Role of Water in the Reaction Mechanism and endo/exo Selectivity of 1,3-Dipolar Cycloadditions Elucidated by Quantum Chemistry and Machine Learning
Role of Water in the Reaction Mechanism and endo/exo Selectivity of 1,3-Dipolar Cycloadditions Elucidated by Quantum Chemistry and Machine Learning
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量子化学和机器学习阐明水在 1,3-偶极环加成反应机制和内/外选择性中的作用
DOI：
10.1002/chem.201900617
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Yang Shengyong
中科院分区：
文献类型：
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作者：
Yang Xin;Zou Jun;Wang Yifei;Xue Ying;Yang Shengyong
甲亚胺叶立德与活化烯烃的不对称1，3-偶极环加成反应是合成对映体富集的吡咯啉和吡咯烷衍生物的最重要和最通用的方法之一。尽管在理论和实践上都很重要，但水分子在反应性和内/外选择性中的作用仍然不清楚。为了探索水如何加速1，3-偶极酞嗪-2-二氰基甲烷（1）和两种亲偶极试剂的环加成反应并提高其内/外选择性，使用了从头算质量的神经网络势，克服了显式考虑水分子的计算瓶颈。结果表明，不仅亲偶极试剂和1，3-偶极试剂的性质，而且溶剂介质也会干扰甚至改变反应机理。发现了1，3-偶极1与甲基乙烯基酮反应的极端情况，其中反应机理从协调模式变为逐步模式，从MeCN到H2O作为溶剂，形成两性离子中间体，其在能量表面上是非常浅的最小值。因此，尽管该机制具有逐步性质，但仍然可以预期高度立体控制。结果表明，水可以诱导全局极化沿着反应坐标，并强调微溶剂化效应和体相效应在再现实验观察到的水加速和增强的内/外选择性中的作用。
Asymmetric 1,3‐dipolar cycloadditions of azomethine ylides with activated olefins are among the most important and versatile methods for the synthesis of enantioenriched pyrroline and pyrrolidine derivatives. Despite both theoretical and practical importance, the role of water molecules in the reactivity andendo/exoselectivity remains unclear. To explore how water accelerates the reactions and improves theendo/exoselectivity of the cycloadditions of 1,3‐dipole phthalazinium‐2‐dicyanomethanide (1) and two dipolarophiles, an ab initio‐quality neural network potential that overcomes the computational bottleneck of explicitly considering water molecules was used. It is demonstrated that not only the nature of both the dipolarophile and the 1,3‐dipole, but also the solvent medium, can perturb or even alter the reaction mechanism. An extreme case was found for the reaction of 1,3‐dipole1with methyl vinyl ketone, in which the reaction mechanism changes from a concerted to a stepwise mode on going from MeCN to H2O as solvent, with formation of a zwitterionic intermediate that is a very shallow minimum on the energy surface. Thus, high stereocontrol can still be expected despite the stepwise nature of the mechanism. The results indicate that water can induce global polarization along the reaction coordinate and highlight the role of microsolvation effects and bulk‐phase effects in reproducing the experimentally observed aqueous acceleration and enhancedendo/exoselectivity.