Haloform reaction
A base-catalyzed reaction producing haloforms from acetyl groups.
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.
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.
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.
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. 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.
- type
- Chemical reaction
- key_contributors
- Georges-Simon Serullas, Justus von Liebig, Adolf Lieben
- field
- Organic chemistry
- known_for
- Production of haloforms, iodoform test for methyl ketones
- substrates
- Methyl ketones, secondary alcohols oxidizable to methyl ketones, ethanol, acetaldehyde, 1,3-diketones, β-ketoacids
Lore & Background
The haloform reaction is a chemical process in which a haloform, such as chloroform, bromoform, or iodoform, is produced through the exhaustive halogenation of an acetyl group in the presence of a base. The reaction can transform acetyl groups into carboxyl groups. Fluoroform cannot be prepared by this method, as it would require the highly unstable hypofluorite ion. The reaction has a distinctive appearance: when iodine and sodium hydroxide are used, the resulting iodoform is a solid at room temperature that precipitates from solution, creating a characteristic cloudiness. The range of applicable substrates is limited to methyl ketones and secondary alcohols that can be oxidized to methyl ketones, such as isopropanol; only ethanol and acetaldehyde among primary alcohols and aldehydes undergo the reaction. 1,3-Diketones and β-ketoacids also react, but acetyl chloride and acetamide do not. The reaction can be performed using chlorine, bromine, iodine, or sodium hypochlorite. Historically, it was used industrially to produce iodoform, bromoform, and chloroform. It also forms the basis of the iodoform test, a classic chemical test for methyl ketones or oxidizable secondary alcohols. The reaction is one of the oldest known organic reactions, first observed in 1822 when potassium metal was added to a solution of iodine in ethanol and water, yielding potassium formate and iodoform. A notable variant is used to manufacture deuterated chloroform. Water chlorination can also produce haloforms as by-products when reactive impurities like humic acid are present, with chloroform being suspected as carcinogenic.
Reader's Guide
The haloform reaction has significant historical and practical importance in organic chemistry. It forms the basis of the iodoform test, which was commonly used as a chemical test to determine the presence of a methyl ketone or a secondary alcohol oxidizable to a methyl ketone. When iodine and sodium hydroxide are used, a positive reaction gives iodoform, a solid at room temperature that precipitates out of solution, causing a distinctive cloudiness. The reaction can also be used to convert a terminal methyl ketone into the analogous carboxylic acid. Industrially, it was formerly used to produce iodoform, bromoform, and chloroform. A variant is used to manufacture deuterated chloroform via reaction of hexachloroacetone with heavy water or decomposition of calcium trichloroacetate in heavy water. Water chlorination can result in the formation of haloforms if water contains suitable reactive impurities such as humic acid; chloroform is suspected to be carcinogenic and is associated with a weak link between chlorinated water consumption and cancer. Substrates are broadly limited to methyl ketones and secondary alcohols oxidizable to methyl ketones, with ethanol and acetaldehyde being the only primary alcohol and aldehyde to undergo the reaction. Acetyl chloride and acetamide do not undergo this reaction.
Did You Know?
- Fluoroform cannot be prepared by the haloform reaction because it would require the highly unstable hypofluorite ion.
- Water chlorination can produce haloforms like chloroform from impurities such as humic acid, and chloroform is suspected to be carcinogenic.
- A variant of the reaction uses hexachloroacetone with heavy water to manufacture deuterated chloroform.
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