Department of Chemistry, Johns Hopkins University , 3400 North Charles Street, Baltimore, Maryland 21218, United States.
J Am Chem Soc. 2017 Oct 25;139(42):14913-14916. doi: 10.1021/jacs.7b09792. Epub 2017 Oct 16.
Electrophilic aromatic substitution (EAS) represents one of the most important classes of reactions in all of chemistry. One of the "iron laws" of EAS is that an electron-rich aromatic ring will react more rapidly than an electron-poor ring with suitable electrophiles. In this report, we present unique examples of electron-deficient arenes instead undergoing preferential substitution in intramolecular competition with more electron-rich rings. These results were made possible by exploiting the heretofore unknown propensity of a hydrogen-bonding OH-arene interaction to switch to the alternative HO-arene interaction in order to provide activation. In an extreme case, this through-space HO-arene activation is demonstrated to overcome the deactivating effect of a trifluoromethyl substituent, making an otherwise highly electron-deficient ring the site of exclusive reactivity in competition experiments. Additionally, the HO-arene activation promotes tetrabromination of an increasingly more electron-deficient arene before the unactivated "control" ring undergoes monobromination. It is our hope that these results will shed light on biological interactions as well as provide new strategies for the electrophilic substitution of aromatic rings.
亲电芳香取代反应（EAS）是化学中最重要的反应类型之一。EAS 的“铁律”之一是，富电子芳香环与合适的亲电试剂反应比缺电子环更快。在本报告中，我们提出了独特的例子，证明缺电子芳环在与富电子环的分子内竞争中优先取代。这些结果之所以成为可能，是因为利用了氢键 OH-芳环相互作用向替代的 HO-芳环相互作用的转变来提供活化。在一个极端的情况下，通过空间 HO-芳环的活化被证明克服了三氟甲基取代基的失活效应，使得一个本来高度缺电子的环成为在竞争实验中唯一反应的位置。此外，HO-芳环的活化促进了越来越缺电子芳环的四溴化，然后未活化的“对照”环才经历单溴化。我们希望这些结果将为生物相互作用提供启示，并为芳香环的亲电取代提供新的策略。
