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

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with formula . Its

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

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 organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

core with four

carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—meaning that its atoms are able to form up to four covalent bonds due to its valence shell exhibiting 4 ...

and two

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

atoms; the formula can also be written as . It is a crystalline colorless solid that is sparingly soluble in water and which decomposes on heating to

carbon dioxide Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...

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

, and a

ketene In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary valence (chemistry), monovalent functional group, chemical groups (or two separate Substituent, substitution sites in the same molecule). The na ...

. Its synthesis was first reported in 1908 by Andrew Norman Meldrum, for whom it is named. Meldrum incorrectly concluded that it was a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

based on its acidity; the correct bislactone structure was not reported until 1948.

Properties

Acidity

The compound can easily lose a hydrogen ion from the methylene () 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 conven ...

is stabilized by

resonance Resonance is a phenomenon that occurs when an object or system is subjected to an external force or vibration whose frequency matches a resonant frequency (or resonance frequency) of the system, defined as a frequency that generates a maximu ...

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

The ionization constant p''K''_a is 4.97; which makes it behave as a monobasic acid even though it contains no

groups. In this and other properties, the compound resembles dimedone 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, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...

tautomer In chemistry, 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 reloca ...

, Meldrum's acid is almost entirely in 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 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 ...

acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the chemical formula, formula . Commonly abbreviated , it is one the simplest organic acid anhydride, anhydrides of a carboxylic acid and is widely used in the production of c ...

and

sulfuric acid Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid (English in the Commonwealth of Nations, Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen, ...

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 , wh ...

with acetone in the presence of

oxalic acid Oxalic acid is an organic acid with the systematic name ethanedioic acid and chemical formula , also written as or or . It is the simplest dicarboxylic acid. It is a white crystalline solid that forms a colorless solution in water. Its name i ...

Uses

and its ester derivatives, and other 1,3-dicarbonyl compounds, Meldrum's acid can 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 a ...

reactions.

Alkylation and acylation

The acidity of carbon 5 (between the two carbonyl groups) allows simple

derivatization Derivatization is a technique used in chemistry which converts a chemical compound into a product (the reaction's derivate) of similar chemical structure, called a derivative. Generally, a specific functional group of the compound participates ...

of Meldrum's acid at this position, through reactions such as

alkylation Alkylation is a chemical reaction that entails transfer of an alkyl group. 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 effecting al ...

and

acylation In chemistry, acylation is a broad class of chemical reactions in which an acyl group () is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the foll ...

. 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.ed ...

and reaction with a simple

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

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

The analogous reaction with an

acyl chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

() 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 organyl group () or hydrogen in the case of formyl grou ...

() 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 Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

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. A 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 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 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 overl ...

reaction that releases

and

and produces a highly reactive

compound:

These ketenes can be isolated using flash vacuum pyrolysis (FVP). Ketenes are highly electrophilic and can undergo

addition reactions Addition (usually signified by the plus symbol, +) is one of the four basic operations of arithmetic, the other three being subtraction, multiplication, and division. The addition of two whole numbers results in the total or '' sum'' of th ...

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 com ...

s, or dimerisation to diketene. 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 chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

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 in which a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy ...

. 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

based on its unusually high acidity, identifying it as the β-

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

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

1,3-dioxane 1,3-Dioxane or ''m''-dioxane is an organic compound with the molecular formula . It is a saturated six-membered heterocycle with two oxygen atoms in place of carbon atoms at the 1- and 3- positions. 1,4-Dioxane, which is of greater commercial va ...

was reported in 1948.