Synthesis and reactivity of heteroaromatic compounds (First part)

Acidity of pyrrole and Indole

Pyrrole and indole are weak acids (pKa=17)

Resonance stabilization of the anion accounts for this dramatic acidity difference compared with aliphatic amine which pKa is around 35

Pyrrole protonates at Carbon rather than Nitrogen and they react with proton and electrophiles preferentially at C2 position.

Pyrrole and Indole are not basic: the lone pair contributes to the aromaticity, protonation would disrupt the aromaticity!

Be careful:

Pyridine has got a basic lone pair. Effectively, the lone pair is orthogonal to the pi-system and doesn’t participate into the aromaticity, However Pyrrole has a non-basic lone pair , effectively the lone pair is well oriented to the pi system and is involved into the pi-system.

But why I write about heterocyclic compounds?

  • Do you know heterocycles are important biological and medicinal compounds
  • The are both: aromatic and non aromatic heterocycles
  • Be careful: pyridine is a base but pyrrole isn’t
  • Five membered aromatic heterocycles are more electron rich than benzene and they react faster in Electrophilic Aromatic Substitution.

Simple five membered aromatic heterocycles react first at C2 position due to resonance stabilisation in the transition state.

Note that the least reactive five membered aromatic heterocycle is the thiophene because it’s the more aromatic ring than fur an, indole and pyrrole. Pyrrole is so the most reactive of the four rings , it has a high density delocalization stabilizes transition state

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