Paal-Knorr Thiophene Synthesis
Paal Thiophene Synthesis

The Paal-Knorr Thiophene Synthesis allows the generation of thiophenes by condensation of a 1,4-dicarbonyl compound in the presence of an excess of a source of sulfur such as phosphorous pentasulfide or Lawesson's reagent.

Attention: some toxic H₂S is formed as a side product regardless of the sulfur source.

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Mechanism of the Paal-Knorr Thiophene Synthesis

Reagents such as phosphorus pentasulfide or Lawesson's reagent act as sulfurizing agents as well as dehydrating agents, allowing a reaction pathway that could lead first to the formation of furans. This hypothesis was tested by Foye (J. Org. Chem., 1952, 17, 1405.) by treatment of different 1,4-dicarbonyl compounds and the corresponding possible furan intermediates (such as acetonylacetone and 2,5-dimethylfuran) with phosphorus pentasulfide. Using the same reaction conditions, the differences in the yields of 2,5-dimethylthiophene excludes the possibility that a predominant reaction pathway could lead through furan intermediates:

Foye suggested the following reaction pathway:

Today, the occurrence of a bis-thioketone intermediate is assumed to be possible but not necessary (J. Schatz, Science of Synthesis, George Thieme Verlag Stuttgart, 2000, Vol. 9, 298.)

The reaction mechanism still needs further elucidation before it is fully understood.

Recent Literature

Microwave-Assisted Paal-Knorr Reaction - Three-Step Regiocontrolled Synthesis of Polysubstituted Furans, Pyrroles and Thiophenes
G. Minetto, L. F. Raveglia, A. Sega, M. Taddei, Eur. J. Org. Chem., 2005, 5277-5288.

Thionation Using Fluorous Lawesson's Reagent
Z. Kaleta, B. T Makowski, T. Soos, R. Dembinski, Org. Lett., 2006, 8, 1625-1628.