Unveiling the electrophilic aromatic substitution reactions of pyridine derivatives with nitronium ion through molecular electron density theory

The electrophilic aromatic substitution (EAS) nitration reactions of pyridine, pyridine-1-oxide, and the corresponding protonate species with nitronium NO2+ ion were studied within MEDT at the omega B97X-D/6-311G(d,p) computational level. These EAS reactions occur via a stepwise polar mechanism involving the formation of a labile tetrahedral cation intermediate. The nitration of pyridine and pyridine-N-oxide with nitronium NO2+ ion presents low activation Gibbs free energy, but in the strongly acid medium demanded the nitration reaction, pyridine is entirely converted into the corresponding protonated species, which is strongly nucleophilically deactivated. Consequently, the EAS nitration reaction of pyridine in an acid medium experiment does not take place. On the other hand, the main product of the kinetic control of the EAS nitration reaction of pyridine-N-oxide is the ortho nitro compound but if the explicit solvation of the oxygen atom of pyridine-N-oxide occurs, the reaction product is the para one, which is the experimental product.

Automated summary

The electrophilic aromatic substitution (EAS) nitration reactions of pyridine, pyridine-1-oxide, and the corresponding protonate species with nitronium NO2+ ion were studied using computational simulations. The reactions follow a stepwise polar mechanism and involve the formation of a labile tetrahedral cation intermediate. In strongly acidic conditions, the nitration reaction of pyridine is entirely converted into the corresponding protonated species, leading to nucleophilic deactivation. However, in the nitration reaction of pyridine-1-oxide, the product is influenced by explicit solvation of the oxygen atom, resulting in either ortho or para nitro compounds.