Chemical Reactivity and Biological Activity of Diketene

• Published in: Chemical research in toxicology Vol. 21; no. 10; pp. 1964 - 1969
• Main Authors: Gómez-Bombarelli, Rafael, González-Pérez, Marina, Pérez-Prior, M. Teresa, Manso, José A, Calle, Emilio, Casado, Julio
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.10.2008
• Subjects: Alkylation; Catalysis; Hydrolysis; Lactones - chemistry; Molecular Structure; Pyridines - chemistry; Spectrophotometry; Temperature
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx800153j

The alkylating potential of diketene (4-methylene-2-oxetanone), the basic unit of many derivatives of pesticides, chemicals, pharmaceuticals, and dyestuffs, was investigated kinetically. The nucleophile 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to DNA bases, was used as an alkylation substrate. The alkylation reactions were performed in water/dioxane solvent mixtures. To gain insight into the effect of the hydrolysis of diketene on its alkylating efficiency, alkylation and competing hydrolysis were studied in parallel. Conclusions were drawn as follows: (i) Although diketene, unlike other four-membered ring lactones, is inactive as a carcinogen in experimental animals, it shows an alkylating potential of about 2 orders of magnitude higher than β-propiolactone or β-butyrolactone, which are classified as possibly carcinogenic to humans by the IARC. (ii) The reactivity of diketene as an alkylating agent is enthalpy-controlled. (iii) The fact that the hydrolysis reaction of diketene is slightly faster than those of other four-membered ring lactones shows that diketene is more efficient than β-propiolactone or β-butyrolactone as an alkylating agent, since the hydrolysis of this species poses less competition to the alkylation reaction. (iv) Diketene undergoes acyl fission in the alkylation reaction, which results in an amide bond in the NBP−diketene adduct. The lability of the amide bond as opposed to the amine bonds formed by β-propiolactone and β-butyrolactone could be one of the differential factors responsible for the lack of carcinogenicity of diketene. (v) Ab initio calculations of the energy barriers help to understand the unusual reactivity of diketene.