Photooxygenation
Encyclopedia
A photooxygenation is a light-induced oxidation reaction in which molecular oxygen
is incorporated into the product(s). Initial research interest in photooxygenation reactions arose from Oscar Raab's observations in 1900 that the combination of light, oxygen and photosensitizers is highly toxic to cells. Early studies of photooxygenation focused on oxidative damage to DNA and amino acids, but recent research has led to the application of photooxygenation in organic synthesis and photodynamic therapy
.
Photooxygenation reactions are initiated by a photosensitizer, which is a molecule that enters an excited state
when exposed to light of a specific wavelength (e.g. dyes and pigments). The excited sensitizer then reacts with either a substrate or ground state molecular oxygen, starting a cascade of energy transfers that ultimately result in an oxygenated molecule. Consequently, photooxygenation reactions are categorized by the type and order of these intermediates (as type I, type II, or type III reactions).
, the involvement of light, and the incorporation of molecular oxygen into the products:
, methylene blue
, and polycyclic aromatic hydrocarbon
s, which are able to absorb electromagnetic radiation
(usually in the visible range of the spectrum) and eventually transfer that energy to molecular oxygen or the substrate of photooxygenation process. Many sensitizers, both naturally occurring and synthetic, rely on extensive aromatic systems
to absorb light in the visible spectrum. When sensitizers are excited by light, they reach a singlet state, 1Sens*. This singlet is then converted into a triplet state
(which is more stable), 3Sens*, via intersystem crossing
. The 3Sens* is what reacts with either the substrate or 3O2 in the three types of photooxygenation reactions.
s, molecular oxygen, O2, is depicted as having a double bond between the two oxygen atoms. However, the molecular orbitals of O2 are actually more complex than Lewis structures seem to suggest. The highest occupied molecular orbital (HO
M
O)
of O2 is a pair of degenerate antibonding
π orbitals, π2px* and π2py*, which are both singly occupied by spin paired electrons. These electrons are the cause of O2 being a triplet
diradical in the ground state (indicated as 3O2).
While many stable molecules’ HOMOs consist of bonding molecular orbitals and therefore require a moderate energy jump from bonding to antibonding to reach their first excited state, the antibonding nature of molecular oxygen’s HOMO allows for a lower energy gap between its ground state and first excited state. This makes excitation of O2 a less energetically restrictive process. In the first excited state of O2, a 22 kcal/mol energy increase from the ground state, both electrons in the antibonding orbitals occupy a degenerate π* orbital, and oxygen is now in a singlet
state (indicated as 1O2). 1O2 is very reactive with a lifetime between 10-100µs.
bond breaking of a hydrogen bond on the substrate. This substrate radical then interacts with 3O2 (ground state) to yield a substrate-O2 radical. Such a radical is generally quenched by abstracting a hydrogen from another substrate molecule or from the solvent. This process allows for chain propagation of the reaction.
species. Mirbach et al. reported on one such reaction in which an azo compound
is lysed via photolysis
to form the diradical hydrocarbon and then trapped in a stepwise fashion by molecular oxygen:
s with olefins
.
to create cis-2-cyclopentene-1,4-diol is a common step involved in the synthesis of prostaglandins. The initial addition singlet oxygen, through the concerted [4+2] cycloaddition, forms an unstable endoperoxide
. Subsequent reduction of the peroxide bound produces the two alcohol groups.
that occurs between the 3Sens* and the substrate resulting in an anionic
Sens and a cationic
substrate. Another electron transfer then occurs where the anionic Sens transfers an electron to 3O2 to form the superoxide anion, O2-
. This transfer returns the Sens to its ground state. The superoxide anion and cationic substrate then interact to from the oxygenated product.
s (heterocyclic aromatic derivates of indole) has been investigated in both mechanistic and synthetic contexts. Rather than proceeding through a Type I or Type II photooxygenation mechanism, some investigators have chosen to use 9,10-dicyanoanthracene (DCA) as a photosensitzer, leading to the reaction of an indolizine derivative with the superoxide anion radical. Note that the reaction proceeds through an indolizine radical cation intermediate that is has not been isolated (and thus is not depicted):
Many of the applications of type II photooxygenations in organic synthesis come from
Waldemar Adam's investigations into the ene-reaction of singlet oxygen with acyclic alkenes. Through the cis effect and the presence of appropriate steering groups the reaction can even provide high regioselectively
and diastereoselectivity
- two valuable stereochemical controls.
. A photosensitizer is injected into the tumor and then specific wavelengths of light are exposed to the tissue to excite the Sens. The excited Sens generally follows a type I or II photooxygenation mechanism to result in oxidative damage
to cells. Extensive oxidative damage to tumor cells will kill tumor cells. Also oxidative damage to nearby blood vessels will cause local agglomeration and cut off nutrient supply to the tumor, thus starving the tumor.
An important consideration when selecting the Sens to be used in PDT is the specific wavelength of light the Sens will absorb to reach an excited state. Since wavelengths around 800 nm have maximum penetration of tissues, selecting Sens that absorb around this range is advantageous as it allows for PDT to be affective on tumors beneath the outer most layer of the dermis. The window of 800 nm light is most effective at penetrating tissues because at wavelengths shorter than 800 nm the light starts to be scattered by the macromolecules of cells and at wavelengths longer than 800 nm water molecules will begin to absorb the light and convert it into heat.
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
is incorporated into the product(s). Initial research interest in photooxygenation reactions arose from Oscar Raab's observations in 1900 that the combination of light, oxygen and photosensitizers is highly toxic to cells. Early studies of photooxygenation focused on oxidative damage to DNA and amino acids, but recent research has led to the application of photooxygenation in organic synthesis and photodynamic therapy
Photodynamic therapy
Photodynamic therapy is used clinically to treat a wide range of medical conditions, including malignant cancers, and is recognised as a treatment strategy which is both minimally invasive and minimally toxic...
.
Photooxygenation reactions are initiated by a photosensitizer, which is a molecule that enters an excited state
Excited state
Excitation is an elevation in energy level above an arbitrary baseline energy state. In physics there is a specific technical definition for energy level which is often associated with an atom being excited to an excited state....
when exposed to light of a specific wavelength (e.g. dyes and pigments). The excited sensitizer then reacts with either a substrate or ground state molecular oxygen, starting a cascade of energy transfers that ultimately result in an oxygenated molecule. Consequently, photooxygenation reactions are categorized by the type and order of these intermediates (as type I, type II, or type III reactions).
Terminology
Photooxygenation reactions are easily confused with a number of processes baring similar names (i.e. photosensitized oxidation). Clear distinctions can be made based on three attributes: oxidationRedox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
, the involvement of light, and the incorporation of molecular oxygen into the products:
Sensitizers
Sensitizers (denoted "Sens") are compounds, such as fluorescein dyesFluorescein
Fluorescein is a synthetic organic compound available as a dark orange/red powder soluble in water and alcohol. It is widely used as a fluorescent tracer for many applications....
, methylene blue
Methylene blue
Methylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
, and polycyclic aromatic hydrocarbon
Polycyclic aromatic hydrocarbon
Polycyclic aromatic hydrocarbons , also known as poly-aromatic hydrocarbons or polynuclear aromatic hydrocarbons, are potent atmospheric pollutants that consist of fused aromatic rings and do not contain heteroatoms or carry substituents. Naphthalene is the simplest example of a PAH...
s, which are able to absorb electromagnetic radiation
Electromagnetic radiation
Electromagnetic radiation is a form of energy that exhibits wave-like behavior as it travels through space...
(usually in the visible range of the spectrum) and eventually transfer that energy to molecular oxygen or the substrate of photooxygenation process. Many sensitizers, both naturally occurring and synthetic, rely on extensive aromatic systems
Aromatic hydrocarbon
An aromatic hydrocarbon or arene is a hydrocarbon with alternating double and single bonds between carbon atoms. The term 'aromatic' was assigned before the physical mechanism determining aromaticity was discovered, and was derived from the fact that many of the compounds have a sweet scent...
to absorb light in the visible spectrum. When sensitizers are excited by light, they reach a singlet state, 1Sens*. This singlet is then converted into a triplet state
Triplet state
A spin triplet is a set of three quantum states of a system, each with total spin S = 1 . The system could consist of a single elementary massive spin 1 particle such as a W or Z boson, or be some multiparticle state with total spin angular momentum of one.In physics, spin is the angular momentum...
(which is more stable), 3Sens*, via intersystem crossing
Intersystem crossing
Intersystem crossing is a radiationless process involving a transition between two electronic states with different spin multiplicity.-Singlet and triplet states:...
. The 3Sens* is what reacts with either the substrate or 3O2 in the three types of photooxygenation reactions.
States of Molecular Oxygen
In classical Lewis structureLewis structure
Lewis structures are diagrams that show the bonding between atoms of a molecule and the lone pairs of electrons that may exist in the molecule. A Lewis structure can be drawn for any covalently bonded molecule, as well as coordination compounds...
s, molecular oxygen, O2, is depicted as having a double bond between the two oxygen atoms. However, the molecular orbitals of O2 are actually more complex than Lewis structures seem to suggest. The highest occupied molecular orbital (HO
HOMO/LUMO
HOMO and LUMO are acronyms for highest occupied molecular orbital and lowest unoccupied molecular orbital, respectively. The energy difference between the HOMO and LUMO is termed the HOMO-LUMO gap...
M
Middlebury College
Middlebury College is a private liberal arts college located in Middlebury, Vermont, USA. Founded in 1800, it is one of the oldest liberal arts colleges in the United States. Drawing 2,400 undergraduates from all 50 United States and over 70 countries, Middlebury offers 44 majors in the arts,...
O)
HOMO/LUMO
HOMO and LUMO are acronyms for highest occupied molecular orbital and lowest unoccupied molecular orbital, respectively. The energy difference between the HOMO and LUMO is termed the HOMO-LUMO gap...
of O2 is a pair of degenerate antibonding
Antibonding
Antibonding is a type of chemical bonding. An antibonding orbital is a form of molecular orbital that is located outside the region of two distinct nuclei...
π orbitals, π2px* and π2py*, which are both singly occupied by spin paired electrons. These electrons are the cause of O2 being a triplet
Triplet oxygen
Triplet oxygen is the ground state of the oxygen molecule. The electron configuration of the molecule has two unpaired electrons occupying two degenerate molecular orbitals...
diradical in the ground state (indicated as 3O2).
While many stable molecules’ HOMOs consist of bonding molecular orbitals and therefore require a moderate energy jump from bonding to antibonding to reach their first excited state, the antibonding nature of molecular oxygen’s HOMO allows for a lower energy gap between its ground state and first excited state. This makes excitation of O2 a less energetically restrictive process. In the first excited state of O2, a 22 kcal/mol energy increase from the ground state, both electrons in the antibonding orbitals occupy a degenerate π* orbital, and oxygen is now in a singlet
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...
state (indicated as 1O2). 1O2 is very reactive with a lifetime between 10-100µs.
Types of Photooxygenation
The three types of photooxygenation reactions are distinguished by the mechanisms that they proceed through, as they are capable of yielding different or similar products depending on environmental conditions. Type I and II reactions proceed through neutral intermediates, while type III reactions proceed through charged species. The absence or presence of 1O2 is what distinguishes type I and type II reactions, respectively.Type I
In type I reactions, the photoactivated 3Sens* interacts with the substrate to yield a radical substrate, usually through the homolyticHomolysis
In general it means breakdown to equal pieces There are separate meanings for the word in chemistry and biology.-Homolysis in chemistry:...
bond breaking of a hydrogen bond on the substrate. This substrate radical then interacts with 3O2 (ground state) to yield a substrate-O2 radical. Such a radical is generally quenched by abstracting a hydrogen from another substrate molecule or from the solvent. This process allows for chain propagation of the reaction.
Example: Oxygen trapping of diradical intermediates
Type I photooxygenation reactions are frequently used in the process of forming and trapping diradicalDiradical
A diradical in organic chemistry is a molecular species with two electrons occupying two degenerate molecular orbitals . They are known by their higher reactivities and shorter lifetimes. In a broader definition diradicals are even-electron molecules that have one bond less than the number...
species. Mirbach et al. reported on one such reaction in which an azo compound
Azo compound
Azo compounds are compounds bearing the functional group R-N=N-R', in which R and R' can be either aryl or alkyl. IUPAC defines azo compounds as: "Derivatives of diazene , HN=NH, wherein both hydrogens are substituted by hydrocarbyl groups, e.g. PhN=NPh azobenzene or diphenyldiazene." The more...
is lysed via photolysis
Photodissociation
Photodissociation, photolysis, or photodecomposition is a chemical reaction in which a chemical compound is broken down by photons. It is defined as the interaction of one or more photons with one target molecule....
to form the diradical hydrocarbon and then trapped in a stepwise fashion by molecular oxygen:
Type II
In type II reactions, the 3Sens* transfers its energy directly with 3O2 via a radiation-less transition to create 1O2. 1O2 then adds to the substrate in a variety of ways including: cycloadditions (most commonly [4+2]), addition to double bonds to yield 1,2-dioxetanes, and ene reactionEne reaction
The Ene reaction is a chemical reaction between an alkene with an allylic hydrogen and a compound containing a multiple bond , in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the...
s with olefins
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
.
Example: Precursor to Prostaglandin Synthesis
The [4+2] cycloaddition of singlet oxygen to cyclopentadieneCyclopentadiene
Cyclopentadiene is an organic compound with the formula C5H6. This colorless liquid has a strong and unpleasant odor. At room temperature, this cyclic diene dimerizes over the course of hours to give dicyclopentadiene via a Diels–Alder reaction...
to create cis-2-cyclopentene-1,4-diol is a common step involved in the synthesis of prostaglandins. The initial addition singlet oxygen, through the concerted [4+2] cycloaddition, forms an unstable endoperoxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
. Subsequent reduction of the peroxide bound produces the two alcohol groups.
Type III
In type III reactions, there is an electron transferElectron transfer
Electron transfer is the process by which an electron moves from an atom or a chemical species to another atom or chemical species...
that occurs between the 3Sens* and the substrate resulting in an anionic
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
Sens and a cationic
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
substrate. Another electron transfer then occurs where the anionic Sens transfers an electron to 3O2 to form the superoxide anion, O2-
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
. This transfer returns the Sens to its ground state. The superoxide anion and cationic substrate then interact to from the oxygenated product.
Example: Indolizine Photooxygenation
Photooxygenation of indolizineIndolizine
Indolizine is a heterocyclic aromatic organic compound that is an isomer of indole. It forms the structural core of a variety of alkaloids such as swainsonine.-External links:*...
s (heterocyclic aromatic derivates of indole) has been investigated in both mechanistic and synthetic contexts. Rather than proceeding through a Type I or Type II photooxygenation mechanism, some investigators have chosen to use 9,10-dicyanoanthracene (DCA) as a photosensitzer, leading to the reaction of an indolizine derivative with the superoxide anion radical. Note that the reaction proceeds through an indolizine radical cation intermediate that is has not been isolated (and thus is not depicted):
Organic Synthesis
All 3 types of photooxygenation have been applied in the context of organic synthesis. In particular, type II photooxygenations have proven to be the most widely used (due to the low amount of energy required to generate singlet oxygen) and have been described as "one of the most powerful methods for the photochemical oxyfunctionalization of organic compounds." These reactions can proceed in all common solvents and with a broad range of sensitizers.Many of the applications of type II photooxygenations in organic synthesis come from
Waldemar Adam's investigations into the ene-reaction of singlet oxygen with acyclic alkenes. Through the cis effect and the presence of appropriate steering groups the reaction can even provide high regioselectively
Regioselectivity
In chemistry, regioselectivity is the preference of one direction of chemical bond making or breaking over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base will abstract from an organic molecule, or where...
and diastereoselectivity
Diastereomer
Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...
- two valuable stereochemical controls.
Photodynamic Therapy
Photodynamic therapy (PDT) uses photooxygenation to destroy cancerous tissueCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. A photosensitizer is injected into the tumor and then specific wavelengths of light are exposed to the tissue to excite the Sens. The excited Sens generally follows a type I or II photooxygenation mechanism to result in oxidative damage
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
to cells. Extensive oxidative damage to tumor cells will kill tumor cells. Also oxidative damage to nearby blood vessels will cause local agglomeration and cut off nutrient supply to the tumor, thus starving the tumor.
An important consideration when selecting the Sens to be used in PDT is the specific wavelength of light the Sens will absorb to reach an excited state. Since wavelengths around 800 nm have maximum penetration of tissues, selecting Sens that absorb around this range is advantageous as it allows for PDT to be affective on tumors beneath the outer most layer of the dermis. The window of 800 nm light is most effective at penetrating tissues because at wavelengths shorter than 800 nm the light starts to be scattered by the macromolecules of cells and at wavelengths longer than 800 nm water molecules will begin to absorb the light and convert it into heat.