Chloral hydrate

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Chloral hydrate
Chloral-hydrate-montage.png
Identifiers
CAS number 302-17-0 YesY
PubChem 2707
ChemSpider 2606 YesY
UNII 418M5916WG YesY
DrugBank DB01563
KEGG D00265 YesY
ChEBI CHEBI:28142 YesY
ChEMBL CHEMBL455917 YesY
ATC code N05CC01
Jmol-3D images Image 1
Properties
Molecular formula C2H3Cl3O2
Molar mass 165.40 g mol−1
Appearance Colorless solid
Density 1.91 g/cm3
Melting point 57 °C (135 °F; 330 K)
Boiling point 98 °C (208 °F; 371 K)
Acidity (pKa) 9.66, 11.0[1]
Pharmacology
Bioavailability well absorbed
Routes of
administration
Oral codeine/syrup, rectal suppository
Metabolism converted to trichloroethanol, hepatic and renal
Elimination
half-life
8–10 hours in plasma
Excretion bile, feces, urine (various metabolites not unchanged)

?(CA)

Schedule IV(US)

Pregnancy
category
Hazards
MSDS External MSDS
EU classification Harmful (Xn)
R-phrases R22 R36 R37 R38
Related compounds
Related compounds Chloral, chlorobutanol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 YesY (verify) (what is: YesY/N?)
Infobox references

Chloral hydrate is an organic compound 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 through the chlorination (halogenation) of ethanol in 1832 by Justus von Liebig in Gießen.[2][3] Its sedative properties were first published in 1869 and subsequently, because of its easy synthesis, its use was widespread.[4] It was widely used recreationally and misprescribed in the late 19th century. Chloral hydrate is soluble in both water and alcohol, readily forming concentrated solutions. A solution of chloral hydrate in alcohol called "knockout drops" was used to prepare a Mickey Finn.[5] 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. To cope with procurement problems, Rutgers scientists have developed a substitute for chloral hydrate for use in microscopy, known as Visikol,[6][7] which has been shown to be an effective replacement for chloral hydrate for clearing plant specimens.[8]

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 list of unapproved drugs that is still prescribed by clinicians.[10] Usage of the drug as a sedative or hypnotic may carry some risk given the lack of clinical trials.

Production[edit]

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.[11]

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

Uses[edit]

Building block in organic synthesis[edit]

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:[12]

Synthesis of isatin.png

Hypnotic[edit]

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[13] and subsequently by benzodiazepines. It was also formerly used in veterinary medicine as a general anesthetic. 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.

Safety[edit]

Chloral hydrate was routinely administered to patients on the gram scale. Prolonged exposure to the vapors is unhealthy however, with a LC50 for 4-h 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 renal, cardiac and hepatic failure.[17]

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.[18]

Pharmacodynamics[edit]

Chloral hydrate is metabolized in vivo[19] to trichloroethanol, which is responsible for its physiological and psychological effects.[20]

The metabolite of Chloral hydrate exerts its pharmacological properties via enhancing the GABA receptor complex[21] 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.[citation needed]

Legal status[edit]

Chloral hydrate is illegal without prescription and a schedule IV controlled substance in the United States. Its properties have sometimes led to its use as a date rape drug.[22][unreliable source?]

Chloral hydrate is not controlled in Canada but a prescription is required to purchase the pharmaceutical forms. Possession without a prescription is not illegal and industrial trade is not regulated.

Chloral hydrate is not a controlled substance in the United Kingdom.

Chloral hydrate is a prescription-only-medicine (POM) in the Netherlands, but possession without a valid prescription will result only in seizure of the drug but not in 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 (Medicin Act).

Hoyer's mounting medium[edit]

Chloral hydrate is also an ingredient used for Hoyer's solution, a mounting medium for microscopic observation of diverse organisms such as bryophytes, ferns, seeds, and small arthropods (especially mites). One recipe for making Hoyer's is dissolving gum arabic (30.0 g) in water (50.0 mL), then adding chloral hydrate (200.0 g), and then finally adding glycerol (16.0 mL). 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). The major disadvantage of Hoyer's is its susceptibility to the effects of rehydration, which causes the mountant to crystallize and threatening the slide to become unusable. It is therefore absolutely necessary, after drying a mounted specimen, to thoroughly ring (2 layers are best) cover slips with a protective coating (e.g., insulating glyptol), which prevents rehydration and mountant deterioration. Chloral hydrate reportedly does not effectively clear larger specimens, or arthropods that are more heavily sclerotized (e.g., larger insects). These should first be cleared with another product (e.g., 10% KOH or NaOH), and then mounted in Hoyer's. Other disadvantages of Hoyer's (principally due to chloral hydrate) include toxicity (see above), and procurement problems due to chloral hydrate being a controlled substance. To cope with the problems of procuring chloral hydrate, a team of Rutgers scientists have developed a working substitute for chloral hydrate in microscopy, known as Visikol,[23] which has been demonstrated to be an effective substitute for chloral hydrate in the clearing of botanical specimens.[24]

Notable uses[edit]

  • The Jonestown mass suicides, which involved the communal drinking of Flavor Aid poisoned with Valium, chloral hydrate, cyanide, and Phenergan
  • Richard Realf (1832–1878) killed himself with a combination of chloral hydrate and laudanum.[25]
  • Jennie Bosschieter (1882–1900) who was murdered with chloral hydrate in Paterson, New Jersey on 12 October 1900.
  • John Tyndall (1820–1893) who died of an accidental overdose.
  • Anna Nicole Smith (1967–2007) who died of an accidental[26] combination of chloral hydrate with four benzodiazepines and several other drugs, as announced by forensic pathologist Dr. Joshua Perper on 26 March 2007. Chloral hydrate was the major factor, but it was unclear if any of these drugs would have been sufficient by itself to cause her death.[27]
  • Marilyn Monroe had chloral hydrate in her system at her death.
  • Hank Williams came under the spell of a man calling himself "Doctor" Toby Marshall (actually a paroled forger), who often supplied him with prescriptions and injections of chloral hydrate, which Marshall claimed was a pain reliever, to deal with the pain from Williams' lifelong severe back problems.[28]
  • William S. Burroughs was expelled from school for experimenting with chloral hydrate along with another pupil. The incident is detailed in the writer's foreword to Junkie.
  • Mary Todd Lincoln was given chloral hydrate for sleep problems. See Mary Todd Lincoln by Jean Baker and Mary: Mrs. A. Lincoln, by Janis Cooke Newman.
  • André Gide (1869–1951) was given chloral hydrate as a boy for sleep problems by a Doctor named Lizart. Gide states in his autobiography, If It Die... that "all my later weaknesses of will or memory I attribute to him."[29]
  • Dante Gabriel Rossetti (1828–1882), the English painter, was a regular user of chloral hydrate, originally against insomnia. He is quoted as saying to his friend Hall Caine: "Everyone has skeletons in their cupboards, and this is mine."
  • Friedrich Nietzsche 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.
  • Antonin Artaud allegedly died of an overdose of chloral hydrate.
  • Oliver Sacks abused chloral hydrate in 1956 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.[30]

See also[edit]

References[edit]

  1. ^ Gawron, O., Draus, F. (1958). J. Am. Chem. Soc. 80 (20): 5392. doi:10.1021/ja01553a018. 
  2. ^ Justus Liebig (1832). "Ueber die Zersetzung des Alkohols durch Chlor". Annalen der Pharmacie 1 (1): 31–32. doi:10.1002/jlac.18320010109. 
  3. ^ Justus Liebig (1832). "Ueber die Verbindungen, welche durch die Einwirkung des Chlors auf Alkohol, Aether, ölbildendes Gas und Essiggeist entstehen". Annalen der Pharmacie 1 (2): 182–230. doi:10.1002/jlac.18320010203. 
  4. ^ Liebreich, Oskar (1869). Das Chloralhydrat : ein neues Hypnoticum und Anaestheticum und dessen Anwendung in der Medicin ; eine Arzneimittel-Untersuchung. Berlin: Müller. 
  5. ^ http://www.justice.gov/dea/concern/chloral_hydrate.html[dead link]
  6. ^ http://visikol.com
  7. ^ "Visikol: Novel Clearing Agent and Mounting Medium to replace Chloral Hydrate Solution for use in Microscopy, Forensics, Quality Control, Education, and Biological, Food, and Earth Sciences". Rutgers Technology #: 2012-146. 
  8. ^ "An Improved Clearing and Mounting Solution to Replace Chloral Hydrate in Microscopic Applications". Applications in Plant Sciences, 1(5). 
  9. ^ "Summary statement - 12.20 Chloral hydrate (trichloroacetaldehyde)". World Health Organization. Retrieved March 14, 2013. 
  10. ^ Michelle Meadows (January–February 2007). "The FDA Takes Action Against Unapproved Drugs". FDA Consumer magazine. 
  11. ^ Takahashi, Yasuo; Onodera, Sukeo; Morita, Masatoshi; and Terao, Yoshiyasu (2003). "A Problem in the Determination of Trihalomethane by Headspace-Gas Chromatography/Mass Spectrometry". Journal of Health Science 49 (1): 3. doi:10.1248/jhs.49.1. 
  12. ^ C. S. Marvel and G. S. Hiers (1941), "Isatin", Org. Synth. ; Coll. Vol. 1: 327 
  13. ^ Tariq, Syed H. and Shailaja Pulisetty; “Pharmacotherapy for Insomnia”, Clinics in Geriatric Medicine (24), 2008 p. 93-105 PMID 18035234
  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". Toxicity Report Series Number 59. National Toxicology Program. p. 10. Retrieved March 14, 2013. 
  17. ^ Gelder, M., Mayou, R. and Geddes, J. (2005). Psychiatry (3rd ed.). New York: Oxford. p. 238. 
  18. ^ R. Baselt (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 259–261. 
  19. ^ Trichloroethanol
  20. ^ 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
  21. ^ 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. 
  22. ^ New York Daily News, 10/25/2008
  23. ^ http://otc.rutgers.edu/pdf/Simon-2012-146.pdf
  24. ^ "An Improved Clearing and Mounting Solution to Replace Chloral Hydrate in Microscopic Applications". Applications in Plant Sciences. 1(5). 
  25. ^ Rathmell, George W. (2002). A Passport to Hell: The Mystery of Richard Realf. Lincoln, Nebraska: Authors Choice Press. pp. ix, 134. ISBN 0-595-21251-4. Retrieved 12 September 2011. 
  26. ^ Anna Nicole Smith Autopsy Report. XI. Manner of death. A. The Exclusion of Homicide The Smoking Gun
  27. ^ Anna Nicole Smith Autopsy Released. Coroner: Ex-Playmate died from accidental sedative overdose The Smoking Gun
  28. ^ Hank Williams summary Book Rags
  29. ^ Gide, André and Dorothy Bussey (trans). If It Die...An Autobiography. New York: Vintage International, 2001. p105
  30. ^ Sacks, Oliver. "Altered States". The New Yorker. The New Yorker. Retrieved 16 April 2014. 

External links[edit]

Media related to Chloral hydrate at Wikimedia Commons