15.34:
Alkylation of β-Diester Enolates: Malonic Ester Synthesis
In malonic ester synthesis, β-diesters bearing acidic α protons in the presence of a base and an alkyl halide generate substituted acetic acids via alkylated malonic ester intermediates.
Initially, the base removes the α proton of the diester to generate a nucleophilic enolate ion that is highly stabilized by three resonance structures.
Alkylating the anionic carbon through an SN2 mechanism produces an alkyl malonic ester intermediate. This undergoes hydrolysis followed by acidification to give the β-diacid.
The β-diacid, at high temperatures, undergoes a concerted process that expels CO2 to produce an enol. This rapidly tautomerizes to the stable keto form of the substituted acetic acid.
As the reaction comprises the elimination of a single proton, the resulting acid is monosubstituted.
If, however, the monoalkylated intermediate is subjected to the second alkylation process, a disubstituted acid will result.
15.34:
Alkylation of β-Diester Enolates: Malonic Ester Synthesis
Malonic ester synthesis is a method to obtain α substituted carboxylic acids from ꞵ-diesters such as diethyl malonate and alkyl halides.
The reaction proceeds via abstraction of the acidic α hydrogen from a ꞵ-diester to produce a doubly stabilized enolate ion. The nucleophilic enolate attacks the alkyl halide in an SN2 manner to form an alkylated malonic ester intermediate with a new C–C bond. Further treating the intermediate with aqueous acid or base results in the hydrolysis of the two ester groups to give a 1,3-dicarboxylic acid. The resulting ꞵ-diacid is unstable at high temperatures and readily eliminates CO2 through a cyclic six-membered transition state, forming an enol. The enol tautomerizes to its more stable keto form producing a monosubstituted carboxylic acid. However, a disubstituted carboxylic acid is achieved if the deprotonation and alkylation steps are repeated before hydrolysis and decarboxylation.