Figure 10.8. Gabriel Synthesis
An amino acid is generated from phthalimide and diethyl bromomalonate, using two SN2 reactions,
hydrolysis, and decarboxylation.In this method, potassium phthalimide is reacted with diethyl bromomalonate. Phthalimide is
acidic and exists in solution as a nucleophilic anion. Diethyl bromomalonate contains a secondary
carbon bonded to bromine, a good leaving group. This setup should sound much like the SN 2
reactions discussed in Chapter 4 of MCAT Organic Chemistry Review. With phthalimide as the
nucleophile, the (secondary) substrate carbon as the electrophile, and bromine as the leaving
group, this reaction generates a phthalimidomalonic ester. Consider the benefits of using such a
large nucleophile. The bulkiness of this group creates steric hindrance, which prevents the substrate
carbon from undergoing multiple substitutions.
Instead, in the presence of base, this carbon (which is the α-carbon between two carbonyls) can
easily be deprotonated. The molecule as a whole can then act as a nucleophile, attacking the
substrate carbon of a bromoalkane. This is another example of an SN2 reaction. The nucleophile is
the large, deprotonated phthalimidomalonic ester, the electrophile is the substrate carbon, and the
leaving group is the bromide anion.
Next, this molecule is hydrolyzed with strong base and heat. Much like converting a cyclic anhydride
into a dioic acid, the phthalimide moiety is removed as phthalic acid (with two carboxylic acids). The
malonic ester is hydrolyzed to a dicarboxylic acid with an amine on the α-carbon.
Finally, this dicarboxylic acid, which is a 1,3-dicarbonyl, can be decarboxylated through the addition
of acid and heat. The loss of a molecule of carbon dioxide results in the formation of the complete
amino acid.