Coumarin () or 2''H''-chromen-2-one is an aromatic organic
chemical compound
A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...
with formula . Its molecule can be described as a
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...
molecule with two adjacent
hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
atoms replaced by a lactone-like chain , forming a second six-membered
heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
that shares two
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon mak ...
s with the benzene ring. It can be placed in the
benzopyrone Benzopyrone may refer to either of two ketone derivatives of benzopyran which constitute the core skeleton of many flavonoid compounds:
*Chromone (1-benzopyran-4-one)
* Coumarin (1-benzopyran-2-one)
Certain simple benzopyrones have clinical medica ...
chemical class and considered as a
lactone
Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring.
Lactones are formed by intramolecular esterification of the co ...
.
Coumarin is a colorless crystalline solid with a sweet
odor resembling the scent of
vanilla
Vanilla is a spice derived from orchids of the genus ''Vanilla (genus), Vanilla'', primarily obtained from pods of the Mexican species, flat-leaved vanilla (''Vanilla planifolia, V. planifolia'').
Pollination is required to make the p ...
and a bitter taste.
[ It is found in many plants, where it may serve as a chemical defense against predators. By inhibiting synthesis of ]vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
, a related compound is used as the prescription drug warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
– an anticoagulant – to inhibit formation of blood clot
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of ...
s, deep vein thrombosis
Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...
, and pulmonary embolism
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
.
Etymology
Coumarin is derived from ''coumarou'', the French word for the tonka bean. The word ''tonka'' for the tonka bean
''Dipteryx odorata'' (commonly known as "cumaru", "kumaru", or "Brazilian teak") is a species of flowering tree in the pea family, Fabaceae. The tree is native to Central America and northern South America
South America is a continent ...
is taken from the Galibi
The Kalina, also known as the Caribs or mainland Caribs and by several other names, are an indigenous people native to the northern coastal areas of South America. Today, the Kalina live largely in villages on the rivers and coasts of Venezuela, ...
(Carib) tongue spoken by natives of French Guiana
French Guiana ( or ; french: link=no, Guyane ; gcr, label=French Guianese Creole, Lagwiyann ) is an overseas department/region and single territorial collectivity of France on the northern Atlantic coast of South America in the Guianas. ...
(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
''Dipteryx'' is a genus containing a number of species of large trees and possibly shrubs. It belongs to the "papilionoid" subfamily – Faboideae – of the family Fabaceae. This genus is native to South and Central America and the Carib ...
'', was formed from another Tupi name for tree, ''kumarú''.
History
Coumarin was first isolated from tonka beans
''Dipteryx odorata'' (commonly known as "cumaru", "kumaru", or "Brazilian teak") is a species of flowering tree in the pea family, Fabaceae. The tree is native to Central America and northern South America and is semi-deciduous. Its seeds are kno ...
in 1820 by A. Vogel of Munich, who initially mistook it for benzoic acid
Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. It is the simplest aromatic carboxylic acid. The name is derived from gum benzoin, ...
.[
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 the ]Académie Royale de Médecine
An academy ( Attic Greek: Ἀκαδήμεια; Koine Greek Ἀκαδημία) is an institution of secondary or tertiary higher learning (and generally also research or honorary membership). The name traces back to Plato's school of philosophy ...
, 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
Sir William Henry Perkin (12 March 1838 – 14 July 1907) was a British chemist and entrepreneur best known for his serendipitous discovery of the first commercial synthetic organic dye, mauveine, made from aniline. Though he failed in tryin ...
.[
Coumarin has been an integral part of the ]fougère
''Fougère'', , is one of the main olfactive families of perfumes. The name comes from the French language word for "fern". ''Fougère'' perfumes are made with a blend of fragrances: top-notes are sweet, with the scent of lavender flowers; ...
genre of perfume since it was first used in Houbigant's Fougère Royale in 1882.
Synthesis
Coumarin can be prepared by a number of name reaction A name reaction is a chemical reaction named after its discoverers or developers. Among the tens of thousands of organic reactions that are known, hundreds of such reactions are well-known enough to be named after people. Well-known examples include ...
s, with the Perkin reaction
The Perkin reaction is an organic reaction developed by English chemist William Henry Perkin that is used to make cinnamic acids. It gives an α,β-unsaturated aromatic acid or α-substituted β-aryl acrylic acid by the aldol condensation of a ...
between salicylaldehyde
Salicylic aldehyde (2-hydroxybenzaldehyde) is the organic compound with the formula (C7 H6 O2) C6H4CHO-2-OH. Along with 3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde, it is one of the three isomers of hydroxybenzaldehyde. This colorless oily ...
and acetic anhydride being a popular example. The Pechmann condensation
The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a carboxylic acid or ester containing a β-carbonyl group. The condensation is performed under acidic conditions. The mechanism involves an esterification/transes ...
provides another route to coumarin and its derivatives, as does the Kostanecki acylation
The Kostanecki acylation is a method used in organic synthesis to form chromones or coumarins by acylation of ''O''-hydroxyaryl ketones with aliphatic acid anhydrides, followed by cyclization. If benzoic anhydride (or benzoyl chloride) is used, ...
, which can also be used to produce chromones
Chromone (or 1,4-benzopyrone) is a derivative of benzopyran with a substituted keto group on the pyran ring. It is an isomer of coumarin.
Derivatives of chromone are collectively known as ''chromones''. Most, though not all, chromones are als ...
.
Biosynthesis
From lactonization
Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring.
Lactones are formed by intramolecular esterification of the co ...
of ''ortho''-hydroxylated ''cis''-hydroxycinnamic acid
Hydroxycinnamic acids (hydroxycinnamates) are a class of aromatic acids or phenylpropanoids having a C6–C3 skeleton. These compounds are hydroxy derivatives of cinnamic acid.
In the category of phytochemicals that can be found in food, there ...
.
Natural occurrence
Coumarin is found naturally in many plant
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclu ...
s. Freshly ground plant parts contain higher amount of desired and undesired phytochemicals than powder. Also, whole plant parts are harder to counterfeit; for example, one study showed that authentic Ceylon cinnamon
''Cinnamomum verum'', called true cinnamon tree or Ceylon cinnamon tree, is a small evergreen tree belonging to the family Lauraceae, native to Sri Lanka. The inner bark of several other ''Cinnamomum'' species are also used to make cinnamon, b ...
bark contained 0.012 to 0.143 mg/g coumarin, but samples purchased at markets contained up to 3.462 mg/g, possibly because those were mixed with other cinnamon varieties.
* Vanilla grass (''Anthoxanthum odoratum
''Anthoxanthum odoratum'', known as sweet vernal grass, is a short-lived perennial grass that is native to acidic grassland in Eurasia and northern Africa. It is grown as a lawn grass and a house plant, due to its sweet scent, and can also be ...
'')
* Sweet woodruff (''Galium odoratum
''Galium odoratum'', the sweet woodruff or sweetscented bedstraw, is a flowering perennial plant in the family Rubiaceae, native to much of Europe from Spain and Ireland to Russia, as well as Western Siberia, Turkey, Iran, the Caucasus, China ...
'')
* Sweet grass (''Hierochloe odorata
''Hierochloe odorata'' or ''Anthoxanthum nitens'' (commonly known as sweet grass, manna grass, Mary’s grass or vanilla grass, and as holy grass in the UK, bison grass e.g. by Polish vodka producers) is an aromatic herb native to northern E ...
'')
* Sweet-clover (genus ''Melilotus
''Melilotus'', known as melilot, sweet clover, and kumoniga (from the Cumans),Bulgarian Folk Customs, Mercia MacDermott, pg 27 is a genus in the family Fabaceae (the same family that also includes the ''Trifolium'' clovers). Members are known ...
'')
* Tonka bean
''Dipteryx odorata'' (commonly known as "cumaru", "kumaru", or "Brazilian teak") is a species of flowering tree in the pea family, Fabaceae. The tree is native to Central America and northern South America
South America is a continent ...
(''Dipteryx odorata'')
* Cinnamon; a 2013 study showed different varieties containing different levels of coumarin:
** Ceylon cinnamon or true cinnamon (''Cinnamomum verum
''Cinnamomum verum'', called true cinnamon tree or Ceylon cinnamon tree, is a small evergreen tree belonging to the family Lauraceae, native to Sri Lanka. The inner bark of several other '' Cinnamomum'' species are also used to make cinnamon, but ...
''): 0.005 to 0.090 mg/g
** Chinese cinnamon or Chinese cassia ('' C. cassia''): 0.085 to 0.310 mg/g
** Indonesian cinnamon or Padang cassia ('' C. burmannii''): 2.14 to 9.30 mg/g
** Saigon cinnamon
Saigon cinnamon (''Cinnamomum loureiroi'', also known as Vietnamese cinnamon or Vietnamese cassia and ''quế trà my'', ''quế thanh'', or " quế trà bồng" in Vietnam) is an evergreen tree indigenous to mainland Southeast Asia. Saigon cinna ...
or Vietnamese cassia (''C. loureiroi''): 1.06 to 6.97 mg/g
* Deertongue (''Carphephorus odoratissimus
''Carphephorus odoratissimus'' (syn. ''Trilisa odoratissima''), common name vanillaleaf, is a species of North American plants in the family Asteraceae. This species is native to the southeastern United States, including the states of Georgia, No ...
''),
* Tilo (''Justicia pectoralis
''Justicia pectoralis'' is an herb in the family Acanthaceae. This water-willow is widely known as tilo in Latin America and in Cuba. In Haiti it is called ''chapantye'' and ''zeb chapantyè'' on Dominica and Martinique. Other folk names are ...
''),[
* Mullein (genus '']Verbascum
''Verbascum'' is a genus of over 450 species of flowering plants, common name mullein (), in the figwort family Scrophulariaceae. They are native to Europe and Asia, with the highest species diversity in the Mediterranean.
Mullein or "mullein le ...
'')
* Many cherry blossom tree varieties (of the genus ''Prunus
''Prunus'' is a genus of trees and shrubs, which includes (among many others) the fruits plums, Cherry, cherries, peaches, Peach#Nectarine, nectarines, apricots, and almonds.
Native to the North American temperate regions, the neotropics of Sou ...
'').[
* Related compounds are found in some but not all specimens of genus ''Glycyrrhiza'', from which the root and flavour ]licorice
Liquorice (British English) or licorice (American English) ( ; also ) is the common name of ''Glycyrrhiza glabra'', a flowering plant of the bean family Fabaceae, from the root of which a sweet, aromatic flavouring can be extracted.
The liq ...
derives.[
Coumarin is found naturally also in many edible plants such as strawberries, ]black currant
The blackcurrant (''Ribes nigrum''), also known as black currant or cassis, is a deciduous shrub in the family Grossulariaceae grown for its edible berry, berries. It is native species, native to temperate climate, temperate parts of central ...
s, apricots, and cherries.[
Coumarins were found to be uncommon but occasional components of ]propolis
Propolis or bee glue is a resinous mixture that honey bees produce by mixing saliva and beeswax with exudate gathered from tree buds, sap flows, or other botanical sources. It is used as a sealant for unwanted open spaces in the beehive. Prop ...
by Santos-Buelga and Gonzalez-Paramas 2017.
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.[
]
Metabolism
The biosynthesis of coumarin in plants is via hydroxylation, glycolysis, and cyclization
A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...
of cinnamic acid
Cinnamic acid is an organic compound with the formula C6H5-CH=CH- COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxylic acid, it occurs na ...
. In humans, the enzyme encoded by the gene '' UGT1A8'' has glucuronidase activity with many substrates, including coumarins.[
]
Related compounds and derivatives
Coumarin and its derivatives are all considered phenylpropanoids
The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
.
Some naturally occurring coumarin derivatives include umbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and ''beta''-umbelliferone, is a natural product of the coumarin family.
It absorbs ultraviolet light strongly at several wavelengths. There are some indications that this ch ...
(7-hydroxycoumarin), aesculetin
Aesculetin (also known as esculetin, 6,7-dihydroxycoumarin and cichorigenin) is a derivative of coumarin. It is a natural lactone that derives from the intramolecular cyclization of a cinnamic acid derivative.
It is present in chicory and in many ...
(6,7-dihydroxycoumarin), herniarin
Herniarin is a natural chemical compound. Chemically, it can be considered a methoxy derivative of coumarin or a methyl derivative of umbelliferone.
Herniarin is found in ''Herniaria glabra'', ''Ayapana triplinervis
''Ayapana triplinervis'' ( ...
(7-methoxycoumarin), psoralen
Psoralen (also called psoralene) is the parent compound in a family of naturally occurring organic compounds known as the linear furanocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered ...
and imperatorin
Imperatorin is a furocoumarin and a phytochemical that has been isolated from ''Urena lobata'' L. (Malvaceae), ''Angelica archangelica'', '' Angelica dahurica'', '' Glehnia littoralis'', '' Saposhnikovia divaricata'', ''Cnidium monnieri'', '' Incar ...
.
4-Phenylcoumarin is the backbone of the neoflavones
Neoflavonoids are a class of polyphenolic compounds. While flavonoids (in the narrow sense) have the 2-phenylchromen-4-one backbone, neoflavonoids have the 4-phenylchromen backbone with no hydroxyl group substitution at position 2.
Types
Neoflav ...
, a type of neoflavonoids.
Coumarin pyrazole hybrids have been synthesized from hydrazones, carbazones and thiocarbazones via Vilsmeier Haack formylation reaction.
Compounds derived from coumarin are also called coumarins or coumarinoids; this family includes:
* brodifacoum
Brodifacoum is a highly lethal 4-hydroxycoumarin vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides. It is typically used as a rodenticide, but is also used to control larger ...
[
* ]bromadiolone
Bromadiolone is a potent anticoagulant rodenticide. It is a second-generation 4-hydroxycoumarin derivative and vitamin K antagonist, often called a "super-warfarin" for its added potency and tendency to accumulate in the liver of the poisoned o ...
[
* ]difenacoum
Difenacoum is an anticoagulant of the 4-hydroxycoumarin vitamin K antagonist type. It has anticoagulant effects and is used commercially as a rodenticide
Rodenticides are chemicals made and sold for the purpose of killing rodents. While co ...
[
* ]auraptene
Auraptene is a natural bioactive monoterpene coumarin ether. It was first isolated from members of the genus ''Citrus
''Citrus'' is a genus of flowering trees and shrubs in the rue family, Rutaceae. Plants in the genus produce citrus fruits ...
* ensaculin
Ensaculin (KA-672) is a drug from the coumarin family, which has been researched as a potential treatment for dementia. It acts on a number of receptor systems, being both a weak NMDA antagonist and a 5HT1A agonist. Animal studies have shown pr ...
* phenprocoumon
Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) b ...
(Marcoumar)
* PSB-SB-487
PSB-SB-487 is a coumarin derivative which is an antagonist at the former orphan receptor GPR55. Unlike older GPR55 antagonists such as O-1918, PSB-SB-487 has good selectivity over the related receptor GPR18, with an IC50 of 113nM at GPR55 vs 1250 ...
* PSB-SB-1202
PSB-SB-1202 is a coumarin derivative which is an agonist at the cannabinoid receptors CB1 and CB2, with a CB1 Ki of 32nM and a CB2 Ki of 49nM. It is also a weak antagonist at the related receptor GPR55, with an IC50 of 6350nM, but has no signif ...
* Scopoletin
Scopoletin is a coumarin. It found in the root of plants in the genus ''Scopolia'' such as ''Scopolia carniolica'' and ''Scopolia japonica'', in chicory, in ''Artemisia scoparia'', in the roots and leaves of stinging nettle ('' Urtica dioica''), i ...
can be isolated from the bark of ''Shorea pinanga''[
* ]warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
(Coumadin)
Coumarin is transformed into the natural anticoagulant dicoumarol
Dicoumarol ( INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases. ...
by a number of species of fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
.[ This occurs as the result of the production of 4-hydroxycoumarin, then further (in the presence of naturally occurring ]formaldehyde
Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
) into the actual anticoagulant dicoumarol
Dicoumarol ( INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases. ...
, a fermentation product and mycotoxin
A mycotoxin (from the Greek μύκης , "fungus" and τοξίνη , "toxin") is a toxic secondary metabolite produced by organisms of kingdom Fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' ...
. Dicoumarol was responsible for the bleeding disease known historically as " sweet clover disease" in cattle eating moldy sweet clover silage
Silage () is a type of fodder made from green foliage crops which have been preserved by fermentation to the point of acidification. It can be fed to cattle, sheep and other such ruminants (cud-chewing animals). The fermentation and storage ...
.[ In ]basic research
Basic research, also called pure research or fundamental research, is a type of scientific research with the aim of improving scientific theories for better understanding and prediction of natural or other phenomena. In contrast, applied rese ...
, preliminary evidence exists for coumarin having various biological activities, including anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
, anti-tumor
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...
, antibacterial
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
, and antifungal properties, among others.[
]
Uses
Medicine
Warfarin – a coumarin – with brand name
A brand is a name, term, design, symbol or any other feature that distinguishes one seller's good or service from those of other sellers. Brands are used in business, marketing, and advertising for recognition and, importantly, to create an ...
, ''Coumadin'', is a prescription drug used as an anticoagulant to inhibit formation of blood clots, and so is a therapy
A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis.
As a rule, each therapy has indications and contraindications. There are many different ...
for deep vein thrombosis
Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...
and pulmonary embolism
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
. It may be used to prevent recurrent blood clot formation from atrial fibrillation, thrombotic stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, and transient ischemic attack
A transient ischemic attack (TIA), commonly known as a mini-stroke, is a minor stroke whose noticeable symptoms usually end in less than an hour. TIA causes the same symptoms associated with strokes, such as weakness or numbness on one side of ...
s.[
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
Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns interstitial fl ...
.[ Both coumarin and 1,3-indandione derivatives produce a ]uricosuric Uricosuric medications (drugs) are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the kidney. ...
effect, presumably by interfering with the renal tubular reabsorption of urate
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of ...
.[
]
Rodenticide precursor
Coumarin is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals similar to dicoumarol
Dicoumarol ( INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases. ...
.[ 4-hydroxycoumarins are a type of ]vitamin K antagonist
Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonise the action of vitamin K in t ...
.[ They block the regeneration and recycling of ]vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...
.[ 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
Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, squirrels, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despi ...
s ("rat poison").[ Death occurs after a period of several days to two weeks, usually from internal hemorrhaging.
]
Laser dyes
Coumarin dyes are extensively used as gain media
The active laser medium (also called gain medium or lasing medium) is the source of optical gain (laser), gain within a laser. The gain results from the stimulated emission of photons through electronic or molecular transitions to a lower energy ...
in blue-green tunable organic dye lasers
A dye is a colored substance that chemically bonds to the substrate to which it is being applied. This distinguishes dyes from pigments which do not chemically bind to the material they color. Dye is generally applied in an aqueous solution and ...
.[ Among the various coumarin ]laser dye
Laser dyes are dyes used as laser medium in a dye laser. Laser dyes include the coumarins and the rhodamines. Coumarin dyes emit in the green region of the spectrum, whereas rhodamine dyes are used for emission in the yellow-red. The color emi ...
s are coumarins 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 in coherent ]OLED
An organic light-emitting diode (OLED or organic LED), also known as organic electroluminescent (organic EL) diode, is a light-emitting diode (LED) in which the emissive electroluminescent layer is a film of organic compound that emits light i ...
emitters.[ and as a sensitizer in older photovoltaic technologies.][
]
Perfumes and aromatizers
Coumarin is often found in artificial vanilla
Vanilla is a spice derived from orchids of the genus ''Vanilla (genus), Vanilla'', primarily obtained from pods of the Mexican species, flat-leaved vanilla (''Vanilla planifolia, V. planifolia'').
Pollination is required to make the p ...
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,[ particularly for sweet ]pipe tobacco
A tobacco pipe, often called simply a pipe, is a device specifically made to smoke tobacco. It comprises a chamber (the bowl) for the tobacco from which a thin hollow stem (shank) emerges, ending in a mouthpiece. Pipes can range from very simp ...
and certain alcoholic drinks.
Toxicity
Coumarin is moderately toxic to the liver and kidneys of rodent, with a median lethal dose (LD50) of 293 mg/kg in the rat, a low toxicity compared to related compounds. Coumarin is hepatotoxic
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...
in rats, but less so in mice. Rodents metabolize it mostly to 3,4-coumarin epoxide
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale ...
, 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, and no adverse affect has been directly measured in humans.] 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
The Occupational Safety and Health Administration'' (OSHA ) is a large regulatory agency of the United States Department of Labor that originally had federal visitorial powers to inspect and examine workplaces. Congress established the agenc ...
(OSHA) of the United States does not classify coumarin as a carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive subs ...
for humans.[
European health agencies have warned against consuming high amounts of Cinnamomum cassia, 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 about 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
''Cinnamomum verum'', called true cinnamon tree or Ceylon cinnamon tree, is a small evergreen tree belonging to the family Lauraceae, native to Sri Lanka. The inner bark of several other '' Cinnamomum'' species are also used to make cinnamon, but ...
'') 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 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 Code of Federal Regulations, CFR 189.130,][ but some natural additives containing coumarin, such as the Flavoring, flavorant sweet woodruff are allowed "in alcoholic beverages only" under 21 Code of Federal Regulations, 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.][
Minor neurological dysfunction was found in children exposed to the anticoagulants acenocoumarol or ]phenprocoumon
Phenprocoumon (marketed under the brand names Marcoumar, Marcumar and Falithrom) is a long-acting blood thinner drug to be taken by mouth, and a derivative of coumarin. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) b ...
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."[
Coumarin's presence in cigarette tobacco caused Brown & Williamson executive][ 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 Food and Drug Administration, 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 an 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 at significant levels.
]
References
[Engineering Resources – Bulk Density Chart]
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Coumarins,
Fluorescent dyes
Fuel dyes
Laser gain media
Plant toxins
Sweet-smelling chemicals