions to find transition states and reactive intermediates, obtaining a significant understanding of their mechanism, and use this knowledge to improve or develop new methods. The use of theoretical-experimental studies offers advantages such as less expenditure of time and resources in relation to the trial and error process. Several methods have been developed for the synthesis of triazoles, in particular 1,4 and 1,5 disubstituted triazoles. The use of metallic catalysis allows high regioselective control, but on the other hand limits its application in biological chemistry. In this context a "metal-free" comes to light, with emphasis on the Paixão proposal, which involves a 1,3-dipolar organocatalyzed cycloaddition between arylazides and an aldehyde and uses a stoichiometric quantity of DBU, and the Ramachary proposal, which involves a cycloaddition 1,3-dipolar interaction between an enolate generated in situ in the catalytic presence of DBU and an arylazide. In both cases, poor reactivity is reported for azides linked to aromatic groups with activating substituents. It was verified by computational studies in our group that the preferred mechanism of the method proposed by Paixão is concerted and the elimination of the catalyst via E1cb is the limiting step. However, in view of the results published by Ramachary, it was questioned the possibility of parallel reactions occurring in the method proposed by Paixão. In addition, since there is no theoretical-experimental work published in literature that contemplates the mechanism of a [3 + 2] enolato-azide cycloaddition, the mechanism of the reaction proposed by Ramachary is unknown. Therefore, using computational methods based on DFT (functional functional theory) with the functionality of Truhlar M06-2x, we intend to study this system in order to find the preferential mechanism. Our objectives includes verify the possible transition states for the concerted and stepwise mechanisms and their energies, search an explanation for the regioselectivity of the reaction, the low reactivity of azides linked to the activated aromatic groups or alkyl and the differences in relation to the reaction time, temperature and DBU use between the proposal of Ramachary and Paixão. (AU)

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