The alternative strategy is to form the mercaptan before introducing theN-oxidemoiety. 2-Mercaptopyridine was originally synthesized in 1931 by heating 2-chloropyridine withcalcium hydrosulfide,[6] an approach similar that first used to prepare pyrithione.[8] The analogous thiourea approach via a uronium salt was reported in 1958 and provides a more convenient route to 2-mercaptopyridine.[7] Oxidation to theN-oxide can then be undertaken.
Dipyrithione is used as afungicide andbactericide,[8] and has been reported to possess novelcytotoxic activity by inducingapoptosis.[21] However, as apoptosis only occurs in higher organisms, this mechanism isn't relevant to the antifungal and bactericidal properties of pyrithione.
Tautomerisation of the sodium salt of pyrithione (thione form on the left, thiolate form on the right)
Pyrithione exists as a pair of prototropes, a form oftautomerism whereby the rapid interconversion ofconstitutional isomers involves the shift of a single proton, in this case between the sulfur and oxygen atoms (shown in the infobox above).[3][22][23]
Salts of theconjugate base of pyrithione can also be considered to exhibit tautomerism by notionally associating the sodium ion with whichever heteroatom bears the negative charge of the anion (as opposed to theformal charges associated with theN-oxide); however, considering the anion alone, this could also be described as an example ofresonance.
Pyrithione can be used as a source ofhydroxyl radical in organic synthesis[24] as it photochemically decomposes to HO• and (pyridin-2-yl)sulfanyl radical.[25]
Structures of 1:2 complexes of zinc and the conjugate base of pyrithione Top: Structural formula of the monomer Bottom:Ball-and-stick model of the dimer
Theconjugate base of pyrithione (pyrithionate ion) is ananion containing twodonor atoms, a sulfur atom and an oxygen atom each bearing a negativeformal charge; the nitrogen atom remains formally positively charged. The thiolate anion can be formed by reaction with sodium carbonate, andzinc pyrithione is formed whenzinc chloride is added.[10] The anion can act as either amonodentate or bidentateligand and forms a 1:2complex with a zinc(II) metal centre. Zinc pyrithione has been used since the 1930s though its preparation was not disclosed until a 1955 British patent[13] in which pyrithione was reacted directly with hydratedzinc sulfate in ethanol.[9] In itsmonomeric form, zinc pyrithione has two of the anionschelated to a zinc centre with atetrahedral geometry. In the solid state, it forms adimer in which each zinc centre adopts atrigonal bipyramidal geometry with two of the anions acting asbridging ligands coordinated through the oxygen atoms in the axial positions.[26] In solution, the dimers dissociate via scission of zinc-oxygen bonds to each bridging ligand. Further dissociation of the monomer into its constituents can occur and is undesirable as the complex is more potent in medical applications; for this reason,zinc carbonate can be added to formulations as it inhibits the monomer dissociation.[27]
^abUS granted 2809971, Bernstein, Jack & Losee, Kathryn A., "Heavy-metal derivatives of 1-hydroxy-2-pyridinethiones and method of preparing same", published 1957-10-15, assigned toOlin MathiesonArchived 2016-12-24 at theWayback Machine
^abUS granted 4396766, Farmer, David A. & Katz, Lawrence E., "Process for producing sodium and zinc pyrithione", published 1983-08-02, assigned toOlin Corporation[1]
^abChernoff, Karen; Lin, Richie; Cohen, Steven R. (2014)."Seborrheic Dermatitis". In Rudikoff, Donald; Cohen, Steven R.; Scheinfeld, Noah (eds.).Atopic Dermatitis and Eczematous Disorders.CRC Press. pp. 275–288.ISBN9781840766530.Archived from the original on 2024-02-24. Retrieved2024-02-24.
^Shaw, Elliott; Bernstein, Jack; Losee, Kathryn; Lott, W. A. (1950). "Analogs of Aspergillic Acid. IV. Substituted 2-Bromopyridine-N-oxides and Their Conversion to Cyclic Thiohydroxamic Acids".J. Am. Chem. Soc.72 (10):4362–4364.Bibcode:1950JAChS..72.4362S.doi:10.1021/ja01166a008.
^abCheng, Hefeng; She, Ji (1990). "14. Improved preparation of 2-mercaptopyridine-N-oxide".Zhongguo Yiyao Gongye Zazhi.21 (2):55–56.
^Block, Eric; Dane, A. John; Cody, Robert B. (2011). "Crushing Garlic and Slicing Onions: Detection of Sulfenic Acids and Other Reactive Organosulfur Intermediates from Garlic and Other Alliums using Direct Analysis in Real-Time Mass Spectrometry (DART-MS)".Phosphorus Sulfur.186 (5):1085–1093.doi:10.1080/10426507.2010.507728.S2CID98520689.
^Smith, Michael B. (2013).March's Advanced Organic Chemistry (7th ed.). Wiley. p. 246.ISBN978-0-470-46259-1.
^DeMatteo, Matthew P.; Poole, James S.; Shi, Xiaofeng; Sachdeva, Rakesh; Hatcher, Patrick G.; Hadad, Christopher M.; Platz, Matthew S. (2005). "On the Electrophilicity of Hydroxyl Radical: A Laser Flash Photolysis and Computational Study".Journal of the American Chemical Society.127 (19):7094–7109.Bibcode:2005JAChS.127.7094D.doi:10.1021/ja043692q.ISSN0002-7863.PMID15884952.
^Barnett, B. L.; Kretschmar, H. C.; Hartman, F. A. (1977). "Structural characterization of bis(N-oxopyridine-2-thionato)zinc(II)".Inorg. Chem.16 (8):1834–1838.doi:10.1021/ic50174a002.
^Bacon, Robert A.; Mizoguchi, Haruko; Schwartz, James R. (2014). "Assessing therapeutic effectiveness of scalp treatments for dandruff and seborrheic dermatitis, part 1: A reliable and relevant method based on the adherent scalp flaking score (ASFS)".J. Dermatolog. Treat.25 (3):232–236.doi:10.3109/09546634.2012.687089.PMID22515728.S2CID30707098.
