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

2-Chloro-3-methoxy-5-nitropyridine is a versatile halogenated nitropyridine building block widely employed in medicinal chemistry and pharmaceutical synthesis as a key intermediate for constructing biologically active heterocyclic scaffolds.

Chemical Name

2-Chloro-3-methoxy-5-nitropyridine

SKU

C194925

Molecular Formula

C6H5ClN2O3

Molecular Weight

188.57 g/mol

CAS Number

147553-88-6

Functional Groups

Chloro, methoxy, nitro substituents on a pyridine ring

Primary Use

Pharmaceutical intermediate and heterocyclic synthesis building block

Chemical Identity and Structure

2-Chloro-3-methoxy-5-nitropyridine (CAS 147553-88-6; SKU C194925) is a substituted pyridine bearing three distinct functional groups: a chlorine atom at the 2-position, a methoxy group at the 3-position, and a nitro group at the 5-position. Its molecular formula is C₆H₅ClN₂O₃, giving a molecular weight of approximately 188.57 g/mol.

The pyridine ring nitrogen acts as an electron-withdrawing center, and together with the nitro group at the 5-position, renders the ring strongly electron-deficient. This electronic profile activates the 2-chloro substituent toward nucleophilic aromatic substitution (S_NAr), making this compound a highly reactive and programmable scaffold for further functionalization. The methoxy group at the 3-position provides an additional handle for both electronic modulation and potential chemical transformation.

Synthesis Applications and Reactivity

The primary utility of 2-Chloro-3-methoxy-5-nitropyridine lies in its role as an electrophilic building block in heterocyclic synthesis. The activated C–Cl bond at position 2 undergoes facile S_NAr reactions with a range of nucleophiles, including amines, thiols, and alkoxides, enabling efficient access to diversely substituted aminopyridines, thioethers, and ether-linked pyridines.

In palladium-catalyzed cross-coupling chemistry, the aryl chloride functionality can participate in reactions such as Suzuki–Miyaura, Buchwald–Hartwig, and Negishi couplings, although milder aryl halides may require optimized catalyst systems. The nitro group at the 5-position can be reduced to a primary amine using conventional reducing agents (e.g., iron/acetic acid, catalytic hydrogenation, or tin(II) chloride), thereby generating 2-substituted-3-methoxy-5-aminopyridine intermediates that are valuable in drug discovery workflows.

The convergence of these orthogonal reaction handles makes this compound a multi-directional intermediate suited to library synthesis and lead optimization campaigns.

Pharmaceutical and Medicinal Chemistry Relevance

Halogenated nitropyridines occupy a privileged position in medicinal chemistry because the pyridine core is a bioisostere of the benzene ring with improved aqueous solubility, metabolic stability, and capacity to engage in hydrogen-bonding interactions with biological targets. The 2-chloro-5-nitropyridine motif in particular has appeared as a precursor or scaffold in the synthesis of kinase inhibitors, antibacterial agents, and other pharmacologically relevant small molecules.

The methoxy group at position 3 further modulates the electronic density of the ring and can influence binding affinity and selectivity when the derived compound interacts with enzyme active sites or receptor binding pockets. Researchers in fragment-based drug discovery and high-throughput synthesis frequently employ such trisubstituted pyridines as core fragments due to their synthetic tractability and drug-like physicochemical properties.

Handling, Storage, and Safety Considerations

As with all aromatic nitro compounds, 2-Chloro-3-methoxy-5-nitropyridine should be handled with appropriate laboratory precautions. Standard personal protective equipment (PPE)—including nitrile gloves, safety glasses, and a laboratory coat—should be worn during handling. Operations involving powders or solutions of this compound should be conducted in a well-ventilated fume hood to prevent inhalation of dust or vapor.

The compound should be stored in a tightly sealed container, away from heat, open flames, and incompatible materials such as strong oxidizers and strong bases. Storage under cool, dry conditions (typically 2–8 °C or room temperature as specified on the Certificate of Analysis) helps maintain purity and long-term stability. Consult the Safety Data Sheet (SDS) provided by Aladdin Scientific for comprehensive hazard classifications, first-aid measures, and disposal guidance before use.

Waste containing this compound must be disposed of in accordance with applicable local, regional, and national regulations governing hazardous chemical waste.

Frequently asked questions

What is 2-Chloro-3-methoxy-5-nitropyridine used for in chemical synthesis?

It is primarily used as an electrophilic building block in heterocyclic and medicinal chemistry. The activated 2-chloro substituent undergoes nucleophilic aromatic substitution with amines, thiols, and alkoxides, while the 5-nitro group can be selectively reduced to an amine, providing orthogonal handles for multi-step synthesis toward pharmaceutically relevant targets.

How should 2-Chloro-3-methoxy-5-nitropyridine (C194925) be stored to maintain its purity?

The compound should be stored in a tightly sealed container under cool, dry conditions, away from heat sources, strong oxidizers, and strong bases. Refer to the Certificate of Analysis and Safety Data Sheet from Aladdin Scientific for the specific recommended storage temperature and conditions.

Can 2-Chloro-3-methoxy-5-nitropyridine participate in palladium-catalyzed cross-coupling reactions?

Yes, the aryl chloride moiety can in principle participate in palladium-catalyzed cross-coupling reactions such as Suzuki–Miyaura, Buchwald–Hartwig, and Negishi couplings. However, aryl chlorides are generally less reactive than aryl bromides or iodides, so optimized catalyst systems—such as bulky phosphine ligands and elevated temperatures—may be required to achieve good conversion.

What safety precautions are necessary when working with 2-Chloro-3-methoxy-5-nitropyridine?

Users should wear appropriate PPE including nitrile gloves, safety glasses, and a laboratory coat, and conduct all operations in a fume hood. The full hazard profile, including GHS classifications and first-aid measures, is detailed in the Safety Data Sheet available from Aladdin Scientific and should be reviewed before use.

References

1. March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed.; Wiley: New York, 1992. (General reference for nucleophilic aromatic substitution and cross-coupling reactions.)
2. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. (Reference for pyridine chemistry and reactivity.)
3. Aladdin Scientific. Product Information Sheet: 2-Chloro-3-methoxy-5-nitropyridine, SKU C194925. (Supplier certificate of analysis and SDS.)

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