Stereoisomer Effects on the Paal-Knorr Synthesis of Pyrroles

Article abstract of DOI:10.1021/jo00355a010

The neurotoxicity of n-hexane has been postulated to result from the reactivity of its γ-diketone metabolite, 2,5-hexanedione (1), with lysil amino groups of proteins to form pyrroles (Paal-Knorr synthesis).We have synthesized a series of 3,4-disubstituted γ-diketones in order to explore the relationship between rate of pyrrole formation and neurotoxicity.The γ-diketones were prepared through oxidative coupling of ketones.Yields were improved to 60-70percent with the use a Soxhlet apparatus containing PbO2 in the extraction thimble.Diketones prepared were 3,4-dimethylhexane-2,5-dione (2), 3,4-diethylhexane-2,5-dione (3), 3,4-diisopropylhexane-2,5-dione (4), and 3,4-diphenylhexane-2,5-dione (5).The reactions yielded mixtures of the d,l (a) and meso (b) diastereomers, which were separated by column chromatography, fractional distillation, or crystallization.Structures of the diastereomeric forms were established by 13C NMR techniques and, in the case of 4b, by single crystal X-ray diffraction.The relative reactivities of the d,l and meso isomers of each γ-diketone were determined with benzylamine in cyclohexane and the rate of pyrrole formation was determined by HPLC.For each pair of diastereomeric diketones the d,l reacted 4-40 times faster than the meso form.The reactivities of the γ-diketones were in the order 2 > 1 > 3 > 5 > 4 with pseudo-first-order rate constants ranging from 4*10^-4 to 3*10^-8 s^-1 at 30 deg C.