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Chloroform,[9] ortrichloromethane (often abbreviated asTCM), is anorganochloride with theformulaCHCl3 and a commonsolvent. It is avolatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor torefrigerants andpolytetrafluoroethylene (PTFE).[10] Chloroform was once used as aninhalational anesthetic between the 19th century and the first half of the 20th century.[11][12] It is miscible with many solvents but it is only very slightly soluble in water (only 8 g/L at 20°C).
The molecule adopts atetrahedral molecular geometry with C3vsymmetry.[13] The chloroform molecule can be viewed as amethane molecule with three hydrogen atoms replaced with three chlorine atoms, leaving a single hydrogen atom.
Many kinds ofseaweed produce chloroform, andfungi are believed to produce chloroform in soil.[14] Abiotic processes are also believed to contribute to natural chloroform productions in soils, although the mechanism is still unclear.[15]
Samuel Guthrie, a U.S. physician fromSackets Harbor, New York, also appears to have produced chloroform in 1831 by reacting chlorinated lime with ethanol, and noted itsanaesthetic properties; however, he also believed that he had prepared chloric ether.[18][19][20]
In 1834, French chemistJean-Baptiste Dumas determined chloroform's empirical formula and named it:[24] "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 oftrichloroacetic acid.
In 1842,Robert Mortimer Glover in London discovered the anaesthetic qualities of chloroform on laboratory animals.[25]
In 1847, Scottish obstetricianJames Y. Simpson was the first to demonstrate the anaesthetic properties of chloroform (provided by local pharmacistWilliam Flockhart of Duncan, Flockhart and company,[26]) in humans, and helped to popularize the drug for use in medicine.[27]
The application of chloroform remained dangerous, and many deaths occurred through accidentaloverdose.[28][29] In 1848,John Snow developed an inhaler that regulated the dosage.[28]
By the 1850s, chloroform was being produced on a commercial basis.[29] An apparatus that could apply it safely and controllably was invented byJoseph Thomas Clover in 1862.[30][31]
In Britain, about 750,000 doses a week were being produced by 1895,[29] using the Liebig procedure, which retained its importance until the 1960s. Today, chloroform – along withdichloromethane – is prepared exclusively and on a massive scale by the chlorination of methane and chloromethane.[10]
Industrially, chloroform is produced by heating a mixture ofchlorine and eithermethyl chloride (CH3Cl) ormethane (CH4).[10] At 400–500 °C,free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds:
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 bydistillation.[10]
In terms of scale, the most important reaction of chloroform is withhydrogen fluoride to givemonochlorodifluoromethane (HCFC-22), a precursor in the production of polytetrafluoroethylene (Teflon) and other fluoropolymers:[10]
Chloroform is used as a precursor to make R-22 (chlorodifluoromethane). This is done by reacting it withhydrofluoric acid (HF) which fluorinates theCHCl3 molecule and releases hydrochloric acid as a byproduct.[41] Before theMontreal Protocol was enforced, most of the chloroform produced in the United States was used in the production ofchlorodifluoromethane. However, its production remains high, as it is a key precursor of PTFE.[42]
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.[43]
In solvents such asCCl4 and alkanes, chloroform hydrogen bonds to a variety of Lewis bases.HCCl3 is classified as ahard acid, and theECW model lists its acid parameters as EA = 1.56 and CA = 0.44.
Chloroform is a powerfulgeneral anesthetic,euphoriant,anxiolytic, andsedative when inhaled or ingested. Theanaesthetic qualities of chloroform were first described in 1842 in a thesis byRobert Mortimer Glover, which won the Gold Medal of theHarveian Society for that year.[47][48] Glover also undertook practical experiments on dogs to prove his theories, refined his theories, and presented them in his doctoral thesis at theUniversity of Edinburgh in the summer of 1847, identifying anaesthetizing halogenous compounds as a "new order of poisonous substances".[47]
The ScottishJames Young Simpson, anobstetrician, 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.[47] 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.[47] 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.[47] 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.[26]
An illustration depicting James Young Simpson and his friends found unconscious.
A few days later, during the course of a dental procedure inEdinburgh,Francis Brodie Imlach became the first person to use chloroform on a patient in a clinical context.[49]
In May 1848,Robert Halliday Gunning made a presentation to the Medico-Chirurgical Society of Edinburgh following a series of laboratoryexperiments 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.[50]
The use of chloroform duringsurgery expanded rapidly in Europe; for instance in the 1850s chloroform was used by the physicianJohn Snow during the births ofQueen Victoria's last two childrenLeopold andBeatrice.[51] In the United States, chloroform began to replaceether as an anesthetic at the beginning of the 20th century;[52] it was abandoned in favor of ether on discovery of its toxicity, especially its tendency to cause fatalcardiac arrhythmias analogous to what is now termed "sudden sniffer's death". Some people used chloroform as a recreational drug or to attempt suicide.[53] One possible mechanism of action of chloroform is that it increases the movement ofpotassium ions through certain types ofpotassium channels innerve cells.[54] Chloroform could also be mixed with other anesthetic agents such as ether to make C.E. mixture,[55] or ether andalcohol to makeA.C.E. mixture.[56][57]
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anaesthetic.[58] Her autopsy establishing the cause of death was undertaken byJohn Fife assisted byRobert Mortimer Glover.[25] 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.[28] Joseph Thomas Clover improved on the design in 1862, further reducing the risk of accidental overdose.[30][31]
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 causeventricular fibrillation.[59] 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.[52] At the same time in the UK the medical journalThe Lancet carried out a questionnaire survey[60] and compiled a report detailing numerous adverse reactions to anesthetics, including chloroform.[61] 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.[52] The rise of gas anaesthesia usingnitrous oxide, improved equipment for administering anesthetics, and the discovery ofhexobarbital in 1932 led to the gradual decline of chloroform narcosis.[62]
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.[63]
In the 1910s in England, a fast-living set calledThe Coterie used chloroform recreationally.Margot Asquith, the wife of the Prime Minister, whose stepsonRaymond Asquith was a member, recorded thatLady Diana Manners, who called it "jolly old chlorors", had said "I must be unconscious by midnight."
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.[64]Serial killerH. H. Holmes used chloroform overdoses to kill his female victims. In September 1900, chloroform was implicated in the murder of the U.S. businessmanWilliam Marsh Rice. The serial killerJohn Wayne Gacy chloroformed many of his victims. Chloroform was deemed a factor in the alleged murder of a woman in 1991, when she was asphyxiated while asleep.[65] In 2002, 13-year-oldKacie 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.[66] In a 2007 plea bargain, a man confessed to usingstun guns and chloroform to sexually assault minors.[67]
The use of chloroform as anincapacitating agent has become widely recognized, bordering oncliché, through the adoption bycrime 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.[68] 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 asalcohol ordiazepam, 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 ananesthesiologist. In 1865, as a direct result of the criminal reputation chloroform had gained, the medical journalThe Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility", i.e. loss of consciousness, using chloroform.[69]
Chloroform is formed as a by-product ofwater chlorination, along with a range of otherdisinfection 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 totaltrihalomethanes (THMs) of 100 μg/L.[70]
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 oftobacco smoke, whereDDT had previously been used as afumigant.[71]
Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.[38] Prolonged dermal exposure can result in the development of sores as a result ofdefatting. Elimination is primarily through the lungs as chloroform and carbon dioxide; less than 1% is excreted in the urine.[39]
Chloroform is metabolized in the liver by thecytochrome P-450 enzymes, by oxidation to trichloromethanol and by reduction to the dichloromethylfree radical. Other metabolites of chloroform includehydrochloric acid and diglutathionyl dithiocarbonate, withcarbon dioxide as the predominant end-product of metabolism.[72]
Like most other general anesthetics and sedative-hypnotic drugs, chloroform is apositive allosteric modulator atGABAA receptors.[73] Chloroform causes depression of thecentral nervous system (CNS), ultimately producing deepcoma and respiratory center depression.[72] 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).[38]
The anesthetic use of chloroform has been discontinued, because it caused deaths from respiratory failure and cardiac arrhythmias. Following chloroform-induced anesthesia, some patients sufferednausea,vomiting,hyperthermia,jaundice, and coma owing tohepatic dysfunction. At autopsy, livernecrosis and degeneration have been observed.[38] The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely tophosgene, one of its metabolites.[72]
Chloroform converts slowly in the presence of UV light and air to the extremely poisonous gasphosgene (COCl2), releasingHCl in the process.[74]
2 CHCl3 + O2 → 2 COCl2 + 2 HCl
To prevent accidents, commercial chloroform is stabilized withethanol oramylene, 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.[75] When ethanol is used as a stabiliser for chloroform, it reacts with phosgene (which is soluble in chloroform) to form the relatively harmlessdiethyl carbonate ester:
2 CH3CH2OH + COCl2 → CO3(CH2CH3)2 + 2 HCl
Phosgene and HCl can be removed from chloroform by washing with saturated aqueouscarbonate solutions, such assodium bicarbonate. This procedure is simple and results in harmless products. Phosgene reacts with water to formcarbon dioxide and HCl,[76] and the carbonate saltneutralizes the resulting acid.[77]
CHCl3 measured by the Advanced Global Atmospheric Gases Experiment (AGAGE) in the lower atmosphere (troposphere) at stations around the world. Abundances are given as pollution free monthly mean mole fractions inparts-per-trillion (ppt).
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"Es scheint mir also erweisen, dass die von mir analysirte Substance, … zur Formel hat:C2H2Cl6." (Thus it seems to me to show that the substance [that was] analyzed by me … has as [its empirical] formula:C2H2Cl6.) [Note: The coefficients of his empirical formula must be halved.]
"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].)
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