Coumarin
Overview
 
Coumarin is a fragrant chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 in the benzopyrone
Benzopyrone
Benzopyrone may refer to either of two ketone derivatives of benzopyran which constitute the core skeleton of many flavonoid compounds:*Chromone *Coumarin...

 chemical class, found in many plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...

s, notably in high concentration in the tonka bean (Dipteryx odorata), vanilla grass (Anthoxanthum odoratum
Anthoxanthum odoratum
-Introduction:Anthoxanthum odoratum, known as sweet vernal grass, holy grass, vanilla grass or buffalo grass, is a short-lived grass found wild in acidic grassland in Eurasia. It is also grown as a lawn grass and a house plant, due to its sweet scent, and can also be found on unimproved pastures...

), sweet woodruff (Galium odoratum), mullein
Mullein
The Mulleins are a genus of about 250 species of flowering plants in the figwort family . They are native to Europe and Asia, with the highest species diversity in the Mediterranean region.They are biennial or perennial plants, rarely annuals or subshrubs, growing to 0.5–3 m tall...

 (Verbascum spp.), sweet grass (Hierochloe odorata), cassia cinnamon (Cinnamomum aromaticum) and sweet clover (Fabaceae spp.).
Encyclopedia
Coumarin is a fragrant chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 in the benzopyrone
Benzopyrone
Benzopyrone may refer to either of two ketone derivatives of benzopyran which constitute the core skeleton of many flavonoid compounds:*Chromone *Coumarin...

 chemical class, found in many plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...

s, notably in high concentration in the tonka bean (Dipteryx odorata), vanilla grass (Anthoxanthum odoratum
Anthoxanthum odoratum
-Introduction:Anthoxanthum odoratum, known as sweet vernal grass, holy grass, vanilla grass or buffalo grass, is a short-lived grass found wild in acidic grassland in Eurasia. It is also grown as a lawn grass and a house plant, due to its sweet scent, and can also be found on unimproved pastures...

), sweet woodruff (Galium odoratum), mullein
Mullein
The Mulleins are a genus of about 250 species of flowering plants in the figwort family . They are native to Europe and Asia, with the highest species diversity in the Mediterranean region.They are biennial or perennial plants, rarely annuals or subshrubs, growing to 0.5–3 m tall...

 (Verbascum spp.), sweet grass (Hierochloe odorata), cassia cinnamon (Cinnamomum aromaticum) and sweet clover (Fabaceae spp.). The name comes from a French word, coumarou, for the tonka bean. It has a sweet odor, readily recognised as the scent of newly-mown hay
Hay
Hay is grass, legumes or other herbaceous plants that have been cut, dried, and stored for use as animal fodder, particularly for grazing livestock such as cattle, horses, goats, and sheep. Hay is also fed to pets such as rabbits and guinea pigs...

, and has been used in perfumes since 1882. Sweet woodruff, sweet grass and sweet clover in particular are named for their sweet smell, which is due to their high content of this substance. It 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 hepatotoxicity coumarin causes in animal models. When it occurs in high concentrations in forage plants, coumarin is a somewhat bitter-tasting appetite suppressant, and is presumed to be produced by plants as a defense chemical to discourage predation.

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
Formaldehyde
Formaldehyde is an organic compound with the formula CH2O. It is the simplest aldehyde, hence its systematic name methanal.Formaldehyde is a colorless gas with a characteristic pungent odor. It is an important precursor to many other chemical compounds, especially for polymers...

) into the actual anticoagulant dicoumarol, a fermentation product and mycotoxin
Mycotoxin
A mycotoxin is a toxic secondary metabolite produced by organisms of the fungus kingdom, commonly known as molds. The term ‘mycotoxin’ is usually reserved for the toxic chemical products produced by fungi that readily colonize crops...

. This substance was responsible for the bleeding disease known historically as "sweet clover disease" in cattle eating moldy sweet clover silage
Silage
Silage is fermented, high-moisture fodder that can be fed to ruminants or used as a biofuel feedstock for anaerobic digesters. It is fermented and stored in a process called ensiling or silaging, and is usually made from grass crops, including corn , sorghum or other cereals, using the entire...

.

Coumarin is used in the pharmaceutical industry as a precursor molecule in the synthesis of a number of synthetic anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

 pharmaceuticals similar to dicoumarol, the notable ones being warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 (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 antagonist
Vitamin K antagonist
Vitamin K antagonists are a class of anticoagulants. They reduce blood clotting by inhibiting the recycling of vitamin K epoxide back to the active reduced form of vitamin K. The term Vitamin K antagonists is a misnomer. These drugs do NOT antagonize the action of Vitamin K...

s 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
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

 modifier. Coumarin and other benzopyrone
Benzopyrone
Benzopyrone may refer to either of two ketone derivatives of benzopyran which constitute the core skeleton of many flavonoid compounds:*Chromone *Coumarin...

s, such as 5,6 benzopyrone, 1,2 benzopyrone, diosmin
Diosmin
Diosmin is a semisynthetic phlebotropic drug , a member of the flavonoid family. It is an oral phlebotropic drug used in the treatment of venous disease, i.e., chronic venous insufficiency and hemorrhoidal disease , in acute or chronic hemorrhoids, in place of rubber-band ligation, in combination...

, and others, are known to stimulate macrophages to degrade extracellular albumen, allowing faster resorption of edematous fluids.. 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 laser
Dye laser
A dye laser is a laser which uses an organic dye as the lasing medium, usually as a liquid solution. Compared to gases and most solid state lasing media, a dye can usually be used for a much wider range of wavelengths. The wide bandwidth makes them particularly suitable for tunable lasers and...

s, and as a sensitizer in older photovoltaic technologies.

Synthesis

The biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 of coumarin in plants is via hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...

, glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...

, and cyclization of cinnamic acid
Cinnamic acid
Cinnamic acid is a white crystalline organic acid, which is slightly soluble in water.It is obtained from oil of cinnamon, or from balsams such as storax. It is also found in shea butter and is the best indication of its environmental history and post-extraction conditions...

. Coumarin can be prepared in a laboratory in a Perkin reaction
Perkin reaction
The Perkin reaction is an organic reaction developed by William Henry Perkin that can be used to make cinnamic acids i.e. α-β-unsaturated aromatic acid by the aldol condensation of aromatic aldehydes and acid anhydrides in the presence of an alkali salt of the acid.Several reviews have been written....

 between salicylaldehyde
Salicylaldehyde
Salicylaldehyde is the chemical compound with the formula C6H4CHO-2-OH. Along with 3-hydroxybenzaldehyde and 4-hydroxybenzaldehyde, it is one of the three isomers of hydroxybenzaldehyde. This colorless oily liquid has a bitter almond odor at higher concentration and a characteristic buckwheat...

 and acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...

.

The Pechmann condensation
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/transesterification followed by attack of the activated...

 provides another synthesis of coumarin and its derivatives.

Biological function

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.

Derivatives

Coumarin and its derivatives are all considered phenylpropanoids.

Some naturally occurring coumarin derivatives include umbelliferone
Umbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and beta-umbelliferone, is a widespread natural product of the coumarin family. It occurs in many familiar plants from the Apiaceae family such as carrot, coriander and garden angelica, as well plants from other families such...

 (7-hydroxycoumarin), aesculetin (6,7-dihydroxycoumarin), herniarin
Herniarin
Herniarin is a methoxy analog of umbelliferone. It can be found in Herniaria glabra, Ayapana triplinervis and in species of the genus Prunus ....

 (7-methoxycoumarin), psoralen
Psoralen
Psoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone...

 and imperatorin
Imperatorin
Imperatorin is a furocoumarin and a phytochemical that has been isolated from Urena lobata L. , Angelica archangelica, Angelica dahurica, Glehnia littoralis, Saposhnikovia divaricata, Cnidium monnieri, Incarvillea younghusbandii, and Zanthoxylum americanum mill...

.

4-Phenylcoumarin is the backbone of the neoflavones, a type of neoflavonoids.

Medical use

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
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...

, antiseptic
Antiseptic
Antiseptics are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction...

, and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 (pain relief). It is also used in the treatment of asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

. Coumarin has been used in the treatment of lymphedema
Lymphedema
Lymphedema , also known as lymphatic obstruction, is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system....

.

Toxicity and use in foods, beverages, tobacco, and cosmetics

Coumarin is moderately toxic to the liver and kidneys, with a "Median Lethal Dose" of 275 mg/kg — low compared to related compounds. Although only somewhat dangerous to humans, coumarin is a potent rodenticide: Rats and other rodents metabolize it largely to 3,4-coumarin epoxide, a toxic compound that can cause internal hemorrhage and death. 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. For example, a person weighing 135 lbs or about 61 kg would have a TDI of approximately 6.1 mg of coumarin.

European health agencies have warned against consuming high amounts of cassia bark, one of the four species of cinnamon
Cinnamon
Cinnamon is a spice obtained from the inner bark of several trees from the genus Cinnamomum that is used in both sweet and savoury foods...

, because of its coumarin content.
According to the German Federal Institute for Risk Assessment, 1 kg of (cassia) cinnamon
Cinnamon
Cinnamon is a spice obtained from the inner bark of several trees from the genus Cinnamomum that is used in both sweet and savoury foods...

 powder contains approximately 2.1 to 4.4 g of coumarin. Powdered Cassia Cinnamon weighs 0.56 g/cc; 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. However, it is important to note that the German Federal Institute for Risk Assessment only cautions against high daily intakes of foods containing coumarin. Chamomile
Chamomile
Chamomile or camomile is a common name for several daisy-like plants of the family Asteraceae. These plants are best known for their ability to be made into an infusion which is commonly used to help with sleep and is often served with either honey or lemon. Because chamomile can cause uterine...

, a common herbal tea, also contains coumarin.

Coumarin is often found in tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...

 products and artificial vanilla
Vanilla
Vanilla is a flavoring derived from orchids of the genus Vanilla, primarily from the Mexican species, Flat-leaved Vanilla . The word vanilla derives from the Spanish word "", little pod...

 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. OSHA
Occupational Safety and Health Administration
The United States Occupational Safety and Health Administration is an agency of the United States Department of Labor. It was created by Congress of the United States under the Occupational Safety and Health Act, signed by President Richard M. Nixon, on December 29, 1970...

 considers this compound to be only a lung-specific carcinogen, and "not classifiable as to its carcinogenicity to humans". 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. Coumarin is currently listed by the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) among "Substances Generally Prohibited From Direct Addition or Use as Human Food", according to 21 CFR
Code of Federal Regulations
The Code of Federal Regulations is the codification of the general and permanent rules and regulations published in the Federal Register by the executive departments and agencies of the Federal Government of the United States.The CFR is published by the Office of the Federal Register, an agency...

 189.130, 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
Code of Federal Regulations
The Code of Federal Regulations is the codification of the general and permanent rules and regulations published in the Federal Register by the executive departments and agencies of the Federal Government of the United States.The CFR is published by the Office of the Federal Register, an agency...

 172.510). In Europe, such beverages are very popular, for example Maiwein (white wine with woodruff) and Żubrówka
Zubrówka
Żubrówka , also known in English as Buffalo Grass Vodka or Bison Grass Vodka, is a brand of dry, herb-flavored vodka that is distilled from rye and bottled at 40% alcohol by volume...

(vodka flavoured with bison grass). However, the coumarin content of these drinks is said to cause headaches.

Coumarin should be avoided by people with perfume allergy.

Related compounds and derivatives

Compounds derived from coumarin are also called coumarins or coumarinoids; this family includes:
  • brodifacoum
    Brodifacoum
    Brodifacoum is a highly lethal vitamin K antagonist anticoagulant poison. In recent years, it has become one of the world's most widely used pesticides...

  • bromadiolone
    Bromadiolone
    Bromadiolone is a potent rodenticide. It is a second-generation 4-hydroxycoumarin derivative, often called a "super-warfarin" for its added potency and tendency to accumulate in the liver of the poisoned organism...

  • coumafuryl
  • difenacoum
    Difenacoum
    Difenacoum is a coumarin derivative. It has anticoagulant effects and is used as a rodenticide.-Uses:Difenacoum is sold as blue-green pellets intended to be ingested by pests such as rats and mice.-Safety and toxicity:...

  • auraptene
    Auraptene
    Auraptene is a natural bioactive monoterpene coumarin ether. It was first isolated from members of the genus Citrus. Auraptene has shown a remarkable effect in the prevention of degenerative diseases. Many studies have reported the effect of auraptene as a chemopreventative agent against cancers...

  • ensaculin
    Ensaculin
    Ensaculin 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 promising nootropic effects, although efficacy in humans has yet...

  • phenprocoumon
    Phenprocoumon
    Phenprocoumon is an anticoagulant drug, a derivative of coumarin. It is a vitamin K antagonist that inhibits coagulation by blocking synthesis of coagulation factors II, VII, IX and X...

     (Marcoumar)
  • Scopoletin
    Scopoletin
    Scopoletin is a coumarin found in the root of plants in the genus Scopolia like Scopolia carniolica or Scopolia japonica, in chicory, in Artemisia scoparia, in the passion flower, in Brunfelsia, in Viburnum prunifolium or Kleinhovia hospita...

     can be isolated from the bark of Shorea pinanga
  • warfarin
    Warfarin
    Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...


Use as pesticides

Many of the above-stated compounds (to be specific, the 4-hydroxycoumarins
4-Hydroxycoumarins
4-Hydroxycoumarins are a class of vitamin K antagonist anticoagulant drug molecules derived from coumarin by adding a hydroxy group at the 4 position to obtain "4-hydroxycoumarin" , then adding a large aromatic substituent at the 3-position 4-Hydroxycoumarins are a class of vitamin K antagonist...

, sometimes loosely called coumarins) are used as anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...

 drugs and/or as rodenticides, which work by the anticoagulant mechanism. They block the regeneration and recycling of vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...

. These chemicals are sometimes also incorrectly referred to as "coumadins" rather than 4-hydroxycoumarins (Coumadin™ is a brand name for warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

).

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
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

 for poisoning by these antirodenticide 4-hydroxycoumarins such as bromadiolone
Bromadiolone
Bromadiolone is a potent rodenticide. It is a second-generation 4-hydroxycoumarin derivative, often called a "super-warfarin" for its added potency and tendency to accumulate in the liver of the poisoned organism...

. 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
Fresh frozen plasma
The term fresh frozen plasma refers to the liquid portion of human blood that has been frozen and preserved after a blood donation and will be used for blood transfusion...

 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.

See also

  • Heubad
    Heubad
    Heubad is an Austrian traditional haybath with more than 200 years of history. Bathers immersethemselves in hay which releases heat from biodecomposition. Coumarincompounds from the hay are said to have beneficial effects on thebathers' blood flow....

  • Żubrówka
    Zubrówka
    Żubrówka , also known in English as Buffalo Grass Vodka or Bison Grass Vodka, is a brand of dry, herb-flavored vodka that is distilled from rye and bottled at 40% alcohol by volume...

  • May wine
    May wine
    May wine, also known as Maitrank, Maiwein, Maibowle and Waldmeisterbowle, is the name of a German beverage that uses aromatized wine as a base . May wine is served in the spring, traditionally on the May Day holiday...

  • Sweet clover
  • Vitamin K antagonist
    Vitamin K antagonist
    Vitamin K antagonists are a class of anticoagulants. They reduce blood clotting by inhibiting the recycling of vitamin K epoxide back to the active reduced form of vitamin K. The term Vitamin K antagonists is a misnomer. These drugs do NOT antagonize the action of Vitamin K...


External links

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