Need help preparing for the Organic Chemistry section of the MCAT? MedSchoolCoach expert, Ken Tao, will teach everything you need to know about Gabriel Synthesis of amino acids. Watch this video to get all the MCAT study tips you need to do well on this section of the exam!
Gabriel Synthesis
Gabriel synthesis is a method of preparing an α- amino acid through the use of a N-phthalimidomalonic ester and an alkyl halide. This method can fairly easily be applied outside of synthesize other, similar, compounds, but it is only its application towards the synthesis of α- amino acids that is of interest for the MCAT.
Simplified Overview
Gabriel synthesis generally proceeds in 3 steps: First through the addition of a phthalimide salt to a malonic ester, then through addition of a base to activate an alpha-carbon as a nucleophile followed by the immediate addition of an alkyl halide, and finally through a base or acid catalyzed hydrolysis step.
Detailed Mechanism
The first step is to actually synthesize our N-phthalimido malonic ester. When a phthalimide salt is in aqueous solution, it dissociates. The α-carbon of an α -alkylated malonic ester undergoes nucleophilic attack by phthalimide anion, forming a N-phthalimido malonic ester.
The α -carbon now again has a fairly labile proton due to the inductive effect of both nearby carbonyl groups and the nitrogen. This allows it to be deprotonated at the α -carbon by a base such as sodium ethoxide. This deprotonation activates the α -carbon for a nucleophilic attack on the electrophilic center of an alkyl halide. The choice of alkyl halide will determine the R-group of the resulting amino acid, as the halide will act as a leaving group and the remaining alkyl chain will remain attached and in the correct position to become the R-group of the resulting α -amino acid.
Before this can happen though, our third and final step most occur: Hydrolysis of our complex phthalidomalonic ester by either an acid or base work-up routine. The details of this are not too critical - simply realize that esters can be hydrolyzed under either condition, and that this occurs more easily at higher temperatures. This will produce a product that will not quite resembling an amino acid yet. However, addition of a strong protic acid and heat will readily decarboxylate the backbone of this structure and produce an α -amino acid.
As a final note, much like Strecker synthesis, Gabriel synthesis of α -amino acids produces racemic mixtures as well and the identity of the final α -amino acid product is entirely dependent on the nature of the R-group we decide to add. In this case, this addition occurs through the alkyl halide.
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