Organic Chemistry

9.8 Radical Reactions in Biological Systems

For a long time, scientists assumed that radical reactions were not important in biolog-
ical systems because a large amount of energy—heat or light—is required to initiate a
radical reaction and it is difficult to control the propagation steps of the chain reaction
once initiation occurs. However, it is now widely recognized that there are biological
reactions that involve radicals. Instead of being generated by heat or light, the radicals
are formed by the interaction of organic molecules with metal ions. These radical re-
actions take place in the active site of an enzyme. Containing the reaction in a specific
site allows the reaction to be controlled.
One biological reaction that involves radicals is the one responsible for the conversion
of toxic hydrocarbons to less toxic alcohols. Carried out in the liver, the hydroxyl-
ation of the hydrocarbon is catalyzed by an iron-porphyrin-containing enzyme called
cytochrome (Section 12.8). An alkyl radical intermediate is created when
abstracts a hydrogen atom from an alkane. In the next step, dissociates
homolytically into and and the immediately combines with the radical
intermediate to form the alcohol.

This reaction can also have the opposite toxicological effect. That is, instead of con-
verting a toxic hydrocarbon into a less toxic alcohol, substituting an OH for an H in
some compounds causes a nontoxic compound to become toxic. Therefore, com-
pounds that are nontoxic in vitroare not necessarily nontoxic in vivo.For example,
studies done on animals showed that substituting an OH for an H caused methylene
chloride to become a carcinogen when it is inhaled.
Another important biological reaction shown to involve a radical intermediate is
the conversion of a ribonucleotide into a deoxyribonucleotide. The biosynthesis of
ribonucleic acid (RNA) requires ribonucleotides, whereas the biosynthesis of de-
oxyribonucleic acid (DNA) requires deoxyribonucleotides (Section 27.1). The first
step in the conversion of a ribonucleotide to the deoxyribonucleotide needed for DNA
biosynthesis involves abstraction of a hydrogen atom from the ribonucleotide to form

(CH 2 Cl 2 )

FeV

an alkane

+ HC FeIII

an alcohol

FeIV + HO C

a radical

intermediate

OOH+ C

FeIII HO–, HO–

FeIV OH

P 450 FeV O

Section 9.8 Radical Reactions in Biological Systems 351

DECAFFEINATED COFFEE

AND THE CANCER SCARE

Animal studies showing that methylene chloride

becomes a carcinogen when inhaled caused some concern be-

cause methylene chloride was the solvent used to extract caf-

feine from coffee beans in the manufacture of decaffeinated

coffee. However, when methylene chloride was added to

drinking water fed to laboratory rats and mice, researchers

found no toxic effects. They observed no toxicological re-

sponses of any kind either in rats that had consumed an

amount of methylene chloride equivalent to the amount that

would be ingested by drinking 120,000 cups of decaffeinated

coffee per day or in mice that had consumed an amount

equivalent to drinking 4.4 million cups of decaffeinated cof-

fee per day. In addition, no increased risk of cancer was

found in a study of thousands of workers exposed daily to in-

haled methylene chloride. (Studies done on humans do not

always agree with those done on animals.) Because of the ini-

tial concern, however, researchers sought alternative methods

for extracting caffeine from coffee beans. Extraction by liq-

uid at supercritical temperatures and pressures was

found to be a better method since it extracts caffeine without

simultaneously extracting some of the flavor compounds that

are removed when methylene chloride is used. There is

essentially no difference in flavor between regular coffee and

coffee decaffeinated with CO 2.

CO 2