Reactions of singlet oxygen

Free Radical Reaction Rate

Molecular oxygen in its ground state has triplet multiplicity but not singlet
multiplicity unlike most natural compounds.
Chemical reactions forming singlet molecules from triplet and singlet reactants
are forbidden by Wigner's spin selection rule. Thus, the triplet multiplicity is the
actual reason, why most reactions of oxygen with organic substances, although
being exergonic, do not proceed at room temperature but upon heating or in the
presence of catalysts.
It is said that reactions of  organic compounds with oxygen are kinetically
inhibited.
This effect enables our life in an oxygen containing atmosphere.  
Electron Configuration of Singlet Oxygen (HOMO)

3 g 1 g 1 g

(ground state) 22 kcal/mol 37.5 kcal/mol

Triplet Singlet
Electron Configuration of Singlet Oxygen (HOMO)
Molecular oxygen has two low-lying singlet excited states, 1 g and 1 -g ; 95 (22.5 kcal mol-
1
) and 158 kJ mol-1 (31.5 kcal mol-1 ) above the triplet state, respectively.

Electronic configurations of these states differ only by the structure of the p-antibonding
orbitals.

In the second excited state, 1 g; the electronic configuration is identical to that of the ground
state, except that the last two electrons have antiparallel spins.

The transition from the 1 g state to the 3  -g state is spin forbidden, thus the 1 g O2 is a
relatively long-lived species.
The second excited state of oxygen, on the other hand, is short-lived due to a spin-allowed
transition to the 1 g state.

Due to the metastability of the 1 g state, the 1g 3

 -g transitions at 1268.7 nm are
observed in absorption and emission spectra despite being spin and symmetry forbidden.
The electronic transitions 1 mnnnng ¬ 3 Sg - and 1 Sg + ¬ 3 Sg - , although highly forbidden, are readily observed by
absorption and emission in the upper atmosphere with zero-zero transition at 1270 and 762 nm, respectively. The
estimated radiative lifetimes of these two states in the gas phase are 45 min and 7-12 s, respectively [19]. In solution, the
lifetimes of these states are reduced drastically, depending on the solvent polarity. 1 Dg state has a relatively long
lifetime (1 to 10 ms) in the absence of molecules with which it can undergo rapid reaction. On the other hand, 1 Sg +
state is short-lived, and usually undergoes rapid decay (with k ~ 1011 s-1 ), rather than chemical reaction
The First Excited State: O2(1g) The Singlet Oxygen
 O2 1O
?
h

2
The fate of singlet oxygen

# deactivated by chemical acceptor

# physical quenching is possible by solvent and sensitizer

# 2+2, 4+2 cycloaddition and ene reaction are the probable reactions

# Nonpolar solvents (halogenated or fluorinated hydrocarbons) suppress electron transfer

reaction hence increase the lifetime of singlet Oxygen

# Weak electron acceptors TPP, metaloporphyrins, with low triplet energies should used as
sensitizers. RB is possible (in polar solvents) in some cases, use of MB should be avoided.
RB: Rose Bengal, (MB) Methylene Blue
# Regio and stereoselectivity for certain transformation should be determined directly at the peroxide stage.
In many cases further transformation (reduction, rearrangement and cleavage) clearly
change the regio as well as stereochemistry of the products.
Singlet Molecular Oxygen Quenching

Chemical Quenching
kr
Q + O2( g) QO2
1

Physical Quenching
kq
Q + O2( g)
1
Q + O2(3g) + heat
Sensitizer excitation is generally achieved via a one photon transition
(h) between the ground state, S0, and a singlet excited state Sn .
Relaxation of the Sn state yields the lowest excited singlet state of the
sensitizer S1.
Intersystem crossing generates the sensitizer triplet state, T1.
The lifetime of the T1 state is longer (s) than that of the S1 state (ns)
allowing this excited state to react in one of two ways, defined as Type I
and II mechanisms.
Type I mechanism involves hydrogen-atom abstraction or electron-
transfer between the excited sensitizer and a substrate, yielding free
radicals. These radicals can react with oxygen to form an active oxygen
species such as the superoxide radical anion.
In a Type II mechanism, singlet oxygen is generated via an energy
transfer process during a collision of the excited sensitizer with triplet
oxygen.
Several types of photosensitizers have been used for the generation of
singlet oxygen.
Molecule used as photosensitizer should exhibit the following
properties:
(a)high absorption coefficient in the spectral region of the excitation
wavelength;
(b)a well-defined triplet state with appropriate energy, ET > 95 kJmol-1
, to allow for efficient energy transfer to ground state oxygen
(c)high quantum yield of the triplet state, T ≥ 0.4
(d)long triplet state lifetime, T>1 ms since the efficiency of the
photosensitizer is dependent on the photophysical properties of its
lowest excited triplet state; and
(e) high photo-stability.

Porphyrins, organic dyes, aromatic hydrocarbons, transition metal

complexes, semiconductor nano-particles, etc., are found to be
Chemically singlet oxygen can be generated in large concentrations (>
10%) using reaction of hydrogen peroxide with hypochlorite. Chlorine
gas is bubbled through alkaline hydrogen peroxide to generate singlet
oxygen
 Chemistry of Singlet Oxygen and Some of its
Applications
 The enormous reactivity of singlet oxygen finds applications in bleaching and disinfection reactions.

 As well as in many chemical syntheses as for example in the reaction of singlet oxygen with aromatic compounds (A), which leads to the formation of  endoperoxides (APO).

 Both the thermal and the photochemical cleveage of APOs leads back again to aromatic compound A and singlet oxygen.

 APOs can be part of highly reversible photochromic systems, some are outstanding chemical actinometers.

 One takes advantage of the toxicity of singlet oxygen in some medical applications as for example in the photodynamic therapy (PDT) of tumors.

 In PDT a suited photosensitizer is adminstered to the patient.

 After 24 to 48 hors most of the sensitizer has disappeared from the sound tissue. The sensitizer is still enriched in the tumor tissue after that time due to a retarded concentration decrease. The sensitizer is excited by irradiation with
red laser light. This leads in the presence of oxygen by energy transfer to the formation of  O2(1g) in the tumor tissue inducing tumor necrosis. Porphin derivatives are mostly used as sensitizers in this treatment.
Oxygen is more oxidizing in its singlet excited state and is therefore significantly more
electrophilic, reacting rapidly with unsaturated carbon/carbon bonds, neutral nucleophiles such as
sulfides and amines, and as well as with anions.
Consequently, organic chemists have found utility in singlet oxygen as a versatile synthetic
reagent
 Reactions of singlet oxygen
• The 1,3 addition of singlet oxygen to dienes and conjugated cis-
dienes, [4/2] cycloaddition, is similar to the Diels/Alder reaction,
where singlet oxygen is the dienophile.
• An example of the utility of this reaction is given by the synthesis
of dibenzoyl benzene from 1,3-diphenylisobenzofuran.

• Singlet oxygen can also react with olefins having two or more
allylic substituents causing a double bond shift and the formation
of an allylic hydroperoxide. This reaction is particularly relevant
to biological systems in the reaction of singlet oxygen with
tryptophan, histidine , and unsaturated fatty acids.

• The formation of dioxetanes is possible via the cycloaddition of

singlet oxygen with p-electron rich olefins. Dioxetanes, which are
generally only stable at low temperatures, will undergo
decomposition to form two carbonyl groups.
Typical Modes of Reaction of Singlet
Oxygen
O
+ 1O 2 endoperoxide
O

+ 1O 2 ene type product

O OH

X X
+ 1O 2 O dioxetane
O
• Singlet oxygen, due to its high electrophilicity, is capable of oxidizing
phenols, sulfides, and amines.

• The reaction of singlet oxygen with phenol results in the formation of

hydroperoxides that dehydrate to form benzoquinones.

• The oxidation of organic sulfides, disulfides, and amines has also been
reported.

• Sulfides are generally oxidized to sulfoxides, while disulfides react to form

thiolsulfinates. Amines with low ionization potentials can be oxidized by
singlet oxygen, possibly through a charge transfer intermediate .

• It is possible that some singlet oxygen reactions may proceed by electron

transfer from the electron rich compound to the electrophilic singlet oxygen.
Phenols can react with singlet oxygen via electron transfer. It has also been
suggested that the photooxidation of polystyrene by singlet oxygen may
occur via a radical mechanism as well as by formation of a hydroperoxide
Ene reaction
 Photooxygenation of 1,3-dienes

1O
2 1O
O 2
O O
O + O
O

Ph Ph
Ph
Ph 1O Ph Ph
2
O O
+ O
O Ph
Ph
Ph
Ph Ph
Ph

O 1O
2 O O
O 1O
2 O O
O O O
O O O
 H
H'

H' H

H H'

H
H'

tBu
1O
2

tBu O O

62%

1O
2

O O
23%
 (CH2)n
1O
2
n
O
O

X
1O
2 O
X
O

X = CH2, (CH2)2, CH=CH

 1O
2 O
O O
O

1O
2
Ph O Ph
O
O
O
 O O
O

+
1O
O O O
2 heat O
O
O O
Ph3P
MeOH

O O
H H
OMe
O
H

S S
1O
2 HN=NH
O O
S O O
Chemoselectivity in photooxygenations of 1,3 dienes

3 factors controlling the reactivity

# the amount of s-cis conformer in the equlibrium necessary for 4+2

# the relative reactivity difference of the C-C double bonds

# the appropriate alignment of allylic H for ene reaction

1O (CH2)n
2
(CH2)n O + ene products
MeOH/DCM
O
RB

n=1 16 84
n=2 20 80
n=3 22 78
n=4 50 50
n=5 67 33
 1O
2

O
O

1O
2

OOH

H H
H Me

Me H
 1O
2
OMe
OMe O
O

OMe OMe

1O
2 OMe
O +
OMe OMe
O
OMe CHO
OMe

OMe
OMe
O
O
 O
O
1O
2 O
+ + +
O OOH
MeOH
OOH

1O OOH
2
+
-Myrcene OOH

O
1O O
2

-Myrcene
OtBu
OtBu OtBu
1O
2
O
+ OMe
OMe O

OMe
 O O
Ar O O
h/O2
H + Ar

Ar H

H Cl OH
N
Ar
N

epibatidine OH
OH OTBS 1O
OTBS
2
O O
OH OTBS h OTBS

OH
OH
MeO OH
O

HO OH
OH
OH

Pinitol
 O
OH O
OH
OH
OH
b
a c
O
+ O O d
O O

e O

g f
O
O
HO O
O

a, b, c; Reduction
d, e; Thermolysis
f; Deoxygenation
g; Acid/base Catalyzed reactions
Reactions of singlet oxygen with antioxidants and other biomolecules

Singlet oxygen reacts with a wide range of biological molecules, including DNA, RNA,
proteins, lipids and sterols.
It is known to react with lipids, forming lipid hydroperoxide, which cause oxidative events
that leads to the cell death.
Singlet oxygen interacts with potential targets by two major pathways, namely, physical and
chemical.
The former results in energy transfer and de-excitation of the singlet state, but causes no
chemical change in the acceptor.
The latter results in chemical modification of the target.

In human physiological condition, antioxidant defense against reactive oxygen species

requires modulation of cellular enzyme, which scavenges the initial radical produced to
prevent the oxidative damage brought by reactive oxygen species.
Antioxidants also have to be efficient singlet oxygen quenchers.
Rate constants of singlet oxygen with well known phenolic antioxidants namely: curcumin,
resveratrol, ferulic acid, caffeic acid, o-hydroxy cinnamic acid and some indole derivatives,
have been determined. All of the phenolic antioxidants show moderate quenching ability
with singlet oxygen and the quenching rate constant were in the order of~10 6 -105 dm3 mol-1
s -1 .