Chloroform

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 Y
UNII	7V31YC746X Y
EC number	200-663-8
KEGG	C13827 Y
ChEBI	CHEBI:35255 Y
ChEMBL	CHEMBL44618 Y
RTECS number	FS9100000
Jmol-3D images	Image 1
SMILES ClC(Cl)Cl
InChI InChI=1S/CHCl3/c2-1(3)4/h1H Y Key: HEDRZPFGACZZDS-UHFFFAOYSA-N Y InChI=1/CHCl3/c2-1(3)4/h1H Key: HEDRZPFGACZZDS-UHFFFAOYAG
Properties
Molecular formula	CHCl3
Molar mass	119.38 g mol−1
Appearance	Colorless liquid
Density	1.483 g/cm3
Melting point	-63.5 °C, 210 K, -82 °F
Boiling point	61.2 °C, 334 K, 142 °F
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
Main hazards	Harmful (Xn), Irritant (Xi), Carc. Cat. 2B
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 (verify) (what is: Y/N?) 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 an organic compound with formula CHCl₃. It is one of the four chloromethanes.^[1] The colorless, sweet-smelling, dense liquid is a trihalomethane, and is 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]

Occurrence

Chloroform has a multitude of natural sources, both biogenic and abiotic. It is estimated that greater than 90% of atmospheric chloroform is of natural origin.^[2]

Marine

In particular, chloroform is produced by brown seaweeds (Laminaria digitata, Laminaria saccharina, Fucus serratus, Pelvetia canaliculata, Ascophyllum nodosum), red seaweeds (Gigartina stellata, Corallina officinalis, Polysiphonia lanosa), and green seaweeds (Ulva lactuca, Enteromorpha sp., Cladophora albida).^[3] Similarly, the macroalga Eucheuma denticulatum, which is cultivated and harvested on a large scale for carrageenan production, produces chloroform,^[4] as do Hypnea spinella, Falkenbergia hillebrandii, and Gracilara cornea along with seven indigenous macroalgae inhabiting a rock pool.^[5] These studies show increased chloroform production with increased light intensity, presumably when photosynthesis is at a maximum. Chloroform is also produced by the brown algae Fucus vesiculosus, the green algae Cladophora glomerata, Enteromorpha ahlneriana, Enteromorpha flexuosa, and Enteromorpha intestinalis, and the diatom Pleurosira laevis.^[6] Other studies observe chloroform in Fucus serratus, Fucus vesiculosis, Corallina officinalis, Cladophora pellucida, and Ulva lactuca,^[7] and Desmarestia antarctica, Lambia antarctica, Laminaria saccharina, Neuroglossum ligulatum.^[8]

Production

Chloroform was discovered by three researchers independently of one another. 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).^[9] The American physician Samuel Guthrie prepared gallons of the material and described its "deliciousness of flavor."^[10] Independently, Justus von Liebig also described the same compound.^[11] All early preparations used variations of the haloform reaction. Chloroform was named and chemically characterized in 1834 by Jean-Baptiste Dumas.^[12]

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 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.^[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.^[13]

Inadvertent formation of chloroform

The haloform reaction can also occur inadvertently in domestic settings.^{[citation needed]} 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.^{[citation needed]}

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 a 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.

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.

Chloroform containing deuterium (heavy hydrogen), CDCl₃, is a common solvent used in NMR spectroscopy.

As a reagent in organic synthesis

As a reagent, chloroform serves as a source of the dichlorocarbene CCl₂ group.^[14] It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl₂.^[15][16] 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.

As an anesthetic

Antique bottles of Chloroform

Chloroform was once a widely-used anesthetic. Its vapor depresses the central nervous system of a patient, allowing a doctor to perform various otherwise painful procedures. In 1847, the Scottish 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 1850s, chloroform was used during the birth of Queen Victoria's last two children.^[17] 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 (~1.5–2.2) ^[18] 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.^[19] Chloroform could also be mixed with other anaesthetic agents such as ether to make C.E. mixture, or ether and alcohol to make A.C.E. mixture.

Chloroform has been used by criminals to knock-out, daze or even murder their victims. Joseph Harris was charged with using chloroform in 1894 to rob people.^[20] Chloroform was used to murder a woman in 1991 as a toxic dose was delivered while she was sleeping.^[21] In 2007 a man was convicted of using chloroform to sexually assault minors.^[22][23]

Safety

Fatal oral dose of chloroform may be as low as 10 mL (14.8 g), with death due to respiratory or cardiac arrest.^[24]

As might be expected for an anesthetic, chloroform vapors depress 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.^[25] Cough syrups containing Chloroform can still be legally purchased in pharmacies and supermarkets in the UK.

The US National Toxicology Program's eleventh report on carcinogens^[26] implicates it as reasonably anticipated to be a human carcinogen, a designation equivalent to International Agency for Research on Cancer class 2A. The IARC itself classifies chloroform as possibly carcinogenic to humans, a Group 2B designation.^[27] It has been most readily associated with hepatocellular carcinoma.^[28][29] 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 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. Amylene has been found ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform.^[30] Dissolved phosgene cannot be removed by distillation or carbon filters, but it is removed by calcium hydroxide or activated alumina.^[31]

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. ^ ^{a b c d e} M. Rossberg et al. “Chlorinated Hydrocarbons” in Ullmann’s Encyclopedia of Industrial Chemistry, 2006, Wiley-VCH, Weinheim. doi:10.1002/14356007.a06_233.pub2
2. ^ http://www.eurochlor.org/upload/documents/document56.pdf
3. ^ Nightingale PB, Malin G, Liss PS (1995). "Production of Chloroform and Other Low- Molecular-Weight Halocarbons by Some Species of Macroalgae". Limnology and Oceanography (American Society of Limnology and Oceanography) 40 (4): 680. JSTOR 2838303. 
4. ^ Mtolera, Matern; Collén, Jonas; Pedersén, Marianne; Ekdahl, Anja; Abrahamsson, Katarina; Semesi, Adelaida (1996). "Stress-induced production of volatile halogenated organic compounds in Eucheuma denticulatum (Rhodophyta) caused by elevated pH and high light intensities". European Journal of Phycology 31 (1): 89. doi:10.1080/09670269600651241. 
5. ^ Ekdahl A, Pedersen M, Abrahamsson K (1998). "A Study of the Diurnal Variation of Biogenic Volatile Halocarbons". Mar Chem 63: 1. 
6. ^ Abrahamsson, K; Choo, KS; Pedersén, M; Johansson, G; Snoeijs, P (2003). "Effects of temperature on the production of hydrogen peroxide and volatile halocarbons by brackish-water algae.". Phytochemistry 64 (3): 725–34. doi:10.1016/S0031-9422(03)00419-9. PMID 13679095. 
7. ^ Baker JM, Sturges WT, Sugier J, Sunnenberg G, Lovett AA, Reeves CE, Nightingale PD, Penkett SA (2001). "Emissions of CH₃Br, Organochlorines, and Organoiodines from Temperate Macroalgae". Chemosphere - Global Change Science 3 (1): 93. doi:10.1016/S1465-9972(00)00021-0. 
8. ^ Laturnus, F; Svensson, T; Wiencke, C; Oberg, G (2004). "Ultraviolet radiation affects emission of ozone-depleting substances by marine macroalgae: results from a laboratory incubation study.". Environmental science & technology 38 (24): 6605–9. doi:10.1021/es049527s. PMID 15669318. 
9. ^ Eugène Soubeiran (1831). Ann. Chim. 48: 131. 
10. ^ Samuel Guthrie (1832). "New mode of preparing a spirituous solution of Chloric Ether". Am. J. Sci. And Arts 21: 64. 
11. ^ 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. 
12. ^ 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. 
13. ^ Canadian Patent 1085423
14. ^ Srebnik, M.; Laloë, E. "Chloroform" Encyclopedia of Reagents for Organic Synthesis" 2001 John Wiley.doi:10.1002/047084289X.rc105
15. ^ "1,6-Methano[10]annulene", Org. Synth., 1988, http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6p0731 ; Coll. Vol. 6: 731 
16. ^ Gokel, G. W.; Widera, R. P.; Weber, W. P. (1988), "Phase-Transfer Hofmann Carbylamine Reaction: tert-Butyl Isocyanide", Org. Synth., http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv6p0232 ; Coll. Vol. 6: 232 
17. ^ http://www.ph.ucla.edu/epi/snow/victoria.html
18. ^ Calderone, F.A. (1935). J. Pharmacology Experimental Therapeutics 55 (1): 24. http://jpet.aspetjournals.org/cgi/reprint/55/1/24.pdf. 
19. ^ 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. 
20. ^ "Knock-out and Chloroform". The Philadelphia record. 9 February 1894. http://news.google.com/newspapers?id=Ec1VAAAAIBAJ&sjid=sEANAAAAIBAJ&pg=2904,2720400&dq=chloroform+knockout&hl=en. Retrieved 31 March 2011. 
21. ^ "Chloroform case retrial underway". Record-Journal. 7 July 1993. http://news.google.com/newspapers?id=I91HAAAAIBAJ&sjid=4f8MAAAAIBAJ&pg=2367,1007950&dq=chloroform+knockout&hl=en. Retrieved 31 March 2011. 
22. ^ "Man Uses Chloroform In Sex Attacks Of Teens". News 5. 6 November 2007. http://www.wlwt.com/news/14519857/detail.html. Retrieved 31 March 2011. 
23. ^ "Man admits to raping friends' daughters". USA Today. 6 November 2007. http://www.usatoday.com/news/nation/2007-11-06-chloroform-rapes_N.htm. Retrieved 31 March 2011. 
24. ^ Chloroform, US Environmental Potection Agency
25. ^ "The National Toxicology Program: Substance Profiles: Chloroform CAS No. 67-66-3" (pdf). http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s038chlo.pdf. Retrieved 2007-11-02. 
26. ^ "11th Report on Carcinogens". http://ntp.niehs.nih.gov/ntp/roc/toc11.html. Retrieved 2007-11-02. 
27. ^ "International Agency for Research on Cancer (IARC) - Summaries & Evaluations: Chloroform". http://www.inchem.org/documents/iarc/vol73/73-05.html. Retrieved 2010-09-02. 
28. ^ "Centers for Disease Control and Prevention: Current Intelligence Bulletin 9". http://www.cdc.gov/Niosh/78127_9.html. 
29. ^ "National Toxicology Program: Report on the carcinogenesis bioassay of chloroform". http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/trChloroform.pdf. 
30. ^ (Turk, Eric, "Phosgene from Chloroform", Chemical & Engineering News (2 March 1998) Vol. 76, No. 9, pp. 6.)
31. ^ (Cone, Edward J., William F. Buckwald, and William D. Darwin, "Analytical controls in Drug Metabolic Studies, II Artifact formation During Chloroform Extraction of Drugs and Metabolites with Amine Substituents",Drug Metabolism & Disposition November 1982 vol. 10 no. 6 561-567)

External links

• Chloroform "The Molecular Lifesaver" An article at Oxford University providing facts about chloroform.
• Concise International Chemical Assessment Document 58
• 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
• ChemSub Online: Chloroform - Methane, trichloro-