Chloral hydrate

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. Its sedative properties were first published in 1869 and subsequently, because of its easy synthesis, its use was widespread. It was widely used recreationally and prescribed 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. 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 semipermanent 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 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. 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. 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. 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 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. 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. In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes. 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. It has a very narrow therapeutic window making this drug difficult to use. Higher doses can depress respiration and blood pressure. 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: