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Malonic acid
Malonic acid
Malonic acid
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Malonic acid
Skeletal formula of malonic acid
Ball-and-stick model of the malonic acid molecule
Names
Preferred IUPAC name
Propanedioic acid[1]
Other names
Methanedicarboxylic acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.005.003 Edit this at Wikidata
UNII
  • InChI=1S/C3H4O4/c4-2(5)1-3(6)7/h1H2,(H,4,5)(H,6,7) checkY
    Key: OFOBLEOULBTSOW-UHFFFAOYSA-N checkY
  • 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 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

[edit]

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]

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.[7] This led to priority dispute with Hans Hübner and Maxwell Simpson who had independently published preliminary results on related reactions.[7]

Structure and preparation

[edit]

The structure has been determined by X-ray crystallography[8] and extensive property data including for condensed phase thermochemistry are available from the National Institute of Standards and Technology.[9] A classical preparation of malonic acid starts from chloroacetic acid:[10]

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.[11] It has also been produced through fermentation of glucose.[12]

Reactions

[edit]

Malonic acid reacts as a typical carboxylic acid forming amide, ester, and chloride derivatives.[13] 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.

Briggs–Rauscher reaction

[edit]

Malonic acid is a key component in the Briggs–Rauscher reaction, the classic example of an oscillating chemical reaction.[14]

Knoevenagel condensation

[edit]

Malonic acid is used to prepare a,b-unsaturated carboxylic acids by condensation and decarboxylation. Cinnamic acids are prepared in this way:

CH2(CO2H)2 + ArCHO → ArCH=CHCO2H + 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.

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.[15][16][17]

The Doebner modification of the Knoevenagel condensation.

Preparation of carbon suboxide

[edit]

Malonic acid does not readily form an anhydride, dehydration gives carbon suboxide instead:

CH2(CO2H)2 → O=C=C=C=O + 2 H2O

The transformation is achieved 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

[edit]

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

[edit]

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

[edit]

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]

In mammals, acyl-CoA synthetase family member 3 (ACSF3) detoxifies malonic acid by converting it into malonyl-CoA.[34] 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).[35][36] 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.[37]

Salts and esters

[edit]
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 HOOCCH2COO− or CH2(COO)2−2. Malonate or propanedioate compounds include salts and esters of malonic acid, such as

References

[edit]
[edit]
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Malonic acid

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from Grokipedia
Malonic acid, systematically named propanedioic acid, is a simple dicarboxylic acid with the molecular formula C₃H₄O₄ and HOOC-CH₂-COOH. It appears as a white crystalline solid that is highly soluble in (763 g/L at 20 °C) and polar organic solvents like and . With a of 132–135 °C, it readily decarboxylates upon heating above 140 °C to yield acetic acid and , a property central to its synthetic utility. First isolated in 1858 by French chemist Victor Dessaignes through the oxidation of malic acid using , malonic acid derives its name from the Greek word malon (apple), reflecting its relation to malic acid found in apples. Industrially, it is primarily synthesized via the of malonic esters, such as , or from through the formation and subsequent of . These methods leverage its active , which facilitates reactions in . Malonic acid serves as a key building block in pharmaceutical production, notably as an intermediate for barbiturates, vitamin B₁ (), and vitamin B₆ (). It is also employed in the fragrance and flavor industries for enhancing and notes, as a buffering agent in , and in synthesis for polyesters and coatings. Additionally, its role as a competitive inhibitor of has made it valuable in biochemical studies of the tricarboxylic acid cycle. Naturally occurring in trace amounts in various fruits such as apples and in plants like beets and , malonic acid underscores its dual significance in both natural and synthetic chemistry.

Properties

Physical properties

Malonic acid possesses the molecular CH₂(COOH)₂, equivalent to C₃H₄O₄, and has a molecular weight of 104.06 g/mol. It manifests as a white crystalline solid that is odorless. The compound exhibits a of 134–135 °C, after which it decomposes above 140 °C into acetic acid and . Malonic acid demonstrates high in , with 73.5 g dissolving in 100 mL at 20 °C; it is also soluble in (57 g/100 mL at 20 °C) and (5.7 g/100 mL at 20 °C). The two groups have pKa values of 2.83 and 5.69, respectively, at 25 °C. Key physical constants are summarized in the following table:
PropertyValueConditions
1.619 g/cm³25 °C
1.478Not specified
0–0.2 Pa25 °C
Under normal storage conditions, malonic acid remains stable but is hygroscopic, readily absorbing moisture from the air.

Chemical properties

Malonic acid, with the molecular formula C₃H₄O₄, features a linear structure HOOC-CH₂-COOH, consisting of two groups connected by a methylene (-CH₂-) bridge. This arrangement imparts C_{2v} symmetry to the in its equilibrium conformation. Bond lengths in the structure are characteristic of , with the central C-C bond measuring approximately 1.53 , the carbonyl C=O bonds at 1.20 , and the hydroxyl O-H bonds at 0.97 . The compound exhibits keto-enol tautomerism, involving proton transfer from the to form an intermediate; however, the keto form predominates due to its substantially higher thermodynamic stability, with the estimated at less than 10^{-4} in dilute aqueous solutions. Malonic acid displays enhanced acidity relative to monocarboxylic acids such as acetic acid (pK_a = 4.76), owing to the inductive electron-withdrawing effect of the adjacent , which stabilizes the monoanionic conjugate base by dispersing negative charge. The first (pK_{a1}) is 2.83 at 25°C, reflecting this stabilization, while the second (pK_{a2}) is 5.69, closer to typical values as the remaining proton experiences less influence from the now-deprotonated group. In both the solid state and gas phase, malonic acid molecules form cyclic dimers through strong intermolecular hydrogen bonding between the hydroxyl oxygen of one carboxyl group and the carbonyl oxygen of another, a common motif for carboxylic acids that enhances molecular association and influences like volatility. Spectroscopic characterization confirms these structural features. In the infrared spectrum, the symmetric and asymmetric stretching vibrations of the C=O bonds appear as broad bands centered around 1700 cm^{-1}, shifted lower due to hydrogen bonding in dimeric forms. Proton NMR spectroscopy reveals the methylene protons as a singlet at approximately 3.4 ppm in deuterated solvents, deshielded by the flanking electron-withdrawing carboxyl groups.

History

Discovery

Malonic acid was first prepared in 1858 by the French chemist Victor Dessaignes, who obtained it through the oxidation of malic acid using . This synthesis marked the initial isolation of the compound in pure form, highlighting its relationship to malic acid, a naturally occurring found in fruits. Dessaignes' work built on earlier studies of fruit-derived acids and provided the foundation for recognizing malonic acid as a distinct entity with the formula CH₂(COOH)₂. In 1864, Hermann Kolbe and Hugo Müller independently achieved a key synthesis of malonic acid by hydrolyzing cyanoacetic acid, a method that allowed for more controlled production and further characterization of the compound. Kolbe reported his results in the Journal für Praktische Chemie, while Müller detailed his parallel efforts in Justus Liebigs Annalen der Chemie, demonstrating the growing interest in synthetic routes to dicarboxylic acids during the mid-19th century. These syntheses confirmed malonic acid's structure and reactivity, distinguishing it from related compounds like succinic acid. The name "malonic acid" originates from its structural similarity to malic acid, with the prefix derived from the Greek word malon for apple, reflecting the fruit-based origins of malic acid research. This nomenclature was adopted following Dessaignes' preparation, emphasizing the compound's derivation from malic acid. Its systematic IUPAC name, propanedioic acid, underscores its position as the simplest member of the alkane series. Early characterization of malonic acid as a also drew from its occurrence in natural sources, particularly beet extracts, where calcium malonate was noted as a component in 19th-century analyses of processing residues. The first natural isolation occurred in 1881 by Edmund O. von Lippmann from calcium malonate deposits in beet sugar processing evaporators. These observations linked malonic acid to plant metabolism and provided evidence of its role in degradation.

Early developments

The structure of malonic acid was confirmed in the 1880s through degradation studies that demonstrated its conversion to acetic acid upon heating, establishing its composition as a methylene group flanked by two carboxylic acid functionalities. This decarboxylation process, first systematically explored by Conrad and Guthzeit in their development of the malonic ester synthesis, provided key evidence for the molecule's linear C3 dicarboxylic framework by yielding acetic acid as the primary product alongside carbon dioxide. By 1900, malonic acid had found early applications as a versatile in , particularly in chain extension reactions via its derivatives, and in the synthesis of dyes through condensations with aromatic aldehydes. The discovery of its property in the late 1880s to 1890s revolutionized synthetic approaches, enabling efficient carbon chain extension by allowing substituted malonic acids to lose CO₂ and form monocarboxylic acids under mild conditions. In , malonic acid played a pivotal role in early biochemical studies, notably as a competitive inhibitor of in Hans Krebs's investigations of the tricarboxylic acid (TCA) cycle using pigeon muscle preparations. This inhibition helped elucidate the cycle's oxidative pathway by blocking succinate oxidation to fumarate, confirming the sequential involvement of C4 dicarboxylic acids in . Early developments were hampered by historical challenges, including low yields in initial oxidations of malic acid—often below 50% due to side reactions forming tarry byproducts—and persistent purity issues arising from incomplete crystallization and contamination with succinic acid.

Synthesis

Laboratory synthesis

One common laboratory method for synthesizing malonic acid involves the conversion of chloroacetic acid via substitution with sodium cyanide followed by hydrolysis. This procedure, detailed in Organic Syntheses, begins by dissolving 500 g (5.3 mol) of chloroacetic acid in 700 mL of water and warming to 50 °C. The solution is neutralized with 290 g (2.7 mol) of anhydrous sodium carbonate, then cooled, and 294 g (6 mol) of 97% sodium cyanide dissolved in 750 mL water is added rapidly while controlling the temperature below 95 °C using an ice bath to prevent hydrogen cyanide liberation. The mixture is heated on a steam bath for 1 hour to form sodium cyanoacetate. Subsequently, 240 g (6 mol) of sodium hydroxide is added, and the mixture is refluxed under a fume hood for at least 3 hours to hydrolyze the nitrile, followed by steam distillation for 45–60 minutes to remove ammonia. Calcium chloride (600 g in 1.8 L water at 40 °C) is added to precipitate calcium malonate, which is filtered, washed, and dried (yield: 800–900 g). The dry salt is then treated with alcohol-free diethyl ether (750–1000 mL) and 12 N hydrochloric acid (1 mL per g salt), and the free malonic acid is extracted continuously, yielding 415–440 g (75–80% overall from chloroacetic acid) of malonic acid upon evaporation of the ether extract. The reaction sequence can be represented as: ClCH₂COOH + NaCN → NCCH₂COONa NCCH₂COONa + 2 H₂O + HCl → HOOCCH₂COOH + NH₄Cl (simplified hydrolysis steps under reflux at ~100 °C). Another straightforward laboratory approach is the hydrolysis of commercially available diethyl malonate. This involves saponification with aqueous sodium hydroxide: a solution of diethyl malonate (1 equiv) in ethanol or water is treated with 2 equiv of NaOH and refluxed for 1–2 hours to form the disodium malonate salt. Acidification with concentrated HCl (excess, under cooling) protonates the salt to malonic acid, which precipitates or is extracted into an organic solvent like ether. The overall yield is typically 90–95%, as the reaction is efficient and minimizes side products. The equation is: (EtO₂C)₂CH₂ + 2 NaOH → (⁻O₂C)₂CH₂ + 2 EtOH (⁻O₂C)₂CH₂ + 2 H⁺ → (HO₂C)₂CH₂ Purification of crude malonic acid from either method is achieved by recrystallization. From extracts, the acid crystallizes upon cooling or partial at low (<20 °C) under reduced pressure to avoid decarboxylation. Alternatively, dissolution in hot water followed by cooling yields colorless crystals, which are filtered and dried in vacuo. This step ensures >98% purity, with melting point confirmation at 134–136 °C. Due to the use of cyanide reagents in the chloroacetic acid route, all operations involving sodium cyanide addition and initial heating must be conducted in a well-ventilated with appropriate . Temperature control is critical to minimize HCN gas evolution, and any spills should be neutralized with solution before disposal.

Industrial production

The primary industrial production of malonic acid relies on the process, in which reacts with to form , followed by acid to yield malonic acid. This method is scaled up using continuous reactors to optimize reaction control, minimize waste, and achieve overall yields exceeding 80%, making it economically viable for large-scale operations. An alternative commercial route involves the of diethyl or esters, which are themselves derived from , under acidic or basic conditions to produce high-purity malonic acid. This process offers better product quality than the cyanohydrin method but incurs higher costs due to additional esterification steps and purification requirements. Emerging bio-based production methods utilize microbial with genetically engineered strains to convert glucose into malonic acid via artificial pathways, such as the of oxaloacetate to malonic semialdehyde followed by oxidation. Recent advances in the have improved titers to up to 3.6 g/L in shake-flask fermentations with E. coli, with higher yields (up to 19.1 g/L) reported in other engineered microbes like Yarrowia lipolytica through metabolic optimization and fed-batch processes, offering a sustainable alternative that avoids hazardous byproducts. Major manufacturing hubs include , which dominates output due to low-cost feedstocks, and , where companies like Lonza and emphasize high-purity grades for pharmaceutical applications. Key cost factors include fluctuating raw material prices, such as at approximately $800-1,000 per ton, and energy efficiency in and purification steps, which account for 30-40% of total production expenses; bio-based routes show promise for through renewable glucose feedstocks but currently face challenges in scaling and downstream recovery.

Reactions

Decarboxylation

Malonic acid undergoes thermal decarboxylation upon heating to 140–160 °C, yielding acetic acid and carbon dioxide according to the equation: \ceHOOC−CH2−COOH−>[140−160∘C]CH3COOH+CO2\ce{HOOC-CH2-COOH ->[140-160^\circ C] CH3COOH + CO2} This reaction proceeds via a mechanism analogous to that of β-keto acids, involving a concerted process through a six-membered transition state where the hydrogen from one carboxylic acid group migrates to the adjacent carboxylate, facilitating the cleavage of the C–C bond and loss of CO₂ to form a vinyl alcohol (enol) intermediate. The enol then tautomerizes to the corresponding carboxylic acid, in this case acetic acid. The follows kinetics with respect to malonic acid concentration. The is approximately 30 kcal/mol, consistent with the energy barrier for the formation. The increases in polar solvents due to enhanced stabilization of the polar , as evidenced by higher rate constants in media with greater constants. A primary application of this is in the , which enables the preparation of monosubstituted acetic acids. The process begins with the of using to form the , followed by with an alkyl (RX) to yield diethyl 2-alkylmalonate. Subsequent under acidic or basic conditions converts the esters to the corresponding dialkylmalonic acid, which upon heating undergoes to afford the target , R–CH₂–COOH. For example, with ethyl bromide (R = CH₂CH₃) produces diethyl 2-ethylmalonate; gives 2-ethylmalonic acid, and at elevated temperature yields butanoic acid (CH₃CH₂CH₂COOH) and CO₂. Substituted malonic acids, such as 2-alkylmalonic acids, follow the same pathway, selectively losing one CO₂ molecule to form the corresponding R–CH₂–COOH product, thereby extending the carbon chain by one unit from the original alkyl substituent.

Condensation reactions

Malonic acid participates in condensation reactions that form carbon-carbon bonds, notably the , where its active reacts with s or ketones under basic catalysis. In this reaction, malonic acid condenses with an aldehyde such as to yield benzylidenemalonic acid, as shown in the following equation: \ceHOOC−CH2−COOH+PhCHO−>[base]HOOC−CH=C(Ph)−COOH+H2O\ce{HOOC-CH2-COOH + PhCHO ->[base] HOOC-CH=C(Ph)-COOH + H2O} The mechanism involves of the active by a base , generating a that undergoes to the carbonyl carbon of the , forming a β-hydroxy intermediate. This intermediate then eliminates water through β-elimination, affording the α,β-unsaturated . Common catalysts include secondary amines like , which facilitate the enolizable nature of malonic acid's methylene protons. Typical conditions for the employ in at , achieving yields of 70–90% for aromatic aldehydes like . These products serve as precursors in the synthesis of dyes and pharmaceutical intermediates, such as those used in the preparation of therapeutic agents and analogs. Variations of the reaction extend to ketones, which typically require harsher conditions; microwave-assisted protocols using catalysts like and in water enhance efficiency, providing higher yields in shorter times. The Doebner modification utilizes as the base, promoting the condensation with aldehydes to form derivatives suitable for further synthetic elaboration.

Other notable reactions

Malonic acid participates in the Briggs–Rauscher reaction, a classical example of a involving (H₂O₂), (KI), and malonic acid in an acidic medium. This reaction exhibits periodic color changes—typically amber to colorless to deep blue—occurring every few seconds to minutes, depending on concentrations, due to the formation and consumption of iodine and starch-iodine complexes. The mechanism proceeds through two coupled processes: a non-radical pathway where consumes free iodine via reaction with malonic acid to form iodomalonic acid, and a radical pathway involving oxidation that regenerates iodine, creating autocatalytic cycles that sustain the oscillations. Another notable transformation is the preparation of (C₃O₂), a reactive cumulene, through the of malonic acid using (P₄O₁₀) at approximately 140 °C under reduced pressure. This reaction proceeds via initial formation of malonic anhydride followed by thermal elimination, yielding as a colorless, foul-smelling gas that polymerizes readily upon exposure to light or air. The process is a dating back to early 20th-century inorganic synthesis and highlights malonic acid's utility in generating unsaturated carbon oxides. Malonic acid can be reduced to , a key precursor for polyesters and other polymers, via catalytic . Using ruthenium-based catalysts under high-pressure conditions, this transformation achieves high selectivity and yields approaching 95%, though often applied to malonic esters to mitigate acidity issues; the product serves as a bio-based alternative to petroleum-derived analogs. at the alpha position occurs readily due to the activated , with chlorination achieved by addition of to a solution of malonic acid in , leading to chloromalonic acid as the primary product. This reaction is slower than for ketones but facilitated by the dicarboxylic acids, and the product can undergo further for synthetic utility. In recent developments from the , photocatalytic methods have enabled the of s, including malonic acid, with s to form amides under visible light irradiation. These protocols typically employ iridium-based photoredox catalysts and aerobic conditions, where the carboxylic acid is activated to an acyl radical intermediate that reacts with the amine, offering a mild, metal-efficient route to functionalized amides with good yields for both primary and tertiary amines.

Applications

Organic synthesis

Malonic acid and its diesters, such as diethyl malonate, are pivotal building blocks in laboratory organic synthesis owing to the enhanced acidity of the alpha protons (pKa ≈ 13), which facilitates enolate formation for selective carbon-carbon bond construction. This reactivity underpins the malonic ester synthesis, a cornerstone method for assembling substituted carboxylic acids from simple alkyl halides, enabling the preparation of complex molecules for pharmaceuticals and fine chemicals. The process exploits the beta-keto acid-like decarboxylation propensity of malonic derivatives, providing a two-carbon unit that is incorporated and then streamlined. In the , is first deprotonated with a base like in to generate the resonance-stabilized . This undergoes SN2 with a primary alkyl (RX), yielding a mono- or dialkylated malonate depending on stoichiometry; excess enolate favors monoalkylation. with aqueous hydrolyzes the esters to the corresponding malonic acid derivative, which, upon acidification to 1-2 and heating (typically 100-150°C), undergoes thermal via a six-membered cyclic , liberating CO₂ and affording the target R-CH₂-COOH or R₂CH-COOH. Yields for this sequence often exceed 70% for simple substrates, with the decarboxylation step proceeding quantitatively under optimized conditions. This is routinely applied in pharmaceutical synthesis; for instance, it constructs the propanoic acid moiety in ibuprofen precursors by alkylating with an isobutylphenyl-derived , followed by the standard hydrolysis-decarboxylation sequence. Barbiturate synthesis leverages the condensation of with under basic conditions (e.g., in at reflux), forming the core through sequential nucleophilic additions and eliminations. This cyclization, yielding 6-hydroxybarbituric acid (), proceeds in 50-80% yield and allows N-alkylation to produce pharmacologically active derivatives. Historically, discovered this reaction in 1903 while seeking analogs, leading to (5,5-diethylbarbituric acid), the first introduced clinically in 1904; the method remains foundational for synthesizing depressants like . Malonic ester derivatives also feature prominently in vitamin synthesis. For vitamin B1 (thiamine), alkylated malonates serve as precursors to the 4-amino-5-hydroxymethyl-2-methylpyrimidine moiety, where the malonate provides the carbon framework for with components under industrial conditions developed in the mid-20th century. In vitamin B6 () routes, malonic acid half-esters or derivatives are condensed with acyclic precursors to build the ring, followed by reduction and functional group adjustments, achieving overall yields of 40-60% in multi-step sequences. The synthesis of via malonic ester involves of with an corresponding to the , followed by conversion to an amino-malonate intermediate (e.g., via Gabriel on a halo-malonate) and hydrolysis-decarboxylation. For derivatives, of with methyl iodide, followed by and processing, yields α- in 60-80% overall efficiency, preserving if chiral auxiliaries are employed. This approach is particularly useful for in mimetic design. To optimize yields and selectivity in malonic ester alkylations, phase-transfer catalysis (PTC) is employed, using quaternary ammonium salts (e.g., ) to solubilize the sodium in non-polar solvents like , promoting interfacial reactions with alkyl halides. This technique minimizes dialkylation by controlling enolate concentration and enhancing SN2 rates, often boosting monoalkylation yields to 85-95% while reducing byproducts from over-alkylation or elimination.

Industrial and other uses

Malonic acid serves as a key precursor in the synthesis of specialty polyesters and resins, which are widely employed in protective coatings to enhance durability against light, oxidation, and . These applications leverage the acid's ability to act as a crosslinker, contributing to the mechanical strength and chemical resistance of the resulting materials. In the flavor and fragrance industry, malonic acid functions as an intermediate for producing various artificial flavors and scents, often incorporated at low concentrations in the parts-per-million range to achieve desired sensory profiles. The pharmaceutical sector represents a major end-use, accounting for over 40% of global malonic acid consumption in , primarily as an intermediate in the bulk production of drugs including barbiturates, antivirals such as inhibitors, and antibacterials. For instance, derivatives of malonic acid are utilized in synthesizing inhibitors and antiviral agents, supporting approximately 10% of the market share in these therapeutic categories. Malonic acid is also applied in water treatment formulations as a biodegradable chelating agent, binding metal ions to prevent scaling and facilitate their removal in . Global production of malonic acid was approximately 17,000 metric tons as of 2022, with steady growth continuing into 2025 driven by demand in pharmaceuticals and polymers, propelled by shifts toward bio-based production methods in response to initiatives. This transition emphasizes sustainable sourcing to reduce environmental impact while meeting rising needs in polymers and pharmaceuticals.

Biological role

Biochemistry

Malonic acid functions as a competitive inhibitor of (SDH), an enzyme in the tricarboxylic acid (TCA) cycle that catalyzes the oxidation of succinate to fumarate. Due to its structural similarity to succinate, malonic acid binds to the of SDH, preventing substrate binding and thus blocking the conversion with an inhibition constant (Ki) of approximately 0.01 mM. This inhibition disrupts electron transport and ATP production in mitochondria, making malonic acid a classic example used in biochemical studies of respiratory chain function. In , malonic acid was instrumental in elucidating the Krebs cycle (TCA cycle) through accumulation studies. Hans Krebs and colleagues observed that adding malonic acid to minced pigeon breast muscle preparations inhibited respiration and led to the buildup of succinate, confirming succinate as a key cycle intermediate and supporting the cyclic nature of the pathway involving citrate formation from oxaloacetate and pyruvate. This approach provided direct evidence for the sequence of reactions in aerobic , highlighting SDH's role in linking the TCA cycle to the . Malonic acid occurs naturally in trace amounts in , including sugar beets () and green , where it arises from the oxidative degradation of malic acid. In animal and human physiology, it is primarily encountered as , the activated form generated by and serving as the two-carbon donor in , thereby regulating and . Upon entry into biological systems, malonic acid undergoes rapid metabolism, primarily through urinary excretion or to , which can then be converted to for entry into the TCA cycle. Pharmacokinetic studies of related malonate derivatives indicate quick clearance from plasma, with tissue distribution but limited persistence due to efficient renal elimination. Recent research in the 2020s has explored malonic acid's potential in modulating the gut microbiome, leveraging its structural analogy to (SCFAs) produced by microbial fermentation. Studies suggest that malonate influences bacterial community dynamics and SCFA profiles, potentially enhancing host-microbe interactions in metabolic regulation, though mechanisms remain under investigation.

Pathology

Malonic aciduria, also known as malonyl-CoA decarboxylase (MCD) deficiency, is an autosomal recessive disorder caused by mutations in the MLYCD gene on 16q24, which encodes the responsible for decarboxylating . This leads to accumulation of malonic acid in tissues and urine, resulting in metabolic disruptions. Clinical manifestations typically appear in early infancy and include , developmental delay, seizures, , , , and . The disorder is very rare, with over 50 cases reported worldwide as of 2023, and additional cases documented in studies through 2025. Combined malonic and methylmalonic aciduria (CMAMMA) is another autosomal recessive inborn error of due to biallelic mutations in the ACSF3 gene, causing elevated levels of both malonic and methylmalonic acids in urine and leading to . Symptoms vary by onset: in childhood, they include , , , developmental delay, , , and ; adult presentations may involve seizures, cognitive decline, and psychiatric disturbances. focuses on supportive care, including carnitine supplementation to enhance acylcarnitine excretion and a to reduce precursors, though no curative treatment exists. Intrastriatal injection of malonic acid in rodent models induces by inhibiting , leading to energy depletion and mimicking aspects of pathology, such as striatal lesions and motor deficits. Lesion size in the correlates positively with the injected dose, typically in the range of 5–10 µmol. Toxicologically, malonic acid has an oral LD50 of 2.75 g/kg in female , indicating moderate . It is mildly irritating to and causes serious eye damage . At high doses, it acts as a mitochondrial poison by reversibly inhibiting , potentially exacerbating energy deficits in susceptible tissues. Despite its pathological associations, malonic acid exhibits therapeutic potential in modulating neuroinflammation; in lipopolysaccharide (LPS)-stimulated BV2 microglia cells, concentrations of 1–10 µM suppress activation by inhibiting the p38 MAPK/NF-κB pathway, thereby reducing production of pro-inflammatory cytokines such as IL-6 and IL-1β.

Derivatives

Salts

Malonic acid forms various salts, known as malonates, through deprotonation of its carboxylic groups, resulting in ionic species with varying solubility in polar solvents. Common salts include disodium malonate (NaOOC-CH₂-COONa), a white to off-white crystalline powder, and calcium malonate (Ca(OOC-CH₂-COO)), which occurs naturally in beetroot and is isolated during processing of sugar beets. Disodium malonate exhibits high water solubility of approximately 148 g/L at 20°C, while calcium malonate has lower solubility, around 6 g/L at 30°C in aqueous media. These salts are typically prepared by neutralization of malonic acid with the corresponding base. For example, disodium malonate is synthesized by treating malonic acid with or in , producing the disodium salt and as a byproduct. Calcium malonate can be obtained by reacting malonic acid with or from natural sources in beet processing effluents. Key properties of malonic acid salts include their ability to act as buffers in the range of approximately 4 to 6, leveraging the second pKa of malonic acid (5.69) for effective proton exchange in biochemical and analytical contexts; disodium malonate solutions, for instance, have a of 8.0 to 10.0 but can be adjusted for buffering. Their ionic nature affects solubility, facilitating applications in solution-based processes. In the solid state, these salts often feature extensive hydrogen-bonded networks involving carboxylate oxygen atoms and any coordinated molecules, stabilizing the crystal lattice as observed in malonates. Malonic acid salts find applications as acidity regulators in food products, where their buffering capacity helps maintain stable pH levels, and as analytical reagents.

Esters

Diethyl malonate (DEM), the diethyl ester of malonic acid, is prepared industrially by esterification of malonic acid with ethanol in the presence of sulfuric acid under controlled conditions to achieve high yield and purity. This colorless liquid has a boiling point of 199 °C and a density of 1.055 g/mL at 25 °C. A key property of DEM is the acidity of its alpha-hydrogen, with a pKa of approximately 13, which allows facile deprotonation using bases such as (NaOEt) to generate a stabilized . This serves as a in the , a classical method for preparing substituted carboxylic acids. In this sequence, the enolate of DEM is alkylated with an alkyl halide (RX) to form R-CH(CO₂Et)₂; subsequent basic yields the corresponding malonic acid derivative R-CH(CO₂H)₂, which undergoes thermal upon heating to afford R-CH₂CO₂H. For example, dialkylation of DEM with methyl bromide followed by and produces 2-methylpropanoic acid. Other malonic acid esters include , which has a lower boiling point (181 °C) and is employed in environmentally benign synthetic routes due to its compatibility with principles, such as reduced volatility and use in solvent-free reactions. Monoethyl malonate, obtained via selective of DEM, is valuable in asymmetric synthesis, where enzymatic or chiral base-mediated resolutions enable access to enantiomerically enriched intermediates for pharmaceuticals. As of , global production capacity of DEM exceeded 20,000 metric tons per year as the predominant malonic ester, reflecting its widespread use in fine chemicals manufacturing. For storage, DEM should be kept in sealed containers away from moisture to prevent hydrolytic decomposition, though it is generally stable under dry conditions at room temperature.

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