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A theoretical investigation on the proton transfer tautomerization mechanisms of 2-thioxanthine within microsolvent and long range solvent

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Abstract

A relative complete study on the mechanisms of the proton transfer reactions of 2-thioxanthine was carried out with density functional theory. The models were designed with monohydrated and dihydrated microsolvent catalyses either with or without the presence of water solvent considered with the polarized continuum model (PCM). A total number of 114 complexes and 67 transition states were found with the B3LYP/6-311+G** calculations. The energies were refined with both B3LYP/aug-cc-pVTZ and PCM-B3LYP/aug-cc-pVTZ methods. The activation energies were reported with respect to the Gibbs free energies obtained in conjunction with the standard statistical thermodynamics. Possible reaction pathways were confirmed with the intrinsic reaction coordinates. Pathways via C8 atom on the imidazole ring, via the bridged C4 and C5 atoms between pyrimidine and imidazole rings and via N, O and S atom on the pyrimidine ring were examined. The results show that the most feasible pathway is the proton transfers within the long range solvent surrounding via the N, O and S atoms in the pyrimidine ring with di-hydrated catalysis: N(7)H + 2H2O → IM89 → IM90 → P13 + 2H2O → IM91 → IM92 → P6 + 2H2O → IM71 → IM72 → P7 + 2H2O → IM107 → IM108 → P18 + 2H2O → IM111 → IM112 → P19 + 2H2O → IM113 → IM114 → P17 + 2H2O → IM105 → IM106 → N(9)H + 2H2O that has the highest energy barrier of 44.0 kJ mol−1 in the transition of IM89 to IM90 via TS54. The small energy barrier is in good agreement with the experimental observation that 2-TX tautomerizes at room temperature in water. In the aqueous phase, the most stable intermediate is found to be IM21 [N(7)H + 2H2O] and the possible co-existing species are the monohydrated IM1, IM9, IM39 and IM46, and the di-hydrated IM5, IM8, IM13, IM16, IM81, IM89, IM90, IM91 and IM106 complexes that have a relative concentration larger than 10−6 (1 ppm) with respect to IM21.

Mechanisms of the proton transfer reactions of 2-thioxanthine were investigated with both B3LYP/aug-cc-pVTZ//B3LYP/6-311+G** and PCM-B3LYP/aug-cc-pVTZ//B3LYP/6-311+G**. The models were designed with monohydrated and dihydrated microsolvent either with or without the presence of water solvent. The results show that the most feasible pathway is the reactions within the long range solvent surrounding via the N, O and S atoms in the pyrimidine ring with di-hydrated catalysis: N(7)H + 2H2O → IM90 → IM91 → P13 + 2H2O → IM92 → IM93 → P6 + 2H2O → IM72 → IM73 → P7 + 2H2O → IM109 → IM110 → P18 + 2H2O → IM113 → IM114 → P19 + 2H2O → IM115 → IM116 → P17 + 2H2O → IM107 → IM108 → N(9)H + 2H2O that has the highest barrier of 44.0 kJ mol−1 in the transition of IM90 to IM91 via TS54. The barrier is adequate for a reaction at room temperature that consists well with the experimental observations.

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Acknowledgments

Part of the calculations were performed in the High Performance Computation Center of the Northwestern Polytechnical University. Support by the Basic Research Foundation of Northwestern Polytechnical University (Grant No. JC201269) and Wenli Special Foundation of Xi’an Science Technology Bureau (CXY1134WL13) is greatly acknowledged.

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Authors and Affiliations

  1. Key Laboratory of Space Applied Physics and Chemistry of the Ministry of Education, School of Natural and Applied Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi, 710072, People’s Republic of China

    Hong-Jiang Ren, Ke-He Su, Yan Liu, Xiao-Jun Li, Jun Xiao & Yan-Li Wang

  2. College of Chemistry and Chemical Engineering, Xi’an University of Arts and Science, Xi’an, Shaanxi, 710065, People’s Republic of China

    Hong-Jiang Ren

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  1. Hong-Jiang Ren
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Correspondence to Ke-He Su.

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Ren, HJ., Su, KH., Liu, Y. et al. A theoretical investigation on the proton transfer tautomerization mechanisms of 2-thioxanthine within microsolvent and long range solvent. J Mol Model 19, 3279–3305 (2013). https://doi.org/10.1007/s00894-013-1858-0

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