Hydantoin
Hydantoin, also known as imidazolidine-2,4-dione, is a five-membered heterocyclic organic compound with the molecular formula C₃H₄N₂O₂ and a molecular weight of 100.08 g/mol.[1] It features a non-aromatic ring consisting of two nitrogen atoms and two carbonyl groups at positions 2 and 4, making it a cyclic urea derivative that serves as a privileged scaffold in medicinal chemistry due to its five potential substitution sites and ability to form hydrogen bonds.[2][1] Physically, hydantoin appears as a white to light yellow fine powder with a melting point of 218–220 °C and an estimated boiling point of 187.47 °C; it has a density of approximately 1.4457 g/cm³ and a vapor pressure of 0 Pa at 25 °C.[1] The compound exhibits slight solubility in water but is more soluble in alcohols and alkali hydroxides, with limited solubility in ether.[1] Chemically stable under standard conditions, hydantoin is often synthesized via the reaction of urea with glycolic acid or through cyclization of aminoacetamide derivatives.[1] In pharmaceutical applications, hydantoin and its derivatives are renowned for their broad spectrum of biological activities, including anticonvulsant, anti-inflammatory, anticancer, antidiabetic, antimicrobial, and anti-HIV effects.[2] Notable examples include phenytoin and mephenytoin, which are used as anticonvulsants for treating epilepsy; nilutamide and enzalutamide, androgen receptor antagonists for prostate cancer therapy; and nitrofurantoin, an antibacterial agent for urinary tract infections.[2] Beyond medicine, hydantoin derivatives find use in cosmetics as preservatives, such as DMDM hydantoin, and in synthetic chemistry as intermediates for diverse compounds.[1]Structure and Properties
Molecular Structure
Hydantoin is a heterocyclic organic compound with the molecular formula C₃H₄N₂O₂ and the systematic IUPAC name imidazolidine-2,4-dione.[3] It features a five-membered ring composed of two nitrogen atoms at positions 1 and 3, two carbonyl groups at positions 2 and 4, and a methylene group (-CH₂-) at position 5, forming a cyclic imide structure.[4] The core ring can be represented in structural formula as: \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 glycolic acid and urea, known historically as glycolylurea.[5] The hydantoin ring exhibits tautomerism, primarily existing in the diketo form (2,4-imidazolidinedione), where the preferred tautomer is stabilized by intramolecular hydrogen bonding between the NH groups and carbonyl oxygens.[6] 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 aromaticity, with maximal atomic deviations from planarity typically below 0.03 Å.[7] 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 methylene group, while 5,5-disubstituted examples like 5,5-dimethylhydantoin impose steric bulk at the quaternary carbon, promoting greater planarity and rigidity in the ring by minimizing torsional strain.[7] Quaternary substituents at C5, such as gem-dimethyl groups, further stabilize the planar ring geometry by reducing conformational entropy.[8]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.[3] This name emphasizes the imidazolidine core with dione functionality, distinguishing it from unsaturated analogs like imidazole derivatives. Common synonyms include glycolylurea, which highlights its relation to urea and glycolic acid precursors, and 2,4-imidazolidinedione, an alternative phrasing used in early chemical literature.[3] The name "hydantoin" originated from its discovery in 1861 by Adolf von Baeyer, who isolated the compound through the hydrogenation of allantoin during investigations into uric acid metabolism; the term combines "hyd(rogen)" from the reduction process and "(all)antoin" from the parent compound, underscoring its status as a cyclic urea derivative. This etymology has persisted despite the adoption of more systematic naming, as hydantoin remains the accepted trivial name for the parent scaffold in chemical and pharmaceutical contexts.[9] Derivatives of hydantoin are named by appending substituent prefixes to the parent "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 anticonvulsant phenytoin is known as 5,5-diphenylhydantoin, denoting two phenyl groups attached to C5.[10] This convention allows precise description of substitution patterns, such as 1-methyl-3-ethylhydantoin for N-substituted variants, facilitating clear communication in synthetic and medicinal chemistry.[11] 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 selenium replaces the sulfur in the analogous position.[12][13] These distinctions in nomenclature reflect variations in chalcogen atoms while maintaining the core imidazolidinedione framework, influencing their distinct chemical reactivities and biological profiles.[14]Synthesis and History
Historical Development
Hydantoin was first isolated in 1861 by the German chemist Adolf von Baeyer during his investigations into uric acid metabolism. Baeyer obtained the compound through the hydrogenation of allantoin, a natural product found in urea cycle 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 alanine sulfate with potassium cyanate in aqueous solution. This method, now known as the Urech hydantoin synthesis, represented a significant advance by demonstrating the feasibility of constructing the hydantoin ring from amino acid precursors, laying groundwork for systematic derivatization. By the early 20th century, hydantoin had been identified as the cyclic double condensate of urea and glycolic acid, 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, phenytoin (5,5-diphenylhydantoin) was introduced in 1938 by neurologists H. Houston Merritt and Tracy J. Putnam at Boston City Hospital after demonstrating its efficacy against seizures in animal models and patients, without the sedative effects of prior barbiturates; it was commercialized shortly thereafter by Parke-Davis as Dilantin.[15] 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, potassium cyanide, and ammonium carbonate 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 curiosity into a cornerstone of commercial chemistry, driven by its versatility in drug design—particularly for neurological agents—and industrial processes like amino acid manufacturing, underscoring its enduring impact across pharmaceuticals, pesticides, and materials science.[16]Synthetic Methods
The Urech method involves the reaction of α-amino acids with potassium cyanate in the presence of hydrochloric acid to form 5-monosubstituted hydantoins. The process proceeds via initial formation of an N-carbamoyl amino acid intermediate, followed by acid-catalyzed cyclization and dehydration. Typical conditions include heating in aqueous media at 80–100°C for several hours, yielding 5-substituted hydantoins such as 5-methylhydantoin from alanine. Yields generally range from 70% to 90%, depending on the amino acid substituent. The reaction can be represented as: \text{R-CH(NH}_2\text{)COOH + KNCO} \xrightarrow{\text{HCl, heat}} \text{5-monosubstituted hydantoin + KCl + H}_2\text{O} This method is valued for its simplicity and use of readily available starting materials derived from natural amino acids. The Bucherer–Bergs reaction is a multicomponent process that converts aldehydes or ketones, potassium cyanide, and ammonium carbonate into 5,5-disubstituted hydantoins. The mechanism begins with nucleophilic addition of cyanide to the carbonyl compound, forming a cyanohydrin intermediate. This undergoes ammonolysis to yield an α-amino amide, which then reacts with carbon dioxide (from ammonium carbonate decomposition) to form a carbamic acid derivative, followed by cyclization and dehydration to the hydantoin ring. The reaction is typically conducted in aqueous ethanol or water at 60–100°C for 4–24 hours, often under reflux. Representative examples include the synthesis of 5,5-diphenylhydantoin from benzophenone, with overall yields of 70–90% under optimized conditions.[17] A simplified scheme is:- \text{R}_2\text{C=O + CN}^- \rightarrow \text{R}_2\text{C(OH)CN (cyanohydrin)}
- \text{R}_2\text{C(OH)CN + NH}_3 \rightarrow \text{R}_2\text{C(NH}_2\text{)CONH}_2
- \text{R}_2\text{C(NH}_2\text{)CONH}_2 + \text{CO}_2/\text{NH}_3 \rightarrow \text{cyclization to hydantoin}