Chloroform, or trichloromethane, is an
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. T ...
with
formula C H Cl3 and a common organic
solvent
A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to
PTFE. It is also a precursor to various
refrigerants.
It is
trihalomethane
In chemistry, trihalomethanes (THMs) are chemical compounds in which three of the four hydrogen atoms of methane () are replaced by halogen atoms. Many trihalomethanes find uses in industry as solvents or refrigerants. THMs are also environmenta ...
. It is a powerful
anesthetic
An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...
,
euphoriant
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...
,
anxiolytic
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...
, and
sedative when inhaled or ingested.
Structure
The molecule adopts a
tetrahedral molecular geometry
In a tetrahedral molecular geometry, a central atom is located at the center with four substituents that are located at the corners of a tetrahedron. The bond angles are arccosine, cos−1(−) = 109.4712206...° ≈ 109.5° when all four substit ...
with C
3v symmetry.
Natural occurrence
The total global flux of chloroform through the environment is approximately tonnes per year, and about 90% of emissions are natural in origin. Many kinds of
seaweed produce chloroform, and
fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
are believed to produce chloroform in soil. Abiotic processes are also believed to contribute to natural chloroform productions in soils although the mechanism is still unclear.
Chloroform volatilizes readily from soil and surface water and undergoes degradation in air to produce
phosgene,
dichloromethane,
formyl chloride,
carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
,
carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...
, and
hydrogen chloride
The compound hydrogen chloride has the chemical formula and as such is a hydrogen halide. At room temperature, it is a colourless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric water vapor. Hydrogen chloride ga ...
. Its
half-life in air ranges from 55 to 620 days.
Biodegradation
Biodegradation is the breakdown of organic matter by microorganisms, such as bacteria and fungi. It is generally assumed to be a natural process, which differentiates it from composting. Composting is a human-driven process in which biodegrada ...
in water and soil is slow. Chloroform does not significantly bioaccumulate in aquatic organisms.
History
Chloroform was synthesized independently by several investigators circa 1831:
*Moldenhawer, a German pharmacist from
Frankfurt an der Oder
Frankfurt (Oder), also known as Frankfurt an der Oder (), is a city in the German state of Brandenburg. It has around 57,000 inhabitants, is one of the easternmost cities in Germany, the fourth-largest city in Brandenburg, and the largest German ...
, appears to have produced chloroform in 1830 by mixing
chlorinated lime with
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
; he mistook it for ''Chloräther'' (chloric ether,
1,2-dichloroethane
The chemical compound 1,2-dichloroethane, commonly known as ethylene dichloride (EDC), is a chlorinated hydrocarbon. It is a colourless liquid with a chloroform-like odour. The most common use of 1,2-dichloroethane is in the production of vin ...
), however.
*
Samuel Guthrie, a U.S. physician from
Sackets Harbor, New York
Sackets Harbor (earlier spelled Sacketts Harbor) is a village in Jefferson County, New York, United States, on Lake Ontario. The population was 1,450 at the 2010 census. The village was named after land developer and owner Augustus Sackett, who ...
, also appears to have produced chloroform in 1831 by reacting chlorinated lime with ethanol, as well as noting its
anaesthetic
An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...
properties; he also believed that he had prepared chloric ether, however.
*
Justus von Liebig carried out the
alkaline cleavage of
chloral
Chloral, also known as trichloroacetaldehyde or trichloroethanal, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless oily liquid that is soluble in a wide range of solvents. It reacts with water to form chloral hydrate ...
.
*
Eugène Soubeiran obtained the compound by the action of
chlorine bleach on both
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
and
acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
.
*In 1834, French chemist
Jean-Baptiste Dumas determined chloroform's empirical formula and named it. In 1835, Dumas prepared the substance by the alkaline cleavage of
trichloroacetic acid
Trichloroacetic acid (TCA; TCAA; also known as trichloroethanoic acid) is an analogue of acetic acid in which the three hydrogen atoms of the methyl group have all been replaced by chlorine atoms. Salts and esters of trichloroacetic acid are calle ...
.
Regnault prepared chloroform by
chlorination Chlorination may refer to:
* Chlorination reaction
In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transform ...
of
chloromethane
Chloromethane, also called methyl chloride, Refrigerant-40, R-40 or HCC 40, is an organic compound with the chemical formula . One of the haloalkanes, it is a colorless, odorless, flammable gas. Methyl chloride is a crucial reagent in industrial ...
.
*In 1842,
Robert Mortimer Glover in London discovered the anaesthetic qualities of chloroform on laboratory animals.
*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
William Flockhart, L.R.C.S.E. (1808 – 1871) was a Scottish chemist, a pharmacist who provided chloroform to Doctor (later Sir) James Young Simpson for his anaesthesia experiment at 52 Queen Street, Edinburgh on 4 November 1847. This was the f ...
of Duncan, Flockhart and company,
and helped to popularise the drug for use in medicine.
By the 1850s, chloroform was being produced on a commercial basis, in Britain about 750,000 doses a week by 1895, by 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.
Production
In industry production, chloroform is produced by heating a mixture of
chlorine
Chlorine is a chemical element with the symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine i ...
and either
chloromethane
Chloromethane, also called methyl chloride, Refrigerant-40, R-40 or HCC 40, is an organic compound with the chemical formula . One of the haloalkanes, it is a colorless, odorless, flammable gas. Methyl chloride is a crucial reagent in industrial ...
(CH
3Cl) or
methane
Methane ( , ) is a chemical compound with the chemical formula (one carbon atom bonded to four hydrogen atoms). It is a group-14 hydride, the simplest alkane, and the main constituent of natural gas. The relative abundance of methane on Ea ...
(CH
4).
[ At 400–500 °C, a ]free radical halogenation
In organic chemistry, free-radical halogenation is a type of halogenation. This chemical reaction is typical of alkanes and alkyl-substituted aromatics under application of UV light. The reaction is used for the industrial synthesis of chloroform ( ...
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
Chloromethane, also called methyl chloride, Refrigerant-40, R-40 or HCC 40, is an organic compound with the chemical formula . One of the haloalkanes, it is a colorless, odorless, flammable gas. Methyl chloride is a crucial reagent in industrial ...
, dichloromethane, chloroform, and carbon tetrachloride), which can then be separated by distillation
Distillation, or classical distillation, is the process of separating the components or substances from a liquid mixture by using selective boiling and condensation, usually inside an apparatus known as a still. Dry distillation is the heat ...
.[
Chloroform may also be produced on a small scale via the ]haloform reaction
In chemistry, the haloform reaction is a chemical reaction in which a haloform (, where X is a halogen) is produced by the exhaustive halogenation of an acetyl group (, where R can be either a hydrogen atom, an alkyl or an aryl group), in the ...
between acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
and sodium hypochlorite
Sodium hypochlorite (commonly known in a dilute solution as bleach) is an Inorganic chemistry, inorganic chemical compound with the chemical formula, formula NaOCl (or NaClO), comprising a sodium cation () and a hypochlorite anion (or ). It may ...
:
:3 NaClO + (CH3)2CO → CHCl3 + 2 NaOH + CH3COONa
Deuterochloroform
Deuterated chloroform
Deuterated chloroform, also known as chloroform-''d'', is the organic compound with the formula C2HCl3 or . Deuterated chloroform is a common solvent used in NMR spectroscopy. The properties of are virtually identical.
Preparation
Deuterated ch ...
is an isotopologue
In chemistry, isotopologues are molecules that differ only in their isotopic composition. They have the same chemical formula and bonding arrangement of atoms, but at least one atom has a different number of neutrons than the parent.
An exampl ...
of chloroform with a single deuterium
Deuterium (or hydrogen-2, symbol or deuterium, also known as heavy hydrogen) is one of two Stable isotope ratio, stable isotopes of hydrogen (the other being Hydrogen atom, protium, or hydrogen-1). The atomic nucleus, nucleus of a deuterium ato ...
atom. CDCl3 is a common solvent used in NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fiel ...
. Deuterochloroform is produced by the haloform reaction
In chemistry, the haloform reaction is a chemical reaction in which a haloform (, where X is a halogen) is produced by the exhaustive halogenation of an acetyl group (, where R can be either a hydrogen atom, an alkyl or an aryl group), in the ...
, the reaction of acetone (or ethanol) with sodium hypochlorite
Sodium hypochlorite (commonly known in a dilute solution as bleach) is an Inorganic chemistry, inorganic chemical compound with the chemical formula, formula NaOCl (or NaClO), comprising a sodium cation () and a hypochlorite anion (or ). It may ...
or calcium hypochlorite.[ 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
Chloral hydrate is a geminal diol with the formula . It is a colorless solid. It has limited use as a sedative and hypnotic pharmaceutical drug. It is also a useful laboratory chemical reagent and precursor. It is derived from chloral (trichl ...
.
Inadvertent formation of chloroform
The haloform reaction can also occur inadvertently in domestic settings. Bleaching
Bleach is the generic name for any chemical product that is used industrially or domestically to remove color (whitening) from a fabric or fiber or to clean or to remove stains in a process called bleaching. It often refers specifically, to ...
with hypochlorite
In chemistry, hypochlorite is an anion with the chemical formula ClO−. It combines with a number of cations to form hypochlorite salts. Common examples include sodium hypochlorite (household bleach) and calcium hypochlorite (a component of ble ...
generates halogenated compounds in side reactions; chloroform is the main byproduct. Sodium hypochlorite solution ( chlorine bleach) mixed with common household liquids such as acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
, methyl ethyl ketone
Butanone, also known as methyl ethyl ketone (MEK), is an organic compound with the formula CH3C(O)CH2CH3. This colourless liquid ketone has a sharp, sweet odor reminiscent of acetone. It is produced industrially on a large scale, but occurs in nat ...
, ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
, or isopropyl alcohol
Isopropyl alcohol (IUPAC name propan-2-ol and also called isopropanol or 2-propanol) is a colorless, flammable organic compound with a pungent alcoholic odor. As an isopropyl group linked to a hydroxyl group (chemical formula ) it is the simple ...
can produce some chloroform, in addition to other compounds such as chloroacetone
Chloroacetone is a chemical compound with the chemical formula, formula . At Standard conditions for temperature and pressure, STP it is a colourless liquid with a pungent odour. On exposure to light, it turns to a dark yellow-amber colour. It wa ...
or dichloroacetone
Bis(chloromethyl) ketone is a chemical substance with formula . It is a solid, and is used in the making of citric acid. Exposures such as contact or inhalation of bis(chloromethyl) ketone can result in irritation or damage to skin, eyes, throat ...
.
Uses
In terms of scale, the most important reaction of chloroform is with hydrogen fluoride
Hydrogen fluoride (fluorane) is an inorganic compound with the chemical formula . This colorless gas or liquid is the principal industrial source of fluorine, often as an aqueous solution called hydrofluoric acid. It is an important feedstock i ...
to give monochlorodifluoromethane (CFC-22), a precursor in the production of polytetrafluoroethylene (Teflon
Polytetrafluoroethylene (PTFE) is a synthetic fluoropolymer of tetrafluoroethylene that has numerous applications. It is one of the best-known and widely applied PFAS. The commonly known brand name of PTFE-based composition is Teflon by Chemou ...
):
:CHCl3 + 2 HF → CHClF2 + 2 HCl
The reaction is conducted in the presence of a catalytic
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
amount of mixed antimony halides. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon
Polytetrafluoroethylene (PTFE) is a synthetic fluoropolymer of tetrafluoroethylene that has numerous applications. It is one of the best-known and widely applied PFAS. The commonly known brand name of PTFE-based composition is Teflon by Chemou ...
. Before the Montreal Protocol
The Montreal Protocol is an international treaty designed to protect the ozone layer by phasing out the production of numerous substances that are responsible for ozone depletion
Ozone depletion consists of two related events observed sinc ...
, chlorodifluoromethane (designated as R-22) was also a popular refrigerant.
Solvent
The hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...
attached to carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent
In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with o ...
in chloroform participates in hydrogen bonding. Worldwide, chloroform is also used in pesticide formulations, as a solvent
A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...
for fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers spec ...
s, oil
An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) & lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturated ...
s, rubber
Rubber, also called India rubber, latex, Amazonian rubber, ''caucho'', or ''caoutchouc'', as initially produced, consists of polymers of the organic compound isoprene, with minor impurities of other organic compounds. Thailand, Malaysia, and ...
, alkaloid
Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s, wax
Waxes are a diverse class of organic compounds that are lipophilic, malleable solids near ambient temperatures. They include higher alkanes and lipids, typically with melting points above about 40 °C (104 °F), melting to giv ...
es, gutta-percha
Gutta-percha is a tree of the genus ''Palaquium'' in the family Sapotaceae. The name also refers to the rigid, naturally biologically inert, resilient, electrically nonconductive, thermoplastic latex derived from the tree, particularly from ' ...
, and resin
In polymer chemistry and materials science, resin is a solid or highly viscous substance of plant or synthetic origin that is typically convertible into polymers. Resins are usually mixtures of organic compounds. This article focuses on natu ...
s, as a cleansing agent, grain fumigant
Fumigation is a method of pest control or the removal of harmful micro-organisms by completely filling an area with gaseous pesticides—or fumigants—to suffocate or poison the pests within. It is used to control pests in buildings ( ...
, in fire extinguishers
A fire extinguisher is a handheld active fire protection device usually filled with a dry or wet chemical used to extinguish or control small fires, often in emergencies. It is not intended for use on an out-of-control fire, such as one which ha ...
, and in the rubber industry. CDCl3 is a common solvent used in NMR spectroscopy
Nuclear magnetic resonance spectroscopy, most commonly known as NMR spectroscopy or magnetic resonance spectroscopy (MRS), is a spectroscopic technique to observe local magnetic fields around atomic nuclei. The sample is placed in a magnetic fiel ...
.
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
In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
, chloroform serves as a source of the dichlorocarbene
In organic chemistry, a carbene is a molecule containing a neutral carbon atom with a valence of two and two unshared valence electrons. The general formula is or where the R represents substituents or hydrogen atoms.
The term "carbene" ma ...
:CCl2 group. It reacts with aqueous sodium hydroxide
Sodium hydroxide, also known as lye and caustic soda, is an inorganic compound with the formula NaOH. It is a white solid ionic compound consisting of sodium cations and hydroxide anions .
Sodium hydroxide is a highly caustic base and alkali ...
usually in the presence of a phase transfer catalyst
In chemistry, a phase-transfer catalyst or PTC is a catalyst that facilitates the transition of a reactant from one phase into another phase where reaction occurs. Phase-transfer catalysis is a special form of heterogeneous catalysis. Ionic reac ...
to produce dichlorocarbene
Dichlorocarbene is the reactive intermediate with chemical formula CCl2. Although this chemical species has not been isolated, it is a common intermediate in organic chemistry, being generated from chloroform. This bent diamagnetic molecule rapidly ...
, :CCl2. This reagent effects ortho-formylation of activated aromatic rings
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to saturat ...
such as phenols
In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of one or more hydroxyl groups (— O H) bonded directly to an aromatic hydrocarbon group. The simplest is phenol, . Phenolic compounds are c ...
, producing aryl aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
s in a reaction known as the Reimer–Tiemann reaction
The Reimer–Tiemann reaction is a chemical reaction used for the ortho-formylation of phenols; with the simplest example being the conversion of phenol to salicylaldehyde. The reaction was discovered by and Ferdinand Tiemann. The Reimer in ques ...
. Alternatively, the carbene
In organic chemistry, a carbene is a molecule containing a neutral carbon atom with a valence of two and two unshared valence electrons. The general formula is or where the R represents substituents or hydrogen atoms.
The term "carbene" ma ...
can be trapped by an alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
to form a cyclopropane
Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane itself ...
derivative. In the Kharasch addition
The Kharasch addition is an organic reaction and a metal-catalysed free radical addition of CXCl3 compounds (X = Cl, Br, H) to alkenes. The reaction is used to append trichloromethyl or dichloromethyl groups to terminal alkenes. The method has ...
, chloroform forms the CHCl2 free radical in addition to alkenes.
Anaesthetic
The anaesthetic
An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia — in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...
qualities of chloroform were first described in 1842 in a thesis by Robert Mortimer Glover, which won the Gold Medal of the Harveian Society
The Harveian Society of London, named after the physician William Harvey, is a medical society and registered charity, founded in 1831. Doctors assemble regularly at the Medical Society of London, Chandos Street, Cavendish Square to converse and d ...
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
The University of Edinburgh ( sco, University o Edinburgh, gd, Oilthigh Dhùn Èideann; abbreviated as ''Edin.'' in post-nominals) is a public research university based in Edinburgh, Scotland. Granted a royal charter by King James VI in 15 ...
in the summer of 1847. The Scottish obstetrician
Obstetrics is the field of study concentrated on pregnancy, childbirth and the postpartum period. As a medical specialty, obstetrics is combined with gynecology under the discipline known as obstetrics and gynecology (OB/GYN), which is a surgi ...
James Young Simpson
Sir James Young Simpson, 1st Baronet, (7 June 1811 – 6 May 1870) was a Scottish obstetrician and a significant figure in the history of medicine. He was the first physician to demonstrate the anaesthetic properties of chloroform on humans ...
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.
A few days later, during the course of a dental procedure in Edinburgh
Edinburgh ( ; gd, Dùn Èideann ) is the capital city of Scotland and one of its 32 Council areas of Scotland, council areas. Historically part of the county of Midlothian (interchangeably Edinburghshire before 1921), it is located in Lothian ...
, Francis Brodie Imlach
Francis Brodie Imlach FRCSEd (1819-1891) was a Scottish pioneer of modern dentistry, and the first person to use chloroform on a dental patient. He helped to raise the profile of dentistry from a back street trade to full professional stat ...
became the first person to use chloroform on a patient in a clinical context.
In May 1848, Robert Halliday Gunning
Robert Halliday Gunning FRSE Royal Physical Society of Edinburgh, PRPSE FSA Legum Doctor, LLD (12 December 1818 – 22 March 1900) was a Scottish surgeon, entrepreneur and philanthropist. He did much to improve social conditions in Brazil and al ...
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. A knighthood
A knight is a person granted an honorary title of knighthood by a head of state (including the Pope) or representative for service to the monarch, the church or the country, especially in a military capacity. Knighthood finds origins in the Gr ...
for Simpson, and massive media coverage of the wonders of chloroform, ensured that Simpson's reputation remained high. The laboratory experiments proving the dangers of chloroform were largely ignored.
The use of chloroform during surgery
Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...
expanded rapidly thereafter in Europe. In the 1850s, chloroform was used by the physician John Snow
John Snow (15 March 1813 – 16 June 1858) was an English physician and a leader in the development of anaesthesia and medical hygiene. He is considered one of the founders of modern epidemiology, in part because of his work in tracing the so ...
during the birth of Queen Victoria
Victoria (Alexandrina Victoria; 24 May 1819 – 22 January 1901) was Queen of the United Kingdom of Great Britain and Ireland from 20 June 1837 until Death and state funeral of Queen Victoria, her death in 1901. Her reign of 63 years and 21 ...
's last two children. In the United States, chloroform began to replace ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
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
Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...
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
Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosphe ...
ions through certain types of potassium channel
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
s in nerve cells
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
. Chloroform could also be mixed with other anaesthetic agents such as ether to make C.E. mixture, or ether and alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
to make A.C.E. mixture
ACE mixture is an historical anaesthetic agent for general anaesthesia. It was first suggested by George Harley and first used in England around 1860. In 1864 it was recommended for use by the Royal Medical and Surgical Society's Chloroform Com ...
.
In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anaesthetic. Her autopsy establishing the cause of death was undertaken by John Fife assisted by Robert Mortimer Glover.[ A number of physically fit patients died after inhaling it. In 1848, however, ]John Snow
John Snow (15 March 1813 – 16 June 1858) was an English physician and a leader in the development of anaesthesia and medical hygiene. He is considered one of the founders of modern epidemiology, in part because of his work in tracing the so ...
developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.
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
Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and has a ...
, improved equipment for administering anaesthetics and the discovery of hexobarbital
Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for su ...
in 1932 led to the gradual decline of chloroform narcosis.
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. Serial killer
A serial killer is typically a person who murders three or more persons,A
*
*
*
* with the murders taking place over more than a month and including a significant period of time between them. While most authorities set a threshold of three ...
H. H. Holmes
Herman Webster Mudgett (May 16, 1861 – May 7, 1896), better known as Dr. Henry Howard Holmes or H. H. Holmes, was an American con artist and serial killer, the subject of more than 50 lawsuits in Chicago alone. Until his execution in 1896, he ...
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
William Marsh Rice (March 14, 1816 – September 23, 1900) was an American businessman who bequeathed his fortune to found Rice University in Houston, Texas. Rice was murdered by his valet Charles F. Jones while sleeping. The murder was pa ...
, the namesake of the institution now known as Rice University
William Marsh Rice University (Rice University) is a Private university, private research university in Houston, Houston, Texas. It is on a 300-acre campus near the Houston Museum District and adjacent to the Texas Medical Center. Rice is ranke ...
. Chloroform was deemed a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping. 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. 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
The term incapacitating agent is defined by the United States Department of Defense as:
:"An agent that produces temporary physiological or mental effects, or both, which will render individuals incapable of concerted effort in the performance o ...
has become widely recognized, bordering on cliché
A cliché ( or ) is an element of an artistic work, saying, or idea that has become overused to the point of losing its original meaning or effect, even to the point of being weird or irritating, especially when at some earlier time it was consi ...
d, due to the popularity of crime fiction
Crime fiction, detective story, murder mystery, mystery novel, and police novel are terms used to describe narratives that centre on criminal acts and especially on the investigation, either by an amateur or a professional detective, of a crime, ...
authors having criminals use chloroform-soaked rags to render victims unconscious. Nonetheless, it is nearly impossible to incapacitate someone using chloroform in this manner. 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
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
or diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
, 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
Anesthesiology, anaesthesiology, or anaesthesia is the medical specialty concerned with the total perioperative care of patients before, during and after surgery. It encompasses anesthesia, intensive care medicine, critical emergency medicine, ...
. In 1865 as a direct result of the criminal reputation chloroform had gained, the medical journal ''The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823.
The journal publishes original research articles, ...
'' offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility", i.e. losing consciousness instantaneously, using chloroform.
Safety
Exposure
Chloroform is known to form as a by-product of water chlorination
Water chlorination is the process of adding chlorine or chlorine compounds such as sodium hypochlorite to water. This method is used to kill bacteria, viruses and other microbes in water. In particular, chlorination is used to prevent the spre ...
along with a range of other disinfection by-product
Disinfection by-products (DBPs) result from chemical reactions between organic and inorganic matter in water with chemical treatment agents during the water disinfection process.
Chlorination disinfection byproducts
Chlorinated disinfection agen ...
s 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
In chemistry, trihalomethanes (THMs) are chemical compounds in which three of the four hydrogen atoms of methane () are replaced by halogen atoms. Many trihalomethanes find uses in industry as solvents or refrigerants. THMs are also environ ...
of 100μg/L. 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
Tobacco smoke is a sooty aerosol produced by the incomplete combustion of tobacco during the tobacco smoking, smoking of cigarettes and other tobacco products. Temperatures in burning cigarettes range from about 400 °C between puffs to abo ...
where DDT
Dichlorodiphenyltrichloroethane, commonly known as DDT, is a colorless, tasteless, and almost odorless crystalline chemical compound, an organochloride. Originally developed as an insecticide, it became infamous for its environmental impacts. ...
had previously been used as a fumigant
Fumigation is a method of pest control or the removal of harmful micro-organisms by completely filling an area with gaseous pesticides—or fumigants—to suffocate or poison the pests within. It is used to control pests in buildings ( ...
.
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. Prolonged dermal exposure can result in the development of sores as a result of defatting
Degreasing, often called defatting or fat trimming, is the removal of fatty acids from an object. In culinary science, degreasing is done with the intention of reducing the fat content of a meal.
Degreasing food
Degreasing is often used by diet ...
. Elimination is primarily through the lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in the urine.
Chloroform is metabolized in the liver by the cytochrome P-450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...
enzymes, by oxidation to chloromethanol and by reduction to the dichloromethyl free radical
A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing.
Ageing
Ailments of unknown cause
Biogerontology
Biological processes
Causes of death
Cellular processes
Gerontology
Life extension
Metabo ...
. Other metabolites of chloroform include hydrochloric acid
Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid
Acid strength is the tendency of an acid, symbol ...
and digluathionyl dithiocarbonate, with carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...
as the predominant end product of metabolism.
Like most other general anesthetics and sedative-hypnotic drugs, chloroform is a positive allosteric modulator
In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...
for the GABAA receptor. Chloroform causes depression of the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS), ultimately producing deep coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
and respiratory center depression. When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of . The mean lethal oral dose for an adult is estimated at .
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
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
, hyperthermia
Hyperthermia, also known simply as overheating, is a condition in which an individual's body temperature is elevated beyond normal due to failed thermoregulation. The person's body produces or absorbs more heat than it dissipates. When extreme ...
, jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
, and coma due to hepatic dysfunction. At autopsy, liver necrosis
Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...
and degeneration have been observed.
Chloroform has induced liver tumor
Liver tumors (also known as hepatic tumors) are abnormal growth of liver cells on or in the liver. Several distinct types of tumors can develop in the liver because the liver is made up of various cell types. Liver tumors can be classified as beni ...
s in mice and kidney tumor
Kidney tumours are tumours, or growths, on or in the kidney. These growths can be benign or malignant (kidney cancer).
Presentation
Kidney tumours may be discovered on medical imaging incidentally (i.e. an incidentaloma), or may be present in pat ...
s in mice and rats. The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene.
Conversion to phosgene
Chloroform converts slowly in air to the extremely poisonous phosgene (COCl2), releasing HCl HCL may refer to:
Science and medicine
* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia
* Harvard Cyclotron Laboratory, from 1961 to 2002, a proton accelerator used for research and development
* Hollow-cathode lamp, a spe ...
in the process.
:2 CHCl3 + O2 → 2 COCl2 + 2 HCl
To prevent accidents, commercial chloroform is stabilized with ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
or amylene
Pentenes are alkenes with the chemical formula . Each contains one double bond within its molecular structure. Six different compounds are in this class, differing from each other by whether the carbon atoms are attached linearly or in a branched ...
, 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. Phosgene and HCl can be removed from chloroform by washing with saturated aqueous carbonate
A carbonate is a salt of carbonic acid (H2CO3), characterized by the presence of the carbonate ion, a polyatomic ion with the formula . The word ''carbonate'' may also refer to a carbonate ester, an organic compound containing the carbonate g ...
solutions, such as sodium bicarbonate
Sodium bicarbonate (IUPAC name: sodium hydrogencarbonate), commonly known as baking soda or bicarbonate of soda, is a chemical compound with the formula NaHCO3. It is a salt composed of a sodium cation ( Na+) and a bicarbonate anion ( HCO3−) ...
. This procedure is simple and results in harmless products. Phosgene reacts with water to form carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...
and HCl, and the carbonate salt neutralizes the resulting acid.
Suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine
Diphenylamine is an organic compound with the formula (C6H5)2NH. The compound is a derivative of aniline, consisting of an amine bound to two phenyl groups. The compound is a colorless solid, but commercial samples are often yellow due to oxidiz ...
, 5% dimethylaminobenzaldehyde in ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...
, and then dried), which turns yellow in phosgene vapor. There are several colorimetric
Colorimetry is "the science and technology used to quantify and describe physically the human color perception".
It is similar to spectrophotometry, but is distinguished by its interest in reducing spectra to the physical correlates of color ...
and fluorometric
Fluorescence spectroscopy (also known as fluorimetry or spectrofluorometry) is a type of electromagnetic spectroscopy that analyzes fluorescence from a sample. It involves using a beam of light, usually ultraviolet light, that excites the electron ...
reagents for phosgene, and it can also be quantified with mass spectrometry
Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...
.
Regulation
Chloroform is suspected of causing cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
(i.e., possibly carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
ic, IARC Group 2B) as per the International Agency for Research on Cancer
The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations.
Its role is to conduct and ...
(IARC) Monographs
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Bioremediation of chloroform
Some anaerobic bacteria
An anaerobic organism or anaerobe is any organism that does not require molecular oxygen for growth. It may react negatively or even die if free oxygen is present. In contrast, an aerobic organism (aerobe) is an organism that requires an oxygenate ...
use chloroform for their respiration, termed organohalide respiration, converting it to dichloromethane.
References
External links
Chloroform "The Molecular Lifesaver"
An article at Oxford University providing facts about chloroform.
*IARC Summaries & Evaluations
*
*
NIST Standard Reference Database
{{Authority control
Endocrine disruptors
Chloroalkanes
Halomethanes
General anesthetics
Hazardous air pollutants
IARC Group 2B carcinogens
Halogenated solvents
Halogen-containing natural products
GABAA receptor positive allosteric modulators
Glycine receptor agonists
Sweet-smelling chemicals
Trichloromethyl compounds