5-Chloro-2-hydroxy-3-nitropyridine: Properties & Applications

5-Chloro-2-hydroxy-3-nitropyridine is a versatile halogenated nitropyridine building block widely employed as a synthetic intermediate in the preparation of pharmaceutically active heterocyclic compounds and agrochemical scaffolds.

Chemical Name

5-Chloro-2-hydroxy-3-nitropyridine

SKU

C132558

Molecular Formula

C₅H₃ClN₂O₃

Molecular Weight

174.54 g/mol

Functional Groups

Chloro, hydroxyl (lactam tautomer), nitro, pyridine ring

Primary Use

Pharmaceutical and agrochemical intermediate; heterocyclic synthesis building block

Storage Recommendation

Cool, dry, well-ventilated location; away from strong oxidizers and bases

Chemical Structure and Key Properties

5-Chloro-2-hydroxy-3-nitropyridine (molecular formula C₅H₃ClN₂O₃, MW ≈ 174.54 g/mol) is a substituted pyridine bearing three electronically influential substituents: a chlorine atom at position 5, a hydroxyl/oxo group at position 2, and a nitro group at position 3. In the solid state and in polar solvents the compound predominantly exists in the 2-pyridinone (lactam) tautomeric form rather than the 2-hydroxypyridine (enol) form, a feature common to 2-hydroxypyridine derivatives.

The electron-withdrawing nitro group at C-3 and the ring nitrogen cooperate to render C-5 and C-4 strongly electrophilically activated toward nucleophilic aromatic substitution (SNAr). The chlorine at C-5, flanked by both the ring nitrogen and the para-positioned nitro group's inductive effect, is therefore an excellent leaving group for displacement by amines, alkoxides, and thiolates. This reactivity profile makes the compound a particularly useful building block for library synthesis and medicinal chemistry campaigns.

Synthesis and Synthetic Utility

5-Chloro-2-hydroxy-3-nitropyridine is typically prepared by controlled nitration of 5-chloro-2-hydroxypyridine or by regioselective chlorination of 2-hydroxy-3-nitropyridine precursors. Its multifunctional structure provides three independent handles for sequential or orthogonal functionalization:

• SNAr at C-5 (C–Cl bond): Displacement of chloride by primary and secondary amines, sodium alkoxides, or thiols under mild conditions affords amino-, alkoxy-, or thio-substituted nitropyridines, which are common pharmacophores.
• Reduction of the nitro group: Catalytic hydrogenation (Pd/C, H₂) or chemical reduction (Fe/AcOH, SnCl₂) of the nitro group yields the corresponding 3-aminopyridine derivatives, which can be further elaborated by acylation, reductive amination, or heterocycle formation.
• O-Alkylation or O-acylation: The 2-oxo oxygen (in the lactam tautomer) or 2-OH (in the enol form) can be alkylated to give 2-alkoxypyridine scaffolds, depending on reaction conditions and base choice.

The combination of these transformations allows rapid access to diverse nitropyridine and aminopyridine libraries relevant to drug discovery programs targeting kinases, GPCRs, and infectious disease targets.

Research and Industrial Applications

Due to its activated aromatic ring and dual leaving-group/nucleophilic-substitution reactivity, 5-Chloro-2-hydroxy-3-nitropyridine finds utility across several domains:

Medicinal Chemistry: The nitropyridine and aminopyridine scaffolds derived from this compound appear in numerous bioactive molecules. Aminopyridines have been reported as fragments and leads against a variety of therapeutic targets. The 2-pyridinone motif itself is a recognized bioisostere for uracil and phenol, enhancing metabolic stability and membrane permeability in drug candidates.

Agrochemical Research: Halogenated nitropyridines serve as intermediates for fungicidal and herbicidal active ingredients. The electron-poor pyridine ring is compatible with cross-coupling strategies (Suzuki, Buchwald-Hartwig) enabling construction of complex biaryl and heteroaryl scaffolds common in crop-protection chemistry.

Material Science: Nitro-substituted heterocycles have been explored as precursors for nitrogen-rich energetic materials and as components in charge-transfer complexes and organic semiconductors, though these applications are secondary to pharmaceutical uses.

Diagnostic and Probe Chemistry: Functionalized aminopyridines obtained by reduction of the nitro group have been used as fluorescent labels or chelating agents in analytical chemistry.

Handling, Safety, and Storage

As a nitroaromatic compound bearing a halogen substituent, 5-Chloro-2-hydroxy-3-nitropyridine should be handled with standard laboratory precautions for reactive aromatic chemicals:

• Personal Protection: Wear appropriate chemical-resistant gloves, safety goggles, and a laboratory coat. Work in a well-ventilated fume hood to avoid inhalation of dust or vapors.
• Storage: Store in a tightly sealed container in a cool (below 25 °C), dry, well-ventilated area. Keep away from strong oxidizing agents, strong bases, and ignition sources. Segregate from reducing agents to prevent accidental reduction of the nitro group.
• Disposal: Dispose of waste in accordance with local, national, and institutional regulations for halogenated aromatic compounds. Do not pour down the drain without appropriate treatment.
• Stability: The compound is expected to be stable under recommended storage conditions. Prolonged exposure to light, moisture, or elevated temperatures may lead to decomposition; always inspect material before use.

Consult the Safety Data Sheet (SDS) provided by Aladdin Scientific (SKU C132558) for complete hazard classifications, first-aid measures, and regulatory information before use.

Ordering Information and Purity Specifications

Aladdin Scientific offers 5-Chloro-2-hydroxy-3-nitropyridine under SKU C132558. The product is intended for research use only and is not approved for clinical, therapeutic, or food applications.

When evaluating reagent suitability, researchers should consider:

• Purity: Confirm the Certificate of Analysis (CoA) for lot-specific purity data (typically assessed by HPLC or GC). Higher purity grades reduce the risk of side reactions in sensitive synthetic sequences.
• Quantity: Available in multiple pack sizes to support both exploratory and scale-up synthesis. Contact Aladdin Scientific for bulk pricing.
• Documentation: Each lot is accompanied by a CoA detailing purity, appearance, and analytical data. SDS is available upon request or via the product page.

For orders, technical inquiries, or custom synthesis requests, contact Aladdin Scientific through the official website or authorized distributors.

Frequently asked questions

What is the tautomeric form of 5-Chloro-2-hydroxy-3-nitropyridine in solution?

In polar solvents and the solid state, 5-Chloro-2-hydroxy-3-nitropyridine predominantly exists in the 2-pyridinone (lactam) tautomeric form rather than the 2-hydroxypyridine (enol) form. This equilibrium is well-established for 2-hydroxypyridine derivatives and influences solubility, reactivity, and intermolecular interactions.

Why is the C-5 chlorine particularly reactive toward nucleophilic aromatic substitution?

The C-5 chlorine is activated toward SNAr by two strong electron-withdrawing groups: the ring nitrogen (in the para position relative to C-5 via the ring) and the nitro group at C-3. These groups stabilize the Meisenheimer complex intermediate, significantly lowering the activation energy for nucleophilic displacement compared to unactivated chlorobenzenes.

What reducing conditions are recommended for converting the nitro group to an amine?

Common reduction methods include catalytic hydrogenation using Pd/C under H₂ atmosphere (typically 1–3 bar, room temperature in ethanol or ethyl acetate) and chemical reduction with iron powder in acetic acid or tin(II) chloride in hydrochloric acid. The choice depends on functional group compatibility; the presence of the C-5 chlorine may require careful condition optimization to avoid concomitant dehalogenation during Pd-catalyzed hydrogenation.

Is 5-Chloro-2-hydroxy-3-nitropyridine compatible with palladium-catalyzed cross-coupling reactions?

Halogenated electron-deficient pyridines are generally compatible with Pd-catalyzed cross-coupling reactions such as Suzuki-Miyaura and Negishi couplings. However, the presence of the nitro group and the 2-pyridinone NH can interact with catalyst systems; optimization of ligand, base, and solvent is typically required. Buchwald-Hartwig amination for C–N bond formation at C-5 is also feasible under suitable conditions.

How should 5-Chloro-2-hydroxy-3-nitropyridine be stored to maintain stability?

Store the compound in a tightly sealed container at room temperature or below (below 25 °C), in a cool, dry, and well-ventilated area away from moisture, direct light, strong oxidizers, and strong bases. Under these conditions the compound is expected to remain stable for an extended period. Always check the Certificate of Analysis for lot-specific stability data.

References

1. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (General SNAr reactivity of activated haloarenes)
2. Katritzky, A. R.; Lagowski, J. M. The Tautomerism of Heterocycles; Academic Press: New York, 1976. (2-Hydroxypyridine/2-pyridinone tautomerism)
3. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. (Pyridine reactivity and substitution chemistry)
4. Aladdin Scientific. Product Page and Safety Data Sheet: 5-Chloro-2-hydroxy-3-nitropyridine, SKU C132558. (Accessed via official Aladdin Scientific website)

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