Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling

Virginia Flores-Morales; Eduardo D. Ayala-Medrano; José García-Elías; Margarita L. Martínez-Fierro; Edgar Marquez; José Mora

LAPSE

Living Archive for Process Systems Engineering

LAPSE:2019.1105

Published Article

LAPSE:2019.1105

Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling

Virginia Flores-Morales, Eduardo D. Ayala-Medrano, José García-Elías, Margarita L. Martínez-Fierro, Edgar Marquez, José Mora

October 26, 2019

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.

Record ID

LAPSE:2019.1105

Keywords

density functional theory, dihydropyrimidinthione derivatives, intermediaries, mechanism reaction, one-pot reaction

Subject

Reaction Engineering

Suggested Citation

Flores-Morales V, Ayala-Medrano ED, García-Elías J, Martínez-Fierro ML, Marquez E, Mora J. Understanding the Lack of Reactivity of 2,4-Dihydroxybenzaldehyde Towards the Biginelli Adduct Using Density Functional Theory Molecular Modeling. (2019). LAPSE:2019.1105

Author Affiliations

Flores-Morales V: Laboratorio de Síntesis Asimétrica y Bioenergética (LSAyB), Ingeniería Química (UACQ), Program of Doctorate in Sciences with orientation in Molecular Medicine, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, C [ORCID]
Ayala-Medrano ED: Laboratorio de Síntesis Asimétrica y Bioenergética (LSAyB), Ingeniería Química (UACQ), Program of Doctorate in Sciences with orientation in Molecular Medicine, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, C
García-Elías J: Laboratorio de Síntesis Asimétrica y Bioenergética (LSAyB), Ingeniería Química (UACQ), Program of Doctorate in Sciences with orientation in Molecular Medicine, Academic Unit of Human Medicine and Health Sciences, Universidad Autónoma de Zacatecas, C [ORCID]
Martínez-Fierro ML: Laboratorio de Medicina Molecular, Program of Doctorate in Sciences with orientation in Molecular Medicine, Academic Unit of Human Medicine and Health Sciences. Universidad Autónoma de Zacatecas, Campus XXI Km 6 Carr. Zac-Gdl Edificio L1, 98160 Zacatecas [ORCID]
Marquez E: Grupo de Investigación en Química y Biología, Departamento de Química y Biología, Universidad del Norte, Km 5 vía Puerto Colombia 1569, 081007 Barranquilla Atlántico, Colombia [ORCID]
Mora J: Grupo de Química Computacional y Teórica (QCT-USFQ) and Instituto de Simulación Computacional (ISC-USFQ), Colegio Politécnico de Ciencias e Ingeniería, Universidad San Francisco de Quito, Diego de Robles y Vía Interoceánica, 17-1200841 Quito, Ecuad
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Journal Name

Processes

Volume

7

Issue

8

Article Number

E521

Year

2019

Publication Date

2019-08-07