Hydantoin

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Hydantoin
Hydantoin.svg
Hydantoin-3D-balls.png
Names
Preferred IUPAC name
Imidazolidine-2,4-dione
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.006.650 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C3H4N2O2/c6-2-1-4-3(7)5-2/h1H2,(H2,4,5,6,7) Yes check.svgY
    Key: WJRBRSLFGCUECM-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C3H4N2O2/c6-2-1-4-3(7)5-2/h1H2,(H2,4,5,6,7)
    Key: WJRBRSLFGCUECM-UHFFFAOYAD
  • O=C1NC(=O)NC1
Properties
C3H4N2O2
Molar mass 100.077 g·mol−1
Melting point 220 °C (428 °F; 493 K)
39.7 g/l (100 °C)
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 ?)

Hydantoin, or glycolylurea, is a heterocyclic organic compound with the formula CH2C(O)NHC(O)NH. It is a colorless solid that arises from the reaction of glycolic acid and urea. It is an oxidized derivative of imidazolidine. In a more general sense, hydantoins can refer to groups or a class of compounds with the same ring structure as the parent compound. For example, phenytoin (mentioned below) has two phenyl groups substituted onto the number 5 carbon in a hydantoin molecule. [1]

Contents

Synthesis

Hydantoin was first isolated in 1861 by Adolf von Baeyer in the course of his study of uric acid. He obtained it by hydrogenation of allantoin, hence the name.

Harnsaureabbau.svg

Friedrich Urech synthesized 5-methylhydantoin in 1873 from alanine sulfate and potassium cyanate in what is now known as the Urech hydantoin synthesis. [2] The method is very similar to the modern route using alkyl and arylcyanates. The 5,5-dimethyl compound can also be obtained from acetone cyanohydrin (also discovered by Urech: see cyanohydrin reaction) and ammonium carbonate. [3] This reaction type is called the Bucherer–Bergs reaction. [4] [5]

Hydantoin can also be synthesized either by heating allantoin with hydroiodic acid or by "heating bromacetyl urea with alcoholic ammonia". [6] The cyclic structure of hydantoins was confirmed by Dorothy Hahn 1913. [7]

Of practical importance, hydantoins are obtained by condensation of a cyanohydrin with ammonium carbonate. Another useful route, which follows the work of Urech, involves the condensation of amino acids with cyanates and isocyanates:

AA+RNCO.png

Uses and occurrence

Pharmaceuticals

The hydantoin group can be found in several medicinally important compounds. [1] In pharmaceuticals, hydantoin derivatives form a class of anticonvulsants; [8] phenytoin and fosphenytoin both contain hydantoin moieties and are both used as anticonvulsants in the treatment of seizure disorders. The hydantoin derivative dantrolene is used as a muscle relaxant to treat malignant hyperthermia, neuroleptic malignant syndrome, spasticity, and ecstasy intoxication. Ropitoin is an example of an antiarrhythmic hydantoin.

Pesticides

The hydantoin derivative Imiprothrin is a pyrethroid insecticide. Iprodione is a popular fungicide containing the hydantoin group. [9]

Synthesis of amino acids

Hydrolysis of hydantoins affords amino acids:

RCHC(O)NHC(O)NH + H2O → RCHC(NH2)COOH + NH3

Hydantoin itself reacts with hot, dilute hydrochloric acid to give glycine. Methionine is produced industrially via the hydantoin obtained from methional. [9]

Methylation

Methylation of hydantoin yields a variety of derivatives. Dimethylhydantoin (DMH) [10] may refer to any dimethyl derivative of hydantoin, but especially 5,5-dimethylhydantoin. [11]

Halogenation

Some N-halogenated derivatives of hydantoin are used as chlorinating or brominating agents in disinfectant/sanitizer or biocide products. The three major N-halogenated derivatives are dichlorodimethylhydantoin (DCDMH), bromochlorodimethylhydantoin (BCDMH), and dibromodimethylhydantoin (DBDMH). A mixed ethyl-methyl analogue, 1,3-dichloro-5-ethyl-5-methylimidazolidine-2,4-dione (bromochloroethylmethylhydantoin), is also used in mixtures with the above.

Iprodione is a popular fungicide containing the hydantoin group. Iprodione.png
Iprodione is a popular fungicide containing the hydantoin group.

DNA oxidation to hydantoins after cell death

A high proportion of cytosine and thymine bases in DNA are oxidized to hydantoins over time after the death of an organism. Such modifications block DNA polymerases and thus prevents PCR from working. Such damage is a problem when dealing with ancient DNA samples. [12]

Related Research Articles

<span class="mw-page-title-main">Ester</span> Compound derived from an acid

In chemistry, an ester is a compound derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. These compounds contain a distinctive functional group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.

Urea, also called carbamide, is an organic compound with chemical formula CO(NH2)2. This amide has two amino groups joined by a carbonyl functional group. It is thus the simplest amide of carbamic acid.

<span class="mw-page-title-main">Thymine</span> Chemical compound of DNA

Thymine is one of the four nucleotide bases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. In RNA, thymine is replaced by the nucleobase uracil. Thymine was first isolated in 1893 by Albrecht Kossel and Albert Neumann from calf thymus glands, hence its name.

<span class="mw-page-title-main">Oxime</span> Organic compounds of the form >C=N–OH

In organic chemistry, an oxime is an organic compound belonging to the imines, with the general formula RR’C=N−OH, where R is an organic side-chain and R' may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds. Amidoximes are oximes of amides with general structure R1C(=NOH)NR2R3.

<span class="mw-page-title-main">Transamination</span> Chemical reaction that transfers an amino group to a ketoacid

Transamination is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids.This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential amino acids to non-essential amino acids.

<span class="mw-page-title-main">Carbamate</span> Chemical group (>N–C(=O)–O–)

In organic chemistry, a carbamate is a category of organic compounds with the general formula R2NC(O)OR and structure >N−C(=O)−O−, which are formally derived from carbamic acid. The term includes organic compounds, formally obtained by replacing one or more of the hydrogen atoms by other organic functional groups; as well as salts with the carbamate anion H2NCOO.

The Wöhler synthesis is the conversion of ammonium cyanate into urea. This chemical reaction was described in 1828 by Friedrich Wöhler. It is often cited as the starting point of modern organic chemistry. Although the Wöhler reaction concerns the conversion of ammonium cyanate, this salt appears only as an (unstable) intermediate. Wöhler demonstrated the reaction in his original publication with different sets of reactants: a combination of cyanic acid and ammonia, a combination of silver cyanate and ammonium chloride, a combination of lead cyanate and ammonia and finally from a combination of mercury cyanate and cyanatic ammonia.

Ethotoin is an anticonvulsant drug used in the treatment of epilepsy. It is a hydantoin, similar to phenytoin. It is not available in the United States.

α-Halo ketone

In organic chemistry, an α-halo ketone is a functional group consisting of a ketone group or more generally a carbonyl group with an α-halogen substituent. α-Halo ketones are alkylating agents. Prominent α-halo ketones include phenacyl bromide and chloroacetone.

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

Etonitazene, also known as EA-4941 or CS-4640, is a benzimidazole opioid, first reported in 1957, that has been shown to have approximately 1,000 to 1,500 times the potency of morphine in animals.

Carbamic acid, which might also be called aminoformic acid or aminocarboxylic acid, is the chemical compound with the formula H2NCOOH. It can be obtained by the reaction of ammonia NH3 and carbon dioxide CO2 at very low temperatures, which also yields ammonium carbamate [NH4]+[NH2CO2]. The compound is stable only up to about 250 K (−23 °C); at higher temperatures it decomposes into those two gases. The solid apparently consists of dimers, with the two molecules connected by hydrogen bonds between the two carboxyl groups –COOH.

The Urech hydantoin synthesis is the chemical reaction of amino acids with potassium cyanate and hydrochloric acid to give hydantoins.

The total synthesis of quinine, a naturally-occurring antimalarial drug, was developed over a 150-year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine. The subject has also been attended with some controversy: Gilbert Stork published the first stereoselective total synthesis of quinine in 2001, meanwhile shedding doubt on the earlier claim by Robert Burns Woodward and William Doering in 1944, claiming that the final steps required to convert their last synthetic intermediate, quinotoxine, into quinine would not have worked had Woodward and Doering attempted to perform the experiment. A 2001 editorial published in Chemical & Engineering News sided with Stork, but the controversy was eventually laid to rest once and for all when Robert Williams and coworkers successfully repeated Woodward's proposed conversion of quinotoxine to quinine in 2007.

Acetone cyanohydrin (ACH) is an organic compound used in the production of methyl methacrylate, the monomer of the transparent plastic polymethyl methacrylate (PMMA), also known as acrylic. It liberates hydrogen cyanide easily, so it is used as a source of such. For this reason, this cyanohydrin is also highly toxic.

<span class="mw-page-title-main">Erlenmeyer–Plöchl azlactone and amino-acid synthesis</span>

The Erlenmeyer–Plöchl azlactone and amino acid synthesis, named after Friedrich Gustav Carl Emil Erlenmeyer who partly discovered the reaction, is a series of chemical reactions which transform an N-acyl glycine to various other amino acids via an oxazolone.

The Bergmann degradation is a series of chemical reactions designed to remove a single amino acid from the carboxylic acid (C-terminal) end of a peptide. First demonstrated by Max Bergmann in 1934, it is a rarely used method for sequencing peptides. The later developed Edman degradation is an improvement upon the Bergmann degradation, instead cleaving the N-terminal amino acid of peptides to produce a hydantoin containing the desired amino acid.

The Bucherer–Bergs reaction is the chemical reaction of carbonyl compounds or cyanohydrins with ammonium carbonate and potassium cyanide to give hydantoins. The reaction is named after Hans Theodor Bucherer.

<span class="mw-page-title-main">Acylurea</span> Class of chemical compounds formally derived from the acylation of urea

Acylureas are a class of chemical compounds formally derived from the acylation of urea.

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

Tobias acid (2-amino-1-naphthalenesulfonic acid) is an organic compound with the formula C10H6(SO3H)(NH2). It is named after the German chemist Georg Tobias. It is one of several aminonaphthalenesulfonic acids, which are derivatives of naphthalene containing both amine and sulfonic acid functional groups. It is a white solid, although commercial samples can appear otherwise. It is used in the synthesis of azo dyes such as C.I. Acid Yellow 19 and C.I. Pigment Red 49. It is prepared via the Bucherer reaction of 2-hydroxynaphthalene-1-sulfonic acid with ammonia and ammonium sulfite.

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

Ethyl cyanoacetate is an organic compound that contains a carboxylate ester and a nitrile. It is a colourless liquid with a pleasant odor. This material is useful as a starting material for synthesis due to its variety of functional groups and chemical reactivity.

References

  1. 1 2 Konnert, Laure; Lamaty, Frédéric; Martinez, Jean; Colacino, Evelina (2017). "Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold" (PDF). Chemical Reviews. 117 (23): 13757–13809. doi:10.1021/acs.chemrev.7b00067. PMID   28644621. S2CID   23653941.
  2. Urech, Friedrich (1873). "Ueber Lacturaminsäure und Lactylharnstoff". Liebigs Ann. (in German). 165 (1): 99–103. doi:10.1002/jlac.18731650110.
  3. Wagner, E. C.; Baizer, Manuel (1940). "5,5-Dimethylhydantoin". Organic Syntheses . 20: 42. doi:10.15227/orgsyn.020.0042 ; Collected Volumes, vol. 3, p. 323.
  4. Bucherer, H. T.; Steiner, W. (1934). "J. Prakt. Chem." (in German). 140: 291.{{cite journal}}: Cite journal requires |journal= (help)
  5. Bergs, Ger. pat. 566,094 (1929) [C. A., 27, 1001 (1933)].
  6. Chisholm, Hugh, ed. (1911). "Hydantoin"  . Encyclopædia Britannica . Vol. 14 (11th ed.). Cambridge University Press. pp. 29–30.
  7. Oakes, Elizabeth H. (2007). Encyclopedia of World Scientists. Facts on File. p. 298. ISBN   9780816061587.
  8. "Hydantoin anticonvulsants". drugs.com.
  9. 1 2 Drauz, Karlheinz; Grayson, Ian; Kleemann, Axel; Krimmer, Hans-Peter; Leuchtenberger, Wolfgang; Weckbecker, Christoph (2007). "Amino Acids". Ullmann's Encyclopedia of Industrial Chemistry . doi:10.1002/14356007.a02_057.pub2. ISBN   978-3527306732.
  10. "5,5-Dimethylhydantoin (DMH) a Highly Effective, Halogen Stabilizer for Wet End Applications, PaperCo".
  11. "5,5-Dimethylhydantoin".
  12. Hofreiter, Michael; Serre, David; Poinar, Hendrik N.; Kuch, Melanie; Pääbo, Svante (2001). "Ancient DNA". Nature Reviews Genetics . 2 (5): 353–359. doi:10.1038/35072071. PMID   11331901. S2CID   205016024.