Chemistry:Barbital

Short description: Chemical compound

Barbital

Clinical data
Trade names	Veronal, Medinal
AHFS/Drugs.com	International Drug Names
MedlinePlus	a682221
Routes of administration	Oral
ATC code	N05CA04 (WHO)
Legal status
Legal status	BR: Class B1 (Psychoactive drugs) 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
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
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Barbital (or barbitone), marketed 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 (known as medinal, a genericised trademark in the United Kingdom) is known also as sodium diethylbarbiturate.

Synthesis

Barbital, then called "Veronal", was first synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering, who published their discovery in 1903. 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.

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.

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

Marketing

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 the Bayer company as "Veronal". A soluble salt of barbital was marketed by the Schering company as "Medinal". It was dispensed for "insomnia induced by nervous excitability". It was provided in either crystal form or in cachets (capsules). The therapeutic dose was ten to fifteen grains (0.6-1 grams). 3.5 to 4.4 grams (55 to 68 grains) is the deadly dose but sleep has also been prolonged up to ten days with recovery.

Pharmacology

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. 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 GABA_A receptors and reversible photoisomerization in water using cyclodextrin.

pH buffer

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 As barbital is a controlled substance, barbital-based buffers have largely been replaced by other substances.

Suicide

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, Germany mathematician Felix Hausdorff in 1942, Austrian writer Stefan Zweig in 1942, France Anarchist Germaine Berton in 1942, and Greek musician Attik in 1944. During the Holocaust, many Jewish residents of Berlin, Dresden, Wiesbaden, and other German cities used Veronal to commit suicide to avoid deportation to concentration camps by the Nazi Regime. 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.

In fiction

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

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

Further reading

• "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. October 1998. doi:10.1016/s0378-1119(98)00436-3. PMID 9852951.