Selectivity in the Addition of Electron Deficient Radicals to the C 2 Position of Indoles.

The addition of electron deficient radicals to the C2 position of indoles has been described in the literature as opposed to electrophilic addition at the C 3 position. Density functional theory calculations were used to understand the switch in regioselectivity from C3 to C2 for indole to undergo radical additions. Electron deficient radicals have a lower barrier for reaction at C 2 and a lower energy radical intermediate that benefits from benzylic radical stabilization. Trifluoromethyl radical addition has a lower energy barrier than acetonitrile radical, and the C 3 addition transition state is just 0.8 kcal/mol higher than C2 . This is supported by experimental observations.