4-Chloro-2-nitropyridine: Properties, Handling & Synthesis Guide

4-Chloro-2-nitropyridine is a halogenated nitropyridine building block widely used in pharmaceutical, agrochemical, and materials-science research as a versatile electrophilic intermediate for nucleophilic aromatic substitution and further functional-group transformations.

CAS Number

13340-68-6

Molecular Formula

C₅H₃ClN₂O₂

Molecular Weight

158.54 g/mol

Appearance

Light yellow to yellow crystalline solid

Key Reactivity

Electrophilic aromatic ring activated toward SNAr at C-4 position by ortho nitro group

Primary Applications

Pharmaceutical and agrochemical intermediate, heterocyclic synthesis

Chemical Identity and Physical Properties

4-Chloro-2-nitropyridine (CAS 13340-68-6) is a six-membered nitrogen-containing heterocycle bearing a chloro substituent at the 4-position and a nitro group at the 2-position. Its molecular formula is C₅H₃ClN₂O₂ with a molecular weight of 158.54 g/mol. The compound typically presents as a light yellow to yellow crystalline solid at room temperature.

The electron-withdrawing nitro group at the 2-position acts synergistically with the ring nitrogen to strongly activate the carbon–chlorine bond at C-4 toward nucleophilic aromatic substitution (SNAr). This electronic activation is the cornerstone of the compound's synthetic utility. The compound should be stored in a cool, dry, well-ventilated location away from moisture, strong oxidizers, and reducing agents to maintain long-term stability.

Safe Handling, Storage, and Waste Disposal

4-Chloro-2-nitropyridine is an irritant and should be handled with appropriate personal protective equipment (PPE), including chemical-resistant gloves, safety goggles, and a laboratory coat. Operations that may generate dust or aerosol should be performed in a fume hood.

Store the material in a tightly sealed container at controlled room temperature (15–25 °C), protected from light and moisture. Avoid contact with strong bases, strong acids, and reducing agents, as these can trigger undesired reactions with the nitro or chloro functional groups. Dispose of waste according to applicable local, regional, and national regulations governing halogenated and nitrogen-containing organic compounds. Do not discharge into drains or waterways.

Synthetic Applications and Reactivity

The principal synthetic value of 4-Chloro-2-nitropyridine lies in its participation in nucleophilic aromatic substitution (SNAr) reactions. The C-4 chlorine is highly susceptible to displacement by nitrogen, oxygen, and sulfur nucleophiles—including amines, alcohols, thiols, and their corresponding anions—under mild to moderate conditions, owing to the combined electron-withdrawing influence of the ring nitrogen and the 2-nitro group.

Following SNAr, the retained nitro group at C-2 can be further elaborated: catalytic hydrogenation or chemical reduction converts it to a primary amine, yielding 2-amino-4-substituted pyridine scaffolds that are prevalent in kinase inhibitors, antibacterials, and other bioactive molecules. The compound is also a precursor in Suzuki–Miyaura and related palladium-catalyzed cross-coupling reactions, where the C–Cl bond serves as the electrophilic coupling partner after appropriate optimization of reaction conditions.

In agrochemical synthesis, nitropyridine scaffolds are recognized building blocks for herbicides, fungicides, and insecticides, making 4-Chloro-2-nitropyridine a strategically important intermediate across multiple industries.

Quality, Purity, and Analytical Characterization

For reliable synthetic outcomes, researchers should source 4-Chloro-2-nitropyridine at high purity (typically ≥97% or ≥98% by HPLC or GC). Aladdin Scientific offers this compound under SKU C185834 to support reproducible research.

Routine characterization methods include: (1) ¹H NMR and ¹³C NMR for structural confirmation and purity assessment; (2) GC or HPLC with UV detection for quantitative purity analysis; (3) melting point determination as a quick identity check; and (4) LC-MS or elemental analysis for additional confirmation when required by regulatory or publication standards. Ensure that the reagent lot certificate of analysis (CoA) confirms purity, water content, and absence of key process impurities before use in critical synthetic steps.

Frequently asked questions

What nucleophiles react most readily with 4-Chloro-2-nitropyridine in SNAr reactions?

Primary and secondary aliphatic amines are among the most reactive nucleophiles toward the C-4 chloride of 4-Chloro-2-nitropyridine, often reacting under mild conditions (room temperature to 80 °C) without additional activation. Oxygen and sulfur nucleophiles such as alkoxides and thiolates also react efficiently, though they may require a base additive to deprotonate the pronucleophile.

How should 4-Chloro-2-nitropyridine be stored to prevent degradation?

The compound should be stored in a tightly sealed container at controlled room temperature (15–25 °C), protected from light, heat, and atmospheric moisture. Exposure to strong bases or reducing agents should be avoided, as these can initiate undesired reactions with the nitro or chloro groups. Under these conditions, the reagent is expected to maintain its integrity over an extended shelf life.

Can 4-Chloro-2-nitropyridine be used directly in palladium-catalyzed cross-coupling reactions?

Yes, the C–Cl bond of 4-Chloro-2-nitropyridine can serve as an electrophilic partner in palladium-catalyzed cross-coupling reactions such as Suzuki–Miyaura coupling, although aryl chlorides generally require more active catalyst systems (e.g., bulky phosphine ligands or N-heterocyclic carbene ligands) compared with aryl bromides or iodides. Optimization of catalyst loading, ligand, base, and solvent is recommended for best yields.

What safety precautions are required when handling 4-Chloro-2-nitropyridine?

Researchers should wear chemical-resistant gloves, safety goggles, and a laboratory coat when handling this compound. Weighing and manipulations that may generate dust should be performed in a ventilated fume hood. In case of skin or eye contact, rinse immediately with copious water and seek medical advice. Waste should be segregated and disposed of in accordance with local regulations for halogenated organic waste.

References

1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.; Wiley-Interscience: New York, 1992. (General SNAr reactions of activated aryl halides)
2. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (Nucleophilic aromatic substitution chapter)
3. Aladdin Scientific product page for 4-Chloro-2-nitropyridine, SKU C185834. (Physical property data and purity specifications)

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.