Chloroform

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Chloroform
Chloroform displayed.svg
Chloroform 3D.svg
IUPAC name Trichloromethane
Other names Chloroform, Formyl trichloride, Methane trichloride, Methyl trichloride, Methenyl trichloride, TCM, Freon 20, R-20, UN 1888
Identifiers
CAS number 67-66-3
PubChem 6212
EINECS number 200-663-8
KEGG C13827
ChEBI 35255
RTECS number FS9100000
SMILES C(Cl)(Cl)Cl
InChI InChI=1/CHCl3/c2-1(3)4/h1H
Properties
Molecular formula CHCl3
Molar mass 119.38 g/mol
Appearance Colorless liquid
Density 1.48 g/cm³, liquid
Melting point

-63.5 °C

Boiling point

61.2 °C

Solubility in water 0.8 g/100 ml at 20 °C
Structure
Molecular shape Tetrahedral
Hazards
Main hazards Harmful (Xn), Irritant (Xi),

Carc. Cat. 2B

NFPA 704

NFPA 704.svg

0
2
0
 
R-phrases R22, R38, R40, R48/20/22
S-phrases (S2), S36/37
Flash point Non-flammable
U.S. Permissible
exposure limit (PEL)
50 ppm (240 mg/m3) (OSHA)
Except where noted otherwise, data are given for
materials in their standard state
(at 25 °C, 100 kPa)

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

Overview

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,[1] and independently a few months later by the French chemist Eugène Soubeiran[2] and Justus von Liebig[3] 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.[4]

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.[citation needed] At 400-500 °C, a free radical halogenation occurs, converting the methane or chloromethane to progressively more chlorinated compounds.

CH4 + Cl2 → CH3Cl + HCl
CH3Cl + Cl2CH2Cl2 + 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.[citation needed]

Chloroform was first produced industrially by the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite, known as the haloform reaction.[citation needed] 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.[citation needed] The haloform process is obsolete for the production of ordinary chloroform. It is, however, used to produce deuterated material industrially.[citation needed] Deuterochloroform may be prepared by the reaction of sodium deuteroxide with chloral hydrate,[citation needed] or from ordinary chloroform.[5]

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 will all produce chloroform.

Uses

The major use of chloroform today is in the production of the freon refrigerant 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. It is sometimes seen used in movies (i.e. Ace Ventura) and TV shows (i.e. Arrested Development) as an agent to knock out an unsuspecting victim.

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 or barber 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 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 commercially used to extract morphine from poppies, 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 (which is also known under the trade name 'Perspex').

As a reagent in organic synthesis

As a reagent, chloroform serves as a source of the dichlorocarbene CCl2 group.[6] It reacts with aqueous sodium hydroxide (usually in the presence of a phase transfer catalyst) to produce dichlorocarbene, CCl2.[7][8] 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.

Safety

As might be expected from its use as an anesthetic, inhaling chloroform vapors depresses the central nervous system. It is immediately dangerous to health and life at approximately 500 ppm according to the United States National Institute for Occupational Saftey and Health. Breathing about 900 parts of chloroform per million parts air (900 parts per million) 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.[9]

The National Toxicology Program's eleventh report on carcinogens[10] 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.[11][12] 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.

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References

  1. Samuel Guthrie (1832). ".". Am. J. Sci. and Arts 21: 64.
  2. Eugène Soubeiran (1831). ".". Ann. Chim. 48: 131.
  3. Justus Liebig (1832). "Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen". Annalen der Pharmacie 1 (2): 182-230. doi:10.1002/jlac.18320010203.
  4. Jean-Baptiste Dumas (1834). "Untersuchung über die Wirkung des Chlors auf den Alkohol". Annalen der Pharmacie 107 (41): 650-656. doi:10.1002/andp.18341074103.
  5. Canadian Patent 1085423
  6. Srebnik, M.; Laloë, E. "Chloroform" Encyclopedia of Reagents for Organic Synthesis" 2001 John Wiley. doi:10.1002/047084289X.rc105
  7. (1988) "1,6-Methano[10]annulene". Org. Synth.; Coll. Vol. 6: 731. 
  8. Gokel, G. W.; Widera, R. P.; Weber, W. P. (1988). "Phase-Transfer Hofmann Carbylamine Reaction: tert-Butyl Isocyanide". Org. Synth.; Coll. Vol. 6: 232. 
  9. The National Toxicology Program: Substance Profiles: Chloroform CAS No. 67-66-3 (pdf). Retrieved on 2007-11-02.
  10. 11th Report on Carcinogens. Retrieved on 2007-11-02.
  11. Centers for Disease Control and Prevention: CURRENT INTELLIGENCE BULLETIN 9.
  12. National Toxicology Program: Report on the carcinogenesis bioassay of chloroform.

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