Paraldehyde is the cyclic trimer of acetaldehyde molecules. Formally, it is a derivative of 1,3,5-trioxane. The corresponding tetramer is metaldehyde. A colourless liquid, it is sparingly soluble in water and highly soluble in ethanol. Paraldehyde slowly oxidizes in air, turning brown and producing an odour of acetic acid. It quickly reacts with most plastics and rubber.
Paraldehyde was first observed in 1835 by the German chemist Justus Liebig; its empirical formula was determined in 1838 by Liebig's student Hermann Fehling. Paraldehyde was first synthesized in 1848 by the German chemist Valentin Hermann Weidenbusch (1821–1893), another student of Liebig; he obtained paraldehyde by treating acetaldehyde with acid (either sulfuric or nitric acid). It has uses in industry and medicine.
Theoretically, four stereoisomeric structures are possible. The structures (1) and (2) are known as cis- and trans-paraldehyde. The structures (3) (a conformer of (2)) and (4) (a conformer of (1)) don't exist for steric reasons.
Since paraldehyde has better handling characteristics, it may be used indirectly or directly as a synthetic equivalent of anhydrous acetaldehyde (b.p. 20 °C). For example, it is used as-is in the synthesis of bromal (tribromoacetaldehyde):
C6H12O3 + 9 Br2 → 3 CBr3CHO + 9 HBr
Paraldehyde was introduced into clinical practice in the UK by the Italian physician Vincenzo Cervello (1854–1918) in 1882.
It was commonly used to induce sleep in sufferers from delirium tremens but has been replaced by other drugs in this regard. It is one of the safest hypnotics and was regularly given at bedtime in psychiatric hospitals and geriatric wards up to the 1970s. Up to 30% of the dose is excreted via the lungs (the rest via the liver). This contributes to a strong unpleasant odour on the breath.
Today, paraldehyde is sometimes used to treat status epilepticus. Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when no resuscitation facilities exist or when the patient's breathing is already compromised. This makes it a useful emergency medication for parents and other caretakers of children with epilepsy. Since the dose margin between the anticonvulsant and hypnotic effect is small, paraldehyde treatment usually results in sleep.
A 5 mL glass ampoule of paraldehyde.
Generic paraldehyde is available in 5 mL sealed glass ampoules. Production in the US has been discontinued, but it was previously marketed as Paral.
Paraldehyde has been given orally, rectally, intravenously and by intramuscular injection. It reacts with rubber and plastic which limits the time it may safely be kept in contact with some syringes or tubing before administration.
Injection. Intramuscular injection can be very painful and lead to sterile abscesses, nerve damage, and tissue necrosis. Intravenous administration can lead to pulmonary edema, circulatory collapse and other complications.
Oral. Paraldehyde has a hot burning taste and can upset the stomach. It is often mixed with milk or fruit juice in a glass cup and stirred with a metal spoon.
Rectal. It may be mixed 1 part paraldehyde with 9 parts saline or, alternatively, with an equal mixture of peanut or olive oil.
^Wankhede, N N; Wankhede, D S; Lande, M K; Arbad, B R (March 2006). "Densities and ultrasonic velocities of bina ry mixtures of 2,4,6-trimethyl-1,3,5- trioxane + n -alcohols at 298.15, 303.15 and 308.15 K". Indian Journal of Chemical Technology. 13: 149–155.
Paraldehyde was first synthesized by Weidenbusch in 1848:
(Editorial staff) (April 15, 1885) "The action of paraldehyde," The Therapeutic Gazette, 9 : 247-250; see p. 247.
See also: Henry Watts, Matthew Moncrieff Pattison Muir, and Henry Forster Morley, Watts' Dictionary of Chemistry, rev'd, vol. 1 (London, England: Longmans, Green, and Co., 1905), p. 106.
For biographical information about Valentin Hermann Weidenbusch, see:
Neill Busse, Der Meister und seine Schüler: Das Netzwerk Justus Liebigs und seiner Studenten [The Master and His Disciples: The network of Justus Liebig and his students] (Hildesheim, Germany: Georg Olms Verlag, 2015); for Weidenbusch's dates, see p. 274.
See also: Joseph S. Fruton (March 1988) "The Liebig research group: A reappraisal," Proceedings of the American Philosophical Society, 132 (1) : 1–66; see p. 59.