Dealkylation of HMPA and DMPU

Barclay, Austin (2002). Dealkylation of HMPA and DMPU. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fbe3

Abstract

Cytochrome P450 metabolises N,N-dialkylamides to their corresponding N-dealkylated products via the formation of an N-hydroxyalkyl-N-alkylamide intermediate. Studies by Iley et. al. have shown that the oxidative dealkylation of these amides occurs via hydrogen abstraction from the alkyl carbon atom a- to the amide nitrogen. This leads to the formation of a carbon-centred radical; it is believed that this radical is the cause of toxicity for these amides. The amide solvents, HMPA and DMPU have similar functional groups. Because of this similarity it is believed that HMPA and DMPU may undergo an analogous metabolic pathway to that of previously studied amide solvents.
Interestingly HMPA is toxic whereas DMPU is not. Investigation into why this is the case would be of use in designing other non-toxic solvents. This model study has shown that methyl group oxidation in HMPA is subject to a deuterium isotope effect of -10. This would imply that H-atom abstraction occurs with the formation of a highly reactive C-centred radical. A deuterium isotope effect was not attempted for DMPU, but product analysis showed single oxidation of the ring to form 4-hydroxyl, 3-dimethyltetrahydropyrimidin-2-one and subsequent oxidation to afford 1,3 dimethyl-5,6-dihydropyrimidine-2,4-dione.

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