Second Year Organic Chemistry

Pyridine (C₆H₅N) is the heteroaromatic analogue of benzene (C₆H₆) in which one of the CH groups has been replaced with nitrogen. The nitrogen lone pair is orthogonal to the aromatic p–system and has far reaching effects upon reactivity. Pyridine is a base and its conjugate acid has a pK_a = 5.2.

Electrophiles react preferentially with the lone pair of the nitrogen to generate the pyridinium ion which, being positively charged, is unreactive towards electrophilic substitution. Neutral pyridine, which can react with electrophiles, is present only in a very low equilibrium concentration and so reaction rate is slow.

Furthermore, pyridine is less reactive than benzene in this regard as the nitrogen polarises the p–system, resulting in decreased electron density on the carbons. The electron withdrawing effect is strongest at positions 2, 4 and 6 and so electrophilic substitution to form 3–substituted products is least disfavoured to much the same degree that a nitro–substituent directs electrophilic substitution of benzene. Electron donating substituents at positions 2, 4 and 6 favour reaction.

The situation may be rationalised by comparing the Wheland intermediates resulting from attack at C–2 and C–4 with that arising from attack at C–3. Intermediates formed by the first two modes of reaction possess unfavourable resonance canonicals in which positive charge is located on nitrogen; whereas this is not the case with C–3 attack. This analysis is valid as the high energy intermediates are good models for the transition states leading to them, in accordance with the Hammond postulate.

Nucleophilic Aromatic Substitution of Pyridine

Pyridines are susceptible to nucleophilic attack at C–2 and C–4 as this leads to anionic intermediates which possess a favourable resonance canonical with the negative charge located on nitrogen. By analogy with nitrobenzene, 2– or 4–halopyridines will undergo preferential substitution of the halide compared to 3–halopyridines by a two step addition–elimination reaction.

Moreover, presence of a good nucleofuge at C–2 or C–4 is not necessary with certain nucleophiles (NH₂^–, alkyl and aryl anions) which will add, almost invariably at C–2, to form the dihydropyridine anion. This may be isolable, but usually undergoes subsequent oxidation to form the 2–substituted pyridine. In the case of NH₂^– the reaction is known as the Chichibabin reaction.

Electrophilic Aromatic Substitution of Quinoline and Isoquinoline

Quinoline and isoquinoline are basic in the same way as pyridine and therefore aromatic substitution occurs on the homoaromatic ring as the heteroaromatic ring is deactivated due to protonation. Substitution is preferred at C–5 and C–8 as the intermediates can profit from resonance stabilization without disrupting the aromaticity of the heteroaromatic ring. Note The numbering system for quinoline and isoquinoline does not follow standard IUPAC convention. In particular, numbering of the isoquinoline nucleus does not start at the heteroatom.

Electrophilic Aromatic Substitution of Pyrrole

The lone pair of the nitrogen in pyrrole is involved in the aromatic p–system and resonance canonicals can be drawn in which negative charge resides on the carbons. Consequently, and in contrast to pyridine, pyrrole is reactive towards electrophilic substitution at either C–2 or C–3.

By analogy with benzene, reaction involves addition of the electrophile, followed by regeneration of the aromatic ring by deprotonation. However, pyrrole is unstable towards oxidising agents and therefore cannot be nitrated using the classical nitrating mixture of a mixture of concentrated nitric and sulfuric acids. Electrophilic substitution is favoured at C–2. Vilsmeier formylation is a particularly efficient reaction with the electron rich pyrrole substrate.

Electrophilic Aromatic Substitution of Indole Indole shows reactivity comparable with that of pyrrole with the exception that electrophilic substitution occurs at C–3 as this can involve stabilization of the intermediate carbocation by mesomeric donation from the nitrogen without destruction of the homoaromatic ring.