Competing Knorr and Fischer–Fink pathways to pyrroles in neutral aqueous solution

A proposed chemical model for the prebiogenesis of tetrapyrrole macrocycles relies on the condensation of a 3-alkyl-substituted 2,4-diketone and an α-aminoketone to form a pyrrole equipped for subsequent self-condensation leading to porphyrinogens. The condensation of acyclic reactants can proceed via competing Knorr (desired) and Fischer–Fink (undesired) pathways. Here, the Knorr and Fischer–Fink pathways are quantitated using (1) analogues of those in the proposed prebiotic route wherein the resulting pyrroles are blocked from subsequent condensation, and (2) a set of internal standards for quantitation of crude reaction mixtures by 1H NMR spectroscopy following extraction into CS2. The reaction of 1-amino-2-butanone and 3-methyl-2,4-pentanedione at 60 °C in aqueous solution at pH 7 for 24 h afforded the Knorr pyrrole and Fischer–Fink pyrrole in yields of 48% and 7%, respectively. The reaction in hot aqueous acid (pH 4.6, reflux, 30 min) afforded the Knorr pyrrole in diminished yield (22%) relative to that of the Fischer–Fink pyrrole (11%). The Knorr pyrrole (4-ethyl-2,3-dimethylpyrrole) is evanescent whereas the Fischer–Fink pyrrole (2,3,4-trimethyl-5-propanoylpyrrole) is quite stable; hence, rapid analysis of the reaction mixture (vs workup and isolation) is essential for accurate analysis.