The alternative strategy is to form the mercaptan before introducing the N-oxide moiety. 2-Mercaptopyridine was originally synthesized in 1931 by heating 2-chloropyridine with calcium hydrosulfide, an approach similar that first used to prepare pyrithione. The analogous thiourea approach via a uronium salt was reported in 1958 and provides a more convenient route to 2-mercaptopyridine. Oxidation to the N-oxide can then be undertaken.
The disulfide dipyrithione, 2,2'-dithiobis(pyridine-N-oxide)
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 of tautomerism whereby the rapid interconversion of constitutional isomers involves the shift of a single proton, in this case between the sulfur and oxygen atoms (shown in the infobox above).
Salts of the conjugate 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 the formal charges associated with the N-oxide); however, considering the anion alone, this could also be described as an example of resonance.
Pyrithione can be used as a source of hydroxyl radical in organic synthesis as it photochemically decomposes to HO• and (pyridin-2-yl)sulfanyl radical.
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
The conjugate base of pyrithione (pyrithionate ion) is an anion containing two donor atoms, a sulfur atom and an oxygen atom each bearing a negative formal charge; the nitrogen atom remains formally positively charged. The thiolate anion can be formed by reaction with sodium carbonate, and zinc pyrithione is formed when zinc chloride is added. The anion can act as either a monodentate or bidentateligand and forms a 1:2 complex 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 in which pyrithione was reacted directly with hydrated zinc sulfate in ethanol. In its monomeric form, zinc pyrithione has two of the anions chelated to a zinc centre with a tetrahedral geometry. In the solid state, it forms a dimer in which each zinc centre adopts a trigonal bipyramidal geometry with two of the anions acting as bridging ligands coordinated through the oxygen atoms in the axial positions. 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.
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