|Molar mass||146.14 g·mol−1|
|Appearance||colorless to white crystals|
|Odor||pleasant, like vanillabeans|
|Density||0.935 g/cm3 (20 °C (68 °F))|
|Melting point||71 °C (160 °F; 344 K)|
|Boiling point||301.71 °C (575.08 °F; 574.86 K)|
|0.17 g/100 mL|
|Solubility||very soluble in ether, diethyl ether, chloroform, oil, pyridine
soluble in ethanol
|Vapor pressure||1.3 hPa (106 °C (223 °F))|
|Flash point||150 °C (302 °F; 423 K)|
LD50 (Lethal dose)
|293 mg/kg (rat, oral)|
Except where noted otherwise, data is given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
|what is: / ?)(|
Coumarin (//; 2H-chromen-2-one) is a fragrant organic chemical compound in the benzopyrone chemical class, which is a colorless crystalline substance in its standard state. It is a natural substance found in many plants.
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 new-mown hay, and has been used in perfumes since 1882. Sweet woodruff, sweet grass and sweet-clover in particular are named for their sweet (i.e., pleasant) smell, which in turn is due 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 rodenticides that work by the same anticoagulant mechanism. So-called "coumarins" (modified coumarins) are a type of vitamin K antagonists. 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. Other biological activities that may lead to other medical uses have been suggested, with varying degrees of evidence.
- 1 History
- 2 Synthesis
- 3 Natural occurrences
- 4 Metabolism
- 5 Biological function
- 6 Derivatives
- 7 Medical use
- 8 Laser applications
- 9 Toxicity and use in foods, beverages, cosmetics and tobacco
- 10 Related compounds and derivatives
- 11 Use as pesticides
- 12 References
- 13 External links
The word "Tonka" for tonka beans is taken from the Galibi (Carib) tongue spoken by natives of French Guiana (one source for the plant); it also appears in 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. The French word for Tonka bean, coumarou, is from this name.
Coumarin, named for coumarou was first isolated from Tonka beans and sweet clover in 1820 by A. Vogel of Munich, who initially mistook it for benzoic acid. Also in 1820, Nicholas Jean Baptiste Gaston Guibourt (1790-1867) of France independently isolated coumarin, but he realized that it was not benzoic acid. In a subsequent essay he presented to the pharmacy section of l'Académie royale de Médecine, Guibourt named the new substance "coumarine". In 1835, the French pharmacist A. Guillemette proved that Vogel and Guibourt had isolated the same substance. Coumarin was first synthesized in 1868 by the English chemist William Henry Perkin.
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 chromoness.
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 contain little coumarin, sweet-clover (Melilotus ssp.), and deertongue (Dichanthelium clandestinum). Coumarin is also found in extracts of Justicia pectoralis.
Metabolism in humans
Coumarin has appetite-suppressing properties, which in plants may reduce the impact of grazing animals. Though the compound has a pleasant sweet odor, it has a bitter taste, and animals tend to avoid it.
Coumarin and its derivatives are all considered phenylpropanoids.
4-Phenylcoumarin is the backbone of the neoflavones, a type of neoflavonoids.
Coumarin dyes are extensively used as gain media in blue-green tunable organic dye lasers. Among the various coumarin laser dyes are the coumarin 480, 490, 504, 521, 504T, and 521T. Coumarin tetramethyl laser dyes offer wide tunability and high laser gain, and they are also used as active medium on OLED devices.
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. 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. The Occupational Safety and Health Administration (OSHA) of the United States does not classify coumarin as a carcinogen for humans.
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. According to the German Federal Institute for Risk Assessment (BFR), 1 kg of (cassia) cinnamon powder contains approximately 2.1 to 4.4 g of coumarin. Powdered cassia cinnamon weighs 0.56 g/cm3, 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. However, the BFR only cautions against high daily intake of foods containing coumarin. Its report 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. The paper also mentions tea as an additional important contributor to the overall coumarin intake, especially for children with a sweet habit.
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. 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, but some natural additives containing coumarin, such as the flavorant sweet woodruff are allowed "in alcoholic beverages only" (21 CFR 172.510). 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 as some people may become sensitized to it, however the evidence that coumarin can cause an allergic reaction in humans is disputed.
Coumarin is still used as a legal flavorant in the tobacco industry, particularly for sweet pipe tobacco. Its presence in cigarette tobacco led former Brown & Williamson executive Jeffrey Wigand to contact CBS's news show 60 Minutes in 1995, charging that there was a “form of rat poison” 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. Under his later testimony he would repeatedly classify coumarin as a "lung-specific carcinogen". In Germany, coumarin is banned as additive in tobacco.
Alcoholic beverages sold in the European Union are limited to a maximum of 10 mg/L coumarin by law. 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
Compounds derived from coumarin are also called coumarins or coumarinoids; this family includes:
- phenprocoumon (Marcoumar)
- Scopoletin can be isolated from the bark of Shorea pinanga
- warfarin (Coumadin)
Although coumarin itself has no anticoagulant properties, it is transformed into the natural anticoagulant dicoumarol by a number of species of fungi. 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 substance was responsible for the bleeding disease known historically as "sweet clover disease" in cattle eating moldy sweet clover silage. Coumarin has anti-tumor activity and anti-fungal properties.
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, which work by the anticoagulant mechanism. 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 poison rodenticides. 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 antirodenticide 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.
- Casley-Smith, J. R., et al. (1993). Treatment of lymphedema of the arms and legs with 5,6-benzo-(alpha)-pyrone. NEJM 329(16) 1158–63.
- Review of benzypyrone drugs and edema. Lymphoedema.org
- Schäfer, F. P. (Ed.). Dye Lasers, 3rd Ed. Berlin, Springer-Verlag. 1990.
- Duarte, F. J. and L. W. Hillman (Eds.). Dye Laser Principles. New York, Academic. 1990.
- Duarte, F. J. Tunable Laser Optics. New York, Elsevier-Academic. 2003. Appendix of Laser Dyes.
- U.S. Pat. No. 4175982 to Loutfy et al., issued Nov 27 1978 to Xerox Corp.
- Vogel, A. (1820). Darstellung von Benzoesäure aus der Tonka-Bohne und aus den Meliloten - oder Steinklee - Blumen (Preparation of benzoic acid from tonka beans and from the flowers of melilot or sweet clover). Annalen der Physik 64(2) 161-66.
- Vogel, A. (1820). De l'existence de l'acide bezoïque dans la feve 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 6 305-09. pages 307-08.
- Guibourt, N. J. B. G. Histoire Abrégée des Droques Simples (Abridged History of Simple Drugs). Volume 2. Paris, L. Colas. 1820. pages 160-161.
- Journal de Chimie Médicale, de Pharmacie et de Toxicologie, 1 : 303 (1825): "… plus récemment, dans un essai de nomenclature chimique, lu à la section of 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. Histoire Naturelle des Drogues Simples, ... , 6th ed. Paris, J. B. Baillière et fils. 1869. bottom of page 377: "… la matière cristalline de la fève tonka (matière que j'ai nommée coumarine) …" (… the crystaline matter of the tonka bean (matter that I named coumarine …).
- Guillemette, A. (1835) Recherches sur la matière cristalline du mélilot (Research into the crystalline material of melilot). Journal de Pharmacie 21 172-78.
- Perkin, W. H. (1868). On the artificial production of coumarin and formation of its homologues. Journal of the Chemical Society 21 53-63.
- What is the difference between cinnamon and cassia? http://www.whfoods.com/genpage.php?tname=newtip&dbid=31
- Leal, L. K. A. M.; A. A. G. Ferreira; G. A. Bezerra; F. J. A. Matos; G. S. B. Viana (May 2000). "Antinociceptive, anti-inflammatory and bronchodilator activities of Brazilian medicinal plants containing coumarin: a comparative study". Journal of Ethnopharmacology 70 (2): 151–159. doi:10.1016/S0378-8741(99)00165-8. ISSN 0378-8741. PMID 10771205. Retrieved 2010-06-26.
- Lino, C. S.; M. L. Taveira; G. S. B. Viana; F. J. A. Matos (1997). "Analgesic and antiinflammatory activities of Justicia pectoralis Jacq and its main constituents: coumarin and umbelliferone". Phytotherapy Research 11 (3): 211–215. doi:10.1002/(SICI)1099-1573(199705)11:3<211::AID-PTR72>3.0.CO;2-W. Retrieved 2010-06-26.
- Ritter, J. K., et al. (Mar 1992). "A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini". J Biol Chem 267 (5): 3257–61. PMID 1339448.
- Link, K. P. (1 January 1959). "The discovery of dicumarol and its sequels". Circulation 19 (1): 97–107. doi:10.1161/01.CIR.19.1.97. PMID 13619027.
- Liu, H. Extraction and Isolation of Compounds from Herbal Medicines. In: Willow, J. and H. Liu (Eds.) Traditional Herbal Medicine Research Methods. John Wiley and Sons, Inc. 2011.
- Farinola, N.; Piller, N. (June 1, 2005). "Pharmacogenomics: Its role in re-establishing coumarin as treatment for lymphedema". Lymphatic Research and Biology 3 (2): 81–86. doi:10.1089/lrb.2005.3.81. PMID 16000056.
- Chen, C. H., Fox, J. L., Duarte, F. J., Lasing characteristics of new-coumarin-analog dyes: broadband and narrow-linewidth performance, Appl. Opt. 27, 443-445 (1988).
- Duarte, F. J., Liao, L. S., Vaeth, K. M., and Miller, A. M., Widely tunable laser emission using the coumarin 545 tetramethyl dye as gain medium, J. Opt. A: Pure Appl. Opt. 8, 172-174 (2006).
- Duarte, F. J., Liao, L. S., and Vaeth, K. M., Coherence characteristics of electrically excited tandem organic light-emitting diodes, Opt. Lett. 30, 3072–3074 (2005).
- Vassallo, J. D., et al. (2004). "Metabolic detoxification determines species differences in coumarin-induced hepatotoxicity". Toxicological sciences : an official journal of the Society of Toxicology 80 (2): 249–57. doi:10.1093/toxsci/kfh162. PMID 15141102.
- Born, S. L., et al. (2003). "Comparative metabolism and kinetics of coumarin in mice and rats". Food and chemical toxicology 41 (2): 247–58. doi:10.1016/s0278-6915(02)00227-2. PMID 12480300.
- "Frequently Asked Questions about coumarin in cinnamon and other foods" (PDF). The German Federal Institute for Risk Assessment. 30 October 2006.
- NPR: German Christmas Cookies Pose Health Danger
- High daily intakes of cinnamon: Health risk cannot be ruled out. BfR Health Assessment No. 044/2006, 18 August 2006
- Engineering Resources - Bulk Density Chart
- Ballin, Nicolai Z.; Ann T. Sørensen. "Coumarin content in cinnamon containing food products on the Danish market". Food Control 38 (2014): 198–203. doi:10.1016/j.foodcont.2013.10.014.
- PubChem - Coumarin
- Marles, R. J., et al. (1986). Coumarin in vanilla extracts: Its detection and significance. Economic Botany 41(1) 41-47. doi:10.1007/BF02859345
- Characterization and Distribution of Coumarin, Cinnamaldehyde and Related Compounds in Cinnamomum spp. by UPLC-UV/MS Combined with PCA (www.thieme-connect.com)
- International Programme on Chemical Safety. "Brodifacoum (pesticide data sheet)". Retrieved 2006-12-14.
- Laposata M, Van Cott EM, Lev MH. (2007). "Case 1-2007—A 40-Year-Old Woman with Epistaxis, Hematemesis, and Altered Mental Status" 356 (2). pp. 174–82.
- International Programme on Chemical Safety. "Bromadiolone (pesticide data sheet)". Retrieved 2006-12-14.
- Compendium of Pesticide Common Names. "Coumafuryl data sheet". Retrieved 2007-08-17.
- International Programme on Chemical Safety. "Difenacoum (health and safety guide)". Retrieved 2006-12-14.
- Syah, Y. M., et al. (2009). "A modified oligostilbenoid, diptoindonesin C, from Shorea pinanga Scheff". Natural Product Research 23 (7): 591–4. doi:10.1080/14786410600761235. PMID 19401910.
- Bye, A. and H. K. King. 1970. The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius. Biochemical Journal 117, 237-45.
- Weber, U. S.; Steffen, B; Siegers, C. P. (1998). "Antitumor-activities of coumarin, 7-hydroxy-coumarin and its glucuronide in several human tumor cell lines". Research communications in molecular pathology and pharmacology 99 (2): 193–206. PMID 9583093.
- Montagner, C; De Souza, S. M.; Groposoa, C; Delle Monache, F; Smânia, E. F.; Smânia Jr, A (2008). "Antifungal activity of coumarins". Zeitschrift fur Naturforschung. C, Journal of biosciences 63 (1-2): 21–8. PMID 18386483.
- More info about coumarin
- Coumarin in tobacco
- Coumarin as an ingredient of perfume.