View source for Malonic acid

{{Distinguish|malic acid|maleic acid}}
{{short description|Carboxylic acid with chemical formula CH2(COOH)2 }}
{{Chembox
| ImageFile = Malonsäure.svg
| ImageAlt = Skeletal formula of malonic acid
| ImageFile1 = Malonic acid molecule ball from xtal.png
| ImageAlt1 = Ball-and-stick model of the malonic acid molecule
| PIN = Propanedioic acid<ref>{{cite book |author=[[International Union of Pure and Applied Chemistry]] |date=2014 |title=Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 |publisher=[[Royal Society of Chemistry|The Royal Society of Chemistry]] |pages=746 |doi=10.1039/9781849733069 |isbn=978-0-85404-182-4}}</ref>
| OtherNames = Methanedicarboxylic acid
|Section1={{Chembox Identifiers
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 141-82-2
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 9KX7ZMG0MK
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 30794
| PubChem = 867
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 7942
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB02175
| SMILES = O=C(O)CC(O)=O
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 844
| SMILES2 = C(C(=O)O)C(=O)O
| InChI = 1/C3H4O4/c4-2(5)1-3(6)7/h1H2,(H,4,5)(H,6,7)
| InChIKey = OFOBLEOULBTSOW-UHFFFAOYAJ
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C3H4O4/c4-2(5)1-3(6)7/h1H2,(H,4,5)(H,6,7)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OFOBLEOULBTSOW-UHFFFAOYSA-N
 }}
|Section2={{Chembox Properties
| C=3 | H=4 | O=4
| MeltingPtC = 135 to 137
| MeltingPt_notes = (decomposes)
| Density = 1.619 g/cm<sup>3</sup>
| Solubility = 763 g/L
| BoilingPt = decomposes
| pKa = pK<sub>a1</sub> = 2.83<ref name="Williams">[http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf pKa Data Compiled by R. Williams (pdf; 77&nbsp;kB)] {{webarchive|url=https://web.archive.org/web/20100602043012/http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf |date=2010-06-02 }}</ref> <br />pK<sub>a2</sub> = 5.69<ref name="Williams" />
| MagSus = -46.3·10<sup>−6</sup> cm<sup>3</sup>/mol
 }}
|Section7={{Chembox Hazards
| ExternalSDS = [https://beta-static.fishersci.com/content/dam/fishersci/en_US/documents/programs/education/regulatory-documents/sds/chemicals/chemicals-m/S25416.pdf External MSDS]
 }}
|Section4={{Chembox Related
| OtherAnions = [[Malonate]]
| OtherFunction_label = [[carboxylic acid]]s
| OtherFunction = [[Oxalic acid]]<br />[[Propionic acid]]<br />[[Succinic acid]]<br />[[Fumaric acid]]
| OtherCompounds = [[Malondialdehyde]]<br />[[Dimethyl malonate]]
 }}
}}

'''Malonic acid'''  is a [[dicarboxylic acid]] with structure CH<sub>2</sub>(COOH)<sub>2</sub>. The [[ion]]ized form of malonic acid, as well as its [[ester]]s and [[salt (chemistry)|salt]]s, are known as '''malonates'''. For example, [[diethyl malonate]] is malonic acid's [[Ethyl group|diethyl]] [[ester]]. The name originates from the [[Greek language|Greek]] word μᾶλον (''malon'') meaning 'apple'.

==History==
Malonic acid<ref name=EB1911>{{cite EB1911 |wstitle=Malonic Acid|volume=17 |page=495}}</ref> is a naturally occurring substance found in many fruits and vegetables.<ref name="gsc">{{cite web |url=http://www.thegoodscentscompany.com/data/rw1030881.html |title=Propanedioic acid |website=The Good Scents Company |access-date=2020-10-07 }}</ref> There is a suggestion that [[citrus]] fruits produced in [[organic farming]] contain higher levels of malonic acid than fruits produced in conventional agriculture.<ref>{{Cite journal| vauthors = Ha CN, Ngoc ND, Ngoc CP, Trung DD, Quang BN |date=2012|url=https://www.researchgate.net/publication/216429503|journal=Acta Horticulturae|volume=933|issue=933|pages=601–606|doi=10.17660/actahortic.2012.933.78|issn=0567-7572|hdl=10400.1/2790|title=Organic Acids Concentration in Citrus Juice from Conventional Versus Organic Farming|hdl-access=free}}</ref>

Malonic acid was first prepared in 1858 by the French chemist [[Victor Dessaignes]] via the oxidation of [[malic acid]].<ref name=EB1911/><ref>{{cite journal| vauthors = Dessaignes V |year=1858| url= http://gallica.bnf.fr/ark:/12148/bpt6k3004t/f76.image.langEN |title=Note sur un acide obtenu par l'oxydation de l'acide malique"] (Note on an acid obtained by oxidation of malic acid)| journal=Comptes rendus| volume=47|pages= 76–79}}</ref>

[[Hermann Kolbe]] and [[Hugo Müller]] independently discovered how to synthesize malonic acid from [[propionic acid]], and decided to publish their results back-to-back in the Chemical Society journal in 1864.<ref name=":0">{{Cite web |title=The Quiet Revolution |url=https://publishing.cdlib.org/ucpressebooks/view?docId=ft5g500723&chunk.id=d0e6983&toc.depth=100&toc.id=d0e6089&brand=ucpress/ |access-date=2025-01-26 |website=publishing.cdlib.org}}</ref> This led to priority dispute with [[Hans Hübner]] and [[Maxwell Simpson]] who had independently published preliminary results on related reactions.<ref name=":0" />

==Structure and preparation==
The structure has been determined by X-ray [[crystallography]]<ref>{{cite journal |doi=10.1016/S0022-2860(99)00293-8 |title=An experimental charge density study of aliphatic dicarboxylic acids |year=2000 | vauthors = Gopalan RS, Kumaradhas P, Kulkarni GU, Rao CN |journal=Journal of Molecular Structure |volume=521 |issue=1–3 |pages=97–106 |bibcode=2000JMoSt.521...97S }}</ref> and extensive property data including for condensed phase thermochemistry are available from the [[National Institute of Standards and Technology]].<ref>{{cite web|url=https://webbook.nist.gov/cgi/inchi/InChI%3D1S/C3H4O4/c4-2(5)1-3(6)7/h1H2%2C(H%2C4%2C5)(H%2C6%2C7) |title=Propanedioic acid |author=NIST Chemistry WebBook}}</ref>
A classical preparation of malonic acid starts from [[chloroacetic acid]]:<ref>{{OrgSynth|title=Malonic acid| vauthors = Weiner N |collvol=2|collvolpages=376|prep=cv2p0376}}</ref>

[[Image:Synthesis of malonic acid.png|thumb|center|650px|Preparation of malonic acid from [[chloroacetic acid]].]]

[[Sodium carbonate]] generates the sodium [[salt (chemistry)|salt]], which is then reacted with [[sodium cyanide]] to provide the sodium salt of [[cyanoacetic acid]] via a [[nucleophilic substitution]]. The [[nitrile]] group can be [[hydrolysis|hydrolyzed]] with [[sodium hydroxide]] to sodium malonate, and acidification affords malonic acid. Industrially, however, malonic acid is produced by hydrolysis of [[dimethyl malonate]] or [[diethyl malonate]].<ref>{{cite patent |country=US |number=2373011 |status=patent |gdate=1945-04-03 |fdate=1942-09-22 | inventor = Britton EC, Ezra M |title=Production of malonic acid |assign1=Dow Chemical Co |class=}}</ref> It has also been produced through [[fermentation]] of [[glucose]].<ref>{{cite patent | title = Recombinant host cells for the production of malonate. | country = US | number = 20200172941| inventor =  Dietrich JA | assign1 = Lygos Inc }}</ref>

==Reactions==
Malonic acid reacts as a typical carboxylic acid forming [[amide]], ester,  and [[acyl chloride|chloride]] derivatives.<ref>{{cite book |doi=10.1002/0471740039.vec1571 |chapter=Malonic Acid and Derivatives |title=Van Nostrand's Encyclopedia of Chemistry |year=2005 |isbn=0471740039 | veditors = Pollak P, Romeder G |last1=Pollak |first1=Peter |last2=Romeder |first2=Gérard }}</ref> [[Malonic anhydride]] can be used as an intermediate to mono-ester or amide derivatives, while [[malonyl chloride]] is most useful to obtain diesters or diamides. 
In a well-known reaction, malonic acid [[condensation reaction|condenses]] with [[urea]] to form [[barbituric acid]]. Malonic acid may also be condensed with [[acetone]] to form [[Meldrum's acid]], a versatile intermediate in further transformations. The esters of malonic acid are also used as a <sup>−</sup>CH<sub>2</sub>COOH [[synthon]] in the [[malonic ester synthesis]].

===Briggs–Rauscher reaction===
Malonic acid is a key component in the [[Briggs–Rauscher reaction]], the classic example of an [[Chemical oscillator|oscillating chemical reaction]].<ref>{{cite journal | vauthors = Csepei LI, Bolla C |title=The Effect of Salicylic Acid on the Briggs-Rauscher Oscillating Reaction |url= http://chem.ubbcluj.ro/~studiachemia/issues/chemia2006_2015/Chemia2011_1.pdf |journal=Studia UBB Chemia|volume=1|pages=285–300}}</ref>

===Knoevenagel condensation===
Malonic acid is used to prepare a,b-unsaturated carboxylic acids by condensation and decarboxylation.  [[Cinnamic acid]]s are prepared in this way:
:{{chem2|CH2(CO2H)2  +  ArCHO  ->  ArCH\dCHCO2H  +  H2O  +  CO2}}
In this, the so-called [[Knoevenagel condensation]], malonic acid condenses with the [[carbonyl]] group of an [[aldehyde]] or [[ketone]], followed by a [[decarboxylation]].
[[Image:KnoevenagelGeneral.png|thumb|center|400px|Z=COOH (malonic acid) or Z=COOR' (malonate ester)]]
When malonic acid is condensed in hot pyridine, the condensation is accompanied by [[decarboxylation]], the so-called [[Doebner modification]].<ref>{{OrgSynth |first1= Peter J. |last1= Jessup |first2= C. Bruce |last2= Petty |first3= Jan |last3= Roos |first4= Larry E. |last4= Overman |author-link4= Larry E. Overman | title = 1-''N''-Acylamino-1,3-dienes from 2,4-Pentadienoic Acids by the Curtius Rearrangement: benzyl ''trans''-1,3-butadiene-1-carbamate | volume = 59 | page = 1 | year = 1979 | doi = 10.15227/orgsyn.059.0001}}</ref><ref>{{cite journal |doi=10.15227/orgsyn.024.0092 |title=Sorbic Acid |journal=Organic Syntheses |date=1944 |volume=24 |page=92|first1=C. F. H. |last1=Allen|first2=J. |last2=VanAllan }}</ref><ref>{{cite journal| vauthors = Doebner O |title=Ueber die der Sorbinsäure homologen, ungesättigten Säuren mit zwei Doppelbindungen|journal=Berichte der Deutschen Chemischen Gesellschaft |year=1902|volume=35|pages=1136–36|doi=10.1002/cber.190203501187 |url = https://zenodo.org/record/1426042}}</ref>
[[Image:Doebner modification.png|center|thumb|600px|The Doebner modification of the Knoevenagel condensation.]]{{clear}}

===Preparation of carbon suboxide===
Malonic acid does not readily form an [[acid anhydride|anhydride]], dehydration gives [[carbon suboxide]] instead:
:{{chem2|CH2(CO2H)2  ->  O\dC\dC\dC\dO  +  2 H2O}}
The transformation is achieved by warming a dry mixture of [[phosphorus pentoxide]] ({{Chem2|P4O10}}) and malonic acid.<ref>{{cite journal|author-link=Otto Diels|vauthors=Diels O, Wolf B|year=1906|title=Ueber das Kohlensuboxyd. I|url=https://zenodo.org/record/1426170|journal=[[Chemische Berichte|Chem. Ber.]]|volume=39|pages=689–697|doi=10.1002/cber.190603901103}}</ref> It reacts in a similar way to [[malonic anhydride]], forming malonates.<ref>{{cite journal|vauthors=Perks HM, Liebman JF|year=2000|title=Paradigms and Paradoxes: Aspects of the Energetics of Carboxylic Acids and Their Anhydrides|journal=Structural Chemistry|volume=11|issue=4|pages=265–269|doi=10.1023/A:1009270411806|s2cid=92816468 }}</ref>

==Applications==
Malonic acid is a precursor to specialty [[polyester]]s. It can be converted into [[1,3-propanediol]] for use in polyesters and polymers (whose usefulness is unclear though). It can also be a component in [[Alkyd|alkyd resins]], which are used in a number of coatings applications for protecting against damage caused by UV light, oxidation, and corrosion. One application of malonic acid is in the coatings industry as a crosslinker for low-temperature cure powder coatings, which are becoming increasingly valuable for heat sensitive substrates and a desire to speed up the coatings process.<ref>{{cite book | vauthors = Facke T, Subramanian R, Dvorchak M, Feng S | chapter = Diethylmalonate blocked isocyanate as crosslinkers for low temperature cure powder coatings. | title = Proceedings of 31st International Waterborene, High-Solids and Powder Coating Symposium | date = February 2004 }}</ref> The global coatings market for automobiles was estimated to be $18.59 billion in 2014 with projected combined annual growth rate of 5.1% through 2022.<ref>{{cite report | vauthors = James S | title = Global Automotive Coatings Market. 2015 Grand View Research Market Report }}</ref>

It is used in a number of manufacturing processes as a high value specialty chemical including the [[Electronics manufacturing services|electronics]] industry, flavors and fragrances industry,<ref name=gsc/> specialty solvents, polymer crosslinking, and pharmaceutical industry. In 2004, annual global production of malonic acid and related diesters was over 20,000 metric tons.<ref>{{Cite web|url = http://www.inchem.org/documents/sids/sids/malonates.pdf|title = Malonic acid diesters|website = Inchem|publisher = UNEP Publications|access-date = 2015-12-11|archive-date = 2017-11-18|archive-url = https://web.archive.org/web/20171118040007/http://www.inchem.org/documents/sids/sids/malonates.pdf|url-status = dead}}</ref> Potential growth of these markets could result from advances in industrial biotechnology that seeks to displace petroleum-based chemicals in industrial applications.

In 2004, malonic acid was listed by the US Department of Energy as one of the top 30 chemicals to be produced from biomass.<ref>{{cite report | vauthors = Werpy TA, Holladay JE, White JF | veditors = Werpy TA, Petersen G |date=August 2004 |title=Top Value Added Chemicals From Biomass. Volume I: Results of Screening for Potential Candidates from Sugars and Synthesis Gas |url=https://www.pnnl.gov/main/publications/external/technical_reports/PNNL-14808.pdf |publisher=US Department of Energy |doi=10.2172/926125 |doi-access=free |osti=926125 |osti-access=free }}</ref>

In food and drug applications, malonic acid can be used to control acidity, either as an excipient in pharmaceutical formulation or natural preservative additive for foods.<ref name=gsc />

Malonic acid is used as a building block chemical to produce numerous valuable compounds,<ref>Hildbrand, S.; Pollak, P. Malonic Acid & Derivatives. March 15, 2001. Ullmann's Encyclopedia of Industrial Chemistry</ref> including the flavor and fragrance compounds gamma-nonalactone, [[cinnamic acid]], and the pharmaceutical compound [[valproate]].

Malonic acid (up to 37.5% w/w) has been used to cross-link corn and potato starches to produce a biodegradable thermoplastic; the process is performed in water using non-toxic catalysts.<ref>{{cite patent | inventor = Netravali AN, Dastidar TG | assign1 = Cornell University | title = Crosslinked native and waxy starch resin compositions and processes for their manufacture. | country = US | number = 9790350 }}</ref><ref name="pmid22944425">{{cite journal | vauthors = Ghosh Dastidar T, Netravali AN | title = 'Green' crosslinking of native starches with malonic acid and their properties | journal = Carbohydrate Polymers | volume = 90 | issue = 4 | pages = 1620–8 | date = November 2012 | pmid = 22944425 | doi = 10.1016/j.carbpol.2012.07.041 }}</ref> Starch-based polymers comprised 38% of the global biodegradable polymers market in 2014 with food packaging, foam packaging, and compost bags as the largest end-use segments.<ref>{{cite report | title = Biodegradable Polymers: Chemical Economics Handbook | date = June 2021 | url = https://ihsmarkit.com/products/biodegradable-polymers-chemical-economics-handbook.html | publisher = IHS Markit }}</ref>

[[Eastman Chemical Company|Eastman]] Kodak company and others use malonic acid and derivatives as a surgical adhesive.<ref>{{cite patent | inventor = Hawkins G, Fassett D | title = Surgical Adhesive Compositions | country = US | number = 3591676 }}</ref>

== Pathology ==
If elevated malonic acid levels are accompanied by elevated [[methylmalonic acid]] levels, this may indicate the metabolic disease [[combined malonic and methylmalonic aciduria]] (CMAMMA). By calculating the malonic acid to methylmalonic acid ratio in blood plasma, CMAMMA can be distinguished from classic [[methylmalonic acidemia]].<ref>{{cite journal | vauthors = de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, van Gassen KL, van Hasselt PM | display-authors = 6 | title = A New Approach for Fast Metabolic Diagnostics in CMAMMA | journal = JIMD Reports | volume = 30 | pages = 15–22 | date = 2016 | pmid = 26915364 | pmc = 5110436 | doi = 10.1007/8904_2016_531 | isbn = 978-3-662-53681-0 | veditors = Morava E, Baumgartner M, Patterson M, Rahman S  | publisher = Springer | place = Berlin, Heidelberg }}</ref>

==Biochemistry==
Malonic acid is the precursor in [[Fatty acid synthesis#Mitochondrial fatty acid synthesis|mitochondrial fatty acid synthesis]] (mtFASII), in which it is converted to [[malonyl-CoA]] by [[ACSF3|acyl-CoA synthetase family member 3]] (ACSF3).<ref>{{Cite journal |last1=Witkowski |first1=Andrzej |last2=Thweatt |first2=Jennifer |last3=Smith |first3=Stuart |date=2011 |title=Mammalian ACSF3 Protein Is a Malonyl-CoA Synthetase That Supplies the Chain Extender Units for Mitochondrial Fatty Acid Synthesis |journal=Journal of Biological Chemistry |language=en |volume=286 |issue=39 |pages=33729–33736 |doi=10.1074/jbc.M111.291591 |doi-access=free |pmc=3190830 |pmid=21846720}}</ref><ref>{{Cite journal |last1=Bowman |first1=Caitlyn E. |last2=Rodriguez |first2=Susana |last3=Selen Alpergin |first3=Ebru S. |last4=Acoba |first4=Michelle G. |last5=Zhao |first5=Liang |last6=Hartung |first6=Thomas |last7=Claypool |first7=Steven M. |last8=Watkins |first8=Paul A. |last9=Wolfgang |first9=Michael J. |date=2017 |title=The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency |journal=Cell Chemical Biology |language=en |volume=24 |issue=6 |pages=673–684.e4 |doi=10.1016/j.chembiol.2017.04.009 |pmc=5482780 |pmid=28479296}}</ref> 

Additionally, the [[coenzyme A]] derivative of malonate, malonyl-CoA, is an important precursor in [[Cytosol|cytosolic]] fatty acid biosynthesis along with [[acetyl CoA]]. Malonyl CoA is formed there from acetyl CoA by the action of [[acetyl-CoA carboxylase]], and the malonate is transferred to an [[acyl carrier protein]] to be added to a fatty acid chain.

Malonic acid is the classic example of a [[Competitive inhibition|competitive inhibitor]] of the [[enzyme]] [[succinate dehydrogenase]] (complex II), in the [[oxidative phosphorylation|respiratory electron transport chain]].<ref name="pardee_potter">{{cite journal | vauthors = Pardee AB, Potter VR | title = Malonate inhibition of oxidations in the Krebs tricarboxylic acid cycle | journal = The Journal of Biological Chemistry | volume = 178 | issue = 1 | pages = 241–250 | date = March 1949 | pmid = 18112108 | doi = 10.1016/S0021-9258(18)56954-4 | doi-access = free }}</ref> It binds to the [[active site]] of the enzyme without reacting, competing with the usual substrate [[Succinic acid|succinate]] but lacking the −CH<sub>2</sub>CH<sub>2</sub>− group required for dehydrogenation.  This observation  was used to deduce the structure of the active site in succinate dehydrogenase. Inhibition of this enzyme decreases cellular respiration.<ref>{{cite journal | vauthors = Potter VR, Dubois KP | title = Studies on the Mechanism of Hydrogen Transport in Animal Tissues : VI. Inhibitor Studies with Succinic Dehydrogenase | journal = The Journal of General Physiology | volume = 26 | issue = 4 | pages = 391–404 | date = March 1943 | pmid = 19873352 | pmc = 2142566 | doi = 10.1085/jgp.26.4.391 }}</ref><ref>{{cite journal |doi=10.1016/0926-6569(64)90182-8 |title=Studies on succinate dehydrogenase |year=1964 | vauthors = Dervartanian DV, Veeger C |journal=Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects |volume=92 |issue=2 |pages=233–247 }}</ref> Since malonic acid is a natural component of many foods, it is present in mammals including humans.<ref>{{cite web |url=https://hmdb.ca/metabolites/HMDB0000691 |title=Metabocard for Malonic acid |website= Human Metabolome Database |access-date=2020-10-06 |date=2020-03-13 }}</ref>

==Salts and esters==
[[Image:Malonate.png|thumb|Chemical structure of the malonate [[dianion]].]]
Malonic acid is [[Acid#Polyprotic_acids|diprotic]]; that is, it can donate two [[Hydron (chemistry)|protons]] per molecule. Its first [[Dissociation_constant#Acid–base_reactions|<math chem>pK_a</math>]] is 2.8 and the second is 5.7.<ref name=Williams /> Thus the '''malonate''' [[ion]] can be {{chem2|HOOCCH2COO(-)}} or {{chem2|CH2(COO)2(2-)}}. Malonate or '''propanedioate''' [[chemical compound|compounds]] include [[salt (chemistry)|salts]] and [[ester]]s of malonic acid, such as
*[[Diethyl malonate]]
*[[Dimethyl malonate]]
*[[Disodium malonate]]
*[[Malonyl-CoA]]

== References ==
{{reflist}}

== External links ==
*[http://www.aim.env.uea.ac.uk/aim/accent2/inputpage.php Calculator: Water and solute activities in aqueous malonic acid]

{{Navbox linear saturated dicarboxylic acids}}

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[[Category:Dicarboxylic acids]]