Thiazole (), or 1,3-thiazole, is a 5-membered 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-like odor and the molecular formula C3H3NS.
Molecular and electronic structure
Thiazoles are members of the
, heterocycles that include
Imidazole and
Oxazole. Thiazole can also be considered a
functional group when part of a larger molecule.
Being planar, thiazoles are characterized by significant pi-electron delocalization and exhibit a degree of aromaticity greater than that of corresponding . This aromaticity is evidenced by the proton NMR chemical shift of the ring protons, which display resonances between 7.27 and 8.77 ppm, indicating a strong diamagnetic ring current. The calculated pi-electron density marks C5 as the primary site for electrophilic substitution, and C2-H as susceptible to deprotonation.
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. Other important thiazole derivatives are
, for example, the firefly chemical
luciferin. Whereas thiazoles are well represented in
, 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 . Thifluzamide, Tricyclazole, and Thiabendazole are marketed for control of various agricultural pests. Another widely used thiazole derivative is the non-steroidal anti-inflammatory drug Meloxicam. The following anthroquinone dyes contain benzothiazole subunits: Algol Yellow 8 (CAS# 6451-12-3), Algol Yellow GC (CAS# 129-09-9), Indanthren Rubine B (CAS# 6371-49-9), Indanthren Blue CLG (CAS# 6371-50-2, and Indanthren Blue CLB (CAS#6492-78-0). These thiazole dye are used for dyeing cotton.
Synthesis
Various laboratory methods exist for the organic synthesis of thiazoles. Prominent is the Hantzsch thiazole synthesis, which is a reaction between
and
. For example, 2,4-dimethylthiazole is synthesized from
thioacetamide and
chloroacetone.
In the Cook-Heilbron synthesis, thiazoles arise by the condensation of α-aminonitrile with
carbon disulfide. Thiazoles can be accessed by acylation of 2-aminothiolates, often available by the
Herz reaction.
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 (pK
a =7).
Deprotonation with strong bases occurs at C2-H. The negative charge on this position is stabilized as an ylide. and organolithium compounds react at this site, replacing the proton. 2-Lithiothiazoles are also generated by metal-halogen exchange from 2-bromothiazole.
Electrophilic aromatic substitution at C5 but require such as a methyl group, as illustrated in bromination:
Nitrogen oxidation gives the aromatic thiazole N-oxide; many oxidizing agents exist, such as mCPBA; a novel one is hypofluorous acid prepared from fluorine and water in acetonitrile; some of the oxidation takes place at sulfur, leading to non-aromatic sulfoxide/sulfone:
-
Thiazoles are formyl ; conversion of R-thia to the R-CHO aldehyde takes place with,
-
Thiazoles can react in , but in general at high temperatures due to favorable aromatic stabilization of the reactant; Diels-Alder reactions with are followed by extrusion of sulfur, and the endproduct is a pyridine; in one study,
Thiazolium salts
Alkylation of thiazoles at nitrogen forms a
thiazolium cation. Thiazolium salts are catalysts in the
Stetter reaction and the Benzoin condensation. Deprotonation of
N-alkyl thiazolium salts give the
and transition metal carbene complexes.
Alagebrium is a thiazolium-based drug.
