Interconversion of pyrithione tautomers thione form on the left, thiol form on the right | |
Names | |
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Preferred IUPAC name 1-Hydroxy-2(1H)-pyridinethione (thione) 2-Pyridinethiol 1-oxide (thiol) | |
Other names Omadine thione: 1-Hydroxypyridine-2-thione N-Hydroxypyridine-2-thione thiol: 2-Mercaptopyridine monoxide 2-Mercaptopyridine N-oxide 2-Mercaptopyridine 1-oxide | |
Identifiers | |
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3D model (JSmol) |
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109936 | |
ChEBI |
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ChEMBL |
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ChemSpider | |
DrugBank | |
ECHA InfoCard | 100.013.027 |
EC Number |
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913415 | |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C5H5NOS | |
Molar mass | 127.16 g·mol−1 |
Appearance | Beige crystalline powder |
Melting point | 70 to 73 °C (158 to 163 °F; 343 to 346 K) |
2.5 g L−1 at 20 °C | |
Solubility | Soluble: benzene, chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide, ethyl acetate [1] Slightly soluble: diethyl ether, ethanol, methyl tert-butyl ether, tetrahydrofuran [1] |
Acidity (pKa) | −1.95 (proton addition), 4.6 [2] [3] |
Hazards | |
GHS labelling: | |
Danger | |
H301, H315, H319, H335 | |
P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501 | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Pyrithione is the common name of an organosulfur compound with molecular formula C
5H
5NOS, chosen as an abbreviation of pyridinethione, and found in the Persian shallot. [4] It exists as a pair of tautomers, the major form being the thione 1-hydroxy-2(1H)-pyridinethione and the minor form being the thiol 2-mercaptopyridine N-oxide; it crystallises in the thione form. [5] It is usually prepared from either 2-bromopyridine, [1] 2-chloropyridine, [6] [7] or 2-chloropyridine N-oxide, [8] and is commercially available as both the neutral compound and its sodium salt. [1] It is used to prepare zinc pyrithione, [9] [10] which is used primarily to treat dandruff and seborrhoeic dermatitis in medicated shampoos, [11] [12] though is also an anti-fouling agent in paints. [13]
The preparation of pyrithione was first reported in 1950 [13] by Shaw [14] and was prepared by reaction of 2-chloropyridine N-oxide with sodium hydrosulfide followed by acidification, [8] or more recently with sodium sulfide. [15] 2-chloropyridine N-oxide itself can be prepared from 2-chloropyridine using peracetic acid. [16] Another approach involves treating the same starting N-oxide with thiourea to afford pyridyl-2-isothiouronium chloride N-oxide which undergoes base hydrolysis to pyrithione. [1] [17] 2-Bromopyridine can be oxidised to its N-oxide using a suitable peracid (as per 2-chloropyridine), both approaches being analogous to that reported in Organic Syntheses for the oxidation of pyridine to its N-oxide. [1] [18] A substitution reaction using either sodium dithionite (Na
2S
2O
4) or sodium sulfide with sodium hydroxide will allow the replacement of the bromo substituent with a thiol functional group. [1] [15]
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, [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 the N-oxide can then be undertaken.
Pyrithione is found as a natural product in the Allium stipitatum plant, an Asian species of onion, also known as the Persian shallot. [4] Its presence was detected using positive ion mass spectrometry using a DART ion source [19] and the disulfide dipyrithione (2,2'-disulfanediylbis(pyridine)-1,1'-dioxide) has been reported from the same species. [20] Dipyrithione can be prepared in a laboratory by oxidation of pyrithione with chlorine in the presence of sodium hydroxide: [16]
Dipyrithione is used as a fungicide and bactericide, [8] and has been reported to possess novel cytotoxic activity by inducing apoptosis. [21] However, as apoptosis only occurs in higher organisms, this mechanism isn't relevant to the antifungal and bacteric idal properties of pyrithione.
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). [3] [22] [23]
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 is a weak acid with pKa values of −1.95 and +4.6 (thiol proton), [2] [3] but is a markedly stronger acid than either of its parent compounds (pyridine-N-oxide and pyridine-2-thiol), both of which have pKa > 8. [22] It is only slightly soluble in water (2.5 g L−1) but is soluble in many organic solvents (including benzene, chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide, and ethyl acetate) and slight solubility in others (diethyl ether, ethanol, methyl tert-butyl ether, and tetrahydrofuran). [1]
Pyrithione can be used as a source of hydroxyl radical in organic synthesis [24] as it photochemically decomposes to HO• and (pyridin-2-yl)sulfanyl radical. [25]
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. [10] The anion can act as either a monodentate or bidentate ligand 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 [13] in which pyrithione was reacted directly with hydrated zinc sulfate in ethanol. [9] 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. [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]
Zinc pyrithione has a long history of use in medicated shampoos to treat dandruff and seborrhoeic dermatitis [28] [29] [30] (dandruff can be considered a mild form of seborrheic dermatitis [12] ). It exhibits both antifungal and antimicrobial properties, inhibiting the Malassezia yeasts which promote these scalp conditions. [27] The mechanisms by which this work are the subject of ongoing study. [31] [32] It can be used as an antibacterial agent against Staphylococcus and Streptococcus infections for conditions such as athlete's foot, eczema, psoriasis, and ringworm. [13] It is known to be cytotoxic against Pityrosporum ovale , especially in combination with ketoconazole, which is the preferred formulation for seborrheic dermatitis. [11] Pyrithione itself inhibits membrane transport processes in fungi. [22] [33]
Paints used in external environments sometimes include zinc pyrithione as a preventive against algae and mildew. [13] [34]
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one methine group (=CH−) replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a distinctive, unpleasant fish-like smell. Pyridine is colorless, but older or impure samples can appear yellow, due to the formation of extended, unsaturated polymeric chains, which show significant electrical conductivity. The pyridine ring occurs in many important compounds, including agrochemicals, pharmaceuticals, and vitamins. Historically, pyridine was produced from coal tar. As of 2016, it is synthesized on the scale of about 20,000 tons per year worldwide.
Dandruff is a skin condition that mainly affects the scalp. Symptoms include flaking and sometimes mild itchiness. It can result in social or self-esteem problems. A more severe form of the condition, which includes inflammation of the skin, is known as seborrhoeic dermatitis.
Zinc pyrithione is a coordination complex of zinc. It has fungistatic and bacteriostatic properties and is used in the treatment of seborrhoeic dermatitis and dandruff.
Keratolytic therapy is a type of medical treatment to remove warts, calluses and other lesions in which the epidermis produces excess skin. In this therapy, acidic topical medicines, such as Whitfield's ointment or Jessner's solution, are applied to the lesion in order to thin the skin on and around it. This therapy causes the outer layer of the skin to loosen and shed.
Tautomers are structural isomers of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydrogen atom within the compound. The phenomenon of tautomerization is called tautomerism, also called desmotropism. Tautomerism is for example relevant to the behavior of amino acids and nucleic acids, two of the fundamental building blocks of life.
In chemistry, an ionophore is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liquid polymeric membranes or lipid bilayers found in the living cells or synthetic vesicles (liposomes). Structurally, an ionophore contains a hydrophilic center and a hydrophobic portion that interacts with the membrane.
Organosulfur compounds are organic compounds that contain sulfur. They are often associated with foul odors, but many of the sweetest compounds known are organosulfur derivatives, e.g., saccharin. Nature abounds with organosulfur compounds—sulfur is vital for life. Of the 20 common amino acids, two are organosulfur compounds, and the antibiotics penicillin and sulfa drugs both contain sulfur. While sulfur-containing antibiotics save many lives, sulfur mustard is a deadly chemical warfare agent. Fossil fuels, coal, petroleum, and natural gas, which are derived from ancient organisms, necessarily contain organosulfur compounds, the removal of which is a major focus of oil refineries.
Cradle cap or cradle hat causes crusty or oily scaly patches on a baby's scalp. The condition is not painful or itchy, but it can cause thick white or yellow scales that are not easy to remove. Cradle cap most commonly begins sometime in the first three months but can occur in later years. Similar symptoms in older children are more likely to be dandruff than cradle cap. The rash is often prominent around the ear, the eyebrows or the eyelids. It may appear in other locations as well, where it is called infantile seborrhoeic dermatitis. Cradle cap is just a special—and more benign—case of this condition. The exact cause of cradle cap is not known. Cradle cap is not spread from person to person (contagious). It is also not caused by poor hygiene. It is not an allergy, and it is not dangerous. Cradle cap often lasts a few months. In some children, the condition can last until age 2 or 3.
Aromatization is a chemical reaction in which an aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cyclohexane into benzene. Aromatization includes the formation of heterocyclic systems.
Selenium disulfide, also known as selenium sulfide, is a chemical compound and medication used to treat seborrheic dermatitis, dandruff, and pityriasis versicolor. It is applied to the affected area as a lotion or shampoo. Symptoms frequently return if treatment is stopped.
Sodium dithionite is a white crystalline powder with a sulfurous odor. Although it is stable in dry air, it decomposes in hot water and in acid solutions.
2-Pyridone is an organic compound with the formula C
5H
4NH(O). It is a colourless solid. It is well known to form hydrogen bonded dimers and it is also a classic case of a compound that exists as tautomers.
Pyridine-N-oxide is the heterocyclic compound with the formula C5H5NO. This colourless, hygroscopic solid is the product of the oxidation of pyridine. It was originally prepared using peroxyacids as the oxidising agent. The compound is used infrequently as an oxidizing reagent in organic synthesis.
Zinc compounds are chemical compounds containing the element zinc which is a member of the group 12 of the periodic table. The oxidation state of zinc in most compounds is the group oxidation state of +2. Zinc may be classified as a post-transition main group element with zinc(II). Zinc compounds are noteworthy for their nondescript behavior, they are generally colorless, do not readily engage in redox reactions, and generally adopt symmetrical structures.
2-Mercaptopyridine is an organosulfur compound with the formula HSC5H4N. This yellow crystalline solid is a derivative of pyridine. The compound and its derivatives serve primarily as acylating agents. A few of 2-mercaptopyridine’s other uses include serving as a protecting group for amines and imides as well as forming a selective reducing agent. 2-Mercaptopyridine oxidizes to 2,2’-dipyridyl disulfide.
In organic chemistry, thiocarboxylic acids are organosulfur compounds related to carboxylic acids by replacement of one of the oxygen atoms with a sulfur atom. Two tautomers are possible: a thione form and a thiol form. These are sometimes also referred to as "carbothioic O-acid" and "carbothioic S-acid" respectively. Of these the thiol form is most common.
Allium stipitatum, Persian shallot, is an Asian species of onion native to central and southwestern Asia.
Anti-seborrheics are drugs effective in seborrheic dermatitis. Selenium sulfide, zinc pyrithione, corticosteroids, imidazole antifungals, and salicylic acid are common anti-seborrheics.
2-Mercaptobenzothiazole is an organosulfur compound with the formula C6H4(NH)SC=S. A white solid, it is used in the sulfur vulcanization of rubber.
2-Bromopyridine is an organic compound with the formula BrC5H4N. It is a colorless liquid that is used as an intermediate in organic synthesis. It can be prepared from 2-aminopyridine via diazotization followed by bromination.