Chloroform



Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. 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.

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.

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). Similarly, the macroalga Eucheuma denticulatum, which is cultivated and harvested on a large scale for carrageenan production, produces chloroform, as do Hypnea spinella, Falkenbergia hillebrandii, and Gracilara cornea along with seven indigenous macroalgae inhabiting a rock pool. These studies show increased chloroform production with increased light intensity, presumably when photosynthesis is at a maximum. Chloroform is also produced by the brown alga Fucus vesiculosus, the green algae Cladophora glomerata, Enteromorpha ahlneriana, Enteromorpha flexuosa, and Enteromorpha intestinalis, and the diatom Pleurosira laevis. Other studies observe chloroform in Fucus serratus, Fucus vesiculosis, Corallina officinalis, Cladophora pellucida, and Ulva lactuca, and Desmarestia antarctica, Lambia antarctica, Laminaria saccharina, Neuroglossum ligulatum.

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). The American physician Samuel Guthrie prepared gallons of the material and described its "deliciousness of flavor." Independently, Justus von Liebig also described the same compound. All early preparations used variations of the haloform reaction. Chloroform was named and chemically characterized in 1834 by Jean-Baptiste Dumas.

Industrial routes
In industry, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane. 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.

Deuterochloroform
An archaic industrial route to chloroform involved the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite, the aforementioned haloform reaction. 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. Deuterochloroform can also be prepared by the reaction of sodium deuteroxide with chloral hydrate, or from ordinary chloroform.

Inadvertent formation of chloroform
The haloform reaction can also occur inadvertently in domestic settings. Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, butanone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone, or dichloroacetone.

Uses
The major use of chloroform today is in the production of the chlorodifluoromethane (R-22), a major precursor to tetrafluoroethylene:
 * CHCl3 + 2 HF → CHClF2 + 2 HCl

The reaction is conducted in the presence of a catalytic amount of antimony pentafluoride. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon. Before the Montreal Protocol, chlorodifluoromethane (R22) was also 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. Chloroform containing deuterium (heavy hydrogen), CDCl3, is a common solvent used in NMR spectroscopy. It can be used to bond pieces of acrylic glass (also known under the trade names Perspex and Plexiglas). A solvent of phenol:chloroform:isoamyl alcohol 25:24:1 is used to dissolve non-nucleic acid biomolecules in DNA and RNA extractions.

As a reagent in organic synthesis
As a reagent, chloroform serves as a source of the dichlorocarbene CCl2 group. It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, CCl2. 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


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. 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) 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. 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. Chloroform was used to murder a woman in 1991 as a toxic dose was delivered while she was sleeping. In 2007 a man was convicted of using chloroform to sexually assault minors.

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

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. 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 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. It has been most readily associated with hepatocellular carcinoma. 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. Dissolved phosgene cannot be removed by distillation or carbon filters, but it is removed by calcium hydroxide or activated alumina.

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.