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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.

enter image description here

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.

enter image description here

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,

enter image description here

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

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    $\begingroup$ See Indole Elctrophilic Substitution in Joule and Mill's Heterocyclic Chemistry $\endgroup$
    – Aditya Roychowdhury
    Aug 1, 2020 at 8:39
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    $\begingroup$ 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 $\endgroup$
    – Yusuf Hasan
    Aug 1, 2020 at 9:28

1 Answer 1

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The traditional explanation for the reactivity of indole at C–3 is that attack at C–3 does not disrupt the aromaticity of the benzene ring in the cationic intermediate (see any organic chemistry book; for heterocycles a good book is Joule and Mills as has been suggested in the comments):

Electrophilic substitution of indole

You have drawn many of the resonance structures for the intermediate, including the two shown above. So I should mention that the major resonance contributor should be the one where the positive charge is borne by the nitrogen. In this case, the positively charged nitrogen has four bonds and a complete octet; whereas if the positive charge is on carbon, that's formally a six-electron, electron-deficient carbocation. Many thanks to Buttonwood for pointing this out.

To a first approximation, one could consider the reactivity of indole to be as if it were a benzene ring plus an enamine, and enamines are very, very happy to react β to nitrogen and not α. This is of course not an enamine, but the idea is the same.

For pyrrole, there is no "other benzene ring" to worry about, so this consideration does not apply.

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    $\begingroup$ Equally to note, back to the original question: For a substitution at C2-position, the intermediate state was drawn including mesomers breaking the aromaticity of the the benzene ring; the analogue for the substitution at C3 is missing. As if the OP recognized the additional price to pay to break aromaticity (but this is a speculation). $\endgroup$
    – Buttonwood
    Aug 1, 2020 at 17:19
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    $\begingroup$ @Buttonwood thanks for pointing out! I think the missing point which I failed to include was that the major resonance structure should be one where the positive charge is on nitrogen (octet complete) vs a 6-electron carbocation. I will edit that in. $\endgroup$
    – orthocresol
    Aug 1, 2020 at 17:20

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