Computational Chemistry and Molecular Modeling
Atomic, Molecular and Optical Physics
Wiley InterScience Backfile Collection 1832-2000
Chemistry and Pharmacology
We have carried out a computational study of the reactive properties of chlorooxirane, the metabolically produced epoxide of vinyl chloride that is believed to be a direct-acting carcinogenic form of this molecule. An ab initio SCF-MO procedure (GAUSSIAN 70) was used to compute the energy requirements for stretching the C—Cl and both C—O bonds (SN1 reactivity) and to determine the course of the epoxide's possible SN2 reactions with ammonia, taken as a model for nucleophilic sites on DNA. The epoxide was assumed to be protonated; both the oxygen- and chloro-protonated forms were considered. At each step along the various reaction pathways, the structure of the system was reoptimized. For the oxygen-protonated epoxide, the C1—O bond has a significantly lower energy barrier to stretching than does the C2—O. (The carbon bearing the chlorine is designated C1.) However, both are very much higher than that of the C—Cl bond in the chloro-protonated form, confirming our earlier finding of the relative weakness of this bond. In the SN2 processes involving ammonia, intermediate complexes are formed with both carbons of the oxygen-protonated epoxide, the C2-complex being the more stable. However, the most stable ammonia complex occurs at C1 of the chloro-protonated epoxide. Our calculated results, both the energies and also the geometry changes, allow us to propose two possible mechanisms for the formation of the 7-N-(2-oxoethyl) derivative of guanine that has been observed to be the major in vivo DNA alkylation product of vinyl chloride and has been suggested as possibly being responsible for its carcinogenicity. One of these mechanisms is SN1 and starts with the chloro-protonated epoxide; the other is SN2 and involves the oxygen-protonated form.
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