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{{Chembox new
__Notoc__
| ImageFileL1 = Chloroform displayed.svg
{{SI}}
| ImageSizeL1 =  
{{CMG}}
| ImageFileR1 = Chloroform 3D.svg
==Overview==
| ImageSizeR1 =  
{{chembox
| Verifiedimages = changed
| Watchedfields = changed
| verifiedrevid = 407464807
| ImageFileL1_Ref = {{chemboximage|correct|??}}
| ImageFileL1 = Chloroform displayed.png
| ImageFileR1 = Chloroform 3D.png
| ImageFile2 = File:Chloroform by Danny S. - 002.JPG
| ImageName2 = Chloroform in its liquid state shown in a test tube
| ImageSize2 = 200px
| IUPACName = Trichloromethane
| IUPACName = Trichloromethane
| OtherNames = Chloroform, Formyl trichloride, Methane trichloride, Methyl trichloride, Methenyl trichloride, TCM, Freon 20, R-20, UN 1888
| OtherNames = Trichloromethane; formyl trichloride; methane trichloride; methyl trichloride; methenyl trichloride; TCM; freon 20; refrigerant-20; R-20; UN 1888
| Section1 = {{Chembox Identifiers
| Section1 = {{Chembox Identifiers
|   CASNo = 67-66-3
| UNII_Ref = {{fdacite|correct|FDA}}
|   EINECS = 200-663-8
| UNII = 7V31YC746X
|   PubChem = 6212
| InChIKey = HEDRZPFGACZZDS-UHFFFAOYAG
|   ChEBI = 35255
| ChEMBL_Ref = {{ebicite|correct|EBI}}
|   KEGG = C13827
| ChEMBL = 44618
|   SMILES = C(Cl)(Cl)Cl
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|   InChI = 1/CHCl3/c2-1(3)4/h1H
| StdInChI = 1S/CHCl3/c2-1(3)4/h1H
|   RTECS = FS9100000
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
  }}
| StdInChIKey = HEDRZPFGACZZDS-UHFFFAOYSA-N
| CASNo = 67-66-3
| CASNo_Ref = {{cascite|correct|CAS}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5977
| EINECS = 200-663-8
| PubChem = 6212
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 35255
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C13827
| SMILES = ClC(Cl)Cl
| InChI = 1/CHCl3/c2-1(3)4/h1H
| RTECS = FS9100000
| ATCCode_prefix = N01
| ATCCode_suffix = AB02
}}
| Section2 = {{Chembox Properties
| Section2 = {{Chembox Properties
|   Formula = CHCl<sub>3</sub>
| C=1|H=1|Cl=3
|   MolarMass = 119.38 g/mol
| Appearance = Colorless liquid
|   Appearance = Colorless liquid
| Odor = Heavy, ethereal odor
|   Density = 1.48 g/cm³, liquid
| Density = 1.564 g/cm<sup>3</sup> (-20 °C)<br> 1.489 g/cm<sup>3</sup> (25 °C)<br> 1.394 g/cm<sup>3</sup> (60 °C)
|   MeltingPt = -63.5 °C
| MeltingPtC = -63.5
|   BoilingPt = 61.2 °C
| BoilingPtC = 61.15
|   Solubility = 0.8 g/100 ml at 20 °C
| Boiling_notes = <br> decomposes at 450&nbsp;°C
  }}
| VaporPressure = 0.62 kPa (-40 °C)<br> 7.89 kPa (0 °C)<br> 25.9 kPa (25 °C)<br> 313 kPa (100 °C)<br> 2.26 MPa (200 °C)
| Solubility = 1.062 g/100 mL (0 °C)<br> 0.809 g/100 mL (20 °C)<br> 0.732 g/100 mL (60 °C)
| SolubleOther = Soluble in [[benzene]]<br> Miscible in [[diethyl ether]], [[oil]]s, [[ligroin]], [[alcohol]], [[carbon tetrachloride|CCl<sub>4</sub>]], [[carbon disulfide|CS<sub>2</sub>]]
| Solubility1 = ≥ 10 g/100 mL (19 °C)
| Solvent1 = acetone
| Solubility2 = ≥ 10 g/100 mL (19 °C)
| Solvent2 = dimethyl sulfoxide
| RefractIndex = 1.4459 (20 °C)
| Lambda-max = 250 nm, 260 nm, 280 nm
| Viscosity = 0.563 cP (20 °C)
| pKa = 15.7 (20 °C)
| HenryConstant = 3.67 L·atm/mol (24 °C)
| ThermalConductivity = 0.13 W/m·K (20 °C)
}}
| Section3 = {{Chembox Structure
| Section3 = {{Chembox Structure
|   CrystalStruct =  
| CrystalStruct =
|   Coordination =  
| Coordination =
|   MolShape = Tetrahedral
| MolShape = Tetrahedral
  }}
| Dipole = 1.15 D
}}
| Section4 = {{Chembox Thermochemistry
|  HeatCapacity = 114.25 J/mol·K
|  Entropy = 202.9 J/mol·K
|  DeltaHf = -134.3 kJ/mol
|  DeltaGf = -71.1 kJ/mol
|  DeltaHc = 473.21 kJ/mol
}}
| Section7 = {{Chembox Hazards
| Section7 = {{Chembox Hazards
|  MainHazards = Harmful ('''Xn'''), Irritant ('''Xi'''),
| MainHazards = carcinogen<ref name=PGCH/>
[[Carcinogen|Carc. Cat. 2B]]
|  GHSPictograms = {{GHS07}}{{GHS08}}
|   NFPA-H = 2
| GHSSignalWord = Warning
|   NFPA-F =  
|  HPhrases = {{H-phrases|302|315|319|332|336|351|361|373}}
|   NFPA-R =  
|  PPhrases = {{P-phrases|261|281|305+351+338}}
|   NFPA-O =  
| EUClass = {{Hazchem Xn}} {{Hazchem Xi}}<br> [[Carcinogen|Carc. Cat. 2B]]
|   RPhrases = {{R22}}, {{R38}}, {{R40}}, {{R48/20/22}}
| NFPA-H = 2
|   SPhrases = {{S2}}, {{S36/37}}
| NFPA-F = 0
|   FlashPt = Non-flammable
| NFPA-R = 0
|   Autoignition =  
| NFPA-O =
|   PEL = 50 ppm (240 mg/m<sup>3</sup>) (OSHA)
| RPhrases = {{R22}}, {{R38}}, {{R40}}, {{R48/20/22}}
  }}
| SPhrases = {{S2}}, {{S36/37}}
| FlashPt = Non-flammable
| Autoignition =
| PEL = 50 ppm (240 mg/m<sup>3</sup>)<ref name=PGCH>{{PGCH|0127}}</ref>
| IDLH = 500 ppm<ref name=PGCH/>
| REL = Ca ST 2 ppm (9.78 mg/m<sup>3</sup>) [60-minute]<ref name=PGCH/>
| LD50 = 1250 mg/kg (rats, oral)
}}
}}
}}
{{SI}}
{{CMG}}


{{EH}}
'''Chloroform''' is an [[organic compound]] with [[chemical formula|formula]] [[Carbon|C]][[Hydrogen|H]][[Chlorine|Cl]]<sub>3</sub>. It is one of the four chloromethanes.<ref name=Ullmann/> 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 [[refrigerant]]s, but its use for refrigerants is being phased out.<ref name=Ullmann>Rossberg, M. ''et al.'' "Chlorinated Hydrocarbons" in ''Ullmann’s Encyclopedia of Industrial Chemistry'', 2006, Wiley-VCH, Weinheim. {{DOI|10.1002/14356007.a06_233.pub2}}</ref> The [[hydrogen]] attached to [[carbon]] in chloroform participates in hydrogen bonding.<ref>{{cite journal|author=Wiley G.R. and Miller S.I. |doi=10.1021/ja00765a001|title=Thermodynamic parameters for hydrogen bonding of chloroform with Lewis bases in cyclohexane. Proton magnetic resonance study|year=1972|journal=Journal of the American Chemical Society|volume=94|issue=10|pages=3287}}</ref><ref>{{cite journal|pmid=18855462|year=2008|last1=Kwak|first1=K|last2=Rosenfeld|first2=DE|last3=Chung|first3=JK|last4=Fayer|first4=MD|title=Solute-solvent complex switching dynamics of chloroform between acetone and dimethylsulfoxide-two-dimensional IR chemical exchange spectroscopy|volume=112|issue=44|pages=13906–15|doi=10.1021/jp806035w|pmc=2646412|journal=The journal of physical chemistry. B}}</ref>
 
==Natural occurrence==
The total global flux of chloroform through the environment is approximately 660&nbsp;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.<ref name="cicad">{{citation | title=Chloroform | series=[[CICAD]] | volume=58 |  publisher=[[World Health Organization]] | year=2004 | url=http://www.who.int/ipcs/publications/cicad/en/cicad58.pdf}}</ref>
 
==History==
Trichloromethane was synthesized independently by two groups in 1831: [[Liebig]] carried out the [[Bond cleavage|alkaline cleavage]] of [[chloral]], whereas [[Eugène Soubeiran|Soubeirain]] obtained the compound by the action of [[chlorine bleach]] on both [[ethanol]] and [[acetone]]. In 1835, [[Jean-Baptiste Dumas|Dumas]] prepared the substance by the alkaline cleavage of [[trichloroacetic acid]]. [[Henri Victor Regnault|Regnault]] prepared trichloromethane by [[Halogenation|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.<ref name="Ullmann" />
 
===Production===
In industry, chloroform is produced by heating a mixture of [[chlorine]] and either [[methyl chloride|chloromethane]] or [[methane]].<ref name=Ullmann/> At 400–500&nbsp;°C, a [[free radical halogenation]] occurs, converting these precursors to progressively more chlorinated compounds:
:CH<sub>4</sub> + Cl<sub>2</sub> → CH<sub>3</sub>Cl + [[hydrogen chloride|HCl]]
:CH<sub>3</sub>Cl + Cl<sub>2</sub> → [[Dichloromethane|CH<sub>2</sub>Cl<sub>2</sub>]] + HCl
:CH<sub>2</sub>Cl<sub>2</sub> + Cl<sub>2</sub> → CHCl<sub>3</sub> + HCl
 
Chloroform undergoes further chlorination to yield [[carbon tetrachloride]] (CCl<sub>4</sub>):
:CHCl<sub>3</sub> + Cl<sub>2</sub> → CCl<sub>4</sub> + 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]].<ref name=Ullmann/>


==Overview==
===Deuterochloroform===
'''Chloroform''', also known as '''trichloromethane''' and '''methyl trichloride''', is a [[chemical compound]] with [[chemical formula|formula]] [[Carbon|C]][[Hydrogen|H]][[Chlorine|Cl]]<sub>3</sub>. 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 [[trihalomethane]]s. Chloroform has myriad uses as a [[reagent]] and a [[solvent]]. It is also considered an environmental hazard.
{{Main|Deuterated chloroform}}
[[Deuterated chloroform]] is an [[isotopologue]] of chloroform with a single [[deuterium]] atom. CDCl<sub>3</sub> is a common solvent used in [[NMR spectroscopy]]. Deuterochloroform is produced by the [[haloform reaction]]{{Citation needed|date=February 2012}}, the reaction of  acetone (or ethanol) with [[sodium hypochlorite]] or calcium hypochlorite.<ref name=Ullmann/> 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|date=December 2007}} or from ordinary chloroform.<ref>Koch, Hans A. [http://patents.ic.gc.ca/cipo/cpd/en/patent/1085423/summary.html Cholorofom Deuteration Process]. Canadian Patent 1085423. Patents.ic.gc.ca. Issued: 1980-09-09. Retrieved on 2012-08-13.</ref>


== History ==
===Inadvertent formation of chloroform===
Chloroform was discovered in July, 1831 by the American physician [[Samuel Guthrie (U.S. physician)|Samuel Guthrie]],<ref>{{cite journal
The haloform reaction can also occur inadvertently in domestic settings. [[Bleaching]] with [[hypochlorite]] generates halogenated compounds in side reactions; chloroform is the main byproduct.<ref name="bleaching">{{citation | author=Hans Ulrich Süss | contribution=Bleaching | title=Ullmann's Encyclopedia of Industrial Chemistry | edition=7th | publisher=Wiley | year=2007 | page=5}}</ref> 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]].
| author = [[Samuel Guthrie (U.S. physician)|Samuel Guthrie]]
| title = .
| journal = Am. J. Sci. and Arts
| volume =  21
| issue = 
| pages = 64
| year =  1832
| doi =  }}</ref> and independently a few months later by the French [[chemist]] [[Eugène Soubeiran]]<ref>{{cite journal
| author = [[Eugène Soubeiran]]
| title = .
| journal = Ann. Chim.
| volume = 48
| issue =
| pages = 131
| year = 1831
| doi = }}</ref> and [[Justus von Liebig]]<ref>{{cite journal
| author =  [[Justus Liebig]]  
| title =  Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen
| journal =  [[Annalen der Pharmacie]]
| volume =  1
| issue = 2
| pages = 182-230
| year =  1832
| doi = 10.1002/jlac.18320010203 }}</ref> in Germany, all of them using variations of the [[haloform reaction]]. Soubeiran produced chloroform through the action of chlorine [[Bleach (chemical)|bleach]] powder (calcium hypochlorite) on [[acetone]] (2-propanone) as well as [[ethanol]]). Chloroform was named and chemically characterised in 1834 by [[Jean-Baptiste Dumas]].<ref>{{cite journal
| author =  [[Jean-Baptiste Dumas]]  
| title =  Untersuchung über die Wirkung des Chlors auf den Alkohol
| journal =  [[Annalen der Pharmacie]]
| volume =  107
| issue = 41
| pages = 650-656
| year =  1834
| doi = 10.1002/andp.18341074103 }}</ref>


In 1847, the [[Edinburgh]] [[obstetrics|obstetrician]] [[James Simpson (doctor)|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 [[Diethyl ether|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 "[[solvent abuse|sudden sniffer's death]]". [[Diethyl ether|Ether]] is still the preferred anesthetic in some [[developing nation]]s 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 [[carcinogen]]ic.
==Uses==
The major use of chloroform today is in the production of the [[chlorodifluoromethane]], a major precursor to [[tetrafluoroethylene]]:
:CHCl<sub>3</sub> + 2 HF → CHClF<sub>2</sub> + 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.


== Production ==
===Solvent===
Industrially, chloroform is produced by heating a mixture of [[chlorine]] and either [[methyl chloride|chloromethane]] or [[methane]].{{Fact|date=December 2007}} At 400-500 °C, a [[free radical halogenation]] occurs, converting the [[methane]] or [[methyl chloride|chloromethane]] to progressively more chlorinated compounds.
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.<ref name="cicad" /><ref name="pth">{{citation | editor=Jerrold B. Leikin | editor2=Frank P. Paloucek | contribution=Chloroform | title=Poisoning and Toxicology Handbook | edition=4th | publisher=Informa | year=2008 | page=774}}</ref> CDCl<sub>3</sub> is a common solvent used in [[NMR spectroscopy]].


:CH<sub>4</sub> +  Cl<sub>2</sub> →  CH<sub>3</sub>Cl  +  [[hydrogen chloride|HCl]]
===Reagent===
:CH<sub>3</sub>Cl  +  Cl<sub>2</sub> → [[Dichloromethane|CH<sub>2</sub>Cl<sub>2</sub>]]  +  HCl
As a [[reagent]], chloroform serves as a source of the dichlorocarbene CCl<sub>2</sub> group.<ref>Srebnik, M.; Laloë, E. (2001) "Chloroform" in ''Encyclopedia of Reagents for Organic Synthesis'', Wiley, {{doi|10.1002/047084289X.rc105}}</ref> It reacts with aqueous [[sodium hydroxide]] usually in the presence of a [[phase transfer catalyst]] to produce [[dichlorocarbene]], CCl<sub>2</sub>.<ref>{{OrgSynth|Vogel, E.; Klug, W.; Breuer. A.|title = <nowiki>1,6-Methano[10]annulene</nowiki>|collvol = 6|collvolpages = 731|year = 1988|prep = cv6p0731}}</ref><ref>{{OrgSynth|author = Gokel, G. W.; Widera, R. P.; Weber, W. P.|title = Phase-Transfer Hofmann Carbylamine Reaction: tert-Butyl Isocyanide|collvol = 6|collvolpages = 232|year = 1988|prep = cv6p0232}}</ref> This reagent affects ortho-formylation of activated [[aromatic rings]] such as [[phenols]], producing aryl [[aldehyde]]s 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 CHCl<sub>2</sub> free radical in addition to alkenes.
:CH<sub>2</sub>Cl<sub>2</sub> + Cl<sub>2</sub> →  CHCl<sub>3</sub> + HCl


Chloroform undergoes further chlorination to give [[carbon tetrachloride|CCl<sub>4</sub>]]:
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]]).<ref name="Ullmann" />
:CHCl<sub>3</sub> +  Cl<sub>2</sub>  →  CCl<sub>4</sub> + 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]].{{Fact|date=December 2007}}
===Anaesthetic===
[[File:Chickamauga 2009, Chloroform.jpg|thumb|left|Antique bottles of chloroform]]
Chloroform was once a widely used [[anesthesia|anesthetic]]. On 4 November 1847, the Scottish [[obstetrics|obstetrician]] [[James Young Simpson]] first used the anaesthetic qualities of chloroform on a human,<ref name="Gordon2002">{{cite book|last=Gordon|first=H. Laing|title=Sir James Young Simpson and Chloroform (1811–1870)|url=http://books.google.com/books?id=pYer05UwKBYC&pg=PA106|accessdate=11 November 2011|date=November 2002|publisher=The Minerva Group, Inc.|isbn=978-1-4102-0291-8|pages=106–109}}</ref> two guests at his dinner party. This was done as an entertainment and not as a medical procedure.


Chloroform was first produced industrially by the reaction of [[acetone]] (or [[ethanol]]) with [[sodium hypochlorite]] or [[calcium hypochlorite]], known as the [[haloform reaction]].{{Fact|date=December 2007}}  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]].{{Fact|date=December 2007}}  The haloform process is obsolete for the production of ordinary chloroform. It is, however, used to produce deuterated material industrially.{{Fact|date=December 2007}} Deuterochloroform may be prepared by the reaction of sodium deuteroxide with [[chloral hydrate]],{{Fact|date=December 2007}}  or from ordinary chloroform.<ref>[http://patents.ic.gc.ca/cipo/cpd/en/patent/1085423/summary.html Canadian Patent 1085423]</ref>
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.<ref>http://historyofdentistry.co.uk/index_htm_files/2004Apr2.pdf</ref>


===Inadvertent synthesis of chloroform===
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.<ref>[http://www.ph.ucla.edu/epi/snow/victoria.html Anesthesia and Queen Victoria]. Ph.ucla.edu. Retrieved on 2012-08-13.</ref> In the United States, chloroform began to replace [[Diethyl ether|ether]] as an anesthetic at the beginning of the 20th century; however, it was quickly abandoned in favor of [[Diethyl ether|ether]] upon discovery of its toxicity, especially its tendency to cause fatal [[cardiac arrhythmia]] analogous to what is now termed "[[Intoxicative inhalant#Sudden sniffing death syndrome|sudden sniffer's death]]". Some people used chloroform as a recreational drug or to attempt suicide.<ref>{{cite journal|author=Martin, William|title=A Case of Chloroform Poisoning; Recovery|journal=Br Med J|date=3 July 1886|volume=2|issue=1331|pages=16–17|pmc=2257365|doi=10.1136/bmj.2.1331.16-a|pmid=20751619}}</ref> One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of [[potassium channels]] in [[nerve cells]].<ref>{{Cite journal|last1 = Patel|first1 = Amanda J.|last2 = Honoré|first2 = Eric|last3 = Lesage|first3 = Florian|last4 = Fink|first4 = Michel|last5 = Romey|first5 = Georges|last6 = Lazdunski|first6 = Michel|publication-date =|date = May 1999|title = Inhalational anesthetics activate two-pore-domain background K+ channels|journal = Nature Neuroscience|volume = 2|pages = 422–426|doi = 10.1038/8084|pmid = 10321245|issue = 5}}</ref> Chloroform could also be mixed with other anesthetic agents such as ether to make C.E. mixture, or ether and [[Ethanol|alcohol]] to make [[A.C.E. mixture]].
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.
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anesthetic.<ref>{{cite journal|title=An Unexplained Death: Hannah Greener and Chloroform |author= Knight, Paul R. III and Bacon, Douglas R. | year=2002 |volume = 96 |issue = 5 |journal=Anesthesiology|doi=10.1097/00000542-200205000-00030|pages=1250–3|pmid=11981167}}</ref> A number of physically fit patients died after inhaling it. However, in 1848 [[John Snow (physician)|John Snow]] developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.<ref>{{cite web|last1 = Snow|first1 = John|publication-date =|year = 1858|title = On Chloroform and Other Anaesthetics and Their Action and Administration| pages = 82–85|url=http://archive.org/stream/onchloroformothe1858snow#page/82/mode/2up/search/inhaler}}</ref>


== Uses ==
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.<ref>Anaesthesiol Reanim. 1997;22(6):144-52. Wawersik J. Clinic of  Christian-Albrechts-Universität of Kiel. http://ncbi.nlm.nih.gov/pubmed/9487785</ref>
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====
=== Criminal use ===
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.
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.<ref>{{Cite news|url=http://news.google.com/newspapers?id=Ec1VAAAAIBAJ&sjid=sEANAAAAIBAJ&pg=2904,2720400&dq=chloroform+knockout&hl=en|title=Knock-out and Chloroform|publisher=[[The Philadelphia Record]]|date=9 February 1894|accessdate=31 March 2011}}</ref> 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.<ref>{{cite web|url=http://news.google.com/newspapers?id=I91HAAAAIBAJ&sjid=4f8MAAAAIBAJ&pg=2367,1007950&dq=chloroform+knockout&hl=en|title=Chloroform case retrial underway|date=7 July 1993|accessdate=31 March 2011|publisher=[[Record-Journal]]}}</ref> In a 2007 plea bargain a man confessed to using [[Electroshock weapon|stun guns]] and chloroform to sexually assault minors.<ref>{{cite web|url=http://www.usatoday.com/news/nation/2007-11-06-chloroform-rapes_N.htm|title=Man admits to raping friends' daughters|date=6 November 2007|accessdate=31 March 2011|publisher=[[USA Today]]}}</ref> Use of chloroform as an [[incapacitating agent]] has become widely recognized, bordering on [[cliché]]d, 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.<ref name="Anaesthesia">{{cite journal|last=Payne|first=J. P.|date=July 1998|title=The criminal use of chloroform|journal=[[Anaesthesia (journal)|Anaesthesia]]|volume=53|issue=7|pages=685–690|doi=10.1046/j.1365-2044.1998.528-az0572.x|url=http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2044.1998.528-az0572.x/pdf}}</ref> 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,<ref>Medical Annotation. Chloroform amongst Thieves. ''[[The Lancet]]'', 1865; 2: 490 – 1.</ref> and {{as of|1998|lc=y}} no such demonstration has been forthcoming.<ref name="Anaesthesia"/>


====As a solvent====
==Safety==
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]]s and [[pesticide]]s. 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 [[poppy|poppies]], [[scopolamine]] from ''[[Datura]]'' plants.  Chloroform containing [[deuterium]] (heavy hydrogen), [[CDCl3|CDCl<sub>3</sub>]], is a common solvent used in [[NMR spectroscopy]].  It can be used to bond pieces of [[polymethyl methacrylate|acrylic glass]] (which is also known under the trade name 'Perspex').
Chloroform is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.<ref name="cicad" /> Prolonged dermal exposure can result in the development of sores as a result of [[Defatting (medical)|defatting]]. Elimination is primarily from lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in urine.<ref name="pth" />


====As a reagent in organic synthesis====
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.<ref name="eot">{{citation | author=Anna M Fan | contribution=Chloroform | title=Encyclopedia of Toxicology | edition=2nd | volume=1 | publisher=Elsevier | year=2005 | pages=561–565}}</ref>
As a reagent, chloroform serves as a source of the dichlorocarbene CCl<sub>2</sub> group.<ref>Srebnik, M.; Laloë, E. "Chloroform" Encyclopedia of Reagents for Organic Synthesis" 2001 John Wiley. {{doi|10.1002/047084289X.rc105}}</ref>  It reacts with aqueous [[sodium hydroxide]] (usually in the presence of a [[phase transfer catalyst]]) to produce [[dichlorocarbene]], CCl<sub>2</sub>.<ref>{{OrgSynth | Vogel, E.; Klug, W.; Breuer. A. | title = <nowiki>1,6-Methano[10]annulene</nowiki> | collvol = 6 | collvolpages = 731 | year = 1988 | prep = cv6p0731}}</ref><ref>{{OrgSynth | author = Gokel, G. W.; Widera, R. P.; Weber, W. P. | title = Phase-Transfer Hofmann Carbylamine Reaction: tert-Butyl Isocyanide | collvol = 6 | collvolpages = 232 | year = 1988 | prep = cv6p0232}}</ref> This reagent effects ortho-formylation of activated [[aromatic rings]] such as [[phenols]], producing aryl [[aldehyde]]s in a reaction known as the [[Reimer-Tiemann reaction]].  Alternatively the [[carbene]] can be trapped by an [[alkene]] to form a [[cyclopropane]] derivative.


== Safety ==
Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression.<ref name="eot" /> When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of 7.5&nbsp;g. The mean lethal oral dose for an adult is estimated to be about 45&nbsp;g.<ref name="cicad" />
As might be expected from its use as an [[general anaesthetic|anesthetic]], inhaling chloroform vapors depresses the [[central nervous system]]. It is [[IDLH|immediately dangerous to health and life]] at approximately 500 ppm according to the [[National Institute for Occupational Safety and Health|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 [[kidney]]s, and some people develop sores when the skin is immersed in chloroform.


Animal studies have shown that [[miscarriage]]s occur in rats and mice that have breathed air containing 30 to 300 [[Parts per million|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 defect]]s, and abnormal [[spermatozoon|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.
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.<ref name="cicad" />


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.<ref>{{cite web| title= The National Toxicology Program: Substance Profiles: Chloroform CAS No. 67-66-3| url=http://ntp.niehs.nih.gov/ntp/roc/eleventh/profiles/s038chlo.pdf| format=pdf| accessdate=2007-11-02}}</ref>
Chloroform has induced liver tumors in mice and kidney tumors in mice and rats.<ref name="cicad" /> The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene.<ref name="eot" />


The National Toxicology Program's eleventh report on carcinogens<ref>{{cite web| title= 11th Report on Carcinogens| url=http://ntp.niehs.nih.gov/ntp/roc/toc11.html| accessdate=2007-11-02}}</ref> 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]].<ref>{{cite web| url=http://www.cdc.gov/Niosh/78127_9.html| title=Centers for Disease Control and Prevention: CURRENT  INTELLIGENCE  BULLETIN 9}}</ref><ref>{{cite web| title= National Toxicology Program: Report on the carcinogenesis bioassay of chloroform|url=http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/trChloroform.pdf}}</ref> 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]], releasing [[HCl]] in the process. To prevent accidents, commercial chloroform is stabilized with [[ethanol]] or [[pentene|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.<ref>{{cite journal|url=http://pubs.acs.org/cen/safety/19980302.html|author=Turk, Eric|title=Phosgene from Chloroform|journal= Chemical & Engineering News |date=2 March 1998|volume=76|issue=9|page=6|doi=10.1021/cen-v076n009.p006}}</ref> 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,<ref>[http://www.britannica.com/EBchecked/topic/457363/phosgene phosgene (chemical compound)]. Encyclopædia Britannica. Retrieved on 2013-08-16.</ref> and the carbonate salt neutralizes the resulting acid.


During prolonged storage hazardous amounts of [[phosgene]] can accumulate in the presence of [[oxygen]] and [[ultraviolet|ultraviolet light]]. To prevent accidents, commercial chloroform is stabilized with [[ethanol]] or [[pentene|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.
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]].


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==
==References==
{{reflist}}
{{reflist|2}}
== External links ==
 
* [http://www.chm.bris.ac.uk/motm/chloroform/chloroformv.htm Chloroform "The Molecular Lifesaver"] An article at Oxford University providing facts about chloroform.
==External links==
* [http://www.inchem.org/documents/cicads/cicads/cicad58.htm Concise International Chemical Assessment Document 58]
{{Commons category|Chloroform}}
* [http://www.general-anaesthesia.com/chloroform.html History of chloroform anesthesia]
*[http://www.chm.bris.ac.uk/motm/chloroform/chloroformv.htm Chloroform "The Molecular Lifesaver"] An article at Oxford University providing facts about chloroform.
* IARC Summaries & Evaluations: [http://www.inchem.org/documents/iarc/vol01/chloroform.html Vol. 1 (1972)], [http://www.inchem.org/documents/iarc/vol20/chloroform.html Vol. 20 (1979)], [http://www.inchem.org/documents/iarc/suppl7/chloroform.html Suppl. 7 (1987)], [http://www.inchem.org/documents/iarc/vol73/73-05.html Vol. 73 (1999)]
*[http://www.inchem.org/documents/cicads/cicads/cicad58.htm Concise International Chemical Assessment Document 58]
* {{ICSC|0027|00}}
*IARC Summaries & Evaluations: [http://www.inchem.org/documents/iarc/vol01/chloroform.html Vol. 1 (1972)], [http://www.inchem.org/documents/iarc/vol20/chloroform.html Vol. 20 (1979)], [http://www.inchem.org/documents/iarc/suppl7/chloroform.html Suppl. 7 (1987)], [http://www.inchem.org/documents/iarc/vol73/73-05.html Vol. 73 (1999)]
* {{PGCH|0127}}
*{{ICSC|0027|00}}
* [http://www.npi.gov.au/database/substance-info/profiles/23.html National Pollutant Inventory - Chloroform and trichloromethane]
*{{PGCH|0127}}
* [http://webbook.nist.gov/cgi/cbook.cgi?ID=67-66-3&Units=SI&cTG=on&cTC=on&cTP=on NIST Standard Reference Database]
*[http://webbook.nist.gov/cgi/cbook.cgi?ID=67-66-3&Units=SI&cTG=on&cTC=on&cTP=on NIST Standard Reference Database]
* [http://www.bbc.co.uk/radio4/science/thematerialworld_20050728.shtml Story on Chloroform] from BBC's [[The Material World]] (28 July 2005)
*[http://www.bbc.co.uk/radio4/science/thematerialworld_20050728.shtml Story on Chloroform] from BBC's The Material World (28 July 2005)
* [http://www.ncpoisoncenter.org/Consumers/Poisons_Inhalants.cfm Sudden Sniffer's Death Syndrome] article at Carolina Poison Center
*[http://www.ncpoisoncenter.org/body.cfm?id=142 Sudden Sniffer's Death Syndrome] article at Carolinas Poison Center
*Calculation of [http://ddbonline.ddbst.de/AntoineCalculation/AntoineCalculationCGI.exe?component=Chloroform vapor pressure], [http://ddbonline.ddbst.de/DIPPR105DensityCalculation/DIPPR105CalculationCGI.exe?component=Chloroform liquid density], [http://ddbonline.ddbst.de/VogelCalculation/VogelCalculationCGI.exe?component=Chloroform dynamic liquid viscosity], [http://ddbonline.ddbst.de/DIPPR106SFTCalculation/DIPPR106SFTCalculationCGI.exe?component=Chloroform surface tension] of chloroform
*[http://chemsub.online.fr/name/chloroform.html ChemSub Online: Chloroform – Methane, trichloro-]
 


{{Hallucinogens}}
{{General anesthetics}}
{{General anesthetics}}
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[[Category:Organochlorides]]
[[Category:Organochlorides]]
[[Category:Halomethanes]]
[[Category:Halomethanes]]
[[Category:Anesthetics]]
[[Category:Hazardous air pollutants]]
[[Category:Hazardous air pollutants]]
[[Category:IARC Group 2B carcinogens]]
[[Category:IARC Group 2B carcinogens]]
[[Category:Halogenated solvents]]
[[Category:Halogenated solvents]]
 
[[Category:Halogen-containing natural products]]
[[ca:Cloroform]]
[[Category:Drug]]
[[cs:Chloroform]]
[[da:Kloroform]]
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[[es:Cloroformo]]
[[fr:Chloroforme]]
[[id:Kloroform]]
[[it:Cloroformio]]
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[[lv:Hloroforms]]
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[[pt:Clorofórmio]]
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Template:Chembox ECNumberTemplate:Chembox E numberTemplate:Chembox RTECSTemplate:Chembox AppearanceTemplate:Chembox OdourTemplate:Chembox DensityTemplate:Chembox MeltingPtTemplate:Chembox BoilingPtTemplate:Chembox SolubilityInWaterTemplate:Chembox SolubilityTemplate:Chembox SolubilityTemplate:Chembox SolubilityTemplate:Chembox VaporPressureTemplate:Chembox HenryConstantTemplate:Chembox pKaTemplate:Chembox ThermalConductivityTemplate:Chembox RefractIndexTemplate:Chembox ViscosityTemplate:Chembox StructureTemplate:Chembox ThermochemistryTemplate:Chembox MainHazardsTemplate:Chembox GHSPictogramsTemplate:Chembox GHSSignalWordTemplate:Chembox HPhrasesTemplate:Chembox PPhrasesTemplate:Chembox NFPATemplate:Chembox FlashPtTemplate:Chembox Lethal amounts (set)Template:Chembox NIOSH (set)
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).
☑Y verify (what is ☑Y☒N ?)
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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