Hydantoin#Methylation

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.

:File:Harnsäureabbau.svg

{{clear left}}

Friedrich Urech synthesized 5-methylhydantoin in 1873 from alanine sulfate and potassium cyanate in what is now known as the Urech hydantoin synthesis.{{cite journal|first = Friedrich|last = Urech|journal = Liebigs Ann.|title = Ueber Lacturaminsäure und Lactylharnstoff|language = de|volume = 165|issue = 1|pages = 99–103|year = 1873|doi = 10.1002/jlac.18731650110|url = https://zenodo.org/record/1427313}} 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.{{OrgSynth|collvol = 3|collvolpages = 323|volume = 20|pages = 42|year = 1940|prep = CV3P0323|doi = 10.15227/orgsyn.020.0042|title = 5,5-Dimethylhydantoin|first1 = E. C.|last1 = Wagner|first2 = Manuel|last2 = Baizer}} This reaction type is called the Bucherer–Bergs reaction.{{cite journal|last1 = Bucherer|first1 = H. T.|author-link1 = Hans Theodor Bucherer|last2 = Steiner|first2 = W.|language = de|title = J. Prakt. Chem.|volume = 140|page = 291|year = 1934}}Bergs, Ger. pat. 566,094 (1929) [C. A., 27, 1001 (1933)].

Hydantoin can also be synthesized either by heating allantoin with hydroiodic acid or by "heating bromacetyl urea with alcoholic ammonia".{{cite EB1911 |wstitle=Hydantoin |volume=14 |pages=29–30}} The cyclic structure of hydantoins was confirmed by Dorothy Hahn 1913.{{cite encyclopedia| title = Encyclopedia of World Scientists|last = Oakes|first = Elizabeth H.|publisher = Facts on File|year = 2007|isbn = 9780816061587|pages = 298}}

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:{{cite journal|last1 = Blanco-Ania|first1 = Daniel|last2 = Hermkens|first2 = Pedro H. H.|last3 = Sliedregt|first3 = Leo A. J. M.|last4 = Scheeren|first4 = Hans W.|last5 = Rutjes|first5 = Floris P. J. T.|title = Synthesis of Hydantoins and Thiohydantoins Spiro-Fused to Pyrrolidines: Druglike Molecules Based on the 2-Arylethyl Amine Scaffold|journal = Journal of Combinatorial Chemistry|year = 2009|volume = 11| issue=4 |pages = 527–538|doi = 10.1021/cc800190z| pmid=19472985 | url=https://repository.ubn.ru.nl//bitstream/handle/2066/75771/75771.pdf }}

:420px

The hydantoin group can be found in several medicinally important compounds. In pharmaceuticals, hydantoin derivatives form a class of anticonvulsants;{{cite web | url = https://www.drugs.com/drug-class/hydantoin-anticonvulsants.html | title = Hydantoin anticonvulsants | publisher = drugs.com}} 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.

The hydantoin derivative Imiprothrin is a pyrethroid insecticide. Iprodione is a popular fungicide containing the hydantoin group.{{cite encyclopedia|encyclopedia = Ullmann's Encyclopedia of Industrial Chemistry|doi = 10.1002/14356007.a02_057.pub2|first1 = Karlheinz|last1 = Drauz|first2 = Ian|last2 = Grayson|first3 = Axel|last3 = Kleemann|first4 = Hans-Peter|last4 = Krimmer|first5 = Wolfgang|last5 = Leuchtenberger|first6 = Christoph|last6 = Weckbecker|year = 2007|isbn = 978-3527306732|chapter = Amino Acids}}

Hydrolysis of hydantoins affords amino acids:

:{{chem2 | 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.

Methylation of hydantoin yields a variety of derivatives. Dimethylhydantoin (DMH) {{Cite web | url=https://www.tappi.org/21969/ | title=5,5-Dimethylhydantoin (DMH) a Highly Effective, Halogen Stabilizer for Wet End Applications, PaperCo}} may refer to any dimethyl derivative of hydantoin, but especially 5,5-dimethylhydantoin.{{Cite web | url=https://pubchem.ncbi.nlm.nih.gov/compound/5_5-dimethylhydantoin | title=5,5-Dimethylhydantoin}}

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.

Image:Iprodione.png is a popular fungicide containing the hydantoin group.]]

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.{{cite journal|last1 = Hofreiter|first1 = Michael|last2 = Serre|first2 = David|last3 = Poinar|first3 = Hendrik N.|last4 = Kuch|first4 = Melanie|last5 = Pääbo|first5 = Svante|title = Ancient DNA|journal = Nature Reviews Genetics|year = 2001|volume = 2|issue = 5|pages = 353–359|doi = 10.1038/35072071|pmid = 11331901|s2cid = 205016024}}

{{wiktionary|dimethylhydantoin}}

• {{cite journal|title = The Chemistry of the Hydantoins|first = Elinor|last = Ware|journal = Chem. Rev.|year = 1950|volume = 46|issue = 3|pages = 403–470|doi = 10.1021/cr60145a001|pmid = 24537833}}
• [http://www.mjlphd.net/translations.html] {{Webarchive|url=https://web.archive.org/web/20201018004942/https://www.mjlphd.net/translations.html |date=2020-10-18 }} English Translation of 1926 German review article on the Preparation of hydantoins by Heinrich Biltz and Karl Slotta

{{reflist}}

{{Anticonvulsants}}

Category:Substances discovered in the 19th century