Barbital

Chemical compound

Not to be confused with Pentobarbital, Phenobarbital, or Sodium thiopental.

Pharmaceutical compound

Barbital

Clinical data
Trade names| Veronal, Medinal
AHFS/Drugs.com| International Drug Names
MedlinePlus| a682221
Routes of
administration| By mouth
Drug class| Barbiturate
ATC code|

* N05CA04 (WHO)

Legal status
Legal status|

* BR: Class B1 (Psychoactive drugs)[1]
* CA: Schedule IV
* DE: Anlage III (Special prescription form required)
* US: Schedule IV

Pharmacokinetic data
Elimination half-life| 30.3 (± 3.2) hours
Identifiers

IUPAC name

* 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione

CAS Number|

* 57-44-3 Y

PubChem CID|

* 2294

DrugBank|

* DB01483 Y

ChemSpider|

* 2206 Y

UNII|

* 5WZ53ENE2P

KEGG|

* D01740 Y

ChEBI|

* CHEBI:31252 Y

ChEMBL|

* ChEMBL444 Y

CompTox Dashboard (EPA)|

* DTXSID5022643

ECHA InfoCard| 100.000.301
Chemical and physical data
Formula| C8H12N2O3
Molar mass| 184.195 g·mol−1
3D model (JSmol)|

* Interactive image

SMILES

* O=C1NC(=O)NC(=O)C1(CC)CC

InChI

* InChI=1S/C8H12N2O3/c1-3-8(4-2)5(11)9-7(13)10-6(8)12/h3-4H2,1-2H3,(H2,9,10,11,12,13) Y

* Key:FTOAOBMCPZCFFF-UHFFFAOYSA-N Y

(verify)

Barbital (or barbitone), sold under the brand names Veronal for the pure acid and Medinal for the sodium salt, was the first commercially available barbiturate. It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s. The chemical names for barbital are diethylmalonyl urea or diethylbarbituric acid; hence, the sodium salt is known also as sodium diethylbarbiturate.

## Synthesis

[edit]

Barbital, then called "Veronal", was first synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering, who published their discovery in 1903.[2] Barbital was prepared by condensing diethylmalonic ester with urea in the presence of sodium ethoxide, or by adding at least two molar equivalents of ethyl iodide to the silver salt of malonylurea (barbituric acid) or possibly to a basic solution of the acid. The result was an odorless, slightly bitter, white crystalline powder.[3]

Its introduction followed the investigations of Fischer and von Mering on the pharmacological properties of certain open and closed acylureas (then called ureides). Led by the impression that hypnotic action appears to be largely dependent on the presence of ethyl groups, they prepared diethylacetyl urea, diethylmalonyl urea (i.e., Barbital itself), and dipropylmalonyl urea. All three were found to be hypnotics: the first was about equal in power to the already-known sulphonal (now sulfonmethane), whilst the third was four times as powerful, but its use was attended by prolonged after-effects. Veronal was found to be midway.[3]

Barbital can also be synthesized in a condensation reaction from urea and diethyl-2,2-diethylmalonate, a diethyl malonate derivative:

## Marketing

[edit]

Bottle for "Veronal" crystals, named after the Italian city of Verona, was the first commercially available barbiturate, manufactured by Bayer.

Barbital was marketed in 1904 by Bayer as "Veronal," while the soluble salt of barbital was marketed by Schering as "Medinal." It was dispensed for "insomnia induced by nervous excitability."[4][unreliable source?] It was provided in either crystal form or in capsules. The therapeutic dose was ten to fifteen grains (0.6-1 grams).[citation needed] 3.5 to 4.4 grams (55 to 68 grains) is considered the lethal dose.[citation needed]

## Pharmacology

[edit]

Barbital was considered to be a great improvement over the existing hypnotics. Its taste was slightly bitter, but better than the strong, unpleasant taste of the commonly used bromides. It had few side effects, and its therapeutic dose was far below the toxic dose. However, prolonged usage resulted in tolerance to the drug, requiring higher doses to reach the desired effect. "I'm literally saturated with it", the Russian tsarina Alexandra Feodorovna confessed to a friend.[5] Fatal overdoses of this slow-acting hypnotic were common. Pioneering aviator Arthur Whitten Brown (of "transatlantic flight of Alcock and Brown" fame) died of an accidental overdose.

A photoswitchable derivative of barbital based on a donor-acceptor Stenhouse adduct (DASA) has been developed for research purposes (photopharmacology). DASA-barbital shows neuronal activity via GABAA receptors and reversible photoisomerization in water using cyclodextrin.[6]

## pH buffer

[edit]

Solutions of sodium barbital have also been used as pH buffers for biological research, e.g., in immunoelectrophoresis or in fixative solutions.[7][8] As barbital is a controlled substance, barbital-based buffers have largely been replaced by other substances.[9]

## Poisoning

[edit]

Veronal from Bayer in glass tubes with cork caps - 10 tablets probably produced around 1940

Japanese writer Ryūnosuke Akutagawa deliberately overdosed on the drug in 1927, as did Un Chien Andalou actor Pierre Batcheff in 1932, Hungarian poet Gyula Juhász in 1937, German mathematician Felix Hausdorff in 1942, Austrian writer Stefan Zweig in 1942, French Anarchist Germaine Berton in 1942,[10] and Greek musician Attik in 1944. During the Holocaust, many Jewish residents of Berlin, Dresden, Wiesbaden, and other German cities used Veronal to take their lives by suicide to avoid deportation to concentration camps by the Nazi[11] Regime.[12] Alfred Kerr, a German theatre critic and essayist, suffered a stroke on a trip to Germany after WWII and decided to end his own life via an overdose of Veronal, which was procured for him by his wife.[13]

Eric Mareo, son of playwright Raimund Pechotsch, murdered his wife Thelma with Veronal. Thelma's lesbian lover Freda Stark was a key witness at the trial.[14]

## In fiction

[edit]

In the D. H. Lawrence story, The Lovely Lady, the titular character dies from a self-administered overdose.[15]

Barbital, under the name of Veronal, has been used as a plot device in the author Agatha Christie's murder mysteries.[16]

Barbital was also used as a plot device in the CBS television legal drama, Perry Mason, in the episode, The Case of the Missing Element (1963).[17]

It was used as a method of suicide in Stephen King’s The Stand by a character named Perion after her partner Mark dies from appendicitis.[citation needed]

## References

[edit]

1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
2. ^ Fischer E, von Mering J (1903). "Ueber eine neue Klasse von Schlafmitteln" [About a new class of sleeping pills]. Therapie der Gegenwart (in German). 44: 97–101.
3. ^ a b One or more of the preceding sentences incorporates text from a publication now in the public domain: Chisholm, Hugh, ed. (1911). "Veronal". Encyclopædia Britannica. Vol. 27 (11th ed.). Cambridge University Press. p. 1037.
4. ^ Finley E (1919). "Veronal". The American Materia Medica, Therapeutics and Pharmacognosy. p. 115. Retrieved 25 July 2015.
5. ^ Dehn L (1922). The Real Tsaritsa. Boston: Little Brown. p. 138.
6. ^ Castagna R, Maleeva G, Pirovano D, Matera C, Gorostiza P (August 2022). "Donor-Acceptor Stenhouse Adduct Displaying Reversible Photoswitching in Water and Neuronal Activity". Journal of the American Chemical Society. 144 (34): 15595–15602\. doi:10.1021/jacs.2c04920. hdl:2445/188733. PMID 35976640. S2CID 251623598.
7. ^ Kuhlmann WD (10 September 2006). "Buffer Solutions" (PDF). Archived from the original (PDF) on 9 November 2016. Retrieved 28 July 2014.
8. ^ Ruzin SE (1999). Plant Microtechnique and Microscopy. Oxford University Press. Archived from the original on 3 June 2019. Retrieved 28 July 2014.
9. ^ Monthony JF, Wallace EG, Allen DM (October 1978). "A non-barbital buffer for immunoelectrophoresis and zone electrophoresis in agarose gels". Clinical Chemistry. 24 (10): 1825–7\. doi:10.1093/clinchem/24.10.1825. PMID 568042.
10. ^ Le Matin (in French), 1942-07-06, retrieved 2022-06-04
11. ^ I Will Bear Witness by Victor Klemperer (Author), Martin Chalmers (Translator) 1998
12. ^ Cargas HJ (1999). Problems Unique to the Holocaust. Univ Pr of Kentucky. p. 44\. ISBN 9780813121017.
13. ^ "Im Interview: Judith Kerr - Wir waren eine Insel \- Kultur - sueddeutsche.de". 2008-06-10. Archived from the original on 2008-06-10. Retrieved 2021-07-08.
14. ^ "Ch. 1 — Introduction". The Trials of Eric Mareo. Retrieved 10 February 2021 - via New Zealand Electronic Text Collection.
15. ^ Lawrence DH (1988). The virgin and the gypsy : and other stories. Internet Archive. London : Marshall Cavendish. ISBN 978-0-86307-694-7.`{{cite book}}`: CS1 maint: publisher location (link)
16. ^ "A quote from The Murder of Roger Ackroyd". www.goodreads.com. Retrieved 2021-10-22.
17. ^ "The Case of the Missing Element (1963)". www.imdb.com. Retrieved 2024-03-05.

## Further reading

[edit]

* Dombrowski SM, Krishnan R, Witte M, Maitra S, Diesing C, Waters LC, Ganguly R (October 1998). "Constitutive and barbital-induced expression of the Cyp6a2 allele of a high producer strain of CYP6A2 in the genetic background of a low producer strain". Gene. 221 (1): 69–77\. doi:10.1016/s0378-1119(98)00436-3. PMID 9852951.

* v
* t
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Hypnotics/sedatives (N05C)

GABAA|

| Alcohols|

* 2M2B
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* Methylpentynol
* Trichloroethanol

|

Barbiturates|

* Allobarbital
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Monoureides|

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Neuroactive steroids|

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Quinazolinones|

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|

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5-HT2A|

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|

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* v
* t
* e

GABAA receptor positive modulators

Alcohols|

* Brometone
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* Chlorobutanol (cloretone)
* Ethanol (alcohol) (alcoholic drink)
* Ethchlorvynol
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* tert-Butanol (2M2P)
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* Tribromoethanol
* Trichloroethanol
* Triclofos
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Barbiturates|

* (-)-DMBB
* Allobarbital
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* Amobarbital
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* Barbexaclone
* Barbital
* Benzobarbital
* Benzylbutylbarbiturate
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* Tetrabarbital
* Thialbarbital
* Thiamylal
* Thiobarbital
* Thiobutabarbital
* Thiopental
* Thiotetrabarbital
* Valofane
* Vinbarbital
* Vinylbital

Benzodiazepines|

* 2-Oxoquazepam
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Carbamates|

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* Meprobamate
* Nisobamate
* Pentabamate
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* Procymate
* Styramate
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Flavonoids|

* 6-Methylapigenin
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* Apigenin
* Baicalein
* Baicalin
* Catechin
* EGC
* EGCG
* Hispidulin
* Linarin
* Luteolin
* Rc-OMe
* Skullcap constituents (e.g., baicalin)
* Wogonin

Imidazoles|

* Etomidate
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* Propoxate

Kava constituents|

* 10-Methoxyyangonin
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* 11-Hydroxyyangonin
* Desmethoxyyangonin
* 11-Methoxy-12-hydroxydehydrokavain
* 7,8-Dihydroyangonin
* Kavain
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* 5,6-Dihydroyangonin
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* 5,6,7,8-Tetrahydroyangonin
* 5,6-Dehydromethysticin
* Methysticin
* 7,8-Dihydromethysticin
* Yangonin

Monoureides|

* Acecarbromal
* Apronal (apronalide)
* Bromisoval
* Carbromal
* Capuride
* Ectylurea

Neuroactive steroids|

* Acebrochol
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* Renanolone
* SAGE-105
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* SAGE-516
* SAGE-689
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* Testosterone
* THDOC
* Zuranolone

Nonbenzodiazepines|

* Cyclopyrrolones: Eszopiclone
* Pagoclone
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* Suproclone
* Suriclone
* Zopiclone

* Imidazopyridines: Alpidem
* DS-1
* Necopidem
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* Pyrazolopyrimidines: Divaplon
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* Others: Adipiplon
* CGS-8216
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* CGS-13767
* CGS-20625
* CL-218,872
* CP-615,003
* CTP-354
* ELB-139
* GBLD-345
* Imepitoin
* JM-1232
* L-838,417
* Lirequinil (Ro41-3696)
* NS-2664
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* NS-11394
* Pipequaline
* ROD-188
* RWJ-51204
* SB-205,384
* SX-3228
* TGSC01AA
* TP-003
* TPA-023
* TP-13
* U-89843A
* U-90042
* Viqualine
* Y-23684

Phenols|

* Fospropofol
* Propofol
* Thymol

Piperidinediones|

* Glutethimide
* Methyprylon
* Piperidione
* Pyrithyldione

Pyrazolopyridines|

* Cartazolate
* Etazolate
* ICI-190,622
* Tracazolate

Quinazolinones|

* Afloqualone
* Cloroqualone
* Diproqualone
* Etaqualone
* Mebroqualone
* Mecloqualone
* Methaqualone
* Methylmethaqualone
* Nitromethaqualone
* SL-164

Volatiles/gases|

* Acetone
* Acetophenone
* Acetylglycinamide chloral hydrate
* Aliflurane
* Benzene
* Butane
* Butylene
* Centalun
* Chloral
* Chloral betaine
* Chloral hydrate
* Chloroform
* Cryofluorane
* Desflurane
* Dichloralphenazone
* Dichloromethane
* Diethyl ether
* Enflurane
* Ethyl chloride
* Ethylene
* Fluroxene
* Gasoline
* Halopropane
* Halothane
* Isoflurane
* Kerosine
* Methoxyflurane
* Methoxypropane
* Nitric oxide
* Nitrogen
* Nitrous oxide
* Norflurane
* Paraldehyde
* Propane
* Propylene
* Roflurane
* Sevoflurane
* Synthane
* Teflurane
* Toluene
* Trichloroethane (methyl chloroform)
* Trichloroethylene
* Vinyl ether

Others/unsorted|

* 3-Hydroxybutanal
* α-EMTBL
* AA-29504
* Alogabat
* Avermectins (e.g., ivermectin)
* Bromide compounds (e.g., lithium bromide, potassium bromide, sodium bromide)
* Carbamazepine
* Chloralose
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* Clomethiazole
* Darigabat
* DEABL
* Deuterated etifoxine
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* Fluoxetine
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* Loreclezole
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* Monastrol
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* Nicotinamide
* Org 25,435
* Phenytoin
* Propanidid
* Retigabine (ezogabine)
* Safranal
* Seproxetine
* Stiripentol
* Sulfonylalkanes (e.g., sulfonmethane (sulfonal), tetronal, trional)
* Terpenoids (e.g., borneol)
* Topiramate
* Valerian constituents (e.g., isovaleric acid, isovaleramide, valerenic acid, valerenol)

* Unsorted benzodiazepine site positive modulators: α-Pinene
* MRK-409 (MK-0343)
* TCS-1105
* TCS-1205

See also: Receptor/signaling modulators • GABA receptor modulators • GABA metabolism/transport modulators
*[BR]: Brazil
*[CA]: Canada
*[DE]: Germany
*[US]: United States
*[CID]: Compound ID
*[EPA]: U.S. Environmental Protection Agency
*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[α2δ]: alpha2delta subunit
*[VDCC]: voltage-gated calcium channel
*[GABA]: γ-Aminobutyric acid