基于密度泛函理论研究噻替哌和替哌水解反应机理

Density functional investigation on the hydrolysis reaction mechanism of thiotepa and tepa

运用DFT中的CAM-B3LYP方法并结合PCM在6-311++G(d,p)基组水平计算研究[Thiotepa(Tepa)-n H_2O](n=1,4)在气相和水相中水解反应的反应物、中间体、过渡态及产物几何结构、势能曲线和电子结构。结果表明:气相中Thiotepa(Tepa)-1H_2O第二步水解过程(X-COM1-2-H_2O→X-TS1-2)为限速步骤,能垒为227.4(206.3)k J?mol-1,速率常数分别为9.30×10-29和4.83×10-25 s-1。气相中Thiotepa(Tepa)-4H_2O水解反应的限速步骤速率常数比Thiotepa(Tepa)-1H_2O增大了1.98×103-4.59×105倍,表明增加第一溶剂层后Thiotepa(Tepa)水解速率加快。考虑远程溶剂化效应后,Thiotepa(Tepa)-1H_2O水解反应限速步骤的活化能垒降低了16.2和21.4 k J?mol-1,而Thiotepa(Tepa)-4H_2O反应限速步骤能垒增加了24.4和35.7 k J?mol-1,水解难度增加,但两种水解途径的氢键复合物及产物能量均降低,热力学有利。气相和水相中的计算结果均表明噻替哌能垒比替哌高,与实验测定水解结果一致。氢键复合物电子密度拓扑分析表明在X—H···Y体系中氢键强度为O···H>Nleaving···H>S···H。

In this work, the hydrolysis processes mechanism of [Thiotepa（Tepa）-nH2O]（n= 1, 4） were calculated at the CAM-B3LYP/6-31 1＋＋G（d, p） level in gaseous phase and aqueous phase by PCM. The geometric structures of reactants, intermediates, transition states and products in the processes have been optimized, potential energies curves and electron topology have been performed. It is found that the second hydrolysis steps （X-COM1-2-H20→X-TS1-2） are the limiting rate steps ofThiotepa（Tepa）- 1H20, the activation energy are 227.4（206.3） kJ·mol^-1, the rate constants are 9.30×10^-29 and 4.83×10-25 s^-1. The limiting rate contants of Thiotepa（Tepa）-4H2O are predicted to be 1.98×10^3-4.59×10^5 times larger than Thiotepa（Tepa）-1H2O reactions, that is, the water molecules in the Thiotepa（Tepa） hydrolysis processes have a positive influence. The results suggest that values of activation energy are lower in the aqueous solution than in gas phase by an extent of 16.2 and 21.4 kJ.molt for the Thiotepa（Tepa）-lH20. Kinetic analyses of Thiotepa（Tepa）-4H20 show that aqueous solution has negative influence, but the thermodynamic properties indicate that aqueous solution is conducive to hydrolysis reactions. All energy barriers of Thiotepa are nearly higher than Tepa＇s values and which are in good agreement with experimental results. Topological analysis of the electron density indicated that hydrogen bond strength of complexes are O...H 〉 N（leaving）…H 〉 S...H.