ORIGINAL PAPER DFT study on tautomerism and natural bond orbital analysis of 4-substituted 1,2,4-triazole and its derivatives: solvation and substituent effects Abolfazl Shiroudi 1 & Zahra Safaei 2,3 & Zahra Kazeminejad 4 & Eveliina Repo 2 & Khalil Pourshamsian 5 Received: 12 December 2019 / Accepted: 30 January 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Density functional theory investigations at the DFT-B3LYP/6-311++G ** theoretical level employed to determine the tautomer- ism, substituent effects of 4-substituted 4-amino-5-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione, and its derivatives (4-R-H, 4- R-CH 3 , 4-R-F, 4-R-NO 2 ) in the selected solvent (acetone, acetonitrile, and dichloromethane) and gas phases using the polarizable continuum method (PCM) model. The substituted 1,2,4-triazoles have two main different tautomers namely N 2 -H and S 7 -H. For considered derivatives, thione forms are more energetically stable and dominant form in the studied solvent and gas phases. In addition, geometrical parameters, charges on atoms, dipole moments, energetic properties, and the nucleus-independent chemical shifts (NICS) are investigated. It has been seen that these molecular features of the studied compound and its derivatives are mostly solvent dependent. For electron-releasing and -withdrawing derivatives in the solution and gas phases, 2-H forms are the more stable and dominant form. The relative stability of the C 4 -substituted 1,2,4-triazole tautomerism is influenced by the possibility for intramolecular interactions between substituent and electron-donor or electron-acceptor centers of the triazole ring. Keywords DFT . 1,2,4-triazole . Tautomerism . Solvent effect . NBO Introduction The relative stability information depends on the understand- ing of the 5-, 6- and 7-member heterocyclic tautomers, and any subsequent conversions between tautomeric forms are very vital for both biologists and chemists [ 1 – 3 ]. Tautomerization is extensively studied both experimentally and by theory as fundamental processes in the bioorganic chemistry that are associated with the most important conden- sation reactions [4–6]. The importance of investigation on tautomerism of the organic compounds is one of the main topics in theoretical studies by means of various quantum- chemical approaches [7]. Nowadays, the determination of the molecular properties and their application areas are impor- tant; therefore, the study of tautomerization received renewed attention. Triazoles are the prominent medicinal moieties in which the carbon atoms are isosterically replaced by nitrogen atom [8]. The chemistry involving triazoles has a vital role because of their medicinal and industrial characteristics in the pharma- ceutical industry [9, 10]. 1,2,4-triazole derivatives are impor- tant compounds in medicinal chemistry [11]. Moreover, the presence of the sulfur atom onto the 3rd position of 1,2,4- triazole is vital for enhancing the biological activities [12, 13]. Understanding of the relative stabilities of tautomeric forms is important from the structural chemistry viewpoints Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00894-020-4316-9) contains supplementary material, which is available to authorized users. * Abolfazl Shiroudi abolfazl.shiroudi@iauet.ac.ir 1 Young Researchers and Elite Club, East Tehran Branch, Islamic Azad University, Tehran, Iran 2 Department of Separation Science, School of Engineering Science, Lut University-Mikkeli, Lappeenranta, Finland 3 Department of Chemistry and Biochemistry, New Mexico State University, 1175 North Horseshoe Drive, Las Cruces, NM 88003, USA 4 Young Researchers and Elite Club, Tonekabon Branch, Islamic Azad University, Tehran, Iran 5 Chemistry Department, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran Journal of Molecular Modeling (2020) 26:57 https://doi.org/10.1007/s00894-020-4316-9