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Depicting radicals in chemical reactions In written chemical equations, free radicals are frequently denoted by a dot placed immediately to the right of the atomic symbol or molecular formula as follows: Radical reaction mechanisms use single-headed arrows to depict the movement of single electrons: The homolytic cleavage of the breaking bond is drawn with a 'fish-hook' arrow to distinguish from the usual movement of two electrons depicted by a standard curly arrow. It should be noted that the second electron of the breaking bond also moves to pair up with the attacking radical electron; this is not explicitly indicated in this case. In chemistry, free radicals take part in radical addition and radical substitution as reactive intermediates. Reactions involving free radicals can usually be divided into three distinct processes: initiation, propagation, and termination. Formation The formation of radicals requires covalent bonds to be broken homolytically, a process that requires significant amounts of energy. For example, splitting H2 into 2H· has a ΔH° of +435 kJ/mol, and Cl2 into 2Cl· has a ΔH° of +243 kJ/mol. This is known as the homolytic bond dissociation energy, and is usually abbreviated as the symbol DH°. The bond energy between two covalently bonded atoms is affected by the structure of the molecule as a whole, not just the identity of the two atoms, and radicals requiring more energy to form are less stable than those requiring less energy. Homolytic bond cleavage most often happens between two atoms of similar electronegativity. In organic chemistry this is often the O-O bond in peroxide species or O-N bonds. However, propagation is a very exothermic reaction. Note that all species are electrically neutral although radical ions do exist. Persistence and stability
Reactivity Radical alkyl intermediates are stabilized by similar criteria as carbocations: the more substituted the radical center is, the more stable it is. This will direct their reactions: formation of a tertiary radical (R3C·) is favored over secondary (R2HC·) or primary (RH2C·). However, radicals next to functional groups, such as carbonyl, nitrile, and ether are even more stable than tertiary alkyl radicals. Radicals attack double bonds, but unlike similar ions, they are not directed by electrostatic interactions. For example, the reactivity of nucleophilic ions with α,β-unsaturated compounds (C=C-C=O) is directed by the electron-withdrawing effect of the oxygen, resulting in a partial positive charge on the carbonyl carbon. There are two reactions that are observed in the ionic case: the carbonyl is attacked in a direct addition to carbonyl, or the vinyl is attacked in conjugate addition, and in either case, the charge on the nucleophile is taken by the oxygen. Radicals add rapidly to the double bond, and the resulting α-radical carbonyl is relatively stable. In intramolecular reactions, precise control can be achieved despite the extreme reactivity of radicals. Radicals will attack the closest reactive site the most readily. Therefore, when there is a choice, a preference for five-membered rings is observed: four-membered rings are too strained, and collisions with carbons five or more atoms away in the chain are infrequent. Combustion Probably the most familiar free-radical reaction for most people is combustion. The oxygen molecule is a stable diradical, best represented by ·O-O·, which is stable because the spins of the electrons are parallel. The ground state of oxygen is an unreactive spin-paired (triplet) radical, but an extremely reactive spin-unpaired (singlet) radical is available. In order for combustion to occur, the energy barrier between these must be overcome. This barrier can be overcome by heat, requiring high temperatures, or can be lowered by enzymes to initiate reactions at the temperatures inside living things. Combustion is comprised of various radical chain reactions that the singlet radical can initiate. The flammability of a given material is strongly dependent on the concentration of free radicals that must be obtained before initiation and propagation reactions dominate leading to combustion of the material. Once the combustible material has been consumed, termination reactions again dominate and the flame dies out. Propagation or termination reactions can be promoted to alter flammability. Tetraethyl lead was once commonly added to gasoline, because it very easily breaks up into radicals, which consume other free radicals in the gasoline-air mixture. This prevents the combustion from initiating prematurely (see engine knock). Polymerization In addition to combustion, many polymerization reactions involve free radicals. As a result many plastics, enamels, and other polymers are formed through radical polymerization. Recent advances in radical polymerization methods, known as Living Radical Polymerization, include: Atmospheric radicals In the upper atmosphere free radicals are produced through dissociation of the source molecules, particularly the normally unreactive chlorofluorocarbons by solar ultraviolet radiation or by reactions with other stratospheric constituents. These free radicals then react with ozone in a catalytic chain reaction which destroys the ozone, but regenerates the free radical, allowing it to participate in additional reactions. Such reactions are believed to be the primary cause of depletion of the ozone layer and this is why the use of chlorofluorocarbons as refrigerants has been restricted. Free radicals in biology Free radicals play an important role in a number of biological processes, some of which are necessary for life, such as the intracellular killing of bacteria by neutrophil granulocytes. Free radicals have also been implicated in certain cell signalling processes. The two most important oxygen-centered free radicals are superoxide and hydroxyl radical. They are derived from molecular oxygen under reducing conditions. However, because of their reactivity, these same free radicals can participate in unwanted side reactions resulting in cell damage. Many forms of cancer are thought to be the result of reactions between free radicals and DNA, resulting in mutations that can adversely affect the cell cycle and potentially lead to malignancy. Some of the symptoms of aging such as atherosclerosis are also attributed to free-radical induced oxidation of many of the chemicals making up the body. In addition free radicals contribute to alcohol-induced liver damage, perhaps more than alcohol itself. Radicals in cigarette smoke have been implicated in inactivation of alpha 1-antitrypsin in the lung. This process promotes the development of emphysema. Free radicals may also be involved in Parkinson's disease, senile and drug-induced deafness, schizophrenia, and Alzheimer's. The classic free-radical syndrome, the iron-storage disease hemochromatosis, is typically-associated with a constellation of free-radical-related symptoms including movement disorder, psychosis, skin pigmentary melanin abnormalities, deafness, arthritis, and diabetes. The free radical theory of aging proposes that free radicals underlie the aging process itself. Because free radicals are necessary for life, the body has a number of mechanisms to minimize free radical induced damage and to repair damage which does occur, such as the enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. In addition, antioxidants play a key role in these defense mechanisms. These are often the three vitamins, vitamin A, vitamin C and vitamin E and polyphenol antioxidants. Further, there is good evidence bilirubin and uric acid can act as antioxidants to help neutralize certain free radicals. Bilirubin comes from the breakdown of red blood cells' contents, while uric acid is a breakdown product of purines. Too much bilirubin, though, can lead to jaundice, which could eventually damage the central nervous system, while too much uric acid causes gout . Reactive oxygen species Main article: Reactive oxygen species Reactive oxygen species or ROS are species such as superoxide, hydrogen peroxide, and hydroxyl radical and are associated with cell damage. Free radicals are also produced inside (and also released towards the cytosol) organelles, such as the mitochondrion. The mitochondria create energy for the cell by producing adenosine triphosphate (ATP). In the cycle of production of the ATP, the third step of reattaching a phosphate group to the adenosine diphosphate to create adenosine triphosphate, is called the electron transport chain. In the electron transport chain, electrons are passed down a series of proteins which lower the energy of an electron so it can be safely harnessed by the mitochondria. The third protein in the electron transport chain is called Coenzyme Q. This “protein” is in fact not a protein at all, but a lipid. it is estimated that ~.1 - 4% of the electrons that pass through CoQ leaks onto an oxygen molecule, giving this electron an extra unpaired electron. This oxygen molecule, O2- is known as superoxide. Superoxide needs an additional electron to make it more stable, so it steals an electron from the nearest source, such as: mitochondrial DNA the mitochondrial membrane (called lipid peroxidation), or from protein, or from reductants such as Vitamins C or E, or, from non enzymatic antioxidants such as glutathione or thioredoxin. If too much damage is caused to the mitochondrion, it goes through apoptosis, or programmed cell death. Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, and activate a class of proteins called Bax, which punch holes in the mitochondrial membrane, causing cytochrome C to leak out. This cytochrome C binds to Apaf-1, or apoptotic protease activating factor-1, which is free-floating in the cell’s cytoplasm. Using energy from the ATPs in the mitochondrion, the Apaf-1 and cytochrome C bind together to form apoptosomes. The apoptosomes binds to and activates caspase-9, another free-floating protein. The caspase-9 then cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and eventually phagocytosis of the cell. According to the Free Radical Theory of Aging, aging occurs (via a loss of energy producing cells) either when mitochondria begin to die out because of free radical damage or, when less functional mitochondria remain within these cells. The focus of the project is to neutralize the effect of these free radicals with antioxidants. Antioxidants neutralize free radicals by donating one of their own electrons. The antioxidant nutrients themselves don’t become free radicals by donating an electron because they are stable in either form. Superoxide dismutase (SOD) is present in two places naturally in the cell. SOD that is present in the mitochondria contains manganese (MnSod). This SOD is transcribed in the nucleus and has a mitochondrial targeting sequence, thereby localizing it to the miotchondrial matrix. SOD that is present in the cytoplasm of the cell contains copper and zinc (CuZnSod). The genes that control the formation of SOD are located on chromosomes 21, 6, and 4. When superoxide dismutase comes in contact with superoxide, it reacts with it and forms hydrogen peroxide. The stoichiometry of this reaction is that for each 2 superoxide radicals encountered by SOD, 1 H2O2 is formed. This hydrogen peroxide is dangerous in the cell because it can easily transform into a hydroxyl radical (via reaction with Fe2+:Fenton chemistry), one of the most destructive free radicals. Catalase, which is concentrated in peroxisomes located next to mitochondria but formed in the rough endoplasmic reticulum and located everywhere in the cell, reacts with the hydrogen peroxide and forms water and oxygen. Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a very small sulfur containing protein called glutathione. The selenium contained in these enzymes acts as the reactive center, carrying reactive electrons from the peroxide to the glutathione. Peroxiredoxins also degrade H2O2, both within the mitochondria, cytosol and nucleus. Diagnostics Free Radical diagnostic techniques include: A widely-used technique for studying free radicals, and other paramagnetic species, is electron spin resonance spectroscopy (ESR). This is alternately referred to as "electron paramagnetic resonance" (EPR) spectroscopy. It is conceptually related to nuclear magnetic resonance, though electrons resonate with higher-frequency fields at a given fixed magnetic field than do most nuclei. Chemical labelling by quenching with free radicals, e.g. with NO or DPPH, followed by spectroscopic methods like X-ray photoelectron spectroscopy (XPS) or absorption spectroscopy, respectively. Stable, specific or non-specific derivates of physiological substances can be measured e.g. lipid peroxidation products (isoprostanes, TBARS), amino acid oxidation products (meta-tyrosine, ortho-tyrosine, hydroxy-Leu, dityrosine etc.), peptide oxidation products (oxidized glutathione - GSSG) Measurement of the decrease in the amount of antioxidants (e.g. TAS, reduced glutathione - GSH) See also | |||||||||||
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