Intermediates in the Paal-Knorr synthesis of pyrroles. 4-Oxoaldehydes

Article abstract of DOI:10.1021/tx00044a008

The mechanism of pyrrole formation between a 4-ketoaldehyde, such as 4- oxohexanal (4), and a primary amine is examined. In organic solvents 4 readily formed the imine 6 that decomposed to pyrrole 9. In phosphate buffer (pH 7.4) the presence of deuteriums in the dideuterio (4-d₂) and hexadeuterio (4-d₆) analogs retarded the reaction rate by factors of 1.9 and 2.6, which are much less than the isotope effects exhibited by reactions involving cleavage of the carbon-hydrogen bond. Moreover, the deuterium labels from the uncyclized ketoaldehyde remained intact. These results suggest that the hemiaminal 5 rather than the enamine 8 is the intermediate undergoing cyclization. Due to the absence of a methyl substituent at one of the carbonyls the rate of pyrrole formation of 4-oxohexanal was 2 orders of magnitude larger than that of 2,5-hexanedione. The higher rate of pyrrole formation may account for the increased rate of pyrrole-mediated cross- linking of proteins caused by γ-ketoaldehydes relative to γ-diketones.