Chloroform

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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Chloroform
Template:Chembox image sbs cell
Chloroform in its liquid state shown in a test tube
Names
IUPAC name
Trichloromethane
Other names
Trichloromethane; formyl trichloride; methane trichloride; methyl trichloride; methenyl trichloride; TCM; freon 20; refrigerant-20; R-20; UN 1888
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
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KEGG
UNII
Properties
CHCl3
Molar mass 119.37 g·mol−1
Hazards
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes.[2] The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered hazardous. Several million tons are produced annually as a precursor to PTFE and refrigerants, but its use for refrigerants is being phased out.[2] The hydrogen attached to carbon in chloroform participates in hydrogen bonding.[3][4]

Natural occurrence

The total global flux of chloroform through the environment is approximately 660 000 tonnes per year, and about 90% of emissions are natural in origin. Many kinds of seaweed produce chloroform, and fungi are believed to produce chloroform in soil.

Chloroform volatilizes readily from soil and surface water and undergoes degradation in air to produce phosgene, dichloromethane, formyl chloride, carbon monoxide, carbon dioxide, and hydrogen chloride. Its halflife in air ranges from 55 to 620 days. Biodegradation in water and soil is slow. Chloroform does not bioaccumulate to any significant extent in aquatic organisms.[5]

History

Trichloromethane was synthesized independently by two groups in 1831: Liebig carried out the alkaline cleavage of chloral, whereas Soubeirain obtained the compound by the action of chlorine bleach on both ethanol and acetone. In 1835, Dumas prepared the substance by the alkaline cleavage of trichloroacetic acid. Regnault prepared trichloromethane by chlorination of monochloromethane. By the 1850s, chloroform was being produced on a commercial basis by using the Liebig procedure, which retained its importance until the 1960s. Today, trichloromethane — along with dichloromethane — is prepared exclusively and on a massive scale by the chlorination of methane and monochloromethane.[2]

Production

In industry, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane.[2] At 400–500 °C, a free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds:

CH4 + Cl2 → CH3Cl + HCl
CH3Cl + Cl2 → CH2Cl2 + HCl
CH2Cl2 + Cl2 → CHCl3 + HCl

Chloroform undergoes further chlorination to yield carbon tetrachloride (CCl4):

CHCl3 + Cl2 → CCl4 + HCl

The output of this process is a mixture of the four chloromethanes (chloromethane, dichloromethane, chloroform, and carbon tetrachloride), which can then be separated by distillation.[2]

Deuterochloroform

Main article: Deuterated chloroform

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 haloform reaction[citation needed], the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite.[2] The haloform process is now obsolete for the production of ordinary chloroform. Deuterochloroform can also be prepared by the reaction of sodium deuteroxide with chloral hydrate,[citation needed] or from ordinary chloroform.[6]

Inadvertent formation of chloroform

The haloform reaction can also occur inadvertently in domestic settings. Bleaching with hypochlorite generates halogenated compounds in side reactions; chloroform is the main byproduct.[7] Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, butanone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone or dichloroacetone.

Uses

The major use of chloroform today is in the production of the chlorodifluoromethane, a major precursor to tetrafluoroethylene:

CHCl3 + 2 HF → CHClF2 + 2 HCl

The reaction is conducted in the presence of a catalytic amount of antimony pentafluoride. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon. Before the Montreal Protocol, chlorodifluoromethane (designated as R-22) was also a popular refrigerant.

Solvent

Worldwide, chloroform is also used in pesticide formulations, as a solvent for fats, oils, rubber, alkaloids, waxes, gutta-percha, and resins, as a cleansing agent, grain fumigant, in fire extinguishers, and in the rubber industry.[5][8] CDCl3 is a common solvent used in NMR spectroscopy.

Reagent

As a reagent, chloroform serves as a source of the dichlorocarbene CCl2 group.[9] It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl2.[10][11] This reagent affects 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 in addition to alkenes.

The most important reaction of chloroform is that with hydrogen fluoride in the presence of antimony pentahalides to give monochlorodifluoromethane (CFC 22), a precursor in the production of polytetrafluoroethylene (Teflon).[2]

Anaesthetic

Antique bottles of chloroform

Chloroform was once a widely used anesthetic. On 4 November 1847, the Scottish obstetrician James Young Simpson first used the anaesthetic qualities of chloroform on a human,[12] two guests at his dinner party. This was done as an entertainment and not as a medical procedure.

This was followed, only three days later, by the first use of chloroform on an actual patient, for a dental procedure, by Francis Brodie Imlach (1819-1891), also in Edinburgh, who, under other circumstances, may have gained the same fame as Simpson.[13]

The use of chloroform during surgery expanded rapidly thereafter in Europe. In the 1850s, chloroform was used during the birth of Queen Victoria's last two children.[14] In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; however, it was quickly abandoned in favor of ether upon discovery of its toxicity, especially its tendency to cause fatal cardiac arrhythmia analogous to what is now termed "sudden sniffer's death". Some people used chloroform as a recreational drug or to attempt suicide.[15] One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of potassium channels in nerve cells.[16] 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 anesthetic.[17] A number of physically fit patients died after inhaling it. However, in 1848 John Snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.[18]

The opponents and supporters of chloroform were mainly at odds with the question of whether the complications were solely due to respiratory disturbance or whether chloroform had a specific effect on the heart. Between 1864 and 1910 numerous commissions in UK 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 cardiac fibrillation. The reservations about chloroform could not halt its soaring popularity. Between about 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in UK and German-speaking countries. In America, however, there was less enthusiasm for chloroform narcosis. In Germany the first comprehensive surveys of the fatality rate during anaesthesia were made by Gurlt between 1890 and 1897. 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 under chloroform the chances were between 1: 3,000 and 1: 6,000. The rise of gas anaesthesia using nitrous oxide, improved equipment for administering anaesthetics and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis.[19]

Criminal use

Chloroform has been reputed to be used by criminals to knock out, daze or even murder their victims. Joseph Harris was charged in 1894 with using chloroform to rob people.[20] In 1901, chloroform was also implicated in the murder of the American businessman William Marsh Rice, the namesake of the institution now known as Rice University. Chloroform was also deemed to be a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping.[21] In a 2007 plea bargain a man confessed to using stun guns and chloroform to sexually assault minors.[22] Use of chloroform as an incapacitating agent has become widely recognized, bordering on clichéd, due to the popularity of crime fiction authors having criminals use chloroform-soaked rags to render victims unconscious. However, it is nearly impossible to incapacitate someone using chloroform.[23] It takes at least five minutes of inhaling an item soaked in chloroform to render a person unconscious. Most criminal cases involving chloroform also involve another drug being co-administered, such as alcohol or diazepam, or the victim being found to have been complicit in its administration. After a person has lost consciousness due to chloroform inhalation, a continuous volume must be administered and the chin must be supported in order to keep the tongue from obstructing the airway, a difficult procedure even for an anesthesiologist. In 1865 as a direct result of the criminal reputation chloroform had gained, medical journal The Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility" using chloroform,[24] and as of 1998 no such demonstration has been forthcoming.[23]

Safety

Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.[5] Prolonged dermal exposure can result in the development of sores as a result of defatting. Elimination is primarily from lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in urine.[8]

Chloroform is metabolized in the liver by the cytochrome P-450 enzymes, by oxidation to phosgene and by reduction to the dichloromethyl free radical. Other metabolites of chloroform include chloromethanol, hydrochloric acid, hydrogen chloride, and digluathionyl dithiocarbonate, with carbon dioxide as the predominant end product of metabolism.[25]

Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression.[25] When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of 7.5 g. The mean lethal oral dose for an adult is estimated to be about 45 g.[5]

The anesthetic use of chloroform has been discontinued because it caused deaths due to respiratory and cardiac arrhythmias and failure. Following chloroform-induced anesthesia, some patients suffered nausea, vomiting, prostration, jaundice, and coma due to hepatic dysfunction. At autopsy, liver necrosis and degeneration have been observed.[5]

Chloroform has induced liver tumors in mice and kidney tumors in mice and rats.[5] The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene.[25]

Conversion to phosgene

During prolonged storage in the presence of oxygen, chloroform converts slowly to phosgene, releasing HCl in the process. 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 ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform.[26] 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,[27] and the carbonate salt neutralizes the resulting acid.

Suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in alcohol, and then dried), which turns yellow in phosgene vapor. There are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified with mass spectrometry.

References

  1. ↑ 1.0 1.1 1.2 1.3 Template:PGCH
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Rossberg, M. et al. "Chlorinated Hydrocarbons" in Ullmann’s Encyclopedia of Industrial Chemistry, 2006, Wiley-VCH, Weinheim. doi:10.1002/14356007.a06_233.pub2
  3. ↑ Wiley G.R. and Miller S.I. (1972). "Thermodynamic parameters for hydrogen bonding of chloroform with Lewis bases in cyclohexane. Proton magnetic resonance study". Journal of the American Chemical Society. 94 (10): 3287. doi:10.1021/ja00765a001.
  4. ↑ Kwak, K; Rosenfeld, DE; Chung, JK; Fayer, MD (2008). "Solute-solvent complex switching dynamics of chloroform between acetone and dimethylsulfoxide-two-dimensional IR chemical exchange spectroscopy". The journal of physical chemistry. B. 112 (44): 13906–15. doi:10.1021/jp806035w. PMC 2646412. PMID 18855462.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Chloroform (PDF), CICAD, 58, World Health Organization, 2004
  6. ↑ Koch, Hans A. Cholorofom Deuteration Process. Canadian Patent 1085423. Patents.ic.gc.ca. Issued: 1980-09-09. Retrieved on 2012-08-13.
  7. ↑ Hans Ulrich Süss (2007), "Bleaching", Ullmann's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, p. 5
  8. ↑ 8.0 8.1 Jerrold B. Leikin; Frank P. Paloucek, eds. (2008), "Chloroform", Poisoning and Toxicology Handbook (4th ed.), Informa, p. 774
  9. ↑ Srebnik, M.; Laloë, E. (2001) "Chloroform" in Encyclopedia of Reagents for Organic Synthesis, Wiley, doi:10.1002/047084289X.rc105
  10. ↑ Template:OrgSynth
  11. ↑ Template:OrgSynth
  12. ↑ Gordon, H. Laing (November 2002). Sir James Young Simpson and Chloroform (1811–1870). The Minerva Group, Inc. pp. 106–109. ISBN 978-1-4102-0291-8. Retrieved 11 November 2011.
  13. ↑ http://historyofdentistry.co.uk/index_htm_files/2004Apr2.pdf
  14. ↑ Anesthesia and Queen Victoria. Ph.ucla.edu. Retrieved on 2012-08-13.
  15. ↑ Martin, William (3 July 1886). "A Case of Chloroform Poisoning; Recovery". Br Med J. 2 (1331): 16–17. doi:10.1136/bmj.2.1331.16-a. PMC 2257365. PMID 20751619.
  16. ↑ Patel, Amanda J.; Honoré, Eric; Lesage, Florian; Fink, Michel; Romey, Georges; Lazdunski, Michel (May 1999). "Inhalational anesthetics activate two-pore-domain background K+ channels". Nature Neuroscience. 2 (5): 422–426. doi:10.1038/8084. PMID 10321245.
  17. ↑ Knight, Paul R. III and Bacon, Douglas R. (2002). "An Unexplained Death: Hannah Greener and Chloroform". Anesthesiology. 96 (5): 1250–3. doi:10.1097/00000542-200205000-00030. PMID 11981167.
  18. ↑ Snow, John (1858). "On Chloroform and Other Anaesthetics and Their Action and Administration". pp. 82–85.
  19. ↑ Anaesthesiol Reanim. 1997;22(6):144-52. Wawersik J. Clinic of Christian-Albrechts-Universität of Kiel. http://ncbi.nlm.nih.gov/pubmed/9487785
  20. ↑ "Knock-out and Chloroform". The Philadelphia Record. 9 February 1894. Retrieved 31 March 2011.
  21. ↑ "Chloroform case retrial underway". Record-Journal. 7 July 1993. Retrieved 31 March 2011.
  22. ↑ "Man admits to raping friends' daughters". USA Today. 6 November 2007. Retrieved 31 March 2011.
  23. ↑ 23.0 23.1 Payne, J. P. (July 1998). "The criminal use of chloroform". Anaesthesia. 53 (7): 685–690. doi:10.1046/j.1365-2044.1998.528-az0572.x.
  24. ↑ Medical Annotation. Chloroform amongst Thieves. The Lancet, 1865; 2: 490 – 1.
  25. ↑ 25.0 25.1 25.2 Anna M Fan (2005), "Chloroform", Encyclopedia of Toxicology, 1 (2nd ed.), Elsevier, pp. 561–565
  26. ↑ Turk, Eric (2 March 1998). "Phosgene from Chloroform". Chemical & Engineering News. 76 (9): 6. doi:10.1021/cen-v076n009.p006.
  27. ↑ phosgene (chemical compound). Encyclopædia Britannica. Retrieved on 2013-08-16.

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