chloral hydrate

Chloral hydrate
IUPAC name	2,2,2-trichloroethane-1,1-diol
Other names	Trichloroacetaldehyde monohydrate Tradenames: Aquachloral, Novo-Chlorhydrate, Somnos, Noctec, Somnote
Identifiers
CAS number	302-17-0 Y
PubChem	2707
SMILES	ClC(Cl)(Cl)C(O)O
InChI	1/C2H3Cl3O2/c3-2(4,5)1(6)7/h1,6-7H
InChI key	RNFNDJAIBTYOQL-UHFFFAOYAY
ChemSpider ID	2606
Properties
Molecular formula	C2H3Cl3O2
Molar mass	165.40 g/mol
Appearance	Colorless solid
Density	1.91 g/cm3
Melting point	57 °C, 330 K, 135 °F
Boiling point	98 °C, 371 K, 208 °F
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)
Legal status	Schedule IV(US)
Pregnancy category	C(US)
Hazards
MSDS	External MSDS
EU classification	Harmful (Xn)
R-phrases	R22 R36 R37 R38
Related compounds
Related compounds	Chloral, chlorobutanol
Y (what is this?)  (verify) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Chloral hydrate is a sedative and hypnotic drug as well as a chemical reagent and precursor. The name chloral hydrate indicates that it is formed from chloral (trichloroacetaldehyde) by the addition of one molecule of water. Its chemical formula is C₂H₃Cl₃O₂.

It was discovered through the chlorination of ethanol in 1832 by Justus von Liebig in Gießen.^[1][2] Its sedative properties were first published in 1869 and subsequently, because of its easy synthesis, its use was widespread.^[3] It was widely abused 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. More reputable uses of chloral hydrate include its use as a clearing agent of chitin (and fibers) and as a key ingredient of Hoyer's mounting medium, which is used for slide-mounted observation of organisms under the microscope.

It is, together with chloroform, a minor side-product of the chlorination of water, if organic residues are present in the water, concentrations rarely exceeding 5 micrograms per litre (µg/L).

Production

Chloral hydrate is produced from chlorine and ethanol in acidic solution. In basic conditions the haloform reaction takes place and chloroform is produced.

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

Uses

Building block

Chloral hydrate is a starting point for the synthesis of more complex chemicals. 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:^[4]

Sedative

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^[5] and subsequently by benzodiazepines. It was also formerly used in veterinary medicine as a general anesthetic. Today, it is commonly used as an ingredient in the veterinary anesthetic Equithesin^{[citation needed]}. 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^{[citation needed]}.

In therapeutic doses for insomnia chloral hydrate is effective within sixty minutes, it is metabolized within 4 minutes into trichloroethanol by erythrocytes and plasma esterases and many hours later into trichloroacetic acid. Higher doses can depress respiration and blood pressure. An overdose is marked by confusion, convulsions, nausea and vomiting, severe drowsiness, slow and irregular breathing, cardiac arrhythmia and weakness. It may also cause liver damage and is 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]}.

Chloral hydrate is now illegal in the United States without a prescription. Chloral hydrate is a schedule IV controlled substance in the United States. Its properties have sometimes led to its use as a date rape drug.^[6]

Pharmacology

Chloral hydrate exerts its pharmacological properties via enhancing the GABA receptor complex.^[7]

Hoyer's Mounting Medium

Chloral hydrate is also an ingredient used for Hoyer's solution, a slide-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 an excellent refraction index and clearing (macerating) properties of the small specimens (especially advantageous if specimens require observation with Nomarski optics). The major disadvantage of Hoyer's is its susceptibility to the effects of hydration, 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% KCl), 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.

See also

• 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^[8] combination of chloral hydrate with three benzodiazepines, as announced by forensic pathologist Dr. Joshua Perper on 26 March 2007. Chloral hydrate was the major factor, but none of these drugs would have been sufficient by itself to cause her death.^[9]
• Marilyn Monroe had chloral hydrate in her possession, and it has been speculated that it contributed to her death.^[10]
• 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.^[11]
• 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."^[12]
• House of Mirth (published in 1905), a novel whose heroine, Lily Bart, dies of an overdose of chloral hydrate.
• Dante Gabriel Rossetti (1830-1882), 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.'

References