A density functional theory study of the mechanism of the Paal–Knorr pyrrole synthesis

The Paal–Knorr pyrrole synthesis, which involves the reaction of 1,4-dicarbonyls with amines, is among the most classical methods of heterocyclic pyrrole ring synthesis. The detailed sequence and the nature of the intermediates that occur in the Paal–Knorr reaction mechanism are not well understood. Density functional theory methods have been employed to investigate the nature of the intermediates and transition states in the Paal–Knorr pyrrole mechanism. Two mechanistic pathways for the reaction were examined: hemiaminal cyclization vs. enamine cyclization. Our calculated reaction potential energy surfaces suggest that the hemiaminal cyclization is the preferred pathway for the reaction both in gas phase and in solution. This conclusion is consistent with the experimental results which suggest that the hemiaminal intermediate undergoes cyclization in the rate-limiting step in the Paal–Knorr reaction mechanism. The preferred mechanism for the Paal–Knorr reaction consists of hemiaminal formation, hemiaminal cyclization and a dehydration step to form the pyrrole ring. Water and hydrogen-bonding interactions play a key role in catalyzing the hydrogen-transfer steps of the reaction.