Through-Space Activation Can Override Substituent Effects in Electrophilic Aromatic Substitution

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.