Abstract
The Biginelli reaction is a multicomponent reaction for obtaining dihydropyrimidinthiones quickly, with multiple substitution patterns. The reaction mechanism remains unclear. Three possible pathways proposed for the reaction are the iminium route, an enamine intermediate, and the Knoevenagel pathway. However, when thiourea was used, no theoretical calculations were reported. Thus, based on the literature, the iminium pathway was used to obtain evidence explaining the lack of reactivity of 2,4-dihydroxybenzaldehyde towards the Biginelli adduct, compared with 4-hydroxybenzaldehyde. This computational study, carried out using the B3LYP/6-31++G(d,p) level of theory, showed an increment of 150 kJ/mol in the activation energy of the slowest pathway, due to the presence of a hydroxyl group in position 2 (ortho) of the aromatic aldehyde, decreasing its reactivity. Natural bond orbital (NBO) calculations suggest that the determinant steps are simultaneous, i.e., the polarization of the carbonyl group and its corresponding protonation by the hydrogen of the SH fragment of the thiourea tautomer. The activation enthalpy values suggest that the nucleophile attack takes place later on the compound 2,4-dihydroxybenzaldehyde compared to 4-hydroxybenzaldehyde-TS, confirming that the OH group in position 2 hinders the condensation reaction.
Highlights
Known as Biginelli adducts, 3,4-Dihydropyrimidinones (DHPMs), are compounds derived from pyrimidine, in which carbon C-4 is entirely saturated, eliminating the characteristic aromaticity of Processes 2019, 7, 521; doi:10.3390/pr7080521 www.mdpi.com/journal/processesProcesses 2019, 7, 521 a pyrimidine; a double bond is formed on the C-5 and a second one towards a heteroatom, on carbonC-2
The potential energy surface (PES) of all species involved in the reactions of 44-hydroxybenzaldehyde and 2,4-dihydroxybenzaldehyde with methyl acetoacetate (MAA) and thiourea was studied hydroxybenzaldehyde and 2,4-dihydroxybenzaldehyde with MAA and thiourea was studied employing density functional theory (DFT) and transition state theory (TST)
The methodology was used from the procedures reported by Stadler and Kappe [32] and Manhas et al [33], with an environmentally friendly approach using microwave conditions, a solvent-free system, and low-cost acid catalyst [30]
Summary
Known as Biginelli adducts, 3,4-Dihydropyrimidinones (DHPMs), are compounds derived from pyrimidine, in which carbon C-4 is entirely saturated, eliminating the characteristic aromaticity of Processes 2019, 7, 521; doi:10.3390/pr7080521 www.mdpi.com/journal/processes. The synthesis of DHPMs (dihydropyrimidines) has become a line of research due to the importance of the antihypertensive [1,2], antibacterial [3,4], antifungal [5,6], antiviral [7], anti-inflammatory, and antineoplastic activity [8,9] they show, through various mechanisms such as calcium channels, GABA agonists, and α1A-adrenergic antagonists [10,11] Such derivatives can quickly be obtained through the Biginelli reaction, developed in 1893 by Pietro Biginelli [12]. Obtaining five DHPMTs from hydroxylated aldehydes, methyl 3-oxobutanoate, and thiourea was crucial in evaluating their synthesis under solvent-free microwave conditions Under these conditions, it was possible to obtain four Biginelli adducts; using 2,4-dihydroxybenzaldehyde, the derivative was not obtained, even after modifying reaction conditions. These results led us to carry out theoretical study in order to understand the unreactivity towards the formation of the Biginelli adduct
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