Editing Paraldehyde

{{Distinguish|Paraformaldehyde}}

{{Chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 464197327
| Name = Paraldehyde
| ImageFile1 = Paraldehyde structure.svg
| ImageSize1 = 115
| ImageAlt1 = Skeletal formula
| IUPACName = 2,4,6-Trimethyl-1,3,5-trioxane
| SystematicName = 2,4,6-Trimethyl-1,3,5-trioxane
| OtherNames =

| Section1 = {{Chembox Identifiers
| Abbreviations =
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = S6M3YBG8QA
| InChI = 1/C6H12O3/c1-4-7-5(2)9-6(3)8-4/h4-6H,1-3H3
| InChIKey = SQYNKIJPMDEDEG-UHFFFAOYAO
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI =1S/C6H12O3/c1-4-7-5(2)9-6(3)8-4/h4-6H,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SQYNKIJPMDEDEG-UHFFFAOYSA-N
| CASNo = 123-63-7
| CASNo_Ref = {{cascite|correct|CAS}}
| EINECS = 204-639-8
| PubChem = 31264
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 21106173
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1410743
| SMILES = CC1OC(C)OC(C)O1
| RTECS = 
| MeSHName = Paraldehyde
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 27909
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D00705
  }}

| Section2 = {{Chembox Properties
| C=6 | H=12 | O=3
| Appearance = Colourless liquid
| Odour = Sweet
| Density = 0.996 g/cm<sup>3</sup>
| MeltingPtC = 12
| MeltingPt_ref = 
| BoilingPtC = 124
| BoilingPt_ref = <ref name = Sigma>{{Sigma-Aldrich|id=76260|name=Paraldehyde|access-date=16/1/2020}}</ref>
| Solubility = soluble 10% vv at 25 Deg.
| SolubleOther =
| Solvent =
| LogP =
| VaporPressure = 13 hPa at 20 °C<ref name = Sigma />
| HenryConstant =
| AtmosphericOHRateConstant =
| pKa =
| pKb =
| MagSus = −86.2·10<sup>−6</sup> cm<sup>3</sup>/mol
  }}

| Section6 = {{Chembox Pharmacology
| ATCCode_prefix = N05
| ATCCode_suffix = CC05
| Bioavail =
| Metabolism =
| HalfLife =
| ProteinBound =
| Excretion =
| Legal_status =
| Legal_US_comment =
| Legal_AU =
| Legal_CA =
  }}

| Section7 = {{Chembox Hazards
| ExternalSDS = <ref name = Sigma />
| GHSPictograms = {{GHS02}}
| GHSSignalWord = Warning
| HPhrases = {{H-phrases|226}}
| PPhrases = {{P-phrases|210|233|303+361+353|370+378|403+235|501}}
| MainHazards = Flammable
| NFPA-H =
| NFPA-F =
| NFPA-R =
| NFPA-S =
| AutoignitionPt =
| ExploLimits = Upper limit: 17 %(V)<BR />Lower limit: 1.3 %(V)
| FlashPt = 24°C - closed cup
| LD50 = Oral - Rat - 1,530 mg/kg<BR /> Dermal - Rabbit - 14,015 mg/kg
| LC50 =
| PEL =
  }}
}}

'''Paraldehyde''' is the cyclic [[trimer (chemistry)|trimer]] of [[acetaldehyde]] molecules.<ref>{{cite journal|last1=Wankhede|first1=N N|last2=Wankhede|first2=D S|last3=Lande|first3=M K|last4=Arbad|first4=B R|title=Densities and ultrasonic velocities of binary mixtures of 2,4,6-trimethyl-1,3,5-trioxane + ''n''-alcohols at 298.15, 303.15 and 308.15 K|journal=Indian Journal of Chemical Technology|date=March 2006|volume=13|issue=2|pages=149–155|url=http://nopr.niscair.res.in/bitstream/123456789/7015/1/IJCT%2013%282%29%20149-155.pdf}}</ref> Formally, it is a derivative of [[1,3,5-trioxane]], with a [[methyl group]] substituted for a [[hydrogen]] atom at each carbon. The corresponding tetramer is [[metaldehyde]]. A colourless liquid, it is sparingly soluble in [[properties of water|water]] and highly soluble in [[ethanol]]. Paraldehyde slowly oxidizes in air, turning brown and producing an odour of [[acetic acid]]. It attacks most plastics and rubbers and should be kept in glass bottles.

Paraldehyde was first observed in 1835 by the German chemist [[Justus Liebig]]; its empirical formula was determined in 1838 by Liebig's student [[Hermann von Fehling|Hermann Fehling]].<ref>Liebig, Justus (1835) [https://babel.hathitrust.org/cgi/pt?id=uva.x002457901;view=1up;seq=523 "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.</ref><ref>Fehling, H. (1838) [https://babel.hathitrust.org/cgi/pt?id=uva.x002457908;view=1up;seq=331 "Ueber zwei dem Aldehyd isomere Verbindungen"] (On two compounds that are isomeric to acetaldehyde), ''Annalen der Chemie'', '''27''' :  319–322; see pp. 321–322.</ref> 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.<ref>Weidenbusch, H. (1848) [https://babel.hathitrust.org/cgi/pt?id=chi.47401598;view=1up;seq=584 "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.</ref><ref>Paraldehyde was first synthesized by Weidenbusch in 1848:
*  (Editorial staff)  (April 15, 1885) "The action of paraldehyde,"  ''The Therapeutic Gazette'', '''9''' :  247-250; [https://books.google.com/books?id=bzWgAAAAMAAJ&pg=PA247 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), [https://books.google.com/books?id=dNznAAAAMAAJ&pg=PA106 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, [https://books.google.com/books?id=PY9KCwAAQBAJ&pg=PA274 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.
*  See also:  [http://www.rambow.de/download/DBE-Buchstabe-W.pdf ''Deutsche Biographische Enzyklopädie''] {{Webarchive|url=https://web.archive.org/web/20140811213150/http://www.rambow.de/download/DBE-Buchstabe-W.pdf |date=2014-08-11 }} (German Biographical Encyclopedia), p. 1154.</ref>

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.<ref>{{cite book | last1=Latscha | first1=Hans Peter | last2=Kazmaier | first2=Uli | last3=Klein | first3=Helmut A. | title=Chemie für Biologen mit 71 Tabellen | publication-place=Berlin | date=2005 | isbn=978-3-540-21161-7 | oclc=76495748 | language=de |page=515}}</ref>

:[[File:Paraldehyde metaldehyde synthesis.svg|400px]]

The reaction of sulfuric acid and acetaldehyde is exothermic, with the heat of reaction being −113&nbsp;kJ·mol<sup>−1</sup>.<ref>{{citation | last1=Eckert | first1=Marc | last2=Fleischmann | first2=Gerald | last3=Jira | first3=Reinhard | last4=Bolt | first4=Hermann M. | last5=Golka | first5=Klaus | title=Ullmann's Encyclopedia of Industrial Chemistry | chapter=Acetaldehyde | publisher=Wiley-VCH Verlag GmbH & Co. KGaA | publication-place=Weinheim, Germany | date=2006-12-15 | doi=10.1002/14356007.a01_031.pub2| isbn=3527306730 }}</ref>

== 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.<ref>{{cite journal|doi=10.1139/v70-136|title=Microwave spectrum of paraldehyde|year=1970|last1=Kewley|first1=R.|journal=Canadian Journal of Chemistry|volume=48|issue=5|pages=852–855|doi-access=free}}</ref><ref>{{cite journal|doi=10.1021/ja01298a053|title=The Electron Diffraction Study of Paraldehyde|year=1936|last1=Carpenter|first1=D. C.|last2=Brockway|first2=L. O.|journal=Journal of the American Chemical Society|volume=58|issue=7|pages=1270–1273|bibcode=1936JAChS..58.1270C }}</ref>

[[File:Paraldehyde stereochemistry 2.PNG|500px|stereochemistry of paraldehyd]]

==Reactions==
Heated with catalytic amounts of acid, it depolymerizes back to [[acetaldehyde]]:<ref>{{OrgSynth | author = Kendall, E. C. | author2 = McKenzie, B. F. | title = dl-Alanine | collvol = 1 | collvolpages = 21 | year = 1941 | prep = cv1p0021}}</ref><ref>{{OrgSynth | title = Methyl isopropyl carbinol | collvol = 2 | collvolpages = 406 | year = 1943 | author = Nathan L. Drake | author2 = Giles B. Cooke | name-list-style=amp | prep = cv2p0406}}</ref>

:C<sub>6</sub>H<sub>12</sub>O<sub>3</sub> → 3CH<sub>3</sub>CHO

Since paraldehyde has better handling characteristics, it may be used indirectly or directly as a synthetic equivalent of anhydrous acetaldehyde (b.p.&nbsp;20&nbsp;°C). For example, it is used as-is in the synthesis of [[bromal]] (tribromoacetaldehyde):<ref>{{OrgSynth | author = F. A. Long | author2 = J. W. Howard | name-list-style=amp | title = Bromal | collvol = 2 | collvolpages = 87 | prep = cv2p0087}}</ref>

: C<sub>6</sub>H<sub>12</sub>O<sub>3</sub> + 9 Br<sub>2</sub> → 3 CBr<sub>3</sub>CHO + 9 HBr

==Medical applications==
Paraldehyde was introduced into clinical practice in the UK by the Italian physician [[Vincenzo Cervello]] (1854–1918) in 1882.<ref>{{cite journal |vauthors=López-Muñoz F, Ucha-Udabe R, Alamo C |title=The history of barbiturates a century after their clinical introduction |journal=Neuropsychiatric Disease and Treatment |volume=1 |issue=4 |pages=329–43 |date=December 2005 |pmid=18568113 |pmc=2424120 }}</ref><ref>See: 
*  Cervello, Vincenzo (1883) [https://babel.hathitrust.org/cgi/pt?id=hvd.32044103019659;view=1up;seq=191 "Sull'azione fisiologica della paraldeide e contributo allo studio del cloralio idrato"] (On the physiological action of paraldehyde and contribution to the study of chloral hydrate), ''Archivio per le Scienze Mediche'', '''6''' (12) :  177–214.
*  Cervello, Vincenzo (1884) [https://books.google.com/books?id=GRNLAAAAYAAJ&pg=PA113 "Recherches cliniques et physiologiques sur la paraldehyde"] (Clinical and physiological investigations into paraldehyde), ''Archives italiennes de biologie'', '''6''' :  113–134.</ref><ref>For biographical information about Vencenzo Cervello, see:  [http://www.treccani.it/enciclopedia/vincenzo-cervello_(Dizionario-Biografico)/ Dizionario Biografico] (in Italian)</ref>

It is a [[central nervous system]] [[depressant]] and was soon found to be an effective [[anticonvulsant]], [[hypnotic]] and [[sedative]]. It was included in some [[cough medicine]]s 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 hospital]]s and [[geriatrics|geriatric]] wards until the 1970s {{citation needed|date=March 2023}}, 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.<ref>{{cite journal
|vauthors=Norris E, Marzouk O, Nunn A, McIntyre J, Choonara I | title = Respiratory depression in children receiving diazepam for acute seizures: a prospective study | journal = Dev Med Child Neurol | volume = 41 | issue = 5 | pages = 340–3 | year = 1999 | pmid = 10378761 | doi = 10.1017/S0012162299000742| doi-broken-date = 9 December 2024 }}</ref> 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===
{{More citations needed section|date=June 2015}}
[[Image:ParaldehydeAmpoule.jpg|left|100px|thumb|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 oil|peanut]] or [[olive oil]].
{{Clear}}

==Industrial applications==
Paraldehyde is used in [[resin]] manufacture as an alternative to [[formaldehyde]] when making [[phenol formaldehyde resin]]s. It has also found use as antimicrobial [[preservative]], and rarely as a [[solvent]]. It has been used in the generation of [[aldehyde fuchsin]].<ref name="pmid6174561">{{cite journal |author=Nettleton GS |title=The role of paraldehyde in the rapid preparation of aldehyde fuchsin |journal=Journal of Histochemistry and Cytochemistry |volume=30 |issue=2 |pages=175–8 |date=February 1982 |pmid=6174561 |doi= 10.1177/30.2.6174561|doi-access=free }}</ref>

==References==
{{Reflist|30em}}

==External links==
{{Commons category}}
* [http://www.medsafe.govt.nz/Profs/Datasheet/p/Paraldehydeinj.htm Paraldehyde Injection B.P Data Sheet]
* [https://www.drugs.com/cons/Paraldehyde.html Drugs.com: Paraldehyde]
* [https://archive.today/20121209054102/http://www.chemicalland21.com/arokorhi/industrialchem/solalc/PARALDEHYDE.htm Paraldehyde Chemical Data]

{{Anticonvulsants}}
{{Hypnotics and sedatives}}
{{GABAAR PAMs}}

[[Category:Acetals]]
[[Category:Anticonvulsants]]
[[Category:Hypnotics]]
[[Category:Solvents]]
[[Category:GABAA receptor positive allosteric modulators]]
[[Category:Trioxanes]]
[[Category:Trimers (chemistry)]]