Paal-Knorr Pyrrole synthesis Mechanism

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

This is an example of the so-called Paal-Knorr pyrrole synthesis. Additionally, there is formation of an unsaturated ester, which suffers a conjugated addition. A plausible mechanism is the following one ... 

Furans are prepared by modification of the chemistry used to make pyrrole derivatives. Because furans have an oxygen atom rather than a nitrogen atom, a modification of the reactive partners is required. When 2,5-hexanedione (115) is treated with acid, the product is a furan, 124. This is called the Paal-Knorr furan synthesis, and it begins with protonation of one carbonyl and attack of the oxygen atom of the second carbonyl to close the ring. Elimination of water leads to the furan because it generates an aromatic system. The reaction of protonated ketones and aldehydes with oxygen nucleophiles was discussed in Chapter 18 (Section 18.6). The mechanism for formation of 124 is therefore related to the chemistry presented in Chapter 18. 

There are two principal routes to pyrroles. One is called the Paal-Knorr synthesis, in which pyrroles are formed by the interaction of 1,4-dicarbonyl compounds and ammonia. No intermediates have ever been isolated, so the mechanism shown in Scheme 6.13 is speculative. 

Chapter 4 discussed two of the traditional methods of pyrrole synthesis, the Paal-Knorr synthesis and the Knorr synthesis. The basic reactions are repeated here as Scheme 9.3. Details of the mechanisms were given in sections 4.2.1 and 4.2.3, respectively. 

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