Fast and accurate prediction of the regioselectivity of electrophilic aromatic substitution reactions†,Chemical Science

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Fast and accurate prediction of the regioselectivity of electrophilic aromatic substitution reactions†
Chemical Science ( IF 7.6 ) Pub Date : 2017-11-13 00:00:00 , DOI: 10.1039/c7sc04156j
Jimmy C Kromann ₁ , Jan H Jensen ₁ , Monika Kruszyk _{2,

3} , Mikkel Jessing ₂ , Morten Jørgensen ₂

Affiliation

While computational prediction of chemical reactivity is possible it usually requires expert knowledge and there are relatively few computational tools that can be used by a bench chemist to help guide synthesis. The RegioSQM method for predicting the regioselectivity of electrophilic aromatic substitution reactions of heteroaromatic systems is presented in this paper. RegioSQM protonates all aromatic C–H carbon atoms and identifies those with the lowest free energies in chloroform using the PM3 semiempirical method as the most nucleophilic center. These positions are found to correlate qualitatively with the regiochemical outcome in a retrospective analysis of 96% of more than 525 literature examples of electrophilic aromatic halogenation reactions. The method is automated and requires only a SMILES string of the molecule of interest, which can easily be generated using chemical drawing programs such as ChemDraw. The computational cost is 1–10 minutes per molecule depending on size, using relatively modest computational resources and the method is freely available via a web server at http://www.regiosqm.org. RegioSQM should therefore be of practical use in the planning of organic synthesis.

中文翻译：

快速准确地预测亲电芳香取代反应的区域选择性†

虽然化学反应性的计算预测是可能的，但通常需要专业知识，并且实验室化学家可以使用的计算工具相对较少来帮助指导合成。本文提出了用于预测杂芳族体系亲电芳族取代反应区域选择性的RegioSQM方法。RegioSQM 将所有芳香族 C–H 碳原子质子化，并使用 PM3 半经验方法将氯仿中自由能最低的碳原子识别为最具亲核中心。对超过 525 个亲电芳香族卤化反应文献实例中的 96% 进行回顾性分析，发现这些位置与区域化学结果定性相关。该方法是自动化的，只需要感兴趣分子的 SMILES 字符串，可以使用 ChemDraw 等化学绘图程序轻松生成。每个分子的计算成本为 1-10 分钟，具体取决于大小，使用相对适度的计算资源，并且该方法可通过http://www.regiosqm.org 的网络服务器免费获得。因此，RegioSQM 在有机合成规划中应该具有实际用途。

更新日期：2017-11-13

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