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 hazardous.
Several million tons are produced annually as a precursor to PTFE 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 over 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 and a number of other species.
These studies show increased chloroform production with increased light intensity, presumably
when photosynthesis is also increased.
Chloroform is also produced by the brown algae Fucus vesiculosus, the green algae Cladophora
glomerata, Enteromorpha ahlneriana, Enteromorpha flexuosa, and Enteromorpha intestinalis, and
the diatom Pleurosira laevis.
Other studies observe chloroform in Fucus serratus, 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: Chloroform undergoes further chlorination
to yield carbon tetrachloride (CCl4): 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 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.
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, or from ordinary chloroform.
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.
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:
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.
As a solvent Chloroform is a common solvent in the laboratory
because it is relatively unreactive, miscible with most organic liquids, not flammable and
conveniently volatile.
Chloroform is used as a solvent in the pharmaceutical industry and for producing dyes and pesticides.
Chloroform is an effective solvent for alkaloids in their base form and thus plant material
is commonly extracted with chloroform for pharmaceutical processing.
For example, it is used in commerce to extract morphine from poppies and scopolamine from
Datura plants.
It can be used to bond pieces of acrylic glass (also known under the trade names Perspex
and Plexiglas).
A solvent of phenol, chloroform, and isoamyl alcohol in a 25:24:1 ratio is used to dissolve
non-nucleic acid biomolecules in DNA and RNA extractions.
Chloroform containing deuterium (heavy hydrogen), CDCl3, is a common solvent used in NMR spectroscopy.
Chloroform exhibits some chemical interaction with polypropylene.
Longer term (multi-hour) storage of chloroform in polypropylene containers is not advised.
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.
On 4 November 1847, the Scottish obstetrician James Young Simpson discovered the anaethestic
qualities of chloroform when he and his friends were experimenting with different substances
on themselves in search of a replacement for ether as a general anesthetic.
He was so astounded by the success of his own trial that the next morning he hired a
chemist and within the next few days was administering it to his patients 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".
Some people used chloroform as a recreational drug or to attempt suicide.
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.
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed,
died after being given the anesthetic.
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.
Chloroform has been reputed to be used by criminals to knock out, daze or even murder
their victims.
Joseph Harris was charged with using chloroform in 1894 to rob people.
In 1901, chloroform was also implicated in the murder 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 asphyxiated while she was sleeping.
In a 2007 plea bargain a man confessed to using stun guns and chloroform to sexually
assault minors.
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.
It takes at least 5 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, the medical
journal Lancet offered a "permanent scientific reputation" to anyone who could demonstrate
"instantaneous insensibility" using chloroform, and no such demonstration has been forthcoming.
As a working fluid in a heat engine At least one experimental heat engine has
been constructed using chloroform as a working fluid in place of steam; similar experiments
had been conducted using ether as a low-boiling-point working fluid, but its highly flammable nature
caused difficulties, so chloroform was tried as a non-flammable alternative.
Such experiments were apparently inspired by the misconception that a fluid with a lower
boiling point than water, being easier to vaporise, would allow the construction of
a more efficient engine; in fact the reverse is the case, but this was not widely appreciated
in the days when thermodynamics was a young science.
Grandiose claims for the efficiency of this engine were reported in Scientific American
in 1848, along with an editorial comment casting grave doubts on them; it appears that the
development of the invention did not proceed further.
Safety A fatal oral dose of chloroform may be as
small 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 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 twelfth 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, 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.
Dissolved phosgene cannot be removed by distillation or carbon filters, but it is removed by calcium
hydroxide or activated alumina.
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, 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.