Salicylic acid is a lipophilic monohydroxybenzoic acid, a type of phenolic acid, a beta hydroxy acid. It has the formula C7H6O3; this colorless crystalline organic acid is used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin. In addition to serving as an important active metabolite of aspirin, which acts in part as a prodrug to salicylic acid, it is best known for its use as a key ingredient in topical anti-acne products; the salts and esters of salicylic acid are known as salicylates. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. Salicylic acid as a medication is used most to help remove the outer layer of the skin; as such, it is used to treat warts, acne, ringworm and ichthyosis. Similar to other hydroxy acids, salicylic acid is a key ingredient in many skincare products for the treatment of seborrhoeic dermatitis, psoriasis, corns, keratosis pilaris, acanthosis nigricans and warts.
Salicylic acid is used in the production of other pharmaceuticals, including 4-aminosalicylic acid and landetimide. Salicylic acid was one of the original starting materials for making acetylsalicylic acid in 1897. Bismuth subsalicylate, a salt of bismuth and salicylic acid, is the active ingredient in stomach relief aids such as Pepto-Bismol, is the main ingredient of Kaopectate and "displays anti-inflammatory action and acts as an antacid and mild antibiotic". Other derivatives include methyl salicylate used as a liniment to soothe joint and muscle pain and choline salicylate used topically to relieve the pain of mouth ulcers. Salicylic acid is used as a bactericidal and an antiseptic. Sodium salicylate is a useful phosphor in the vacuum ultraviolet spectral range, with nearly flat quantum efficiency for wavelengths between 10 and 100 nm, it fluoresces in the blue at 420 nm. It is prepared on a clean surface by spraying a saturated solution of the salt in methanol followed by evaporation. Aspirin can be prepared by the esterification of the phenolic hydroxyl group of salicylic acid with the acetyl group from acetic anhydride or acetyl chloride.
Salicylic acid directly and irreversibly inhibits the activity of both types of cyclo-oxygenases to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Salicylate may competitively inhibit prostaglandin formation. Salicylate's antirheumatic actions are a result of its anti-inflammatory mechanisms. Salicylic acid works by causing the cells of the epidermis to slough off more preventing pores from clogging up, allowing room for new cell growth. Salicylic acid inhibits the oxidation of uridine-5-diphosphoglucose competitively with nicotinamide adenosine dinucleotide and noncompetitively with UDPG, it competitively inhibits the transferring of glucuronyl group of uridine-5-phosphoglucuronic acid to the phenolic acceptor. The wound-healing retardation action of salicylates is due to its inhibitory action on mucopolysaccharide synthesis; as a topical agent and as a beta-hydroxy acid, salicylic acid is capable of penetrating and breaking down fats and lipids, causing moderate chemical burns of the skin at high concentrations.
It may damage the lining of pores if the solvent is acetone or an oil. Over-the-counter limits are set at 2% for topical preparations expected to be left on the face and 3% for those expected to be washed off, such as acne cleansers or shampoo. For wart removal, such a solution should be applied once or twice a day – more frequent use may lead to an increase in side-effects without an increase in efficacy; some people are hypersensitive to related compounds. If high concentrations of salicylic ointment are applied to a large percentage of body surface, high levels of salicylic acid can enter the blood, requiring hemodialysis to avoid further complications. Salicylic acid has the formula C6H4COOH, it is known as 2-hydroxybenzoic acid. It is poorly soluble in water. Salicylic acid is biosynthesized from the amino acid phenylalanine. In Arabidopsis thaliana it can be synthesized via a phenylalanine-independent pathway. Sodium salicylate is commercially prepared by treating sodium phenolate with carbon dioxide at high pressure and high temperature – a method known as the Kolbe-Schmitt reaction.
Acidification of the product with sulfuric acid gives salicylic acid: It can be prepared by the hydrolysis of aspirin or methyl salicylate with a strong acid or base. Hippocrates, Pliny the Elder and others knew that willow bark could ease pain and reduce fevers, it was used in China to treat these conditions. This remedy is mentioned in texts from ancient Egypt and Assyria; the Cherokee and other Native Americans used an infusion of the bark for fever and other medicinal purposes. In 2014, archaeologists identified traces of salicylic acid on 7th century pottery fragments found in east central Colorado; the Reverend Edward Stone, a vicar from Chipping Norton, Engla
In chemistry, resonance is a way of describing bonding in certain molecules or ions by the combination of several contributing structures into a resonance hybrid in valence bond theory. It has particular value for describing delocalized electrons within certain molecules or polyatomic ions where the bonding cannot be expressed by one single Lewis structure. Under the framework of valence bond theory, resonance is an extension of the idea that the bonding in a chemical species can be described by a Lewis structure. For many chemical species, a single Lewis structure, consisting of atoms obeying the octet rule bearing formal charges, connected by bonds of positive integer order, is sufficient for describing the chemical bonding and rationalizing experimentally determined molecular properties like bond lengths and dipole moment. However, in some cases, more than one Lewis structure could be drawn, experimental properties are inconsistent with any one structure. In order to address this type of situation, several contributing structures are considered together as an average, the molecule is said to be represented by a resonance hybrid in which several Lewis structures are used collectively to describe its true structure.
For instance, in NO2–, nitrite anion, the two N–O bond lengths are equal though no single Lewis structure has two N–O bonds with the same formal bond order. However, its measured structure is consistent with a description as a resonance hybrid of the two major contributing structures shown above: it has two equal N–O bonds of 125 pm, intermediate in length between a typical N–O single bond and N–O double bond. According to the contributing structures, each N–O bond is an average of a formal single and formal double bond, leading to a true bond order of 1.5. By virtue of this averaging, the Lewis description of the bonding in NO2– is reconciled with the experimental fact that the anion has equivalent N–O bonds; the resonance hybrid represents the actual molecule as the "average" of the contributing structures, with bond lengths and partial charges taking on intermediate values compared to those expected for the individual Lewis structures of the contributors, were they to exist as "real" chemical entities.
The contributing structures differ only in the formal apportionment of electrons to the atoms, not in the actual physically and chemically significant electron or spin density. While contributing structures may differ in formal bond orders and in formal charge assignments, all contributing structures must have the same number of valence electrons and the same spin multiplicity; because electron delocalization lowers the potential energy of a system, any species represented by a resonance hybrid is more stable than any of the contributing structures. The difference in potential energy between the actual species and the energy of the contributing structure with the lowest potential energy is called the resonance energy or delocalization energy; the magnitude of the resonance energy depends on assumptions made about the hypothetical "non-stabilized" species and the computational methods used and does not represent a measurable physical quantity, although comparisons of resonance energies computed under similar assumptions and conditions may be chemically meaningful.
Molecules with an extended π system such as linear polyenes and polyaromatic compounds are well described by resonance hybrids as well as by delocalised orbitals in molecular orbital theory. Resonance is to be distinguished from isomerism. Isomers are molecules with the same chemical formula but are distinct chemical species with different arrangements of atomic nuclei in space. Resonance contributors of a molecule, on the other hand, can only differ in the way electrons are formally assigned to atoms in the Lewis structure depictions of the molecule; when a molecular structure is said to be represented by a resonance hybrid, it does not mean that electrons of the molecule are "resonating" or shifting back and forth between several sets of positions, each one represented by a Lewis structure. Rather, it means that the set of contributing structures represents an intermediate structure, with a single, well-defined geometry and distribution of electrons, it is incorrect to regard resonance hybrids as interconverting isomers though the term "resonance" might evoke such an image.
Symbolically, the double headed arrow A ⟷ B is used to indicate that A and B are contributing forms of a single chemical species. A non-chemical analogy is illustrative: one can describe the characteristics of a real animal, the narwhal, in terms of the characteristics of two mythical creatures: the unicorn, a creature with a single horn on its head, the leviathan, a large, whale-like creature; the narwhal is not a creature that goes back and forth between being a unicorn and being a leviathan, nor do the unicorn and leviathan have any physical existence outside the collective human imagination. Describing the narwhal in terms of these imaginary creatures provides a reasonably good description of its physical characteristics. Due to confusion
Benzene is an organic chemical compound with the chemical formula C6H6. The benzene molecule is composed of six carbon atoms joined in a ring with one hydrogen atom attached to each; as it contains only carbon and hydrogen atoms, benzene is classed as a hydrocarbon. Benzene is one of the elementary petrochemicals. Due to the cyclic continuous pi bond between the carbon atoms, benzene is classed as an aromatic hydrocarbon, the second -annulene, it is sometimes abbreviated PhH. Benzene is a colorless and flammable liquid with a sweet smell, is responsible for the aroma around petrol stations, it is used as a precursor to the manufacture of chemicals with more complex structure, such as ethylbenzene and cumene, of which billions of kilograms are produced annually. As benzene has a high octane number, aromatic derivatives like toluene and xylene comprise up to 25% of gasoline. Benzene itself has been limited to less than 1 % in gasoline. Most non-industrial applications have been limited as well for the same reason.
The word "benzene" derives from "gum benzoin", an aromatic resin known to European pharmacists and perfumers since the 15th century as a product of southeast Asia. An acidic material was derived from benzoin by sublimation, named "flowers of benzoin", or benzoic acid; the hydrocarbon derived from benzoic acid thus acquired benzol, or benzene. Michael Faraday first isolated and identified benzene in 1825 from the oily residue derived from the production of illuminating gas, giving it the name bicarburet of hydrogen. In 1833, Eilhard Mitscherlich produced it by distilling benzoic lime, he gave the compound the name benzin. In 1836, the French chemist Auguste Laurent named the substance "phène". In 1845, Charles Mansfield, working under August Wilhelm von Hofmann, isolated benzene from coal tar. Four years Mansfield began the first industrial-scale production of benzene, based on the coal-tar method; the sense developed among chemists that a number of substances were chemically related to benzene, comprising a diverse chemical family.
In 1855, Hofmann used the word "aromatic" to designate this family relationship, after a characteristic property of many of its members. In 1997, benzene was detected in deep space; the empirical formula for benzene was long known, but its polyunsaturated structure, with just one hydrogen atom for each carbon atom, was challenging to determine. Archibald Scott Couper in 1858 and Joseph Loschmidt in 1861 suggested possible structures that contained multiple double bonds or multiple rings, but too little evidence was available to help chemists decide on any particular structure. In 1865, the German chemist Friedrich August Kekulé published a paper in French suggesting that the structure contained a ring of six carbon atoms with alternating single and double bonds; the next year he published a much longer paper in German on the same subject. Kekulé used evidence that had accumulated in the intervening years—namely, that there always appeared to be only one isomer of any monoderivative of benzene, that there always appeared to be three isomers of every disubstituted derivative—now understood to correspond to the ortho and para patterns of arene substitution—to argue in support of his proposed structure.
Kekulé's symmetrical ring could explain these curious facts, as well as benzene's 1:1 carbon-hydrogen ratio. The new understanding of benzene, hence of all aromatic compounds, proved to be so important for both pure and applied chemistry that in 1890 the German Chemical Society organized an elaborate appreciation in Kekulé's honor, celebrating the twenty-fifth anniversary of his first benzene paper. Here Kekulé spoke of the creation of the theory, he said that he had discovered the ring shape of the benzene molecule after having a reverie or day-dream of a snake seizing its own tail. This vision, came to him after years of studying the nature of carbon-carbon bonds; this was 7 years after he had solved the problem of how carbon atoms could bond to up to four other atoms at the same time. Curiously, a similar, humorous depiction of benzene had appeared in 1886 in a pamphlet entitled Berichte der Durstigen Chemischen Gesellschaft, a parody of the Berichte der Deutschen Chemischen Gesellschaft, only the parody had monkeys seizing each other in a circle, rather than snakes as in Kekulé's anecdote.
Some historians have suggested that the parody was a lampoon of the snake anecdote already well known through oral transmission if it had not yet appeared in print. Kekulé's 1890 speech in which this anecdote appeared has been translated into English. If the anecdote is the memory of a real event, circumstances mentioned in the story suggest that it must have happened early in 1862; the cyclic nature of benzene was confirmed by the crystallographer Kathleen Lonsdale in 1929. The German chemist Wilhelm Körner suggested the prefixes ortho-, meta-, para- to distinguish di-substituted benzene derivatives in 1867, it was the German chemist Karl Gräbe who, in 1869, first used the prefixes ortho-, meta-, para- to denote specific relative locations of the substituents on a di-substituted aromatic ring (viz, nap
A coupling reaction in organic chemistry is a general term for a variety of reactions where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M reacts with an organic halide of the type R'-X with formation of a new carbon-carbon bond in the product R-R' Richard F. Heck, Ei-ichi Negishi, Akira Suzuki were awarded the 2010 Nobel Prize in Chemistry for developing palladium-catalyzed cross coupling reactions. Broadly speaking, two types of coupling reactions are recognized: Heterocouplings couple two different partners, such as in the Heck reaction of an alkene and an alkyl halide to give a substituted alkene. Homocouplings couple two identical partners, as in the Glaser coupling of two acetylides to form a dialkyne; the reaction mechanism begins with the oxidative addition of an organic halide to the catalyst. Subsequently, the second partner undergoes transmetallation, which places both coupling partners on the same metal center while eliminating the functional groups.
The final step is reductive elimination of the two coupling fragments to regenerate the catalyst and give the organic product. Unsaturated organic groups couple more in part because they add readily; the intermediates are less prone to beta-hydride elimination. In one computational study, unsaturated organic groups were shown to undergo much easier coupling reaction on the metal center; the rates for reductive elimination followed the following order: vinyl-vinyl > phenyl-phenyl > alkynyl-alkynyl > alkyl-alkyl. The activation barriers and the reaction energies for unsymmetrical R-R′ couplings were found to be close to the averages of the corresponding values of the symmetrical R-R and R′-R′ coupling reactions. Another mechanistic approach proposes that in aqueous solutions, coupling occurs via a radical mechanism rather than a metal-assisted one. Most of the coupling reaction's mechanisms vary from this generalized form; the most common catalyst is palladium. Other catalysts include copper, iron and amines.
Palladium is robust catalyst and is used due to high functional group tolerance, low sensitivity of organopalladium compounds towards water and air. However, palladium is a costly noble metal. Additionally palladium catalysts are notoriously difficult to remove. Purification involves extensive column chromatography, recrystallization, metal scavengers, distillation, or extraction to name a few techniques. Most methods do not remove the catalyst; this causes issues for the pharmaceutical industry which faces extensive regulation regarding heavy metals. Many pharmaceutical chemists attempt to use coupling reactions early in production to minimize metal traces in the product. Nickel catalysts, while less robust than palladium ones, are cheaper, easier to remove, less toxic. Nickel catalysts require energetic substrates or co-catalysts such as Photoredox catalysts. Many research groups are trying to create heterogeneous reusable catalysts to minimize cost and reduce purification needs. Most catalysts use bulky L type ligands such as triphenylphosphine, In depth-reviews have been written for example on cobalt and nickel mediated reactions and on applications The leaving group X in the organic partner is a halogen.
Chloride is the most ideal group due to their low cost, but have issues with reactivity. The main group metal in the organometallic partner is tin, silates or boron. While many coupling reactions involve reagents that are susceptible to presence of water or oxygen, it is unreasonable to assume that all coupling reactions need to be performed with strict exclusion of water, it is possible to perform palladium-based coupling reactions in aqueous solutions using the water-soluble sulfonated phosphines made by the reaction of triphenyl phosphine with sulfuric acid. Another example of coupling in aqueous media, with the main reacting agent being trimolybdenum-alkylidyne clusters, is that of Bogoslavsky et al. In general, the oxygen in the air is more able to disrupt coupling reactions, because many of these reactions occur via unsaturated metal complexes that do not have 18 valence electrons. For example, in nickel and palladium cross couplings, a zerovalent complex with two vacant sites reacts with the carbon halogen bond to form a metal halogen and a metal carbon bond.
Such a zerovalent complex with labile ligands or empty coordination sites is very reactive toward oxygen. Some catalysts might be poisoned by heterocycles under prolonged reaction at elevated temperature. To avoid this, chemists use pressure reactors to accelerate reactions at high temperature and pressure. Q-Tube and microwave synthesizer are available safe pressure reactors. Coupling reactions include: In one study, an unusual coupling reaction was described in which an organomolybdenum compound, 2 not only sat on a shelf for 30 years without any sign of degradation but decomposed in water to generate 2-butyne, the coupling adduct of its two ethylidyne ligands. This, according to the researchers, opens another way for aqueous organometallic chemistry. One method for palladium-catalyzed cross-coupling reactions of aryl halides with fluorinated arenes was reported by Keith Fagnou and co-workers, it is unusual in. Many coupling reactions have found their way i
Friedrich August Kekulé Friedrich August Kekule von Stradonitz, was a German organic chemist. From the 1850s until his death, Kekulé was one of the most prominent chemists in Europe in theoretical chemistry, he was the principal founder of the theory of chemical structure. Kekulé never used his first given name. After he was ennobled by the Kaiser in 1895, he adopted the name August Kekule von Stradonitz, without the French acute accent over the second "e"; the French accent had been added to the name by Kekulé's father during the Napoleonic occupation of Hesse by France, to ensure that French-speaking people pronounced the third syllable. The son of a civil servant, Kekulé was born in the capital of the Grand Duchy of Hesse. After graduating from secondary school, in the fall of 1847 he entered the University of Giessen, with the intention of studying architecture. After hearing the lectures of Justus von Liebig in his first semester, he decided to study chemistry. Following four years of study in Giessen and a brief compulsory military service, he took temporary assistantships in Paris, in Chur, in London, where he was decisively influenced by Alexander Williamson.
His Giessen doctoral degree was awarded in the summer of 1852. In 1856 Kekulé became Privatdozent at the University of Heidelberg. In 1858 he was hired as full professor at the University of Ghent in 1867 he was called to Bonn, where he remained for the rest of his career. Basing his ideas on those of predecessors such as Williamson, Edward Frankland, William Odling, Auguste Laurent, Charles-Adolphe Wurtz and others, Kekulé was the principal formulator of the theory of chemical structure; this theory proceeds from the idea of atomic valence the tetravalence of carbon and the ability of carbon atoms to link to each other, to the determination of the bonding order of all of the atoms in a molecule. Archibald Scott Couper independently arrived at the idea of self-linking of carbon atoms, provided the first molecular formulas where lines symbolize bonds connecting the atoms. For organic chemists, the theory of structure provided dramatic new clarity of understanding, a reliable guide to both analytic and synthetic work.
As a consequence, the field of organic chemistry developed explosively from this point. Among those who were most active in pursuing early structural investigations were, in addition to Kekulé and Couper, Wurtz, Alexander Crum Brown, Emil Erlenmeyer, Alexander Butlerov. Kekulé's idea of assigning certain atoms to certain positions within the molecule, schematically connecting them using what he called their "Verwandtschaftseinheiten", was based on evidence from chemical reactions, rather than on instrumental methods that could peer directly into the molecule, such as X-ray crystallography; such physical methods of structural determination had not yet been developed, so chemists of Kekulé's day had to rely entirely on so-called "wet" chemistry. Some chemists, notably Hermann Kolbe criticized the use of structural formulas that were offered, as he thought, without proof. However, most chemists followed Kekulé's lead in pursuing and developing what some have called "classical" structure theory, modified after the discovery of electrons and the development of quantum mechanics.
The idea that the number of valences of a given element was invariant was a key component of Kekulé's version of structural chemistry. This generalization suffered from many exceptions, was subsequently replaced by the suggestion that valences were fixed at certain oxidation states. For example, periodic acid according to Kekuléan structure theory could be represented by the chain structure I-O-O-O-O-H. By contrast, the modern structure of periodic acid has all four oxygen atoms surrounding the iodine in a tetrahedral geometry. Kekulé's most famous work was on the structure of benzene. In 1865 Kekulé published a paper in French suggesting that the structure contained a six-membered ring of carbon atoms with alternating single and double bonds; the following year he published a much longer paper in German on the same subject. The empirical formula for benzene had been long known, but its unsaturated structure was a challenge to determine. Archibald Scott Couper in 1858 and Joseph Loschmidt in 1861 suggested possible structures that contained multiple double bonds or multiple rings, but the study of aromatic compounds was in its earliest years, too little evidence was available to help chemists decide on any particular structure.
More evidence was available by 1865 regarding the relationships of aromatic isomers. Kekulé argued for his proposed structure by considering the number of isomers observed for derivatives of benzene. For every monoderivative of benzene only one isomer was found, implying that all six carbons are equivalent, so that substitution on any carbon gives only a single possible product. For diderivatives such as the toluidines, C6H4, three isomers were observed, for which Kekulé proposed structures with the two substituted carbon atoms separated by one and three carbon-carbon bonds named ortho and para isomers respectively; the counting of possible isomers for diderivatives was however criticized by Albert Ladenburg, a for
A cycloaddition is a chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction. Many but not all cycloadditions are concerted and thus pericyclic. Nonconcerted cycloadditions are not pericyclic; as a class of addition reaction, cycloadditions permit carbon–carbon bond formation without the use of a nucleophile or electrophile. Cycloadditions can be described using two systems of notation. An older but still common notation is based on the size of linear arrangements of atoms in the reactants, it uses parentheses:. The product is a cycle of size. In this system, the standard Diels-Alder reaction is a -cycloaddition, the 1,3-dipolar cycloaddition is a -cycloaddition and cyclopropanation of a carbene with an alkene a -cycloaddition. A more recent, IUPAC-preferred notation, first introduced by Woodward and Hoffmann, uses square brackets to indicate the number of electrons, rather than carbon atoms, involved in the formation of the product.
In the notation, the standard Diels-Alder reaction is a -cycloaddition, while the 1,3-dipolar cycloaddition is a -cycloaddition. Thermal cycloadditions are those cycloadditions where the reactants are in the ground electronic state, they have π electrons participating in the starting material, for some integer n. These reactions occur for reasons of orbital symmetry in a suprafacial-suprafacial or antarafacial-antarafacial manner. There are a few examples of thermal cycloadditions; these proceed in a suprafacial-antarafacial sense, such as the dimerisation of ketene, in which the orthogonal set of p orbitals allows the reaction to proceed via a crossed transition state. Cycloadditions in which 4n π electrons participate can occur via photochemical activation. Here, one component has an electron promoted from the HOMO to the LUMO. Orbital symmetry is such that the reaction can proceed in a suprafacial-suprafacial manner. An example is the DeMayo reaction. Another example is shown below, the photochemical dimerization of cinnamic acid.
The two trans alkenes react head-to-tail, the isolated isomers are called truxillic acids. Supramolecular effects can influence these cycloadditions; the cycloaddition of trans-1,2-bisethene is directed by resorcinol in the solid-state in 100% yield. Some cycloadditions instead of π bonds operate through strained cyclopropane rings, as these have significant π character. For example, an analog for the Diels-Alder reaction is the quadricyclane-DMAD reaction: In the cycloaddition notation i and j refer to the number of atoms involved in the cycloaddition. In this notation, a Diels-Alder reaction is a cycloaddition and a 1,3-dipolar addition such as the first step in ozonolysis is a cycloaddition; the IUPAC preferred notation however, with takes electrons into not atoms. In this notation, the DA reaction and the dipolar reaction both become a cycloaddition; the reaction between norbornadiene and an activated alkyne is a cycloaddition. The Diels-Alder reaction is the most important and taught cycloaddition reaction.
Formally it is a cycloaddition reaction and exists in a huge range of forms, including the inverse electron-demand Diels–Alder reaction, Hexadehydro Diels-Alder reaction and the related alkyne trimerisation. The reaction can be run in reverse in the retro-Diels–Alder reaction. Reactions involving heteroatoms are known; the Huisgen cycloaddition reaction is a cycloaddition. The Nitrone-olefin cycloaddition is a cycloaddition. Iron catalysts contain a redox active ligand in which the central iron atom can coordinate with two simple, unfunctionalized olefin double bonds; the catalyst can be written as a resonance between a structure containing unpaired electrons with the central iron atom in the II oxidation state, one in which the iron is in the 0 oxidation state. This gives it the flexibility to engage in binding the double bonds as they undergo a cyclization reaction, generating a cyclobutane structure via C-C reductive elimination. Efficiency of the reaction varies depending on the alkenes used, but rational ligand design may permit expansion of the range of reactions that can be catalyzed.
Cheletropic reactions are a subclass of cycloadditions. The key distinguishing feature of cheletropic reactions is that on one of the reagents, both new bonds are being made to the same atom; the classic example is the reaction of sulfur dioxide with a diene. Other cycloaddition reactions exist: cycloadditions, photocycloadditions, photocycloadditions Cycloadditions have metal-catalyzed and stepwise radical analogs, however these are not speaking pericyclic reactions; when in a cycloaddition charged or radical intermediates are involved or when the cycloaddition result is obtained in a series of reaction steps they are sometimes called formal cycloadditions to make the distinction with true pericyclic cycloadditions. One example of a formal cycloaddition between a cyclic enone and an enamine catalyzed by n-butyllithium is a Stork enamine / 1,2-addition cascade reaction
The Bergman cyclization or Bergman reaction or Bergman cycloaromatization is an organic reaction and more a rearrangement reaction taking place when an enediyne is heated in presence of a suitable hydrogen donor. It is the most well-studied member of the general class of cycloaromatization reactions, it is named for the American chemist Robert G. Bergman; the reaction product is a derivative of benzene. The reaction proceeds by a thermal reaction or pyrolysis forming a short-lived and reactive para-benzyne biradical species, it will react with any hydrogen donor such as 1,4-cyclohexadiene. When quenched by tetrachloromethane the reaction product is a 1,4-dichlorobenzene and with methanol the reaction product is benzyl alcohol; when the enyne moiety is incorporated into a 10-membered hydrocarbon ring the reaction, taking advantage of increased ring strain in the reactant, is possible at the much lower temperature of 37 °C. Occurring compounds such as calicheamicin contain the same 10-membered ring and are found to be cytotoxic.
These compounds generate the diradical intermediate described above which can cause single and double stranded DNA cuts. There are novel drugs which attempt to make use of this property, including monoclonal antibodies such as mylotarg. A biradical mechanism is proposed for the formation of certain biomolecules found in marine sporolides that have a chlorobenzene unit as part of their structure. In this mechanism a halide salt provides the halogen. A model reaction with the enediyene cyclodeca-1,5-diyn-3-ene, lithium bromide as halogen source and acetic acid as hydrogen source in DMSO at 37 °C supports the theory: The reaction is found to be first-order in enediyne with the formation of p-benzyne A as the rate-limiting step; the halide ion donates its two electrons in the formation of a new Br-C bond and radical electron involved is believed to shuttle over a transient C1-C4 bond forming the anion intermediate B. The anion is a powerful base, stripping protons from DMSO to final product; the dibromide or dihydrogen product never form.
In 2015 IBM scientists demonstrated that a reversible Bergman cyclisation of diyne can be induced by a tip of an atomic force microscope. They recorded images of individual diyne molecules during this process; when learning about this direct experimental demonstration Bergman commented, "When we first reported this reaction I had no idea that it would be biologically relevant, or that the reaction could someday be visualized at the molecular level. Bergman Cycloaromatization Powerpoint Whitney M. Erwin 2002