Pharmaceutical Chemistry: Fused Ring Heterocycles

Study Notes

Quinoline and isoquinoline are two isomeric benzo pyridines, with quinoline being benzo[b]pyridine and isoquinoline being benzo[c]pyridine.
These heterocyclic units are important because their derivatives occur widely in nature as alkaloids, such as the antimalarial quinine and the pain reliever morphine.

Both quinoline and isoquinoline are basic in nature.
The lone pair of electrons on the nitrogen atom is not utilized in the internal resonance for the aromaticity of the compounds.
Unlike benzene, the bond lengths of both compounds are irregular, and both possess considerable dipole moment directed toward the nitrogen atom.
Both compounds react with acids and Lewis acids at the basic nitrogen atom, forming quinolium and isoquinolium salts, respectively.

Electrophilic substitutions of quinoline and isoquinoline take place in the benzene ring due to the lower electron density of the pyridine ring compared to the benzene ring.
Nitration of quinoline with fuming nitric acid in concentrated sulfuric acid gives a mixture of 5-nitro- and 8-nitroquinolines, whereas isoquinoline reacts to give a mixture of 5- and 8- nitro isoquinolines.
Sulfonation of quinoline with oleum gives mainly quinoline-8-sulfonic acid, whereas isoquinoline gives isoquinoline-5-sulfonic acid.
Alkyl and acyl halides react directly with the basic nitrogen atom of both compounds to give quaternary salts.

Quinoline undergoes an addition-substitution reaction with acetyl nitrate at 20°C to give 3-nitroquinoline, whereas isoquinoline does not undergo such a reaction.
The C=N bond of the pyridine ring in both compounds undergoes nucleophilic addition at low temperature with KNH2, and the adduct on oxidation with KMnO4 gives 2-aminoquinoline and 1-aminoisoquinoline in a Chichibabin-type reaction.

Quinoline can be synthesized through Skraup synthesis, which involves the reaction of glycerol, aniline, sulfuric acid, nitrobenzene, and ferrous sulfate.
This method can be applied to synthesize benzene ring-substituted quinoline provided the substituents are not strongly deactivating in nature.
Isoquinoline can be synthesized through Bischler–Napieralski synthesis and Pomeranz–Fritsch reaction.