Paal-Knorr synthesis

Paal-Knorr synthesis
Named after	Carl Paal Ludwig Knorr
Reaction type	Ring forming reaction
Identifiers
RSC ontology ID	RXNO:0000161

Paal-Knorr furan synthesis
Identifiers
Organic Chemistry Portal	paal-knorr-furan-synthesis
RSC ontology ID	RXNO:0000162

Paal-Knorr pyrrole synthesis
Identifiers
Organic Chemistry Portal	paal-knorr-pyrrole-synthesis
RSC ontology ID	RXNO:0000164

Paal-Knorr thiophene synthesis
Identifiers
Organic Chemistry Portal	paal-knorr-thiophene-synthesis
RSC ontology ID	RXNO:0000163

Knorr pyrazole synthesis
Named after	Ludwig Knorr
Reaction type	Ring forming reaction
Identifiers
RSC ontology ID	RXNO:0000391

The Paal–Knorr Synthesis in organic chemistry is a reaction that generates either furans, pyrroles, or thiophenes from 1,4-diketones. It is a synthetically valuable method for obtaining substituted furans and pyrroles, common structural components of many natural products. It was initially reported independently by German chemists Carl Paal and Ludwig Knorr in 1884 as a method for the preparation of furans, and has been adapted for pyrroles and thiophenes. Although the Paal–Knorr synthesis has seen widespread use, the mechanism wasn't fully understood until it was elucidated by V. Amarnath et al. in the 1990s.

The furan synthesis requires an acid catalyst:

In the pyrrole synthesis a primary amine participates:

and in that of thiophene for instance the compound phosphorus pentasulfide:

The acid catalyzed furan synthesis proceeds by protonation of one carbonyl which is attacked by the forming enol of the other carbonyl. Dehydration of the hemiacetal gives the resultant furan.

The mechanism of the Paal–Knorr furan synthesis was elucidated in 1995 by V. Amarnath et al. Amarnath's work showed that the diastereomers of 3,4-disubstituted-2,5-hexane diones react at different rates. In the commonly accepted mechanism, these diones would go through a common enol intermediate, meaning that the meso and d,l-racemic isomers would cyclize at the same rate as they form from a common intermediate. The implication of different reaction is that cyclization needs to occur in a concerted step with enol formation. Thus the mechanism was proposed to occur via attack of the protonated carbonyl with the forming enol. Amarnath also found that the unreacted dione had not undergone conformational isomerization, which also indicated that an enol was not an intermediate.

The mechanism for the synthesis of the pyrrole was investigated by V. Amarnath et al. in 1991. His work suggests that the protonated carbonyl is attacked by the amine to form the hemiaminal. The amine attacks the other carbonyl to form a 2,5-dihydroxytetrahydropyrrole derivative which undergoes dehydration to give the corresponding substituted pyrrole.

The reaction is typically run under protic or Lewis acidic conditions, with a primary amine. Use of ammonium hydroxide or ammonium acetate (as reported by Paal) gives the N-unsubstituted pyrrole.

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