INTRODUCTION 1
The major pathway of dioxygen use in aerobic organisms is four-electron reduction
to give two molecules of water per dioxygen molecule: 2
(5.1)
This reaction represents the major source of energy in aerobic organisms when
coupled with the oxidation of electron-rich organic foodstuffs, such as glucose.
Biological oxidation of this type is called respiration, and has been estimated to
account for 90 percent or more of the dioxygen consumed in the biosphere. It
is carried out by means of a series of enzyme-catalyzed reactions that are coupled
to ATP synthesis, and the ATP produced is the major source of energy for
the organism. The actual site of the reduction of dioxygen in many organisms
is the enzyme cytochrome c oxidase. 2
Another use of dioxygen in aerobic organisms is to function as a source of
oxygen atoms in the biosynthesis of various molecules in metabolic pathways,
or in conversions of lipid-soluble molecules to water-soluble forms for purposes
of excretion. These reactions are also enzyme-catalyzed, and the enzymes involved
are either monooxygenase or dioxygenase enzymes, depending on whether
one or both of the oxygen atoms from dioxygen are incorporated in the final
organic product. Many of these enzymes are metalloenzymes. 2~
The advantages of life in air are considerable for an aerobic organism as
compared to an anaerobic organism, mainly because the powerful oxidizing power
of dioxygen can be controlled and efficiently converted to a form that can be
stored and subsequently used. 5 But aerobic metabolism has its disadvantages as
well. The interior of a living cell is a reducing environment, and many of the
components of the cell are fully capable thermodynamically of reacting directly
with dioxygen, thus bypassing the enzymes that control and direct the beneficial
reactions of dioxygen. 6 Luckily, for reasons that are discussed below, these 253
254 5 / DIOXYGEN REACTIONS
reactions generally are slow, and therefore represent minor pathways of biological
dioxygen consumption. Otherwise, the cell would just bum up, and aerobic
life as we know it would be impossible. Nevertheless, there are small but significant
amounts of products formed from nonenzymatic and enzymatic reactions
of dioxygen that produce partially reduced forms of dioxygen, i.e. ,superoxide,
O2 , and hydrogen peroxide, H20 2 , in aerobic cells. These forms of
reduced dioxygen or species derived from them could carry out deleterious reactions,
and enzymes have been identified that appear to protect against such
hazards. These enzymes are, for superoxide, the superoxide dismutase enzymes,
and, for peroxide, catalase and the peroxidase enzymes. All of these enzymes
are metalloenzymes. 2-4
Much of the fascination of the subject of biological reactions of dioxygen
stems from the fact that the mechanisms of the biological, enzyme-catalyzed
reactions are clearly quite different from those of the uncatalyzed reactions of
dioxygen or even those of dioxygen reactions catalyzed by a wide variety of
nonbiological metal-containing catalysts. 7 Investigators believe, optimistically,
that once they truly understand the biological reactions, they will be able to
design synthetic catalysts that mimic the 9iological catalysts, at least in reproducing
the reaction types, even if these new catalysts do not match the enzymes
in rate and specificity. To introduce this tJpic, therefore, we first consider the
factors that determine the characteristics of ,nonbiological reactions of dioxygen.
II. CHEMISTRY OF DIOXYGEN
A. Thermodynamics
The reduction potential for the four-electron reduction of dioxygen (Reaction
5.1) is a measure of the great oxidizing power of the dioxygen molecule. 8 However,
the reaction involves the transfer of four electrons, a process that rarely,
if ever, occurs in one concerted step, as shown in Reaction (5.2).
e - e ,2H + e - , H + e ,H-j-
02~ O2- ~ H202~H20 + OH~ 2H20 (5.2)
dioxygen superoxide
hydrogen water + hydroxyl water
peroxide radical
Since most reducing agents can transfer at most one or two electrons at a time
to an oxidizing agent, the thermodynamics of the one- and two-electron reductions
of dioxygen must be considered in order to understand the overall mechanIsm.
In aqueous solution, the most common pathway for dioxygen reduction in
the absence of any catalyst is one-electron reduction to give superoxide. But
this is the least favorable of the reaction steps that make up the full four-electron
reduction (see Table 5.l) and requires a moderately strong reducing agent. Thus
II. CHEMISTRY OF DIOXYGEN 255
Table 5.1
Standard reduction potentials for dioxygen species in
water.s
Reaction
O2 + e~ ~ °2 -
O2 - + e - + 2H + ~ H20 z
H20 Z + e ~ + H + ~ H20 + OH
OH + e - + H + ~ H20
O2 + 2e - + 2H + ~ H20 2
H20 2 + 2e- + 2H+ ~ 2HzO
O2 + 4H + + 4e - ~ 2HzO
EO, V vs. NHE, pH 7, 25°C
-0.33 a
+0.89
+0.38
+2.31
+0.281"
+ 1.349
+0.815"
" The standard state used here is unit pressure. If unit activity is used
for the standard state of O2 , the redox potentials for reactions of that
species must be adjusted by +0.17 V. 8.9
if only one-electron pathways are available for dioxygen reduction, the low reduction
potential for one-electron reduction of O2 to O2 - presents a barrier that
protects vulnerable species from the full oxidizing power of dioxygen that comes
from the subsequent steps. If superoxide is formed (Reaction 5.3), however, it
disproportionates quite rapidly in aqueous solution (except at very high pH) to
give hydrogen peroxide and dioxygen (Reaction 5.4). The stoichiometry of the
overall reaction is therefore that of a net two-electron reduction (Reaction 5.5).
It is thus impossible under normal conditions to distinguish one-electron and
two-electron reaction pathways for the reduction of dioxygen in aqueous solution
on the basis of stoichiometry alone.
202 + 2e ~ 202
202 - + 2H + ~ H20 2 + O2
O2 + 2e - + 2H + ~ H20 2
(5.3)
(5.4)
(5.5)
The thermodynamics of dioxygen reactions with organic substrates is also
of importance in understanding dioxygen reactivity. The types of reactions that
are of particular interest to us here are hydroxylation of aliphatic and aromatic
C- H bonds and epoxidation of olefins, since these typical reactions of oxygenase
enzymes are ones that investigators are trying to mimic using synthetic reagents.
Some of the simpler examples of such reactions (plus the reaction of H2
for comparison) are given in the reactions in Table 5.2. It is apparent that all
these reactions of dioxygen with various organic substrates in Table 5.2 are
thermodynamically favorable. However, direct reactions of dioxygen with organic
substrates in the absence of a catalyst are generally very slow, unless the
substrate is a particularly good reducing agent. To understand the sluggishness
of dioxygen reactions with organic substrates, we must consider the kinetic barriers
to these reactions.
The major pathway of dioxygen use in aerobic organisms is four-electron reduction
to give two molecules of water per dioxygen molecule: 2
(5.1)
This reaction represents the major source of energy in aerobic organisms when
coupled with the oxidation of electron-rich organic foodstuffs, such as glucose.
Biological oxidation of this type is called respiration, and has been estimated to
account for 90 percent or more of the dioxygen consumed in the biosphere. It
is carried out by means of a series of enzyme-catalyzed reactions that are coupled
to ATP synthesis, and the ATP produced is the major source of energy for
the organism. The actual site of the reduction of dioxygen in many organisms
is the enzyme cytochrome c oxidase. 2
Another use of dioxygen in aerobic organisms is to function as a source of
oxygen atoms in the biosynthesis of various molecules in metabolic pathways,
or in conversions of lipid-soluble molecules to water-soluble forms for purposes
of excretion. These reactions are also enzyme-catalyzed, and the enzymes involved
are either monooxygenase or dioxygenase enzymes, depending on whether
one or both of the oxygen atoms from dioxygen are incorporated in the final
organic product. Many of these enzymes are metalloenzymes. 2~
The advantages of life in air are considerable for an aerobic organism as
compared to an anaerobic organism, mainly because the powerful oxidizing power
of dioxygen can be controlled and efficiently converted to a form that can be
stored and subsequently used. 5 But aerobic metabolism has its disadvantages as
well. The interior of a living cell is a reducing environment, and many of the
components of the cell are fully capable thermodynamically of reacting directly
with dioxygen, thus bypassing the enzymes that control and direct the beneficial
reactions of dioxygen. 6 Luckily, for reasons that are discussed below, these 253
254 5 / DIOXYGEN REACTIONS
reactions generally are slow, and therefore represent minor pathways of biological
dioxygen consumption. Otherwise, the cell would just bum up, and aerobic
life as we know it would be impossible. Nevertheless, there are small but significant
amounts of products formed from nonenzymatic and enzymatic reactions
of dioxygen that produce partially reduced forms of dioxygen, i.e. ,superoxide,
O2 , and hydrogen peroxide, H20 2 , in aerobic cells. These forms of
reduced dioxygen or species derived from them could carry out deleterious reactions,
and enzymes have been identified that appear to protect against such
hazards. These enzymes are, for superoxide, the superoxide dismutase enzymes,
and, for peroxide, catalase and the peroxidase enzymes. All of these enzymes
are metalloenzymes. 2-4
Much of the fascination of the subject of biological reactions of dioxygen
stems from the fact that the mechanisms of the biological, enzyme-catalyzed
reactions are clearly quite different from those of the uncatalyzed reactions of
dioxygen or even those of dioxygen reactions catalyzed by a wide variety of
nonbiological metal-containing catalysts. 7 Investigators believe, optimistically,
that once they truly understand the biological reactions, they will be able to
design synthetic catalysts that mimic the 9iological catalysts, at least in reproducing
the reaction types, even if these new catalysts do not match the enzymes
in rate and specificity. To introduce this tJpic, therefore, we first consider the
factors that determine the characteristics of ,nonbiological reactions of dioxygen.
II. CHEMISTRY OF DIOXYGEN
A. Thermodynamics
The reduction potential for the four-electron reduction of dioxygen (Reaction
5.1) is a measure of the great oxidizing power of the dioxygen molecule. 8 However,
the reaction involves the transfer of four electrons, a process that rarely,
if ever, occurs in one concerted step, as shown in Reaction (5.2).
e - e ,2H + e - , H + e ,H-j-
02~ O2- ~ H202~H20 + OH~ 2H20 (5.2)
dioxygen superoxide
hydrogen water + hydroxyl water
peroxide radical
Since most reducing agents can transfer at most one or two electrons at a time
to an oxidizing agent, the thermodynamics of the one- and two-electron reductions
of dioxygen must be considered in order to understand the overall mechanIsm.
In aqueous solution, the most common pathway for dioxygen reduction in
the absence of any catalyst is one-electron reduction to give superoxide. But
this is the least favorable of the reaction steps that make up the full four-electron
reduction (see Table 5.l) and requires a moderately strong reducing agent. Thus
II. CHEMISTRY OF DIOXYGEN 255
Table 5.1
Standard reduction potentials for dioxygen species in
water.s
Reaction
O2 + e~ ~ °2 -
O2 - + e - + 2H + ~ H20 z
H20 Z + e ~ + H + ~ H20 + OH
OH + e - + H + ~ H20
O2 + 2e - + 2H + ~ H20 2
H20 2 + 2e- + 2H+ ~ 2HzO
O2 + 4H + + 4e - ~ 2HzO
EO, V vs. NHE, pH 7, 25°C
-0.33 a
+0.89
+0.38
+2.31
+0.281"
+ 1.349
+0.815"
" The standard state used here is unit pressure. If unit activity is used
for the standard state of O2 , the redox potentials for reactions of that
species must be adjusted by +0.17 V. 8.9
if only one-electron pathways are available for dioxygen reduction, the low reduction
potential for one-electron reduction of O2 to O2 - presents a barrier that
protects vulnerable species from the full oxidizing power of dioxygen that comes
from the subsequent steps. If superoxide is formed (Reaction 5.3), however, it
disproportionates quite rapidly in aqueous solution (except at very high pH) to
give hydrogen peroxide and dioxygen (Reaction 5.4). The stoichiometry of the
overall reaction is therefore that of a net two-electron reduction (Reaction 5.5).
It is thus impossible under normal conditions to distinguish one-electron and
two-electron reaction pathways for the reduction of dioxygen in aqueous solution
on the basis of stoichiometry alone.
202 + 2e ~ 202
202 - + 2H + ~ H20 2 + O2
O2 + 2e - + 2H + ~ H20 2
(5.3)
(5.4)
(5.5)
The thermodynamics of dioxygen reactions with organic substrates is also
of importance in understanding dioxygen reactivity. The types of reactions that
are of particular interest to us here are hydroxylation of aliphatic and aromatic
C- H bonds and epoxidation of olefins, since these typical reactions of oxygenase
enzymes are ones that investigators are trying to mimic using synthetic reagents.
Some of the simpler examples of such reactions (plus the reaction of H2
for comparison) are given in the reactions in Table 5.2. It is apparent that all
these reactions of dioxygen with various organic substrates in Table 5.2 are
thermodynamically favorable. However, direct reactions of dioxygen with organic
substrates in the absence of a catalyst are generally very slow, unless the
substrate is a particularly good reducing agent. To understand the sluggishness
of dioxygen reactions with organic substrates, we must consider the kinetic barriers
to these reactions.
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