1,3-Thiazole-5-Carboxaldehyde
|
HS Code |
131103 |
| Chemical Formula | C4H3NOS |
| Molecular Weight | 113.14 g/mol |
| Appearance | Solid (usually) |
| Odor | Characteristic odor |
| Melting Point | Data varies, needs specific determination |
| Boiling Point | Data varies, needs specific determination |
| Solubility In Water | Poor solubility |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol |
| Density | Data varies, needs specific determination |
| Stability | Stable under normal conditions but may react with strong oxidizing agents |
As an accredited 1,3-Thiazole-5-Carboxaldehyde factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1,3 - Thiazole - 5 - Carboxaldehyde packaged in a sealed glass vial. |
| Shipping | 1,3 - Thiazole - 5 - Carboxaldehyde, a chemical, is shipped with strict adherence to safety regulations. It's carefully packaged to prevent leakage and damage, transported via approved carriers handling hazardous substances. |
| Storage | 1,3 - Thiazole - 5 - Carboxaldehyde should be stored in a cool, dry, well - ventilated area. Keep it away from sources of heat, ignition, and incompatible substances like strong oxidizing agents. Store in a tightly sealed container to prevent evaporation and contamination. It is advisable to store it in a dedicated chemical storage cabinet for proper segregation and safety. |
In parallel medicinal chemistry campaigns targeting ATP-competitive kinase inhibitors, 1,3-thiazole-5-carboxaldehyde serves as a versatile C5 aldehyde building block for constructing 5,6-fused heterocyclic systems through sequential condensation–cyclization protocols. The aldehyde is typically reacted with a slight excess of hydrazine hydrate or arylhydrazines (1.02–1.10 eq) in anhydrous ethanol at reflux (78–80 °C) under nitrogen for 4–8 hours to yield the corresponding hydrazone intermediate; in situ monitoring by UPLC–PDA (λ = 254 nm) tracks consumption of the aldehyde peak at tR ≈ 2.3 min on a C18 column using a water/acetonitrile gradient with 0.1% formic acid. Following solvent removal under reduced pressure (40 mbar, 45 °C), the crude hydrazone is either purified by silica gel flash chromatography (ethyl acetate/hexane, 30–50%) or telescoped directly into a thermal cyclization step with polyphosphoric acid at 120 °C to generate thiazolo[5,4-d]pyrimidines. From a regulatory standpoint, when these intermediates are destined for Phase I clinical supplies, the synthesis must comply with ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, with specific attention to residual solvent limits as per ICH Q3C (Class 2 ethanol limit 5,000 ppm; Class 3 ethyl acetate 5,000 ppm), and impurity profiling following ICH Q3A where any unspecified impurity exceeding 0.10% by HPLC area requires structural characterization. The terminal products from this scaffold include lead-optimized molecules with in vitro IC50 values against recombinant kinases in the low nanomolar range, which are subsequently formulated as hydrochloride salts for oral administration in preclinical efficacy models.Succinate Dehydrogenase Inhibitor (SDHI) Backbone Construction via Oxidative AmidationThe industrial-scale synthesis of N-(2-chlorophenyl)-1,3-thiazole-5-carboxamide — a structural analogue within the SDHI fungicide class — commences with oxidation of 1,3-thiazole-5-carboxaldehyde to the corresponding acid using buffered sodium chlorite (1.2–1.4 eq NaClO₂) in a two-phase system consisting of acetonitrile/phosphate buffer (pH 4.2) in the presence of a 3–5 mol% 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) co-catalyst and 10% aqueous NaOCl as the terminal oxidant. The biphasic mixture is stirred vigorously at 0–5 °C for 2–3 hours until IPC by TLC (silica gel GF254, hexane:ethyl acetate 2:1 v/v) indicates complete consumption of the aldehyde (Rf 0.55). The organic layer is separated, dried over anhydrous Na₂SO₄, and concentrated to a pale yellow solid of 1,3-thiazole-5-carboxylic acid, typical isolated yield 85–92% at 100 kg input scale. This acid is then converted to the acyl chloride by treatment with thionyl chloride (2.5 eq) in toluene containing catalytic DMF (0.5 mol%) at 70–75 °C for 4 hours; evolved SO₂ and HCl are scrubbed through a caustic trap. The resulting acid chloride is immediately reacted with 2-chloroaniline (1.05 eq) in anhydrous dichloromethane with triethylamine (1.2 eq) as a scavenger at –5 to 0 °C, forming the target amide after aqueous workup and crystallization from isopropanol/water. The final active ingredient must satisfy FAO pesticide specifications for technical-grade material: purity ≥ 96% (GC-FID area normalization), water content ≤ 0.5% by Karl Fischer, and acetone-insoluble matter ≤ 0.2%. For regulatory registration under EU 1107/2009, a five-batch analysis demonstrating impurity profiles against a certified reference standard is mandatory; any impurity exceeding 0.1% requires toxicological qualification per SANCO/30299. The amide product is commercialized as a 25% suspension concentrate (SC) formulated with nonionic ethoxylated tristyrylphenol surfactants and xanthan gum rheology modifier, delivered to cereal growers for control of Rhizoctonia solani in paddy rice.Commercially significant roasted peanut, toasted sesame, and coffee-like notes in compounded savory flavors are frequently constructed around 1,3-thiazole-5-carboxaldehyde as a trace-impact aroma chemical, used at application levels ranging from 0.25 to 8.0 ppm in finished food products depending on the matrix. The neat aldehyde is typically supplied as a 1% (w/w) solution in triacetin or propylene glycol to facilitate accurate metering during flavor blending; masterbatches diluted further to 0.1% are employed for snack seasoning dusts to prevent localized hotspot formation. During production of a thermally processed flavor, the aldehyde is incorporated into a Maillard reaction system containing hydrolyzed vegetable protein, reducing sugars, and cysteine at 0.05–0.20% of total reactant mass, and the mixture is refluxed in water at 98–100 °C for 2–3 hours under controlled pH 5.0–5.5 to generate the full spectrum of roast aroma. Sub-micron filtration (0.45 µm) followed by spray-drying with maltodextrin (DE 15–18) as a carrier yields an encapsulated flavor powder with a particle size D50 of 80–120 µm and a bulk density of 0.45–0.55 g/cm³, which is shelf-stable for 12 months at 25 °C/60% RH in aluminum laminate packaging. Regulatory compliance follows the EU Flavourings Regulation (EC 1334/2008), where the substance must appear in the Union List of flavouring substances with an assigned FL number or be covered by an approved pending application; in the United States, a FEMA GRAS determination is required, and until such is published, any commercial-use flavor containing this aldehyde is self-limited to confidential industrial evaluations. Current finished goods incorporating the ingredient include microwave popcorn seasoning powders, liquid cheese sauces, and extruded corn snack base doughs.What Are the Reusability Profiles of Thiazolyl Schiff Base Zn(II) Catalysts in Carbonate Synthesis?Condensation of 1,3-thiazole-5-carboxaldehyde with 2-aminophenol in absolute methanol under nitrogen at room temperature for 12 hours affords the corresponding Schiff base ligand as a yellow crystalline solid in 88–94% isolated yield after recrystallization from ethanol/water (7:3 v/v). The bidentate NO-donor ligand is then metallated with ZnCl₂ (1.0 eq) in hot methanol, precipitating the neutral Zn(II) complex as an off-white powder after solvent evaporation and trituration with diethyl ether. Single-crystal X-ray diffraction of structurally analogous thiazole-derived Zn(II) complexes confirms a distorted tetrahedral N₂O₂ coordination geometry, with coordination bond metrics indistinguishable from well-characterized homologues in the CCDC structural database. In the catalytic conversion of propylene oxide to propylene carbonate under CO₂ pressure (10 bar), the complex loaded at 0.5 mol% relative to epoxide, in combination with tetrabutylammonium bromide (1.0 mol%) as a nucleophilic co-catalyst, achieves turnover frequencies (TOF) in the range 150–180 h⁻¹ at 80 °C in a stirred 100 mL stainless steel autoclave. On recycling, the catalyst retains > 90% of its initial activity over 6 consecutive runs after simple filtration and vacuum drying, with negligible zinc leaching (< 0.5 ppm by ICP-OES) into the product phase. Industrial production of cyclic carbonates using such a catalyst must adhere to REACH regulation for intermediates under strictly controlled conditions (REACH Article 17/18), and the catalyst itself must meet a purity of ≥ 98% by elemental analysis (C, H, N, S within ±0.4% of theoretical). The terminal product, propylene carbonate, is a high-boiling (242 °C) polar aprotic solvent sold into lithium-ion battery electrolyte formulations and reactive diluent markets.Weight loss measurements on API 5L X65 pipeline steel exposed to 15% (w/w) hydrochloric acid at 60–90 °C provide direct evidence for film-forming corrosion inhibition by N-(thiazol-5-ylmethylene)-4-methoxyaniline, a Schiff base synthesized quantitatively by solvent-free grinding of 1,3-thiazole-5-carboxaldehyde with p-anisidine (1:1 molar ratio) in a pestle mortar over 10 minutes. The neat organic inhibitor is dosed into the acid medium at concentrations between 100 and 500 mg/L, whereupon the protonated imine and thiazole nitrogen atoms adsorb onto the cathodic sites of the steel surface, as corroborated by potentiodynamic polarization curves (scan rate 0.5 mV/s) revealing a mixed-type inhibition mechanism with predominance of cathodic suppression. Inhibition efficiency, derived from Tafel extrapolation in accordance with ASTM G102, falls within the range > 88% at 500 mg/L and 60 °C, with a decline to approximately 80% at 90 °C consistent with the van’t Hoff temperature effect on adsorption equilibria. Field application of such inhibitors in industrial pickling baths requires compliance with local effluent discharge limits for zinc and phosphorus, and the substance is inventoried under an appropriate regulatory list such as TSCA or DSL; pre-registration under REACH at 1–10 tonnes per annum may involve a read-across approach to structurally similar thiazoles with available ecotoxicity data. Commercial scale-up of the exothermic Schiff base formation is best performed in a ribbon blender under nitrogen sweep to avoid aldehyde oxidation, with subsequent double cone vacuum drying (50 °C, 10 mbar) to reduce the residual p-anisidine monomer below 150 ppm before packaging in antistatic LDPE drums. The final inhibited acid solution is employed for descaling of boiler tubes and heat exchangers in petrochemical plants, often in conjunction with non-ionic wetting agents (0.5% v/v) to ensure uniform film coverage. |
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1,3-Thiazole-5-carboxaldehyde (CAS 100-24-1; molecular formula C4H3NOS; molar mass 113.14 g·mol−1) is supplied as a pale-yellow to amber liquid that partially solidifies at temperatures below approximately 10 °C, forming a low-melting crystalline mass with a congealing point in the range of 2 °C to 6 °C. Commercial lots are routinely standardized to a minimum assay of 98.0% (GC, area normalization, FID detection, column: DB-5, 30 m × 0.25 mm × 0.25 µm), with the principal impurity invariably being the corresponding carboxylic acid arising from aerial oxidation. Water content, determined by Karl Fischer coulometry (USP <921> Method Ic), is controlled to ≤ 0.3%. The compound is packaged under argon-blanketed headspace in amber glass or epoxy-lined steel containers because prolonged exposure to ambient oxygen at temperatures exceeding 25 °C promotes measurable aldehyde degradation within 72 h. Storage at 2–8 °C under an inert atmosphere is mandatory for retention of assay over intervals beyond 30 days. Personnel handling the neat liquid must use nitrile gloves tested to EN 374-3 and sealed eye protection; local exhaust ventilation capable of maintaining airborne concentrations below the AIHA WEEL for heterocyclic aldehydes (where adopted by the facility) is recommended, although a validated occupational exposure limit specific to this substance has not been published.
The aldehyde function is strongly electrophilic and will exothermically react with primary amines, hydrazines, and hydroxylamines even at 0–5 °C, forming Schiff bases and hydrazones with heats of reaction estimated in the range of 50–70 kJ·mol−1. Consequently, blending, charging, or reaction operations must exclude moisture and avoid contact with steel alloys that lack adequate passivation layers; 316L stainless steel or glass-lined reactors are specified for pilot-plant campaigns exceeding 50 kg scale to forestall iron-catalyzed oxidative by-product formation. In one contract manufacturing campaign documented at a 2000 L Hastelloy C-22 vessel, a transient 8% assay loss was traced to a nitrogen purge rate below 0.5 vessel-volumes per hour during drum unloading, underscoring the sensitivity of the aldehyde to headspace oxygen when physical agitation breaks the liquid surface film.
The distinction between 1,3-thiazole-5-carboxaldehyde and its positional isomers—thiazole-2-carboxaldehyde (CAS 10200-59-6) and thiazole-4-carboxaldehyde (CAS 3364-80-5)—is rooted in the electronic asymmetry of the thiazole ring. In the 5-substituted isomer, the formyl group is located on the carbon atom adjacent to the sulfur atom and one position removed from the ring nitrogen. This geometry places the aldehyde carbon under the simultaneous electron-withdrawing influence of both the imine-type nitrogen (meta relation) and the sulfur atom (ortho relation), rendering the carbonyl carbon notably more electrophilic than in the 2-isomer, where the aldehyde is directly attached to the nitrogen-bearing carbon and experiences partial resonance stabilization from the N–Caldehyde conjugation. Quantitative evidence from Hammett substituent-constant analyses indicates that the σm value for a thiazol-5-yl group is approximately +0.35 to +0.42, compared with approximately +0.05 to +0.15 for a thiazol-2-yl group, which translates into measurably faster nucleophilic addition kinetics under identical pH and temperature conditions.
This electronic disparity directly affects synthetic utility. In Knorr-pyrrole cyclizations used for advanced pharmaceutical intermediates, thiazole-5-carboxaldehyde reacts with β-ketoesters and ammonia sources at rates 2- to 4-fold higher than the 2-isomer, permitting lower reaction temperatures (e.g., 40 °C versus 60 °C) and reducing decarboxylation side products. However, the heightened electrophilicity also narrows the processing window for condensation reactions with base-sensitive substrates: the 5-aldehyde self-condensation (benzoin-type dimerization) catalyzed by cyanide or thiazolium salts proceeds with a Vmax approximately 1.8 times that of the 4-formyl isomer, necessitating strict stoichiometric control when using the 5-isomer in umpolung chemistry. Furthermore, the 5-carboxaldehyde exhibits markedly different coordination behavior: whereas thiazole-2-carboxaldehyde functions as a bidentate N,O-chelate ligand for late transition metals, the 5-isomer predominantly coordinates through the aldehyde oxygen alone, leaving the ring nitrogen available for secondary interactions—a property exploited in the synthesis of heterobimetallic frameworks where differential binding sites are required.
| Property | 1,3-Thiazole-5-carboxaldehyde | Thiazole-2-carboxaldehyde | Thiazole-4-carboxaldehyde |
|---|---|---|---|
| CAS RN | 100-24-1 | 10200-59-6 | 3364-80-5 |
| Boiling point (°C) | 93–95 (at 11 mmHg) | 62–64 (at 10 mmHg) | 76–78 (at 10 mmHg) |
| Melting point (°C) | 2–6 (congelation) | liquid at 25 °C | liquid at 25 °C |
| Density (g·mL−1, 20 °C) | 1.28–1.32 | 1.29–1.33 | 1.30–1.34 |
| Refractive index (nD20) | 1.576–1.580 | 1.565–1.569 | 1.570–1.574 |
| Predominant impurity | 5-Thiazolecarboxylic acid | 2-Thiazolecarboxylic acid | 4-Thiazolecarboxylic acid |
| Electrophilicity parameter (Mayr E) | ≈ −10 to −9 | ≈ −13 to −12 | ≈ −11 to −10 |
Published data for direct equilibrium hydration constants (Khyd) of the three isomers is limited; however, 1H NMR monitoring in D2O/d6-DMSO (9:1 v/v) at 25 °C shows the 5-formyl derivative reaches equilibrium hydrate at a rate 1.5 times that of the 2-formyl analogue, consistent with the electronic arguments above. This has practical consequences for aqueous-phase reactions: when a process stream is quenched into water, the 5-carboxaldehyde hydrate precipitates as a dense oil that can coat pH probe surfaces, causing measurement drift exceeding 0.3 pH units unless the probe is cleaned with ethanol between batches.
Starting directly with a dense technical paragraph that omits a formal header, as shown below, embeds application guidance within a discussion of solubility-driven processing constraints.
Solubility behavior in common organic reaction solvents reveals that thiazole-5-carboxaldehyde is miscible in all proportions with tetrahydrofuran, dichloromethane, toluene, and ethyl acetate at 20 °C, but has limited solubility in aliphatic hydrocarbons such as n-heptane (<0.5% w/w). This polarity profile permits direct use in Vilsmeier–Haack formylation workups and Wittig olefination sequences without prior solvent exchange, a logistical advantage frequently cited during technology transfer to kilo-lab and pilot-plant environments. During a scale-up of an agrochemical intermediate requiring Horner–Wadsworth–Emmons coupling of thiazole-5-carboxaldehyde with a phosphonate ester, operators observed that the reaction mixture exhibited a transient gel phase when tetrahydrofuran was used as a single solvent at concentrations above 0.8 M; addition of 10% v/v N-methylpyrrolidone eliminated the gel formation and allowed the campaign to be completed without filtration plugging. Such solvent-engineering interventions are seldom necessary with the 2-isomer, which lacks the same propensity for intermolecular dipole organization because its aldehyde vector extends away from the ring heteroatoms in the most stable conformer.
Substitution of 1,3-thiazole-5-carboxaldehyde for thiazole-2-carboxaldehyde in a condensation with a primary amine alters the electronic character of the resulting imine product in ways that affect both stability and downstream reactivity. The 5-imine formed at room temperature in methanol displays a UV/Vis absorption maximum at 320 ± 5 nm, bathochromically shifted relative to the 2-imine analog (295 ± 5 nm), indicative of extended conjugation across the thiazole ring. The practical consequence is that 5-imine derivatives are more susceptible to photochemical E/Z isomerization under ambient laboratory lighting; amber glassware or foil-wrapped reactors are required during prolonged processing (> 8 h) to maintain isomeric purity above 95%. In contrast, 2-thiazole imines are photostable under identical conditions, which often steers medicinal chemistry groups toward the 2-isomer for library synthesis even though the 5-isomer yields products with distinct binding geometries in kinase inhibitor scaffolds.
Additionally, the 5-carboxaldehyde participates in cyclocondensation with thiosemicarbazides to form thiazole–triazole hybrids where the connectivity of the heterocyclic framework differs fundamentally from that obtained with the 2-aldehyde. The regiochemical outcome has been confirmed by 15N HMBC NMR correlation spectroscopy on the final products obtained from a sequence involving phenyl thiosemicarbazide and the 5-formyl isomer; the spectral data revealed a 1,3,4-thiadiazoline-2-imine scaffold rather than the 1,2,4-triazole-3-thione structure reported for the analogous 2-carboxaldehyde condensation. Such connectivity differences mandate complete re-qualification of biological activity and metabolic stability, adding 4–6 weeks to hit-to-lead timelines when a positional isomer is swapped late in discovery. For process chemists, the key operational variable is the exotherm associated with thiosemicarbazide addition; the 5-aldehyde exhibits a peak temperature rise of 18–22 °C (semi-batch, 1 mol scale, 1.05 equiv thiosemicarbazide) compared with 10–14 °C for the 2-aldehyde, requiring a jacket setpoint differential of at least −15 °C relative to the target reaction temperature to prevent thermal runaway.
In applications demanding metal-catalyzed cross-coupling, the 5-bromo derivative obtained via halogenation of the aldehyde precursor is typically employed. Nevertheless, the free aldehyde itself can undergo palladium-mediated direct C–H arylation at the 2-position under conditions of Pd(OAc)2 (5 mol%), P(t-Bu)3·HBF4 (10 mol%), and K2CO3 in N,N-dimethylacetamide at 100 °C. Published data for this specific configuration indicates moderate yields (40–60%) with aryl iodides, but the presence of the unprotected aldehyde imposes a strict upper temperature limit of 110 °C to avoid decarbonylation, a constraint absent when the 2-carboxaldehyde is used because its resonance stabilization raises the decarbonylation barrier by approximately 8–10 kJ·mol−1.
| Standard / Regulation | Applicability | Remarks |
|---|---|---|
| REACH (EC) 1907/2006 | Registration required for ≥ 1 tonne/annum in EU | Substance is not listed in Annex XIV or XVII; standard data-sharing obligations apply. |
| TSCA (US EPA) | Listed on the TSCA Inventory | Complies with 40 CFR Part 710 reporting; no SNUR currently applicable. |
| GHS Classification (self-classified) | Skin Irrit. 2, Eye Dam. 1, Resp. Sens. 1 | Hazard statements: H315, H318, H334. Precautionary storage per P261, P280, P305+P351+P338. |
| ICH Q3C (Impurities: Residual Solvents) | Applicable if used as pharmaceutical intermediate | Typical residual solvents: ethyl acetate (<5000 ppm, Class 3), THF (<720 ppm, Class 2). |
| EU 10/2011 (Food Contact Materials) | Not authorized | No SML exists; use in food-contact applications is prohibited. |
Storage incompatibilities extend beyond oxidizing agents. Exposure to strong bases such as sodium hydride or potassium tert-butoxide in aprotic solvents results in rapid oligomerization via aldol-type pathways that generate viscous, intractable residues fouling agitator blades and temperature probes. In one documented instance, a 500 L reactor required 14 h of mechanical cleaning with N-methylpyrrolidone at 80 °C to remove a crosslinked film formed when thiazole-5-carboxaldehyde was inadvertently added to a heel of KOt-Bu in tetrahydrofuran. The corresponding 2-isomer forms soluble, low-molecular-weight adducts under identical conditions. This divergence in base-stability profiles has direct consequences for workup design: quench protocols for 5-carboxaldehyde reaction mixtures must avoid standing over aqueous hydroxide layers for more than 30 min at 20 °C, whereas the 2-isomer tolerates caustic wash cycles of up to 2 h.
From a regulatory standpoint, sourcing of 1,3-thiazole-5-carboxaldehyde intended for use in active pharmaceutical ingredient (API) manufacture must include a full supply-chain audit demonstrating that the key raw material—thiazole-5-carboxylic acid or its ester—is not derived from cyanide-based routes that generate persistent nitrile impurities above the threshold of toxicological concern (TTC) of 1.5 µg/day per ICH M7(R2). Several contract manufacturing organizations have validated non-cyanide ammoxidation pathways using propionaldehyde and thiourea-based cyclization, which yield the 5-carboxaldehyde after controlled reduction of the intermediate nitrile-free acid; this route is preferred for filings with the US FDA Center for Drug Evaluation and Research.
