DFT analysis of the [3 + 2] heterocyclization reaction of ((1,2,4-triazole(1,3,4-oxadiazole)-3(2)-yl)methyl)thiopyrimidines

Abstract

The article examines the mechanisms of the heterocyclization reaction using density functional theory (DFT) methods. A quantum-chemical analysis of the starting compounds, transition states, and products was conducted, with energy barriers and key reaction stages identified. Particular attention was given to the influence of electronic and steric effects on the stability of the resulting heterocycles. The application of solvent models (PCM) allowed for more realistic simulation of reaction conditions. The study’s findings provide a deeper understanding of chemical transformations in heterocyclic systems and can be utilized to optimize synthetic methods in medicine, agrochemistry, and materials science.

The aim of this work is to perform a DFT analysis of the heterocyclization reaction of ((1,2,4-triazole(1,3,4-oxadiazol)-3(2)-yl)methyl)thiopyrimidines and to evaluate the stability of the transition states, as well as the influence of substituents on the activation energy.

Materials and methods. ¹H and ¹³C NMR spectra were recorded on a Bruker AC-500 spectrometer (500 MHz and 125 MHz, respectively) in DMSO-d₆, using TMS as the internal standard (Agilent Technologies, Santa Clara, California, USA). LC-MS analysis was performed using an Agilent 1260 Infinity HPLC System equipped with a diode-array detector and proton ionization. Elemental analysis (C, H, N, S) was conducted on an ELEMENTAR vario EL cube, with sulfanilamide as the standard. Melting points were determined using the capillary method on a Stanford Research Systems Melting Point Apparatus 100 (SRS, USA). The reagents were sourced from Sigma-Aldrich (Merck). All calculations were performed using the molecular visualization program GaussView 5.0.8 and the Gaussian 09 Rev E.01 software package.

Results. This article presents the results of a study on the mechanisms of [3 + 2] and [4 + 1] heterocyclization for the synthesis of 1,2,4-triazole and 1,3,4-oxadiazole derivatives. The reaction stages are analyzed in detail, including the formation of intermediates and cyclization, culminating in aromatization and the formation of stable heterocyclic structures. Thermodynamic analysis was conducted using the Gaussian 09 software package, incorporating calculations of enthalpy, entropy, and Gibbs free energy in both the gas phase and ethanol medium. The resulting energy profiles illustrate the key stages of the reactions and define the temperature conditions required for their execution. Special attention is given to the role of the solvent and other factors influencing process efficiency.

Conclusions. The DFT analysis revealed that the [3 + 2] heterocyclization reaction for forming the 1,2,4-triazole ring proceeds through several sequential stages, with the cyclization stage being the most energy-intensive. The obtained thermodynamic parameters confirm the feasibility of the reaction at temperatures above 85 °C in the gas phase and 78 °C in ethanol solution. The heterocyclization mechanism involves a nucleophilic attack by the amino group of hydrazide, thiol-thiourea tautomerism, ring closure, and structure aromatization. The most significant energy transitions are associated with the activation of the thiourea group and the formation of a new heterocyclic bond.