4-(3-Bromo-5-nitropyridin-2-yl)morpholine: Synthesis & Use Protocol

4-(3-Bromo-5-nitropyridin-2-yl)morpholine is a versatile halogenated nitropyridine building block widely employed in medicinal chemistry and materials science for nucleophilic aromatic substitution, transition-metal-catalyzed cross-coupling reactions, and the elaboration of pharmacologically relevant nitrogen-containing heterocyclic scaffolds.

Product Name

4-(3-Bromo-5-nitropyridin-2-yl)morpholine

SKU

B179106

Molecular Formula

C9H10BrN3O3

Molecular Weight

288.10 g/mol

Key Functional Groups

Aryl bromide, nitro group, morpholine ring, pyridine ring

Primary Applications

SNAr reactions, Pd-catalyzed cross-coupling, heterocycle synthesis

Storage Conditions

Store in a cool, dry, well-ventilated area away from light and moisture

Chemical Identity and Properties

4-(3-Bromo-5-nitropyridin-2-yl)morpholine (SKU B179106, molecular formula C₉H₁₀BrN₃O₃, MW ≈ 288.10 g/mol) features a pyridine core substituted at C-2 with a morpholine nitrogen, at C-3 with a bromine atom, and at C-5 with a nitro group. This combination of electron-withdrawing substituents (nitro and pyridyl nitrogen) activates the ring toward nucleophilic aromatic substitution (S_NAr) while the C–Br bond serves as a handle for palladium- or copper-catalyzed cross-coupling reactions (e.g., Suzuki–Miyaura, Miyaura borylation, Buchwald–Hartwig amination). The morpholine moiety contributes favorable aqueous solubility and is a pharmacophore frequently found in approved drugs, enhancing the compound's relevance as a medicinal chemistry intermediate.

Safety and Handling Precautions

Before working with 4-(3-Bromo-5-nitropyridin-2-yl)morpholine, consult the current Safety Data Sheet (SDS) supplied by Aladdin Scientific. General precautions for aromatic nitro compounds and organobromine reagents apply:

• Personal Protective Equipment (PPE): Wear chemical-resistant gloves (nitrile recommended), a laboratory coat, and safety goggles. Where dust or aerosols may be generated, use a NIOSH-approved dust/mist respirator.
• Ventilation: Handle in a fume hood or well-ventilated area to avoid inhalation of dust or vapors.
• Skin and Eye Contact: In the event of skin contact, wash thoroughly with soap and water for at least 15 minutes. For eye contact, irrigate with copious water and seek medical attention.
• Waste Disposal: Dispose of all waste in accordance with local, regional, and national regulations for halogenated organic compounds containing nitro groups.
• Incompatibilities: Keep away from strong reducing agents, strong acids, and open flames. Nitro-aromatic compounds may be shock- or heat-sensitive at elevated concentrations; avoid grinding or prolonged exposure to heat.

Storage and Stability

Store 4-(3-Bromo-5-nitropyridin-2-yl)morpholine in a tightly sealed container in a cool (2–25 °C), dry, well-ventilated location protected from light and moisture. Moisture can promote hydrolysis of sensitive functional groups over extended periods. Upon receipt, inspect the material for any signs of discoloration or caking, which may indicate degradation. For long-term storage, an inert atmosphere (nitrogen or argon) inside the container is advisable. Always allow cold-stored material to equilibrate to room temperature before opening to prevent condensation on the solid.

Note: Specific shelf-life data should be confirmed from the certificate of analysis (CoA) provided with each lot.

Synthetic Application Protocol

The following general procedures outline two of the most common applications of 4-(3-Bromo-5-nitropyridin-2-yl)morpholine in research synthesis.

Procedure A: Suzuki–Miyaura Cross-Coupling

1. Charge a dry, argon-purged round-bottom flask with 4-(3-Bromo-5-nitropyridin-2-yl)morpholine (1.0 equiv), the desired arylboronic acid or ester (1.2–1.5 equiv), and Pd catalyst (e.g., Pd(PPh₃)₄ or Pd(dppf)Cl₂, 2–5 mol%).
2. Add an inorganic base (e.g., K₂CO₃ or Cs₂CO₃, 2–3 equiv) and a suitable solvent system (e.g., DMF/H₂O 4:1 or dioxane/H₂O 4:1).
3. Heat at 80–100 °C under inert atmosphere for 4–16 h, monitoring by TLC or HPLC.
4. Upon completion, cool to room temperature, dilute with ethyl acetate, wash with brine, dry over MgSO₄, filter, and concentrate. Purify by column chromatography.

Procedure B: Nucleophilic Aromatic Substitution (S_NAr) at C-3

1. Dissolve 4-(3-Bromo-5-nitropyridin-2-yl)morpholine (1.0 equiv) in a polar aprotic solvent (e.g., DMSO or DMF).
2. Add the nucleophile (amine, thiol, or alkoxide; 1.2–2.0 equiv) and an appropriate base (e.g., K₂CO₃ or Et₃N, 1.5–2.0 equiv).
3. Stir at 60–100 °C for 2–12 h; monitor reaction progress by TLC or LC-MS.
4. Work up by precipitation or extraction, then purify by recrystallization or chromatography.

Caution: Reaction conditions are generalized. Optimize stoichiometry, temperature, and reaction time for each specific transformation. All procedures should be performed under appropriate safety controls.

Quality Control and Analytical Characterization

Each lot of 4-(3-Bromo-5-nitropyridin-2-yl)morpholine supplied by Aladdin Scientific is accompanied by a Certificate of Analysis (CoA) specifying purity and analytical data. Researchers should confirm identity and purity using one or more of the following techniques before use in critical experiments:

• ¹H and ¹³C NMR Spectroscopy: Confirm the characteristic pyridyl ring proton signals (typically 2 aromatic H), morpholine CH₂ protons (two sets of apparent triplets ~3.7 and ~3.8 ppm), and absence of unexpected impurities.
• HPLC Purity: Reverse-phase HPLC (C18 column, UV detection at 254 nm or 280 nm) should confirm purity ≥95% unless otherwise specified on the CoA.
• Mass Spectrometry: ESI-MS or APCI-MS should display the expected [M+H]⁺ and the characteristic bromine isotope pattern (1:1 ratio of ⁷⁹Br:⁸¹Br).
• Melting Point: Verify against the value reported on the CoA as a purity indicator.

Note: Specific NMR chemical shift values and melting point data should be taken from the lot-specific CoA; values cited here are general guidance only.

Frequently asked questions

What are the main synthetic uses of 4-(3-Bromo-5-nitropyridin-2-yl)morpholine?

This compound serves as a bifunctional building block. The aryl C–Br bond participates in palladium-catalyzed cross-coupling reactions such as Suzuki–Miyaura and Buchwald–Hartwig couplings, while the electron-withdrawing nitro group activates the ring for nucleophilic aromatic substitution (SNAr). Together these features make it highly versatile for constructing complex nitrogen-containing heterocyclic scaffolds in medicinal chemistry programs.

How should I store 4-(3-Bromo-5-nitropyridin-2-yl)morpholine to maintain its integrity?

Store the compound in a tightly sealed container away from light, heat, and moisture at 2–25 °C. For long-term storage, use an inert atmosphere (nitrogen or argon) inside the container. Always allow the material to reach room temperature before opening to avoid condensation. Refer to the lot-specific Certificate of Analysis for confirmed shelf-life information.

What safety precautions are required when handling this compound?

As an aromatic nitro-organobromine compound, it should be handled with nitrile gloves, a lab coat, and safety goggles in a fume hood. Avoid inhalation of dust or vapors. Keep away from strong reducing agents, strong acids, and open flames. In case of skin or eye contact, rinse immediately with copious water and seek medical attention. Dispose of waste in compliance with regulations governing halogenated nitroaromatic compounds.

How can I confirm the purity and identity of my lot before use?

Check the Certificate of Analysis (CoA) supplied by Aladdin Scientific for lot-specific purity data. Independently verify identity by 1H/13C NMR (characteristic morpholine and pyridyl signals) and HPLC purity (≥95% by reverse-phase C18 with UV detection). ESI-MS confirming [M+H]+ with the diagnostic 1:1 bromine isotope pattern provides additional confirmation.

References

1. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. (General reference for pyridine and morpholine chemistry.)
2. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
3. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, 2012. (Nucleophilic aromatic substitution and cross-coupling chapters.)

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