1,3-Thiazole-2-Carbaldehyd
|
HS Code |
428539 |
| Chemical Formula | C4H3NOS |
| Molar Mass | 113.14 g/mol |
| Appearance | Colorless to pale yellow liquid |
| Boiling Point | 204 - 205 °C |
| Melting Point | N/A |
| Density | 1.339 g/cm³ |
| Solubility In Water | Slightly soluble |
| Solubility In Organic Solvents | Soluble in common organic solvents like ethanol, ether |
| Flash Point | 87 °C |
| Odor | Pungent odor |
As an accredited 1,3-Thiazole-2-Carbaldehyd factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of 1,3 - Thiazole - 2 - Carbaldehyde packaged in a sealed, chemical - resistant bottle. |
| Shipping | 1,3 - Thiazole - 2 - Carbaldehyde is shipped in carefully sealed containers, ensuring no leakage. Shipment follows strict chemical transportation regulations, with appropriate labeling for safe handling during transit to the destination. |
| Storage | 1,3 - Thiazole - 2 - Carbaldehyde should be stored in a cool, dry, well - ventilated area, away from heat sources and open flames. Keep it in a tightly sealed container to prevent evaporation and contact with air, which could lead to oxidation. Store it separately from incompatible substances like oxidizing agents and bases. Protect from sunlight to maintain its chemical integrity. |
During the synthesis of late-stage oxime ether cephalosporin intermediates, the carbonyl group of 1,3-thiazole-2-carbaldehyde acts as the electrophilic anchor point for constructing the 2-aminothiazole oxime pharmacophore that confers β-lactamase stability. The aldehyde is introduced at a molar ratio of 1.02–1.10 relative to the 7-amino core in a glass-lined steel reactor (2,500–5,000 L jacket volume) to compensate for minor evaporative losses through the nitrogen sweep while preventing the accumulation of unreacted aldehyde that crosslinks amine-bearing intermediates into insoluble oligomers. The primary conversion protocol proceeds under anhydrous dimethylacetamide (water content ≤150 ppm by Karl Fischer) with anhydrous hydroxylamine hydrochloride added as a free-flowing powder, carefully controlling the exotherm so that the internal temperature never exceeds -8 °C during the first 90 minutes; a jacket setpoint of -15 °C is standard across multi-ton campaigns. Plant-scale data recorded across 11 batches in a 3,000 L facility confirm that a deviation of merely +4 °C within this critical window shifts the oxime geometric ratio from (E):(Z) = 94:6 to 78:22, lowering the coupling efficiency with the subsequent chloroacetyl cephalosporin nucleus by 18–23% and forcing a labour-intensive recrystallization from isopropanol/water (3:1 v/v) that adds 14 hours to cycle time. Validated analytical release for the resulting intermediate mandates reversed-phase HPLC per USP <621> with a purity acceptance criterion of ≥98.5 area% and single unknown impurities limited to 0.15 area%. Residual solvent limits are aligned with ICH Q3C Option 2: dimethylacetamide not exceeding 1,090 ppm, acetone below 5,000 ppm. The entire workflow is conducted under ICH Q7 GMP for active pharmaceutical ingredient starting materials, with change control records linking every batch to a specific manufacturing authorization number under EU GMP Part II. Operational boundaries are rigid: exposure to relative humidity above 55% during post-reaction work-up causes rapid dimerisation of the aldehyde to a thiazole-fused imidazolidinone, therefore all centrifuge operations must be executed under a nitrogen blanket with an oxygen threshold of ≤2.0 vol%. The terminal product stream entering the next GMP step is an off-white crystalline 2-(thiazolyl)oxime intermediate that serves as the direct precursor to fourth-generation cephalosporin APIs whose monographs appear in the European Pharmacopoeia monographs 10.0.
What Limits Condensation Yield in SDHI Fungicide Intermediate Production?When 1,3-thiazole-2-carbaldehyde is employed as the carbonyl partner in the assembly of thiazole-core succinate dehydrogenase inhibitor fungicides, the critical performance bottleneck resides in the condensation with aniline derivatives bearing electron-withdrawing substituents on the para position—a motif essential for mitochondrial complex II binding. In a standard industrial protocol run in a jacketed 2,000 L enamel reactor equipped with a packed distillation column, the aldehyde is charged at a mole fraction of 1.05:1.0 relative to the substituted aniline, combined with 0.5 mol% of p-toluenesulfonic acid monohydrate, and suspended in cyclohexane that azeotropically removes water. The internal temperature profile follows a ramp-and-hold loop: initial reflux at 81–83 °C for 3.5 hours, then stepwise dehydration until the overhead water content drops below 200 ppm by online Karl Fischer, at which point the setpoint is raised to 105 °C for 1.5 hours to drive the equilibrium past 97% conversion. Plant data collected during a 14-batch validation exercise showed that when the temperature overshoot exceeds 6 °C during the dehydration plateau, the formation of a dark-coloured bisanil impurity accelerates from 0.3% w/w to 1.8% w/w, contributing a brown chromophore to the crude isolate that persists through the final recrystallization from toluene/n-heptane (1:3 v/v). To meet the FAO Specification 483/TC colour limit—a Gardner value ≤5.0 for the technical grade active ingredient—a post-synthesis adsorption step over 2.0 wt% activated charcoal (Norit SX Plus, sieved through 150 mesh) is mandatory whenever the batch absorbance at 450 nm exceeds 0.35 AU in a 1 cm cell at 10 mg/mL in acetonitrile. The final product, a pale-yellow crystalline thiazole carboxamide, enters the formulation chain as a 980 g/kg minimum technical concentrate used to manufacture flowable suspension concentrates for seed treatment of cereals and legumes; shelf-life stability under 54 °C accelerated storage (CIPAC MT 46.1) must demonstrate less than 0.5% weekly degradation over 14 weeks. It is imperative to exclude any residual tertiary amines in the aldehyde feedstock because even 0.05% w/w triethylamine triggers premature aldol oligomerisation in the storage tank, forming a sludge that clogs the micronising jet mill during formulation.Thermal processing of meat flavour reaction bases intended for dry-mix soups and retorted pet food formulations often demands a carbonyl donor that can simultaneously bind cysteine-derived sulfhydryl groups and release volatile thiazole odorants under extrusion shear. 1,3-Thiazole-2-carbaldehyde can be pre-dispersed in a vegetable fat carrier at 5.0 wt% loading and injected into the barrel of a co-rotating twin-screw extruder (L/D = 32:1) operating at a screw speed of 280 rpm and a barrel temperature profile of 110 °C / 125 °C / 140 °C / 120 °C. Under these conditions the aldehyde reacts with free cysteine and reducing xylose in a sequential Maillard cascade, generating a volatile profile dominated by 2-acetylthiazole and 5-methyl-2-thiazolecarboxaldehyde, with a cumulative aroma dilution factor exceeding 104 in model aqueous systems. The dosage rarely exceeds 0.15 wt% of the final reaction mass because concentrations above 0.22 wt% yield an undesirable sulfurous burnt note characterised by a headspace methanethiol concentration > 50 ng/L (quantified by SPME-GC-PFPD). Regulatory compliance for the precursor is framed by EU Regulation 1334/2008, meaning the substance must be declared as a flavour precursor or processing aid; its status under FEMA GRAS is indirect—the agency evaluates the entire reaction product, not the isolated aldehyde input—so commercial distributors provide a food-grade certificate of analysis referencing FCC 13 identity tests and a heavy metals ceiling of ≤2 ppm lead. The resulting process flavour complexes, pelletised immediately after the extruder die and dried to a water activity below 0.4, function as the base note in cooked beef and roasted coffee flavour systems that target a shelf stability of 18 months in laminate packaging. A well-documented failure mode emerges when the barrel residence time exceeds 45 seconds: the thiazole ring undergoes oxygen-mediated scission to form non-volatile N-formyl-cysteamine derivatives, slashing the total flavour yield by 40–55% and creating a bitter aftertaste detectable by a trained QDA panel.Luminescent Heteroleptic Iridium(III) Complexes and Coordination PolymersThe electron-deficient thiazole ring of the aldehyde makes it a suitable precursor for synthesizing bidentate Schiff base ligands that stabilise heavy metal centres in luminescent materials and solvent extraction agents. A representative procedure adds 1 equivalent of 1,3-thiazole-2-carbaldehyde to 1 equivalent of 2-aminopyridine or hydrazine hydrate in degassed absolute ethanol, heating the mixture at 70 °C for 6 hours under argon to furnish a shelf-stable imine ligand in yields typically exceeding 90%. The ligand is subsequently metallated with iridium trichloride hydrate in a 2‑ethoxyethanol/water mixture (3:1 v/v) to yield cyclometalated iridium(III) dimers that, after cleavage with acetylacetone, produce phosphorescent dopants emitting in the orange-red region (λPL = 605–620 nm) with photoluminescence quantum yields reaching 0.48 in degassed dichloromethane. The shelf life of the free aldehyde under ambient laboratory light is limited because photochemical [2+2] cycloaddition produces a head-to-tail dimer within 72 hours; therefore, bulk stocks are stored in dark amber glass vessels under refrigeration at +4 °C ± 2 °C. Industrial-scale supply for this application does not fall under pharmacopoeial or food-chemical regulations, but suppliers typically comply with ISO 9001:2015 quality management and provide a REACH registration dossier confirming the substance’s status as an exempted intermediate under strictly controlled conditions. Coordination compounds built from the aldehyde-derived ligands have been incorporated into polymeric matrix sensors for naked-eye copper(II) detection, where a colourimetric response from yellow to red develops within 10 seconds at analyte concentrations as low as 1.2 μM. Published peer-reviewed data for large-scale device integration of this specific thiazole ligand remains sparse, limiting process design to bench-scale synthesis without validated continuous flow parameters; attempts to adapt the condensation to a Corning® Advanced-Flow reactor at a partial filling factor of 30% resulted in unacceptable clogging after 45 minutes due to nucleophilic attack of the product imine on the aldehyde feed. |
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1,3‑Thiazole‑2‑carbaldehyde (CAS 10200‑59‑6, molecular formula C₄H₃NOS, formula weight 113.14 g mol⁻¹) is supplied as a pale yellow, low‑melting solid (mp 35‑37 °C) that transitions to a clear liquid above 40 °C. The heterocyclic aldehyde, also referred to as 2‑formylthiazole, bears the reactive formyl group at the 2‑position of the 1,3‑thiazole ring, directly adjacent to both the sulfur and nitrogen heteroatoms. This structural arrangement imparts a distinctive electronic profile: the ring nitrogen acts as an electron‑withdrawing element, enhancing the electrophilicity of the carbonyl carbon and rendering the compound a versatile electrophile in condensation, nucleophilic addition, and cross‑coupling reactions. Commercial batches are routinely employed as a key building block in the synthesis of pharmaceutical active ingredients—including histamine H₃ receptor antagonists and kinase inhibitors—as well as agrochemical fungicides such as thifluzamide. The product is manufactured under an ISO 9001:2015‑certified quality management system and is typically offered in 100 g, 1 kg, and 25 kg net‑weight packs tailored to laboratory‑scale to pilot‑plant demand.
| Parameter | Specification | Method |
|---|---|---|
| Assay (GC FID) | ≥ 98.0 % area | Agilent 7890B GC, DB‑5 capillary column (30 m × 0.25 mm I.D., 0.25 μm film), temperature program 80 °C (1 min hold) to 250 °C at 15 °C min⁻¹, split ratio 50:1; quantification against an external standard of 99.5 % purity (traceable to NIST SRM). |
| Water content | ≤ 0.5 % w/w | Coulometric Karl Fischer titration (Metrohm 831 KF Coulometer) per USP 〈921〉 Method Ia. |
| Melting point | 35.0 – 37.0 °C | Capillary tube method, Büchi B‑545 apparatus, heating rate 1 °C min⁻¹ near the melt, conforming to USP 〈741〉 Class II. |
| Appearance | Pale yellow liquid above 40 °C; may solidify upon cooling | Visual inspection against a white background under D65 illumination. |
| Heavy metals (as Pb) | ≤ 10 ppm | Inductively coupled plasma optical emission spectrometry (ICP‑OES) after digestion, following USP 〈233〉. |
| Residual solvents | Toluene ≤ 200 ppm, Dichloromethane ≤ 50 ppm | Headspace GC‑MS per USP 〈467〉 Procedure A. |
The electron‑withdrawing influence of the thiazole ring nitrogen (σm ≈ 0.53 for the 2‑position) activates the aldehyde towards nucleophilic addition, making Knoevenagel-type condensations with active methylene compounds proceed under mild conditions. In a representative procedure, 100 mmol of 1,3‑thiazole‑2‑carbaldehyde is stirred with 105 mmol of ethyl cyanoacetate in 100 mL of ethanol containing 0.5 mL piperidine as catalyst at 60 °C for 3 h. The resulting α‑cyanoacrylate derivative precipitates upon cooling and is isolated by filtration, washed with cold ethanol (2 × 10 mL), and dried at 40 °C under vacuum (10 mbar) to yield 85 % of a pale yellow solid with HPLC purity > 99.5 % (C18 column, acetonitrile/water 75:25, UV detection at 254 nm). The same reaction with 4‑thiazolecarbaldehyde under identical conditions requires 8 h to reach comparable conversion, reflecting the attenuated electrophilicity at the 4‑position. This differential reactivity is a key distinguishing feature exploited in the design of consecutive one‑pot transformations where selective mono‑functionalisation is required.
While the aldehyde itself can engage in palladium‑catalyzed couplings as a substrate if suitably functionalized, the most common role of 1,3‑thiazole‑2‑carbaldehyde in late‑stage diversification is as the core structure where halogen substituents—introduced regioselectively at the 5‑position—undergo Suzuki‑Miyaura or Sonogashira cross‑coupling with the aldehyde remaining intact. A routine coupling employs 5‑bromo‑1,3‑thiazole‑2‑carbaldehyde, arylboronic acid (1.2 eq.), Pd(PPh₃)₄ (2 mol%), and 2 M K₂CO₃ in dioxane/water (4:1 v/v) at 80 °C for 12 h. After extraction with ethyl acetate, the biaryl aldehyde is obtained in 72–88 % isolated yield after flash chromatography (silica gel 60, hexane/EtOAc gradient). The tolerance of the aldehyde moiety to aqueous base is noteworthy; no evidence of Cannizzaro disproportionation is observed under these conditions, an advantage over certain pyridine‑2‑carbaldehydes where side reactions can reduce yield by 15–20 %. This robustness stems from the greater electronegativity difference between the sulfur and nitrogen atoms in the thiazole ring, which stabilizes the negative charge on the ring during potential hydride shifts. The yield range reflects the electronic nature of the arylboronic acid partner; electron‑withdrawing substituents on the boronate generally accelerate transmetallation, pushing yields towards the upper bound.
Carboxylic acid surrogates derived from 1,3‑thiazole‑2‑carbaldehyde are frequently employed in amide‑coupled pharmacophores. Oxidation with sodium chlorite (NaClO₂) in the presence of 2‑methyl‑2‑butene as a hypochlorite scavenger at 0 °C cleanly converts the aldehyde to thiazole‑2‑carboxylic acid in 90 % yield after acidification. Subsequent activation with HATU and N,N‑diisopropylethylamine (3 eq.) in DMF allows rapid amidation with primary or secondary amines at room temperature (2 h), a method widely adopted in combinatorial library synthesis. Compared to the analogous pyridine‑2‑carboxylic acid, the thiazole acid exhibits a lower pKₐ (~2.1 vs. ~2.8 for the pyridinium conjugate acid), which favours faster activation under basic coupling conditions. Importantly, the thiazole ring’s resistance to reductive hydrogenation enables global deprotection of benzyl‑protected amines via catalytic hydrogenation (10 % Pd/C, 1 atm H₂, ethanol) without ring saturation—a distinct advantage over pyridine‑based scaffolds that can undergo partial reduction under the same conditions.
The position of the aldehyde group on the thiazole ring strongly modulates reactivity. Under competitive semicarbazone formation in 50 % aqueous ethanol at 25 °C (pseudo‑first‑order conditions, semicarbazide hydrochloride 10× excess, monitored by UV at 280 nm), the three regioisomeric aldehydes display distinct kinetics. The data below summarise the comparative reactivity and ancillary physical properties relevant to synthetic planning.
| Parameter | 2‑CHO | 4‑CHO | 5‑CHO |
|---|---|---|---|
| CAS registry | 10200‑59‑6 | 3364‑80‑5 | 1003‑04‑9 |
| Molecular weight (g mol⁻¹) | 113.14 | 113.14 | 113.14 |
| Melting point (°C) | 35‑37 | 52‑54 | oil at 25 °C |
| pKa of conjugate acid (ring N) | 2.4 (est.) | 2.5 (est.) | 3.0 (est.) |
| 13C NMR δC=O (ppm, CDCl3) | 184.2 | 181.5 | 182.9 |
| Rate constant (k, M−1 s−1) for semicarbazone formation | 0.48 | 0.19 | 0.36 |
| Suzuki coupling efficiencya | 72‑88 % | 52‑70 %b | 60‑78 %b |
aTypical yield of 5‑aryl derivatives using Pd(PPh3)4 (2 mol%) with 4‑methoxyphenylboronic acid under the conditions described above. bFor 4‑ and 5‑formylthiazoles, the bromo precursor was prepared via direct electrophilic bromination of the corresponding aldehyde.
The softer sulfur donor atom in the thiazole ring shifts the coordination chemistry of 1,3‑thiazole‑2‑carbaldehyde away from that of pyridine‑2‑carbaldehyde. When reacted with 1 eq. of CuCl2·2H2O in ethanol at reflux, 2‑formylthiazole yields a neutral, mononuclear complex formulated as [Cu(C4H3NOS)2Cl2]. Single‑crystal X‑ray diffraction data (collected at 100 K on a Bruker D8 Venture diffractometer, Mo Kα radiation) reveal a distorted octahedral geometry where the thiazole ligands chelate via the aldehyde oxygen and the ring nitrogen, with the sulfur atom remaining uncoordinated. The Cu–O bond length of 2.18 Å and the Cu–N bond length of 2.02 Å create a bite angle of 72°, significantly narrower than the 79° bite angle observed for the analogous pyridine‑2‑carbaldehyde complex. This geometric distortion weakens ligand field splitting and modifies the complex’s redox potential, making the thiazole‑based complex a more labile pre‑catalyst in atom‑transfer radical addition reactions. By contrast, the pyridine analog overwhelmingly favours square‑planar geometry with noticeably slower ligand exchange rates (t½ ≈ 4 h vs. 0.5 h for the thiazole complex in acetonitrile at 25 °C, measured by 1H NMR line broadening).
The product is moisture‑sensitive; exposure leads to hydration of the aldehyde group to the gem‑diol, detectable by the appearance of a new 13C NMR resonance at δ 93.5 ppm. At 25 °C and 75 % relative humidity, the assay drops below 95 % within 24 h when stored in a loosely capped container. Consequently, all containers must be purged with dry nitrogen (dew point ‑40 °C) and sealed with a PTFE‑lined cap. For long‑term storage, the material is packaged under argon in amber glass bottles with molecular sieve 4A (activation at 300 °C for 4 h) as in‑bottle desiccant. Under these conditions, retest dating of 12 months is assigned, supported by real‑time stability data at 25 °C/60 % RH and accelerated 40 °C/75 % RH per ICH Q1A(R2).
In a 500 L glass‑lined reactor (Pfaudler, jacket temperature range ‑10 °C to 150 °C) commissioned for an imine intermediate serving the fungicide thifluzamide, 45.0 kg (398 mol) of 1,3‑thiazole‑2‑carbaldehyde was charged through a DN 100 top‑entry nozzle under a nitrogen sweep. The vessel was pre‑cooled to ‑5 °C before adding 1.05 eq. of 2‑chloro‑4‑(trifluoromethyl)aniline in 200 L of toluene. Triethylamine (0.05 eq.) was then dosed over 45 min, maintaining the internal temperature below 0 °C to avoid a runaway condensation exotherm (estimated ΔTad > 80 °C under adiabatic conditions). After 6 h at 0‑5 °C, in‑process HPLC indicated 98 % conversion. The reaction mass was warmed to 20 °C, washed with water (2 × 100 L), and concentrated to 80 L. Crystallisation from isopropanol/water (3:1 v/v) at ‑10 °C furnished 49.2 kg of the imine as a pale yellow crystalline solid, isolated yield 91 % with 99.2 % HPLC purity. Batch records show that the process is sensitive to agitation speed: at stirring rates below 80 rpm (retreat‑curve impeller, diameter‑to‑tank ratio 0.5), localised hotspots develop, leading to impurity formation at 2‑3 % higher than specification.
The substance is manufactured in compliance with EU REACH Regulation (EC) No 1907/2006; the supply chain benefits from a fully registered dossier that includes a Chemical Safety Report (CSR) covering the lifecycle stages from production to formulation. Transport classification under UN3077 (Environmentally hazardous substance, solid, n.o.s.) requires packaging in UN‑certified containers (4G fibreboard boxes with inner PE liner). Toxicological screening according to OECD TG 402 (acute dermal toxicity) and TG 403 (acute inhalation toxicity) indicates a moderate hazard profile with an oral LD₅₀ (rat) of 315 mg kg⁻¹, placing the compound in GHS Category 4 for acute toxicity. No monograph exists in major pharmacopoeias; however, in‑house analytical methods are validated per ICH Q2(R1) guidelines, and the product is supplied with a certificate of analysis that includes traceability to NIST SRM 1647f (Priority Pollutant Metals) for the heavy metals specification.
