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

Abstract

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.

Sulfonylation of Five‐Membered Aromatic Heterocycles Compounds through Nucleophilic Aromatic Substitution: Concerted or Stepwise Mechanism?

“…The reactivity order was NO 2 ( v )>CHO( ii )>COCH 3 ( iii )>COOC 2 H 5 ( iv )>H( i ). This result is in agreement with the substituent effects in aromatic rings described in the literature, i. e. the more electron‐withdrawing group is NO 2 which facilitates the SNAr reaction on the aromatic ring (model v ), while the carbonyl group has a moderate effect. For the unsubstituted aromatic compound, (NG=Hydrogen), the profile indicates a concerted mechanism, and the energy of activation is the highest.…”

Spectroscopic Characterization of a [C−F−C]+ Fluoronium Ion in Solution

“…In all cases, we observed decomposition, likely resulting from the protonation and putative dissociation of the fairly basic anhydride group. This result led us to conclude, erroneously, that the basic system represented by 2 and 3 was not appropriate for Lewis acid studies, though it had proved to be extremely versatile for investigating other phenomena . Some time later, as a final approach, we attempted to form the desired cation in solution through ionization of difluoride 4 , which was synthesized from alcohol 3 by treatment with Xtalfluor‐E and DBU .…”

“…The fluorine atom is part of a molecule that is more complex than the ammonium and oxonium examples, and its chemical shifts in both the precursor and cation arise from a multitude of different factors. The inward‐pointing fluorine of the starting difluoride experiences “jousting” interactions with the in‐hydrogen atom on the opposing bridge, leading to orbital compression and strong nuclear deshielding. Thus the fact that the 19 F nucleus becomes more shielded as it is transformed from difluoride 4 into fluoronium 1 is not dominated by factors that would be present for a generalized alkyl fluoride.…”

Tracking intramolecular energy redistribution dynamics in aryl halides: the effect of halide mass

“…The substituent effect is one of the most important concepts in chemistry, biochemistry, and related elds. [1][2][3][4] When substituted benzenes became the subject of a spectroscopic study, [5][6][7][8] there was much confusion regarding the results, such as the inuence of substituents on reactivity and stability of the very wide range of organic species containing aromatic moieties. [9][10][11][12] Analysis of mono-substituted benzenes reveals that the inuence of a single group will be essential.…”