Yang Lian, Zhao Jianming, Yang Xin, Chen Ming, Xue Ying
College of Chemistry, Key Lab of Green Chemistry and Technology in Ministry of Education, Sichuan University Chengdu 610064 People's Republic of China
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy Chengdu 610041 People's Republic of China.
RSC Adv. 2019 Feb 8;9(9):4932-4941. doi: 10.1039/c9ra00082h. eCollection 2019 Feb 5.
The mechanism of the DABCO-catalyzed vinylogous Henry reaction of isatin with 3,5-dimethyl-4-nitroisoxazole and solvent effects on it have been investigated using density functional theory (DFT) methods and QM/MM Monte Carlo (MC) simulation under "on-water" conditions as well as in methanol and THF solutions. The DFT calculations concluded that Path A, in which DABCO directly catalyzes the reaction of isatin 1a with 3,5-dimethyl-4-nitroisoxazole 2 in water, is the most favorable and the first step, the proton transfer process, is the rate-determining step for the reaction. For the roles of solvents in the reaction, QM/MM MC simulations using free energy perturbation theory and PDDG/PM3 as the QM method have been utilized to predict the free energy profiles. The results indicated that the QM/MM method reproduced well the large rate increases on-water. Solute-solvent energy pair distribution and radial distribution functions were also analyzed and illustrated that hydrogen bonding plays a significant role in stabilizing the transition structures. This work reveals the feasible reaction mechanisms and provides new insight into solvent effects for the DACBO-catalyzed vinylogous Henry reaction.
利用密度泛函理论（DFT）方法以及在“水相”条件下以及甲醇和四氢呋喃溶液中的量子力学/分子力学蒙特卡罗（MC）模拟，研究了1,4-二氮杂双环[2.2.2]辛烷（DABCO）催化的异吲哚酮与3,5-二甲基-4-硝基异恶唑的乙烯基类似物亨利反应的机理及其溶剂效应。DFT计算得出，路径A是最有利的，即在水中DABCO直接催化异吲哚酮1a与3,5-二甲基-4-硝基异恶唑2的反应，第一步质子转移过程是该反应的速率决定步骤。对于溶剂在反应中的作用，已利用基于自由能微扰理论并以PDDG/PM3作为量子力学方法的量子力学/分子力学MC模拟来预测自由能分布。结果表明，量子力学/分子力学方法很好地再现了水相上大幅的速率增加。还分析了溶质-溶剂能量对分布和径向分布函数，结果表明氢键在稳定过渡结构中起重要作用。这项工作揭示了可行的反应机理，并为DABCO催化的乙烯基类似物亨利反应的溶剂效应提供了新的见解。
