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Chloroform
IUPAC name Chloroform
Systematic name Trichloromethane
other names Formyl trichloride, Methane trichloride, Methyl trichloride, Methenyl trichloride, TCM, Freon 20, R-20, UN 1888
Identifiers
CAS number	67-66-3 Y
PubChem	6212
ChemSpider	5977
EC number	200-663-8
KEGG	C13827
ChEBI	35255
RTECS number	FS9100000
SMILES	ClC(Cl)Cl
InChI	1/CHCl3/c2-1(3)4/h1H
InChI key	HEDRZPFGACZZDS-UHFFFAOYAG
Properties
Molecular formula	CHCl3
Molar mass	119.38 g/mol
Appearance	Colorless liquid
Density	1.483 g/cm3
Melting point	-63.5 °C
Boiling point	61.2 °C
Solubility in water	0.8 g/100 ml (20 °C)
Refractive index (nD)	1.4459
Structure
Molecular shape	Tetrahedral
Hazards
MSDS	External MSDS
R-phrases	R22, R38, R40, R48/20/22
S-phrases	(S2), S36/37
NFPA 704	0 2 0
Flash point	Non-flammable
U.S. Permissible exposure limit (PEL)	50 ppm (240 mg/m3) (OSHA)
Supplementary data page
Structure and properties	n, εr, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Y (what is this?)  (verify) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Chloroform in its liquid state shown in a test tube

Chloroform is the organic compound with formula CHCl₃. This colorless, sweet-smelling, dense liquid is a trihalomethane. It is also considered somewhat hazardous. Several million tons are produced annually as a precursor to Teflon and refrigerants, but its use for refrigerants is being phased out.^[1]

Production

Chloroform was reported in 1831 by the French chemist Eugène Soubeiran, who prepared it from acetone (2-propanone) as well as ethanol through the action of chlorine bleach powder (calcium hypochlorite).^[2] The American physician Samuel Guthrie prepared gallons of the material and described its "deliciousness of flavor."^[3] Independently, Justus von Liebig also described the same compound.^[4] All early preparations used variations of the haloform reaction. Chloroform was named and chemically characterised in 1834 by Jean-Baptiste Dumas.^[5]

Industrial routes

In industry, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane.^[1] 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 give CCl₄:

CHCl₃ + Cl₂ → CCl₄ + HCl

The output of this process is a mixture of the four chloromethanes, chloromethane, dichloromethane, chloroform, and carbon tetrachloride, which are then separated by distillation.^[1]

Deuterochloroform

An archaic industrial route to chloroform involved the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite, the aforementioned haloform reaction.^[1] The chloroform can be removed from the coproducts by distillation. A related reaction is still used in the production of bromoform and iodoform. Although the haloform process is obsolete for the production of ordinary chloroform, it is used to produce CDCl₃.^{[citation needed]} 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. 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 (R-22), 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 (R22) was also popular refrigerant.

As a solvent

Chloroform is a common solvent in the laboratory because it is relatively unreactive, miscible with most organic liquids, and conveniently volatile. Chloroform is used as a solvent in the pharmaceutical industry and for producing dyes 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 used in commerce to extract morphine from poppies and scopolamine from Datura plants. Chloroform containing deuterium (heavy hydrogen), CDCl₃, is a common solvent used in NMR spectroscopy. It can be used to bond pieces of acrylic glass (also known under the trade names Perspex and Plexiglas). A solvent of phenol:chloroform:isoamyl alcohol 25:24:1 is used to dissolve non-nucleic acid biomolecules in DNA and RNA extractions.

As a reagent in organic synthesis

As a reagent, chloroform serves as a source of the dichlorocarbene CCl₂ group.^[7] It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl₂.^[8][9] 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 in addition to alkenes.

As an anesthetic

Chloroform was once a popular anesthetic; its vapor depresses the central nervous system of a patient, allowing a doctor to perform various otherwise painful procedures. 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 favour 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 (~1.5-2.2) ^[10] and low price. One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of potassium channels in nerve cells.^[11]

Safety

A fatal oral dose of chloroform is about 10 mL (14.8 g), with death due to respiratory or cardiac arrest.^[12]

As might be expected for an anesthetic, chloroform vapors depresses the central nervous system. It is immediately dangerous to life and health at approximately 500 ppm, according to the U. S. National Institute for Occupational Safety and Health. Breathing about 900 ppm for a short time can cause dizziness, fatigue, and headache. Chronic chloroform exposure can damage 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 of 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 as a consumer product in the US since 1976.^[13]

The US National Toxicology Program's eleventh report on carcinogens^[14] 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.^[15][16] 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.

Conversion to phosgene

During prolonged storage in the presence of oxygen and ultraviolet light, chloroform converts slowly to phosgene. To prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer. Suspicious samples can be tested for phosgene using 5% diphenylamine, 5% dimethylaminobenzaldehyde, and then dried, turn yellow in phosgene vapor.

References

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
• NIOSH Pocket Guide to Chemical Hazards 0127
• 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
• Calculation of vapor pressure, liquid density, dynamic liquid viscosity, surface tension of chloroform

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