Chloroform

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style="background: #F8EABA; text-align: center;" colspan="2"	Chloroform
File:Chloroform displayed.svg	File:Chloroform 3D.svg
IUPAC name Trichloromethane
Identifiers
CAS number	67-66-3
PubChem	6212
SMILES	C(Cl)(Cl)Cl
Properties
Molecular formula	CHCl3
Molar mass	119.38 g/mol
Melting point	-63.5 °C
Structure
Hazards
NFPA 704	0 2 0
style="background: #F8EABA; text-align: center;" colspan="2"	Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references

Chloroform, also known as trichloromethane and methyl trichloride, is a chemical compound with formula CHCl₃. It does not undergo combustion in air, although it will burn when mixed with more flammable substances. It is a member of a group of compounds known as trihalomethanes. Chloroform has myriad uses as a reagent and a solvent. It is also considered an environmental hazard.

History

Chloroform was discovered in July, 1831 by the American physician Samuel Guthrie, and independently a few months later by the French chemist Eugène Soubeiran and Justus von Liebig in Germany, all of them using variations of the haloform reaction. Soubeiran produced chloroform through the action of chlorine bleach powder (calcium hypochlorite) on acetone (2-propanone) as well as ethanol). Chloroform was named and chemically characterised in 1834 by Jean-Baptiste Dumas.

In 1847, the Edinburgh obstetrician James Young Simpson first used chloroform for general anesthesia during childbirth. The use of chloroform during surgery expanded rapidly thereafter in Europe. 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". Ether is still the preferred anesthetic in some developing nations due to its high therapeutic index and low price. Trichloroethylene, a halogenated aliphatic hydrocarbon related to chloroform, was proposed as a safer alternative, though it too was later found to be carcinogenic.

Production

Industrially, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane.^{[How to reference and link to summary or text]} At 400-500 °C, a free radical halogenation occurs, converting the methane or chloromethane to progressively more chlorinated compounds.

CH₄ + Cl₂ → CH₃Cl + HCl

CH₃Cl + Cl₂ → CH₂Cl₂ + HCl

CH₂Cl₂ + Cl₂ → CHCl₃ + HCl

Chloroform undergoes further chlorination to give CCl₄:

CHCl₃ + Cl₂ → CCl₄ + HCl

The output of this process is a mixture of the four chloromethanes: chloromethane, dichloromethane, chloroform (trichloromethane), and carbon tetrachloride, which are then separated by distillation.^{[How to reference and link to summary or text]}

Chloroform was first produced industrially by the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite, known as the haloform reaction.^{[How to reference and link to summary or text]} The chloroform can be removed from the attendant acetate salts (or formate salts if ethanol is the starting material) by distillation. This reaction is still used for the production of bromoform and iodoform.^{[How to reference and link to summary or text]} The haloform process is obsolete for the production of ordinary chloroform. It is, however, used to produce deuterated material industrially.^{[How to reference and link to summary or text]} Deuterochloroform may be prepared by the reaction of sodium deuteroxide with chloral hydrate,^{[How to reference and link to summary or text]} or from ordinary chloroform.

Inadvertent synthesis 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 may produce some chloroform, in addition to other compounds such as chloroacetone, or dichlroacetone.

Uses

The major use of chloroform today is in the production of the freon refrigerant Chlorodifluoromethane|R-22. However, as the Montreal Protocol takes effect, this use can be expected to decline as R-22 is replaced by refrigerants that are less liable to result in ozone depletion. In addition, it is used under research conditions to anesthetize mosquitoes for experiments, most frequently for the study of malaria. In film and television, it is sometimes used in a fictional manner to knock out an unsuspecting victim, leaving no trace.

Anesthetic

Chloroform was developed in the mid-1800s and was mainly used as an anesthetic. Inhaling chloroform vapors depressed the central nervous system of a patient, causing dizziness, fatigue and unconsciousness, allowing a doctor to perform simple surgery or other painful operations.

As a solvent

Chloroform is a common solvent because it is relatively unreactive, miscible with most organic liquids, and conveniently volatile. Small amounts of chloroform are used as a solvent in the pharmaceutical industry and for producing dye and pesticides. Chloroform is an effective solvent for alkaloids in their base form and thus plant material is commonly extracted with chloroform for pharmaceutical processing. For example, it is commercially used to extract morphine from poppies, scopolamine from Datura plants.

Safety

As might be expected for an anesthetic, inhaling chloroform vapors depresses the central nervous system. It is immediately dangerous to health and life at approximately 500 parts per million according to the United States National Institute for Occupational Safety and Health. Breathing about 900 ppm for a short time can cause dizziness, fatigue, and headache. Chronic chloroform exposure may cause damage to the liver (where chloroform is metabolized to phosgene) and to the kidneys, and some people develop sores when the skin is immersed in chloroform.

Animal studies have shown that miscarriages occur in rats and mice that have breathed air containing 30 to 300 ppm chloroform during pregnancy and also in rats that have ingested chloroform during pregnancy. Offspring of rats and mice that breathed chloroform during pregnancy have a higher incidence of birth defects, and abnormal sperm have been found in male mice that have breathed air containing 400 ppm chloroform for a few days. The effect of chloroform on reproduction in humans is unknown.

Chloroform once appeared in toothpastes, cough syrups, ointments, and other pharmaceuticals, but it has been banned in consumer products in the United States since 1976.

The National Toxicology Program's eleventh report on carcinogens implicates it as reasonably anticipated to be a human carcinogen, a designation equivalent to International Agency for Research on Cancer class 2A. It has been most readily associated with hepatocellular carcinoma. Caution is mandated during its handling in order to minimize unnecessary exposure; safer alternatives, such as dichloromethane, have resulted in a substantial reduction of its use as a solvent.

During prolonged storage hazardous amounts of phosgene can accumulate in the presence of oxygen and ultraviolet light. To prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer and caution must be taken. Suspicious bottles should be tested for phosgene. Filter-paper strips, wetted with 5% diphenylamine, 5% dimethylaminobenzaldehyde, and then dried, turn yellow in phosgene vapor.

Commonly used in DNA extractions and generally in conjunction with phenol to form a biolayer with extraction buffer (tris etc). DNA will form in the supernatant while protein and non soluble cell materials will precipitate between the buffer chloroform layers.

See also

• Haloalkane
• Halomethane
• Chloromethane
• Dichloromethane
• Carbon tetrachloride (Tetrachloromethane)
• Fluoroform
• Bromoform
• Iodoform

References

• Cole, W. H. (1927). Measurements of fatal doses of chloroform in the brains of white rats: Proceedings of the Society for Experimental Biology & Medicine 24 1927, 340-341.
• Feldman, J. M., & Roche, J. M. (1976). Effect of ether, chloroform and carbon dioxide on monoamine inactivation: Pharmacology, Biochemistry and Behavior Vol 4(4) Apr 1976, 447-453.
• Hubner, R. P. (2007). Estimation of Health and Safety Risks from Exposure to Chlorine and Chloroform for Swimmers in Pools. San Francisco, CA: Jossey-Bass.
• Jones, E. E. (1909). The waning of consciousness under chloroform: Psychological Review Vol 16(1) Jan 1909, 48-54.
• King, R. B. (1993). Topical aspirin in chloroform and the relief of pain due to herpes zoster and postherpetic neuralgia: Archives of Neurology Vol 50(10) Oct 1993, 1046-1053.
• Muller, U., Fletcher, P. C., & Steinberg, H. (2006). The origin of pharmacopsychology: Emil Kraepelin's experiments in Leipzig, Dorpat and Heidelberg (1882-1892): Psychopharmacology Vol 184(2) Jan 2006, 131-138.
• No authorship, i. (1899). Experience under the influence of ether: Psychological Review Vol 6(1) Jan 1899, 104-106.
• Spiegel, A. D., & Suskind, P. B. (1997). Chloroform-induced insanity defence confounds lawyer Lincoln: History of Psychiatry Vol 8(32, Pt 4) Dec 1997, 487-500.
• Stefan, M., Gheorghe, N., & Boerescu, J. (1975). Circadian oscillation in rat liver tyrosine aminotransferase activity after chloroform inhalation: Biochemical Pharmacology Vol 24(4) Feb 1975, 479-480.
• Storms, W. W. (1973). Chloroform parties: JAMA: Journal of the American Medical Association Vol 225(2) Jul 1973, 160.
• Yamamoto, T., & Kawamura, Y. (1974). Chloroform responses of the chorda tympani nerve in the rat: Physiology & Behavior Vol 13(2) Aug 1974, 245-250.

External links

• Chloroform "The Molecular Lifesaver" An article at Oxford University providing facts about chloroform.
• Concise International Chemical Assessment Document 58
• History of chloroform anesthesia
• IARC Summaries & Evaluations: Vol. 1 (1972), Vol. 20 (1979), Suppl. 7 (1987), Vol. 73 (1999)
• International Chemical Safety Card 0027

• Template:PGCH
• National Pollutant Inventory - Chloroform and trichloromethane
• NIST Standard Reference Database
• Story on Chloroform from BBC's The Material World (28 July 2005)
• Sudden Sniffer's Death Syndrome article at Carolina Poison Center