# Regioselectivity in Electrophilic Aromatic Substitution of Pyrrole and Indole

If we look into the structures of Pyrrole and Indole, they are very similar. Only Indole has one extra Benzene ring attached to it, i.e. if we attach one Benzene ring to Pyrrole, what we'll have is nothing but Indole.

But if we delve into the preferable positions of Electrophilic Aromatic Subsitutions for these compounds, it's pretty well known that Pyrrole undergoes EAS preferentially at the $$2$$-position, whereas for Indole it's the $$3$$-position which is favoured.

A typical example of an Elcetophilic Aromatic substitution reaction where this distinct feature between Pyrrole and Indole can be clearly visible is the Vilsmeier-Haack Reaction. The major outcomes of the reaction in the two cases clearly show the difference.

Now, the preference of $$2$$-position in case of Pyrrole can be justified easily by considering the greater stability of the $$\sigma$$-complex intermidiate formed in case of substitution at $$2$$-position due to more number of resonating structures as clearly been described in the answer to the question Regioselectivity in Electrophilic Substitution of Pyrrole

Now my question is, applying the similar logic Electrophilic substitution at the $$2$$-position should be even more favoured in case of Indole, as the $$\sigma$$-complex in that case should be further more stabilised due to resonance with the Benzene ring as well. Therefore, the preference of substitution at $$2$$-position should be exceptionally higher than at $$3$$-position in case of Indole. But in reality, it's actually the opposite. Why is this anomaly observed in case of Indole ?

The resonating structures in case of two different substituent positions in Indole are shown below,

P.S. Thoughtful answers are highly appreciated. Any kind of Quantum Mechanical Calculations or Computations or Orbital Analogy are also welcome.

• See Indole Elctrophilic Substitution in Joule and Mill's Heterocyclic Chemistry – Aditya Roychowdhury Aug 1 '20 at 8:39
• An abstract from the book referred above by Aditya, under Reactions with Electrophilic reagents for Indoles: Reactions and Synthesis: "By NMR and UV examination, only the 3 - protonated cation (3 H - indolium cation) is detectable; it is the thermodynamically stablest cation, retaining full benzene aromaticity (in contrast to the 2 - protonated cation) with delocalization of charge over the nitrogen and α - carbon". It seems like the argument is that EAS at position 2 disturbs the aromaticity, hence position 3 is preferred – Yusuf Hasan Aug 1 '20 at 9:28