Electrophilic aromatic substitution on benzofuran and indole: Possible explanation through Wheland intermediates, frontier orbitals control, and charges control

Benzofuran and indole are structurally similar compounds, but they show different reactivity patterns. Benzofuran can undergo electrophilic substitution at either the α or β position depending on the electrophile, whereas indole reacts preferentially at the β position. Density functional theory (DFT) calculations of the Wheland intermediates in the Vilsmeier-Haack formylation and nitration reactions are consistent with the experimental results for formylation, but cannot explain the regioselectivity observed in the nitration of of benzofuran. A frontier orbital approach successfully explains the regiochemistry of Vilsmeier-Haack reaction: electron density favors substitution at the α position in benzofuran and at the β position in indole. In contrast, nitration at the β position in both benzofuran and indole can be explained by assuming charge control as the dominant factor governing the reaction.