PRODUCTS

MELDRUM'S ACID

Meldrum's acid is an important cyclic malonate derivative that is extensively employed as a multifunctional building block in modern organic synthesis because of its high reactivity and ability to undergo a wide variety of transformations.
Meldrum's acid's activated methylene center makes it particularly useful for constructing carbon–carbon bonds, introducing functional groups, and generating carboxylic acid, ester, ketone, and heterocyclic derivatives through controlled synthetic reactions.
Meldrum's acid has broad value in pharmaceutical chemistry, fine chemical production, medicinal research, and advanced laboratory synthesis where efficient preparation of structurally diverse and highly functionalized organic molecules is required.

CAS Number: 2033-24-1
EC Number: 217-992-8
Molecular Formula: C6H8O4
Molecular Weight: 144.13

Synonyms: Meldrum's Acid-13C, 123254-02-4, DTXSID70444255, RefChem:1088929, DTXCID70395076, Meldrum's Acid 5-13C, 2,2-dimethyl-(513C)1,3-dioxane-4,6-dione, 2,2-Dimethyl-1,3-dioxane-4,6-dione-5-13C, 2,2-Dimethyl(5-~13~C)-1,3-dioxane-4,6-dione, 1,3-Dioxane-4,6-dione, 2,2-dimethyl-, 2,2-Dimethyl-1,3-dioxan-4,6-dion, 2,2-Dimethyl-1,3-dioxane-4,6-dione, 2,2-Diméthyl-1,3-dioxane-4,6-dione, 2,2-Dimethyl-4,6-diketo-1,3-dioxane, 2033-24-1, 217-992-8, cycl-Isopropylidene malonate, isopropylidene malonate, Malonic acid cyclic isopropylidene ester, Meldrum's acid, sub-Isopropyl malonate, 2,2-Dimethyl-1,3-dioxan-4,6-dione, 2,2-Dimethyl-1,3-dioxane-4,6-dione (Meldrum's Acid), 2,2-dimethyl-1,3-dioxane-4,6-quinone, 2,2-Dimethyl-4,6-dioxo-1,3-dioxane, 2,2-Dimethyl-4,6-dioxo-m-dioxane, 2,2-Dimethyl-m-dioxane-4,6-dione, 2,2-dimethyl-1,3-dioxane-4,6-dione, 4,6-Diketo-2,2-dimethyl-1,3-dioxane, 5-19-05-00008, 98%, Cyclic isopropylidene malonate, EINECS 217-992-8, Isopropylidene malonate, AI3-39039, m-Dioxane-4,6-dione, 2,2-dimethyl-, Malonic acid cyclicisopropylidene ester, Malonic acid isopropylidene cyclic ester, Malonic acid, cyclic isopropylidene ester, Malonic acid, cyclic isopropylidene ester (8CI), MeldruM acid, Meldrum's Acid-[13C], Meldrums acid, Meldrums acid, Malonic acid cyclic isopropylidene ester, MELDRUM′S ACID, Methyl Meldrum's acid, 米氏酸

Meldrum’s acid is an organic compound, discovered in 1908 by A. N. Meldrum.
Meldrum misidentified the structure as b-lactone with carboxylic acid group at position, and the correct cyclic acylal structure was only assigned 40 years later.

Meldrum’s acid has attracted considerable attention due to its high acidity (pKa = 4.97) and rigid cyclic structure.
Acylated derivatives (synthetic equivalents of mixed ketenes) readily undergo alcoholysis to give b-keto esters.

Alkylidene derivatives are strong electrophiles and can undergo Diels-Alder reactions with high diasteroselectivity.
This versatile tool is a key intermediate for a large number of important building blocks and there remains much to discover.

Meldrum's acid is widely used in organic synthesis, especially for multiple C-C bond formations due to its adequate acidity (pKa 4.83) and steric rigidity.
Knoevenagel condensation reaction between aldehydes and Meldrum′s acid are accelerated in ionic liquids.

Meldrum's acid is a cyclic organic compound widely used as a versatile reagent and synthetic intermediate in organic chemistry.
Meldrum's acid's highly activated methylene group readily participates in condensation, alkylation, acylation, and carbon–carbon bond-forming reactions.
Meldrum's acid is particularly valuable in the synthesis of carboxylic acid derivatives, heterocyclic compounds, pharmaceutical intermediates, and complex organic molecules.

Meldrum’s acid is an organic compound with formula C6H8O4.
Meldrum's acid's molecule has a heterocyclic core with four carbon and two oxygen atoms; the formula can also be written as [−O−C(CH3)2−O−(C=O)−CH2−(C=O)−].

Meldrum's acid is a crystalline colorless solid that is sparingly soluble in water and which decomposes on heating to carbon dioxide, acetone, and a ketene.
Meldrum's acid's synthesis was first reported in 1908 by Andrew Norman Meldrum for whom it is named.
Meldrum incorrectly concluded that it was a carboxylic acid based on its acidity; the correct bislactone structure was not reported until 1948.

Meldrum′s acid is used as a valuable starting material to synthesize heterocycles and as intermediates in organic synthesis reactions.

Meldrum’s acid is an organic compound with the formula C6H8O4.
Meldrum's acid was first made in 1908 by Andrew Norman Meldrum by a condensation reaction of malonic acid with acetone in acetic anhydride and sulfuric acid.

Meldrum misidentified the structure as a β-lactone of β-hydroxyisopropylmalonic acid.
Yet Meldrum's acid has a high acidity with a pKa of 4.97, because like ascorbic acid, deprotonation at the methylene next to the carbonyls produces a stable enolate.
Because of this property Meldrum's acid like malonic acid is a reactant in Knoevenagel condensations.

Meldrum’s acid is an organic compound.
The main ring structure is a dioxane.

Meldrum's acid was discovered in 1908 by A.N. Meldrum and it is prepared by a condensation reaction of malonic acid with acetone in acetic anhydride with sulfuric acid.
Meldrum misidentified the structure as a beta-lactone with a fully fledged carboxylic acid group.

Yet Meldrum's acid has a high acidity with a pKa of 4.97, because like ascorbic acid, deprotonation at the methylene next to the carbonyls produces a stable enolate.
Because of this property Meldrum's acid like malonic acid is a reactant in Knoevenagel condensations.

Applications of Meldrum's Acid:
Meldrum's acid is widely used as a versatile reagent and intermediate in organic synthesis.
Meldrum's acid is employed in alkylation, acylation, condensation, and carbon–carbon bond-forming reactions due to its highly reactive methylene group.

Meldrum's acid is useful for preparing carboxylic acids, esters, ketones, and other functionalized derivatives.
Meldrum's acid is also applied in the synthesis of heterocyclic compounds, pharmaceutical intermediates, and fine chemicals.

Meldrum's acid is frequently used in research laboratories for multistep synthesis and the construction of complex organic molecules.
Meldrum's acid is used in organic synthesis.

Meldrum’s acid was used in the synthesis of:
macrocyclic β-keto lactone
4-pyridyl-substituted heterocycles
2-substituted indoles
isofraxidin.

Uses of Meldrum's Acid:
Meldrum's acid serves as an intermediate in a variety of organic synthesis reactions.
Meldrum's acid is commonly used as an alternative to acyclic malonic esters and generally acts as a C3O2 synthon in organic synthesis.
Like malonic acid and its ester derivatives, and other 1,3-dicarbonyl compounds, Meldrum's acid can serve as a reactant for a variety of nucleophilic reactions.

Alkylation and acylation:
The acidity of carbon 5 (between the two carbonyl groups) allows simple derivatization of Meldrum's acid at this position, through reactions such as alkylation and acylation.
For example, deprotonation and reaction with a simple alkyl halide (R−Cl) attaches the alkyl group (R−) at that position.
The analogous reaction with an acyl chloride (R−(C=O)−Cl) attaches the acyl (R−(C=O)−) instead.

These two reactions allow Meldrum's acid to serve as a starting scaffold for the synthesis of many different structures with various functional groups.
The alkylated products can be further manipulated to produce various amide and ester compounds.

Heating the acyl product in the presence of an alcohol leads to ester exchange and decarboxylation in a process similar to the malonic ester synthesis.
The reactive nature of the cyclic-diester allows good reactivity even for alcohols as hindered as t-butanol and this reactivity of Meldrum's acid and its derivatives has been used to develop a range of reactions.
Ketoesters formed from the reaction of alcohols with Meldrum's acid derivatives are useful in the Knorr pyrrole synthesis.

Synthesis of ketenes:
At temperatures greater than 200 °C (392 °F) Meldrum's acid undergoes a pericyclic reaction that releases acetone and carbon dioxide and produces a highly reactive ketene compound.
These ketenes can be isolated using flash vacuum pyrolysis (FVP).

Ketenes are highly electrophilic and can undergo addition reactions with a range of other chemicals, particularly ketene cycloadditions, or dimerisation to diketene.
With this approach Meldrum's acid is possible to form new C–C bonds, rings, amides, esters, and acids.

Alternately, the pyrolysis can be performed in solution, to obtain the same results without isolating the ketene, in a one-pot reaction.
The ability to form such diverse products makes Meldrum's acid a very useful reagent for synthetic chemists.

Uses and pharmacokinetics:
For organic synthesis; Used as pharmaceutical intermediates; Accelerating Knoevenagel condensations between aldehydes and Michaelis acid in ionic liquids.
In the field of organic synthesis, Michaelis acid can be used as raw material to synthesize a variety of compounds with biological and pharmaceutical activities because of its important reaction characteristics.

Properties of Meldrum's Acid:

Acidity:
Meldrum's acid can easily lose a hydrogen ion from the methylene (CH2) in the ring (carbon 5); which creates a double bond between it and one of the adjacent carbons (number 4 or 6), and a negative charge in the corresponding oxygen.
The resulting anion [C6H7O4]− is stabilized by resonance between the two alternatives, so that the double bond is delocalized and each oxygen in the carbonyls has a formal charge of −1/2.

The ionization constant pKa is 4.97; which makes Meldrum's acid behave as a monobasic acid even though it contains no carboxylic acid groups.
In this and other properties, Meldrum's acid resembles dimedone and barbituric acid.
However, while dimedone exists in solution predominantly as the mono-enol tautomer, Meldrum's acid is almost entirely in the diketone form.

The unusually high acidity of this compound was long considered anomalous—it is 8 orders of magnitude more acidic than the closely related compound dimethyl malonate.
In 2004, Ohwada and coworkers determined that the energy-minimizing conformation structure of Meldrum's acid places the alpha proton's σ*CH orbital in the proper geometry to align with the π*CO, so that the ground state poses unusually strong destabilization of the C-H bond.[6]

Chemical Properties:
Meldrum's acid appears as white to beige crystals.
Meldrum's acid has a melting point of 94-95℃ (decomposition), is insoluble in water, and is soluble in ethanol and acetone.

Preparation of Meldrum's Acid:
Meldrum’s acid is usually prepared by condensation of malonic acid with acetone in acetic anhydride in the presence of sulfuric acid.
Excellent yield of the product was achieved when acetic anhydride was added in a slow, controlled manner to a mixture of acetone, malonic acid and an acid catalyst.

Original synthesis:
Meldrum's acid was first made by Meldrum by a condensation reaction of acetone with malonic acid in acetic anhydride and sulfuric acid.

Alternative syntheses:
As an alternative to its original preparation, Meldrum's acid can be synthesized from malonic acid, isopropenyl acetate (an enol derivative of acetone), and catalytic sulfuric acid.
A third route is the reaction of carbon suboxide C3O2 with acetone in the presence of oxalic acid.

Synthesis of Meldrum's Acid:
The chemistry of Meldrum’s acid has been surveyed in comprehensive reviews and a micro-review.
A single review is devoted to synthetic applications of the pyrolysis of Meldrum’s acid derivatives.

Meldrum's acid can be classified as a cyclic acylal.
Acylals are a group of organic compounds that share the functional group with the general structure R1R2C(OOCR3)2.

Meldrum’s acid is usually prepared by condensation of malonic acid with acetone in acetic anhydride in the presence of sulfuric acid.
Excellent yield of the product was achieved when acetic anhydride was added in a slow, controlled manner to a mixture of acetone, malonicacid and an acid catalyst.

1. The natural environment continues to be an abundant source of biologically active and structurally diverse compounds.
The mounting demand for new leads in medicinal chemistry stimulates research in the field of natural product chemistry.

Total syntheses of such substances not only provide sufficient amounts of material for biological studies, but also result in novel synthetic methods and strategies.
Due to their unique reactivity Meldrum’s acid and its derivatives have proven to be valuable reagents and intermediates in the synthesis of complex organic compounds such as natural products and their analogs.

The ability of acyl derivatives of Meldrum’s acid to generate acylketene species under pyrolysis conditions is the most fruitful field of their applications.
For example, b-ketothioesters, easily accessible from reaction of thiols with Meldrum’s acid, can be regarded as analogs of acyl-SCoA and exploited in biomimetic syntheses of polyketide derived natural products.

As demonstrated in the present review, cyclic acylals have a potential for application in stereoselective synthesis of complex organic molecules.
Another direction in their chemistry is the development of novel multicomponent and domino reactions, producing variously substituted privi-leged scaffolds.

These reactions, along with Meldrum’s acid based solid phase syntheses, are ideally suited for parallel and combinatorial processing.
Parallelization techniques provide easy exploration of the chemical space around the biologically active scaffolds, enabling generation of natural product-like libraries for biological screening and SAR studies.

2. The pyrolysis of Meldrum’s acid derivatives in solution and in gas phase takes place by loss of acetone and carbon dioxide to provide ketene intermediates.
In particular, methylene derivatives of ten provide methyleneketenes, which act as substrates for internal hydrogen transfer, leading to cyclization reactions.
These cyclization reactions are used for the efficient preparation of a diverse range of cyclic compounds such as quinolinones, 3-hydroxythiophenes, naphthols, azepin-3(2H)-ones or pyrrolizin-3-ones, initiated respectively by 1,3-, 1,4-, 1,5-, 1,6 or 1,7-prototropic shifts.

History of Meldrum's Acid:
Meldrum's acid is named after Andrew Norman Meldrum who reported its synthesis in 1908.
He misidentified its structure as a carboxylic acid based on its unusually high acidity, identifying it as the β-lactone of β-hydroxyisopropylmalonic acid; the correct structure, the bislactone of 1,3-dioxane was reported in 1948.[5]

Stability and Reactivity of Meldrum's Acid:

Chemical stability:
Stable under normal storage and handling conditions.

Conditions to avoid:
Avoid excessive heat, moisture, and incompatible materials.

Incompatible materials:
Strong oxidizing agents, strong acids, and strong bases.

Hazardous decomposition products:
Thermal decomposition may produce carbon oxides and irritating fumes.

Handling and Storage of Meldrum's Acid:

Safe handling:
Avoid dust formation and contact with skin and eyes.
Use adequate ventilation.

Storage conditions:
Store tightly closed in a cool, dry, well-ventilated place.

First Aid Measures of Meldrum's Acid:

Inhalation:
Move to fresh air and seek medical attention if symptoms persist.

Skin contact:
Wash thoroughly with soap and water.

Eye contact:
Rinse cautiously with water for several minutes.

Ingestion:
Rinse mouth and seek medical advice if discomfort occurs.

Firefighting Measures of Meldrum's Acid:

Suitable extinguishing media:
Use water spray, foam, dry chemical, or CO₂.

Protective equipment:
Firefighters should wear suitable protective equipment.

Accidental Release Measures of Meldrum's Acid:

Personal precautions:
Avoid dust formation and ensure adequate ventilation.

Cleanup methods:
Collect spilled material carefully into a suitable closed container.

Exposure Controls / Personal Protective Equipment of Meldrum's Acid:

Engineering controls:
Provide adequate ventilation.

Personal protection:
Wear protective gloves, safety glasses, and suitable protective clothing.
Use respiratory protection if dust is generated.

Identifiers of Meldrum's Acid:
CAS No.: 2033-24-1
Chemical Name: 2,2-Dimethyl-1,3-dioxane-4,6-dione
CBNumber: CB8411057
Molecular Formula: C6H8O4
Molecular Weight: 144.13
MDL Number: MFCD00006638
MOL File: 2033-24-1.mol

CAS Number: 2033-24-1
ChemSpider: 15418
ECHA InfoCard: 100.016.358
EC Number: 217-992-8
PubChem CID: 16249
UNII: DD139RP1SC
CompTox Dashboard (EPA): DTXSID7051846
InChI: InChI=1S/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3
Key: GXHFUVWIGNLZSC-UHFFFAOYSA-N
InChI: InChI=1/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3
Key: GXHFUVWIGNLZSC-UHFFFAOYAM
InChI: InChI=1/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3
Key: GXHFUVWIGNLZSC-UHFFFAOYAM
SMILES: O=C1OC(OC(=O)C1)(C)C

Product Number: M0799
Purity / Analysis Method: >98.0%(T)
Molecular Formula / Molecular Weight: C6H8O4 = 144.13
Physical State (20 deg.C): Solid
Storage Temperature: Refrigerated (0-10°C)
Condition to Avoid: Heat Sensitive
CAS RN: 2033-24-1
Reaxys Registry Number: 117310
PubChem Substance ID: 87572798
SDBS (AIST Spectral DB): 15476
Merck Index (14): 5817
MDL Number: MFCD00006638

Empirical Formula (Hill Notation): C6H8O4
CAS Number: 2033-24-1
Molecular Weight: 144.13
UNSPSC Code: 12352100
NACRES: NA.22
PubChem Substance ID: 24852618
EC Number: 217-992-8
Beilstein/REAXYS Number: 117310
MDL number: MFCD00006638
Assay: 98%

Properties of Meldrum's Acid:
Chemical Formula: C6H8O4
Molar Mass: 144.126 g·mol−1
Appearance: Beige solid
Odor: Odorless
Melting Point: 94 to 95 °C (201 to 203 °F; 367 to 368 K) (decomposes)
Solubility in Water: Soluble
Acidity (pKa): 4.97

Molecular Weight: 145.12 g/mol
XLogP3-AA: 0.6
Hydrogen Bond Donor Count: 0
Hydrogen Bond Acceptor Count: 4
Rotatable Bond Count: 0
Exact Mass: 145.04561357 Da
Monoisotopic Mass: 145.04561357 Da
Topological Polar Surface Area: 52.6 Å²
Heavy Atom Count: 10
Complexity: 164
Isotope Atom Count: 1
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes

Quality Segment: 200
Assay: 98%
Form: Solid
Melting Point: 92-96 °C
Solubility: Dioxane: soluble 5%, clear to very slightly hazy, colorless to faintly yellow
Functional Group: Ester, ketal
Storage Temperature: 2-8°C
SMILES String: CC1(C)OC(=O)CC(=O)O1
InChI: 1S/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3
InChI Key: GXHFUVWIGNLZSC-UHFFFAOYSA-N

Melting Point: 92-96 °C
Boiling Point: 182.71°C (rough estimate)
Density: 1.1311 (rough estimate)
Vapor Pressure: 0.044-133 Pa at 25℃
Refractive Index: 1.4434 (estimate)
Storage Temperature: 2-8°C
Solubility: Dioxane: soluble 5%, clear to very slightly hazy, colorless to faintly yellow
pKa: 5.1 (at 25℃)
Form: Crystals or Powder
Color: Brownish-white to beige-brown
Water Solubility: 2.5 g/100 mL (20 ºC)
Merck: 14,5817
BRN: 117310
InChI: 1S/C6H8O4/c1-6(2)9-4(7)3-5(8)10-6/h3H2,1-2H3
InChIKey: GXHFUVWIGNLZSC-UHFFFAOYSA-N
SMILES: CC1(C)OC(=O)CC(=O)O1
LogP: -1.58-4.786 at 25℃
CAS DataBase Reference: 2033-24-1
EWG's Food Scores: 1
FDA UNII: DD139RP1SC
NIST Chemistry Reference: 1,3-Dioxane-4,6-dione, 2,2-dimethyl-(2033-24-1)
EPA Substance Registry System: 1,3-Dioxane-4,6-dione, 2,2-dimethyl- (2033-24-1)
UNSPSC Code: 12352100
NACRES: NA.22

Specifications of Meldrum's Acid:
Appearance: White to Light yellow to Dark green powder to crystal
Purity (Neutralization titration): min. 98.0 %
Melting Point: 94.0 to 97.0 °C
NMR: confirm to structure

Names of Meldrum's Acid:

Preferred IUPAC name:
2,2-Dimethyl-1,3-dioxane-4,6-dione

Other names:
Isopropylidene malonate