Chloral hydrate

Chloral hydrate
Names
Preferred IUPAC name
2,2,2-Trichloroethane-1,1-diol
Other names
Trichloroacetaldehyde monohydrate
Tradenames: Aquachloral, Novo-Chlorhydrate, Somnos, Noctec, Somnote
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.005.562
EC Number 206-117-5
KEGG
RTECS number FM875000
UNII
Properties
C2H3Cl3O2
Molar mass 165.39 g·mol−1
Appearance Colorless solid
Odor Aromatic, slightly acrid
Density 1.9081 g/cm3
Melting point 57 °C (135 °F; 330 K)
Boiling point 98 °C (208 °F; 371 K)
660 g/100 ml[1]
Solubility Very soluble in benzene, ethyl ether, ethanol
log P 0.99
Acidity (pKa) 9.66, 11.0[2]
Structure
Monoclinic
Pharmacology
N05CC01 (WHO)
  • US: C (Risk not ruled out)
    Oral syrup, rectal suppository
    Pharmacokinetics:
    Well absorbed
    Hepatic and renal (converted to trichloroethanol)
    8–10 hours
    Bile, feces, urine (various metabolites not unchanged)
    Legal status
    Hazards
    Safety data sheet External MSDS
    Harmful (Xn)
    R-phrases (outdated) R22 R36 R37 R38
    Lethal dose or concentration (LD, LC):
    1100 mg/kg (mouse, oral)
    Related compounds
    Related compounds
    		 Chloral, chlorobutanol
    Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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    Infobox references

    Chloral hydrate is a geminal diol with the formula C2H3Cl3O2. 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 (trichloroacetaldehyde) by the addition of one equivalent of water.

    It was discovered in 1832 by Justus von Liebig in Gießen when a chlorination (halogenation) reaction was performed on ethanol.[3][4] Its sedative properties were first published in 1869 and subsequently, because of its easy synthesis, its use was widespread.[5] It was widely used recreationally and misprescribed in the late 19th century. Chloral hydrate is soluble in both water and ethanol, readily forming concentrated solutions. A solution of chloral hydrate in ethanol called "knockout drops" was used to prepare a Mickey Finn.[6] More reputable uses of chloral hydrate include its use as a clearing agent for chitin and fibers and as a key ingredient in Hoyer's mounting medium, which is used to prepare permanent or semi-permanent microscope slides of small organisms, histological sections, and chromosome squashes. Because of its status as a regulated substance, chloral hydrate can be difficult to obtain. This has led to chloral hydrate being replaced by alternative reagents[7][8] in microscopy procedures.

    It is, together with chloroform, a minor side-product of the chlorination of water when organic residues such as humic acids are present. It has been detected in drinking water at concentrations of up to 100 micrograms per litre (µg/L) but concentrations are normally found to be below 10 µg/L. Levels are generally found to be higher in surface water than in ground water.[9]

    Chloral hydrate has not been approved by the FDA in the United States or the EMA in the European Union for any medical indication and is on the FDA list of unapproved drugs that are still prescribed by clinicians.[10] Usage of the drug as a sedative or hypnotic may carry some risk given the lack of clinical trials. However, there are chloral hydrate products, licensed for short-term management of severe insomnia, available in the United Kingdom.[11]

    Uses

    Hypnotic

    Chloral hydrate is used for the short-term treatment of insomnia and as a sedative before minor medical or dental treatment. It was largely displaced in the mid-20th century by barbiturates[12] and subsequently by benzodiazepines. It was also formerly used in veterinary medicine as a general anesthetic but is not considered acceptable for anesthesia or euthanasia of small animals due to adverse effects.[13] It is also still used as a sedative prior to EEG procedures, as it is one of the few available sedatives that does not suppress epileptiform discharges.[14]

    In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes.[15] In humans it is metabolized within 7 hours into trichloroethanol and trichloroethanol glucuronide by erythrocytes and plasma esterases and into trichloroacetic acid in 4 to 5 days.[16] It has a very narrow therapeutic window making this drug difficult to use. Higher doses can depress respiration and blood pressure.

    Building block in organic synthesis

    Chloral hydrate is a starting point for the synthesis of other organic compounds. It is the starting material for the production of chloral, which is produced by the distillation of a mixture of chloral hydrate and sulfuric acid, which serves as the desiccant.

    Notably, it is used to synthesize isatin. In this synthesis, chloral hydrate reacts with aniline and hydroxylamine to give a condensation product which cyclicizes in sulfuric acid to give the target compound:[17]

    Botany

    Hoyer's mounting medium

    Chloral hydrate is also an ingredient used for Hoyer's solution, a mounting medium for microscopic observation of diverse plant types such as bryophytes, ferns, seeds, and small arthropods (especially mites). Other ingredients may include gum arabic and glycerol . An advantage of this medium include a high refraction index and clearing (macerating) properties of the small specimens (especially advantageous if specimens require observation with differential interference contrast microscopy).

    Melzer's reagent

    Chloral hydrate is an ingredient used to make Melzer's reagent, an aqueous solution that is used to identify certain species of fungi. The other ingredients are potassium iodide, and iodine. Whether tissue or spores react to this reagent is vital for the correct identification of some mushrooms.

    Safety

    Chloral hydrate was routinely administered in gram quantities. Prolonged exposure to the vapors is unhealthy however, with a LD50 for 4-hour exposure of 440 mg/m3. Long-term use of chloral hydrate is associated with a rapid development of tolerance to its effects and possible addiction as well as adverse effects including rashes, gastric discomfort and severe kidney, heart, and liver failure.[18]

    Acute overdosage is often characterized by nausea, vomiting, confusion, convulsions, slow and irregular breathing, cardiac arrhythmia, and coma. The plasma, serum or blood concentrations of chloral hydrate and/or trichloroethanol, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Accidental overdosage of young children undergoing simple dental or surgical procedures has occurred. Hemodialysis has been used successfully to accelerate clearance of the drug in poisoning victims.[19] It is listed as having a "conditional risk" of causing torsades de pointes.[20]

    Production

    Chloral hydrate is produced from chlorine and ethanol in acidic solution. In basic conditions the haloform reaction takes place and chloral hydrate is decomposed by hydrolysis to form chloroform.[21]

    4 Cl2 + C2H5OH + H2O → Cl3CCH(OH)2 + 5 HCl

    Pharmacodynamics

    Chloral hydrate is metabolized in vivo[22] to trichloroethanol, which is responsible for its physiological and psychological effects.[23]

    The metabolite of chloral hydrate exerts its pharmacological properties via enhancing the GABA receptor complex[24] and therefore is similar in action to benzodiazepines, nonbenzodiazepines and barbiturates. It can be moderately addictive, as chronic use is known to cause dependency and withdrawal symptoms. The chemical can potentiate various anticoagulants and is weakly mutagenic in vitro and in vivo.

    In the United States, chloral hydrate is a schedule IV controlled substance and requires a physician's prescription. Its properties have sometimes led to its use as a date rape drug.[25][26] Chloral hydrate is not commonly prescribed in the United States and is relatively uncommon in pharmacy inventories. It has largely been abandoned for the treatment of insomnia in favor of newer drugs such as the Z-drugs family, which includes zolpidem, zaleplon, zopiclone and eszopiclone. A small number of medical practitioners continue to prescribe it to treat insomnia when all other more modern medications have failed. In the United States, it is commonly supplied in syrup form in a 500 mg/5mL concentration. It is also supplied in suppository form, though the use of this method of administration is extremely rare.

    It is not controlled in Canada except that a prescription is required to purchase the pharmaceutical forms. Possession without a prescription is not illegal and industrial trade is not regulated.

    The United Kingdom does not consider chloral hydrate to be a controlled substance.

    Chloral hydrate is a prescription-only-medicine (POM) in the Netherlands, but possession without a valid prescription will result only in the seizure of the drug, not prosecution. Production, sale and distribution are however punishable by law. It is not listed under the Dutch Opium Law, but when the intent is human consumption, it is covered by the Geneesmiddelenwet (Medicine Act).

    Chloral Hydrate is not approved for medical use in Australia.

    History

    Chloral hydrate was first synthesized by the chemist Justus von Liebig in 1832 at the University of Giessen.[27] Through experimentation physiologist Claude Bernard clarified that the chloral hydrate was hypnotic as opposed to an analgesic.[28] It was the first of a long line of sedatives, most notably the barbiturates, manufactured and marketed by the German pharmaceutical industry.[27] Historically, chloral hydrate was utilized primarily as a psychiatric medication. In 1869, German physician and pharmacologist Oscar Liebreich began to promote its use to calm anxiety, especially when it caused insomnia.[29][28] Chloral hydrate had certain advantages over morphine for this application, as it worked quickly without injection and had a consistent strength. It achieved wide use in both asylums and the homes of those socially refined enough to avoid asylums. Upper and middle class women, well-represented in the latter category, were particularly susceptible to chloral hydrate addiction. After the 1904 invention of barbital, the first of the barbiturate family, chloral hydrate began to disappear from use among those with means.[27] It remained common in asylums and hospitals until the Second World War as it was quite cheap. Chloral hydrate had some other important advantages that kept it in use for five decades despite the existence of more advanced barbiturates. It was the safest available sedative until the middle of the twentieth century, and thus was particularly favored for children.[28] It also left patients much more refreshed after a deep sleep than more recently invented sedatives. Its frequency of use made it an early and regular feature in The Merck Manual.[30]

    Chloral hydrate was also a significant object of study in various early pharmacological experiments. In 1875, Claude Bernard tried to tell if chloral hydrate exerted its action through a metabolic conversion to chloroform. This was not only the first attempt to determine whether different drugs were converted to the same metabolite in the body but also the first to measure the concentration of a particular pharmaceutical in the blood. The results were inconclusive.[31] In 1899 and 1901 Hans Horst Meyer and Ernest Overton respectively made the major discovery that the general anaesthetic action of a drug was strongly correlated to its lipid solubility. But, chloral hydrate was quite polar but nonetheless a potent hypnotic. Overton was unable to explain this mystery. Thus, chloral hydrate remained one of the major and persistent exceptions to this breakthrough discovery in pharmacology. This anomaly was eventually resolved in 1948, when Claude Bernard's experiment was repeated. While chloral hydrate was converted to a different metabolite than chloroform, it was found that was converted into the more lipophilic molecule 2,2,2-Trichloroethanol. This metabolite fit much better with the Meyer-Overton correlation than chloral had. Prior to this, it had not been demonstrated that general anesthetics could undergo chemical changes to exert their action in the body.[32]

    Finally, chloral hydrate was also the first hypnotic to be used intravenously as a general anesthetic. In 1871, Pierre-Cyprien Oré began experiments on animals, followed by humans. While a state of general anesthesia could be achieved, the technique never caught on because its administration was more complex and less safe than the oral administration of chloral hydrate, and less safe for intravenous use than later general anesthetics were found to be.[33]

    Society and culture

    Chloral hydrate was used as one of the earliest synthetic drugs to treat insomnia until 1912, when Phenobarbital replace it and made its use unnecessary.

    In 1897, Bram Stoker's epistolary novel, Dracula, one of its characters; Dr. John Seward recorded his use and his molecular formula in his phonographic diary:

    I cannot but think of Lucy, and how different things might have been. If I don't sleep at once, chloral, the modern Morpheus— C2HCl3O. H2O! I should be careful not to let it grow into a habit. No I shall take none to-night! I have thought of Lucy, and I shall not dishonor her by mixing the two.[34]

    In the conclusion of Edith Wharton's 1905 novel The House of Mirth, Lily Bart, the novel's heroine, becomes addicted to chloral hydrate and overdoses on the substance:

    She put out her hand and measured the soothing drops into a glass; but as she did so, she knew they would be powerless against the supernatural lucidity of her brain. She had long since raised the dose to its highest limit, but to-night she felt she must increase it. She knew she took a slight risk in doing so; she remembered the chemist's warning. If sleep came at all, it might be a sleep without waking.[35]

    Chloral hydrate was also featured in "Bad Blood", the twelfth episode of the fifth season of the American science fiction television series The X-Files. In the episode, the drug was used by a vampire to incapacitate his victims prior to drinking their blood.

    Notable users

    • Dante Gabriel Rossetti (1828–1882) became addicted to chloral, with whisky chasers, after the death of his wife Elizabeth Siddal from a laudanum overdose in 1862. He had a mental breakdown in 1872. He lived out the last ten years of his life addicted to chloral and alcohol, in part to mask the pain of botched surgery to an enlarged testicle in 1877.
    • Irish physicist John Tyndall (1820 – 1893) died of an accidental overdose of chloral administered by his wife.
    • Friedrich Nietzsche (1844–1900) regularly used chloral hydrate in the years leading up to his nervous breakdown, according to Lou Salome and other associates. Whether the drug contributed to his insanity is a point of controversy.[36]
    • André Gide (1869–1951) was given chloral hydrate as a boy for sleep problems by a physician named Lizart. Gide states in his autobiography, If It Die... that "all my later weaknesses of will or memory I attribute to him."[37]
    • Marilyn Monroe (1926–1962) died from an overdose of chloral hydrate and pentobarbital (Nembutal).[38][39]
    • Oliver Sacks (1933–2015) abused chloral hydrate in 1965 as a depressed insomniac. He found himself taking fifteen times the usual dose of chloral hydrate every night before he eventually ran out, causing violent withdrawal symptoms.[40]
    • The Jonestown mass suicides in 1978, involved the communal drinking of Flavor Aid poisoned with Valium, chloral hydrate, cyanide, and Phenergan.[41]

    See also

    References

    1. ↑ "Chemical Book: Chloral hydrate". Retrieved 27 February 2017.
    2. ↑ Gawron O, Draus F (1958). "Kinetic Evidence for Reaction of Chloralate Ion with p-Nitrophenyl Acetate in Aqueous Solution". J. Am. Chem. Soc. 80 (20): 5392–5394. doi:10.1021/ja01553a018.
    3. ↑ Justus Liebig (1832). "Ueber die Zersetzung des Alkohols durch Chlor" [On the degradation of alcohol by chlorine]. Annalen der Pharmacie. 1 (1): 31–32. doi:10.1002/jlac.18320010109.
    4. ↑ Justus Liebig (1832). "Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen" [On compounds that arise by the reaction of chlorine with alcohol, oil-forming gas [i.e., ethane], and acetone]. Annalen der Pharmacie. 1 (2): 182–230. doi:10.1002/jlac.18320010203.
    5. ↑ Liebreich, Oskar (1869). Das Chloralhydrat : ein neues Hypnoticum und Anaestheticum und dessen Anwendung in der Medicin ; eine Arzneimittel-Untersuchung. Berlin: Müller.
    6. ↑ "Chloral Hydrate". Drug Enforcement Administration. Archived from the original on 11 May 2012. Retrieved 27 June 2018.
    7. ↑ "An Improved Clearing and Mounting Solution to Replace Chloral Hydrate in Microscopic Applications". Applications in Plant Sciences. 1 (5): 1300016. doi:10.3732/apps.1300016.
    8. ↑ Li, J; Pan, L; Naman, CB; Deng, Y; Chai, H; Keller, WJ; Kinghorn, AD. "Pyrrole Alkaloids with Potential Cancer Chemopreventive Activity Isolated from a Goji Berry-Contaminated Commercial Sample of African Mango". Journal of Agricultural and Food Chemistry. 62 (22): 5054–5060. doi:10.1021/jf500802x. PMC 4047925. PMID 24792835.
    9. ↑ "Summary statement - 12.20 Chloral hydrate (trichloroacetaldehyde)" (PDF). World Health Organization. Retrieved 14 March 2013.
    10. ↑ Meadows, Michelle (January–February 2007). "The FDA Takes Action Against Unapproved Drugs" (PDF). FDA Consumer Magazine. Retrieved 13 July 2018.
    11. ↑ "EMC Search: chloral hydrate". Electronic Medicines Compendium. Retrieved 6 March 2018.
    12. ↑ Tariq, Syed H.; Pulisetty, Shailaja (2008). "Pharmacotherapy for Insomnia". Clinics in Geriatric Medicine. 24 (1): 93–105. doi:10.1016/j.cger.2007.08.009. PMID 18035234.
    13. ↑ Baxter, Mark G.; Murphy, Kathy L.; Taylor, Polly M.; Wolfensohn, Sarah E. (2009-07-01). "Chloral Hydrate Is Not Acceptable for Anesthesia or Euthanasia of Small Animals". Anesthesiology. 111 (1): 209–209. doi:10.1097/aln.0b013e3181a8617e. ISSN 0003-3022.
    14. ↑ http://jcc.kau.edu.sa/Files/140/Researches/11822_Chloral.pdf
    15. ↑ Gauillard J, Cheref S, Vacherontrystram MN, Martin JC (May–Jun 2002). "Chloral hydrate: a hypnotic best forgotten?". Encephale. 28 (3 Pt 1): 200–204. PMID 12091779.
    16. ↑ Beland, Frederick A. "NTP Technical Report on the Toxicity and Metabolism Studies of Chloral Hydrate" (PDF). Toxicity Report Series Number 59. National Toxicology Program. p. 10. Retrieved 14 March 2013.
    17. ↑ C. S. Marvel and G. S. Hiers (1941). "Isatin". Organic Syntheses. ; Collective Volume, 1, p. 327
    18. ↑ Gelder M, Mayou R, Geddes J (2005). Psychiatry (3rd ed.). New York: Oxford. p. 238.
    19. ↑ R. Baselt (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 259–261.
    20. ↑ "crediblemeds.org".
    21. ↑ Takahashi, Yasuo; Onodera, Sukeo; Morita, Masatoshi; Terao, Yoshiyasu (2003). "A Problem in the Determination of Trihalomethane by Headspace-Gas Chromatography/Mass Spectrometry" (PDF). Journal of Health Science. 49 (1): 3. doi:10.1248/jhs.49.1.
    22. ↑ Trichloroethanol
    23. ↑ Reinhard Jira, Erwin Kopp, Blaine C. McKusick, Gerhard Röderer, Axel Bosch and Gerald Fleischmann "Chloroacetaldehydes" in Ullmann's Encyclopedia of Industrial Chemistry, 2007, Wiley-VCH, Weinheim. doi:10.1002/14356007.a06_527.pub2
    24. ↑ Lu, J; Greco, MA (2006). "Sleep circuitry and the hypnotic mechanism of GABAA drugs". Journal of Clinical Sleep Medicine. 2 (2): S19–26. PMID 17557503.
    25. ↑ McGregor MJ, Ericksen J, Ronald LA, Janssen PA, Van Vliet A, Schulzer M (2004). "Rising incidence of hospital-reported drug-facilitated sexual assault in a large urban community in Canada. Retrospective population-based study". Can J Public Health. 95 (6): 441–5. PMID 15622794.
    26. ↑ "Attacked by the Gang". New York Daily News. 25 October 2008.
    27. 1 2 3 Edward., Shorter, (1998-01-01). A history of psychiatry : from the era of the asylum to the age of Prozac. Wiley. ISBN 0471245313. OCLC 60169541.
    28. 1 2 3 Thomas., Dormandy, (2006-01-01). The worst of evils : the fight against pain. Yale University Press. ISBN 0300113226. OCLC 878623979.
    29. ↑ Edward., Shorter, (2009-01-01). Before Prozac : the troubled history of mood disorders in psychiatry. Oxford University Press. ISBN 9780195368741. OCLC 299368559.
    30. ↑ Cuadrado, Fernando F.; Alston, Theodore A. (2016-10-01). "Book Review". Journal of Anesthesia History. 2 (4): 153–155. doi:10.1016/j.janh.2016.01.004. ISSN 2352-4529.
    31. ↑ Alston, Theodore A. (2016-07-01). "Noteworthy Chemistry of Chloroform". Journal of Anesthesia History. 2 (3): 85–88. doi:10.1016/j.janh.2016.04.008. ISSN 2352-4529.
    32. ↑ Krasowski, Matthew D. "Contradicting a Unitary Theory of General Anesthetic Action: a History of Three Compounds from 1901 to 2001". Bulletin of Anesthesia History. 21 (3): 1–24. doi:10.1016/s1522-8649(03)50031-2. PMC 2701367.
    33. ↑ Roberts, Matthew; Jagdish, S. (2016-01-01). "A History of Intravenous Anesthesia in War (1656-1988)". Journal of Anesthesia History. 2 (1): 13–21. doi:10.1016/j.janh.2015.10.007. ISSN 2352-4529.
    34. ↑ Stoker, Bram (28 February 1897). "Dracula". New York Grosset & Dunlap. Retrieved 28 February 2018 – via Internet Archive.
    35. ↑ "House of Mirth". www.gutenberg.org. Retrieved 2018-07-02.
    36. ↑ Cate, Curtis (2005). Friedrich Nietzsche. Woodstock, NY: The Overlook Press. p. 453.
    37. ↑ Gide, André and Dorothy Bussey (trans). If It Die...An Autobiography. New York: Vintage International, 2001. p105
    38. ↑ Banner, Lois (2012). Marilyn: The Passion and the Paradox. Bloomsbury. pp. 411–412. ISBN 978-1-40883-133-5.
    39. ↑ Spoto, Donald (2001). Marilyn Monroe: The Biography. Cooper Square Press. pp. 580–583. ISBN 0-8154-1183-9.
    40. ↑ Sacks, Oliver (27 Aug 2012). "Altered States". The New Yorker. Retrieved 2 September 2015.
    41. ↑ Hall, John R. (1987). Gone from the Promised Land: Jonestown in American Cultural History. Transaction Publishers. p. 282. ISBN 9780887388019.
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