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Hydantoin
Hydantoin
Hydantoin
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Hydantoin
Skeletal formula of hydantoin
Ball-and-stick model of hydantoin
Names
Preferred IUPAC name
Imidazolidine-2,4-dione
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.006.650 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C3H4N2O2/c6-2-1-4-3(7)5-2/h1H2,(H2,4,5,6,7) checkY
    Key: WJRBRSLFGCUECM-UHFFFAOYSA-N checkY
  • 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).
checkY verify (what is checkY☒N ?)

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]

Synthesis

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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.

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 or ⍺-amino esters with cyanates and isocyanates:[8]

Uses and occurrence

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Pharmaceuticals

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The hydantoin group can be found in several medicinally important compounds.[1] In pharmaceuticals, hydantoin derivatives form a class of anticonvulsants;[9] 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

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The hydantoin derivative Imiprothrin is a pyrethroid insecticide. Iprodione is a popular fungicide containing the hydantoin group.[10]

Synthesis of amino acids

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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.[10]

Methylation

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Methylation of hydantoin yields a variety of derivatives. Dimethylhydantoin (DMH) [11] may refer to any dimethyl derivative of hydantoin, but especially 5,5-dimethylhydantoin.[12]

Halogenation

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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.

DNA oxidation to hydantoins after cell death

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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.[13]

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Hydantoin

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from Grokipedia
Hydantoin, also known as imidazolidine-2,4-dione, is a five-membered heterocyclic with the molecular formula C₃H₄N₂O₂ and a molecular weight of 100.08 g/mol. It features a non-aromatic ring consisting of two atoms and two carbonyl groups at positions 2 and 4, making it a cyclic derivative that serves as a privileged scaffold in due to its five potential substitution sites and ability to form bonds. Physically, hydantoin appears as a white to light yellow fine with a of 218–220 °C and an estimated boiling point of 187.47 °C; it has a of approximately 1.4457 g/cm³ and a of 0 Pa at 25 °C. The compound exhibits slight in but is more soluble in alcohols and hydroxides, with limited in . Chemically stable under standard conditions, hydantoin is often synthesized via the reaction of with or through cyclization of aminoacetamide derivatives. In pharmaceutical applications, hydantoin and its derivatives are renowned for their broad spectrum of biological activities, including , , anticancer, antidiabetic, , and anti-HIV effects. Notable examples include and mephenytoin, which are used as anticonvulsants for treating ; nilutamide and , androgen antagonists for therapy; and nitrofurantoin, an antibacterial agent for urinary tract infections. Beyond medicine, hydantoin derivatives find use in as preservatives, such as , and in synthetic chemistry as intermediates for diverse compounds.

Structure and Properties

Molecular Structure

Hydantoin is a heterocyclic with the molecular formula C₃H₄N₂O₂ and the systematic IUPAC name imidazolidine-2,4-dione. It features a five-membered ring composed of two atoms at positions 1 and 3, two carbonyl groups at positions 2 and 4, and a (-CH₂-) at position 5, forming a cyclic structure. The core ring can be represented in as: \chemfig∗∗5(−(−NH−)−C(=O)−(−NH−)−C(=O)−(−CH2−)−)\chemfig{**5(-(-NH-)-C(=O)-(-NH-)-C(=O)-(-CH_2-)-)} This arrangement arises conceptually as an oxidized derivative of imidazolidine, analogous to the condensation product of and , known historically as glycolylurea. The hydantoin ring exhibits , primarily existing in the diketo form (2,4-imidazolidinedione), where the preferred is stabilized by intramolecular hydrogen bonding between the NH groups and carbonyl oxygens. Due to conjugation between the electron-withdrawing carbonyl groups and the adjacent nitrogen atoms, the ring adopts a nearly planar conformation, resembling aromatic-like delocalization despite lacking full , with maximal atomic deviations from planarity typically below 0.03 . Derivatives of hydantoin commonly feature substitutions at the 5-position, influencing the ring's conformational stability through steric and electronic effects. For instance, 5-monosubstituted variants, such as 5-methylhydantoin, introduce asymmetry that can enhance flexibility in the , while 5,5-disubstituted examples like 5,5-dimethylhydantoin impose steric bulk at the carbon, promoting greater planarity and rigidity in the ring by minimizing torsional strain. substituents at C5, such as gem-dimethyl groups, further stabilize the planar ring geometry by reducing conformational .

Physical Properties

Hydantoin appears as a colorless to white crystalline solid. Its molar mass is 100.08 g/mol. The compound has a melting point of 220 °C, at which point it decomposes without a distinct boiling point being observed. Density is estimated at approximately 1.45 g/cm³ based on computational models. Hydantoin exhibits limited solubility in cold water but becomes more soluble in hot water, reaching 39.7 g/L at 100 °C; it is also soluble in hot ethanol and alkaline solutions. The compound demonstrates thermal stability up to its decomposition temperature but undergoes hydrolysis under acidic or basic conditions to yield glycine.

Nomenclature

Hydantoin is systematically named imidazolidine-2,4-dione under IUPAC nomenclature, reflecting its structure as a saturated five-membered ring containing two nitrogen atoms and carbonyl groups at positions 2 and 4. This name emphasizes the imidazolidine core with dione functionality, distinguishing it from unsaturated analogs like derivatives. Common synonyms include glycolylurea, which highlights its relation to and precursors, and 2,4-imidazolidinedione, an alternative phrasing used in early chemical literature. The name "hydantoin" originated from its discovery in 1861 by , who isolated the compound through the hydrogenation of during investigations into metabolism; the term combines "hyd(rogen)" from the reduction process and "(all)antoin" from the parent compound, underscoring its status as a cyclic derivative. This etymology has persisted despite the adoption of more systematic naming, as hydantoin remains the accepted for the parent scaffold in chemical and pharmaceutical contexts. Derivatives of hydantoin are named by appending prefixes to the "hydantoin" with locants to indicate positions of modification, primarily at N1, N3 (the ring nitrogens), and C5 (the methylene carbon between the carbonyls). For example, the widely used is known as 5,5-diphenylhydantoin, denoting two phenyl groups attached to C5. This convention allows precise description of substitution patterns, such as 1-methyl-3-ethylhydantoin for N-substituted variants, facilitating clear communication in synthetic and . Hydantoin is differentiated from related heterocycles like thiohydantoin, its sulfur analog with the IUPAC name 2-sulfanylideneimidazolidin-4-one (featuring a thiocarbonyl at position 2 instead of the C2 carbonyl), and selenohydantoin, where replaces the in the analogous position. These distinctions in nomenclature reflect variations in atoms while maintaining the core imidazolidinedione framework, influencing their distinct chemical reactivities and biological profiles.

Synthesis and History

Historical Development

Hydantoin was first isolated in 1861 by the German chemist during his investigations into metabolism. Baeyer obtained the compound through the of , a found in intermediates, marking the initial recognition of hydantoin as a distinct heterocyclic entity. In 1873, Friedrich Urech achieved the first targeted synthesis of a hydantoin derivative, producing 5-methylhydantoin by treating sulfate with in . This method, now known as the Urech hydantoin synthesis, represented a significant advance by demonstrating the feasibility of constructing the hydantoin ring from precursors, laying groundwork for systematic derivatization. By the early 20th century, hydantoin had been identified as the cyclic double condensate of and , commonly referred to as glycolylurea, highlighting its structural relation to simple biomolecules. During the 1930s and 1940s, research shifted toward pharmaceutical applications, with hydantoin serving as a key scaffold for anticonvulsants. Notably, (5,5-diphenylhydantoin) was introduced in 1938 by neurologists H. Houston Merritt and Tracy J. Putnam at after demonstrating its efficacy against seizures in animal models and patients, without the sedative effects of prior barbiturates; it was commercialized shortly thereafter by as Dilantin. A pivotal development occurred in 1934 when Hans T. Bucherer and Walter Steiner formalized the Bucherer–Bergs reaction, a multicomponent process involving ketones or aldehydes, , and to yield 5-substituted hydantoins efficiently. This reaction, building on an earlier 1929 patent by Bergs, enabled scalable industrial production and broadened hydantoin's utility beyond academic synthesis. Prior to 2020, hydantoin evolved from a biochemical into a of commercial chemistry, driven by its versatility in —particularly for neurological agents—and industrial processes like manufacturing, underscoring its enduring impact across pharmaceuticals, pesticides, and .

Synthetic Methods

The Urech method involves the reaction of α-amino acids with in the presence of to form 5-monosubstituted hydantoins. The process proceeds via initial formation of an N-carbamoyl amino acid intermediate, followed by acid-catalyzed cyclization and . Typical conditions include heating in aqueous media at 80–100°C for several hours, yielding 5-substituted hydantoins such as 5-methylhydantoin from . Yields generally range from 70% to 90%, depending on the amino acid substituent. The reaction can be represented as: R-CH(NH2)COOH + KNCO→HCl, heat5-monosubstituted hydantoin + KCl + H2O\text{R-CH(NH}_2\text{)COOH + KNCO} \xrightarrow{\text{HCl, heat}} \text{5-monosubstituted hydantoin + KCl + H}_2\text{O}
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