Thiazole, or 1,3-thiazole, is a
heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a
pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...
-like odor and the molecular formula C
3H
3NS. The thiazole ring is notable as a component of the
vitamin
A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
thiamine
Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...
(B
1).
Molecular and electronic structure
Thiazoles are members of the
azole
Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom (i.e. nitrogen, sulfur, or oxygen) as part of the ring.
Their names originate from the Hantzsch–Widman nomenclature. T ...
s, heterocycles that include imidazoles and oxazoles. Thiazole can also be considered a
functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...
.
Oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a weak ...
s are related compounds, with sulfur replaced by oxygen. Thiazoles are structurally similar to
imidazole
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-a ...
s, with the thiazole sulfur replaced by nitrogen.
Thiazole rings are planar and
aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
. Thiazoles are characterized by larger pi-electron
delocalization
In chemistry, delocalized electrons are electrons in a molecule, ion or solid metal that are not associated with a single atom or a covalent bond.IUPAC Gold Boo''delocalization''/ref>
The term delocalization is general and can have slightly dif ...
than the corresponding
oxazole
Oxazole is the parent compound for a vast class of heterocyclic aromatic organic compounds. These are azoles with an oxygen and a nitrogen separated by one carbon. Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a weak ...
s and have therefore greater
aromaticity
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
. This aromaticity is evidenced by the chemical shift of the ring protons in
proton NMR
Proton nuclear magnetic resonance (proton NMR, hydrogen-1 NMR, or 1H NMR) is the application of nuclear magnetic resonance in NMR spectroscopy with respect to hydrogen-1 nuclei within the molecules of a substance, in order to determine the struct ...
spectroscopy (between 7.27 and 8.77 ppm), clearly indicating a strong
diamagnetic ring current
An aromatic ring current is an effect observed in aromatic molecules such as benzene and naphthalene. If a magnetic field is directed perpendicular to the plane of the aromatic system, a ring current is induced in the delocalized π electrons ...
. The calculated pi-electron density marks C5 as the primary site for electrophilic substitution, and C2 as the site for nucleophilic substitution.
:
Occurrence of thiazoles and thiazolium salts
Thiazoles are found in a variety of specialized products, often fused with benzene derivatives, the so-called benzothiazoles. In addition to vitamin B
1, the thiazole ring is found in
epothilone
Epothilones are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.
, epothilones A t ...
. Other important thiazole derivatives are
benzothiazole
Benzothiazole is an aromatic heterocyclic compound with the chemical formula . It is colorless, slightly viscous liquid. Although the parent compound, benzothiazole is not widely used, many of its derivatives are found in commercial products or ...
s, for example, the firefly chemical
luciferin
Luciferin (from the Latin ''lucifer'', "light-bearer") is a generic term for the light-emitting compound found in organisms that generate bioluminescence. Luciferins typically undergo an enzyme-catalyzed reaction with molecular oxygen. The resul ...
. Whereas thiazoles are well represented in
biomolecules, oxazoles are not. It is found in naturally occurring peptides, and utilised in the development of peptidomimetics (i.e. molecules that mimic the function and structure of peptides).
Commercial significant thiazoles include mainly dyes and
fungicides. Thifluzamide, Tricyclazole, and
Thiabendazole
Tiabendazole (INN, BAN), also known as thiabendazole (AAN, USAN) or TBZ and the trade names Mintezol, Tresaderm, and Arbotect, is a preservative, an antifungal agent, and an antiparasitic agent.
Uses
Preservative
Tiabendazole is used primar ...
are marketed for control of various agricultural pests. Another widely used thiazole derivative is the non-steroidal anti-inflammatory drug
Meloxicam
Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory medication (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is used by mouth or by injection into a vein. It i ...
. The following
anthroquinone
Anthraquinone, also called anthracenedione or dioxoanthracene, is an aromatic organic compound with formula . Isomers include various quinone derivatives. The term anthraquinone however refers to the isomer, 9,10-anthraquinone (IUPAC: 9,10-dioxoan ...
dyes contain benzothiazole subunits: Algol Yellow 8 (CAS#
451-12-3, Algol Yellow GC (CAS#
29-09-9, Indanthren Rubine B (CAS#
371-49-9, Indanthren Blue CLG (CAS#
371-50-2 and Indanthren Blue CLB (CAS#
492-78-0. These thiazole dye are used for dyeing
cotton
Cotton is a soft, fluffy staple fiber that grows in a boll, or protective case, around the seeds of the cotton plants of the genus '' Gossypium'' in the mallow family Malvaceae. The fiber is almost pure cellulose, and can contain minor pe ...
.
Organic synthesis
Various laboratory methods exist for the
organic synthesis of thiazoles. Prominent is the Hantzsch thiazole synthesis is a reaction between
haloketone
In organic chemistry, an α-haloketone is a functional group consisting of a ketone group or more generally a carbonyl group with an α-halogen substituent. α-haloketones are alkylating agents. Prominent α-haloketones include phenacyl bromide ...
s and
thioamide
A thioamide (rarely, thionamide, but also known as thiourylenes) is a functional group with the general structure R–CS–NR′R″, where R, R′, and R″ are organic groups. They are analogous to amides but they exhibit greater multiple bond ch ...
s. For example, 2,4-dimethylthiazole is synthesized from
thioacetamide
Thioacetamide is an organosulfur compound with the formula C2 H5 N S. This white crystalline solid is soluble in water and serves as a source of sulfide ions in the synthesis of organic and inorganic compounds. It is a prototypical thioamide.
...
and
chloroacetone
Chloroacetone is a chemical compound with the chemical formula, formula . At Standard conditions for temperature and pressure, STP it is a colourless liquid with a pungent odour. On exposure to light, it turns to a dark yellow-amber colour. It wa ...
. Another example
is given below:
:
* In an adaptation of the
Robinson-Gabriel synthesis, a 2-acylamino-ketones reacts with
phosphorus pentasulfide
Phosphorus pentasulfide is the inorganic compound with the formula (monomer) or (dimer). This yellow solid is the one of two phosphorus sulfides of commercial value. Samples often appear greenish-gray due to impurities. It is soluble in carbon d ...
.
* In the
Cook-Heilbron synthesis, an α-aminonitrile reacts with
carbon disulfide
Carbon disulfide (also spelled as carbon disulphide) is a neurotoxic, colorless, volatile liquid with the formula and structure . The compound is used frequently as a building block in organic chemistry as well as an industrial and chemical n ...
.
* Certain thiazoles can be accessed through application of the
Herz reaction The Herz reaction, named after the chemist Richard Herz, is the chemical conversion of an aniline-derivative (1) to a so-called Herz salt (2) with disulfur dichloride, followed by hydrolysis of this Herz salt (2) to the corresponding sodium thiolat ...
.
Biosynthesis
Thiazoles are generally formed via reactions of
cysteine, which provides the N-C-C-S backbone of the ring. Thiamine does not fit this pattern however. Several biosynthesis routes lead to the thiazole ring as required for the formation of thiamine. Sulfur of the thiazole is derived from cysteine. In anaerobic bacteria, the CN group is derived from dehydroglycine.
Reactions
With a pK
a of 2.5 for the conjugate acid, thiazoles are far less basic than
imidazole
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non-a ...
(pK
a =7).
[Thomas L. Gilchrist "Heterocyclic Chemistry" 3rd ed. Addison Wesley: Essex, England,
1997. 414 pp. .]
Deprotonation
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...
at C2: the negative charge on this position is stabilized as an
ylide An ylide or ylid () is a neutral dipolar molecule containing a formally negatively charged atom (usually a carbanion) directly attached to a heteroatom with a formal positive charge (usually nitrogen, phosphorus or sulfur), and in which both atoms ...
;
Hauser bases and
organolithium compounds react at this site, replacing the proton
: 2-(trimethylsiliyl)thiazole
(with a
trimethylsilyl
A trimethylsilyl group (abbreviated TMS) is a functional group in organic chemistry. This group consists of three methyl groups bonded to a silicon atom minus;Si(CH3)3 which is in turn bonded to the rest of a molecule. This structural group is ch ...
group in the 2-position) is a stable substitute and reacts with a range of electrophiles such as
aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
s,
acyl halide
In organic chemistry, an acyl halide (also known as an acid halide) is a chemical compound derived from an oxoacid by replacing a hydroxyl group () with a halide group (, where X is a halogen).
If the acid is a carboxylic acid (), the compoun ...
s, and
ketene
In organic chemistry, a ketene is an organic compound of the form , where R and R' are two arbitrary monovalent chemical groups (or two separate substitution sites in the same molecule). The name may also refer to the specific compound ethen ...
s
*
Electrophilic aromatic substitution
Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic n ...
at C5 requires
activating group In electrophilic aromatic substitution reactions, existing substituent groups on the aromatic ring influence the overall reaction rate or have a directing effect on positional isomer of the products that are formed. An electron donating group (ED ...
s such as a
methyl group in this
bromination
In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polyme ...
:
:
*
Nucleophilic aromatic substitution
A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compou ...
often requires a leaving group such as
chlorine
Chlorine is a chemical element with the symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine i ...
at C2 with
:
* Organic
oxidation at nitrogen
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
gives the aromatic thiazole
''N''-oxide; many oxidizing agents exist, such as
mCPBA; a novel one is
hypofluorous acid
Hypofluorous acid, chemical formula H O F, is the only known oxyacid of fluorine and the only known oxoacid in which the main atom gains electrons from oxygen to create a negative oxidation state. The oxidation state of the oxygen in hypofluorite ...
prepared from
fluorine and water in
acetonitrile; some of the oxidation takes place at sulfur, leading to non-aromatic
sulfoxide/
sulfone
In organic chemistry, a sulfone is a organosulfur compound containing a sulfonyl () functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of ...
:
:
* Thiazoles are
formyl synthon
In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1 ...
s; conversion of R-thia to the R-CHO aldehyde takes place with,
respectively,
methyl iodide (''N''-methylation),
organic reduction
Organic reductions or organic oxidations or organic redox reactions are redox reactions that take place with organic compounds. In organic chemistry oxidations and reductions are different from ordinary redox reactions, because many reactions car ...
with
sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds applica ...
, and
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolys ...
with
Mercury(II) chloride
Mercury(II) chloride (or mercury bichloride, mercury dichloride), historically also known as sulema or corrosive sublimate, is the inorganic chemical compound of mercury and chlorine with the formula HgCl2. It is white crystalline solid and is ...
in water.
* Thiazoles can react in
cycloaddition
In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity". T ...
s, but in general at high temperatures due to favorable aromatic stabilization of the reactant;
Diels-Alder reactions with
alkynes are followed by extrusion of sulfur, and the endproduct is a
pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...
; in one study,
[ a very mild reaction of a ''2-(dimethylamino)thiazole'' with ''dimethyl acetylenedicarboxylate'' (DMAD) to a pyridine was found to proceed through a ]zwitterion
In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups.
: With amino acids, for example, in solution a chemical equilibrium wil ...
ic intermediate in a formal +2ycloaddition to a cyclobutene, then to a ''1,3-thiazepine'' in a 4-electron electrocyclic ring openening and then to a ''7-thia-2-azanorcaradiene'' in a 6-electron electrocyclic ring, closing before extruding the sulfur atom.
:
Thiazolium salts
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...
of thiazoles at nitrogen forms a thiazolium cation. Thiazolium salts are catalysts in the Stetter reaction and the Benzoin condensation
The benzoin addition is an addition reaction involving two aldehydes. The reaction generally occurs between aromatic aldehydes or glyoxals, and results in formation of an acyloin
Acyloins or α-hydroxy ketones are a class of organic compounds w ...
. Deprotonation of ''N''-alkyl thiazolium salts give the free carbenes and transition metal carbene complex
A transition metal carbene complex is an organometallic compound featuring a divalent organic ligand. The divalent organic ligand coordinated to the metal center is called a carbene. Carbene complexes for almost all transition metals have been r ...
es.
:
Alagebrium is a thiazolium-based drug.
References
{{Authority control
Aromatic bases
Simple aromatic rings