Haloform reaction

The haloform reaction, also known as the Lieben haloform reaction, produces a haloform (CHX₃, where X is a halogen) through the complete halogenation of an acetyl group (R−C(=O)CH₃) in a basic environment. This process can convert acetyl groups into carboxyl groups or generate chloroform, bromoform, or iodoform. Fluoroform cannot be made using this method.

Mechanism

The mechanism begins with the halogen reacting with hydroxide to form a halide and a hypohalite. If a secondary alcohol is present, the hypohalite oxidizes it to a ketone. For a methyl ketone, the reaction proceeds in three steps: first, under basic conditions, the ketone undergoes keto-enol tautomerization, and the enolate is attacked by the hypohalite.

Second, after the alpha position is fully halogenated, the molecule reacts with hydroxide, with a leaving group stabilized by three electron-withdrawing groups. Third, the resulting anion picks up a proton from the solvent or the carboxylic acid formed earlier, yielding the haloform. In some cases, such as with chloral hydrate, the reaction can stop at an intermediate if conditions are acidic and hypohalite is used.

Scope

Suitable substrates are mostly methyl ketones and secondary alcohols that can be oxidized to methyl ketones, like isopropanol. The only primary alcohol and aldehyde that work are ethanol and acetaldehyde. 1,3-Diketones such as acetylacetone also react, as do β-ketoacids like acetoacetic acid when heated.

Acetyl chloride and acetamide do not undergo this reaction. The halogens used can be chlorine, bromine, iodine, or sodium hypochlorite. Fluoroform cannot be made this way because it would require the unstable hypofluorite ion, though ketones with the structure RCOCF₃ do cleave with base to produce fluoroform, which is equivalent to the last two steps of the process.

Laboratory scale

On a laboratory scale, the reaction is the basis of the iodoform test, historically used to detect methyl ketones or secondary alcohols that can be oxidized to them. Using iodine and sodium hydroxide, a positive test yields iodoform, a solid at room temperature that precipitates as a cloudy suspension. The reaction can also convert a terminal methyl ketone into the corresponding carboxylic acid.

As a by-product of water chlorination

Industrially, it was once used to produce iodoform, bromoform, and chloroform. A variant produces deuterated chloroform by reacting hexachloroacetone with heavy water in the presence of a base, or by decomposing calcium trichloroacetate in heavy water. In water chlorination, haloforms can form if the water contains reactive impurities like humic acid; chloroform, in particular, is suspected to be carcinogenic and is linked to a weak association between chlorinated water consumption and cancer.

The haloform reaction is one of the oldest known organic reactions. In 1822, Georges-Simon Serullas reacted potassium metal with iodine in ethanol and water to produce potassium formate and iodoform.

In 1832, Justus von Liebig reported the reaction of chloral with calcium hydroxide to form chloroform and calcium formate. Adolf Lieben rediscovered the reaction in 1870, and the iodoform test is also called the Lieben iodoform reaction. A review of the haloform reaction including its history was published in 1934.