Intermediates in the Paal-Knorr synthesis of pyrroles. 4-Oxoaldehydes.
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 gamma-ketoaldehydes relative to gamma-diketones.
Amarnath
V
V
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Amarnath
K
K
Valentine
W M
WM
Eng
M A
MA
Graham
D G
DG
D000447:Aldehydes / Q000138:chemical synthesis*; D007700:Kinetics; D011758:Pyrroles / Q000138:chemical synthesis*
D000447:Aldehydes; D011758:Pyrroles