Kromann Jimmy C, Jensen Jan H, Kruszyk Monika, Jessing Mikkel, Jørgensen Morten
Department of Chemistry , University of Copenhagen , Copenhagen , Denmark . Email:
Discovery Chemistry , DMPK , Neuroscience Drug Discovery , H. Lundbeck A/S, Valby , Denmark . Email:
Chem Sci. 2017 Nov 13;9(3):660-665. doi: 10.1039/c7sc04156j. eCollection 2018 Jan 21.
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 a web server at ; http://www.regiosqm.org. RegioSQM should therefore be of practical use in the planning of organic synthesis.
虽然化学反应性的计算预测是可行的，但通常需要专业知识，而且可供实验化学家用于指导合成的计算工具相对较少。本文介绍了用于预测杂芳族体系亲电芳香取代反应区域选择性的RegioSQM方法。RegioSQM对所有芳香族C-H碳原子进行质子化，并使用PM3半经验方法确定在氯仿中具有最低自由能的那些原子作为最亲核中心。在对525多个文献中亲电芳香卤化反应实例的96%进行回顾性分析时，发现这些位置与区域化学结果在定性上相关。该方法是自动化的，只需要目标分子的SMILES字符串，使用诸如ChemDraw等化学绘图程序可以轻松生成该字符串。根据分子大小，计算成本为每个分子1 - 10分钟，使用的计算资源相对适中，并且该方法可通过网络服务器免费获取，网址为：http://www.regiosqm.org。因此，RegioSQM在有机合成规划中应具有实际用途。
