School of Medical Engineering, Jining Medical University, Jining, Shandong, 272000, P. R. China.
School of Pharmacy, Jining Medical University, Rizhao, Shandong, 276800, P. R. China.
Org Biomol Chem. 2022 Apr 6;20(14):2831-2842. doi: 10.1039/d2ob00056c.
Trifluoromethylation reaction is one of the significant and practical organic chemical reactions, and the design and discovery of novel trifluoromethylation reagents have been attracting more and more attention. Trifluoromethyl-substituted organic hydride compounds (XH) have the potential to be novel trifluoromethylation reagents in organic synthesis due to the favorable tendency of XH˙ releasing ˙CF to form stable aromatic structures in terms of thermodynamics. The key elementary step of the trifluoromethylation is the radical cation (XH˙) generation by catalysis or single-electron activation releasing ˙CF to form a stable aromatic structure, which also provides the thermodynamic driving force of the chemical process. In this work, 47 new trifluoromethylation reagent candidates of XHs were designed and calculated for the Gibbs free energy and activation free energy [Δ(XH˙)] of XH˙ releasing ˙CF using the density functional theory (DFT) method, in order to quantitatively measure the reactivity of XHs as trifluoromethylation reagents, and to establish the molecular library as well as reactivity database of novel trifluoromethylation reagents for synthetic chemists. According to the and Δ(XH˙) values, all the XHs can be reasonably divided into 3 classes, including class 1 (excellent trifluoromethylation reagents), class 2 (potential trifluoromethylation reagents) and class 3 (not trifluoromethylation reagents). To our delight, 15 XHs with a 1,4-dihydropyridine structure and 3 XHs with a 3,4-dihydropyrimidin-2-one structure are identified to be novel excellent and potential trifluoromethylation reagents, respectively, according to their reactivity data. The relationship between the structural features, including methylation, heteroatom, substituents, conjugated structure and so on, and the reactivity of XHs as trifluoromethylation reagents are also discussed in this work. The computation results indicate that trifluoromethyl-substituted 1,4-dihydropyridine compounds and 3,4-dihydropyrimidin-2-one analogues could be possible trifluoromethylation reagents in organic synthesis. This work may provide the theoretical basis and references for discovering organic hydride compounds as novel reagents for trifluoromethylation or other alkylation reactions.
三氟甲基化反应是重要且实用的有机化学反应之一，新型三氟甲基化试剂的设计和发现越来越受到关注。由于有机氢化物化合物 (XH) 释放˙CF 形成稳定芳香结构的热力学趋势有利，因此三氟甲基取代的有机氢化物化合物 (XH) 有可能成为有机合成中的新型三氟甲基化试剂。三氟甲基化的关键基元步骤是通过催化或单电子活化生成自由基阳离子 (XH˙)，释放˙CF 形成稳定的芳香结构，这也为化学反应提供了热力学驱动力。在这项工作中，使用密度泛函理论 (DFT) 方法设计和计算了 47 种新型 XH 的三氟甲基化试剂候选物，以计算 XH˙释放˙CF 的吉布斯自由能和活化自由能 [Δ(XH˙)]，从而定量衡量 XH 作为三氟甲基化试剂的反应性，并为合成化学家建立新型三氟甲基化试剂的分子库和反应性数据库。根据和 Δ(XH˙) 值，所有 XH 可以合理地分为 3 类，包括第 1 类 (优秀的三氟甲基化试剂)、第 2 类 (潜在的三氟甲基化试剂) 和第 3 类 (非三氟甲基化试剂)。令我们高兴的是，根据其反应性数据，确定 15 种具有 1,4-二氢吡啶结构的 XH 和 3 种具有 3,4-二氢嘧啶-2-酮结构的 XH 分别为新型优秀和潜在的三氟甲基化试剂。此外，还讨论了 XH 作为三氟甲基化试剂的反应性与结构特征之间的关系，包括甲基化、杂原子、取代基、共轭结构等。计算结果表明，三氟甲基取代的 1,4-二氢吡啶化合物和 3,4-二氢嘧啶-2-酮类似物可能是有机合成中三氟甲基化或其他烷基化反应的新型试剂。这项工作可能为发现有机氢化物化合物作为新型三氟甲基化或其他烷基化反应试剂提供理论依据和参考。
