Chloroform

• 1. Introduction

  ›

  Chloroform is a colorless, sweet-smelling liquid that once put patients to sleep on operating tables across Europe and the United States. In 1987, the last doctor in the Western world who still used it as an anaesthetic retired. That retirement came roughly 140 years after its first use. Yet the liquid itself never went away. So what exactly is this substance, and who first made it? Who deserves the credit for showing that it could switch off pain? What eventually drove it out of the operating room? And why does a compound with such a record still matter to modern industry?

  18285137

• 2. Mistaken Identity

  ›

  In 1830, a pharmacist named Moldenhawer in Frankfurt an der Oder appears to have produced chloroform by mixing chlorinated lime with ethanol. He mistook it for chloric ether, a different compound. A year later, Samuel Guthrie, a physician from Sackets Harbor, New York, seems to have made it the same way. Guthrie noticed that the liquid had anaesthetic properties, yet he too believed he had prepared chloric ether.

  Justus von Liebig reached the compound by splitting chloral with an alkali. He got its formula wrong and called it Chlorkohlenstoff, meaning carbon chloride. Eugène Soubeiran arrived at it as well, by treating both ethanol and acetone with chlorine bleach.

  The French chemist Jean-Baptiste Dumas finally sorted out the confusion in 1834. He determined the formula and chose the name still in use today. Writing in German, he explained that this had caused him to impose the name 'chloroform' upon the substance. His published formula, C2H2Cl6, needs its numbers halved to match the modern one. The word itself blends terchloride, meaning a trichloride, with formyle, an obsolete name for a radical derived from formic acid.

  Three chlorine atoms replace three of the four hydrogen atoms in methane to give the molecule Dumas named, and it takes a tetrahedral shape. In 1835 he prepared it again, this time by splitting trichloroacetic acid with an alkali. The name he chose would soon be familiar far beyond chemistry.

  1415161722

• 3. The Edinburgh Quarrel

  ›

  Robert Mortimer Glover described chloroform's anaesthetic qualities in a thesis in 1842, and it won the Gold Medal of the Harveian Society that year. He tested his ideas on dogs. In the summer of 1847, he refined them in a doctoral thesis at the University of Edinburgh. There he called anaesthetizing halogenous compounds a 'new order of poisonous substances'.

  Examining that thesis was among the duties of James Young Simpson, a Scottish obstetrician. Simpson later claimed he had never read it and had reached his conclusions independently. Perkins-McVey and others doubt this. Simpson's own publications on the subject in 1847 echo Glover's, and as an examiner he probably knew what the thesis contained.

  On the 4th of November 1847, Simpson argued that he had discovered chloroform's anaesthetic effect in humans. He and two colleagues had been entertaining themselves by trying various substances, and those experiments revealed its medical promise. The chloroform came from a local pharmacist, William Flockhart of Duncan, Flockhart and company. Simpson's demonstration helped popularize the drug in medicine.

  A few days later, Francis Brodie Imlach used it during a dental procedure in Edinburgh. That was the first clinical use on a patient.

  Glover, meanwhile, wrote a series of heated letters in 1847 and 1848 accusing Simpson of stealing his discovery. In May 1848, Robert Halliday Gunning told the Medico-Chirurgical Society of Edinburgh about a series of experiments on rabbits. They confirmed Glover's findings and refuted Simpson's claim to originality. Those same experiments also showed how dangerous chloroform could be, and hardly anyone took notice.

  4546472649

• 4. Taming the Dose

  ›

  Doctors in the nineteenth century sometimes blended chloroform with ether, producing what they called C.E. mixture. Adding alcohol to the ether gave A.C.E. mixture. On its own, chloroform is a powerful general anaesthetic that also sedates, eases anxiety and produces euphoria. One possible mechanism is that it increases the movement of potassium ions through certain potassium channels in nerve cells. Like most general anaesthetics, it also strengthens the action of GABAA receptors.

  In 1848-15-year-old Hannah Greener died after receiving chloroform while an infected toenail was being removed. John Fife performed the autopsy that established the cause of death, with Glover assisting. Other physically fit patients died after inhaling it, and accidental overdose was a constant risk.

  Still in 1848, the English physician John Snow developed an inhaler that regulated the dose, and deaths fell. In 1862, another English physician, Joseph Thomas Clover, invented an apparatus that could deliver chloroform safely and controllably. His design improved on Snow's and cut the risk of overdose further.

  By the 1850s chloroform was being made commercially, and its use in surgery spread quickly across Europe. In that decade Snow used it during the births of Queen Victoria's last two children, Leopold and Beatrice.

  2553725750

• 5. Counting the Dead

  ›

  Between 1864 and 1910, numerous commissions in Britain examined chloroform and reached no clear conclusions. Supporters and opponents disagreed over whether the complications came from disturbed breathing or from a specific effect on the heart. In 1911, a researcher named Levy showed in animal experiments that chloroform can cause ventricular fibrillation, a disordered rhythm of the heart.

  Even so, between 1865 and 1920, chloroform was used in 80 to 95% of all narcoses in the UK and German-speaking countries. Surveys tried to measure the toll. In Germany, Gurlt compiled comprehensive figures on deaths during anaesthesia between 1890 and 1897. In the UK, the medical journal The Lancet ran a questionnaire survey and compiled a report on numerous adverse reactions to anaesthetics, chloroform among them.

  In 1934, Killian pooled all the statistics gathered so far. Under ether, the chance of a fatal complication ranged from one in 14,000 to one in 28,000. Under chloroform, it ranged from one in 3,000 to one in 6,000.

  At the start of the 20th century, American doctors began replacing ether with chloroform. They went back to ether once its toxicity came to light, especially its tendency to cause fatal heart arrhythmias, a danger now compared to sudden sniffer's death.

  Gas anaesthesia with nitrous oxide, better equipment for giving anaesthetics, and the discovery of hexobarbital in 1932 gradually ended the age of chloroform narcosis.

  5960585161

• 6. Vice and Crime

  ›

  In the 1910s in England, a fast-living set called The Coterie used chloroform recreationally. Raymond Asquith, stepson of the Prime Minister's wife Margot Asquith, belonged to the group. Margot recorded that Lady Diana Manners, who called the drug 'jolly old chlorors', had said 'I must be unconscious by midnight.'

  Criminals have used chloroform to knock out, daze or murder victims. In 1894, Joseph Harris was charged with using it to rob people. The serial killer H. H. Holmes used overdoses to kill his female victims. In September 1900, chloroform was implicated in the murder of the American businessman William Marsh Rice. Another serial killer, John Wayne Gacy, chloroformed many of his victims.

  Crime fiction authors turned the chloroform-soaked rag into a plot staple, bordering on cliché. Reality is far less tidy. It takes at least five minutes of inhalation to make a person unconscious. Afterward, a continuous volume must be administered and the chin supported so the tongue does not block the airway. That is difficult and typically requires an anesthesiologist. Most real criminal cases also involved another drug, such as alcohol or diazepam, or a victim who went along with it.

  In 1865, reacting to the criminal reputation chloroform had gained, The Lancet offered a 'permanent scientific reputation' to anyone who could demonstrate 'instantaneous insensibility'.

  6263676818

• 7. The Industrial Workhorse

  ›

  At 400 to 500 degrees Celsius, a hot mixture of chlorine and either methyl chloride or methane undergoes free radical halogenation. The reaction produces progressively more chlorinated compounds, and chloroform itself can be chlorinated further to give carbon tetrachloride. The result is a blend of four chloromethanes: chloromethane, methylene chloride, chloroform and carbon tetrachloride. Distillation separates them.

  By 1895, Britain was producing about 750,000 doses of chloroform a week using the Liebig procedure, which stayed important until the 1960s. Today chloroform and dichloromethane are prepared exclusively, and on a massive scale, by chlorinating methane and chloromethane.

  On a small scale, chemists can make it from acetone and sodium hypochlorite through the haloform reaction. The same reaction can happen by accident at home. Chlorine bleach mixed with acetone, methyl ethyl ketone, ethanol or isopropyl alcohol can yield some chloroform, along with chloroacetone or dichloroacetone.

  The biggest use by scale starts with hydrogen fluoride. With a catalytic amount of mixed antimony halides, the reaction gives monochlorodifluoromethane, known as HCFC-22 or R-22. That compound is converted to tetrafluoroethylene, the main precursor of Teflon, also called PTFE. Before the Montreal Protocol was enforced, most American chloroform went into making R-22, a refrigerant. Production remains high because chloroform is a key precursor of PTFE.

  Chloroform has a low boiling point and a global warming potential of only 31, against 1760 for R-22. Even so, little suggests it has seen widespread use as a refrigerant in consumer products.

  In water, chloroform dissolves only 8 grams per liter at 20 degrees Celsius, but it mixes with many other solvents. The hydrogen attached to its carbon forms hydrogen bonds, making it a good solvent for lipids, rubber, alkaloids, waxes, gutta-percha and resins. Worldwide it also appears in pesticide formulations, cleaning agents, grain fumigation, fire extinguishers and the rubber industry. A heavier version, deuterochloroform, contains one deuterium atom and is a common solvent in NMR spectroscopy. It is made by reacting hexachloroacetone with heavy water, or sodium deuteroxide with chloral hydrate.

  Chemists also use chloroform as a source of dichlorocarbene, a reactive fragment. It forms when chloroform meets aqueous sodium hydroxide, usually with a phase transfer catalyst. Dichlorocarbene adds a formyl group to activated aromatic rings such as phenols, making aryl aldehydes, in the Reimer-Tiemann reaction. Alternatively, an alkene can trap it to form a cyclopropane derivative. In the Kharasch addition, chloroform instead forms a free radical that adds to alkenes.

  3443442932

• 8. Poison in the Bottle

  ›

  Serious illness has followed swallowing 7.5 grams of chloroform, and the mean lethal oral dose for an adult is estimated at 45 grams. Swallowed, it causes symptoms like those of inhalation. It depresses the central nervous system, ultimately producing deep coma and depression of the respiratory center. Mammals absorb, metabolize and eliminate it rapidly. Most leaves through the lungs as chloroform and carbon dioxide, and less than 1% appears in urine. In the liver, cytochrome P-450 enzymes oxidize it to trichloromethanol and reduce it to the dichloromethyl free radical, with carbon dioxide as the main end product.

  After chloroform anaesthesia, some patients suffered nausea, vomiting, hyperthermia, jaundice and coma from liver dysfunction. Autopsies showed liver necrosis and degeneration. The harm to liver and kidneys is thought to come largely from phosgene, one of its metabolites.

  Phosgene also forms in the bottle. In the presence of UV light and air, chloroform slowly converts into this extremely poisonous gas, releasing hydrochloric acid. Commercial chloroform is stabilized with ethanol or amylene. Amylene has proved ineffective, and recovered or dried samples no longer contain any stabilizer. Phosgene can then affect lipids and nucleic acids dissolved in the chloroform. Ethanol reacts with phosgene to form diethyl carbonate, which is relatively harmless. Washing with a saturated carbonate solution such as sodium bicarbonate removes phosgene and hydrochloric acid. Filter paper treated with 5% diphenylamine and 5% dimethylaminobenzaldehyde in ethanol, then dried, turns yellow in the presence of phosgene vapour.

  Water chlorination creates chloroform as a by-product, so it often turns up in municipal tap water and swimming pools. Reported levels vary but generally stay below the health standard of 100 micrograms per liter for total trihalomethanes. Historically, exposure may have been higher through cough syrups and through tobacco smoke, where DDT had previously been used as a fumigant. Splashes in the eyes cause irritation, and prolonged skin contact can produce sores as the skin is defatted.

  The International Agency for Research on Cancer places chloroform in Group 2B, meaning possibly carcinogenic, though there is no convincing evidence that it causes cancer in humans. In the United States it is classified as an extremely hazardous substance under Section 302 of the Emergency Planning and Community Right-to-Know Act. Facilities that produce, store or use significant quantities face strict reporting requirements.

  Many kinds of seaweed produce chloroform, and fungi are believed to make it in soil. Non-biological processes in soils are thought to contribute as well, though the mechanism is unclear. Some anaerobic bacteria go further and use chloroform for respiration, a process called organohalide respiration that converts it to dichloromethane.

  3771737469