Meldrum's acid
Encyclopedia
Meldrum's acid or 2,2-dimethyl-1,3-dioxane-4,6-dione is an organic compound
. The compound 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. The correct structure is shown on this page.
As an alternative to its original preparation, Meldrum's acid can be synthesized from malonic acid, isopropenyl acetate, and catalytic sulfuric acid. Meldrum's acid has a high acidity with a pKa
of 4.97. Meldrum's acid high acidity was long considered "anomalous" given it is 8 orders of magnitude more acidic than the highly related compound, dimethyl malonate (whose aqueous pKa is around 13). In 2004, Ohwada and coworkers resolved the Meldrum acid anomaly by performing several calculations. Ohwada noticed that the energy-minimizing conformation structure of the compound places the alpha proton's σCH 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.
Because of its great acidity, Meldrum's acid, like malonic acid, can serve as a reactant in Knoevenagel condensation
s.
and carbon dioxide
and produces a highly reactive ketene
compound. Ketene intermediates can be isolated using flash vacuum pyrolysis
(FVP) of Meldrum's acid at high temperatures. These highly electrophilic ketenes allow various chemical reactions to take place by reaction the unstable ketene with other chemicals. Alternately, the pyrolysis can be performed in solution, allowing a one-pot reaction with chemicals already present rather than isolating the unstable ketene intermediate. With relative simplicity, is possible to form new C–C bonds, rings, amides, esters, and acids. The ability to form such diverse products makes Meldrum's acid a very useful reagent for synthetic chemists.
and reaction with a simple alkyl halide allows formation of products containing carbon chains attached to the ring. Alternatively, this position can be acyl
ated with a carboxylic acid chloride (RCOCl).
These two reactions allow Meldrum's acid to serve as a starting scaffold for the synthesis of many different structures with various functional groups. Paired with the pyrolysis and nucleophilic trapping reaction, above, the alkylated products can be carried on to produce a range of different 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
. Ketoesters of this type are useful in the Knorr pyrrole synthesis
.
Organic compound
An organic compound is any member of a large class of gaseous, liquid, or solid chemical compounds whose molecules contain carbon. For historical reasons discussed below, a few types of carbon-containing compounds such as carbides, carbonates, simple oxides of carbon, and cyanides, as well as the...
. The compound was first made in 1908 by Andrew Norman Meldrum
Andrew Norman Meldrum
Andrew Norman Meldrum was a Scottish scientist known for his work in organic chemistry and for his studies of the history of chemistry. It has been claimed that Meldrum's acid "is the only chemical to be named after a Scotsman."He was educated at Gordon's College in Aberdeen, the Royal College of...
by a condensation reaction
Condensation reaction
A condensation reaction is a chemical reaction in which two molecules or moieties combine to form one single molecule, together with the loss of a small molecule. When this small molecule is water, it is known as a dehydration reaction; other possible small molecules lost are hydrogen chloride,...
of malonic acid
Malonic acid
Malonic acid is a dicarboxylic acid with structure CH22. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ethyl ester...
with acetone
Acetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
in acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
and sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...
. Meldrum misidentified the structure as a β-lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
of β-hydroxyisopropylmalonic acid. The correct structure is shown on this page.
As an alternative to its original preparation, Meldrum's acid can be synthesized from malonic acid, isopropenyl acetate, and catalytic sulfuric acid. Meldrum's acid has a high acidity with a pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
of 4.97. Meldrum's acid high acidity was long considered "anomalous" given it is 8 orders of magnitude more acidic than the highly related compound, dimethyl malonate (whose aqueous pKa is around 13). In 2004, Ohwada and coworkers resolved the Meldrum acid anomaly by performing several calculations. Ohwada noticed that the energy-minimizing conformation structure of the compound places the alpha proton's σCH 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.
Because of its great acidity, Meldrum's acid, like malonic acid, can serve as a reactant in Knoevenagel condensation
Knoevenagel condensation
The Knoevenagel condensation reaction is an organic reaction named after Emil Knoevenagel. It is a modification of the Aldol condensation.A Knoevenagel condensation is a nucleophilic addition of an active hydrogen compound to a carbonyl group followed by a dehydration reaction in which a molecule...
s.
Ketene formation
Meldrum's acid displays thermal instability. At high temperatures, Meldrum's acid undergoes a pericyclic reaction that releases acetoneAcetone
Acetone is the organic compound with the formula 2CO, a colorless, mobile, flammable liquid, the simplest example of the ketones.Acetone is miscible with water and serves as an important solvent in its own right, typically as the solvent of choice for cleaning purposes in the laboratory...
and carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
and produces a highly reactive ketene
Ketene
A ketene is an organic compound of the form R'RC=C=O. The term is also used specifically to mean ethenone, the simplest ketene, where R' and R are hydrogen atoms.Ketenes were first studied as a class by Hermann Staudinger.-Formation:...
compound. Ketene intermediates can be isolated using flash vacuum pyrolysis
Pyrolysis
Pyrolysis is a thermochemical decomposition of organic material at elevated temperatures without the participation of oxygen. It involves the simultaneous change of chemical composition and physical phase, and is irreversible...
(FVP) of Meldrum's acid at high temperatures. These highly electrophilic ketenes allow various chemical reactions to take place by reaction the unstable ketene with other chemicals. Alternately, the pyrolysis can be performed in solution, allowing a one-pot reaction with chemicals already present rather than isolating the unstable ketene intermediate. With relative simplicity, is possible to form new C–C bonds, rings, amides, esters, and acids. The ability to form such diverse products makes Meldrum's acid a very useful reagent for synthetic chemists.
Alkylation and acylation
The position between the two carbonyl groups in Meldrum's acid is acidic, allowing simple alkylation and acylation at this position. For example, deprotonationDeprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...
and reaction with a simple alkyl halide allows formation of products containing carbon chains attached to the ring. Alternatively, this position can be acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
ated with a carboxylic acid chloride (RCOCl).
These two reactions allow Meldrum's acid to serve as a starting scaffold for the synthesis of many different structures with various functional groups. Paired with the pyrolysis and nucleophilic trapping reaction, above, the alkylated products can be carried on to produce a range of different 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
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 to both carbonyl groups, and then converted to a substituted acetic acid. The major drawback of malonic ester synthesis is that the alkylation stage can also...
. The reactive nature of the cyclic-diester allows good reactivity even for alcohols as hindered as t-butanol
Tert-Butanol
tert-Butanol, or 2-methyl-2-propanol, is the simplest tertiary alcohol. It is one of the four isomers of butanol. tert-Butanol is a clear liquid with a camphor-like odor. It is very soluble in water and miscible with ethanol and diethyl ether...
. Ketoesters of this type are useful in the Knorr pyrrole synthesis
Knorr pyrrole synthesis
The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles '. The method involves the reaction of an α-amino-ketone ' and a compound containing a methylene group α- to a carbonyl group '.-Method:The mechanism requires zinc and acetic acid as catalysts...
.
External links
- Synlett Spotlight Website
- Meldrum's acid in Organic SynthesesOrganic SynthesesOrganic Syntheses is a scientific journal that since 1921 has provided the chemistry community with annual collections of detailed and checked procedures for the organic synthesis of organic compounds. The journal is peer reviewed...
Website