Barbituric acid

Last updated
Barbituric acid
Barbituric-acid-structural.svg
Barbituric-acid-3D-balls.png
Names
Preferred IUPAC name
1,3-Diazinane-2,4,6-trione
Other names
  • 2,4,6(1H,3H,5H)-Pyrimidinetrione
  • Pyrimidine-2,4,6(1H,3H,5H)-trione
  • 2,4,6-Trioxohexahydropyrimidine
  • 2,4,6-Trihydroxypyrimidine
  • 2,4,6-Trioxypyrimidine
  • 2,4,6-Pyrimidinetriol
  • 2,4,6-Pyrimidinetrione
  • Pyrimidinetriol
  • 2,4,6-Trihydroxy-1,3-diazine
  • N,N-Malonylurea
  • Malonylurea
  • 6-Hydroxyuracil
  • 6-Hydroxy-hydrouracil
  • N,N-(1,3-Dioxo-1,3-propanediyl)urea
Identifiers
3D model (JSmol)
3DMet
120502
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.598 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-658-0
101571
KEGG
PubChem CID
UNII
  • InChI=1S/C4H4N2O3/c7-2-1-3(8)6-4(9)5-2/h1H2,(H2,5,6,7,8,9) Yes check.svgY
    Key: HNYOPLTXPVRDBG-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H4N2O3/c7-2-1-3(8)6-4(9)5-2/h1H2,(H2,5,6,7,8,9)
    Key: HNYOPLTXPVRDBG-UHFFFAOYAE
  • O=C1NC(=O)NC(=O)C1
Properties
C4H4N2O3
Molar mass 128.087 g·mol−1
AppearanceWhite crystals
Melting point 245 °C (473 °F; 518 K)
Boiling point 260 °C (500 °F; 533 K)
142 g/L (20 °C)
Acidity (pKa)4.01 (H2O) [1]
  • -78.6·10−6 cm3/mol crystal+2H20
  • -53.8·10−6 cm3/mol Anhy.
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H315, H319, H335
P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501
NFPA 704 (fire diamond)
NFPA 704.svgHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
1
0
Safety data sheet (SDS) External MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Barbituric acid or malonylurea or 6-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in water. Barbituric acid is the parent compound of barbiturate drugs, although barbituric acid itself is not pharmacologically active. The compound was first synthesised by Adolf von Baeyer.

Contents

Naming

It remains unclear why Baeyer chose to name the compound that he discovered "barbituric acid". In his textbook Organic Chemistry, the American organic chemist Louis Frederick Fieser (1899–1977) initially speculated that the name stemmed from the German word Schlüsselbart (literally, the beard (Bart, Latin: barba) of a key (Schlüssel), that is, the bit of a key), because Baeyer had regarded barbituric acid as central (or "key") to understanding uric acid and its derivatives. However, Fieser subsequently decided that Baeyer had named the compound after a young lady whom he had met and who was called "Barbara"' hence the name "barbituric acid" was a combination of the name "Barbara" and "uric acid". [2] [3] [4] Other sources claim that Baeyer named the compound after Saint Barbara, either because he discovered it on the feast day of St. Barbara (December 4) or because he sometimes lunched with artillery officers and St. Barbara is their patron saint. [5] [6]

Synthesis

Barbituric acid was first prepared and named in 1864 by the German chemist Adolf von Baeyer, by reducing what Baeyer called Alloxanbromid (alloxan dibromide, now: 5,5-dibromobarbituric acid) with hydrocyanic acid, [7] and later by reducing dibromobarbituric acid with a combination of sodium amalgam and hydrogen iodide. [8] In 1879, the French chemist Édouard Grimaux synthesized barbituric acid from malonic acid, urea, and phosphorus oxychloride (POCl3). [9] Malonic acid has since been replaced by diethyl malonate, [10] [11] because using the ester avoids the problem of having to deal with the acidity of the carboxylic acid and its unreactive carboxylate.

The synthesis of barbituric acid from malonic acid and urea Barbituric acid synthesis.svg
The synthesis of barbituric acid from malonic acid and urea

Properties

The α-carbon has a reactive hydrogen atom and is quite acidic (pKa = 4.01) even for a diketone species (cf. dimedone with pKa 5.23 and acetylacetone with pKa 8.95) because of the additional aromatic stabilization of the carbanion.

Aromatic stabilization of barbiturate carbanion Barbituric acid, acid reaction.svg
Aromatic stabilization of barbiturate carbanion

Uses

Using the Knoevenagel condensation reaction, barbituric acid can form a large variety of barbiturate drugs that behave as central nervous system depressants. As of 2007, more than 2550 barbiturates and related compounds have been synthesised, with 50 to 55 in clinical use around the world at present. The first to be used in medicine was barbital (Veronal) starting in 1903, and the second, phenobarbital was first marketed in 1912. [12]

Barbituric acid is a chemical building block in the laboratory synthesis of riboflavin (vitamin B2) and in a method of producing the pharmaceutical drug minoxidil. [13] It is one of the four ingredients in the synthesis of riboflavin. Before barbituric acid was substituted in the synthesis of riboflavin, it was too expensive to synthesize riboflavin.

Health and safety

Overdose of barbiturate drugs can cause respiratory depression and death. [14] [15] [16] [17] Barbiturates are dependence-producing, and abrupt cessation of high doses can result in a very medically serious, even lethal, withdrawal syndrome. Barbituric acid derivatives are considered DEA Schedule III controlled substances. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Hermann Kolbe</span> German chemist (1818–1884)

Adolph Wilhelm Hermann Kolbe was a major contributor to the birth of modern organic chemistry. He was a professor at Marburg and Leipzig. Kolbe was the first to apply the term synthesis in a chemical context, and contributed to the philosophical demise of vitalism through synthesis of the organic substance acetic acid from carbon disulfide, and also contributed to the development of structural theory. This was done via modifications to the idea of "radicals" and accurate prediction of the existence of secondary and tertiary alcohols, and to the emerging array of organic reactions through his Kolbe electrolysis of carboxylate salts, the Kolbe-Schmitt reaction in the preparation of aspirin and the Kolbe nitrile synthesis. After studies with Wöhler and Bunsen, Kolbe was involved with the early internationalization of chemistry through work in London. He was elected to the Royal Swedish Academy of Sciences, and won the Royal Society of London's Davy Medal in the year of his death. Despite these accomplishments and his training important members of the next generation of chemists, Kolbe is best remembered for editing the Journal für Praktische Chemie for more than a decade, in which his vituperative essays on Kekulé's structure of benzene, van't Hoff's theory on the origin of chirality and Baeyer's reforms of nomenclature were personally critical and linguistically violent. Kolbe died of a heart attack in Leipzig at age 66, six years after the death of his wife, Charlotte. He was survived by four children.

Pyrimidine is an aromatic, heterocyclic, organic compound similar to pyridine. One of the three diazines, it has nitrogen atoms at positions 1 and 3 in the ring. The other diazines are pyrazine and pyridazine.

Mesitylene or 1,3,5-trimethylbenzene is a derivative of benzene with three methyl substituents positioned symmetrically around the ring. The other two isomeric trimethylbenzenes are 1,2,4-trimethylbenzene (pseudocumene) and 1,2,3-trimethylbenzene (hemimellitene). All three compounds have the formula C6H3(CH3)3, which is commonly abbreviated C6H3Me3. Mesitylene is a colorless liquid with sweet aromatic odor. It is a component of coal tar, which is its traditional source. It is a precursor to diverse fine chemicals. The mesityl group (Mes) is a substituent with the formula C6H2Me3 and is found in various other compounds.

<span class="mw-page-title-main">Malonic acid</span> Carboxylic acid with chemical formula CH2(COOH)2

Malonic acid (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's diethyl ester. The name originates from the Greek word μᾶλον (malon) meaning 'apple'.

<span class="mw-page-title-main">Emil Fischer</span> German chemist (1852–1919)

Hermann Emil Louis Fischer was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms. He also hypothesized lock and key mechanism of enzyme action. He never used his first given name, and was known throughout his life simply as Emil Fischer.

<span class="mw-page-title-main">Adolf von Baeyer</span> German chemist (1835–1917)

Johann Friedrich Wilhelm Adolf von Baeyer was a German chemist who synthesised indigo and developed a nomenclature for cyclic compounds. He was ennobled in the Kingdom of Bavaria in 1885 and was the 1905 recipient of the Nobel Prize in Chemistry.

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Alloxan, sometimes referred to as alloxan hydrate, is an organic compound with the formula OC(N(H)CO)2C(OH)2. It is classified as a derivative of pyrimidine. The anhydrous derivative OC(N(H)CO)2CO is also known, as well as a dimeric derivative. These are some of the earliest known organic compounds. They exhibit a variety of biological activities.

<span class="mw-page-title-main">Viktor Meyer</span> German chemist (1848-1897)

Viktor Meyer was a German chemist and significant contributor to both organic and inorganic chemistry. He is best known for inventing an apparatus for determining vapour densities, the Viktor Meyer apparatus, and for discovering thiophene, a heterocyclic compound. He is sometimes referred to as Victor Meyer, a name used in some of his publications.

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Methohexital or methohexitone is a drug which is a barbiturate derivative. It is classified as short-acting, and has a rapid onset of action. It is similar in its effects to sodium thiopental, a drug with which it competed in the market for anesthetics.

<span class="mw-page-title-main">Dibenzylideneacetone</span> Chemical compound

Dibenzylideneacetone or dibenzalacetone, often abbreviated dba, is an organic compound with the formula C17H14O. It is a pale-yellow solid insoluble in water, but soluble in ethanol.

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Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.

<span class="mw-page-title-main">Indole</span> Chemical compound

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<span class="mw-page-title-main">Methylcyclopentane</span> Chemical compound

Methylcyclopentane is an organic compound with the chemical formula CH3C5H9. It is a colourless, flammable liquid with a faint odor. It is a component of the naphthene fraction of petroleum. It usually is obtained as a mixture with cyclohexane. It is mainly converted in naphthene reformers to benzene. The C6 core of methylcyclopentane is not perfectly planar and can pucker to alleviate stress in its structure.

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References

  1. Haynes, William M., ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. pp. 5–89. ISBN   978-1498754286.
  2. Levi, Leo (1957) "The barbituric acids, their chemical structure, synthesis and nomenclature," United Nations: Office on Drugs and Crime.
  3. Fiesler, L. F., Organic Chemistry (Boston, Massachusetts: D.C. Heath and Company, 1944), p. 247.
  4. See also:
    • Willstätter, Richard Martin, Aus meinen Leben: von Arbeit, Musse und Freunden [From my life: of work, leisure and friends] (Weinheim, Germany: Arthur Stoll, 1949). English translation: Willstätter, R. with L. S. Hornig, trans., From My Life: The Memoirs of Richard Willstätter (New York, New York: W. A. Benjamin, 1965), "Memories of Adolf von Baeyer," p. 119.
    • Cohen, W. A. T. (1943) "Chemisch-Historische Aanteekenigen: De nomenclatur van enkele organische zuren" (Chemical-historical notes: the nomenclature of some organic acids), Chemisch Weekblad, 40: 176.
    • Kauffman, George B. (1980) "Adolf von Baeyer and the naming of barbituric acid," Journal of Chemical Education, 57: 222–223.
  5. Jie Jack Li, Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use (Oxford, England: Oxford University Press, 2006), p. 204.
  6. Alex Nickon, Ernest F. Silversmith, Organic Chemistry: The Name Game: Modern Coined Terms and Their Origins (New York, New York: Pergamon Press, 1987), pp. 133–134.
  7. Baeyer, Adolf (1863) "Untersuchungen über die Harnsäuregruppe" (Investigations of the uric acid group), Annalen der Chemie, 127: 1–27' 199–236' see especially pages 231–235. Baeyer names barbituric acid on page 3: "Man wird sehen, wie sich diese Materialien in einfachster Weise um die Substanz N2C4O3H4, die ich Barbitursäure nennen will, gruppieren lassen und wie also die Frage nach der Konstitution der Harnsäure und ihrer Derivate auf die Untersuchung dieser Substanz zurückgekehrt ist." (One will see how these materials can be grouped most simply around the substance N2C4O3H4, which I will call "barbituric acid", and thus how the question of the constitution of uric acid and its derivatives is traced back to the investigation of this substance.)
  8. Baeyer, Adolf (1864) "Untersuchungen über die Harnsäuregruppe" (Investigations of the uric acid group), Annalen der Chemie, 130: 129–175; p. 136.
  9. Grimaux, Edouard (1879) "Synthèse des dérivés uriques de la série de l'alloxane" (Synthesis of uric derivatives of the alloxan series), Bulletin de la Société chimique de Paris, 2nd series, 31: 146–149.
  10. Michael, Arthur (1887) "Ueber neue Reactionen mit Natriumacetessig- und Natriummalonsäureäthern" (On new reactions with sodium acetoacetic- and sodium malonic acid esters), Journal für Praktische Chemie, 2nd series, 35: 449-459; p. 456.
  11. J. B. Dickey & A. R. Gray (1943). "Barbituric acid". Organic Syntheses .; Collective Volume, vol. 2, p. 60
  12. López-Muñoz, Francisco; Ucha-Udabe, Ronaldo; Alamo, Cecilio (December 2005). "The history of barbiturates a century after their clinical introduction". Neuropsychiatric Disease and Treatment. 1 (4): 329–343. ISSN   1176-6328. PMC   2424120 . PMID   18568113.
  13. U.S. patent 3,461,461
  14. Boyd E M, Pearl M. Can nalorphine hydrochloride prevent respiratory depression and death from overdose of barbiturates?[J]. Canadian Medical Association Journal, 1955, 73(1):35-8.
  15. Koppanyi T, Fazekas J F. Acute Barbiturate Poisoning Analysis and Evaluation of Current Therapy[J]. American Journal of the Medical Sciences, 1950, 220(5):559-576.
  16. Shulman A, Shaw F H, Cass N M, et al. A New Treatment of Barbiturate Intoxication[J]. British Medical Journal, 1955, 1(4924):1238-44.
  17. Bateman C H. Barbiturate Poisoning[J]. Lancet, 1963, 282(7303):357.
  18. Title 21, Subchapter I, Part B §812. Schedules of controlled substances https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm Archived 2021-11-04 at the Wayback Machine