Coumarin

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Not to be confused with coumadin or dicoumarol.
This article is about the sweet-smelling plant substance called coumarin. For the anticoagulant rodenticide poisons often called "coumarins" or "coumadins", see 4-hydroxycoumarins.
Coumarin
IUPAC name

2H-chromen-2-one
Other names

1-benzopyran-2-one
Identifiers
CAS number 91-64-5 YesY
PubChem 323
ChemSpider 13848793 YesY
UNII A4VZ22K1WT YesY
EC number 202-086-7
DrugBank DB04665
KEGG D07751 YesY
ChEBI CHEBI:28794 YesY
ChEMBL CHEMBL6466 YesY
RTECS number GN4200000
Jmol-3D images Image 1
Properties
Molecular formula C9H6O2
Molar mass 146.14 g mol−1
Appearance colorless to white crystals
Odor pleasant, like vanillabeans
Density 0.935 g/cm3 (20 °C)
Melting point

71 °C, 344 K, 160 °F
Boiling point

301.71 °C, 575 K, 575 °F
Solubility in water 0.17 g/100 mL
Solubility very soluble in ether, diethyl ether, chloroform, oil, pyridine
soluble in ethanol
log P 1.39
Vapor pressure 1.3 hPa (106 °C)
Structure
Crystal structure orthorhombic
Hazards
MSDS Sigma-Aldrich
NFPA 704
NFPA 704.svg
0
0
0
Flash point 150 °C (302 °F)
LD50 293 mg/kg (rat, oral)
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Coumarin (/ˈkuːmərɪn/; 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 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 aromaticum), melilot/sweet clover (Melilotus ssp.), and deers tongue (Panicum clandestinum). The name comes from a French word, coumarou, for the tonka bean. 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 smell, which in turn is due to their high content of this substance. 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 in order to discourage predation.

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 about coumarin's hepatotoxicity in animal models.

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. This substance was responsible for the bleeding disease known historically as "sweet clover disease" in cattle eating moldy sweet clover silage.[1]

Coumarin is used in the pharmaceutical industry as a precursor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to dicoumarol, the notable ones being warfarin (tradenamed "Coumadin," not to be confused with coumarin) and some even more potent rodenticides that work by the same anticoagulant mechanism. See 4-hydroxycoumarin and the relevant section of vitamin K antagonists for a discussion and listing of this class of drugs. All of these agents were historically discovered by analyzing sweet clover disease.

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 albumen, 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]

Coumarin was first isolated in 1820 by A. Vogel of Munich; he mistook it for benzoic acid.[8] Also in 1820, Nicholas Jean Baptiste Gaston Guibourt (1790-1867) of France independently isolated coumarin; he realized that it was not benzoic acid.[9] In a subsequent essay that he read before the pharmacy section of the L'Académie royale de médecine, Guibourt named the new substance "coumarine".[10] In 1835, the French pharmacist A. Guillemette proved that Vogel and Guibourt had isolated the same substance.[11] Coumarin was first synthesized in 1868 by the English chemist William Henry Perkin.[12]

Contents

Synthesis[edit]

Coumarin can be prepared in a laboratory in a Perkin reaction between salicylaldehyde and acetic anhydride.

The Pechmann condensation provides another synthesis of coumarin and its derivatives.

Metabolism[edit]

The biosynthesis of coumarin in plants is via hydroxylation, glycolysis, and cyclization of cinnamic acid.

Metabolism in humans[edit]

The enzyme encoded by the gene UGT1A8 has glucuronidase activity with many substrates including coumarins.[13]

Biological function[edit]

Coumarin has appetite-suppressing properties, suggesting one reason for its widespread occurrence in plants, especially grasses and clovers, is because of its effect of reducing the impact of grazing animals on these forages. Although the compound has a pleasant sweet odor and is responsible for the names of sweet clover and sweet grass, these plants are not named for their taste. Coumarin has a bitter taste, and animals will avoid it, if possible.[14]

Derivatives[edit]

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[edit]

Coumarins have shown some evidence of many biological activities, although they are approved for few medical uses as pharmaceuticals. The activity reported for coumarin and coumarins includes anti-HIV, anti-tumor, anti-hypertension, anti-arrhythmia, anti-inflammatory, anti-osteoporosis, antiseptic, and analgesic (pain relief). It is also used in the treatment of asthma.[15] Coumarin has been used in the treatment of lymphedema.[16]

Toxicity and use in foods, beverages, cosmetics and tobacco[edit]

Coumarin is moderately toxic to the liver and kidneys, with a "Median Lethal Dose" (LD50) of 275 mg/kg — low compared to related compounds.[clarification needed] Although only somewhat dangerous to humans, coumarin is hepatotoxic in rats (but less so in mice). Rodents metabolize it largely to 3,4-coumarin epoxide, a toxic unstable compound that on further differential metabolism may explain coumarin's ability to cause liver cancer in rats and lung tumors in mice.[17][18] Humans metabolize it largely 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, [if] this level is exceeded for a short time only, there is no threat to health.[19] For example, a person weighing 60 kg (about 132 lbs) would have a TDI of approximately 6.0 mg of coumarin. The U.S. Occupational Safety and Health Administration (OSHA) regards Coumarin to be not classifiable as to its carcinogenicity to humans.[20]

European health agencies have warned against consuming high amounts of cassia bark, one of the four species of cinnamon, because of its coumarin content.[not in citation given][21] 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.[22] Powdered Cassia Cinnamon weighs 0.56 g/cc;[23] therefore, 1 kg of Cassia Cinnamon powder is equal to 362.29 teaspoons (1000 g divided by 0.56 g/cc multiplied by 0.20288 tsp/cc). This means 1 teaspoon of cinnamon powder contains 5.8 to 12.1 mg of coumarin, which may be above the Tolerable Daily Intake for smaller individuals.[22] However, the BFR only cautions against high daily intakes of foods containing coumarin. Its report[22] specifically states that "Ceylon" cinnamon, Cinnamomum verum, contains "hardly any" coumarin. Chamomile, a common herbal tea, also contains coumarin.

Coumarin is found naturally in edible plants such as strawberries, black currants, apricots, and cherries. [24]

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 hepatotoxicity results in rodents.[25] The U.S. OSHA considers this compound to be only a lung-specific carcinogen,[citation needed] and "not classifiable as to its carcinogenicity to humans".[26] Coumarin was banned as an adulterant in cigarettes by tobacco companies in 1997, but due to the lack of reporting requirements to the US Department of Health and Human Services it was still being used as a flavoring additive in pipe tobacco.[citation needed] Coumarin is currently listed by the United States Food and Drug Administration (FDA) among "Substances Generally Prohibited From Direct Addition or Use as Human Food", according to 21 CFR 189.130,[27][28] but some natural additives containing coumarin, such as sweet woodruff (Galium odoratum) due to its coumarin odor, are allowed "in alcoholic beverages only" (21 CFR 172.510).[29] In Europe, such beverages are very popular, for example Maiwein (white wine with woodruff) and Żubrówka (vodka flavoured with bison grass).

Coumarin is subject to restrictions on its use in perfumery [30] as some people may become sensitised to it, however the evidence that coumarin can cause an allergic reaction in humans is disputed.[31]

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[32] Jeffrey Wigand to contact CBS' 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.[33] Under his later testimony he would repeatedly classify coumarin as a "lung-specific carcinogen".[34] 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.[35] 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[edit]

Compounds derived from coumarin are also called coumarins or coumarinoids; this family includes:

Use as pesticides[edit]

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 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.[citation needed]

See also[edit]

References[edit]

  1. ^ Bye, A., King, H. K., 1970. The biosynthesis of 4-hydroxycoumarin and dicoumarol by Aspergillus fumigatus Fresenius. Biochemical Journal 117, 237-245.
  2. ^ full content of NEJM article. Treatment of Lymphedema of the Arms and Legs with 5,6-Benzo-[alpha]-pyrone. John R. Casley-Smith, Robert Gwyn Morgan, and Neil B. Piller Volume 329:1158–1163 October 14, 1993 Number 16.
  3. ^ Review of benzypyrone drugs and edema
  4. ^ F. P. Schäfer (Ed.), Dye Lasers, 3rd Ed. (Springer-Verlag, Berlin, 1990).
  5. ^ F. J. Duarte and L. W. Hillman (Eds.), Dye Laser Principles (Academic, New York, 1990).
  6. ^ F. J. Duarte, Tunable Laser Optics (Elsevier-Academic, New York, 2003) Appendix of Laser Dyes.
  7. ^ U.S. Pat. No. 4175982 to Loutfy et al, issued Nov 27 1978 to Xerox Corp.
  8. ^ See:
    • A. Vogel (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) : 161-166.
    • A. Vogel (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 : 305-309; see pages 307-308.
  9. ^ Nicholas Jean Baptiste Gaston Guibourt, Histoire Abrégée des Droques Simples (Abridged History of Simple Drugs [i.e., not mixed / "compounded" with other drugs]) (Paris, France: L. Colas, 1820), volume 2, pages 160-161.
  10. ^ See:
    • 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 …).
    • N. J. B. G. Guibourt, Histoire naturelle des drogues simples, ... , 6th ed. (Paris, France: 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 …).
  11. ^ A. Guillemette (1835) "Recherches sur la matière cristalline du mélilot" (Research into the crystalline material of melilot), Journal de Pharmacie … , 21 : 172-178.
  12. ^ W. H. Perkin (1868) "On the artificial production of coumarin and formation of its homologues," Journal of the Chemical Society, 21 : 53-63.
  13. ^ Ritter JK, Chen F, Sheen YY, Tran HM, Kimura S, Yeatman MT, Owens IS (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. 
  14. ^ Link KP (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. 
  15. ^ Liu H., "Extraction and Isolation of compounds from Herbal medicines" in 'Traditional Herbal Medicine Research Methods', ed by Willow JH Liu 2011 John Wiley and Sons, Inc
  16. ^ Farinola, Nicholas; Piller, Neil (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. 
  17. ^ Vassallo, JD; Hicks, SM; Daston, GP; Lehman-Mckeeman, LD (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. 
  18. ^ Born, SL; Api, AM; Ford, RA; Lefever, FR; Hawkins, DR (2003). "Comparative metabolism and kinetics of coumarin in mice and rats". Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 41 (2): 247–58. PMID 12480300. 
  19. ^ "Frequently Asked Questions about coumarin in cinnamon and other foods" (PDF). The German Federal Institute for Risk Assessment. 30 October 2006. 
  20. ^ https://www.osha.gov/dts/chemicalsampling/data/CH_229620.html
  21. ^ NPR: German Christmas Cookies Pose Health Danger
  22. ^ a b c High daily intakes of cinnamon: Health risk cannot be ruled out. BfR Health Assessment No. 044/2006, 18 August 2006
  23. ^ Engineering Resources - Bulk Density Chart
  24. ^ PubChem - Coumarin
  25. ^ Economic Botany Volume 41, Number 1, 41-47, 1986 doi:10.1007/BF02859345 Coumarin in vanilla extracts: Its detection and significance Robin J. Marles, CÉsar M. Compadre and Norman R. Farnsworth.
  26. ^ http://www.osha.gov/dts/chemicalsampling/data/CH_229620.html
  27. ^ http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr189_06.html
  28. ^ http://www.cfsan.fda.gov/~dms/eafus.html
  29. ^ http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr172_06.html
  30. ^ http://www.ifraorg.org/en-us/standards_restricted/s3/p3
  31. ^ http://www.leffingwell.com/Cropwatch%20Claims%20Victory%20Over%2026%20Allergens.pdf
  32. ^ http://www.jeffreywigand.com/60minutes.php
  33. ^ http://www.tobacco-on-trial.com/2005/01/31/dr-wigand-and-the-solicitous-solicitor/
  34. ^ http://legacy.library.ucsf.edu/tid/tnt32e00
  35. ^ Characterization and Distribution of Coumarin, Cinnamaldehyde and Related Compounds in Cinnamomum spp. by UPLC-UV/MS Combined with PCA (www.thieme-connect.com)
  36. ^ International Programme on Chemical Safety. "Brodifacoum (pesticide data sheet)". Retrieved 2006-12-14. 
  37. ^ 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. 
  38. ^ International Programme on Chemical Safety. "Bromadiolone (pesticide data sheet)". Retrieved 2006-12-14. 
  39. ^ Compendium of Pesticide Common Names. "Coumafuryl data sheet". Retrieved 2007-08-17. 
  40. ^ International Programme on Chemical Safety. "Difenacoum (health and safety guide)". Retrieved 2006-12-14. 
  41. ^ Syah, Yana M.; Hakim, Euis H.; Ghisalberti, Emilio L.; Jayuska, Afghani; Mujahidin, Didin; Achmad, Sjamsul A. (2009). "A modified oligostilbenoid, diptoindonesin C, fromShorea pinangaScheff". Natural Product Research 23 (7): 591–4. doi:10.1080/14786410600761235. PMID 19401910. 

External links[edit]
Classes of phenylpropanoids
Examples
Types of coumarins
Aglycones
glycosides
derivatives
Aglycones
Furanocoumarin glycosides
Meroterpene furanocoumarin ether
Oligomers
Synthetic
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