Chloroform

Chloroform, also known by its systematic name trichloromethane, is an organochlorine compound historically significant both as a laboratory solvent and as an early inhalational anaesthetic. It appears as a colourless, sweet-smelling, volatile and dense liquid that has been produced on a large industrial scale since the nineteenth century. Although its anaesthetic use declined sharply during the twentieth century due to safety concerns, chloroform remains an important chemical precursor in the manufacture of refrigerants and high-performance polymers.

Structural Characteristics and Nomenclature

Chloroform possesses the molecular formula CHCl₃ and adopts a tetrahedral molecular geometry associated with the C₃v symmetry group. Structurally, the molecule can be regarded as a methane derivative in which three hydrogen atoms have been replaced by chlorine atoms, leaving a single hydrogen atom attached to carbon. The name “chloroform” is a portmanteau derived from terchloride (a trichloride) and formyl, an obsolete term connected to the methylylidene radical originating from formic acid.
The compound is only very slightly soluble in water, with a solubility of about 8 g L⁻¹ at 20°C, but it mixes readily with many organic solvents. Due to the polarised C–H bond, chloroform participates in weak hydrogen bonding, contributing to its versatility as an organic solvent.

Natural Occurrence

Although most chloroform is of anthropogenic origin, the compound also forms naturally in several environments. Marine algae and seaweed are known to produce chloroform, and soil fungi are believed to generate it as part of their metabolic processes. In addition, abiotic mechanisms may contribute to its formation in soils, although the exact pathways remain a subject of ongoing environmental research. These natural processes mean that chloroform is present at trace levels in the atmosphere as a volatile organic compound.

Early History and Discovery

Chloroform was independently synthesised by numerous researchers during the early nineteenth century. In 1830 a German pharmacist, Samuel Moldenhawer, produced the substance by reacting chlorinated lime with ethanol, although he misidentified the product as a form of chloric ether. In 1831 the American physician Samuel Guthrie prepared the same compound using a similar method, again mistaking it for chloric ether despite observing its anaesthetic qualities.
Further work in the 1830s refined its identification. Several chemists obtained chloroform by reacting bleaching powder with ethanol or acetone. Justus von Liebig contributed to these studies, although he initially assigned an incorrect empirical formula and referred to the substance as Chlorkohlenstoff (carbon chloride). The definitive clarification came in 1834, when Jean-Baptiste Dumas determined the correct empirical formula and recognised the relationship between chloroform and formic acid derivatives. He subsequently coined the term chloroform, noting that alkaline hydrolysis produced potassium formate. In 1835, Dumas also prepared the compound through the alkaline cleavage of trichloroacetic acid.
The anaesthetic potential of chloroform was formally recognised in the 1840s. Robert Mortimer Glover, working in London, documented anaesthetic effects in animals in 1842. In 1847, the Scottish obstetrician James Young Simpson conducted the first demonstrations of its anaesthetic action in humans, using samples supplied by the pharmacist William Flockhart. Simpson’s advocacy greatly increased the compound’s medical popularity during the nineteenth century.
By the late nineteenth century chloroform was being manufactured commercially on a large scale. In Britain, production reached approximately 750,000 doses per week by 1895, primarily using the Liebig process, which remained important until the mid-twentieth century.

Industrial Production

Modern production of chloroform relies almost exclusively on the chlorination of methane or methyl chloride. At temperatures between 400°C and 500°C, free radical halogenation produces a mixture of chlorinated methanes. Continued chlorination yields carbon tetrachloride as a more highly substituted product. The resulting mixture contains chloromethane, dichloromethane, trichloromethane and tetrachloromethane, which are then isolated by fractional distillation. Smaller-scale production via the haloform reaction between acetone and sodium hypochlorite is now uncommon.

Deuterated Chloroform

A widely used isotopic derivative is deuterochloroform (CDCl₃), an essential solvent for proton-decoupled nuclear magnetic resonance spectroscopy. It is typically prepared by reacting hexachloroacetone with heavy water, or alternatively by reacting sodium deuteroxide with chloral hydrate. Although the haloform reaction is obsolete for general chloroform manufacture, it remains relevant for producing deuterated variants.

Inadvertent Domestic Formation

The haloform reaction can occasionally take place unintentionally in household settings. When sodium hypochlorite solutions, such as domestic bleach, encounter organic compounds like acetone, methyl ethyl ketone, ethanol or isopropyl alcohol, small quantities of chloroform may form alongside other chlorinated by-products such as chloroacetone or dichloroacetone.

Major Uses and Applications

Chloroform continues to be a significant industrial reagent, particularly in the chemical and polymer industries.

• Precursor to Chlorodifluoromethane (HCFC-22): The principal large-scale use of chloroform is its reaction with hydrogen fluoride to form chlorodifluoromethane. Conducted in the presence of antimony trifluoride, this transformation forms an important step in manufacturing fluoropolymers such as polytetrafluoroethylene (PTFE).
• Step in Producing Tetrafluoroethylene: Chlorodifluoromethane prepared from chloroform can be converted into tetrafluoroethylene, a key monomer in PTFE production.
• Solvent Applications: Chloroform dissolves fats, waxes, rubber, alkaloids, resins and numerous organic compounds, making it valuable in pesticide formulations, the rubber industry, laboratory cleaning, grain fumigation and various extraction processes. The deuterated form is extensively used in NMR spectroscopy.

While chloroform possesses characteristics desirable in refrigerant applications, such as a low boiling point and low global warming potential, there is limited evidence that it has been widely used directly as a refrigerant in consumer systems.

Lewis Acid Properties

In non-polar solvents and alkanes, chloroform can hydrogen bond to several Lewis bases. It is classified as a hard–soft acid–base (HSAB) acid, with ECW model parameters of Eₐ = 1.56 and Cₐ = 0.44. These properties influence its interactions in organic synthesis and solvent systems.

Synthetic Reagent Chemistry

Chloroform is a key precursor for dichlorocarbene, formed by treating it with aqueous sodium hydroxide in the presence of a phase-transfer catalyst. Dichlorocarbene supports several important organic transformations:

• Reimer–Tiemann reaction: Formylation of activated aromatic rings, particularly phenols, producing aryl aldehydes.
• Cyclopropanation: Trapping of the carbene by alkenes to generate cyclopropane derivatives.
• Kharasch addition: Formation of trichloromethyl radicals that can add across alkenes.