chloroform

[klawr-uh-fawrm, klohr-]

chloroform or trichloromethane, CHCl₃, volatile, colorless, nonflammable liquid that has a sweetish taste and a somewhat pungent odor; it boils at 61.7°C;. It dissolves freely in ethanol and ether but does not mix with water. Chloroform is produced by reaction of chlorine with ethanol and by the reduction of carbon tetrachloride with moist iron. It was once used as a general anesthetic in surgery but has been replaced by less toxic, safer anesthetics, such as ether. Chemically, it is employed as a solvent for fats, alkaloids, iodine, and other substances. When exposed to sunlight and air it reacts to form phosgene, a poisonous gas.

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chloroform

Clear, colourless, heavy, nonflammable liquid organic compound with a pleasant etherlike odour, chemical formula CHCl₃. It was the first substance successfully used as a surgical anesthetic (1847); being somewhat toxic, it has been increasingly displaced by other substances for this purpose. It has some industrial uses, primarily as a solvent.

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Encyclopedia Britannica, 2008. Encyclopedia Britannica Online.

Chloroform

}} Chloroform, also known as trichloromethane and methyl trichloride, is a chemical compound with formula C H Cl₃. It does not undergo combustion in air, although it will burn when mixed with more flammable substances. It is a member of a group of compounds known as trihalomethanes. Chloroform has myriad uses as a reagent and a solvent. It is also considered an environmental hazard.

History

Chloroform was discovered in July 1831 by the American physician Samuel Guthrie , and independently a few months later by the French chemist Eugène Soubeiran and Justus von Liebig in Germany, all of them using variations of the haloform reaction. Soubeiran produced chloroform through the action of chlorine bleach powder (calcium hypochlorite) on acetone (2-propanone) as well as ethanol. Chloroform was named and chemically characterised in 1834 by Jean-Baptiste Dumas.

In 1847, the Edinburgh obstetrician James Young Simpson first used chloroform for general anesthesia during childbirth. The use of chloroform during surgery expanded rapidly thereafter in Europe. In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; however, it was quickly abandoned in favor of ether upon discovery of its toxicity, especially its tendency to cause fatal cardiac arrhythmia analogous to what is now termed "sudden sniffer's death". Ether is still the preferred anesthetic in some developing nations due to its high therapeutic index (~1.5-2.2) and low price. Trichloroethylene, a halogenated aliphatic hydrocarbon related to chloroform, was proposed as a safer alternative, though it too was later found to be carcinogenic.

Production

Industrially, chloroform is produced by heating a mixture of chlorine and either chloromethane or methane. At 400-500 °C, a free radical halogenation occurs, converting the methane or chloromethane to progressively more chlorinated compounds.

CH₄ + Cl₂ → CH₃Cl + HCl

CH₃Cl + Cl₂ → CH₂Cl₂ + HCl

CH₂Cl₂ + Cl₂ → CHCl₃ + HCl

Chloroform undergoes further chlorination to give CCl₄:

CHCl₃ + Cl₂ → CCl₄ + HCl

The output of this process is a mixture of the four chloromethanes: chloromethane, dichloromethane, chloroform (trichloromethane), and carbon tetrachloride, which are then separated by distillation.

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

Inadvertent synthesis of chloroform

The haloform reaction can also occur inadvertently in domestic settings. Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, methyl ethyl ketone, ethanol, or isopropyl alcohol may 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 refrigerant R-22, commonly used in the air conditioning business. 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. In film and television, it is sometimes used in a fictional manner to knock out an unsuspecting victim, leaving no trace.

Anesthetic

Chloroform was developed in the mid-1800s and was mainly used as an anesthetic. Inhaling chloroform vapors depresses the central nervous system of a patient, causing dizziness, fatigue and unconsciousness, allowing a doctor to perform simple surgery or other otherwise painful operations.

The precise mechanism by which chloroform produces anesthesia is not certain. This is due, in part, to the fact that the mechanism of anesthesia itself is uncertain. There are two main theories of how drugs produce anesthesia. The Meyer-Overton theory states that anesthetics dissolve in cellular membranes, causing structural distortion of the membranes. The distortion may reduce the conduction of a nerve impulse along a nerve cell. This theory is based on the observation that the potency of most anesthetic drugs is correlated with their solubility in oil. As an alternative to the Meyer-Overton theory, it has been proposed that anesthetics interact with specific proteins. Examples of proteins that may be altered by binding of an anesthetic are neurotransmitter receptors and ion channels. Anesthetics may change the conformation (structure) of the protein. Other theories include actions at the interface between proteins and lipids.

One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of potassium channels in nerve cells. A paper by Patel et al. published in Nature Neuroscience (May 1999, Volume 2, Number 5, pp. 422-426) shows that chloroform activates potassium channels. This can lead to hyperpolarization of membranes. Hyperpolarization of a nerve cell membrane makes it less excitable. When this occurs presynaptically, it will decrease the release of neurotransmitters. When this effect occurs postsynaptically, it reduces the response to a neurotransimitter.

In general, most anesthetics enhance inhibitory neurotransmission in the brain. Many of them do this by increasing the actions of the primary inhibitory neurotransmitter in the brain, gamma-aminobutyric acid (GABA). Chloroform may also act by increasing GABA neurotransmission.

As a solvent

Chloroform is a common solvent because it is relatively unreactive, miscible with most organic liquids, and conveniently volatile. Small amounts of chloroform are used as a solvent in the pharmaceutical industry and for producing dyes and pesticides. Chloroform is an effective solvent for alkaloids in their base form and thus plant material is commonly extracted with chloroform for pharmaceutical processing. For example, it is commercially used to extract morphine from poppies, scopolamine from Datura plants. Chloroform containing deuterium (heavy hydrogen), CDCl₃, is a common solvent used in NMR spectroscopy. It can be used to bond pieces of acrylic glass (which is also known under the trade name 'Perspex').

As a reagent in organic synthesis

As a reagent, chloroform serves as a source of the dichlorocarbene CCl₂ group. It reacts with aqueous sodium hydroxide (usually in the presence of a phase transfer catalyst) to produce dichlorocarbene, CCl₂. This reagent effects ortho-formylation of activated aromatic rings such as phenols, producing aryl aldehydes in a reaction known as the Reimer-Tiemann reaction. Alternatively the carbene can be trapped by an alkene to form a cyclopropane derivative.

Safety

As might be expected for an anesthetic, inhaling chloroform vapors depresses the central nervous system. It is immediately dangerous to life and health at approximately 500 ppm according to the United States National Institute for Occupational Safety and Health. Breathing about 900 ppm for a short time can cause dizziness, fatigue, and headache. Chronic chloroform exposure may cause damage to the liver (where chloroform is metabolized to phosgene) and to the kidneys, and some people develop sores when the skin is immersed in chloroform.

Animal studies have shown that miscarriages occur in rats and mice that have breathed air containing 30 to 300 ppm 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 United States since 1976.

The 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. 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.

During prolonged storage hazardous amounts of phosgene can accumulate in the presence of oxygen and ultraviolet light. To prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer and caution must be taken. Suspicious bottles should be tested for phosgene. Filter-paper strips, wetted with 5% diphenylamine, 5% dimethylaminobenzaldehyde, and then dried, turn yellow in phosgene vapor.

Commonly used in DNA extractions and generally in conjunction with phenol to form a biolayer with extraction buffer (tris etc). DNA will form in the supernatant while protein and non soluble cell materials will precipitate between the buffer chloroform layers.