Chemistry:Chloroform

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Short description: Organic compound with the formula CHCl3
Chloroform
Chloroform displayed.svg
Chloroform-3D-balls.png
Chloroform in its liquid state shown in a test tube
Names
Preferred IUPAC name
Trichloromethane
Other names
Chloroform[1]
Methane trichloride
Methyl trichloride
Methenyl trichloride
Methenyl chloride
TCM
Freon 20
Refrigerant-20
R-20
UN 1888
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
EC Number
  • 200-663-8
KEGG
RTECS number
  • FS9100000
UNII
Properties
CHCl3
Molar mass 119.37 g·mol−1
Appearance Highly refractive colorless liquid
Odor Strong smell reminiscent of dry-cleaner's shops
Density 1.564 g/cm3 (−20 °C)
1.489 g/cm3 (25 °C)
1.394 g/cm3 (60 °C)
Melting point −63.5 °C (−82.3 °F; 209.7 K)
Boiling point 61.15 °C (142.07 °F; 334.30 K)
decomposes at 450 °C
10.62 g/L (0 °C)
8.09 g/L (20 °C)
7.32 g/L (60 °C)
Solubility Soluble in benzene
Miscible in diethyl ether, oils, ligroin, alcohol, CCl4, CS2
Solubility in acetone ≥ 100 g/L (19 °C)
Solubility in dimethyl sulfoxide ≥ 100 g/L (19 °C)
Vapor pressure 0.62 kPa (−40 °C)
7.89 kPa (0 °C)
25.9 kPa (25 °C)
313 kPa (100 °C)
2.26 MPa (200 °C)
3.67 L·atm/mol (24 °C)
Acidity (pKa) 15.7 (20 °C)
UV-vis (λmax) 250 nm, 260 nm, 280 nm
−59.30·10−6 cm3/mol
Thermal conductivity 0.13 W/m·K (20 °C)
1.4459 (20 °C)
Viscosity 0.563 cP (20 °C)
Structure
Tetrahedral
1.15 D
Thermochemistry
114.25 J/mol·K
202.9 J/mol·K
−134.3 kJ/mol
−71.1 kJ/mol
473.21 kJ/mol
Pharmacology
1=ATC code }} N01AB02 (WHO)
Hazards[7]
Main hazards Carcinogen – Reproductive toxicity – Specific target organ toxicity (STOT)[2][3][4]
Safety data sheet [1]
GHS pictograms GHS06: Toxic GHS08: Health hazard
GHS Signal word Danger
H302, H315, H319, H331, H336, H351, H361d, H372
P201, P202, P260, P264, P270, P271, P280, P281, P301+330+331, P310, P302+352, P304+340, P311, P305+351+338, P308+313, P314, P332+313, P337+313, P362, P403+233, P235, P405, P501
NFPA 704 (fire diamond)
Flammability code 0: Will not burn. E.g. waterHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
0
2
0
Flash point Non-flammable
Lethal dose or concentration (LD, LC):
704 mg/kg (mouse, dermal)[5]
9,617 ppm (rat, 4 hr)[6]
20,000 ppm (guinea pig, 2 hr)
7,056 ppm (cat, 4 hr)
25,000 ppm (human, 5 min)[6]
NIOSH (US health exposure limits):
PEL (Permissible)
 50 ppm (240 mg/m3)[3]
REL (Recommended)
 Ca ST 2 ppm (9.78 mg/m3) [60-minute][3]
IDLH (Immediate danger)
 500 ppm[3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Chloroform, or trichloromethane, is an organic compound with the formula CHCl3 and a common organic solvent. It is a very volatile, colorless, strong-smelling, dense liquid produced on a large scale as a precursor to PTFE and refrigerants[8] and is a trihalomethane that serves as a powerful anesthetic, euphoriant, anxiolytic, and sedative when inhaled or ingested. It is also part of a wider class of substances known as volatile organic compounds.[9][10]

Structure

The molecule adopts a tetrahedral molecular geometry with C3v symmetry.[11] The chloroform molecule can be viewed as a methane molecule with three hydrogen atoms replaced with three chlorine atoms, leaving a single hydrogen atom.

Natural occurrence

The total global flux of chloroform through the environment is approximately 660000 tonnes per year,[12] and about 90% of emissions are natural in origin. Many kinds of seaweed produce chloroform, and fungi are believed to produce chloroform in soil.[13] Abiotic processes are also believed to contribute to natural chloroform productions in soils, although the mechanism is still unclear.[14]

As chloroform is a volatile organic compound,[15] it dissipates 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 half-life in air ranges from 55 to 620 days. Biodegradation in water and soil is slow. Chloroform does not significantly bioaccumulate in aquatic organisms.[16]

History

Chloroform was synthesized independently by several investigators circa 1831:

  • Moldenhawer, a German pharmacist from Frankfurt an der Oder, appears to have produced chloroform in 1830 by mixing chlorinated lime with ethanol; he mistook it for Chloräther (chloric ether, 1,2-dichloroethane), however.[17][18]
  • Samuel Guthrie, a U.S. physician from Sackets Harbor, New York, also appears to have produced chloroform in 1831 by reacting chlorinated lime with ethanol, as well as noting its anaesthetic properties; he also believed that he had prepared chloric ether, however.[19][20][21]
  • Justus von Liebig carried out the alkaline cleavage of chloral.[22][23]
  • Eugène Soubeiran obtained the compound by the action of chlorine bleach on both ethanol and acetone.[24]
  • In 1834, French chemist Jean-Baptiste Dumas determined chloroform's empirical formula and named it.Cite error: Closing </ref> missing for <ref> tag
  • In 1847, Scottish obstetrician James Y. Simpson was the first to demonstrate the anaesthetic properties of chloroform on humans, provided by local pharmacist William Flockhart of Duncan, Flockhart and company,[25] and helped to popularise the drug for use in medicine.[26] By the 1850s, chloroform was being produced on a commercial basis. In Britain, about 750,000 doses a week were being produced by 1895[27] using the Liebig procedure, which retained its importance until the 1960s. Today, chloroform – along with dichloromethane – is prepared exclusively and on a massive scale by the chlorination of methane and chloromethane.[8]

Production

Industrially, chloroform is produced by heating a mixture of chlorine and either chloromethane (CH3Cl) or methane (CH4).[8] 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, trichloromethane (chloroform), and tetrachloromethane (carbon tetrachloride). This can then be separated by distillation.[8]

Chloroform may also be produced on a small scale via the haloform reaction between acetone and sodium hypochlorite:

3 NaClO + (CH3)2CO → CHCl3 + 2 NaOH + CH3COONa

Deuterochloroform

Main page: Chemistry: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, the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite.[8] The haloform process is now obsolete for the production of ordinary chloroform. Deuterochloroform can be prepared by the reaction of sodium deuteroxide with chloral hydrate.[28][29]

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.[30] Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, methyl ethyl ketone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone or dichloroacetone.

Uses

In terms of scale, the most important reaction of chloroform is with hydrogen fluoride to give monochlorodifluoromethane (CFC-22), a precursor in the production of polytetrafluoroethylene (Teflon) and other fluoropolymers:[8]

CHCl3 + 2HF → CHClF2 + 2 HCl

The reaction is conducted in the presence of a catalytic amount of mixed antimony halides. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon.[31]

Solvent

The hydrogen attached to carbon in chloroform participates in hydrogen bonding,[32][33] thus making it a good solvent for many materials.

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.[16][34] CDCl3 is a common solvent used in NMR spectroscopy.[35]

Refrigerant

Trichloromethane has been used as a precursor to make R-22 (Chlorodifluoromethane). This is done by reacting it with a solution of Hydrofluoric acid (HF) which will fluorinate the CHCl3 molecule and release hydrochloric acid as a byproduct.[36] Prior to the enforcement of the Montreal Protocol, the majority of the trichloromethane produced in the United States, was used for the production of Chlorodifluoromethane. [37]

Although trichloromethane has properties such as its low boiling point and its low global warming potential of only 31 (compared to the 1,760 of R-22) which result in it having good refrigeration properties, there is little information to suggest that it has seen widespread use as a refrigerant in any consumer products.[38]

Lewis acid

In solvents such as CCl4 and alkanes, chloroform hydrogen bonds to a variety of Lewis bases. HCCl3 is classified as a hard acid and the ECW model lists its acid parameters as EA = 1.56 and CA = 0.44.

Reagent

As a reagent, chloroform serves as a source of the dichlorocarbene :CCl2 group.[39] It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, :CCl2.[40][41] 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.

Anaesthetic

Antique bottles of chloroform

The anaesthetic qualities of chloroform were first described in 1842 in a thesis by Robert Mortimer Glover, which won the Gold Medal of the Harveian Society for that year. Glover also undertook practical experiments on dogs to prove his theories. Glover further refined his theories and presented them in the thesis for his doctorate at the University of Edinburgh in the summer of 1847. The Scottish obstetrician James Young Simpson was one of the persons required to read the thesis, but later claimed to have never read the thesis and to have come to his conclusions independently.

On 4 November 1847, Simpson first discovered the anaesthetic qualities of chloroform on humans. He and two colleagues were entertaining themselves by trying the effects of various substances, and thus revealed the potential for chloroform in medical procedures.[25]

A few days later, during the course of a dental procedure in Edinburgh, Francis Brodie Imlach became the first person to use chloroform on a patient in a clinical context.[42]

In May 1848, Robert Halliday Gunning made a presentation to the Medico-Chirurgical Society of Edinburgh following a series of laboratory experiments on rabbits that confirmed Glover's findings and also refuted Simpson's claims of originality. The laboratory experiments proving the dangers of chloroform were largely ignored.[43]

The use of chloroform during surgery expanded rapidly thereafter in Europe. In the 1850s, chloroform was used by the physician John Snow during the birth of Queen Victoria's last two children.[44] In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; it was quickly abandoned in favor of ether upon discovery of its toxicity, however, 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.[45] One possible mechanism of action for chloroform is that it increases the movement of potassium ions through certain types of potassium channels in nerve cells.[46] 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.

In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anaesthetic.[47] Her autopsy establishing the cause of death was undertaken by John Fife assisted by Robert Mortimer Glover.[48] A number of physically fit patients died after inhaling it. In 1848, however, John Snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.[49]

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 Britain 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 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in the UK and German-speaking countries. In the United States, 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.[50]

Criminal use

Chloroform has reputedly been used by criminals to knock out, daze, or even murder victims. Joseph Harris was charged in 1894 with using chloroform to rob people.[51] Serial killer H. H. Holmes used chloroform overdoses to kill his female victims. In September 1900, chloroform was implicated in the murder of the U.S. businessman William Marsh Rice, the namesake of the institution now known as Rice University. Chloroform was deemed a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping.[52] In 2002, 13-year-old Kacie Woody was sedated with chloroform when she was abducted by David Fuller and during the time that he had her, before he shot and killed her.[53] In a 2007 plea bargain, a man confessed to using stun guns and chloroform to sexually assault minors.[54]

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. Nonetheless, it is nearly impossible to incapacitate someone using chloroform in this manner.[55] 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 to keep the tongue from obstructing the airway, a difficult procedure typically requiring the skills of an anesthesiologist. In 1865 as a direct result of the criminal reputation chloroform had gained, the medical journal The Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility", i.e. losing consciousness instantaneously, using chloroform.[56]

Safety

Exposure

Chloroform is known to form as a by-product of water chlorination along with a range of other disinfection by-products and as such is commonly present in municipal tap water and swimming pools. Reported ranges vary considerably but are generally below the current health standard for total trihalomethanes of 100μg/L.[57] Nonetheless, the presence of chloroform in drinking water at any concentration is considered controversial by some.

Historically, chloroform exposure may well have been higher due to its common use as an anaesthetic, as an ingredient in cough syrups, and as a constituent of tobacco smoke where DDT had previously been used as a fumigant.[58]

Pharmacology

It is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation.[16] Prolonged dermal exposure can result in the development of sores as a result of defatting. Elimination is primarily through the lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in the urine.[34]

Chloroform is metabolized in the liver by the cytochrome P-450 enzymes, by oxidation to chloromethanol and by reduction to the dichloromethyl free radical. Other metabolites of chloroform include hydrochloric acid and digluathionyl dithiocarbonate, with carbon dioxide as the predominant end product of metabolism.[59]

Like most other general anesthetics and sedative-hypnotic drugs, chloroform is a positive allosteric modulator for the GABAA receptor.[60] Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression.[59] When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of 7.5 g (0.26 oz). The mean lethal oral dose for an adult is estimated at 45 g (1.6 oz).[16]

The anesthetic use of chloroform has been discontinued because it caused deaths due to respiratory failure and cardiac arrhythmias. Following chloroform-induced anesthesia, some patients suffered nausea, vomiting, hyperthermia, jaundice, and coma due to hepatic dysfunction. At autopsy, liver necrosis and degeneration have been observed.[16]

Chloroform has induced liver tumors in mice and kidney tumors in mice and rats.[16] The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene.[59]

Conversion to phosgene

Chloroform converts slowly in air to the extremely poisonous phosgene (COCl2), releasing HCl in the process.[61]

2 CHCl3 + O2 → 2 COCl2 + 2 HCl

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.[62] 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,[63] and the carbonate salt neutralizes the resulting acid.[64]

Suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in ethanol, and then dried), which turns yellow in phosgene vapour. There are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified with mass spectrometry.[65]

Regulation

Chloroform is suspected of causing cancer (i.e., possibly carcinogenic, IARC Group 2B) as per the International Agency for Research on Cancer (IARC) Monographs. [PDF]

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[66]

Bioremediation of chloroform

Some anaerobic bacteria use chloroform for their respiration, termed organohalide respiration, converting it to dichloromethane.[67][68]

References

  1. ↑ "Front Matter". Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 661. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4. "The retained names 'bromoform' for HCBr3, 'chloroform' for HCCl3, and 'iodoform' for HCI3 are acceptable in general nomenclature. Preferred IUPAC names are substitutive names." 
  2. ↑ "Part 3 Health Hazards". Globally Harmonized System of Classification and Labelling of Chemicals (GHS). United Nations. http://www.unece.org/fileadmin/DAM/trans/danger/publi/ghs/ghs_rev02/English/03e_part3.pdf. 
  3. ↑ 3.0 3.1 3.2 3.3 NIOSH Pocket Guide to Chemical Hazards. "#0127". National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/npg/npgd0127.html. 
  4. ↑ Toxicity on PubChem
  5. ↑ Lewis, Richard J. (2012). Sax's Dangerous Properties of Industrial Materials (12th ed.). ISBN 978-0-470-62325-1. 
  6. ↑ 6.0 6.1 "Chloroform". Immediately Dangerous to Life and Health Concentrations (IDLH). National Institute for Occupational Safety and Health (NIOSH). https://www.cdc.gov/niosh/idlh/67663.html. 
  7. ↑ "PubChem: Safety and Hazards – GHS Classification". National Center for Biotechnology Information, U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/6212#section=Safety-and-Hazards. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 Rossberg, M.. "Ullmann's Encyclopedia of Industrial Chemistry". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a06_233.pub2. 
  9. ↑ "Ether and Chloroform". http://www.history.com/topics/ether-and-chloroform. 
  10. ↑ "Chloroform [MAK Value Documentation, 2000]". The MAK-Collection for Occupational Health and Safety. 2012. pp. 20–58. doi:10.1002/3527600418.mb6766e0014. ISBN 978-3527600410. 
  11. ↑ "Illustrated Glossary of Organic Chemistry - Chloroform". http://www.chem.ucla.edu/~harding/IGOC/C/chloroform.html. 
  12. ↑ Gribble, Gordon W. (2004). "Natural Organohalogens: A New Frontier for Medicinal Agents?". Journal of Chemical Education 81 (10): 1441. doi:10.1021/ed081p1441. Bibcode: 2004JChEd..81.1441G. 
  13. ↑ Cappelletti, M. (2012). "Microbial degradation of chloroform". Applied Microbiology and Biotechnology 96 (6): 1395–409. doi:10.1007/s00253-012-4494-1. PMID 23093177. 
  14. ↑ Jiao, Yi (2018). "Halocarbon Emissions from a Degraded Forested Wetland in Coastal South Carolina Impacted by Sea Level Rise". ACS Earth and Space Chemistry 2 (10): 955–967. doi:10.1021/acsearthspacechem.8b00044. Bibcode: 2018ESC.....2..955J. 
  15. ↑ "Complete list of VOC's". http://aqt-vru.com/emissions/complete-list-of-vocs/. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 Chloroform, CICAD, 58, World Health Organization, 2004, https://www.who.int/ipcs/publications/cicad/en/cicad58.pdf 
  17. ↑ Moldenhawer (1830). "Verfahren den Spiritus von dem Fuselöl auf leichte Weise zu befreien". Magazin für Pharmacie 8 (31): 222–227. https://books.google.com/books?id=a_E3AAAAMAAJ&pg=PA222. Retrieved 6 May 2016. 
  18. ↑ Defalque, Ray J.; Wright, A. J. (2000). "Was chloroform produced before 1831?". Anesthesiology 92 (1): 290–291. doi:10.1097/00000542-200001000-00060. PMID 10638939. 
  19. ↑ Guthrie, Samuel (1832). "New mode of preparing a spirituous solution of chloric ether". The American Journal of Science and Arts 21: 64–65 and 405–408. https://books.google.com/books?id=iuzRAAAAMAAJ&pg=PA64. Retrieved 6 May 2016. 
  20. ↑ Guthrie, Ossian (1887). Memoirs of Dr. Samuel Guthrie, and the History of the Discovery of Chloroform. Chicago: George K. Hazlitt & Co.. p. 1. https://archive.org/details/39002011125375.med.yale.edu. 
  21. ↑ Stratmann, Linda (2003). "Chapter 2". Chloroform: The Quest for Oblivion. Stroud: Sutton Publishing. ISBN 9780752499314. https://books.google.com/books?id=VvA7AwAAQBAJ&pg=PT30. Retrieved 6 May 2016. 
  22. ↑ Liebig, Justus von (1831). "Ueber die Zersetzung des Alkohols durch Chlor". Annalen der Physik und Chemie 99 (11): 444. doi:10.1002/andp.18310991111. Bibcode: 1831AnP....99..444L. https://babel.hathitrust.org/cgi/pt?id=uc1.a0002753747;view=1up;seq=462. Retrieved 6 May 2016. 
  23. ↑ Liebig, Justus von (1832). "Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen". Annalen der Physik und Chemie 100 (2): 243–295. doi:10.1002/andp.18321000206. Bibcode: 1832AnP...100..243L. https://babel.hathitrust.org/cgi/pt?id=wu.89048351662&view=1up&seq=861. 
    On pages 259–265, Liebig describes Chlorkohlenstoff ("carbon chloride", chloroform), but on p. 264, Liebig incorrectly states that the empirical formula of chloroform is C2Cl5.
  24. ↑ Soubeiran, Eugène (1831). "Recherches sur quelques combinaisons du chlore". Annales de Chimie et de Physique. Série 2 48: 113–157. https://babel.hathitrust.org/cgi/pt?id=ien.35556014127963;view=1up;seq=115. Retrieved 6 May 2016. 
  25. ↑ 25.0 25.1 Gordon, H. Laing (November 2002). Sir James Young Simpson and Chloroform (1811–1870). Minerva Group. pp. 106–109. ISBN 978-1-4102-0291-8. https://books.google.com/books?id=pYer05UwKBYC&pg=PA106. Retrieved 5 January 2016. 
  26. ↑ "Sir James Young Simpson". Encyclopædia Britannica. https://www.britannica.com/EBchecked/topic/545447/Sir-James-Young-Simpson-1st-Baronet. Retrieved 23 August 2013. 
  27. ↑ Worling, P.M. (1998). "Duncan and Flockhart: the Story of Two Men and a Pharmacy". Pharmaceutical Historian 28 (2): 28–33. PMID 11620310. 
  28. ↑ Breuer, F. W. (1935). "Chloroform-d (Deuteriochloroform)1". Journal of the American Chemical Society 57 (11): 2236–2237. doi:10.1021/ja01314a058. 
  29. ↑ Kluger, Ronald (1964). "A Convenient Preparation of Chloroform-d1". The Journal of Organic Chemistry 29 (7): 2045–2046. doi:10.1021/jo01030a526. 
  30. ↑ Süss, Hans Ulrich. "Ullmann's Encyclopedia of Industrial Chemistry". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. 
  31. ↑ "Chlorodifluoromethane | chemical compound" (in en). https://www.britannica.com/science/chlorodifluoromethane. 
  32. ↑ Wiley, G. R.; 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): 3287–3293. doi:10.1021/ja00765a001. 
  33. ↑ Kwak, K.; Rosenfeld, D. E.; Chung, J. K.; Fayer, M. D. (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): 13906–13915. doi:10.1021/jp806035w. PMID 18855462. 
  34. ↑ 34.0 34.1 Leikin, Jerrold B.; Paloucek, Frank P., eds (2008). "Chloroform". Poisoning and Toxicology Handbook (4th ed.). Informa. p. 774. 
  35. ↑ Fulmer, Gregory R.; Miller, Alexander J. M.; Sherden, Nathaniel H.; Gottlieb, Hugo E.; Nudelman, Abraham; Stoltz, Brian M.; Bercaw, John E.; Goldberg, Karen I. (2010). "NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist". Organometallics 29 (9): 2176–2179. doi:10.1021/om100106e. https://authors.library.caltech.edu/18475/2/om100106e_si_001.pdf. 
  36. ↑ "Chloroform (CHEBI:35255)". https://www.ebi.ac.uk/chebi/es/searchId.do?printerFriendlyView=true&locale=null&chebiId=35255&viewTermLineage=null&structureView=&. 
  37. ↑ https://www.atsdr.cdc.gov/ToxProfiles/tp6-c4.pdf
  38. ↑ http://encyclopedia.uia.org/en/problem/chloroform-pollutant#:~:text=Most%20chloroform%20is%20manufactured%20to,spot%20removers%2C%20and%20various%20solvents.
  39. ↑ Srebnik, M.; Laloë, E. (2001). Encyclopedia of Reagents for Organic Synthesis. Wiley. doi:10.1002/047084289X.rc105. ISBN 978-0471936237. 
  40. ↑ Vogel, E.; Klug, W.; Breuer, A. (1988). "1,6-Methano[10annulene"]. Organic Syntheses. http://www.orgsyn.org/demo.aspx?prep=cv6p0731. ; Collective Volume, 6, pp. 731 
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  48. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named pdf1
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  56. ↑ "Medical Annotation: Chloroform amongst Thieves". The Lancet 2 (2200): 490–491. 1865. doi:10.1016/s0140-6736(02)58434-8. 
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  66. ↑ 40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities (1 July 2008 ed.). Government Printing Office. http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf. Retrieved 29 October 2011. 
  67. ↑ Shuiquan Tang; Elizabeth A. Edwards (2013). "Identification of Dehalobacter reductive dehalogenases that catalyse dechlorination of chloroform, 1,1,1-trichloroethane and 1,1-dichloroethane". Philos Trans R Soc Lond B Biol Sci 368 (1616): 20120318. doi:10.1098/rstb.2012.0318. PMID 23479748. 
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