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Nucleophilic Substitution on Carcinogenic N-Acetoxy-N-arylacetamides¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706

Previous studies from this laboratory, especially with N-hydroxy-N-2-fluorenylacetamide, have pointed to esters of certain N-hydroxy-N-arylacetamides as carcinogenic and reactive metabolites of the corresponding amides and hydroxamic acids in vivo. The ¹⁴C-labeled acetic acid esters of these acethydroxamic acids were investigated in this study as models of the reactive esters presumed to be formed in vivo, and the acetoxy group was shown to undergo nucleophilic displacement in aqueous media. In the presence of nucleophiles less basic than acetate ion, the 2-fluorenyl and 4-stilbenyl N-acetoxy-acetamides showed unimolecular ionization, whereas the corresponding 4-biphenylyl and 2-phenanthryl derivatives appeared to form acetate ion by bimolecular displacement. In the presence of the more basic citrate trianion, all four compounds showed increased rates of decomposition, and these approached maximal levels with increasing concentrations of nucleophile. These observations are explicable by postulating the formation of an intermediate ion pair in which the unshared pair of electrons of the nitrogen of the amidonium ion is in a nonbonding sp²-orbital and the nitrogen p-orbital is vacant. The extent to which this ion pair reacts further or returns to the ground state would be determined by the stabilization provided by the aryl group. Hückel MO values calculated on the basis of this model showed a correspondence with the free energies of activation calculated for the reaction of these compounds and were used to predict the relative rates of decomposition of the two isomeric N-acetoxy-N-naphthylacetamides.

Those N-acetoxy-N-arylacetamides which decompose slowly also gave low yields of product on reaction with methionine or guanosine. However, the yields of products from reaction of N-acetoxy-N-4-stibenylacelamide and N-acetoxy-N-1-naphthyl-acetamide with these nucleophiles were below the levels expected from their dissociation rates.

The syntheses of two new compounds, N-acetoxy-N-2-phenanthrylacetamide and N-acetoxy-N-4-biphenylylacetamide, are described.

¹ This work was supported by Grants CA-07175 and CRTY-5002 of the National Cancer Institute, USPHS, by a grant from the Jane Coffin Childs Memorial Fund for Medical Research, and by the Alexander and Margaret Stewart Trust Fund.

² National Science Foundation Cooperative Graduate Fellow, 1965 to 1966.

Received 10/27/69. Accepted 1/21/70.