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 | ImageClass = skin-invert | ImageFile1 = Malonic acid molecule ball from xtal.png | ImageAlt1 = Ball-and-stick model of the malonic acid molecule | ImageClass1 = bg-transparent | 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=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/cm3 | Solubility = 763 g/L | BoilingPt = decomposes | pKa = pKa1 = 2.83<ref name="Williams">[http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf pKa Data Compiled by R. Williams (pdf; 77 kB)] {{webarchive|url=https://web.archive.org/web/20100602043012/http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf |date=2010-06-02 }}</ref> pKa2 = 5.69<ref name="Williams" /> | MagSus = −46.3·10−6 cm3/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 acids | OtherFunction = Oxalic acid Propionic acid Succinic acid Fumaric acid | OtherCompounds = Malondialdehyde Dimethyl malonate }} }}

'''Malonic acid''' is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as '''malonates'''. For example, diethyl malonate is malonic acid's diethyl ester. The name originates from the 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, which is then reacted with sodium cyanide to provide the sodium salt of cyanoacetic acid via a nucleophilic substitution. The nitrile group can be 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 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 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 −CH2COOH synthon in the malonic ester synthesis.

===Oscillating reactions=== Malonic acid is a key component in both the Briggs–Rauscher reaction and the Belousov-Zhabotinsky reaction, two classic examples of an 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 acids 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. 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> center|thumb|600px|The Doebner modification of the Knoevenagel condensation.{{clear}}

===Preparation of carbon suboxide=== Malonic acid does not readily form an 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=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 polyesters. 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 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 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 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 classic example of a competitive inhibitor of the enzyme succinate dehydrogenase (complex II), in the respiratory electron transport chain.<ref name="pardee_potter">{{cite journal |vauthors=Pardee AB, Potter VR |date=March 1949 |title=Malonate inhibition of oxidations in the Krebs tricarboxylic acid cycle |journal=The Journal of Biological Chemistry |volume=178 |issue=1 |pages=241–250 |doi=10.1016/S0021-9258(18)56954-4 |pmid=18112108 |doi-access=free}}</ref> It binds to the active site of the enzyme without reacting, competing with the usual substrate succinate but lacking the −CH2CH2− 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 |date=March 1943 |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 |doi=10.1085/jgp.26.4.391 |pmc=2142566 |pmid=19873352}}</ref><ref>{{cite journal |vauthors=Dervartanian DV, Veeger C |year=1964 |title=Studies on succinate dehydrogenase |journal=Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects |volume=92 |issue=2 |pages=233–247 |doi=10.1016/0926-6569(64)90182-8}}</ref> Since malonic acid is a natural component of many foods, it is present in mammals including humans.<ref>{{cite web |date=2020-03-13 |title=Metabocard for Malonic acid |url=https://hmdb.ca/metabolites/HMDB0000691 |access-date=2020-10-06 |website=Human Metabolome Database}}</ref>

In mammals, acyl-CoA synthetase family member 3 (ACSF3) detoxifies malonic acid by converting it into malonyl-CoA.<ref name=":1">{{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> Along with malonyl-CoA derived from acetyl-CoA by mitochondrial acetyl-CoA carboxylase 1 (mtACC1), this contributes to the mitochondrial malonyl-CoA pool, which is required for lysine malonylation and mitochondrial fatty acid synthesis (mtFAS).<ref>{{Cite journal |last1=Monteuuis |first1=Geoffray |last2=Suomi |first2=Fumi |last3=Kerätär |first3=Juha M. |last4=Masud |first4=Ali J. |last5=Kastaniotis |first5=Alexander J. |date=2017-11-15 |title=A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3 |url=https://portlandpress.com/biochemj/article/474/22/3783/49536/A-conserved-mammalian-mitochondrial-isoform-of |journal=Biochemical Journal |language=en |volume=474 |issue=22 |pages=3783–3797 |doi=10.1042/BCJ20170416 |issn=0264-6021 |pmid=28986507 |url-access=subscription}}</ref><ref>{{Cite journal |last1=Bowman |first1=Caitlyn E. |last2=Wolfgang |first2=Michael J. |date=January 2019 |title=Role of the malonyl-CoA synthetase ACSF3 in mitochondrial metabolism |journal=Advances in Biological Regulation |language=en |volume=71 |pages=34–40 |doi=10.1016/j.jbior.2018.09.002 |pmc=6347522 |pmid=30201289}}</ref> In the cytosol, malonyl-CoA is likewise generated from acetyl-CoA by acetyl-CoA carboxylase. In both cytosolic and mitochondrial fatty acid synthesis, malonyl-CoA transfers its malonate group (C2) to an acyl carrier protein (ACP) to be added to a fatty acid chain.<ref>{{Cite journal |last1=Wedan |first1=Riley J. |last2=Longenecker |first2=Jacob Z. |last3=Nowinski |first3=Sara M. |date=January 2024 |title=Mitochondrial fatty acid synthesis is an emergent central regulator of mammalian oxidative metabolism |journal=Cell Metabolism |language=en |volume=36 |issue=1 |pages=36–47 |doi=10.1016/j.cmet.2023.11.017 |pmc=10843818 |pmid=38128528 |doi-access=free}}</ref>

==Salts and esters== [[Image:Malonate.png|thumb|Chemical structure of the malonate dianion.]] Malonic acid is diprotic; that is, it can donate two protons per molecule. Its first <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''' compounds include salts and esters 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] {{Webarchive|url=https://web.archive.org/web/20090511021547/http://www.aim.env.uea.ac.uk/aim/accent2/inputpage.php |date=2009-05-11 }}

Category:Dicarboxylic acids