Gabriel Synthesis of Amino Acids

The synthesis reaction begins with the addition of sodium ethoxide (NaOEt), a strong base to a solution of N-phthalimidomalonic ester. Sodium ethoxide removes the hydrogen atom attached to the α -carbon of N-phthalimidomalonic ester’s two ester groups, forming an enolate. When an alkyl halide is introduced, the enolate ion acts as a nucleophile, and a nucleophilic substitution reaction (specifically, an S_N2 reaction) occurs. The structure of the alkyl halide determines the side chain of the amino acid. Then, a hydrolysis reaction is performed under acidic conditions. This removes the protecting groups and ester groups from around the amino group and carboxylic acid groups, respectively. The final step is introducing heat to stimulate decarboxylation, producing the α-amino acid product. Recall that decarboxylation can occur when heat is added to a compound that has two carboxylic acid groups that are β to each other.

As a final note, just like the Strecker synthesis, the Gabriel synthesis of α -amino acids produces racemic mixtures and the identity of the final α -amino acid product is entirely dependent on the nature of the R-group-containing reactant added. In this case, this addition occurs through the alkyl halide.