2-Chlorothiophene-3-carboxylic Acid: Properties & Lab Guide

2-Chlorothiophene-3-carboxylic acid is a halogenated thiophene-based heterocyclic carboxylic acid widely employed as a versatile building block in pharmaceutical synthesis, agrochemical research, and the preparation of advanced organic intermediates.

CAS Number

4553-39-3

Molecular Formula

C5H3ClO2S

Molecular Weight

162.59 g/mol

Appearance

White to off-white crystalline solid

Functional Groups

Aromatic chloride, carboxylic acid, thiophene ring

Aladdin SKU

C185082

Chemical Identity and Physical Properties

2-Chlorothiophene-3-carboxylic acid (CAS 4553-39-3) is a chlorine-substituted thiophene ring system bearing a carboxylic acid group at the 3-position. Its molecular formula is C5H3ClO2S with a molecular weight of approximately 162.59 g/mol. The compound typically presents as a white to off-white crystalline solid at ambient temperature.

The simultaneous presence of an electron-withdrawing chloro substituent at the 2-position and a carboxylic acid group at the 3-position imparts distinctive reactivity to the thiophene ring. The carboxylic acid moiety enables participation in esterification, amide bond formation, and decarboxylation reactions, while the C–Cl bond serves as a handle for metal-catalyzed cross-coupling reactions such as Suzuki, Negishi, and Buchwald–Hartwig couplings. The compound is expected to be sparingly soluble in water but soluble in common polar organic solvents such as methanol, ethanol, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF).

Synthesis Applications and Reactivity

2-Chlorothiophene-3-carboxylic acid serves as a key heterocyclic building block in medicinal chemistry and materials science. Its bifunctional nature — combining a reactive aryl chloride with a carboxylic acid on a sulfur-containing aromatic scaffold — makes it highly valuable for multi-step synthesis strategies.

Carboxylic acid reactivity: The –COOH group can be converted to acid chlorides using thionyl chloride or oxalyl chloride, to esters via Fischer esterification or DCC-mediated coupling, and to amides through coupling reagents such as EDC/HOBt or HATU. These transformations provide direct access to thiophene-containing esters, amides, and peptidomimetic fragments relevant to drug discovery.

Cross-coupling reactions: The aryl C–Cl bond, though less reactive than aryl bromides or iodides, participates in palladium- and nickel-catalyzed cross-coupling reactions under optimized conditions. Selective functionalization at C-2 allows construction of complex biaryl or heteroaryl architectures.

Pharmaceutical relevance: Thiophene carboxylic acid derivatives are recurring structural motifs in bioactive molecules targeting enzymes, ion channels, and G-protein-coupled receptors (GPCRs). The chloro substituent can modulate lipophilicity and electronic properties, influencing potency and selectivity.

Handling, Storage, and Stability Guidelines

Personal protective equipment (PPE): When handling 2-Chlorothiophene-3-carboxylic acid, researchers should wear appropriate PPE including chemical-resistant gloves (nitrile recommended), safety goggles, and a laboratory coat. Work should be performed in a well-ventilated fume hood to avoid inhalation of dust or aerosols.

Storage conditions: Store the compound in a tightly sealed container in a cool, dry, well-ventilated area, away from incompatible materials such as strong oxidizers and strong bases. Refrigerated storage (2–8 °C) is generally recommended to preserve long-term stability. Keep away from moisture to prevent hydrolysis or degradation of the solid.

Stability: As a solid aromatic carboxylic acid, 2-Chlorothiophene-3-carboxylic acid is expected to be stable under recommended storage conditions. Avoid prolonged exposure to heat, light, and moisture. The compound should be re-sealed promptly after each use.

Disposal: Dispose of in accordance with local, regional, and national regulations governing halogenated organic waste. Do not discharge into drains or the environment without appropriate treatment.

Purity, Quality Specifications, and Procurement

For research applications, 2-Chlorothiophene-3-carboxylic acid should be obtained at the highest achievable purity to ensure reproducibility of experimental results. Aladdin Scientific offers this compound under SKU C185082.

Typical quality checks for heterocyclic carboxylic acid building blocks include:

• Purity assessment: High-performance liquid chromatography (HPLC) or gas chromatography (GC) purity determination.
• Structural confirmation: Nuclear magnetic resonance (NMR) spectroscopy (1H and 13C) and mass spectrometry (MS) to confirm identity.
• Halogen content: Elemental analysis or ion chromatography to verify chlorine content consistent with the molecular formula.
• Melting point: Determination and comparison with literature values as an additional purity indicator.

Researchers should request a Certificate of Analysis (CoA) at the time of purchase to confirm lot-specific purity and quality data. For scale-up or GMP-adjacent work, additional documentation may be required from the supplier.

Frequently asked questions

What solvents are suitable for dissolving 2-Chlorothiophene-3-carboxylic acid?

2-Chlorothiophene-3-carboxylic acid is expected to dissolve readily in polar organic solvents such as methanol, ethanol, DMSO, and THF. It is sparingly soluble in water due to its aromatic, lipophilic character; solubility in water can be improved by deprotonating the carboxylic acid with dilute base to form the corresponding carboxylate salt.

Can 2-Chlorothiophene-3-carboxylic acid undergo palladium-catalyzed cross-coupling reactions?

Yes, the aryl C–Cl bond in 2-Chlorothiophene-3-carboxylic acid can participate in palladium-catalyzed cross-coupling reactions, though aryl chlorides typically require more active catalyst systems (e.g., bulky phosphine or NHC ligands) compared to aryl bromides or iodides. Careful optimization of catalyst loading, ligand, base, and temperature is recommended for efficient coupling.

How should 2-Chlorothiophene-3-carboxylic acid be stored to maintain stability?

The compound should be stored in a tightly sealed container under cool, dry, and well-ventilated conditions, preferably at 2–8 °C, away from moisture, strong oxidizers, and strong bases. Consistent refrigerated storage and prompt re-sealing after each use are recommended to ensure long-term stability and preserve analytical purity.

What are the primary synthetic uses of 2-Chlorothiophene-3-carboxylic acid in medicinal chemistry?

In medicinal chemistry, 2-Chlorothiophene-3-carboxylic acid is used as a bifunctional building block to introduce a sulfur-containing heteroaromatic scaffold into drug candidates. The carboxylic acid group enables amide bond formation and esterification, while the aryl chloride allows further diversification via cross-coupling. Thiophene-based fragments are present in a range of pharmacologically active compounds targeting diverse therapeutic areas.

References

1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed. Wiley-Interscience, 1992. (General reference for carboxylic acid and aryl halide reactivity.)
2. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed. Wiley-Blackwell, 2010. (Thiophene chemistry and reactivity reference.)
3. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis. VCH, 1996. (Illustrative reference for building block strategy in complex molecule synthesis.)

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