Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and polytetrafluoroethylene (PTFE). Chloroform was once used as an inhalational anesthetic between the 19th century and the first half of the 20th century. It is miscible with many solvents but it is only very slightly soluble in water (only 8 g/L at 20°C).
Structure and name The molecule adopts a tetrahedral molecular geometry with C3v symmetry. The chloroform molecule can be viewed as a methane molecule with three hydrogen atoms replaced with three chlorine atoms, leaving a single hydrogen atom.
The name "chloroform" is a portmanteau of terchloride (tertiary chloride, a trichloride) and formyle, an obsolete name for the methylylidene radical (CH) derived from formic acid.
Natural occurrence Many kinds of seaweed produce chloroform, and fungi are believed to produce chloroform in soil. Abiotic processes are also believed to contribute to natural chloroform productions in soils, although the mechanism is still unclear.
History Chloroform was synthesized independently by several investigators : Moldenhawer, a German pharmacist from Frankfurt an der Oder, appears to have produced chloroform in 1830 by mixing chlorinated lime with ethanol; however, he mistook it for Chloräther (chloric ether, 1,2-dichloroethane). Samuel Guthrie, a U.S. physician from Sackets Harbor, New York, also appears to have produced chloroform in 1831 by reacting chlorinated lime with ethanol, and noted its anaesthetic properties; however, he also believed that he had prepared chloric ether. Justus von Liebig carried out the alkaline cleavage of chloral. Liebig incorrectly states that the empirical formula of chloroform was and named it "Chlorkohlenstoff" ("carbon chloride").On pages 259–265, Liebig describes Chlorkohlenstoff ("carbon chloride", chloroform), but on p. 264, Liebig incorrectly states that the empirical formula of chloroform is C2Cl5. Eugène Soubeiran obtained the compound by the action of chlorine bleach on both ethanol and acetone.Reprinted in Reprinted in
In 1834, French chemist Jean-Baptiste Dumas determined chloroform's empirical formula and named it:Reprinted in On p. 653, Dumas states chloroform's empirical formula: "Es scheint mir also erweisen, dass die von mir analysirte Substance, … zur Formel hat: ." (Thus it seems to me to show that the substance [that was] analyzed by me … has as [its empirical] formula: .) [Note: The coefficients of his empirical formula must be halved.] Dumas then notes that chloroform's simple empirical formula resembles that of formic acid. Furthermore, if chloroform is boiled with potassium hydroxide, one of the products is potassium formate. On p. 654, Dumas names chloroform: "Diess hat mich veranlasst diese Substanz mit dem Namen 'Chloroform' zu belegen." (This caused me to bestow this substance with the name "chloroform" [i.e., formyl chloride or chloride of formic acid].) Reprinted in "Es scheint mir also erweisen, dass die von mir analysirte Substanz, … zur Formel hat: C2H2Cl6." (Thus it seems to me to show that the substance I analyzed … has as [its empirical] formula: C2H2Cl6.). [Note: The coefficients of his empirical formula should be halved.] ... "Diess hat mich veranlasst diese Substanz mit dem Namen 'Chloroform' zu belegen." (This had caused me to impose the name "chloroform" upon this substance [i.e., formyl chloride or chloride of formic acid].)
In 1835, Dumas prepared the substance by alkaline cleavage of trichloroacetic acid.
In 1842, Robert Mortimer Glover in London discovered the anaesthetic qualities of chloroform on laboratory animals.
In 1847, Scottish obstetrician James Y. Simpson was the first to demonstrate the anaesthetic properties of chloroform (provided by local pharmacist William Flockhart of Duncan, Flockhart and company,) in humans, and helped to popularize the drug for use in medicine.
The application of chloroform remained dangerous, and many deaths occurred through accidental overdose. In 1848, English physician John Snow developed an inhaler that regulated the dosage.
By the 1850s, chloroform was being produced on a commercial basis. An apparatus that could apply it safely and controllably was invented by English physician Joseph Thomas Clover in 1862.
In Britain, about 750,000 doses a week were being produced by 1895, using the Liebig procedure, which retained its importance until the 1960s. Today, chloroform – along with dichloromethane – is prepared exclusively and on a massive scale by the chlorination of methane and chloromethane.
Production Industrially, chloroform is produced by heating a mixture of chlorine and either methyl chloride () or methane (). At 400–500 °C, free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds:
Chloroform undergoes further chlorination to yield carbon tetrachloride ():
The output of this process is a mixture of the four chloromethanes: chloromethane, methylene chloride (dichloromethane), trichloromethane (chloroform), and tetrachloromethane (carbon tetrachloride). These can then be separated by distillation.
Chloroform may also be produced on a small scale via the haloform reaction between acetone and sodium hypochlorite:
Deuterochloroform
Deuterated chloroform is an isotopologue of chloroform with a single deuterium atom. is a common solvent used in NMR spectroscopy. Deuterochloroform is produced by the reaction of hexachloroacetone with heavy water. The haloform process is now obsolete for production of ordinary chloroform. Deuterochloroform can also be prepared by reacting sodium deuteroxide with chloral hydrate.
Inadvertent formation of chloroform The haloform reaction can also occur inadvertently in domestic settings. Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, methyl ethyl ketone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds, such as chloroacetone or dichloroacetone.
Uses In terms of scale, the most important reaction of chloroform is with hydrogen fluoride to give monochlorodifluoromethane (HCFC-22), a precursor in the production of polytetrafluoroethylene (Teflon) and other fluoropolymers:
The reaction is conducted in the presence of a catalytic amount of mixed antimony halides. Chlorodifluoromethane is then converted to tetrafluoroethylene, the main precursor of Teflon.
Solvent The hydrogen attached to carbon in chloroform participates in hydrogen bonding, making it a good solvent for many materials.
Worldwide, chloroform is also used in pesticide formulations, as a solvent for lipids, rubber, alkaloids, waxes, gutta-percha, and resins, as a cleaning agent, as a grain fumigant, and in fire extinguishers. is a common solvent used in NMR spectroscopy.
Refrigerant Chloroform is used as a precursor to make R-22 (chlorodifluoromethane). This is done by reacting it with hydrofluoric acid (HF) which fluorinates the molecule and releases hydrochloric acid as a byproduct. Before the Montreal Protocol was enforced, most of the chloroform produced in the United States was used in the production of chlorodifluoromethane. However, its production remains high, as it is a key precursor of PTFE.
Although chloroform has properties such as a low boiling point, and a low global warming potential of only 31 (compared to the 1760 of R-22), which are appealing properties for a refrigerant, there is little information to suggest that it has seen widespread use as a refrigerant in any consumer products.
Lewis acid In solvents such as and alkanes, chloroform hydrogen bonds to a variety of Lewis bases. is classified as a hard acid, and the ECW model lists its acid parameters as EA = 1.56 and CA = 0.44.
Reagent As a reagent, chloroform serves as a source of the dichlorocarbene intermediate . It reacts with aqueous sodium hydroxide, usually in the presence of a phase transfer catalyst, to produce dichlorocarbene, . This reagent effects ortho-formylation of activated aromatic rings, such as phenols, producing aryl aldehydes in a reaction known as the Reimer–Tiemann reaction. Alternatively, the carbene can be trapped by an alkene to form a cyclopropane derivative. In the Kharasch addition, chloroform forms the free radical which adds to alkenes.
Anaesthetic
Chloroform is a powerful general anesthetic, euphoriant, anxiolytic, and sedative when inhaled or ingested. The anaesthetic qualities of chloroform were first described in 1842 in a thesis by Robert Mortimer Glover, which won the Gold Medal of the Harveian Society for that year. Glover also undertook practical experiments on dogs to prove and refine his theories, and subsequently presented them in his doctoral thesis at the University of Edinburgh in the summer of 1847, identifying anaesthetizing halogenous compounds as a "new order of poisonous substances".
James Young Simpson, a Scottish obstetrician, was one of those examiners required to read the thesis, but later claimed to have never read it and to have come to his own conclusions independently. Perkins-McVey, among others, have raised doubts about the credibility of Simpson's claim, noting that Simpson's publications on the subject in 1847 explicitly echo Glover's and, being one of the thesis examiners, Simpson was likely aware of the content of Glover's study, even if he skirted his duties as an examiner. In 1847 and 1848, Glover would pen a series of heated letters accusing Simpson of stealing his discovery, which had already earned Simpson considerable notoriety. Whatever the source of his inspiration, on 4 November 1847, Simpson argued that he had discovered the anaesthetic qualities of chloroform in humans. He and two colleagues entertained themselves by trying the effects of various substances, and thus revealed the potential for chloroform in medical procedures.
A few days later, during the course of a dental procedure in Edinburgh, Francis Brodie Imlach became the first person to use chloroform on a patient in a clinical context.
In May 1848, Robert Halliday Gunning made a presentation to the Medico-Chirurgical Society of Edinburgh following a series of laboratory experiments on rabbits that confirmed Glover's findings and also refuted Simpson's claims of originality. The laboratory experiments that proved the dangers of chloroform were largely ignored.
The use of chloroform during surgery expanded rapidly in Europe; in the 1850s chloroform was used by the physician John Snow during the births of Queen Victoria's last two children Leopold and Beatrice. In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; it was abandoned in favor of ether on discovery of its toxicity, especially its tendency to cause fatal cardiac arrhythmias analogous to what is now termed "sudden sniffer's death". Some people used chloroform as a recreational drug or to attempt suicide. One possible mechanism of action of chloroform is that it increases the movement of potassium ions through certain types of potassium channels in nerve cells. Chloroform could also be mixed with other anesthetic agents such as ether to make C.E. mixture, or ether and alcohol to make A.C.E. mixture.
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anaesthetic. Her autopsy establishing the cause of death was undertaken by John Fife assisted by Robert Mortimer Glover. A number of physically fit patients died after inhaling it. In 1848, however, John Snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths. Joseph Thomas Clover improved on the design in 1862, further reducing the risk of accidental overdose.