2-Chloro-4-(trifluoromethyl)pyridine: Properties & Uses

2-Chloro-4-(trifluoromethyl)pyridine is a halogenated, electron-deficient fluorinated pyridine building block widely used in pharmaceutical and agrochemical synthesis as a versatile electrophilic intermediate.

CAS Number

65753-47-1

Molecular Formula

C6H3ClF3N

Molecular Weight

181.54 g/mol

Appearance

Colorless to pale yellow liquid

Key Functional Groups

Chloro substituent at C-2; trifluoromethyl group at C-4 of the pyridine ring

Primary Application Areas

Pharmaceutical synthesis, agrochemical synthesis, materials research

Chemical Identity and Structure

2-Chloro-4-(trifluoromethyl)pyridine (CAS 65753-47-1, SKU C124360) is a disubstituted pyridine bearing a chlorine atom at the 2-position and a trifluoromethyl (–CF3) group at the 4-position of the aromatic ring. Its molecular formula is C6H3ClF3N with a molecular weight of approximately 181.54 g/mol. The combination of two strongly electron-withdrawing substituents renders the pyridine ring highly electron-deficient, making the compound an activated electrophile susceptible to nucleophilic aromatic substitution (SNAr) at the C-2 chloro position. This reactivity profile distinguishes it from simple chloropyridines and underpins its broad utility as a synthetic building block.

Physical and Chemical Properties

2-Chloro-4-(trifluoromethyl)pyridine is typically encountered as a colorless to pale yellow liquid at room temperature. The trifluoromethyl group imparts high lipophilicity, metabolic stability, and strong inductive electron-withdrawal to molecules in which it is incorporated. The C–Cl bond at the ortho position relative to the ring nitrogen is activated toward displacement by a range of nucleophiles including amines, alkoxides, and thiolates under mild conditions, often without the need for transition-metal catalysis. The compound is moisture-sensitive and should be handled under inert-atmosphere conditions when high purity is required for sensitive reactions.

Research and Synthetic Applications

The principal application of 2-Chloro-4-(trifluoromethyl)pyridine is as a key building block in medicinal chemistry and agrochemical synthesis. In drug discovery, trifluoromethylpyridine motifs are incorporated into candidate molecules to improve bioavailability, binding affinity, and metabolic stability. The C-2 chloro group serves as a handle for SNAr reactions with amine nucleophiles to construct 2-aminopyridine pharmacophores, or with organometallic reagents (e.g., Suzuki, Negishi, or Kumada coupling partners) to access biaryl frameworks. In agrochemistry, trifluoromethylpyridine-containing compounds are important in the design of insecticides, herbicides, and fungicides. The compound is also useful in materials science for the preparation of fluorinated ligands and coordination polymers.

Safe Handling, Storage, and Disposal

As with all halogenated aromatic compounds, 2-Chloro-4-(trifluoromethyl)pyridine should be handled with appropriate personal protective equipment including nitrile gloves, safety goggles, and a laboratory coat. Work should be conducted in a well-ventilated fume hood. The compound should be stored in a tightly sealed container in a cool, dry, well-ventilated area, away from incompatible materials such as strong bases and oxidizers. Consult the Safety Data Sheet (SDS) supplied with the product for complete hazard classification, first-aid measures, and regulatory information before use. Disposal must comply with local, regional, and national regulations for halogenated organic waste.

Ordering, Specification, and Quality

2-Chloro-4-(trifluoromethyl)pyridine is available from Aladdin Scientific under SKU C124360. Researchers should confirm purity specification (e.g., GC purity ≥97% or ≥98%) against their application requirements at the time of ordering, as multiple purity grades may be offered. Certificate of Analysis (CoA) documents, including NMR, GC, and other quality-control data, are available upon request or via the product page. For bulk quantities or custom specifications, contact Aladdin Scientific's sales team directly. Proper lot-specific documentation supports regulatory submissions and internal quality-management requirements.

Frequently asked questions

What is 2-Chloro-4-(trifluoromethyl)pyridine used for in organic synthesis?

It is primarily used as an electrophilic building block in SNAr reactions, where the C-2 chloro group is displaced by amine, alkoxide, or thiolate nucleophiles to form new C–N, C–O, or C–S bonds. It also serves as a coupling partner in transition-metal-catalyzed cross-coupling reactions (e.g., Suzuki, Negishi) to construct biaryl scaffolds relevant to drug discovery and agrochemical development.

Why is the trifluoromethyl group important in pharmaceutical and agrochemical applications?

The –CF3 group simultaneously increases lipophilicity, enhances metabolic stability against oxidative degradation, and exerts a strong inductive electron-withdrawing effect that can improve binding affinity at biological targets. These properties make trifluoromethylated heterocycles highly desirable in drug and crop-protection molecule design.

How should 2-Chloro-4-(trifluoromethyl)pyridine be stored to maintain stability?

The compound should be stored in a tightly sealed container under cool, dry, and well-ventilated conditions, away from moisture, strong bases, and oxidizing agents. For long-term storage, an inert atmosphere (nitrogen or argon) is recommended. Always consult the current SDS and CoA for lot-specific stability data.

Is nucleophilic aromatic substitution at C-2 selective over other positions?

Yes. The C-2 position is strongly activated toward SNAr because it is both ortho to the ring nitrogen (which stabilizes the Meisenheimer complex) and bears the chloro leaving group. The C-4 position is occupied by the trifluoromethyl group, further activating C-2 and C-6 toward nucleophilic attack, but C-2 is typically the preferred site for displacement under standard conditions.

What purity grades are available, and how do I obtain a Certificate of Analysis?

Aladdin Scientific offers 2-Chloro-4-(trifluoromethyl)pyridine under SKU C124360; available purity grades should be confirmed on the current product page at time of ordering. Certificates of Analysis (CoA) including GC and NMR data can be requested from Aladdin Scientific customer service or downloaded directly from the product listing using the batch/lot number.

References

1. Uneyama, K. Organofluorine Chemistry. Blackwell Publishing, 2006. (General reference for fluorinated building blocks in synthesis.)
2. Hird, A. W. Trifluoromethyl groups in drug design. In: Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, 2009.
3. Ritter, S. K. 'Fluorine in pharmaceuticals: Looking beyond the fluorine fad.' Chemical & Engineering News, 2009.

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