Heterocyclic Chemistry at a Glance, Second Edition. John A. Joule and Keith Mills.
© 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.
Electrophilic substitution at carbon
Indoles are not basic – they do not form salts by protonation on the nitrogen – this would destroy the aromaticity of
the pyrrole ring and produce a localised (non-resonance-stabilised) ammonium ion.
Electrophilic addition of a proton to an indole -position does occur, to a minor degree, however if the small equilib-
rium concentration of the resulting cation can be trapped, products resulting from that 3-protonated species (known
as a 3H-indolium cation or indoleninium cation) can be isolated. Thus, an N-protected tryptophan ester can be con-
verted into a tricyclic product via a small concentration of the indoleninium cation, as shown.
Similarly, indole does not add electrophiles at the nitrogen, but does readily undergo electrophilic C-substitution
in the much more electron-rich pyrrole ring. Indoles are attacked by electrophiles much more easily than benzene.
Attack is preferentially at the -position but will also, and only slightly less rapidly, take place at an -position when
the-position is blocked. Positional selectivity and the high reactivity are both well explained by a consideration of
the resonance contributors to the intermediates for electrophilic substitution. Intermediate cations from both - and
-attack are stabilised (and both retain a complete benzene ring), however delocalisation, involving donation of elec-
tron density from the heteroatom, is greater in the intermediate from -attack compared with the -intermediate, but
note that the latter is only slightly less stabilised, being a benzylic cation.
The high reactivity of indole towards electrophiles is demonstrated by the several substitution reactions illustrated
below. Thus, the bromination of indole uses bromine alone; its acylation with a reactive acid chloride does not require