Meldrum's acid or 2,2-dimethyl-1,3-dioxane-4,6-dione is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. T ...

with formula . Its

molecule A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...

has a

heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...

core with four

carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon mak ...

and two

oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...

atoms; the formula can also be written as . It is a crystalline colorless solid, sparingly soluble in water. It decomposes on heating with release of

carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...

and

acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscib ...

Properties

Acidity

The compound can easily lose a hydrogen ion from the methylene element 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 An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

is stabilized by

resonance Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied Periodic function, periodic force (or a Fourier analysis, Fourier component of it) is equal or close to a natural frequency of the system ...

between the two alternatives, so that the double bond is

delocalized In chemistry, delocalized electrons are electrons in a molecule, ion or solid metal that are not associated with a single atom or a covalent bond.IUPAC Gold Boo''delocalization''/ref> The term delocalization is general and can have slightly dif ...

and each oxygen in the

carbonyls In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

has a formal charge of −1/2. Meldrum-anion-resonance

The

ionization constant In chemistry, an acid dissociation constant (also known as acidity constant, or acid-ionization constant; denoted ) is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction :HA ...

p''K''_a is 4.97; which makes it behave as a

monobasic acid In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...

even though it contains no carboxylic acid groups. In this and other properties, the compound resembles

dimedone Dimedone is a cyclic diketone used in organic chemistry to determine whether a compound contains an aldehyde group. Cyclohexanediones in general can be used as catalysts in the formation of transition-metal complexes. Other uses include applicatio ...

and

barbituric acid 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 i ...

. However, while dimedone exists in solution predominantly as the mono-

enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The t ...

tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...

, Meldrum's acid is almost entirely as the

diketone In organic chemistry, a dicarbonyl is a molecule containing two carbonyl () groups. Although this term could refer to any organic compound containing two carbonyl groups, it is used more specifically to describe molecules in which both carbonyls ...

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 the compound 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.

Preparation

Original synthesis

The compound was first made by Meldrum by a

condensation reaction In organic chemistry, a condensation reaction is a type of chemical reaction in which two molecules are combined to form a single molecule, usually with the loss of a small molecule such as water. If water is lost, the reaction is also known as a ...

of acetone with

malonic acid 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' ...

in acetic anhydride and sulfuric acid. Meldrum-acid-original-synthesis

Alternative syntheses

As an alternative to its original preparation, Meldrum's acid can be synthesized from malonic acid, isopropenyl acetate (an

derivative of acetone), and catalytic sulfuric acid. A third route is the reaction of

carbon suboxide Carbon suboxide, or tricarbon dioxide, is an organic, oxygen-containing chemical compound with formula and structure . Its four cumulative double bonds make it a cumulene. It is one of the stable members of the series of linear oxocarbons , w ...

with acetone in the presence of oxalic acid.

Uses

and its ester derivatives, and other 1,3-dicarbonyl compounds, Meldrum's acid can and serve as a reactant for a variety of

nucleophilic In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

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 Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...

and

acylation In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent. Because they form a strong electrophile when treated with ...

. For example,

deprotonation Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...

and reaction with a simple

alkyl halide The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely us ...

() attaches the alkyl group () at that position: Meldrum-anion-alkylation

The analogous reaction with an acyl chloride () attaches the

acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...

() instead: Meldrum-anion-acylation

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

. 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 it's 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 The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles (3). The method involves the reaction of an α-amino-ketone (1) and a compound containing an electron-withdrawing group (e.g. an ester as shown) � ...

Synthesis of ketenes

At temperatures greater than 200 °C Meldrum's acid undergoes a

pericyclic In organic chemistry, a pericyclic reaction is the type of organic reaction wherein the transition state of the molecule has a cyclic geometry, the reaction progresses in a concerted fashion, and the bond orbitals involved in the reaction overlap ...

reaction that releases

and

and produces a highly reactive

ketene In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary monovalent chemical groups (or two separate substitution sites in the same molecule). The name may also refer to the specific compound ethen ...

compound:

These ketenes can be isolated using

flash vacuum pyrolysis Flash vacuum pyrolysis (FVP) is a technique in organic synthesis. It entails heating a precursor molecule intensely and briefly. Two key parameters are the temperature and duration (or residence time), which are adjusted to optimize yield, conver ...

(FVP). Ketenes are highly electrophilic and can undergo

addition reaction In organic chemistry, an addition reaction is, in simplest terms, an organic reaction where two or more molecules combine to form a larger one (the adduct).. Addition reactions are limited to chemical compounds that have multiple bonds, such as ...

with a range of other chemicals, particularly

ketene cycloaddition Ketene cycloadditions are the reactions of the pi system of ketenes with unsaturated compounds to provide four-membered or larger rings. +2 +2 and +2variants of the reaction are known. Introduction Ketenes may react with unsaturated compounds to ...

s, or dimerisation to

diketene Diketene is an organic compound with the molecular formula , and which is sometimes written as . It is formed by dimerization of ketene, . Diketene is a member of the oxetane family. It is used as a reagent in organic chemistry. It is a colorles ...

. With this approach it is possible to form new C–C bonds, rings,

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

s, esters, and acids: Ketene-amine-addition

Alternately, the pyrolysis can be performed in solution, to obtain the same results without isolating the ketene, in a

one-pot reaction In chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy sepa ...

. The ability to form such diverse products makes Meldrum's acid a very useful reagent for synthetic chemists.

History

The compound is named after Andrew Norman Meldrum who reported its synthesis in 1908. He misidentified its structure as a β-

lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

of β-hydroxyisopropylmalonic acid; the correct structure, the bislactone of

1,3-dioxane 1,3-Dioxane or ''m''-dioxane is a chemical compound with the molecular formula C4H8O2. It is a saturated six-membered heterocycle with two oxygen atoms in place of carbon atoms at the 1- and 3- positions. The corresponding five-membered rings are ...

was reported in 1948.