Hubbry Logo
ThiazoleThiazoleMain
Open search
Thiazole
Community hub
Thiazole
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Thiazole
Thiazole
Thiazole
View on Wikipedia
from Wikipedia
Thiazole
Full structural formula
Skeletal formula with numbers
Ball-and-stick model
Space-filling model
Names
Preferred IUPAC name
1,3-Thiazole
Other names
Thiazole
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.475 Edit this at Wikidata
UNII
  • InChI=1S/C3H3NS/c1-2-5-3-4-1/h1-3H checkY
    Key: FZWLAAWBMGSTSO-UHFFFAOYSA-N checkY
  • InChI=1/C3H3NS/c1-2-5-3-4-1/h1-3H
    Key: FZWLAAWBMGSTSO-UHFFFAOYAI
  • n1ccsc1
Properties
C3H3NS
Molar mass 85.12 g·mol−1
Boiling point 116 to 118 °C (241 to 244 °F; 389 to 391 K)
Acidity (pKa) 2.5 (of conjugate acid) [1]
−50.55·10−6 cm3/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Thiazole (/ˈθaɪ.əzoʊl/), 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.[2] The thiazole ring is notable as a component of the vitamin thiamine (B1).

Molecular and electronic structure

[edit]

Thiazoles are members of the azoles, heterocycles that include imidazoles and oxazoles. 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 oxazoles. This aromaticity is evidenced by the 1H 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

[edit]
Bleomycin is a thiazole-containing anti-cancer drug.

Thiazoles are found in a variety of specialized products, often fused with benzene derivatives, the so-called benzothiazoles. In addition to vitamin B1, the thiazole ring is found in epothilone. Other important thiazole derivatives are benzothiazoles, for example, the firefly chemical luciferin. 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).[3]

Commercial significant thiazoles include mainly dyes and fungicides. 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

[edit]

Various laboratory methods exist for the organic synthesis of thiazoles. Prominent is the Hantzsch thiazole synthesis, which is a reaction between haloketones and thioamides. For example, 2,4-dimethylthiazole is synthesized from thioacetamide and chloroacetone.[4] 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

[edit]

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.[5] Sulfur of the thiazole is derived from cysteine. In anaerobic bacteria, the CN group is derived from dehydroglycine.

Reactions

[edit]

With a pKa of 2.5 for the conjugate acid, thiazoles are far less basic than imidazole (pKa =7).[6]

Deprotonation with strong bases occurs at C2-H. The negative charge on this position is stabilized as an ylide. Hauser bases and organolithium compounds react at this site, replacing the proton. 2-Lithiothiazoles are also generated by metal-halogen exchange from 2-bromothiazole.[7]

Thiazole deprotonation

Electrophilic aromatic substitution at C5 but require activating groups such as a methyl group, as illustrated in bromination:

Thiazole bromination
Thiazole bromination
Thiazole Nucleophilic Aromatic Substitution
Thiazole Nucleophilic Aromatic Substitution

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:[8] Thiazole N-oxides are useful in Palladium-catalysed C-H arylations, where the N-oxide is able to shift the reactivity to reliably favor the 2-position, and allows for these reactions to be carried out under much more mild conditions.[9]

Thiazole oxidation
Thiazole oxidation
Thiazole cycloaddition
Thiazole cycloaddition

Thiazolium salts

[edit]

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 free carbenes[11] and transition metal carbene complexes.

Structure of thiazoles (left) and thiazolium salts (right)

Alagebrium is a thiazolium-based drug.

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Thiazole

View on Grokipedia
from Grokipedia
Thiazole is a five-membered heterocyclic featuring adjacent and atoms at the 1 and 3 positions, respectively, with the molecular formula C₃H₃NS and CAS number 288-47-1. It exhibits physical properties including a of 115–118 °C at 760 mm Hg, slight in , in , and miscibility with . Chemically, thiazole behaves as an organosulfide amine that is incompatible with acids, potentially generating heat and liberating . The thiazole ring is a privileged scaffold in , contributing to the structure of numerous biologically active compounds and FDA-approved drugs such as (vitamin B₁), (for ), (for ), (for ), and (for ). Although free thiazole itself is not found in nature, the thiazole moiety occurs naturally in biomolecules like alkaloids, metabolites, antibiotics such as penicillins, and flavor compounds in foods. Thiazole derivatives display diverse biological activities, including , antibacterial, , anticancer, , antimalarial, antiviral, anti-Alzheimer's, and antidiabetic effects, making them valuable in . Industrially, thiazoles serve as intermediates in the synthesis of pharmaceuticals, fungicides, dyes, rubber accelerators, and food flavoring agents. The most common synthetic route is the Hantzsch thiazole synthesis, involving the condensation of α-haloketones or α-haloaldehydes with thioamides or thioureas under mild conditions to yield substituted thiazoles. This versatility has led to extensive research on thiazole-based hybrids and analogs for enhanced therapeutic applications.

Structure and Properties

Molecular Structure

Thiazole is a five-membered heterocyclic with the molecular formula C₃H₃NS, consisting of three carbon atoms, one atom, and one atom arranged in a planar ring. The ring features at position 1 and at position 3 according to the standard numbering established by the International Union of Pure and Applied Chemistry (IUPAC), with the remaining positions (2, 4, and 5) occupied by carbon atoms. This arrangement positions the and in a 1,3-relationship, distinguishing thiazole from related azoles such as isothiazole, which has adjacent (position 1) and (position 2) atoms in a 1,2-configuration, and from , which replaces with oxygen. The basic of thiazole can be represented in its Kekulé form as a ring with a C=N between positions 2 and 3 and a C=C between positions 4 and 5, connected by single bonds involving the at position 1. However, thiazole exhibits significant delocalization, with multiple contributing structures that distribute the π electrons across the ring, including forms where the double bonds shift to involve the sulfur-nitrogen linkage. This is key to its aromatic character, as the system satisfies with 6 π electrons: four from the two localized double bonds and two from the on occupying a p-orbital perpendicular to the ring plane. The resides in an sp² orbital in the molecular plane and does not contribute to the π system, making it available for or coordination. Unsubstituted thiazole does not undergo significant tautomerism under standard conditions, as its aromatic stability favors the neutral ring form without proton migration between heteroatoms or adjacent carbons.

Electronic Structure

Thiazole exhibits aromatic character as a five-membered , satisfying (4n + 2 π electrons, where n = 1) through a conjugated, planar π-system containing exactly six delocalized π electrons. These electrons arise from the contributions of the C4=C5 double bond (two electrons), the C2=N3 imine bond (two electrons), and the sulfur atom's perpendicular p-orbital housing a (two electrons), enabling full cyclic conjugation across the ring. The lone pair occupies an sp² hybrid orbital in the molecular plane, akin to , and does not participate in the π-system, preserving the aromatic while allowing the nitrogen to act as a basic site. This electron distribution imparts stability and influences thiazole's reactivity, with the delocalized system evidenced by equalized bond orders throughout the ring. Structural data from confirm the aromatic delocalization, revealing bond lengths indicative of partial double-bond character: the C-S bonds measure approximately 1.724 (S-C2) and 1.713 (C5-S), the C2-N bond is 1.304 , the N-C4 bond is 1.372 , and the C4-C5 bond is 1.367 . These values, shorter than typical single bonds but longer than pure double bonds, reflect the stabilization of the aromatic system, with no significant deviations from planarity (all atoms sp² hybridized). Computational methods, such as (DFT), reproduce these geometries closely, further validating the electronic delocalization. Quantum chemical analyses of thiazole's molecular orbitals highlight the heteroatoms' roles in electron distribution. The highest occupied molecular orbital (HOMO) features substantial density on the sulfur and nitrogen atoms, particularly along the S-C2-N segment, rendering it electron-rich and susceptible to electrophilic attack at C2. In contrast, the lowest unoccupied molecular orbital (LUMO) is predominantly localized on the carbon atoms (C4 and C5), facilitating electron acceptance and explaining thiazole's behavior in donor-acceptor systems. This HOMO-LUMO configuration underscores the molecule's polarity and reactivity patterns. The electronic asymmetry due to the electronegative and imparts a permanent dipole moment of approximately 1.70 D to thiazole, with components μ_a ≈ 1.55 D and μ_b ≈ 0.70 D along the principal inertial axes, as determined from . This polarity arises from charge separation, with the pulling toward itself and the contributing to the overall vector. The weak basicity of the is quantified by the pK_a of 2.5 for the thiazolium conjugate acid, indicating that disrupts less severely than in more basic heterocycles, owing to the pyridine-like and the stabilizing π-system.

Physical Properties

Thiazole is a colorless to pale yellow liquid at , characterized by a distinctive sulfurous or foul . With the molecular formula C₃H₃NS, it has a molecular weight of 85.13 g/mol.

Key Physical Properties

PropertyValueConditionsSource
Melting Point-33 °C-https://www.chemicalbook.com/ProductChemicalPropertiesCB7853436_EN.htm
117–118 °C760 mmHghttps://www.sigmaaldrich.com/US/en/product/aldrich/151645
1.2 g/cm³25 °Chttps://www.sigmaaldrich.com/US/en/product/aldrich/151645
1.53820 °C (n₂₀/D)https://www.sigmaaldrich.com/US/en/product/aldrich/151645
Solubility in Slightly soluble20 °Chttps://pubchem.ncbi.nlm.nih.gov/compound/Thiazole
Thiazole exhibits good solubility in common organic solvents, being fully miscible with and . Under standard ambient conditions, thiazole remains stable, though it decomposes upon exposure to high temperatures beyond its .

Chemical Properties

Thiazole acts as a , with the nitrogen available in an sp² orbital in the molecular plane (not participating in the π-system), but its basicity reduced by the electron-withdrawing nature of the ring; the pKa of its conjugate acid is 2.5, making it less basic than (pKa 5.2) but more basic than (pKa 0.8). preferentially occurs at the N3 position due to the distribution in the ring. This basicity profile influences its interactions in acidic environments, where the protonated form enhances electron deficiency at certain ring positions. In terms of spectroscopic properties, thiazole displays a characteristic UV absorption band around 240–242 nm attributable to the π–π* transition within its aromatic system. Infrared spectroscopy reveals key vibrational modes, including a moderate band near 1496–1500 cm⁻¹ for the C–N stretch and lower-frequency bands around 700–862 cm⁻¹ associated with C–S and ring deformations. These signatures aid in structural identification and confirm the heterocyclic framework's integrity. Thiazole demonstrates notable oxidation stability, with its conferring resistance to mild oxidants; however, exposure to strong agents like or peracids can lead to reactive degradation or N-oxidation. Thermally, thiazole and its derivatives exhibit good stability, with decomposition typically initiating above 200–260°C in related thiazolium systems, often yielding volatile fragments. Compared to , thiazole is more electron-deficient overall due to the electronegative , which lowers the and alters reactivity patterns, akin to but distinct from imidazole's dual nitrogen influence.

Natural Occurrence and Biological Role

Occurrence in Nature

Thiazole and its simple derivatives occur as minor components in sources such as . In , particularly from medium- and low-temperature processes, thiazole-containing compounds like thiazole-thioketones are identified among sulfur-heterocyclic structures, contributing to the complex mixture of heteroatoms that affect processing and properties. Thiazole derivatives are also generated in roasted and thermally processed foods through the , a non-enzymatic browning process involving reducing sugars and sulfur-containing like . These reactions produce thiazoles and thiazolines that impart characteristic roasted, nutty, and meaty aromas in products such as , , and ; for instance, 2-acetylthiazole is a key contributor to popcorn-like flavors in heated grains. In , unsubstituted thiazole is rare, but simple derivatives such as thiazoline appear in minor s from certain species, often as part of structures with defensive roles. These are sporadically isolated from terrestrial plants alongside more common counterparts, though marine sources dominate natural thiazole diversity. Detection of thiazole in these natural extracts typically relies on gas chromatography-mass spectrometry (GC-MS), which separates and identifies volatile heterocycles based on retention times and mass spectra. This method has confirmed thiazole presence in food volatiles, distillates, and environmental samples, enabling quantification at trace levels (e.g., ).

Biochemical Significance

Thiazole serves as a fundamental structural component in (vitamin B1), where the thiazolium ring functions as an electrophilic center in enzymatic catalysis. The thiazole moiety, linked to a ring via a , enables thiamine's role as an essential cofactor in metabolic pathways, particularly in the of α-keto acids. This structural feature allows the C-2 position of the thiazolium to be deprotonated, forming a nucleophilic that attacks carbonyl groups in substrates. In its active form as (TPP), the thiazolium ring of thiazole plays a pivotal role as a cofactor for enzymes such as , facilitating the of pyruvate to through ylide-mediated stabilization of intermediates. This mechanism links to the , underscoring thiazole's importance in . Deficiency in disrupts these TPP-dependent enzymes, leading to conditions like beriberi, characterized by cardiovascular and neurological symptoms due to impaired α-keto acid and activity. The thiazolidine ring in penicillin, a five-membered saturated heterocycle formed biosynthetically from , forms the core of β-lactam antibiotics, contributing to their stability and ability to inhibit bacterial synthesis by acylating . Evolutionarily, thiazole motifs appear in non-ribosomal peptides, where cyclodehydration domains in non-ribosomal peptide synthetases convert cysteine residues into thiazolines that oxidize to thiazoles, enhancing bioactivity in compounds like siderophores for microbial . Similarly, thiazole-based peptides from marine sources, such as and ascidians, exhibit potent and antimicrobial properties, reflecting thiazole's conserved role in diverse biological defenses.

Synthesis

Laboratory Synthesis

The Hantzsch thiazole synthesis, first reported in 1887, is the classical method for preparing thiazoles in the laboratory and involves the condensation of an α-haloketone with a thioamide to form 2,4-disubstituted thiazoles. The reaction proceeds via initial S-alkylation of the thioamide by the α-haloketone, followed by intramolecular nucleophilic attack of the nitrogen on the to form a hydroxythiazoline intermediate, and subsequent dehydration to the aromatic thiazole. This method is versatile, allowing control over substitution at the 2- and 4-positions through choice of thioamide and haloketone substituents. The general reaction is represented as: \ceR−C(O)−CH2X+R′−C(S)−NH2−>[heat]thiazole(2−R′,4−R)+HX+H2O\ce{R-C(O)-CH2X + R'-C(S)-NH2 ->[heat] thiazole (2-R', 4-R) + HX + H2O} where X is typically Br or Cl. A common variation employs thioureas instead of thioamides, yielding 2-aminothiazoles in good yields, which are valuable intermediates in pharmaceutical synthesis. Classical conditions often involve refluxing in or acetone, with yields ranging from 50% to 90% depending on substituents, followed by purification via or recrystallization. Modern adaptations enhance efficiency and sustainability; for instance, ionic liquids such as [bmim]BF₄ or [bmim]Br serve as recyclable solvents and catalysts, enabling reactions at ambient or mild temperatures (up to 50°C) with yields of 70–97% and reduced waste. These greener protocols maintain the core mechanism while minimizing volatile organic solvents. Alternative laboratory routes include the cyclization of α-thiocyanatoketones under acidic conditions, such as in aqueous or acetic acid, which affords 2-mercapto- or 2-hydroxythiazoles through intramolecular attack and elimination. Yields for this method typically fall in the 60–85% range, offering access to sulfur-functionalized thiazoles not directly obtainable via Hantzsch conditions.

Biosynthesis

Thiazole biosynthesis occurs as a dedicated step in the formation of (vitamin B1), where the thiazole ring serves as one of the two heterocyclic moieties of the cofactor. In prokaryotes such as , this process involves a multi-component pathway leading to the production of 4-methyl-5-(2-hydroxyethyl)thiazole phosphate (ThzP), the activated thiazole precursor. The key , thiazole synthase , catalyzes the final cyclization and to form ThzP by condensing three main precursors: dehydro (derived from ), the thiocarboxylate of the sulfur carrier protein ThiS (sulfur sourced from via persulfide transfer by IscS/ThiI), and 1-deoxy-D-xylulose 5-phosphate (DXP). The pathway begins with sulfur mobilization from to ThiS, forming ThiS-COSH, while is converted to dehydroglycine by the radical S-adenosylmethionine (SAM) enzyme ThiH (or ThiO in some like ). ThiH employs a 5'-deoxyadenosyl radical, generated from SAM and a reducing system involving flavodoxin and NADPH, to abstract a hydrogen from , yielding the reactive dehydroglycine intermediate and facilitating subsequent C-S bond formation during ThiG-mediated assembly with DXP. This radical mechanism ensures precise carbon- linkage in the thiazole ring, with ThiG proceeding via an imine intermediate between DXP and dehydroglycine, followed by nucleophilic attack by the ThiS sulfur and rearrangement to the aromatic product. Overall, the process incorporates elements from (sulfur and partial carbon framework), (C2-N3 unit), and DXP (C4-methyl and C5 side chain), though NAD is not directly involved in the bacterial ThiG reaction but supports upstream reducing equivalents. In and , thiazole synthesis operates as a discrete module, with ThzP subsequently coupled to 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP-PP) by monophosphate synthase to form monophosphate (TMP); in some , phosphorylates the hydroxyethyl side chain of free thiazole intermediates as part of salvage or activation steps. employ a related but simplified pathway using the THI1 (homologous to eukaryotic THI4), which integrates thiazole formation in a single polypeptide, producing ThzP for ThiE-mediated assembly. Fungi utilize an alternative route dominated by the multifunctional thiazole synthase Thi4p, a single-turnover "suicide" that directly consumes , NAD+, and its own internal residue to generate the thiazole moiety, bypassing the multi-enzyme complex of the bacterial system; in some cases, can be sourced from degradation of 4-thiouridine (s⁴U) in tRNA via shared desulfurase activities like IscS/ThiI. This eukaryotic mechanism allows aerobic compatibility but limits catalytic cycles due to covalent adduct formation at the active-site . Biosynthesis of the thiazole moiety is tightly regulated to prevent overproduction. In , the pathway experiences feedback inhibition by , which allosterically modulates key enzymes like ThiE and represses thi gene via (TPP)-binding riboswitches, ensuring coordination with cellular thiamine demand.

Reactions and Derivatives

General Reactivity

Thiazole undergoes primarily at the 5-position, the most electron-rich carbon in the ring, due to the electron-donating effect of the atom and the overall π-electron distribution. This preference is evident in reactions. Other electrophiles, such as those for or sulfonation, also target this site unless it is blocked by a , in which case the 4-position may react instead. Nucleophilic reactions on the thiazole ring are less common, with addition occurring preferentially at the electron-deficient C2 position in unsubstituted derivatives, as this carbon bears partial positive charge from the adjacent . However, such additions are rare under mild conditions because the aromatic character of thiazole stabilizes the ring against disruption. The electronic structure of thiazole, featuring greater delocalization than in analogous heterocycles, underpins this site selectivity and overall reactivity pattern. For synthetic functionalization, metalation provides a key route, with lithiation using deprotonating at C2 in unsubstituted thiazole or at C5 when C2 is occupied, enabling subsequent trapping with electrophiles like carbonyl compounds or halides. Compared to oxazoles, thiazole exhibits enhanced stability toward and related degradative processes, such as the Wasserman rearrangement involving ring cleavage, owing to its higher and the less polarizable heteroatom. This resistance allows thiazole derivatives to maintain integrity in aqueous or protic environments where oxazoles may hydrolyze more readily, with half-lives differing by factors of 2–6 in model peptidic systems.

Thiazolium Salts

Thiazolium salts are formed by of the thiazole ring at the atom (N3), which has a available for electrophilic attack by acids, or by quaternization of the with alkyl halides, such as methyl , yielding stable cationic species with halides or other anions as counterions. These processes introduce a positive charge on the ring, significantly altering its electronic properties and reactivity compared to neutral thiazole. The positive charge in thiazolium cations enhances the acidity of the C2 hydrogen, with pKa values typically in the range of 17–19 in aqueous media, making feasible with mild bases. at C2 generates a nucleophilic , often represented as 2-ylidene-thiazoline, which exhibits carbene-like reactivity and enables of the in aldehydes. This adds to the electrophilic carbon of a , forming an intermediate that facilitates C–C bond formation, as seen in analogs of the where two aldehydes couple to produce α-hydroxy ketones. The reaction sequence can be summarized as follows: Thiazolium salt+base→2-ylidene-thiazoline (ylide)+H-base+\text{Thiazolium salt} + \text{base} \rightarrow \text{2-ylidene-thiazoline (ylide)} + \text{H-base}^+ Ylide+RCHO→Enamine intermediate→Addition product\text{Ylide} + \text{RCHO} \rightarrow \text{Enamine intermediate} \rightarrow \text{Addition product} This umpolung reactivity is pivotal in organocatalysis and mirrors the mechanism in thiamine pyrophosphate (TPP), where the thiazolium ylide initiates biochemical transformations. In proton NMR spectra, the C2–H proton of thiazolium salts experiences a downfield shift to approximately 9–10 ppm (compared to ~7.8 ppm in neutral thiazole), due to the deshielding effect of the adjacent positive charge, providing a diagnostic for these . This spectroscopic feature aids in characterizing the salts and monitoring their .

Key Derivatives

2-Aminothiazoles represent a prominent class of thiazole derivatives featuring an amino group at the 2-position, which imparts unique reactivity due to the electron-donating nature of the substituent. These compounds are typically synthesized through the Hantzsch thiazole synthesis, involving the condensation of α-halocarbonyl compounds, such as α-haloaldehydes or ketones, with thioureas under neutral or anhydrous conditions. This method yields 2-aminothiazoles efficiently and is widely employed for preparing substituted variants with aryl or alkyl groups at the 4- and 5-positions. As versatile intermediates, 2-aminothiazoles serve in the synthesis of azo dyes, where they act as components to produce disperse dyes with favorable dyeing properties on substrates like . 4-Methylthiazole is a simple monosubstituted thiazole bearing a at the 4-position, contributing to the structural framework of essential biomolecules. It forms a key moiety in (vitamin B1), where it is integrated as part of the 4-methyl-5-(2-hydroxyethyl)thiazolium ring, essential for coenzyme functions in . Thiazolines, or 4,5-dihydrothiazoles, are partially saturated analogs of thiazole, lacking full due to the sp3-hybridized carbon at position 5, which results in a more flexible ring system. These derivatives occur in natural products, notably as a component in , the bioluminescent substrate in Photinus species, where the thiazoline ring is fused to a and bears a at the 4-position: (S)-2-(6-hydroxybenzothiazol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid. Fused thiazole systems extend the core heterocycle by with other rings, enhancing stability and biological relevance. Thiazolopyrimidines consist of a thiazole ring fused to a at the 4,5-positions of thiazole, forming a bicyclic [5,6] system analogous to bases. feature a ring fused to thiazole at the 4,5-positions, yielding a planar, electron-rich scaffold with the thiazole at position 3 and at 1. Among commercial thiazole derivatives, 2,4,5-trimethylthiazole stands out as a flavorant, characterized by methyl substituents at the 2-, 4-, and 5-positions, imparting nutty, roasted, and chocolate-like aromas reminiscent of cooked meats and potatoes. It arises as a product and is incorporated into food formulations at low concentrations, such as 2-6 ppm in soups, confections, and condiments.

Applications

Pharmaceutical Uses

Thiazole derivatives have emerged as important scaffolds in pharmaceutical development due to their versatile biological activities, particularly in antimicrobial and anticancer therapies. These compounds often exhibit targeted mechanisms that disrupt essential microbial or cellular processes, making them valuable for treating infections and proliferative diseases. In antifungal applications, thiazole-based agents like abafungin demonstrate potent activity against dermatophytes and yeasts by inhibiting sterol C-24-methyltransferase, which disrupts ergosterol biosynthesis in fungal cell membranes, leading to impaired membrane integrity and fungal cell death. This mechanism allows abafungin to act on both resting and proliferating fungal forms, providing broad-spectrum efficacy against skin infections caused by organisms such as Trichophyton species. Sulfathiazole, a classic antibiotic containing a thiazole ring, serves as a primarily used to combat bacterial infections that underlie inflammatory conditions, such as staphylococcal and pneumococcal diseases. It exerts its effect by competitively inhibiting (DHPS), an enzyme critical for folic acid synthesis in , thereby halting production and bacterial replication. Although now less commonly used systemically due to availability of safer alternatives, its benefits stem from reducing infection-driven . Ritonavir, an inhibitor featuring thiazole moieties in its structure, plays a key role in antiretroviral therapy by binding to the viral , preventing the cleavage of polyproteins essential for HIV maturation and replication. The thiazole nitrogen in coordinates with iron in off-target interactions, such as with enzymes, which enhances its pharmacokinetic boosting effects when combined with other antiretrovirals. While primarily antiviral, ritonavir's use in HIV management indirectly supports cardiovascular health by mitigating HIV-associated complications like . Recent advancements post-2020 have focused on thiazole-based inhibitors for , building on scaffolds like , a thiazole-containing BCR-ABL and inhibitor approved for . Analogs, such as novel 2-aminothiazole derivatives, have shown enhanced potency against tyrosine kinases like EGFR and VEGFR, inducing and inhibiting tumor proliferation in preclinical models of and cancers through ATP-competitive binding at the kinase active site. These developments emphasize thiazole's role in overcoming resistance in targeted therapies. Toxicity profiles of thiazole derivatives are generally favorable, with low systemic absorption for topical agents like abafungin; however, sulfonamide-based thiazoles such as sulfathiazole can trigger reactions, including skin rashes, fever, and like Stevens-Johnson syndrome. These reactions often arise from reactive metabolites like nitroso-sulfonamides that haptenate cellular proteins, eliciting T-cell mediated immune responses. Monitoring for is essential, particularly in therapies.

Other Industrial Applications

Thiazole derivatives find extensive use in the production of dyes and pigments, particularly azo dyes applied in textile coloring due to their vibrant hues and stability. For instance, thioflavin, a benzothiazole-based compound, serves as a fluorescent dye for staining applications, enabling visualization in materials like textiles and biological samples through its affinity for beta-sheet structures. These dyes exhibit high solubility in polar solvents, enhancing their utility in industrial dyeing processes. In agrochemicals, thiazole-based compounds act as effective fungicides for crop protection. Thifluzamide, a systemic thiazole derivative, provides protective and curative action against rice blast caused by Pyricularia oryzae, significantly reducing disease incidence and improving yield in cultivation. Field trials have demonstrated its efficacy at concentrations of 0.8 g/L, controlling both leaf and neck blast stages when applied foliarly. Its mode of action involves inhibition, targeting fungal respiration without substantial impact on non-target . Thiazoles serve as key additives in polymer manufacturing, especially in rubber processing. As vulcanization accelerators, compounds like 2-mercaptobenzothiazole (MBT) facilitate sulfur crosslinking in natural and synthetic rubbers, improving mechanical properties such as tensile strength and elasticity during curing. MBT operates by forming reactive intermediates that enhance cure rates at lower temperatures, typically 140–160°C, while minimizing scorch risk. Additionally, certain thiazole derivatives function as antioxidants, stabilizing polymers against oxidative degradation from heat and ozone exposure, thereby extending product lifespan in tires and seals. In the flavor and fragrance industry, thiazoles contribute to aroma profiles through products. 2-Acetylthiazole imparts a characteristic nutty, popcorn-like scent essential to roasted , with detection thresholds as low as 0.1 ppb, making it a pivotal volatile in beverage formulations. This compound arises from interactions between and alpha-dicarbonyls during thermal processing, enhancing sensory appeal in food products. Its high substantivity, lasting up to 16 hours, supports its use in synthetic aroma blends. Emerging applications of thiazole derivatives extend to , particularly in organic light-emitting diodes () for their electron-transporting and conductive properties. Benzothiazole-based materials, when linked to donor moieties via phenyl bridges, exhibit balanced charge transport, achieving external quantum efficiencies exceeding 20% in tandem architectures. Thiazolo[5,4-d]thiazole oligomers further enable printable due to their thermal stability and high , up to 0.1 cm²/V·s, supporting technologies. These attributes stem from the thiazole ring's electron-withdrawing nature, facilitating efficient carrier injection.

References

  1. https://pubchem.ncbi.nlm.nih.gov/compound/Thiazole
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC9268695/
  3. https://www.organic-chemistry.org/synthesis/heterocycles/thiazoles.shtm
  4. https://www.sciencedirect.com/topics/chemistry/isothiazole
  5. https://chem.libretexts.org/Courses/Smith_College/Organic_Chemistry_(LibreTexts)/24%3A_Amines_and_Heterocycles/24.10%3A_Heterocyclic_Amines
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC7865802/
  7. https://apps.dtic.mil/sti/tr/pdf/ADA284326.pdf
  8. https://www.sciencedirect.com/science/article/pii/0022285262902308
  9. https://pubs.acs.org/doi/pdf/10.1021/j100852a057
  10. https://www.chemicalbook.com/ProductChemicalPropertiesCB7853436_EN.htm
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC10675556/
  12. https://www.pharmaguideline.com/2022/02/synthesis-reactions-and-medicinal-uses-of-thiazole.html
  13. https://pubs.acs.org/doi/10.1021/acsomega.2c02473
  14. https://pubs.rsc.org/en/content/articlehtml/2017/ra/c6ra27496j
  15. https://pubs.acs.org/doi/10.1021/acs.joc.8b02684
  16. https://www.sciencedirect.com/science/article/abs/pii/S0167732221022789
  17. https://pubs.acs.org/doi/10.1021/accountsmr.2c00237
  18. https://pubs.acs.org/doi/10.1021/acsomega.1c00355
  19. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/thiazole
  20. https://pubs.acs.org/doi/abs/10.1021/jf970066m
  21. https://pubs.rsc.org/en/content/articlehtml/2016/np/c6np00067c
  22. https://pubmed.ncbi.nlm.nih.gov/21535804/
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC10568373/
  24. https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Map%253A_Organic_Chemistry_(Bruice)/25%253A_Compounds_Derived_from_Vitamins/25.03%253A_Thiamine_Pyrophosphate-_Vitamin_B1
  25. https://pubs.acs.org/doi/10.1021/ja01547a064
  26. https://www.ncbi.nlm.nih.gov/books/NBK537204/
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC8528271/
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC12173477/
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC7345825/
  30. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cber.188702002200
  31. https://www.sciencedirect.com/topics/chemistry/imidothioate
  32. https://www.sciencedirect.com/science/article/pii/S2046206925030815
  33. https://pubmed.ncbi.nlm.nih.gov/15012138/
  34. https://pubmed.ncbi.nlm.nih.gov/15489164/
  35. https://www.jbc.org/article/S0021-9258(19)75524-0/fulltext
  36. https://academic.oup.com/plphys/article/179/3/958/6116723
  37. https://www.sciencedirect.com/science/article/pii/S0021925819893109
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC2536526/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC3020362/
  40. https://portlandpress.com/biochemj/article/478/17/3265/229602/Structure-and-function-of-aerotolerant-multiple
  41. https://academic.oup.com/jb/article-abstract/65/3/407/797934
  42. https://www.pnas.org/doi/10.1073/pnas.0705786105
  43. https://www.sciencedirect.com/topics/chemistry/1-3-thiazole
  44. https://www.sciencedirect.com/topics/chemistry/thiazole
  45. https://www.ias.ac.in/public/Volumes/seca/038/01/0045-0057.pdf
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC2556205/
  47. https://pubs.acs.org/doi/10.1021/ja01486a042
  48. https://advanced.onlinelibrary.wiley.com/doi/10.1002/adsc.70087
  49. https://www.sciencedirect.com/topics/chemistry/hantzsch-thiazole-synthesis
  50. https://pubs.acs.org/doi/10.1021/jo01084a010
  51. https://pubchem.ncbi.nlm.nih.gov/compound/4-Methylthiazole
  52. https://pubchem.ncbi.nlm.nih.gov/compound/Firefly-Luciferin
  53. https://www.tandfonline.com/doi/abs/10.1080/00397911.2023.2212096
  54. https://pubchem.ncbi.nlm.nih.gov/compound/Benzothiazole
  55. https://pubchem.ncbi.nlm.nih.gov/compound/2_4_5-Trimethylthiazole
  56. http://www.thegoodscentscompany.com/data/rw1008832.html
  57. https://www.sciencedirect.com/science/article/pii/S2211715624005162
  58. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/abafungin
  59. https://www.sciencedirect.com/topics/chemistry/abafungin
  60. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/sulfathiazole
  61. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/sulfathiazole
  62. https://pubmed.ncbi.nlm.nih.gov/20937904/
  63. https://www.sciencedirect.com/topics/chemistry/ritonavir
  64. https://pubs.acs.org/doi/abs/10.1021/jm060727j
  65. https://www.nature.com/articles/s41598-024-81294-1
  66. https://pubmed.ncbi.nlm.nih.gov/31495421/
  67. https://pubmed.ncbi.nlm.nih.gov/38175321/
  68. https://doi.org/10.1177/15.3.172
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC6331669/
  70. https://onlinelibrary.wiley.com/doi/10.1111/jph.13444
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC11412917/
  72. https://www.vanderbiltworldwide.com/markets/rubber-accelerators-thiazoles
  73. https://www.sciencedirect.com/science/article/pii/S0160412022006420
  74. https://www.sciencedirect.com/science/article/abs/pii/S0308814620326236
  75. https://www.thegoodscentscompany.com/data/rw1025671.html
  76. https://www.sciencedirect.com/science/article/abs/pii/S1385894723037543
  77. https://pubs.acs.org/doi/10.1021/cm049473l
Add your contribution
Related Hubs
User Avatar
No comments yet.