Institute for Computational Science and Engineering, Laboratory of New Fiber Materials and Modern Textile, the Growing Base for State Key Laboratory, Qingdao University, Qingdao 266071, China.
Org Biomol Chem. 2014 Mar 28;12(12):1908-18. doi: 10.1039/c3ob42157k. Epub 2014 Feb 12.
The detailed mechanism of the chiral phosphoric acid-catalyzed diarylation reaction between acetophenone and indole has been investigated by DFT methods and compared with that of the reaction between 2,2,2-trifluoroacetophenone and indole. The calculated results confirm our previous hypothesis that the CF3 group in the ketone plays a perfect double role in activating the substrate and stabilizing the single arylation product of tertiary alcohol. It is also demonstrated that the different ratio of the F-substitution in the CH3 group of methyl ketone (CH3-nFn, n = 0, 1, 2, 3) affects the activation energy of the key dehydration step for the proposed diarylation process differently, and determines whether the subsequent re-arylation proceeds or is being suppressed. The computational prediction that the prohibitive barriers for CF3 and CHF2 ketones in the rate-determining dehydration step for the diarylation process could be overcome at higher reaction temperature has been validated by our additional experiments at 80 °C. Furthermore, the origin of the high enantioselectivity of the chiral phosphoric acid-catalyzed single arylation of trifluoromethyl ketone has been studied with the two-layer ONIOM method. The experimentally observed enantiomeric excess can be successfully rationalized.
通过 DFT 方法研究了手性磷酸催化的苯乙酮与吲哚的二芳基化反应的详细机理，并与 2,2,2-三氟苯乙酮与吲哚的反应进行了比较。计算结果证实了我们之前的假设，即酮中的 CF3 基团在激活底物和稳定叔醇的单芳基化产物方面发挥了完美的双重作用。还表明，甲基酮（CH3-nFn，n = 0,1,2,3）中 CH3 基团的 F 取代的不同比例对所提出的二芳基化过程中关键脱水步骤的活化能有不同的影响，并决定随后的再芳基化是否进行或被抑制。我们在 80°C 进行的额外实验验证了计算预测，即在二芳基化过程中，CF3 和 CHF2 酮的速率决定脱水步骤的高能垒可以在更高的反应温度下克服。此外，使用两层 ONIOM 方法研究了手性磷酸催化的三氟甲基酮单芳基化的高对映选择性的起源。实验观察到的对映体过量可以得到合理的解释。
