Chloroform

Deuterochloroform

Deuterated chloroform is an isotopologue of chloroform with a single deuterium atom. CDCl₃ is a common solvent used in NMR spectroscopy. Deuterochloroform is produced by the reaction of hexachloroacetone with heavy water.^[31] The haloform process is now obsolete for production of ordinary chloroform. Deuterochloroform can also be prepared by reacting sodium deuteroxide with chloral hydrate.^[32][33]

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.^{[citation needed]}

Solvent

The hydrogen attached to carbon in chloroform participates in hydrogen bonding,^[35][36] 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, in fire extinguishers, and in the rubber industry.^[37][38] CDCl₃ is a common solvent used in NMR spectroscopy.^[39]

Refrigerant

Chloroform is used as a precursor to make R-22 (chlorodifluoromethane). This is done by reacting it with a solution of hydrofluoric acid (HF) which fluorinates the CHCl₃ molecule and releases hydrochloric acid as a byproduct.^[40] 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.^[41]

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.^[42]

Lewis acid

In solvents such as CCl₄ and alkanes, chloroform hydrogen bonds to a variety of Lewis bases. HCCl₃ is classified as a hard acid, and the ECW model lists its acid parameters as E_A = 1.56 and C_A = 0.44.

Reagent

As a reagent, chloroform serves as a source of the dichlorocarbene intermediate CCl₂.^[43] It reacts with aqueous sodium hydroxide, usually in the presence of a phase transfer catalyst, to produce dichlorocarbene, CCl₂.^[44][45] 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 •CHCl₂ free radical which adds to alkenes.^{[citation needed]}

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.^[46][47] Glover also undertook practical experiments on dogs to prove his theories, refined his theories, and 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".^[48]

The Scottish obstetrician James Young Simpson 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. ^[49] 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. ^[50] In 1847 and 1848, Glover would pen a series of heated letters accusing Simpson of stealing his discovery, which had already earned Simpson considerably notoriety. ^[51] 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.^[28]

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.^[52]

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.^[53]

The use of chloroform during surgery expanded rapidly in Europe; for instance in the 1850s chloroform was used by the physician John Snow during the births of Queen Victoria's last two children Leopold and Beatrice.^[54] In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century;^{[citation needed]} 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.^[55] 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.^[56] Chloroform could also be mixed with other anaesthetic agents such as ether to make C.E. mixture, or ether and alcohol to make A.C.E. mixture.^{[citation needed]}

In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anaesthetic.^[57] Her autopsy establishing the cause of death was undertaken by John Fife assisted by Robert Mortimer Glover.^[27] 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.^[58]

The opponents and supporters of chloroform disagreed on the question of whether the medical complications were due to respiratory disturbance or whether chloroform had a specific effect on the heart. Between 1864 and 1910, numerous commissions in Britain studied chloroform but failed to come to any clear conclusions. It was only in 1911 that Levy proved in experiments with animals that chloroform can cause ventricular fibrillation.^{[citation needed]} Despite this, between 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in the UK and German-speaking countries. In Germany, comprehensive surveys of the fatality rate during anaesthesia were made by Gurlt between 1890 and 1897.^{[citation needed]} At the same time in the UK the medical journal The Lancet carried out a questionnaire survey^[59] and compiled a report detailing numerous adverse reactions to anesthetics, including chloroform.^[60] In 1934, Killian gathered all the statistics compiled until then and found that the chances of suffering fatal complications under ether were between 1:14,000 and 1:28,000, whereas with chloroform the chances were between 1:3,000 and 1:6,000.^{[citation needed]} The rise of gas anaesthesia using nitrous oxide, improved equipment for administering anesthetics, and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis.^[61]

The latest reported anaesthetic use of chloroform in the Western world dates to 1987, when the last doctor who used it retired, about 140 years after its first use.^[62]

Criminal use

Chloroform has been used by criminals to knock out, daze, or murder victims. Joseph Harris was charged in 1894 with using chloroform to rob people.^[63] Serial killer H. H. Holmes used chloroform overdoses to kill his female victims. In September 1900, chloroform was implicated in the murder of the U.S. businessman William Marsh Rice. Chloroform was deemed a factor in the alleged murder of a woman in 1991, when she was asphyxiated while asleep.^[64] In 2002, 13-year-old Kacie Woody was sedated with chloroform when she was abducted by David Fuller and during the time that he had her, before he shot and killed her.^[65] In a 2007 plea bargain, a man confessed to using stun guns and chloroform to sexually assault minors.^[66]

The use of chloroform as an incapacitating agent has become widely recognized, bordering on cliché, through the adoption by crime fiction authors of plots involving criminals' use of chloroform-soaked rags to render victims unconscious. However, it is nearly impossible to incapacitate someone using chloroform in this way.^[67] It takes at least five minutes of inhalation of chloroform to render a person unconscious. Most criminal cases involving chloroform involve co-administration of another drug, such as alcohol or diazepam, or the victim being complicit in its administration. After a person has lost consciousness owing to chloroform inhalation, a continuous volume must be administered, and the chin must be supported to keep the tongue from obstructing the airway, a difficult procedure, typically requiring the skills of an anesthesiologist. In 1865, as a direct result of the criminal reputation chloroform had gained, the medical journal The Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility", i.e. loss of consciousness, using chloroform.^[68]

Exposure

Chloroform is formed as a by-product of water chlorination, along with a range of other disinfection by-products, and it is therefore often present in municipal tap water and swimming pools. Reported ranges vary considerably, but are generally below the current health standard for total trihalomethanes (THMs) of 100 μg/L.^[69] However, when considered in combination with other trihalomethanes often present in drinking water, the concentration of THMs often exceeds the recommended limit of exposure.^[70]

While few studies have assessed the risks posed by chloroform exposure through drinking water in isolation from other THMs, many studies have shown that exposure to the general category of THMs, including chloroform, is associated with an increased risk of cancer of the bladder or lower GI tract.^[71]

Historically, chloroform exposure may well have been higher, owing to its common use as an anesthetic, as an ingredient in cough syrups, and as a constituent of tobacco smoke, where DDT had previously been used as a fumigant.^[72]

Pharmacology

Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.^[37] Prolonged dermal exposure can result in the development of sores as a result of defatting. Elimination is primarily through the lungs as chloroform and carbon dioxide; less than 1% is excreted in the urine.^[38]

Chloroform is metabolized in the liver by the cytochrome P-450 enzymes, by oxidation to trichloromethanol and by reduction to the dichloromethyl free radical. Other metabolites of chloroform include hydrochloric acid and diglutathionyl dithiocarbonate, with carbon dioxide as the predominant end-product of metabolism.^[73]

Like most other general anesthetics and sedative-hypnotic drugs, chloroform is a positive allosteric modulator at GABA_A receptors.^[74] Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression.^[73] When ingested, chloroform causes symptoms similar to those seen after inhalation. Serious illness has followed ingestion of 7.5 g (0.26 oz). The mean lethal oral dose in an adult is estimated at 45 g (1.6 oz).^[37]

The anesthetic use of chloroform has been discontinued, because it caused deaths from respiratory failure and cardiac arrhythmias. Following chloroform-induced anesthesia, some patients suffered nausea, vomiting, hyperthermia, jaundice, and coma owing to hepatic dysfunction. At autopsy, liver necrosis and degeneration have been observed.^[37] The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene, one of its metabolites.^[73]

Conversion to phosgene

Chloroform converts slowly in the presence of UV light and air to the extremely poisonous gas, phosgene (COCl₂), releasing HCl in the process.^[75]

2 CHCl₃ + O₂ → 2 COCl₂ + 2 HCl

To prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer. Amylene has been found to be ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform.^[76] When ethanol is used as a stabiliser for chloroform, it reacts with phosgene (which is soluble in chloroform) to form the relatively harmless diethyl carbonate ester:

2 CH₃CH₂OH + COCl₂ → CO₃(CH₂CH₃)₂ + 2 HCl

Phosgene and HCl can be removed from chloroform by washing with saturated aqueous carbonate solutions, such as sodium bicarbonate. This procedure is simple and results in harmless products. Phosgene reacts with water to form carbon dioxide and HCl,^[77] and the carbonate salt neutralizes the resulting acid.^[78]

Suspected samples can be tested for phosgene using filter paper which when treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in ethanol, and then dried, turns yellow in the presence of phosgene vapour.^[79] There are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified using mass spectrometry.^[80]

Regulation

Chloroform is suspected of causing cancer (i.e. it is possibly carcinogenic, IARC Group 2B) as per the International Agency for Research on Cancer (IARC) Monographs.^[81]

It is classified as an extremely hazardous substance in the United States, as defined in Section 302 of the US Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.^[82]