Zhang Jun, Yang Yi Isaac, Yang Lijiang, Gao Yi Qin
†Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, and ‡Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China.
J Phys Chem B. 2015 Apr 30;119(17):5518-30. doi: 10.1021/jp511057f. Epub 2015 Apr 17.
An efficient sampling method was implemented in QM/MM hybrid molecular simulations to study aliphatic Claisen rearrangement in aqueous solutions. On the basis of the computational results, the necessary conformational adjustment to trap the reactant into a favorable compact conformation specifically in water was observed. The conformational equilibrium was shown to be important to the elucidation of the "water-acceleration" effect of Claisen rearrangement. Thus, a two-step process of aqueous Claisen rearrangement was proposed. It was similar to the pseudodiaxial-pseudodiequatorial conformational equilibrium observed in the enzymatic reaction of chorismate acid but with explicit inclusion of the solvent coordinates to explain the solvation effects. Polarization was found to occur during the reactant conformational transition. A solvent with high cohesive energy density (CED) like water was suggested to accommodate compact conformers better, thus facilitating the following reaction by concentrating the real "active" reactant. The substituent effects also manifested, leading to varied conformational distributions of different substituted allyl vinyl ethers (AVEs). The application of the enhanced sampling method allowed a systematic analysis of thermodynamic information without loss of solvent coordinates. These data showed the conformational transition of AVEs was an entropy-driving process which was sensitive to the substituent, and enthalpy played an important role in the solvation effect on the conformational equilibrium.
在量子力学/分子力学（QM/MM）混合分子模拟中实施了一种高效采样方法，以研究水溶液中的脂肪族克莱森重排反应。基于计算结果，观察到为了将反应物捕获到特别是在水中有利的紧凑构象中所需的构象调整。构象平衡对于阐明克莱森重排反应的“水加速”效应很重要。因此，提出了水相克莱森重排的两步过程。它类似于在分支酸的酶促反应中观察到的假双轴-假双赤道构象平衡，但明确包含溶剂坐标以解释溶剂化效应。发现在反应物构象转变过程中发生了极化。有人提出，像水这样具有高内聚能密度（CED）的溶剂能更好地容纳紧凑构象体，从而通过浓缩真正的“活性”反应物促进后续反应。取代基效应也很明显，导致不同取代的烯丙基乙烯基醚（AVE）具有不同的构象分布。增强采样方法的应用允许在不丢失溶剂坐标的情况下对热力学信息进行系统分析。这些数据表明，AVE的构象转变是一个受取代基影响的熵驱动过程，并且焓在对构象平衡的溶剂化效应中起重要作用。
