Reactivity of Molecular Oxygen

 From a thermodynamic standpoint oxygen is very reactive

molecule. It will react with nearly all elements, usually with a
large release of energy. Kinetically however molecular oxygen
is relatively inert, at least at room temperature, and catalysts
with specific properties have to be involved in its reactions.
There are several such catalysts in the cell and many of them
are iron-containing metalloproteins.
It is found in practice that the direct reaction of a compound
having two unpaired electrons with opposing spins is very
slow. This is because (at least) one electron would have to
invert its spin and, in analogy with a spinning top or gyroscope,
this is energetically unfavorable. Uncatalyzed reactions of
molecular oxygen at room temperature are therefore very slow.
If it were not for this kinetic block, there would be little free
oxygen in the environment and aerobic life would not
exist. At higher temperatures, spin inversion is no problem.
Excitation of various organic molecules by visible or
near-UV light will generate singlet oxygen by excitation-
transfer to normal oxygen. In biological systems,
chlorophyll can act as an effective photosensitizer for the
production of singlet oxygen during photosynthesis.
 Dioxygen Activation
O-O bond (118 kcal mol-1)
Thermodynamics: very reactive molecule
Kinetics: relatively inert, under ordinary conditions --
allows for control and tuning of its reactions in biological
systems
Kinetics: Spin conservation (*)  
Thermodynamics ([H+] ~ 1.0 M)
Eo, V vs NHE
· O2 + 4e- + 4H+  2H2O 1.23
· O2 + 2e- + 2H+  2H2O2 0.69
· O2 + e-  O2- -0.33

The mediation of a metal-ion catalyst:

* greater spin-orbit coupling in metal ions reduces the kinetic
barrier to the change in spin
* bonding of the metal to O2 itself may provide enough energy to
overcome spin-pairing energy barriers
Chem. Rev. 1973, 73, 235-245
Chem. Rev. 1973, 73, 235-245
 The Heme Prosthetic Group

deoxy-form: oxy-form:
five-coordinate six-coordinate
hs Fe(II) diamagnetic
4 unpaired [hs Fe(II) + O2 
electrons ls Fe(III)-O2(-.)]
Fe(II) is out of Fe(III) is in the
porphyrin ring plane of the
by ~0.5 Å towards porphyrin ring.
histidine.
Crystal-Field Splitting Diagrams

dx2-y2, dz2
dx2-y2

dz2

dxy

dxy, dxz, dyz dxz, dyz

free-ion
five d orbitals octahedral field tetragonal field
degenerate elongation (z-out)
Proc. Natl. Acad. Sci. (USA)
1977, 74, 1780-1784
Proc. Natl. Acad. Sci. (USA)
1977, 74, 1780-1784
Proc. Natl. Acad. Sci. (USA)
1977, 74, 1780-1784
Electronic structure of M-porphyrin complexes

Cr(II) (d4) + O2  Cr(III)-O2(1-) (S = 1)

Mn(II) (d5) + O2  Mn(IV)-O2(2-) (S = 3/2)
Fe(II) (d6) + O2  Fe(III)-O2(1-) (S = 0)
Co(II) (d7) + O2  Co(III)-O2(1-) (S = 1/2)
 Cytochrome P-450
Enzymes in the cytochrome P-450 family are remarkably versatile 02-activating
catalysts that can incorporate one of the two oxygen atoms of 02 into a broad variety
of substrates with concomitant reduction of the other oxygen atom by two electrons to
water. In addition to the conversion of unactivated alkanes to alcohols (Eq. 1),

R-H + 02 + 2H+ + 2e-  R-OH + H20 (1)

P450 enzymes transfer oxygen atoms to a wide range of substrates, transforming

alkenes to epoxides, arenes to phenols, and sulfides to sulfoxides and then to
sulfones. P450 enzymes also oxidatively cleave C-N and C-O bonds in the
metabolism of amines and ethers, respectively, and C-C bonds in the biosynthesis of
steroid hormones. Under anaerobic conditions, P-450 will reductively dehalogenate
halocarbons to the corresponding alkanes.

P-450 enzymes are generally membrane bound and have been found in plants,
animals, yeasts, and bacteria. The best characterized P-450 enzyme is the soluble
camphor-metabolizing P450-CAM isolated from Pseudomna putida.
Cytochrome P450: hydroxylation (monooxygenase)

Chem. Rev.
1987, 87, 1255-1276
 Catalytic Cycle of Cytochrome P450

Chem. Rev.
1987, 87, 1255-1276
 Science 1988,
240, 433-439
Peroxidase
(2  7  8  2)
oxidizing substrates
with simultaneous
reduction of
H202 to H20

Catalase
(2  7  2)
H202 to
02 and H20

Halogenation catalyst: Chloro-

peroxidase (2  7  9  2)
AH+ X- + H+ + H202  AX + 2H20
 Horseradish Peroxidase
Horseradish peroxidase catalyzes the oxidation of organic substrates with
H202 as the ultimate electron acceptor (Eq. 3).
AH2 + H202  A + 2H20 (3)
As with chloroperoxidase, the first step of the peroxidase reaction path
involves the addition of H202 to the FeIII resting state to form a high-valent
iron-oxo derivative known as compound I, which is formally two oxidation
equivalents above the FeIII state (see next slide).
Compound I is then reduced back to the FeIII state in two steps through
compound II.
The enzyme ''cytochrome c oxidase'' is a large transmembrane protein complex
found in bacteria and the mitochondrion. It is the last protein in the electron transport
chain. It receives an electron from each of four cytochrome c molecules, and
transfers them to one oxygen molecule, converting molecular oxygen to two
molecules of water. In the process, it translocates four protons, helping to establish a
chemiosmotic potential that the ATP synthase then uses to synthesize Adenosine
triphosphate (ATP).

Summary reaction:

4 Fe2+-cytochrome c + 2 H+in + O2 → 4 Fe3+-cytochrome c + 2H2O + 4 H+out

The complex is a large lipoprotein composed of several metal prosthetic sites and 13
protein subunits in mammals. In mammals, ten subunits are nuclear in origin and
three are synthesized mitochondrially. The complex contains two hemes, the ''a'' and
''a3'' hemes, and two copper centers, the CuA and CuB centers. In fact, the heme ''a3''
and CuB are a binuclear center that is the site of oxygen reduction. The mechanism
of action of this large complex is still an active research topic.
 Respiration: Aerobic Metabolism
Oxidation of food generates electrons

- 0.32 V        +0.82 V
NAD+ + H+ + 2e-  NADH
O2 + 4H+ + 4e-  2H2O
Cytochrome c Oxidase

Adenosine diphosphate (ADP)

Adenosine 5'-triphosphate (ATP)
+ PO43-
ATP Synthases
 CuA

Heme a
 CuB

a3-CuB
Chem. Rev. 1980, 90, 1247–1260
Chem. Rev. 2017, 117, 3717−3797
Chem. Rev. 2018, 118, 2491−2553
Chem. Rev. 2018, 118, 10840−11022