What is the correct sequence of steps for the Gabriel synthesis of amino acids?
a) I, II, III, IV
b) I, IV, II, III
c) IV, I, II, III
d) IV, III, IV, I
C is correct. IV, I, II, III.
In the first step of Gabriel synthesis, N-phthalimidomalonic ester is deprotonated. Next, the molecule undergoes an SN2 reaction with an alkyl halide. The third step is the hydrolysis of the protecting groups to reveal the amino group and carboxylic acids. Finally, a carboxylic acid is decarboxylated to produce the amino acid. Answer choices A, B, and D are incorrect because they present an incorrect sequence of steps.
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There are two methods used to synthesize α-amino acids that you need to know for the MCAT: Gabriel synthesis and Strecker synthesis. This post covers Gabriel synthesis.
Gabriel synthesis prepares α- amino acids from N-phthalimidomalonic ester and an alkyl halide. This should seem reasonable, since the structure of N-phthalimidomalonic ester is similar to that of an amino acid attached to large protecting groups. These protecting groups are important for ensuring that the acidic carboxylic acid and the basic amine group of the structure do not react in unnecessary acid-base reactions.
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 SN2 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.
That covers the procedure and mechanism of Gabriel amino acid synthesis. Our other MCAT posts cover the Strecker synthesis, as well as the basic structure and stereochemistry of amino acids.
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