Quantum-chemical calculations of transitional states thermodynamic parameters of tautomers of initial N,N’-disubstituted thiourea derivative during the cyclization reaction in the conditions of different solvents application

L. O. Perekhoda, H. O. Yeromina, Z. G. Ieromina © 2019 L. O. Perekhoda et al.; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited UDC 54.057:547.789: 544.18


Introduction
Modern quantum-chemical methods gain widespread acceptance in the study of structure and reactivity of organic compounds [1][2][3]. One of the most important and interesting Molecular Biophysics ISSN 1993-6842 (on- directions of their application is related to the study of chemical reactions paths. The results of the theoretical research allow complementation and deepening of the interpretation of the experiment, and in some cases even its improvement by using in the synthesis more suitable solvent. It was proved earlier that the molecule of N-ethyl-N'- [4-(6,7,8,9-tetrahydro-5H- [1,2,4]triazol [4,3-a]azepin-3-yl)phenyl]thiourea has a higher analgesic activity than ketorolac, the most common analogue with the same pharmacological action [4].
The next step of this research was theoretical substantiation of the direction of the cyclization reaction in conditions of synthesis in different solvents. The selection of the optimal solvent for synthesis was carried out by calculating the thermodynamic parameters of the initial tautomers in the medium of ethanol, DMFA, dioxane and tetrachlormethane using the licensed software product Gaussian W09, Revision A.02. This program provides an opportunity to calculate the physical and chemical parameters of the raw materials for synthesis both in gas phase and condensed state with high precision and reliability [6].
The most popular DFT functionals and PCM models nowadays allows the solution of such tasks as calculation and comparison of structural, electronic characteristics, relative energy of tautomers that theoretically may exis t and energy barriers to their transformation; definition of the structure of intermediate pro ducts of the reaction.
It is known that during choosing a method of calculation the nature of a particular problem should be taken into account since various methods used in quantum-chemical calculations have specific disadvantages that limit their application.
The methods of the density functional theory of B3LYP and M06-2X were chosen as the main calculation methods for our purpose -the selection of solvent with the most favorable parameters for synthesis; the basis set 6-31 + G (d) and the continuum model PCM implemented in Gaussian W09, Revision A.02 were used. [7].These models are widely applied in the practice of solvation effects in heterocyclic compounds.
The popularity of the hybrid method Beck3-Lee-Yang-Parr (B3LYP) is due to the fact that its applying allows description of the processes that include a wide range of chemical transformations. However, a significant disad-vantage of this method is that it does not take into account the dispersion interactions, which results in the underestimation of the activation energy value and inaccuracies in describing the processes where the essential role is played by the effects associated with Van der Waals interaction [1]. Thus, more accurate and at the same time accessible methods are necessary for describing complex chemical processes. For the calculations of thermochemical kinetics, weak intermolecular interaction and excited states, we proposed a complex of metahybrid functionals M06 [7], which is based on an improved generalized gradient approximation (GGA). The M06-2X method was specially designed for kinetic studies, it has 54 % of HF exchange function and is most effective in solving our problem.
The frequencies of harmonic oscillations were calculated for the determination of stationary points (minima with all positive frequencies; the transition state is corresponded to the presence of one imaginary frequency).
An analysis of the solvation effects, that we have carried out earlier for tautomers of N, N'-disubstituted thiourea in the frame of the PCM model with bases of medium size (B3LYP / 6-31 + G (d) and M06-2X / 6-31 + G (d)), found a fairly strong influence of the solvent on the position of tautomeric equilibrium in the studied compounds [5]. According to the research results, the additional optimization of tautomers geometry in solutions with the application of larger bases leads only to small changes in the activation energy and is not necessary. The estimated and experimental data are consistently identical, and this fact allows us to rely on the correctness of predic-tions of the influence of solvents on the thermodynamic characteristics of the compounds studied. [4-(6,7,8,9-tetrahydro-5H- [1,2,4]triazol[4,3-a]azepin-3-yl)phenyl]thiourea I has two mobile hydrogen atoms in positions N and N', so the molecule can exist in different tautomeric forms I A and I B as it is shown in the Scheme 1.
Using the meta-hybrid method M06-2X applying a basis functions set 6-31 + G (d), the local minima and transition states (saddle points) of I, IA and IB molecules in a medium of water, dioxane, ethanol, DMFA, tetrachlor-methane were investigated. For the spatial structures obtained, the thermodynamic parameters were calculated as well as the relative energies and activation energies of tautomeric transformations for the transition states I ↔ I A and I ↔ I В. The calculations were carried out in the framework of the traditional B3LYP method.

Results and Discussion
The presence of only one set of Hydrogen protons signals in the 1 Н NMR spectrum of the cyclized product synthesized testifies to the formation of one of the possible structures -IV А or IV В [5].
The theoretical results of calculations of thermodynamic parameters of N-ethyl-N'- [4-(6,7,8,9-tetrahydro-5Н- [1,2,4]triazol [4,3-а] azepin-3-yl)phenyl]thiourea I tautomers were obtained by the methods B3LYP and M06-2X after optimization of the molecules spatial structure in the medium of dioxane, ethanol, DMFA and tetrachlormethane. The calculated parameters -relative energy, activation energy, free energy of Gibbs and enthalpy -are given  As can be seen from the data in Tab. 1-4, in most cases for energy and energy barriers there is a reliable (1-2 kcal / mol) coincidence of the calculations results obtained by the methods M06-2X and B3LYP. The calculated data and the obtained data of the physicalchemical researches of the interaction product more accurately coincide with the application of the method М06-2Х.
As can be seen from Table 1, a transition state I↔I A in dioxane has the lowest values of activation energy. The graphical representation of the 3D isomers of structure I and the activation energy of tautomeric transformations for the transition states IA↔I↔I B in dioxane for both methods is shown in Fig. 3 Despite the fact that the values of the thermodynamic potentials for transition states in dioxane and tetrachlormethane are the same, the activation energy and the relative energy    (Table 1-4), and hence, the synthesis in these solvents will be slower and will require additional conditions. Taking into account these data, we can conclude that according to the two methods of quantum-chemical calculations, the reaction pathway by A, which indicates the formation of hydrobromide 3-ethyl-4-phenyl-N- [4-(6,7,8,9-tetrahydro-5H- [1,2,4]triazol [4,3-a] azepin-3-yl)phenyl]-1,3-thiazol-2(3H)-imine IV A, is the most probable, and the synthesis of the substance is the most energy-efficient in the environment of dioxane.