Malonic acid

Last updated
Malonic acid
Malonsaure.svg
Malonic acid molecule ball from xtal.png
Names
Preferred IUPAC name
Propanedioic acid [1]
Other names
Methanedicarboxylic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.005.003 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C3H4O4/c4-2(5)1-3(6)7/h1H2,(H,4,5)(H,6,7) Yes check.svgY
    Key: OFOBLEOULBTSOW-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C3H4O4/c4-2(5)1-3(6)7/h1H2,(H,4,5)(H,6,7)
    Key: OFOBLEOULBTSOW-UHFFFAOYAJ
  • O=C(O)CC(O)=O
  • C(C(=O)O)C(=O)O
Properties
C3H4O4
Molar mass 104.061 g·mol−1
Density 1.619 g/cm3
Melting point 135 to 137 °C (275 to 279 °F; 408 to 410 K) (decomposes)
Boiling point decomposes
763 g/L
Acidity (pKa)pKa1 = 2.83 [2]
pKa2 = 5.69 [2]
-46.3·10−6 cm3/mol
Related compounds
Other anions
Malonate
Oxalic acid
Propionic acid
Succinic acid
Fumaric acid
Related compounds
 Malondialdehyde
Dimethyl malonate
Hazards
Safety data sheet (SDS) External MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Malonic acid (IUPAC systematic name: propanedioic 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'.

Contents

History

Malonic acid [3] is a naturally occurring substance found in many fruits and vegetables. [4] There is a suggestion that citrus fruits produced in organic farming contain higher levels of malonic acid than fruits produced in conventional agriculture. [5]

Malonic acid was first prepared in 1858 by the French chemist Victor Dessaignes via the oxidation of malic acid. [3] [6]

Structure and preparation

The structure has been determined by X-ray crystallography [7] and extensive property data including for condensed phase thermochemistry are available from the National Institute of Standards and Technology. [8] A classical preparation of malonic acid starts from chloroacetic acid: [9]

Preparation of malonic acid from chloroacetic acid. Synthesis of malonic acid.png
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. [10] It has also been produced through fermentation of glucose. [11]

Organic reactions

Malonic acid reacts as a typical carboxylic acid: forming amide, ester, anhydride, and chloride derivatives. [12] 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.

Mitochondrial fatty acid synthesis

Malonic acid is the starting substrate of mitochondrial fatty acid synthesis (mtFASII), in which it is converted to malonyl-CoA by malonyl-CoA synthetase (ACSF3). [13] [14]

Additionally, the coenzyme A derivative of malonate, malonyl-CoA, is an important precursor in 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.

Briggs–Rauscher reaction

Malonic acid is a key component in the Briggs–Rauscher reaction, the classic example of an oscillating chemical reaction. [15]

Knoevenagel condensation

In Knoevenagel condensation, malonic acid or its diesters are reacted with the carbonyl group of an aldehyde or ketone, followed by a dehydration reaction.

Z=COOH (malonic acid) or Z=COOR' (malonate ester) KnoevenagelGeneral.png
Z=COOH (malonic acid) or Z=COOR' (malonate ester)

When malonic acid itself is used, it is normally because the desired product is one in which a second step has occurred, with loss of carbon dioxide, in the so-called Doebner modification. [16]

The Doebner modification of the Knoevenagel condensation. Doebner modification.png
The Doebner modification of the Knoevenagel condensation.

Thus, for example, the reaction product of acrolein and malonic acid in pyridine is trans-2,4-Pentadienoic acid with one carboxylic acid group and not two. [17]

Preparation of carbon suboxide

Carbon suboxide is prepared by warming a dry mixture of phosphorus pentoxide (P4O10) and malonic acid. [18] It reacts in a similar way to malonic anhydride, forming malonates. [19]

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. [20] 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. [21]

It is used in a number of manufacturing processes as a high value specialty chemical including the electronics industry, flavors and fragrances industry, [4] specialty solvents, polymer crosslinking, and pharmaceutical industry. In 2004, annual global production of malonic acid and related diesters was over 20,000 metric tons. [22] 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. [23]

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. [4]

Malonic acid is used as a building block chemical to produce numerous valuable compounds, [24] 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. [25] [26] 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. [27]

Eastman Kodak company and others use malonic acid and derivatives as a surgical adhesive. [28]

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. [29]

Biochemistry

Malonic acid is the classic example of a competitive inhibitor of the enzyme succinate dehydrogenase (complex II), in the respiratory electron transport chain. [30] 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. [31] [32] Since malonic acid is a natural component of many foods, it is present in mammals including humans. [33]

The fluorinated version of malonic acide is difluoromalonic acid.

Chemical structure of the malonate dianion. Malonate.png
Chemical structure of the malonate dianion.

Malonic acid is diprotic; that is, it can donate two protons per molecule. Its first is 2.8 and the second is 5.7. [2] Thus the malonate ion can be H OOCCH2COO− or C H 2(COO)2−2. Malonate or propanedioate compounds include salts and esters of malonic acid, such as

Related Research Articles

<span class="mw-page-title-main">Phthalic anhydride</span> Chemical compound

Phthalic anhydride is the organic compound with the formula C6H4(CO)2O. It is the anhydride of phthalic acid. Phthalic anhydride is a principal commercial form of phthalic acid. It was the first anhydride of a dicarboxylic acid to be used commercially. This white solid is an important industrial chemical, especially for the large-scale production of plasticizers for plastics. In 2000, the worldwide production volume was estimated to be about 3 million tonnes per year.

<span class="mw-page-title-main">Diethyl malonate</span> Chemical compound

Diethyl malonate, also known as DEM, is the diethyl ester of malonic acid. It occurs naturally in grapes and strawberries as a colourless liquid with an apple-like odour, and is used in perfumes. It is also used to synthesize other compounds such as barbiturates, artificial flavourings, vitamin B1, and vitamin B6.

<span class="mw-page-title-main">Michael addition reaction</span> Reaction in organic chemistry

In organic chemistry, the Michael reaction or Michael 1,4 addition is a reaction between a Michael donor and a Michael acceptor to produce a Michael adduct by creating a carbon-carbon bond at the acceptor's β-carbon. It belongs to the larger class of conjugate additions and is widely used for the mild formation of carbon-carbon bonds.

Barbituric acid or malonylurea or 6-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in water. Barbituric acid is the parent compound of barbiturate drugs, although barbituric acid itself is not pharmacologically active. The compound was first synthesised by Adolf von Baeyer.

<span class="mw-page-title-main">Maleic anhydride</span> Chemical compound

Maleic anhydride is an organic compound with the formula C2H2(CO)2O. It is the acid anhydride of maleic acid. It is a colorless or white solid with an acrid odor. It is produced industrially on a large scale for applications in coatings and polymers.

<span class="mw-page-title-main">Malonyl-CoA</span> Chemical compound

Malonyl-CoA is a coenzyme A derivative of malonic acid.

<span class="mw-page-title-main">Meldrum's acid</span> Chemical compound

Meldrum's acid or 2,2-dimethyl-1,3-dioxane-4,6-dione is an organic compound with formula C6H8O4. Its molecule has a heterocyclic core with four carbon and two oxygen atoms; the formula can also be written as [−O−(C 2)−O−(C=O)−(CH2)−(C=O)−].

The malonic ester synthesis is a chemical reaction where diethyl malonate or another ester of malonic acid is alkylated at the carbon alpha to both carbonyl groups, and then converted to a substituted acetic acid.

<span class="mw-page-title-main">Methylmalonic acid</span> Chemical compound

Methylmalonic acid (MMA) is a dicarboxylic acid that is a C-methylated derivative of malonic acid.

<span class="mw-page-title-main">Cellulose acetate phthalate</span> Chemical compound

Cellulose acetate phthalate (CAP), also known as cellacefate (INN) and cellulosi acetas phthalas, is a commonly used polymer phthalate in the formulation of pharmaceuticals, such as the enteric coating of tablets or capsules and for controlled release formulations. It is a cellulose polymer where about half of the hydroxyls are esterified with acetyls, a quarter are esterified with one or two carboxyls of a phthalic acid, and the remainder are unchanged. It is a hygroscopic white to off-white free-flowing powder, granules, or flakes. It is tasteless and odorless, though may have a weak odor of acetic acid. Its main use in pharmaceutics is with enteric formulations. It can be used together with other coating agents, e.g. ethyl cellulose. Cellulose acetate phthalate is commonly plasticized with diethyl phthalate, a hydrophobic compound, or triethyl citrate, a hydrophilic compound; other compatible plasticizers are various phthalates, triacetin, dibutyl tartrate, glycerol, propylene glycol, tripropionin, triacetin citrate, acetylated monoglycerides, etc.

<span class="mw-page-title-main">Dimethyl malonate</span> Chemical compound

Dimethyl malonate is a diester derivative of malonic acid. It is a common reagent for organic synthesis used, for example, as a precursor for barbituric acid. It is also used in the malonic ester synthesis. It can be synthesized from dimethoxymethane and carbon monoxide.

1,4-Cyclohexanedione is an organic compound with the formula (CH2)4(CO)2. This white solid is one of the three isomeric cyclohexanediones. This particular diketone is used as a building block in the synthesis of more complex molecules.

<span class="mw-page-title-main">ACSF3</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA synthetase family member 3 is an enzyme that in humans is encoded by the ACSF3 gene.

<span class="mw-page-title-main">Diethyl succinate</span> Chemical compound

Diethyl succinate is the diethyl ester of succinate.

<span class="mw-page-title-main">Ethyl cyanoacetate</span> Chemical compound

Ethyl cyanoacetate is an organic compound that contains a carboxylate ester and a nitrile. It is a colourless liquid with a pleasant odor. This material is useful as a starting material for synthesis due to its variety of functional groups and chemical reactivity.

<span class="mw-page-title-main">Diethyl oxomalonate</span> Chemical compound

Diethyl oxomalonate is the diethyl ester of mesoxalic acid (ketomalonic acid), the simplest oxodicarboxylic acid and thus the first member (n = 0) of a homologous series HOOC–CO–(CH2)n–COOH with the higher homologues oxalacetic acid (n = 1), α-ketoglutaric acid (n = 2) and α-ketoadipic acid (n = 3) (the latter a metabolite of the amino acid lysine). Diethyl oxomalonate reacts because of its highly polarized keto group as electrophile in addition reactions and is a highly active reactant in pericyclic reactions such as the Diels-Alder reactions, cycloadditions or ene reactions. At humid air, mesoxalic acid diethyl ester reacts with water to give diethyl mesoxalate hydrate and the green-yellow oil are spontaneously converted to white crystals.

α,β-Unsaturated carbonyl compound Functional group of organic compounds

α,β-Unsaturated carbonyl compounds are organic compounds with the general structure (O=CR)−Cα=Cβ-R. Such compounds include enones and enals, but also carboxylic acids and the corresponding esters and amides. In these compounds, the carbonyl group is conjugated with an alkene. Unlike the case for carbonyls without a flanking alkene group, α,β-unsaturated carbonyl compounds are susceptible to attack by nucleophiles at the β-carbon. This pattern of reactivity is called vinylogous. Examples of unsaturated carbonyls are acrolein (propenal), mesityl oxide, acrylic acid, and maleic acid. Unsaturated carbonyls can be prepared in the laboratory in an aldol reaction and in the Perkin reaction.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

<span class="mw-page-title-main">Alkoxide</span> Conjugate base of an alcohol

In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as RO−, where R is the organyl substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands. Alkoxides, although generally not stable in protic solvents such as water, occur widely as intermediates in various reactions, including the Williamson ether synthesis. Transition metal alkoxides are widely used for coatings and as catalysts.

<span class="mw-page-title-main">Diethyl acetamidomalonate</span> Chemical compound

Diethyl acetamidomalonate (DEAM) is a derivative of malonic acid diethyl ester. Formally, it is derived through the acetylation of ester from the unstable aminomalonic acid. DEAM serves as a starting material for racemates including both, natural and unnatural α-amino acids or hydroxycarboxylic acids. It is also usable as a precursor in pharmaceutical formulations, particularly in the cases of active ingredients like fingolimod, which is used to treat multiple sclerosis.

References

  1. ↑ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. p. 746. doi:10.1039/9781849733069. ISBN   978-0-85404-182-4.
  2. 1 2 3 pKa Data Compiled by R. Williams (pdf; 77 kB) Archived 2010-06-02 at the Wayback Machine
  3. 1 2 Chisholm, Hugh, ed. (1911). "Malonic Acid"  . Encyclopædia Britannica . Vol. 17 (11th ed.). Cambridge University Press. p. 495.
  4. 1 2 3 "Propanedioic acid". The Good Scents Company. Retrieved 2020-10-07.
  5. ↑ Ha CN, Ngoc ND, Ngoc CP, Trung DD, Quang BN (2012). "Organic Acids Concentration in Citrus Juice from Conventional Versus Organic Farming". Acta Horticulturae. 933 (933): 601–606. doi:10.17660/actahortic.2012.933.78. hdl: 10400.1/2790 . ISSN   0567-7572.
  6. ↑ Dessaignes V (1858). "Note sur un acide obtenu par l'oxydation de l'acide malique"] (Note on an acid obtained by oxidation of malic acid)". Comptes rendus. 47: 76–79.
  7. ↑ Gopalan RS, Kumaradhas P, Kulkarni GU, Rao CN (2000). "An experimental charge density study of aliphatic dicarboxylic acids". Journal of Molecular Structure. 521 (1–3): 97–106. Bibcode:2000JMoSt.521...97S. doi:10.1016/S0022-2860(99)00293-8.
  8. ↑ NIST Chemistry WebBook. "Propanedioic acid".
  9. ↑ Weiner N. "Malonic acid". Organic Syntheses ; Collected Volumes, vol. 2, p. 376.
  10. ↑ USpatent 2373011,Britton EC, Ezra M,"Production of malonic acid",issued 1945-04-03, assigned to Dow Chemical Co
  11. ↑ US 20200172941,Dietrich JA,"Recombinant host cells for the production of malonate.", assigned to Lygos Inc
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  13. ↑ Witkowski, Andrzej; Thweatt, Jennifer; Smith, Stuart (2011). "Mammalian ACSF3 Protein Is a Malonyl-CoA Synthetase That Supplies the Chain Extender Units for Mitochondrial Fatty Acid Synthesis". Journal of Biological Chemistry. 286 (39): 33729–33736. doi: 10.1074/jbc.M111.291591 . PMC   3190830 . PMID   21846720.
  14. ↑ Bowman, Caitlyn E.; Rodriguez, Susana; Selen Alpergin, Ebru S.; Acoba, Michelle G.; Zhao, Liang; Hartung, Thomas; Claypool, Steven M.; Watkins, Paul A.; Wolfgang, Michael J. (2017). "The Mammalian Malonyl-CoA Synthetase ACSF3 Is Required for Mitochondrial Protein Malonylation and Metabolic Efficiency". Cell Chemical Biology. 24 (6): 673–684.e4. doi:10.1016/j.chembiol.2017.04.009. PMC   5482780 . PMID   28479296.
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  16. ↑ Doebner O (1902). "Ueber die der Sorbinsäure homologen, ungesättigten Säuren mit zwei Doppelbindungen". Berichte der Deutschen Chemischen Gesellschaft. 35: 1136–36. doi:10.1002/cber.190203501187.
  17. ↑ Jessup PJ, Petty CB, Roos J, Overman LE (1988). "1-N-Acylamino-1,3-dienes from 2,4-pentadienoic acids by the Curtius rearrangement: benzyl trans-1,3-butadiene-1-carbamate". Organic Syntheses ; Collected Volumes, vol. 6, p. 95.
  18. ↑ Diels O, Wolf B (1906). "Ueber das Kohlensuboxyd. I". Chem. Ber. 39: 689–697. doi:10.1002/cber.190603901103.
  19. ↑ Perks HM, Liebman JF (2000). "Paradigms and Paradoxes: Aspects of the Energetics of Carboxylic Acids and Their Anhydrides". Structural Chemistry. 11 (4): 265–269. doi:10.1023/A:1009270411806. S2CID   92816468.
  20. ↑ Facke T, Subramanian R, Dvorchak M, Feng S (February 2004). "Diethylmalonate blocked isocyanate as crosslinkers for low temperature cure powder coatings.". Proceedings of 31st International Waterborene, High-Solids and Powder Coating Symposium.
  21. ↑ James S. Global Automotive Coatings Market. 2015 Grand View Research Market Report (Report).
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  23. ↑ Werpy TA, Holladay JE, White JF (August 2004). Werpy TA, Petersen G (eds.). Top Value Added Chemicals From Biomass. Volume I: Results of Screening for Potential Candidates from Sugars and Synthesis Gas (PDF) (Report). US Department of Energy. doi: 10.2172/926125 . OSTI   926125 .
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  25. ↑ US 9790350,Netravali AN, Dastidar TG,"Crosslinked native and waxy starch resin compositions and processes for their manufacture.", assigned to Cornell University
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  27. ↑ Biodegradable Polymers: Chemical Economics Handbook (Report). IHS Markit. June 2021.
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