Paraldehyde is the cyclic trimer of acetaldehyde molecules.
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.[Liebig, Justus (1835) "Ueber die Producte der Oxydation des Alkohols" (On the products of the oxidation of ethanol), Annalen der Chemie, 14 : 133–167; see especially p. 141.][Fehling, H. (1838) "Ueber zwei dem Aldehyd isomere Verbindungen" (On two compounds that are isomeric to acetaldehyde), Annalen der Chemie, 27 : 319–322; see pp. 321–322.] The German chemist Valentin Hermann Weidenbusch (1821–1893), another of Liebig's students, synthesized paraldehyde in 1848 by treating acetaldehyde with acid (either sulfuric or nitric acid) and cooling to 0°C. He found it quite remarkable that when paraldehyde was heated with a trace of the same acid, the reaction went the other way, recreating acetaldehyde.[Weidenbusch, H. (1848) "Ueber einige Producte der Einwirkung von Alkalien und Säuren auf den Aldehyd" (On some products of the reaction of alkalies and acids with acetaldehyde), Annalen der Chemie, 66 : 152-165; see pp. 155–158.][Paraldehyde was first synthesized by Weidenbusch in 1848:
]
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(Editorial staff) (April 15, 1885) "The action of paraldehyde," The Therapeutic Gazette, 9 : 247-250; see p. 247.
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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:
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Neill Busse, Der Meister und seine Schüler: Das Netzwerk Justus Liebigs und seiner Studenten The (Hildesheim, Germany: Georg Olms Verlag, 2015); for Weidenbusch's dates, see p. 274.
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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.
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See also: Deutsche Biographische Enzyklopädie (German Biographical Encyclopedia), p. 1154.
Paraldehyde has uses in industry and medicine.
Preparation
Paraldehyde can be produced by the direct reaction of
acetaldehyde and
sulfuric acid. The product of the reaction is dependent on the temperature. At room temperature and higher, the formation of trimer is preferred, but at lower temperatures, around −10 °C, the
tetramer metaldehyde is more likely to be produced.
The reaction of sulfuric acid and acetaldehyde is exothermic, with the heat of reaction being −113 kJ·mol−1.
Stereochemistry
Paraldehyde is produced and used as a mixture of two diastereomers, known as
cis- and
trans-paraldehyde. For each diastereomer, two chair conformers are possible. The structures (1), (4) and (2), (3) are conformers of
cis- and
trans-paraldehyde, respectively. The structures (3) (a conformer of (2)) and (4) (a conformer of (1)) are high energy conformers on steric grounds (1,3-diaxial interactions are present) and do not exist to any appreciable extent in a sample of paraldehyde.
Reactions
Heated with catalytic amounts of acid, it depolymerizes back to
acetaldehyde:
- C6H12O3 → 3CH3CHO
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
Medical applications
Paraldehyde was introduced into clinical practice in the UK by the Italian physician Vincenzo Cervello (1854–1918) in 1882.
[See:
][For biographical information about Vencenzo Cervello, see: Dizionario Biografico (in Italian)]
It is a central nervous system depressant and was soon found to be an effective anticonvulsant, hypnotic and sedative. It was included in some as an expectorant (though there is no known mechanism for this function beyond the placebo effect).
Paraldehyde was the last injection given to Edith Alice Morrell in 1950 by the suspected serial killer John Bodkin Adams. He was tried for her murder but acquitted.
As a hypnotic/sedative
It was commonly used to induce sleep in sufferers from
delirium tremens but has been replaced by other drugs in this regard. It was considered to have been one of the safest hypnotics and was regularly given at bedtime in psychiatric hospitals and
geriatrics wards until the 1970s , but after it was confirmed that acetaldehyde is a confirmed category-1 human carcinogen, it could no longer be considered appropriately safe to use. 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.
As anti-seizure drug
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.
Administration
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.
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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.
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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.
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Rectal. It may be mixed 1 part paraldehyde with 9 parts saline or, alternatively, with an equal mixture of peanut oil or olive oil.
Industrial applications
Paraldehyde is used in
resin manufacture as an alternative to
formaldehyde when making phenol formaldehyde resins. It has also found use as antimicrobial
preservative, and rarely as a
solvent. It has been used in the generation of
aldehyde fuchsin.
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