Malonic and acetoacetic syntheses

The malonic ester synthesis is a reaction in which an ester of malonic acid is alkylated at the carbon between the carbonyl groups and then converted into a substituted acetic acid by final hydrolysis and decarboxylation.

The malonic ester loses a proton to a base, the anion is alkylated by a halide and the alkylated diester is hydrolysed and decarboxylated to the substituted acetic acid

Enolate formation

The hydrogens on the carbon between the carbonyl groups are quite acidic because the negative charge of the conjugate-base carbanion is stabilized by both C=O groups. An alkoxide is enough to form the enolate completely.

Ethoxide removes a hydrogen from diethyl malonate, pKa 14, and an anion with three resonance forms results: the charge on the central carbon and on each carbonyl oxygen

Mechanism

The resulting carbanion is very nucleophilic and can perform a nucleophilic substitution on a compound with a good leaving group, such as an alkyl halide or sulfonate. The alkylated diester is then saponified and, on heating, the substituted malonic acid easily loses CO₂ through a six-membered cyclic transition state, giving an alkylated acetic acid:

The substituted malonic acid forms a cyclic hydrogen-bonded transition state, loses carbon dioxide and gives an enol that tautomerizes to the substituted acetic acid

Think retrosynthetically! The malonic diester can be regarded as a synthetic equivalent of the ⁻CH₂COOH synthon (see the synthon).

Double alkylation

If the alkylation is done twice, the outcome is a dialkylated acetic acid:

Diethyl malonate is alkylated successively with R–X and R′–X, and acid hydrolysis with decarboxylation gives the dialkylated acid

Cycloalkanecarboxylic acids can be obtained in this way by using alkyl dihalides of different lengths: the second alkylation is intramolecular.

Diethyl malonate is alkylated with 1,4-dibromobutane; a second deprotonation causes cyclization to a cyclopentane-1,1-dicarboxylate, which gives cyclopentanecarboxylic acid

Meldrum’s acid

A very interesting malonate-related molecule is Meldrum’s acid, named after its discoverer (1908): it is a cyclic diester of malonic acid with acetone hydrate. Meldrum’s acid is even more acidic than malonate; its pK_a, close to that of acetic acid, is due to the ring holding both carbonyls in a conformation that stabilizes the charge very well.

Three resonance forms of the anion of Meldrum’s acid: the charge on the central carbon or on either carbonyl oxygen

The resulting carbanion is also very nucleophilic and undergoes alkylation and acylation; after hydrolysis, an alkylated or acylated acetic acid is obtained (with release of acetone and CO₂):

The Meldrum’s acid anion is alkylated by R–X and hot acid hydrolysis gives the acid R–CH2–COOH, acetone and carbon dioxide

The Meldrum’s acid anion is acylated by an acyl chloride and hydrolysis gives a beta-keto acid, acetone and carbon dioxide

Acetoacetic ester synthesis

The acylacetates obtained from Meldrum’s acid can be used further in synthesis because, as happens with malonic derivatives and with Meldrum’s acid itself, the hydrogens on the carbon between the carbonyls are relatively acidic and the resulting anion can take part in nucleophilic reactions. The simplest one, ethyl acetoacetate, is alkylated just like malonate; depending on how the product is hydrolysed, a methyl ketone (ketonic cleavage) or an ester (acid cleavage) is obtained:

Ethyl acetoacetate is alkylated with ethoxide and R′–X; with acid or dilute base CO2 is lost to give a methyl ketone, and with concentrated base acetate is lost to give an ester

The Knoevenagel reaction

The carbanions of dicarbonyl compounds such as malonic esters, Meldrum’s acid, acetoacetates and many other related compounds can react with aldehydes or ketones, lose a molecule of water and give, after (hydrolysis and) decarboxylation, an α,β-unsaturated acid. This is the Knoevenagel condensation, named after its discoverer; it is studied in more detail in topic 7.

An aldehyde or ketone condenses with a compound bearing two electron-withdrawing groups on the same CH2, in the presence of an amine, to give the alkene with loss of water

In the Doebner modification malonic acid itself is used in pyridine: condensation is followed by spontaneous decarboxylation and the α,β-unsaturated acid is obtained directly.

Acrolein and malonic acid in pyridine give 2,4-pentadienoic acid with loss of carbon dioxide

The Knoevenagel condensation of benzaldehydes with nitroalkanes is a classic general method for preparing nitroalkenes, which are very valuable synthetic intermediates (see the Henry reaction):

Benzaldehyde and 1-nitropropane with base give the nitro alcohol, which loses water to give 2-nitro-1-phenyl-1-butene

A synthesis example

Synthesis of valproic acid