View source for Fumaric acid

{{Short description|Organic compound}}
{{chembox
| Watchedfields  = changed
| verifiedrevid  = 443828437
| Name           = Fumaric acid
| ImageFile      = Fumarsäure.svg
| ImageClass     = skin-invert
| ImageSize      = 
| ImageName      = Skeletal formula of fumaric acid
| ImageFile1     = Fumaric-acid-3D-balls.png
| ImageClass1 = bg-transparent  
| ImageSize1     = 
| ImageName1     = Ball-and-stick model of the fumaric acid molecule
| PIN            = (2''E'')-But-2-enedioic acid<!-- Nomenclature of Organic Chemistry – IUPAC Recommendations and Preferred Names 2013 (Blue Book) -->
| OtherNames     = {{ubl
 | Fumaric acid
 | ''trans''-1,2-Ethylenedicarboxylic acid
 | 2-Butenedioic acid
 | ''trans''-Butenedioic acid
 | Allomaleic acid
 | Boletic acid
 | Donitic acid
 | Lichenic acid
 }}
| Section1       = {{Chembox Identifiers
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB04299
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 18012
| SMILES = C(=C/C(=O)O)\C(=O)O
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10197150
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 503160
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 88XHZ13131
| Gmelin = 49855
| Beilstein = 605763
| PubChem = 444972
| RTECS = LS9625000
| UNNumber = 9126
| InChI = 1/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
| InChIKey = VZCYOOQTPOCHFL-OWOJBTEDBF
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = VZCYOOQTPOCHFL-OWOJBTEDSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 110-17-8
| EINECS = 203-743-0
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C00122
  }}
| Section2       = {{Chembox Properties
| C=4 | H=4 | O=4
| Dipole = non zero
| Appearance = White solid
| Density = 1.635{{nbsp}}g/cm<sup>3</sup>
| Solubility = 6.3{{nbsp}}g/L at 25{{nbsp}}°C<ref>{{GESTIS|ZVG=33440}}</ref>
| SolubleOther = 
| Solvent = Ethanol
| MeltingPtC = 287 
| MeltingPt_notes = (decomposes)<ref>
 {{cite web
 | url=https://pubchem.ncbi.nlm.nih.gov/compound/fumaric_acid|title=Fumaric acid
 | last=Pubchem
 | website=pubchem.ncbi.nlm.nih.gov
 }}</ref>
| pKa = {{nowrap|p''k''<sub>a1</sub> {{=}} 3.03}}, {{nowrap|p''k''<sub>a2</sub> {{=}} 4.44}} (15{{nbsp}}°C, cis isomer)
| MagSus = −49.11·10<sup>−6</sup>{{nbsp}}cm<sup>3</sup>/mol
  }}
| Section7       = {{Chembox Hazards
| NFPA-H = 2
| NFPA-F = 1
| NFPA-R = 0
| NFPA-S = 
| AutoignitionPtC = 375
| GHSPictograms = {{GHS07}}
| GHSSignalWord = Warning
| HPhrases = {{H-phrases|319}}
| PPhrases = {{P-phrases|264|280|305+351+338|313}}
  }}
| Section6       = {{Chembox Pharmacology
| ATCCode_prefix = D05
| ATCCode_suffix = AX01
}}
| Section8       = {{Chembox Related
| OtherFunction_label = [[carboxylic acid]]s
| OtherFunction = {{ubl
 | [[Maleic acid]]
 | [[Succinic acid]]
 | [[Crotonic acid]]
 }}
| OtherCompounds = {{ubl
 | [[Fumaryl chloride]]
 | Fumaronitrile
 | [[Dimethyl fumarate]]
 | [[Ammonium fumarate]]
 | [[Iron(II) fumarate]]
 }}
  }}
}}

'''Fumaric acid''' or '''''trans''-butenedioic acid''' is an [[organic compound]] with the formula HO<sub>2</sub>CCH=CHCO<sub>2</sub>H. A white solid, fumaric acid occurs widely in nature.  It has a [[fruit]]-like [[taste]] and has been used as a [[food additive]]. Its [[E number]] is E297.<ref name=Ullmann>{{cite book|doi=10.1002/14356007.a16_053|chapter=Maleic and Fumaric Acids|title=Ullmann's Encyclopedia of Industrial Chemistry|year=2000|last1=Lohbeck|first1=Kurt|last2=Haferkorn|first2=Herbert|last3=Fuhrmann|first3=Werner|last4=Fedtke|first4=Norbert|isbn=3-527-30673-0}}
</ref> The [[salt (chemistry)|salts]] and [[ester]]s are known as '''fumarates'''.  Fumarate can also refer to the {{chem|C|4|H|2|O|4|2−}} ion (in solution). Fumaric acid is the ''trans'' [[Cis–trans isomerism|isomer]] of butenedioic acid, while [[maleic acid]] is the ''cis'' isomer.

==Biosynthesis and occurrence==
It is produced in [[eukaryotic]] organisms from [[succinate]] in complex 2 of the electron transport chain via the [[enzyme]] [[succinate dehydrogenase]]. 

Fumaric acid is found in [[fumitory]] (''Fumaria officinalis''), [[bolete]] [[mushroom]]s (specifically ''Boletus fomentarius var. pseudo-igniarius''), [[lichen]], and [[Iceland moss]].

Fumarate is an [[Reaction intermediate|intermediate]] in the [[citric acid cycle]] used by [[cell (biology)|cells]] to produce energy in the form of [[adenosine triphosphate]] (ATP) from [[food]].  It is formed by the [[oxidation]] of [[succinate]] by the enzyme [[succinate dehydrogenase]].  Fumarate is then converted by the enzyme [[fumarase]] to [[malic acid|malate]].

Human skin naturally produces fumaric acid when exposed to [[sunlight]].<ref>[https://books.google.com/books?id=tWJLUWT06BEC&dq=Human+skin+fumaric+acid&pg=PA159 Active Ingredients Used in Cosmetics: Safety Survey], Council of Europe. Committee of Experts on Cosmetic Products</ref><ref>{{Cite news|url=http://healthyeating.sfgate.com/fumaric-acid-foods-12220.html|archive-url=https://web.archive.org/web/20141004041648/http://healthyeating.sfgate.com/fumaric-acid-foods-12220.html|url-status=dead|archive-date=October 4, 2014|title=Fumaric Acid Foods|access-date=2018-04-22|language=en}}</ref>

Fumarate is also a product of the [[urea cycle]].

{{TCACycle_WP78|highlight=Fumaric_acid}}

==Uses==

===Food===
Fumaric acid has been used as a food acidulant since 1946. It is approved for use as a food additive in the EU,<ref>UK Food Standards Agency: {{cite web |url=http://www.food.gov.uk/safereating/chemsafe/additivesbranch/enumberlist |title=Current EU approved additives and their E Numbers |access-date=2011-10-27}}</ref> USA<ref>US Food and Drug Administration: {{cite web |url=https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm#ftnT |archive-url=https://web.archive.org/web/20100108135705/http://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/ucm191033.htm#ftnT |url-status=dead |archive-date=January 8, 2010 |title=Listing of Food Additives Status Part II |website=[[Food and Drug Administration]] |access-date=2011-10-27}}</ref> and Australia and New Zealand.<ref>Australia New Zealand Food Standards Code{{cite web |url=http://www.comlaw.gov.au/Details/F2011C00827 |title=Standard 1.2.4 - Labelling of ingredients |date=8 September 2011 |access-date=2011-10-27}}</ref> As a [[food additive]], it is used as an [[acidity regulator]] and can be denoted by the [[E number]] E297. It is generally used in beverages and [[baking powder]]s for which requirements are placed on purity. Fumaric acid is used in the making of [[wheat tortilla]]s as a food preservative and as the acid in leavening.<ref>{{Cite news|url=https://thechemco.com/chemical/fumaric-acid/|title=Fumaric Acid - The Chemical Company|work=The Chemical Company|access-date=2018-04-22|language=en-US}}</ref> It is generally used as a substitute for [[tartaric acid]] and occasionally in place of [[citric acid]], at a rate of 1&nbsp;g of fumaric acid to every ~1.5&nbsp;g of citric acid, in order to add [[Taste#Sourness|sourness]], similarly to the way [[malic acid]] is used. As well as being a component of some artificial vinegar flavors, such as "Salt and Vinegar" flavored potato chips,<ref>{{cite web|url=http://www.seriouseats.com/2012/09/the-best-salt-and-vinegar-chips-tasting-brands-most-acidic.html|title=The Science Behind Salt and Vinegar Chips|first=Serious|last=Eats|website=www.seriouseats.com}}</ref> it is also used as a [[flocculation|coagulant]] in stove-top pudding mixes.

The European Commission Scientific Committee on Animal Nutrition, part of [[Directorate-General for Health and Food Safety|DG Health]], found in 2014 that fumaric acid is "practically non-toxic" but high doses are probably [[Nephrotoxicity|nephrotoxic]] after long-term use.<ref name=ecscfa>European Commission: {{cite web |url=http://ec.europa.eu/food/fs/sc/scan/out112_en.pdf |title=European Commission Report of the Scientific Committee on Animal Nutrition on the Safety of Fumaric Acid |access-date=2014-03-07}}</ref>

===Medicine===
Fumaric acid was developed as a medicine to treat the autoimmune condition [[psoriasis]] in the 1950s in Germany as a tablet containing 3 [[ester]]s, primarily [[dimethyl fumarate]], and marketed as Fumaderm by [[Biogen]] Idec in Europe. Biogen would later go on to develop the main ester, dimethyl fumarate, as a treatment for [[multiple sclerosis]]. 

In patients with relapsing-remitting multiple sclerosis, the ester dimethyl fumarate (BG-12, Biogen) significantly reduced relapse and disability progression in a phase 3 trial. It activates the [[Nrf2]] antioxidant response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress.<ref name="Gold">{{cite journal| title = Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis| journal = N Engl J Med | date = September 20, 2012|author1=Gold R. |author2=Kappos L. |author3=Arnold D.L. | s2cid = 6614191 | volume =367| issue =12| pages =1098–1107| doi =10.1056/NEJMoa1114287| pmid =22992073| display-authors=etal| doi-access =free| hdl =2078.1/124401| hdl-access =free}}</ref>

===Other uses===
Fumaric acid is used in the manufacture of [[polyester]] [[resin]]s and [[polyhydric alcohol]]s and as a [[mordant]] for dyes.

Fumaric acid can be used to make [[6-methylcoumarin]].<ref>{{cite journal | last1=Thompson | first1=T. J. | last2=Edee | first2=R. Herbert | title=Preparation of 6-Methylcoumarin and ITS Derivatives | journal=Journal of the American Chemical Society | volume=47 | issue=10 | date=1925 | issn=0002-7863 | doi=10.1021/ja01687a019 | pages=2556–2559 | bibcode=1925JAChS..47.2556T }}</ref>

When fumaric acid is added to their feed, lambs produce up to 70% less methane during digestion.<ref>{{Cite news | url = https://m.phys.org/news/2008-03-scientists-cow-flatulence.html | title = Scientists look to cut cow flatulence | date = March 21, 2008 | publisher = phys.org }}</ref>
==Synthesis==
Fumaric acid is produced based on [[catalyst|catalytic]] [[isomerisation]] of [[maleic acid]]  in aqueous solutions at low p''H''.  It precipitates from the reaction solution.  Maleic acid is accessible in large volumes as a [[hydrolysis]] product of maleic anhydride, produced by catalytic oxidation of [[benzene]] or [[butane]].<ref name=Ullmann/>
===Historic and laboratory routes===
Fumaric acid was first prepared from [[succinic acid]].<ref>Volhard, J. "Darstellung von Maleïnsäureanhydrid" Justus Liebig's Annalen der Chemie 1892, volume 268, page 255-6. {{doi|10.1002/jlac.18922680108}}</ref>  A traditional synthesis involves oxidation of [[furfural]] (from the processing of [[maize]]) using [[sodium chlorate|chlorate]] in the presence of a [[vanadium]]-based [[catalyst]].<ref>{{cite journal|doi=10.15227/orgsyn.011.0046 |title=Fumaric Acid |journal=Organic Syntheses |date=1931 |volume=11 |page=46|author=Nicholas A. Milas }}</ref>

==Reactions==
The chemical properties of fumaric acid can be anticipated from its component [[functional group]]s.  This weak acid forms a di[[ester]], it undergoes [[bromination]] across the [[alkene|double bond]],<ref>{{cite journal |doi=10.15227/orgsyn.018.0017 |title=α,β-Dibromosuccinic Acid |journal=Organic Syntheses |date=1938 |volume=18 |page=17|author=Herbert S. Rhinesmith }}</ref> and it is a good [[dienophile]].
<!--Fumaric acid does not combust in a [[bomb calorimeter]] under conditions where [[maleic acid]] deflagrates smoothly.  For teaching experiments designed to measure the difference in energy between the cis- and trans- isomers, a measured quantity of carbon can be ground with the subject compound and the enthalpy of combustion computed by difference.-->

==Safety==
The oral {{LD50}} is 10 g/kg.<ref name=Ullmann/>

==See also==
*[[Citric acid cycle]] (TCA cycle)
*[[Fumarate reductase]]
*[[Photosynthesis]]
*[[Maleic acid]], the ''cis'' isomer of fumaric acid
*[[Succinic acid]]

==References==
<references/>

==External links==
*[http://www.inchem.org/documents/icsc/icsc/eics1173.htm International Chemical Safety Card 1173]

{{citric acid cycle}}
{{Urea cycle}}
{{Antipsoriatics}}
{{Amino acid metabolism intermediates}}

{{Authority control}}

[[Category:Dicarboxylic acids]]
[[Category:Food additives]]
[[Category:Food acidity regulators]]
[[Category:Fumarates| ]]
[[Category:Urea cycle]]
[[Category:Citric acid cycle compounds]]
[[Category:Nephrotoxins]]
[[Category:E-number additives]]
[[Category:Alkene derivatives]]
[[Category:Metabolic intermediates]]
[[Category:Biomolecules]]
[[Category:Carboxylic acid-based monomers]]