15.9:
Multiple Halogenation of Methyl Ketones: Haloform Reaction
The haloform reaction is a method to obtain carboxylic acids from methyl ketones in the presence of an excess of base and halogen. It is named after the by-product of the reaction—haloform.
The reaction commences with generation of an enolate, followed by halogenation to give an α-halo ketone.
This continues until all α protons are replaced by halogens to form a trihalomethyl ketone.
The resulting molecule is unstable and undergoes a nucleophilic acyl substitution reaction with a hydroxide base to expel trihalomethyl carbanion—a good leaving group—and form carboxylic acid.
The carbanion is stabilized by the electron-withdrawing effect of the three halogens, which irreversibly deprotonates the carboxylic acid to produce carboxylate ion and haloform.
This step drives the haloform reaction to completion. Further, acidification of the carboxylate generates carboxylic acid.
With chlorine and bromine, the by-products are chloroform and bromoform which are liquids and immiscible in the reaction mixture.
The use of iodine forms iodoform—a yellow precipitate. This forms the basis of the iodoform test for the qualitative detection of methyl ketones.
15.9:
Multiple Halogenation of Methyl Ketones: Haloform Reaction
A method involving the transformation of methyl ketones to carboxylic acids using excess base and halogen is called the haloform reaction. It begins with the deprotonation of α hydrogen to form an enolate ion which reacts with the electrophilic halogen to give an α-halo ketone. The step continues until all the α protons are substituted to form a trihalomethyl ketone. The resulting molecule is unstable, and in the presence of a hydroxide base, it readily undergoes nucleophilic acyl substitution. This leads to the expulsion of trihalomethyl carbanion and produces carboxylic acid. The carbanion generated is stable owing to the electron-withdrawing effect of the three halogens. Subsequent deprotonation of the acid by carbanion forms a carboxylate and haloform, which is the driving force of the reaction. Finally, acidification of the carboxylate gives the desired product, and the reaction is named after the by-product. Using chlorine or bromine results in immiscible liquids of chloroform and bromoform. In contrast, iodine forms a yellow precipitate of iodoform, often used to detect methyl ketones in unknown substrates.