View source for Coumarin

{{short description|Aromatic chemical compound}}
{{About|the natural compound|the anticoagulants and rodenticides called "coumarins" or "coumadins"|4-Hydroxycoumarins|5=Coumarin derivatives}}
{{Distinguish|text=the medication [[warfarin]], often known by the trade name "Coumadin"}}
{{Chembox
| Watchedfields = changed
| verifiedrevid = 443678400
| ImageFile1=Coumarin acsv.svg
| ImageSize1=
| ImageFile2=Coumarin.png
| ImageSize2= 
| ImageFile3=Coumarin_spacefill.png
| ImageSize3=
| IUPACName = 2''H''-Chromen-2-one
| PIN = 2''H''-1-Benzopyran-2-one
| OtherNames=1-Benzopyran-2-one
|Section1={{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A4VZ22K1WT
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07751
| InChI = 1/C9H6O2/c10-9-6-5-7-3-1-2-4-8(7)11-9/h1-6H
| InChIKey = ZYGHJZDHTFUPRJ-UHFFFAOYAC
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 6466
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H6O2/c10-9-6-5-7-3-1-2-4-8(7)11-9/h1-6H
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ZYGHJZDHTFUPRJ-UHFFFAOYSA-N
| CASNo=91-64-5
| CASNo_Ref = {{cascite|correct|CAS}}
| PubChem=323
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28794
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB04665
| SMILES = O=C1C=Cc2ccccc2O1
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 13848793
| EINECS = 202-086-7
| RTECS = GN4200000
| Gmelin = 165222
| Beilstein = 383644
  }}
|Section2={{Chembox Properties
| C=9 | H=6 | O=2
| Appearance= colorless to white crystals
| Odor = pleasant, like vanilla beans
| Density=0.935 g/cm<sup>3</sup> ({{convert|20|C}})
| MeltingPtC=71
| BoilingPtC=301.71
| Solubility=0.17&nbsp;g / 100&nbsp;mL
| SolubleOther = very soluble in [[diethyl ether|ether]], [[diethyl ether]], [[chloroform]], [[oil]], [[pyridine]] <br /> soluble in [[ethanol]]
| LogP = 1.39
| VaporPressure = 1.3 hPa ({{convert|106|C}})
| MagSus = {{val|−82.5|e=−6|u=cm<sup>3</sup>/mol}}
  }}
|Section3={{Chembox Structure
| CrystalStruct = orthorhombic
  }}
|Section7={{Chembox Hazards
| ExternalSDS = [http://www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do?country=PL&language=EN-generic&productNumber=W504300&brand=ALDRICH&PageToGoToURL=http%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fproduct%2Faldrich%2Fw504300%3Flang%3Dpl Sigma-Aldrich]
| MainHazards=
| NFPA-H = 2 | NFPA-F = 1 | NFPA-R = 0
| FlashPtC = 150
| AutoignitionPtC =
| LD50 = 293 mg/kg (rat, oral)
| GHS_ref = {{efn|Coumarin's GHS classification varies between regulators. For a more complete listing, see PubChem.<ref>{{cite web |title=Coumarin {{!}} GHS Classification |url=https://pubchem.ncbi.nlm.nih.gov/compound/323#section=GHS-Classification&fullscreen=true |website=pubchem.ncbi.nlm.nih.gov |archive-url=https://web.archive.org/web/20250721143237/https://pubchem.ncbi.nlm.nih.gov/compound/323#section=GHS-Classification&fullscreen=true |archive-date=21 July 2025}}</ref>}}
| GHSPictograms = {{GHS07}}{{GHS08}}
| GHSSignalWord = Warning
| HPhrases = {{H-phrases|302|317|373}}
| PPhrases = {{P-phrases|260|261|264|270|272|280|301+312|302+352|314|321|330|333+313|363|501}}
  }}
|Section9={{Chembox Related
| OtherAnions = 
| OtherCations = 
| OtherFunction = 
| OtherFunction_label = 
| OtherCompounds = [[Chromone]]; [[2-Cumaranone]]
  }}
}}

'''Coumarin''' ({{IPAc-en|ˈ|k|uː|m|ər|ɪ|n}}) or '''2''H''-chromen-2-one''' is an aromatic organic [[chemical compound]] with formula {{chem2|C9H6O2}}.  Its molecule can be described as a [[benzene]] molecule with two adjacent [[hydrogen]] atoms replaced by an unsaturated [[lactone]] ring {{chem2|\s(CH)\d(CH)\s(C\dO)\sO\s}}, forming a second six-membered [[heterocycle]] that shares two [[carbon]]s with the benzene ring. It belongs to the [[benzopyrone]] chemical class and is considered a lactone.<ref name="pubchem19">{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/323 |title=Coumarin |date=4 April 2019 |publisher=PubChem, National Library of Medicine, US National Institutes of Health |access-date=13 April 2019}}</ref>

Coumarin is a colorless [[Crystal|crystalline solid]] with a sweet [[odor]] resembling the scent of [[vanilla]] and a bitter taste.<ref name=pubchem19/> It is found in many plants, where it may serve as a [[Plant defense against herbivory|chemical defense against predators]]. While coumarin is not an anticoagulant, its 3-alkyl-4-hydroxy derivatives, such as the fungal metabolite [[dicoumarol]], inhibit synthesis of [[vitamin K]], a key component in [[blood clotting]].<ref>{{cite book |author-last1=Low Dog |author-first1=Tieraona |author-last2=Markham |author-first2=Merry Jennifer |chapter=Dietary Supplements and Hemostasis |title=Consultative Hemostasis and Thrombosis |date=2007 |publisher=Elsevier Health Sciences |location=Philadelphia, PA |isbn=9781437710601 |edition=2nd |page=564 |url=https://books.google.com/books?id=sr7CU__45dEC&q=%22coumarin+drugs%22 |doi=10.1016/B978-141602401-9.10033-1}}</ref> A related compound, the [[prescription drug]] [[anticoagulant]] [[warfarin]], is used to inhibit formation of [[blood clot]]s, [[deep vein thrombosis]], and [[pulmonary embolism]].<ref name=pubchem19/><ref name="drugs19">{{cite web |url=https://www.drugs.com/drug-class/coumarins-and-indandiones.html |title= Coumarins and indandiones |publisher=Drugs.com |date=2016 |access-date=24 December 2016}}</ref>

==Etymology==
Coumarin is derived from {{lang|fr|coumarou}}, the French word for the [[tonka bean]], from the [[Tupi language|Old Tupi]] word for its tree, {{lang|tup|kumarú}}.<ref>{{Cite web |title=Warfarin, Molecule of the Month for February 2011, by John Maher |url=https://www.chm.bris.ac.uk/motm/warfarin/ |access-date=2023-12-20 |website=www.chm.bris.ac.uk}}</ref>

== History ==
Coumarin was first isolated from [[tonka beans]] in 1820 by A. Vogel of Munich, who initially mistook it for [[benzoic acid]].<ref name=vogel1820a/><ref name=vogel1820b/>

Also in 1820, Nicholas Jean Baptiste Gaston Guibourt (1790–1867) of France independently isolated coumarin, but he realized that it was not benzoic acid.<ref name=guib1820/>  In a subsequent essay he presented to the pharmacy section of the [[Académie Royale de Médecine]], Guibourt named the new substance ''coumarine''.<ref name=guib1825/><ref name=guib1869/>

In 1835, the French pharmacist A. Guillemette proved that Vogel and Guibourt had isolated the same substance.<ref name=guil1835/> Coumarin was first synthesized in 1868 by the English chemist [[William Henry Perkin]].<ref name=perkin1868/>

Coumarin has been an integral part of the [[fougère]] genre of perfume since it was first used in Houbigant's Fougère Royale in 1882.<ref name=fragrantica>{{cite web|url=https://www.fragrantica.com/groups/aromatic+fougere.html|title=Olfactory Groups - Aromatic Fougere|website=fragrantica.com|access-date=13 November 2020}}</ref>

== Synthesis ==
Coumarin can be prepared by a number of [[name reaction]]s, with the [[Perkin reaction]] between [[salicylaldehyde]] and [[acetic anhydride]] being a popular example. The [[Pechmann condensation]] provides another route to coumarin and its derivatives starting from [[phenol]], as does the [[Kostanecki acylation]],<ref>{{Cite journal | doi = 10.1021/cr60113a001| title = The Chemistry of Coumarins| journal = Chemical Reviews| volume = 36| pages = 1–62| year = 1945| last1 = Sethna | first1 = S. M. | last2 = Shah | first2 = N. M. }}</ref> which can also be used to produce [[chromones]].

==Biosynthesis==
From [[lactonization]] of ''ortho''-hydroxylated ''cis''-[[hydroxycinnamic acid]].<ref name="Jacobowitz-Weng-2020">{{cite journal | last1=Jacobowitz | first1=Joseph R. | last2=Weng | first2=Jing-Ke | title=Exploring Uncharted Territories of Plant Specialized Metabolism in the Postgenomic Era | journal=[[Annual Review of Plant Biology]] | publisher=[[Annual Reviews (publisher)|Annual Reviews]] | volume=71 | issue=1 | date=2020-04-29 | issn=1543-5008 | doi=10.1146/annurev-arplant-081519-035634 | pages=631–658| pmid=32176525 | bibcode=2020AnRPB..71..631J | s2cid=212740956 }}</ref>

==Natural occurrence==
Coumarin is found naturally in many plants. Freshly ground plant parts contain higher amount of desired and undesired phytochemicals than powder. In addition, whole plant parts are harder to counterfeit; for example, one study showed that authentic [[Ceylon cinnamon]] bark contained 0.012 to 0.143&nbsp;mg/g coumarin, but samples purchased at markets contained up to 3.462&nbsp;mg/g, possibly because those were mixed with other cinnamon varieties.<ref>{{cite journal |last1=Ananthakrishnan |first1=R. |last2=Chandra |first2=Preeti |last3=Kumar |first3=Brijesh |last4=Rameshkumar |first4=K. B. |title=Quantification of coumarin and related phenolics in cinnamon samples from south India using UHPLC-ESI-QqQLIT-MS/MS method |journal=International Journal of Food Properties |pages=50–57 |doi=10.1080/10942912.2018.1437629 |date=1 January 2018|volume=21 |s2cid=104289832 |doi-access=free }}</ref>

* Vanilla grass (''[[Anthoxanthum odoratum]]'')
* Sweet woodruff (''[[Galium odoratum]]'')
* Sweet grass (''[[Hierochloe odorata]]'')
* Sweet-clover (genus ''[[Melilotus]]'')
* Meranti trees (genus ''[[Shorea]]'')
* [[Dipteryx odorata|Tonka bean]] (''Dipteryx odorata'')
* [[Fenugreek]] (''Trigonella foenum-graecum'')
* [[Cinnamon]]; a 2013 study showed different varieties containing different levels of coumarin:
** Ceylon cinnamon or true cinnamon (''[[Cinnamomum verum]]''): 0.005 to 0.090&nbsp;mg/g<ref name=":0">[https://www.cinnamonzone.hk/DOWNLOADS/Cinnamon_and_coumarin.pdf Cassia Cinnamon as a Source of Coumarin in Cinnamon-Flavored Food and Food Supplements in the United States] ''J. Agric. Food Chem.'', '''61 (18)''', 4470–4476</ref>
** Chinese cinnamon or Chinese cassia (''[[Cinnamomum cassia|C. cassia]]''): 1.74 to 7.67&nbsp;mg/g<ref>{{Cite journal |last1=Woehrlin |first1=Friederike |last2=Fry |first2=Hildburg |last3=Abraham |first3=Klaus |last4=Preiss-Weigert |first4=Angelika |date=2010-09-20 |title=Quantification of Flavoring Constituents in Cinnamon: High Variation of Coumarin in Cassia Bark from the German Retail Market and in Authentic Samples from Indonesia |url=https://www.pismin.com/10.1021/jf102112p |journal=Journal of Agricultural and Food Chemistry |volume=58 |issue=19 |pages=10568–10575 |doi=10.1021/jf102112p |pmid=20853872 |bibcode=2010JAFC...5810568W |issn=0021-8561}}</ref>
** Indonesian cinnamon or Padang cassia (''[[Cinnamomum burmannii|C. burmannii]]''): 2.14 to 9.30&nbsp;mg/g<ref name=":0" />
** [[Saigon cinnamon]] or Vietnamese cassia (''C. loureiroi''): 1.06 to 6.97&nbsp;mg/g<ref name=":0" />
* Deertongue (''[[Carphephorus odoratissimus]]''),<ref>{{cite book |last1=Khan |first1=Ikhlas A. |last2=Ehab |first2=Abourashed A. |title=Leung's Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics |date=2010 |publisher=John Wiley & Sons |location=Hoboken, NJ USA |isbn=978-9881607416 |pages=240–242 |url=https://naturalingredient.org/wp/wp-content/uploads/leungs-encyclopedia-of-common-natural-ingredients-3rd-edition.pdf |access-date=21 September 2020}}</ref>
* Tilo (''[[Justicia pectoralis]]''),<ref name=leal2010/><ref name=lino1997/>
* Mullein (genus ''[[Verbascum]]'')
* Many [[cherry blossom]] tree varieties (of the genus ''[[Prunus]]'').<ref name=ieri2012/>
* Related compounds are found in some but not all specimens of genus ''[[Glycyrrhiza]]'', from which the root and flavour [[licorice]] derives.<ref name=hata2018/>

Coumarin is found naturally also in many edible plants such as [[strawberries]], [[black currant]]s, [[apricot]]s, and [[cherries]].<ref name=pubchem19/>

Coumarins were found to be uncommon but occasional components of [[propolis]] by Santos-Buelga and Gonzalez-Paramas 2017.<ref name="Berenbaum-Calla-2021">{{cite journal | last1=Berenbaum | first1=May R. | last2=Calla | first2=Bernarda | title=Honey as a Functional Food for ''Apis mellifera'' | journal=[[Annual Review of Entomology]] | publisher=[[Annual Reviews (publisher)|Annual Reviews]] | volume=66 | issue=1 | date=2021-01-07 | issn=0066-4170 | doi=10.1146/annurev-ento-040320-074933 | pages=185–208| pmid=32806934 | s2cid=221165130 }}</ref>

=== Biological function ===
Coumarin has appetite-suppressing properties, which may discourage animals from eating plants that contain it. Though the compound has a pleasant sweet odor, it has a bitter taste, and animals tend to avoid it.<ref name=link1959/>

=== Metabolism ===
The [[biosynthesis]] of coumarin in plants is via [[hydroxylation]], [[glycolysis]], and [[cyclization]] of [[cinnamic acid]].{{citation needed|date=December 2018}} In humans, the enzyme encoded by the gene ''[[UGT1A8]]'' has [[wikt:glucuronidase|glucuronidase]] activity with many substrates, including coumarins.<ref name=ritter1992/>

==Derivatives==
{{main|4-Hydroxycoumarins|Coumarin derivatives}}
Coumarin is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to [[dicoumarol]].<ref name=pubchem19/> [[4-hydroxycoumarins]] are a type of [[vitamin K antagonist]].<ref name=pubchem19/> They block the regeneration and recycling of [[vitamin K]].<ref name=pubchem19/><ref name="warfarin">{{cite web |title=Warfarin |url=https://www.drugs.com/ppa/warfarin.html |publisher=Drugs.com |access-date=13 April 2019 |date=7 March 2019}}</ref> These chemicals are sometimes also incorrectly referred to as "coumadins" rather than 4-hydroxycoumarins. Some of the 4-hydroxycoumarin anticoagulant class of chemicals are designed to have high potency and long residence times in the body, and these are used specifically as [[rodenticide]]s ("rat poison").<ref name=pubchem19/> Death occurs after a period of several days to two weeks, usually from internal hemorrhaging.

==Uses==
Coumarin is often found in [[artificial vanilla]] substitutes, despite having been banned as a food additive in numerous countries since the mid-20th century. It is still used as a legal flavorant in soaps, rubber products, and the tobacco industry,<ref name=pubchem19/> particularly for sweet [[pipe tobacco]] and certain alcoholic drinks.{{which|date=February 2024}}{{cn|date=February 2024}}

== Toxicity ==
Coumarin is moderately [[Hepatotoxicity|toxic to the liver]] and [[Renal toxicity|kidneys]] of rodents, with a [[median lethal dose]] (LD<sub>50</sub>) of 293&nbsp;mg/kg in the rat,<ref>[http://www.palomar.edu/ehs/Chemistry%20MSDS/COUMARIN.pdf Coumarin Material Safety Data Sheet (MSDS)] {{webarchive|url=https://web.archive.org/web/20041021205840/http://www.palomar.edu/ehs/Chemistry%20MSDS/COUMARIN.pdf |date=2004-10-21 }}</ref> a low toxicity compared to related compounds. 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.<ref name=vassa2004/><ref name=born203/> Humans metabolize it mainly to [[7-hydroxycoumarin]], a compound of lower toxicity, and no adverse effect has been directly measured in humans.<ref>{{cite journal |title=Coumarin Metabolism, Toxicity and Carcinogenicity: Relevance for Human Risk Assessment |journal=Food and Chemical Toxicology |year=1999 |issue=4 |doi=10.1016/S0278-6915(99)00010-1|last1=Lake |first1=B.G |volume=37 |pages=423–453 |pmid=10418958 }}</ref> The German Federal Institute for Risk Assessment has established a tolerable daily intake (TDI) of 0.1&nbsp;mg coumarin per kg body weight, but also advises that higher intake for a short time is not dangerous.<ref name=bfrtdi/> The [[Occupational Safety and Health Administration]] (OSHA) of the United States does not classify coumarin as a [[carcinogen]] for humans.<ref name=osha2015/>

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.<ref name=bund2015/><ref name=npr2015/>  According to the German [[Federal Institute for Risk Assessment]] (BFR), 1&nbsp;kg of (cassia) cinnamon powder contains about 2.1 to 4.4&nbsp;g of coumarin.<ref name=bund2006/>  Powdered cassia cinnamon weighs 0.56&nbsp;g/cm<sup>3</sup>,<ref name=powd2002/> so a kilogram of cassia cinnamon powder equals 362.29&nbsp;teaspoons. One teaspoon of cassia cinnamon powder therefore contains 5.8 to 12.1&nbsp;mg of coumarin, which may be above the tolerable daily intake value for smaller individuals.<ref name=bund2006/> 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.<ref name=bund2006/>

The European Regulation (EC) No 1334/2008 describes the following maximum limits for coumarin: 50&nbsp;mg/kg in traditional and/or seasonal bakery ware containing a reference to cinnamon in the labeling, 20&nbsp;mg/kg in breakfast cereals including [[muesli]], 15&nbsp;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&nbsp;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&nbsp;mg/kg) in almost 50% of the cases.<ref name=ball2014/> The paper also mentions tea as an additional important contributor to the overall coumarin intake, especially for children with a habit for sweets.

Coumarin was banned as a food additive in the United States in 1954, largely because of the hepatotoxicity results in rodents.<ref name=marles1986/> 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 [[Code of Federal Regulations|CFR]] 189.130,<ref name=fodru2015/><ref name=eafus/> but some natural additives containing coumarin, such as the [[Flavoring|flavor]]ant [[Galium odoratum|sweet woodruff]] are allowed "in alcoholic beverages only" under 21 [[Code of Federal Regulations|CFR]] 172.510.<ref name=fodu2015b/> In Europe, popular examples of such beverages are ''[[Maiwein]],'' white wine with woodruff, and ''[[Żubrówka]],'' vodka flavoured with [[Hierochloe odorata|bison grass]].

Coumarin is subject to restrictions on its use in perfumery,<ref name=ifraorg/> as some people may become sensitized to it, however the evidence that coumarin can cause an allergic reaction in humans is disputed.<ref name=crowat/>

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."<ref name=wess2001/>

Coumarin's addition to [[cigarette]] tobacco by [[Brown & Williamson]] caused executive<ref name=60minutes/> Dr. [[Jeffrey Wigand]] to contact [[CBS]]'s news show ''[[60 Minutes]]'' in 1995, charging that a "form of [[rat poison]]" was being used as an additive. He held that from a chemist’s point of view, coumarin is an "immediate precursor" to the rodenticide (and prescription drug) [[coumadin]].<ref name="drugs19"/> Dr. Wigand later stated that coumarin itself is dangerous, pointing out that the [[Food and Drug Administration|FDA]] had banned its addition to human food in 1954.<ref name=tobtri/> Under his later testimony, he would repeatedly classify coumarin as a "lung-specific carcinogen."<ref name=indoc/> In Germany, coumarin is banned as an additive in tobacco.

Alcoholic beverages sold in the [[European Union]] are limited to a maximum of 10&nbsp;mg/L coumarin by law.<ref name=thieme/> 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 at significant levels.{{cn|date=February 2024}}

== Notes ==
{{notelist}}

== References ==
<references>
<ref name=vogel1820a>{{cite journal | last1 = Vogel | first1 = A. | year = 1820 | title = Darstellung von Benzoesäure aus der Tonka-Bohne und aus den Meliloten- oder Steinklee-Blumen |trans-title=Preparation of benzoic acid from tonka beans and from the flowers of melilot or sweet clover |language=de | url = https://zenodo.org/record/1423496| journal = Annalen der Physik | volume = 64 | issue = 2| pages = 161–166 | doi=10.1002/andp.18200640205| bibcode = 1820AnP....64..161V }}</ref>

<ref name=vogel1820b>{{cite journal|last1=Vogel |first1=A. |date=1820 |title=De l'existence de l'acide benzoïque dans la fève de tonka et dans les fleurs de mélilot |trans-title=On the existence of benzoic acid in the tonka bean and in the flowers of melilot|language=fr |journal=Journal de Pharmacie |volume=6 |pages=305–309 |url=http://gallica.bnf.fr/ark:/12148/bpt6k78140v/f311.image}}</ref>

<ref name=guib1820>{{cite book|last=Guibourt |first=N. J. B. G. |title=Histoire Abrégée des Drogues Simples |trans-title=Abridged History of Simple Drugs |language=fr |volume=2 |location=Paris |publisher=L. Colas |date=1820 |url=http://babel.hathitrust.org/cgi/pt?id=ucm.5324210081#view=1up;seq=166 |pages=160–161}}</ref>

<ref name=guib1825>{{cite journal|journal=Journal de Chimie Médicale, de Pharmacie et de Toxicologie|title=Societe du Pharmacie de Paris |volume=1 |url=https://books.google.com/books?id=L_IwAAAAYAAJ&pg=PA303 |page=303 |date=1825 |quote=... 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'' ...]}}</ref>

<ref name=guib1869>{{cite book|last=Guibourt |first=N. J. B. G. |title=Histoire Naturelle des Drogues Simples |edition=6th |location=Paris |publisher=J. B. Baillière et fils |date=1869 |url=http://gallica.bnf.fr/ark:/12148/bpt6k5810074h/f378.image.langEN |page=377 |quote= ... 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'' ...]}}</ref>

<ref name=guil1835>{{cite journal | last1 = Guillemette | first1 = A. | year = 1835 | title = Recherches sur la matière cristalline du mélilot |trans-title=Research into the crystalline material of melilot | url = https://books.google.com/books?id=vMJhd3_lpnkC&pg=PA172 | journal = Journal de Pharmacie | volume = 21 | pages = 172–178 }}</ref>

<ref name=perkin1868>{{cite journal | last1 = Perkin | first1 = W. H. | year = 1868 | title = On the artificial production of coumarin and formation of its homologues | url = https://books.google.com/books?id=ETrPAAAAMAAJ&pg=PA53 | journal = Journal of the Chemical Society | volume = 21 | pages = 53–63 | doi=10.1039/js8682100053| url-access = subscription }}</ref>

<!-- <ref name=wang2013>{{cite journal | last1 = Wang | first1 = Yan-Hong | last2 = Avula | first2 = Bharathi | last3 = Nanayakkara | first3 = N. P. Dhammika | last4 = Zhao | first4 = Jianping | last5 = Khan | first5 = Ikhlas A. | year = 2013 | title = Cassia Cinnamon as a Source of Coumarin in Cinnamon-Flavored Food and Food Supplements in the United States | journal = Journal of Agricultural and Food Chemistry | volume = 61 | issue = 18| pages = 4470–4476 | doi = 10.1021/jf4005862 | pmid = 23627682 }}</ref> -->

<ref name=ieri2012>{{cite journal | last1 = Ieri | first1 = Francesca | last2 = Pinelli | first2 = Patrizia | last3 = Romani | first3 = Annalisa | year = 2012 | title = Simultaneous determination of anthocyanins, coumarins and phenolic acids in fruits, kernels and liqueur of ''Prunus mahaleb'' L | journal = Food Chemistry | volume = 135 | issue = 4| pages = 2157–2162 | doi = 10.1016/j.foodchem.2012.07.083 | pmid = 22980784 | hdl = 2158/775163 | s2cid = 14467019 | hdl-access = free }}</ref>

<ref name=leal2010>{{Cite journal|doi = 10.1016/S0378-8741(99)00165-8| pmid = 10771205| issn = 0378-8741| volume = 70| issue = 2| pages = 151–159| last1 = Leal| first1 = L. K. A. M.| first2=A. A. G.|last2= Ferreira |first3=G. A. |last3=Bezerra |first4=F. J. A.|last4= Matos |first5=G. S. B. |last5=Viana | title = Antinociceptive, anti-inflammatory and bronchodilator activities of Brazilian medicinal plants containing coumarin: a comparative study| journal = Journal of Ethnopharmacology| date = May 2000}}</ref>

<ref name=lino1997>{{Cite journal| doi = 10.1002/(SICI)1099-1573(199705)11:3<211::AID-PTR72>3.0.CO;2-W| volume = 11| issue = 3| pages = 211–215| last1 = Lino| first1 = C. S.| first2=M. L. |last2=Taveira |first3=G. S. B. |last3=Viana |first4=F. J. A. |last4=Matos | title = Analgesic and antiinflammatory activities of ''Justicia pectoralis'' Jacq. and its main constituents: coumarin and umbelliferone| journal = Phytotherapy Research| access-date = 2010-06-26| year = 1997| s2cid = 84525194| url = http://www3.interscience.wiley.com/journal/12627/abstract
| archive-url = https://archive.today/20130105093057/http://www3.interscience.wiley.com/journal/12627/abstract
| url-status = dead| archive-date = 2013-01-05| url-access = subscription}}</ref>

<ref name=hata2018>{{cite journal|title=Phenolic constituents of licorice. IV. Correlation of phenolic constituents and licorice specimens from various sources, and inhibitory effects of...|last=Hatano |first=T. |display-authors=etal|pmid=1941536|volume=111|issue=6 |year=1991|journal=Yakugaku Zasshi|pages=311–21|doi=10.1248/yakushi1947.111.6_311 |doi-access=free}}</ref>

<ref name=link1959>{{cite journal |last=Link |first=K. P. |title=The discovery of dicumarol and its sequels |journal=Circulation |volume=19 |issue=1 |pages=97–107 |date=1 January 1959|pmid=13619027 |doi=10.1161/01.CIR.19.1.97 |doi-access=free}}</ref>

<ref name=ritter1992>{{cite journal |last=Ritter |first=J. K. |title=A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini |journal=J. Biol. Chem. |volume=267 |issue=5 |pages=3257–3261 |date=Mar 1992 |doi=10.1016/S0021-9258(19)50724-4 |pmid=1339448 |display-authors=etal |doi-access=free}}</ref>

<!--
<ref name=ipcs2007>{{cite web |author=International Programme on Chemical Safety |title=Brodifacoum (pesticide data sheet) |access-date=2006-12-14 |url=http://www.inchem.org/documents/pds/pds/pest57_e.htm |url-status=dead |archive-url=https://web.archive.org/web/20061209133155/http://inchem.org/documents/pds/pds/pest57_e.htm |archive-date=2006-12-09}}</ref>

<ref name=lev2007>{{cite journal |volume=356 |pages=174–82 |year=2007 |issue=2 |title=Case 1-2007—A 40-Year-Old Woman with Epistaxis, Hematemesis, and Altered Mental Status |journal=New England Journal of Medicine |last1=Laposata |first1=M |last2=Van Cott |first2=E. M. |last3=Lev |first3=M. H. |doi=10.1056/NEJMcpc069032 | pmid=17215536}}</ref>

<ref name=ipcs2006a>{{cite web |author=International Programme on Chemical Safety |title=Bromadiolone (pesticide data sheet) |access-date=2006-12-14 |url=http://www.inchem.org/documents/pds/pds/pest88_e.htm |url-status=dead |archive-url=https://web.archive.org/web/20061221043656/http://www.inchem.org/documents/pds/pds/pest88_e.htm |archive-date=2006-12-21}}</ref>

<ref name=ipcs2006b>{{cite web |author=International Programme on Chemical Safety |title=Difenacoum (health and safety guide) |access-date=2006-12-14 |url=http://www.inchem.org/documents/hsg/hsg/hsg095.htm}}</ref>

<ref name=syah2009>{{cite journal |doi=10.1080/14786410600761235 |title=A modified oligostilbenoid, diptoindonesin C, from ''Shorea pinanga'' Scheff |year=2009 |last1=Syah |first1=Y. M. |journal=Natural Product Research |volume=23 |issue=7 |pages=591–594 |pmid=19401910 |s2cid=20216115 |display-authors=etal}}</ref>

<ref name=venu2013>{{cite journal |pmc=3622347 |year=2013 |last1=Venugopala |first1=K. N. |title=Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity |journal=BioMed Research International |volume=2013 |pages=1–14 |last2=Rashmi |first2=V |last3=Odhav |first3=B |doi=10.1155/2013/963248 |pmid=23586066 |doi-access=free}}</ref>

<ref name=bye1970>{{cite journal |last1=Bye |first1=A. |last2=King |first2=H. K. |year=1970 |title=The biosynthesis of 4-hydroxycoumarin and dicoumarol by ''Aspergillus fumigatus'' Fresenius |journal=Biochemical Journal |volume=117 |issue=2 |pages=237–45 |doi=10.1042/bj1170237 |pmid=4192639 |pmc=1178855}}</ref>
-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=lymphedema>{{cite journal |last1=Farinola |first1=N. |first2=N. |last2=Piller |journal=Lymphatic Research and Biology |date=June 1, 2005 |volume=3 |issue=2 |pages=81–86 |doi=10.1089/lrb.2005.3.81 |title=Pharmacogenomics: Its role in re-establishing coumarin as treatment for lymphedema |pmid=16000056}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=chris1964>{{cite journal |doi=10.1111/j.0954-6820.1964.tb00594.x |issn=0954-6820 |volume=175 |issue=4 |pages=461–468 |last=Christensen |first=Flemming |title=Uricosuric Effect of Dicoumarol |journal=Acta Medica Scandinavica |date=1964-01-12 |pmid=14149651}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=chen1988>{{cite journal |last1=Chen |first1=C. H. |last2=Fox |first2=J. L. |last3=Duarte |first3=F. J. |title=Lasing characteristics of new-coumarin-analog dyes: broadband and narrow-linewidth performance |journal=Appl. Opt. |volume=27 |issue=3 |pages=443–445 |date=1988 |doi=10.1364/ao.27.000443|pmid=20523615 |bibcode=1988ApOpt..27..443C}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=dua2006>{{cite journal |last1=Duarte |first1=F. J. |last2=Liao |first2=L. S. |last3=Vaeth |first3=K. M. |last4=Miller |first4=A. M. |title=Widely tunable laser emission using the coumarin 545 tetramethyl dye as gain medium |journal=J. Opt. A |volume=8 |issue=2 |pages=172–174 |date=2006 |doi=10.1088/1464-4258/8/2/010 |bibcode=2006JOptA...8..172D}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=dua2005>{{cite journal |last1=Duarte |first1=F. J. |last2=Liao |first2=L. S. |last3=Vaeth |first3=K. M. |title=Coherence characteristics of electrically excited tandem organic light-emitting diodes |journal=Opt. Lett. |volume=30 |issue=22 |pages=3072–3074 |date=2005 |doi=10.1364/ol.30.003072 |pmid=16315725 |bibcode=2005OptL...30.3072D}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=DL>{{cite book |editor1-link=F. P. Schäfer |editor1-last=Schäfer |editor1-first=F. P. |title=Dye Lasers |edition=3rd |location=Berlin |publisher=Springer-Verlag |date=1990}} {{ISBN missing}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=DLP>{{cite book |editor1-link=F. J. Duarte |editor1-last=Duarte |editor1-first=F. J. |editor2-first=L. W. |editor2-last=Hillman |title=Dye Laser Principles |location=New York |publisher=Academic |date=1990}} {{ISBN missing}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=TLO>{{cite book|last=Duarte|first=F. J.|title=Tunable Laser Optics|location=New York|publisher=Elsevier-Academic|date=2003|chapter=Appendix of Laser Dyes}}{{ISBN missing}}</ref-->

<!--(this citation is not used in content and was thus giving a cite error)
<ref name=xer1978>{{cite patent|country=US|number=4175982|inventor=Loutfy et al.|gdate=Nov. 27, 1978|assign1=Xerox Corp}}</ref-->

<ref name=vassa2004>{{cite journal |pmid=15141102 |year=2004 |last1=Vassallo |first1=J. D.|title=Metabolic detoxification determines species differences in coumarin-induced hepatotoxicity |volume=80 |issue=2 |pages=249–57 |doi=10.1093/toxsci/kfh162 |journal=Toxicological Sciences |display-authors=etal| doi-access=free}}</ref>

<ref name=born203>{{cite journal |pmid=12480300 |year=2003 |last1=Born |first1=S. L. |title=Comparative metabolism and kinetics of coumarin in mice and rats |volume=41 |issue=2 |pages=247–58 |journal=Food and Chemical Toxicology |doi=10.1016/s0278-6915(02)00227-2 |display-authors=etal}}</ref>

<ref name=bfrtdi>{{cite web |url=http://www.bfr.bund.de/cm/279/frequently_asked_questions_about_coumarin_in_cinnamon_and_other_foods.pdf |title=Frequently Asked Questions about coumarin in cinnamon and other foods |work=The German Federal Institute for Risk Assessment |date=30 October 2006 |url-status=dead |archive-url=https://web.archive.org/web/20090419200255/http://www.bfr.bund.de/cm/279/frequently_asked_questions_about_coumarin_in_cinnamon_and_other_foods.pdf |archive-date=19 April 2009}}</ref>

<ref name=osha2015>{{cite web |url=https://www.osha.gov/dts/chemicalsampling/data/CH_229620.html |title=Chemical Sampling Information – Coumarin|website=Osha.gov |access-date=30 December 2015}}</ref>

<ref name=bund2015>{{cite web |url=http://www.bfr.bund.de/en/press_information/2012/26/cassia_cinnamon_with_high_coumarin_contents_to_be_consumed_in_moderation-131836.html |title=Cassia cinnamon with high coumarin contents to be consumed in moderation - BfR |website=Bfr.bund.de |access-date=30 December 2015}}</ref>

<ref name=npr2015>{{cite web |url=https://www.npr.org/templates/story/story.php?storyId=6672644 |title=German Christmas Cookies Pose Health Danger |date=25 December 2006 |work=NPR.org |access-date=30 December 2015}}</ref>

<ref name=bund2006>{{cite web |url=http://www.bfr.bund.de/cm/245/high_daily_intakes_of_cinnamon_health_risk_cannot_be_ruled_out.pdf |title=High daily intakes of cinnamon: Health risk cannot be ruled out. BfR Health Assessment No. 044/2006, 18 August 2006 <!-- Bot generated title --> |website=bund.de |access-date=28 March 2018 |archive-date=12 June 2007 |archive-url=https://web.archive.org/web/20070612191901/http://www.bfr.bund.de/cm/245/high_daily_intakes_of_cinnamon_health_risk_cannot_be_ruled_out.pdf |url-status=dead }}</ref>

<ref name=powd2002>[http://www.powderandbulk.com/resources/bulk_density/material_bulk_density_chart_c.htm Engineering Resources – Bulk Density Chart<!-- Bot generated title -->] {{webarchive |url=https://web.archive.org/web/20021027095738/http://www.powderandbulk.com/resources/bulk_density/material_bulk_density_chart_c.htm |date=2002-10-27}}</ref>

<ref name=ball2014>{{cite journal |last1=Ballin |first1=Nicolai Z. |first2=Ann T. |last2=Sørensen |title=Coumarin content in cinnamon containing food products on the Danish market |journal=Food Control |volume=38 |issue=2014 |pages=198–203 |doi=10.1016/j.foodcont.2013.10.014 |date=April 2014}}</ref>

<ref name=marles1986>{{cite journal |last1=Marles |first1=R. J. |display-authors=etal |year=1986 |title=Coumarin in vanilla extracts: Its detection and significance |journal=Economic Botany |volume=41 |issue=1 |pages=41–47 |doi=10.1007/BF02859345 |s2cid=23232507}}</ref>

<ref name=fodru2015>{{cite web |url=http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr189_06.html |title=Food and Drugs |website=Access.gpo.gov |archive-url=https://web.archive.org/web/20120205004801/http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr189_06.html |archive-date=5 February 2012 |url-status=dead |df=dmy-all |access-date=30 December 2015}}</ref>

<ref name=eafus>{{cite web |url=http://www.cfsan.fda.gov/~dms/eafus.html |title=FDA/CFSAN/OPA: EAFUS List |website=www.cfsan.fda.gov |archive-url=https://web.archive.org/web/20000903071509/http://www.cfsan.fda.gov/~dms/eafus.html |archive-date=3 September 2000 |url-status=dead |access-date=17 January 2022}}</ref>

<ref name=fodu2015b>{{cite web|url=http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr172_06.html|title=Food and Drugs|website=Access.gpo.gov|access-date=30 December 2015|archive-url=https://web.archive.org/web/20120205004805/http://www.access.gpo.gov/nara/cfr/waisidx_06/21cfr172_06.html|archive-date=5 February 2012|url-status=dead}}</ref>

<ref name=ifraorg>{{cite web |url=http://www.ifraorg.org/en-us/standards_restricted/s3/p3 |title=Standards Restricted - IFRA International Fragrance Association |access-date=2012-07-19 |url-status=dead |archive-url=https://web.archive.org/web/20120106222844/http://www.ifraorg.org/en-us/standards_restricted/s3/p3 |archive-date=2012-01-06 }}</ref>

<ref name=crowat>{{cite web|url=http://www.leffingwell.com/Cropwatch%20Claims%20Victory%20Over%2026%20Allergens.pdf|title=Cropwatch Claims Victory Regarding "26 Allergens" Legislation : Modified from article originally written for Aromaconnection, Feb 2008|website=Leffingwell.com|access-date=2 December 2018}}</ref>

<ref name=wess2001>{{cite journal |last1=Wessling |first1=J. |year=2001 |title=Neurological outcome in school-age children after in utero exposure to coumarins |journal=Early Human Development |volume=63 |issue=2 |pages=83–95 |doi=10.1016/S0378-3782(01)00140-2 |pmid=11408097}}</ref>

<ref name=60minutes>{{cite web |url=http://www.jeffreywigand.com/60minutes.php |title=Jeffrey Wigand : Jeffrey Wigand on 60 Minutes |website=Jeffreywigand.com |access-date=30 December 2015}}</ref>

<ref name=tobtri>{{cite web|url=http://www.tobacco-on-trial.com/2005/01/31/dr-wigand-and-the-solicitous-solicitor/|archive-url=https://web.archive.org/web/20061211102059/http://www.tobacco-on-trial.com/2005/01/31/dr-wigand-and-the-solicitous-solicitor/|url-status=usurped|archive-date=December 11, 2006|title=Tobacco On Trial|website=Tobacco-on-trial.com|access-date=30 December 2015}}</ref>

<ref name=indoc>{{cite web|url=http://legacy.library.ucsf.edu/tid/tnt32e00|title=Industry Documents Library|website=Legacy.library.ucsf.edu|access-date=2 December 2018}}</ref>

<ref name=thieme>{{cite journal|title= Characterization and Distribution of Coumarin, Cinnamaldehyde and Related Compounds in Cinnamomum spp. by UPLC-UV/MS Combined with PCA|journal=Planta Medica|volume=76|issue=5|doi=10.1055/s-0030-1251793|year = 2010|last1 = Wang|first1 = YH|last2=Avula|first2=B.|last3=Zhao|first3=J.|last4=Smillie|first4=TJ|last5=Nanayakkara|first5=NPD|last6=Khan|first6=IA|bibcode=2010PlMed..7651793W }}</ref>

</references>

{{Phenylpropanoids}}
{{Coumarin}}

{{Authority control}}

[[Category:Coumarins| ]]
[[Category:Fluorescent dyes]]
[[Category:Fuel dyes]]
[[Category:Laser gain media]]
[[Category:Plant toxins]]
[[Category:Sweet-smelling chemicals]]