This article is about the sweet-smelling plant substance called coumarin. For the anticoagulant rodenticide poisons often called "coumarins" or "coumadins", see 4-hydroxycoumarins.
very soluble in ether, diethyl ether, chloroform, oil, pyridine soluble in ethanol
log P
1.39
Vapor pressure
1.3 hPa (106 °C (223 °F))
Magnetic susceptibility (χ)
3004175000000000000♠−82.5×10−6 cm3/mol
Structure
Crystal structure
orthorhombic
Hazards
Safety data sheet
Sigma-Aldrich
NFPA 704
Flash point
150 °C (302 °F; 423 K)
Lethal dose or concentration (LD, LC):
LD50 (median dose)
293 mg/kg (rat, oral)
Related compounds
Related compounds
Chromone
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Coumarin (/ˈkuːmərɪn/; 2H-chromen-2-one) is an aromatic organic chemical compound in the benzopyrone chemical class, although it may also be seen as a subclass of lactones.[1] It is a natural substance found in many plants, and a colorless crystalline substance in its standard state.
The name comes from a French term for the tonka bean, coumarou, one of the sources from which coumarin was first isolated as a natural product in 1820. It has a sweet odor, readily recognised as the scent of newly-mown hay, and has been used in perfumes since 1882. Sweet woodruff, meadowsweet, sweet grass and sweet-clover in particular are named for their sweet (i.e., pleasant) smell, which in turn is related to their high coumarin content. When it occurs in high concentrations in forage plants, coumarin is a somewhat bitter-tasting appetite suppressant, and is presumed to be produced by plants as a defense chemical to discourage predation.
Coumarin is used in certain perfumes and fabric conditioners. Coumarin has been used as an aroma enhancer in pipe tobaccos and certain alcoholic drinks, although in general it is banned as a flavorant food additive, due to concerns regarding its hepatotoxicity in animal models.
Coumarin was first synthesized in 1868. It is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to dicoumarol, the notable ones being warfarin (brand name Coumadin) and some even more potent substances (see rat poison/rodenticide) that work by the same anticoagulant mechanism. 4-hydroxycoumarins are a type of vitamin K antagonist. Pharmaceutical (modified) coumarins were all developed from the study of sweet clover disease; see warfarin for this history. However, unmodified coumarin itself, as it occurs in plants, has no effect on the vitamin K coagulation system, or on the action of warfarin-type drugs.
Coumarin has clinical medical value by itself, as an edema modifier. Coumarin and other benzopyrones, such as 5,6-benzopyrone, 1,2-benzopyrone, diosmin, and others, are known to stimulate macrophages to degrade extracellular albumin, allowing faster resorption of edematous fluids.[2][3] Other biological activities that may lead to other medical uses have been suggested, with varying degrees of evidence.
Coumarin is also used as a gain medium in some dye lasers,[4][5][6] and as a sensitizer in older photovoltaic technologies.[7]
Contents
1History
2Etymology
3Synthesis
4Natural occurrences
5Metabolism
6Biological function
7Derivatives
8Medical use
9Laser applications
10Toxicity and use in foods, beverages, cosmetics, and tobacco
11Related compounds and derivatives
12Use as pesticides
13See also
14References
15External links
History
Coumarin was first isolated from tonka beans and sweet clover in 1820 by A. Vogel of Munich, who initially mistook it for benzoic acid.[8][9] Also in 1820, Nicholas Jean Baptiste Gaston Guibourt (1790–1867) of France independently isolated coumarin, but he realized that it was not benzoic acid.[10] In a subsequent essay he presented to the pharmacy section of the Académie Royale de Médecine, Guibourt named the new substance "coumarine."[11][12] In 1835, the French pharmacist A. Guillemette proved that Vogel and Guibourt had isolated the same substance.[13] Coumarin was first synthesized in 1868 by the English chemist William Henry Perkin.[14]
Etymology
Coumarin is derived from coumarou, the French word for the tonka bean. The word tonka for the tonka bean is taken from the Galibi (Carib) tongue spoken by natives of French Guiana (one source for the plant); it also appears in Old Tupi, another language of the same region, as the name of the tree. The old genus name, Coumarouna, was formed from another Tupi name for tree, kumarú.
Synthesis
Coumarin can be prepared by a number of name reactions with the Perkin reaction between salicylaldehyde and acetic anhydride being a popular example. The Pechmann condensation provides another route to coumarin and its derivatives; as does the Kostanecki acylation which can also be used to produce chromones.
Natural occurrences
Coumarin is found naturally in many plants, notably in high concentration in the tonka bean (Dipteryx odorata), vanilla grass (Anthoxanthum odoratum), sweet woodruff (Galium odoratum), mullein (Verbascum spp.), sweet grass (Hierochloe odorata), cassia cinnamon (Cinnamomum cassia) not to be confused with true cinnamon ("Ceylon cinnamon", Cinnamomum zeylanicum which contains little coumarin), sweet-clover (Melilotus sp.), deertongue (Dichanthelium clandestinum), and the leaves of many cherry blossom tree varieties (of the genus Prunus).[citation needed] Coumarin is also found in extracts of Justicia pectoralis.[15][16][non-primary source needed] Related compounds are found in some but not all specimens of genus Glycyrrhiza, from which the root and flavour licorice derives.[17][non-primary source needed]
Metabolism
The biosynthesis of coumarin in plants is via hydroxylation, glycolysis, and cyclization of cinnamic acid.[citation needed] In humans, the enzyme encoded by the gene UGT1A8 has glucuronidase activity with many substrates including coumarins.[clarification needed][18]
Biological function
Coumarin has appetite-suppressing properties, which may discourage animals from eating plants which contain it. Though the compound has a pleasant sweet odor, it has a bitter taste, and animals tend to avoid it.[19]
Derivatives
Coumarin and its derivatives are all considered phenylpropanoids.
Some naturally occurring coumarin derivatives include umbelliferone (7-hydroxycoumarin), aesculetin (6,7-dihydroxycoumarin), herniarin (7-methoxycoumarin), psoralen and imperatorin.
4-Phenylcoumarin is the backbone of the neoflavones, a type of neoflavonoids.
Medical use
Coumarins have shown some evidence of biological activity and have limited approval for few medical uses as pharmaceuticals, such as in the treatment of lymphedema[20] and their ability to increase plasma antithrombin levels.[21] Both coumarin and indandione derivatives produce a uricosuric effect, presumably by interfering with the renal tubular reabsorption of urate.[22]
Laser applications
Coumarin dyes are extensively used as gain media in blue-green tunable organic dye lasers.[4][5][6] Among the various coumarin laser dyes are coumarins 480, 490, 504, 521, 504T, and 521T.[6] Coumarin tetramethyl laser dyes offer wide tunability and high laser gain,[23][24] and they are also used as active medium in coherent OLED emitters.[25]
Toxicity and use in foods, beverages, cosmetics, and tobacco
Coumarin is moderately toxic to the liver and kidneys, with a median lethal dose (LD50) of 275 mg/kg, a low toxicity compared to related compounds. Though it is only somewhat dangerous to humans, coumarin is hepatotoxic in rats, but less so in mice. Rodents metabolize it mostly to 3,4-coumarin epoxide, a toxic, unstable compound that on further differential metabolism may cause liver cancer in rats and lung tumors in mice.[26][27] Humans metabolize it mainly to 7-hydroxycoumarin, a compound of lower toxicity. The German Federal Institute for Risk Assessment has established a tolerable daily intake (TDI) of 0.1 mg coumarin per kg body weight, but also advises that higher intake for a short time is not dangerous.[28] The Occupational Safety and Health Administration (OSHA) of the United States does not classify coumarin as a carcinogen for humans.[29]
European health agencies have warned against consuming high amounts of cassia bark, one of the four main species of cinnamon, because of its coumarin content.[30][31] According to the German Federal Institute for Risk Assessment (BFR), 1 kg of (cassia) cinnamon powder contains about 2.1 to 4.4 g of coumarin.[32] Powdered cassia cinnamon weighs 0.56 g/cm3,[33] so a kilogram of cassia cinnamon powder equals 362.29 teaspoons. One teaspoon of cassia cinnamon powder therefore contains 5.8 to 12.1 mg of coumarin, which may be above the tolerable daily intake value for smaller individuals.[32] However, the BFR only cautions against high daily intake of foods containing coumarin. Its report[32] specifically states that Ceylon cinnamon (Cinnamomum verum) contains "hardly any" coumarin.
The European Regulation (EC) No 1334/2008 describes the following maximum limits for coumarin: 50 mg/kg in traditional and/or seasonal bakery ware containing a reference to cinnamon in the labeling, 20 mg/kg in breakfast cereals including muesli, 15 mg/kg in fine bakery ware, with the exception of traditional and/or seasonal bakery ware containing a reference to cinnamon in the labeling, and 5 mg/kg in desserts. An investigation from the Danish Veterinary and Food Administration in 2013 shows that bakery goods characterized as fine bakery ware exceeds the European limit (15 mg/kg) in almost 50% of the cases.[34] The paper also mentions tea as an additional important contributor to the overall coumarin intake, especially for children with a sweet habit.
Coumarin is found naturally in many edible plants such as strawberries, black currants, apricots, and cherries.[35]
Coumarin is often found in artificial vanilla substitutes, despite having been banned as a food additive in numerous countries since the mid-20th century. Coumarin was banned as a food additive in the United States in 1954, largely because of the hepatotoxicity results in rodents.[36] Coumarin is currently listed by the Food and Drug Administration (FDA) of the United States among "Substances Generally Prohibited From Direct Addition or Use as Human Food," according to 21 CFR 189.130,[37][38] but some natural additives containing coumarin, such as the flavorant sweet woodruff are allowed "in alcoholic beverages only" under 21 CFR 172.510.[39] In Europe, popular examples of such beverages are Maiwein, white wine with woodruff, and Żubrówka, vodka flavoured with bison grass.
Coumarin is subject to restrictions on its use in perfumery,[40] as some people may become sensitized to it, however the evidence that coumarin can cause an allergic reaction in humans is disputed.[41]
Minor neurological dysfunction was found in children exposed to the anticoagulants acenocoumarol or phenprocoumon during pregnancy. A group of 306 children were tested at ages 7–15 years to determine subtle neurological effects from anticoagulant exposure. Results showed a dose response relationship between anticoagulant exposure and minor neurological dysfunction. Overall, a 1.9 (90%) increase in minor neurological dysfunction was observed for children exposed to these anticoagulants, which are collectively referred to as "coumarins." In conclusion, researchers stated, "The results suggest that coumarins have an influence on the development of the brain which can lead to mild neurologic dysfunctions in children of school age."[42]
Coumarin is still used as a legal flavorant in the tobacco industry, particularly for sweet pipe tobacco. Its presence in cigarette tobacco Brown & Williamson executive[43] Dr. Jeffrey Wigand to contact CBS's news show 60 Minutes in 1995, charging that a “form of rat poison” was in the tobacco. He held that from a chemist’s point of view, coumarin is an “immediate precursor” to the rodenticide coumadin. Dr. Wigand later stated that coumarin itself is dangerous, pointing out that the FDA had banned its addition to human food in 1954.[44] Under his later testimony, he would repeatedly classify coumarin as a "lung-specific carcinogen."[45] In Germany, coumarin is banned as an additive in tobacco.
Alcoholic beverages sold in the European Union are limited to a maximum of 10 mg/l coumarin by law.[46] Cinnamon flavor is generally cassia bark steam-distilled to concentrate the cinnamaldehyde, for example, to about 93%. Clear cinnamon-flavored alcoholic beverages generally test negative for coumarin, but if whole cassia bark is used to make mulled wine, then coumarin shows up in significant levels.
Related compounds and derivatives
Main article: 4-Hydroxycoumarins
Compounds derived from coumarin are also called coumarins or coumarinoids; this family includes:
brodifacoum[47][48]
bromadiolone[49]
difenacoum[50]
auraptene
ensaculin
phenprocoumon (Marcoumar)
PSB-SB-487
PSB-SB-1202
Scopoletin can be isolated from the bark of Shorea pinanga[51]
warfarin (Coumadin)
Coumarin is transformed into the natural anticoagulant dicoumarol by a number of species of fungi.[52] This occurs as the result of the production of 4-hydroxycoumarin, then further (in the presence of naturally occurring formaldehyde) into the actual anticoagulant dicoumarol, a fermentation product and mycotoxin. Dicoumarol was responsible for the bleeding disease known historically as "sweet clover disease" in cattle eating moldy sweet clover silage.[52][53] In basic research, preliminary evidence exists for coumarin having various biological activities, including anti-inflammatory, anti-tumor, antibacterial, and antifungal properties, among others.[52]
Use as pesticides
Many of the above-stated compounds (to be specific, the 4-hydroxycoumarins, sometimes loosely called coumarins) are used as anticoagulant drugs and/or as rodenticides. They block the regeneration and recycling of vitamin K. These chemicals are sometimes also incorrectly referred to as "coumadins" rather than 4-hydroxycoumarins. Coumadin is a brand name for the drug warfarin.
Some of the 4-hydroxycoumarin anticoagulant class of chemicals are designed to have very high potency and long residence times in the body, and these are used specifically as rodenticides ("rat poison"). Death occurs after a period of several days to two weeks, usually from internal hemorrhaging.
Vitamin K is a true antidote for poisoning by these anticoagulant 4-hydroxycoumarins such as bromadiolone. Treatment usually comprises a large dose of vitamin K given intravenously immediately, followed by doses in pill form for a period of at least two weeks, though usually three to four, afterwards. Treatment may even continue for several months. If caught early, the prognosis is good, even when large amounts are ingested. In the short term, transfusion with fresh frozen plasma to provide clotting factors, provides time for vitamin K to reverse enzyme poisoning in the liver, and allow new clotting factors to be synthesized there.[citation needed]
^Casley-Smith, J. R.; et al. (1993). "Treatment of lymphedema of the arms and legs with 5,6-benzo-(alpha)-pyrone". N. Engl. J. Med.329 (16): 1158–63. doi:10.1056/nejm199310143291604. PMID 8377779.
^Review of benzypyrone drugs and edema. Lymphoedema.org
^ abDuarte, F. J.; Hillman, L. W., eds. (1990). Dye Laser Principles. New York: Academic. [ISBN missing]
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^US 4175982, Loutfy et al., issued Nov. 27, 1978, assigned to Xerox Corp
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^Vogel, A. (1820). "De l'existence de l'acide benzoïque dans la fève de tonka et dans les fleurs de mélilot" [On the existence of benzoic acid in the tonka bean and in the flowers of melilot]. Journal de Pharmacie (in French). 6: 305–309.
^Guibourt, N. J. B. G. (1820). Histoire Abrégée des Drogues Simples [Abridged History of Simple Drugs] (in French). 2. Paris: L. Colas. pp. 160–161.
^"Societe du Pharmacie de Paris". Journal de Chimie Médicale, de Pharmacie et de Toxicologie. 1: 303. 1825. … plus récemment, dans un essai de nomenclature chimique, lu à la section de Pharmacie de l'Académie royale de Médecine, il l'a désignée sous le nom de coumarine, tiré du nom du végétal coumarouna odorata … [… more recently, in an essay on chemical nomenclature, [which was] read to the pharmacy section of the Royal Academy of Medicine, he [Guibourt] designated it by the name "coumarine," derived from the name of the vegetable Coumarouna odorata …]
^Guibourt, N. J. B. G. (1869). Histoire Naturelle des Drogues Simples (6th ed.). Paris: J. B. Baillière et fils. p. 377. … la matière cristalline de la fève tonka (matière que j'ai nommée coumarine) … [… the crystalline matter of the tonka bean (matter that I named coumarine …]
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^"Coumarins and indandiones". Drugs.com. 2016. Retrieved 24 December 2016.
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^Duarte, F. J.; Liao, L. S.; Vaeth, K. M.; Miller, A. M. (2006). "Widely tunable laser emission using the coumarin 545 tetramethyl dye as gain medium". J. Opt. A. 8 (2): 172–174. Bibcode:2006JOptA...8..172D. doi:10.1088/1464-4258/8/2/010.
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Coumarin portal