DFT-analysis of protolytic equivalents of 5-(aryl)-4-(methyl,amino)-1,2,4-triazole-3(2H)-thione
Authors: Bihdan O. A. , Alk Khalaf N. A. 
Published: September 2022

The use of modern computer methods in aspects of quantum chemistry and systematic analysis of their results give an idea of the reactivity of organic compounds, as well as to understand the essence of known experimental data, correct predictions, and quantitative estimates. Undoubtedly, theoretical calculations are useful in solving such an urgent problem of modern chemistry as prototropic equilibria and properties of substances in the gas phase, solutions, and solid-state.
The aim of the work – until recently assigned to a theoretical vivification in the infusion of solvents on tautomeric equilibrium and acid-base powers і know more broadly practical stasis in the pharmaceutical industry.
Materials and methods. The effect of solvation effects on tautomerism and antitropic properties of 1,2,4-triazole derivatives was studied on the example of model compounds. All calculations were performed using the Gauss-View 6.0.1 molecular link visualization program and Gaussian 98, Gaussian 03 software packages and the use of default convergence criteria. After optimizing the geometry, frequency calculations followed. Thus, the stationary structures are confirmed by checking that all ground states have only real frequencies, and all transition states have only one imaginary frequency. The same method and established basis were used to optimize the geometry. Solvation calculations were performed in the framework of continuous models (D-PCM, C-PCM, IEF-PCM, IPCM, SCIPCM) of discrete and combined models using the Hartree–Fock constraint method, the method of density functional theory B3LYP with basic sets 6-31G (d), 6-31G (d,p), 6-31G++ (d,p), cc-pVDZ, as well as semi-empirical methods in the MOPAC6 package.
Results. For the first time, various quantum chemical calculations of solvated model compounds using different approaches and models, variation of the basis in non-empirical calculations, identification of the role of electronic correlation effects, method of geometry optimization, etc. were carried out within the theory of self-consistent reaction field. The main stage of this study was to compare trends in the equilibrium change in the relative stability of tautomeric forms of thione-thiol tautomerism of 1,2,4-triazole-2(3H)-thions in the gas phase and different prototropic solvents due to the possibility of using different models and calculation methods for quality predictions of the effect of solvation on the position of tautomeric equilibrium in compounds of this class. It was found that the selected various solvents according to all used quantum chemical methods and models (D-PCM, C-PCM. IEF-PCM, IPCM, SCIPCM) reduce the difference in the stability of tautomeric forms of the investigated compounds in comparison with the gas phase, while the greatest stabilizing effect is observed in the solvation of NH-tautomers derived from 1,2,4-triazole-2(3H)-thiones. Using all energy parameters (∆Etot, ∆E0, ∆H298, ∆G298) allowed to determine the effect of complexation on the relative stability of tautomeric forms of the studied compounds. The difference in the values of the energy levels of HOMO and LUMO – orbitals indicate the reactivity of the molecule and its activation energy, which indicates the chemical reactivity of the molecule to electronic transport and the manifestation of biological activity with intramolecular charge transfer.
Conclusions. For the first time, complex quantum chemical calculations of thione-thiol tautomers of 5-(aryl)-4-(methyl, amino)-1,2,4-triazole-3(2H)-thiones were performed and it was found that prototropic solvents reduce the difference in all models. In the stability of tautomeric forms of the investigated compounds in comparison with the gas phase. The calculated values of electronic correlation models on the hydrogen atom make a significant contribution to the relative stability of tautomeric forms, while the use of polarization functions of quantum chemical methods on hydrogen atoms has practically no effect on the tautomeric equilibrium. From the obtained data it becomes clearer that in the gas phase and aprotic solvents the thione tautomer with the center of NH-acidity is the most stable, and the thiol tautomer of 1,2,4-triazole-3(2H)-thione predominates in the transition to polar proton-donor solvents. The obtained data indicate the possibility of conducting an electrophilic substitution reaction (eg, alkylation) in the form of an anion. The partially negative charge of the Nitrogen atoms of the 1,2,4-triazole ring promotes electrophilic addition reactions. In the thionic form, on the contrary, electrophilic substitution reactions are possible.