The Paal-Knorr pyrrole synthesis was first published in 1885 by Carl Paal and Ludwig Knorr. It is a spontaneous, moderately exothermic reaction, which can also be used in the synthesis of furans and thiophenes. Due to its exothermic nature, the reaction is of not much use in the chemical industry, since batch scale-up reaches its limits very quickly.

Paal-Knorr pyrrole synthesis
(R = ethyl; 2-hydroxyethyl; 4-hydroxybutyl)

The Paal-Knorr pyrrole synthesis is a fast and exothermic reaction, which limits the feasibility of batch process up-scaling. FutureChemistry has therefore translated this reaction from a batch process to a continuous flow process. FutureChemistry’s typical three-tier approach led to a protocol which can be adapted to any viable amine/diketone substrate couple:

       1) Translation of batch process to continuous flow process:
           a) Stock solutions approach, yielding a homogeneous reaction mixture.
           b) Quenching solution to follow the reaction in time.
           c) Flow markers approach to accurately assess reaction parameters.
      2) Automated reaction optimisation.
      3) Out scaling to preparative synthesis

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