Researchers want to synthesize valine from isovaleric acid. The enol shown below, with certain carbon atoms labeled, is formed from the reaction of isovaleric acid with PBr₃. If Br₂ and then water are added to the enol, which of the following carbon atoms will be brominated in the final product?

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11ecba2d_127c_dc93_a3bf_5d13a057c6ae_MD0008_00 Substitution of bromine on the α-carbon of a carboxylic acid, known as the Hell-Volhard-Zelinsky (HVZ) reaction, begins with the addition of PBr₃. This step converts the carboxylic acid to an acyl bromide, which can then tautomerize from the keto form to the enol form. When Br₂ is added to the reaction, the enol form of the acyl bromide acts as the nucleophile and attacks bromine. One of the bromine atoms in Br₂ withdraws electrons away from the other, giving it a partial positive charge and making it a good electrophile. The electrophilic bromine is added to the α-carbon, forming an α-bromo acyl bromide and HBr. Finally, when water is added, it attacks the electrophilic carbonyl carbon, and the bromine on the carbonyl carbon acts as the leaving group. This yields an α-bromoacid, which is a useful intermediate in the synthesis of α-amino acids such as valine. The carbon adjacent to the carbonyl group (carbon 2) is the α-carbon. The α-carbons in enols are susceptible to substitution because the carbocation formed is stabilized by resonance with the enol hydroxyl group. In this case, the α-carbon becomes brominated after the addition of Br₂. The bromine on the carbonyl carbon (carbon 3) is eliminated during hydrolysis. Carbon 2 is the only carbon to remain brominated after hydrolysis, yielding the final product, an α-bromoacid. (Choices A, C, and D) Although carbon 2 is brominated in the final product, carbon 1 does not participate in the reaction. The bromine on carbon 3 is eliminated during hydrolysis when water is added. Educational objective: The α-carbon of a carboxylic acid is the carbon atom adjacent to the carbonyl carbon, and it is susceptible to substitution reactions such as bromination. The carbonyl carbon of a carboxylic acid may be temporarily brominated, but this carbon is susceptible to hydrolysis when water is added.

Researchers Want to Synthesize Valine from Isovaleric Acid