A segment of DNA460 CHAPTER 12 Reactions of Alcohols, Ethers, Epoxides, and Sulfur-Containing CompoundsSome aromatic hydrocarbons are carcinogens—compounds that cause cancer.
Investigation has revealed, however, that it is not the hydrocarbon itself that is
carcinogenic, but rather the arene oxide into which the hydrocarbon is converted.
How do arene oxides cause cancer? We have seen that nucleophiles react with
epoxides to form addition products. a component of DNA
(Section 27.1), has a nucleophilic group that is known to react with certain
arene oxides. Once becomes covalently attached to an arene
oxide, can no longer fit into the DNA double helix. Thus, the
genetic code cannot be properly transcribed, which can lead to mutations that
cause cancer. Cancer results when cells lose their ability to control their growth
and reproduction.Not all arene oxides are carcinogenic. Whether a particular arene oxide is carcino-
genic depends on the relative rates of its two reaction pathways—rearrangement or
reaction with a nucleophile. Arene oxide rearrangement leads to phenolic products
that are not carcinogenic, whereas formation of addition products from nucleophilic
attack by DNA can lead to cancer-causing products. Thus, if the rate of arene oxide re-
arrangement is greater than the rate of nucleophilic attack by DNA, the arene oxide
will be harmless. If, however, the rate of nucleophilic attack is greater than the rate of
rearrangement, the arene oxide will be a carcinogen.
Because the rate of arene oxide rearrangement depends on the stability of the carbo-
cation formed in the first step of the rearrangement,an arene oxide’s cancer-causing
potential depends on the stability of this carbocation. If the carbocation is relatively sta-
ble, rearrangement will be fast and the arene oxide will tend to be noncarcinogenic. If
the carbocation is relatively unstable, rearrangement will be slow and the arene oxide
will be more likely to undergo nucleophilic attack and be carcinogenic. This means that
the more reactive the arene oxide (the more easily it opens to form a carbocation), the
less likely it is to be carcinogenic.PROBLEM 23 SOLVEDWhich compound is more likely to be carcinogenic?a. b.SOLUTION TO 23a The nitro-substituted compound is more likely to be carcinogenic.
The nitro group destabilizes the carbocation formed when the ring opens by withdrawing
electrons from the ring by resonance. In contrast, the methoxy group stabilizes the
carbocation by resonance electron donation into the ring. Carbocation formation leads to
the harmless product, so the nitro-substituted compound with a less stable (harder-to-form)
carbocation will be less likely to undergo rearrangement to a harmless product. In addition,OorOOCH 3OorNO 2OH 2 NHOOHOONONHN NHNONONHN NHOHOHOan arene oxide2 ′-deoxyguanosinecovalently attached
to the arene oxide2 ¿-deoxyguanosine2 ¿-deoxyguanosineNH 22 ¿-Deoxyguanosine,BRUI12-437_480r3 27-03-2003 11:51 AM Page 460