Gómez-Bombarelli Rafael, González-Pérez Marina, Pérez-Prior M Teresa, Manso José A, Calle Emilio, Casado Julio
Departamento de Química física, Universidad de Salamanca, E-37008 Salamanca, Spain.
Chem Res Toxicol. 2008 Oct;21(10):1964-9. doi: 10.1021/tx800153j. Epub 2008 Aug 30.
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 beta-propiolactone or beta-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 beta-propiolactone or beta-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 beta-propiolactone and beta-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.
对双乙烯酮（4-亚甲基-2-氧杂环丁烷酮）的烷基化潜力进行了动力学研究，双乙烯酮是许多农药、化学品、药品和染料衍生物的基本单元。亲核试剂4-（对硝基苄基）吡啶（NBP）是一种用于捕获具有与DNA碱基相似亲核特性的烷基化剂的物质，被用作烷基化底物。烷基化反应在水/二氧六环溶剂混合物中进行。为了深入了解双乙烯酮水解对其烷基化效率的影响，同时研究了烷基化和竞争性水解。得出以下结论：（i）尽管双乙烯酮与其他四元环内酯不同，在实验动物中无致癌活性，但它显示出的烷基化潜力比β-丙内酯或β-丁内酯高约2个数量级，β-丙内酯和β-丁内酯被国际癌症研究机构列为对人类可能致癌的物质。（ii）双乙烯酮作为烷基化剂的反应活性受焓控制。（iii）双乙烯酮的水解反应比其他四元环内酯的水解反应略快，这一事实表明，双乙烯酮作为烷基化剂比β-丙内酯或β-丁内酯更有效，因为该物质的水解对烷基化反应的竞争较小。（iv）双乙烯酮在烷基化反应中发生酰基裂解，这导致在NBP-双乙烯酮加合物中形成酰胺键。与β-丙内酯和β-丁内酯形成的胺键相比，酰胺键的不稳定性可能是双乙烯酮缺乏致癌性的差异因素之一。（v）对能垒的从头算有助于理解双乙烯酮不同寻常的反应活性。
