Paal-Knorr Furan Synthesis
Paal-Knorr Thiophene Synthesis
Synthesis of pyrroles
Paal-Knorr Pyrrole Synthesis
The Paal-Knorr Pyrrole Synthesis is the condensation of a 1,4-dicarbonyl compound with an excess of a primary amine or ammonia to give a pyrrole.
The reaction can be conducted under neutral or weakly acidic conditions. Addition of a weak acid such as acetic acid accelerates the reaction, but the use of amine/ammonium hydrochloride salts or reactions at pH < 3 lead to furans as main products (Paal-Knorr Furan Synthesis).
Mechanism of the Paal-Knorr Pyrrole Synthesis
Venkataraman Amarnath has shown (J. Org. Chem., 1991, 56, 6924) that meso- and dl-3,4-diethyl-2,5-hexanediones cyclize at unequal rates, and that the stereochemical configuration of the unchanged dione is preserved during the reaction. Any mechanism such as the following one that involves the formation of an enamine before the rate-determining step - the cyclization - must be ruled out.
If the ring is formed from an imine that is generated from a primary amine, a charged immonium ion must be an intermediate. Amarnath tried to stabilize or destabilize the immonium ion with different aryl groups as substituents:
The use of ammonia should give an uncharged intermediate and is therefore less affected by the choice of substitutents. The substituents also influence the basicity of the imine, with the nitro group leading to a more basic nucleophile. The rates of cyclization have been compared using ammonia and methylamine. The nitro group has in every situation had a positive effect on the reaction rate. The methoxy group has a negative effect on the cyclization rate in each case. Comparison of the relative reaction rates of all substrates (R: H, Me) showed no specific stabilization/destabilization effect for a possible mechanism involving an immonium ion.
A mechanism that accounts for the influence of different substitution patterns (meso, dl) and explains the influence of a p-nitrophenyl group making a nucleophile more reactive (although not as the imine) includes the cyclization of a hemiacetal which is followed by different dehydration steps:
A more detailed description can be found in the work by Venkataraman Amarnath, and references cited therein (J. Org. Chem., 1991, 56, 6924).
Iron-Catalyzed Inexpensive and Practical Synthesis of N-Substituted Pyrroles in Water
N. Azizi, A. Khajeh-Amiri, H. Ghafuri, M. Bolourtchian, M. R. Saidi, Synlett, 2009, 2245-2248.
Magnesium Nitride as a Convenient Source of Ammonia: Preparation of Pyrroles
G. E. Veitch, K. L. Bridgwood, K. Rands-Trevor, S. V. Ley, Synlett, 2008, 2597-2600.
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.
Microwave mediated facile one-pot synthesis of polyarylpyrroles from but-2-ene- and but-2-yne-1,4-diones
H. S. P. Rao, S. Jothilingam, H. W. Scheeren, Tetrahedron, 2004, 60, 1625-1630.