1-Bromo-4-chloro-2-morpholinobenzene: Properties & Uses

1-Bromo-4-chloro-2-morpholinobenzene is a multifunctional aryl halide building block featuring both bromo and chloro leaving groups alongside a morpholine ring, making it a versatile intermediate for palladium-catalyzed cross-coupling reactions and medicinal chemistry applications.

IUPAC Name

4-(2-bromo-5-chlorophenyl)morpholine

SKU

B180738

Molecular Formula

C10H11BrClNO

Molecular Weight

276.56 g/mol

Key Functional Groups

Aryl bromide, aryl chloride, morpholine (tertiary amine + ether)

Primary Application

Synthetic building block for cross-coupling and medicinal chemistry

Chemical Structure and Identity

1-Bromo-4-chloro-2-morpholinobenzene (SKU B180738) is an aromatic compound in which a morpholine ring is attached at the 2-position of a benzene ring that also bears a bromine substituent at the 1-position and a chlorine substituent at the 4-position. This substitution pattern places the morpholine nitrogen ortho to the aryl bromide, which has significant steric and electronic consequences for downstream reactions.

The morpholine moiety contributes both a tertiary amine and an ether oxygen to the molecule, imparting moderate basicity, hydrogen-bond-accepting capacity, and improved aqueous solubility relative to purely carbocyclic analogs. The combination of two distinct halogen leaving groups (C–Br and C–Cl) on the same ring provides chemists with the opportunity to exploit the well-established reactivity difference between aryl bromides and aryl chlorides under palladium or nickel catalysis.

Physicochemical Properties

The molecular formula of 1-Bromo-4-chloro-2-morpholinobenzene is C₁₀H₁₁BrClNO, corresponding to a molecular weight of approximately 276.56 g/mol. The presence of the electron-donating morpholine group and the two electron-withdrawing halogens creates a push-pull electronic environment on the aromatic ring, influencing both the chemical shift pattern observed by ¹H NMR and the compound's reactivity toward nucleophilic or electrophilic processes.

The morpholine substituent raises the boiling point and reduces volatility compared with simple dihalobenzenes, and the ether oxygen can participate in coordination interactions relevant to catalytic cycles. Researchers should consult the product specification sheet for confirmed melting point, purity, and storage conditions, as these parameters are batch-dependent.

Synthetic Applications and Reactivity

The primary utility of 1-Bromo-4-chloro-2-morpholinobenzene lies in its role as a difunctional aryl halide building block. In palladium-catalyzed cross-coupling chemistry—including Suzuki–Miyaura, Buchwald–Hartwig, and Negishi couplings—the aryl C–Br bond is generally more reactive than the aryl C–Cl bond under standard conditions, enabling selective mono-functionalization at the bromide site. Subsequent or orthogonal activation of the aryl chloride can then be achieved under more forcing conditions or with specialized catalyst systems, enabling the sequential installation of two different substituents.

The morpholine ring itself is a privileged scaffold in medicinal chemistry, frequently incorporated into drug candidates to modulate pharmacokinetic properties such as solubility, metabolic stability, and membrane permeability. Consequently, this compound is well-suited as a starting material for the preparation of morpholine-containing biologically active molecules, particularly kinase inhibitors and CNS-targeted agents where morpholine is a common pharmacophore element.

The ortho relationship between the morpholine and the bromide may introduce steric congestion that affects coupling efficiency; optimization of ligand choice and reaction temperature is recommended when this substrate is used in hindered cross-coupling scenarios.

Handling, Safety, and Storage

As with all organohalide compounds, 1-Bromo-4-chloro-2-morpholinobenzene should be handled in a well-ventilated fume hood with appropriate personal protective equipment, including chemical-resistant gloves, safety glasses, and a laboratory coat. Users should consult the Safety Data Sheet (SDS) provided by Aladdin Scientific prior to use for specific hazard classifications, first-aid measures, and disposal guidance.

The compound should be stored in a cool, dry location away from strong oxidizing agents and incompatible bases. Containers should be kept tightly sealed to prevent moisture ingress and to minimize exposure to atmospheric conditions. Specific recommended storage temperature and shelf-life data should be verified against the current product label and SDS, as these are subject to revision.

Frequently asked questions

What is the difference in reactivity between the bromo and chloro groups in 1-Bromo-4-chloro-2-morpholinobenzene?

Under standard palladium-catalyzed cross-coupling conditions, the aryl C–Br bond is significantly more reactive than the aryl C–Cl bond due to the lower bond dissociation energy of C–Br and the more favorable oxidative addition into palladium(0). This selectivity allows chemists to functionalize the bromide position first, then engage the chloride under more forcing conditions or with specialized phosphine ligands designed for aryl chloride activation.

Why is the morpholine substituent valuable in pharmaceutical intermediate synthesis?

Morpholine is a widely used pharmacophore in medicinal chemistry because it simultaneously provides a hydrogen-bond acceptor (both the nitrogen and the ether oxygen), improves aqueous solubility, and tends to confer favorable metabolic stability compared with simple aliphatic amines. Its incorporation into drug candidates often improves pharmacokinetic profiles, which is why morpholine-containing building blocks such as 1-Bromo-4-chloro-2-morpholinobenzene are popular starting materials for drug discovery programs.

How should 1-Bromo-4-chloro-2-morpholinobenzene (B180738) be stored to maintain stability?

The compound should be stored in a tightly sealed container in a cool, dry environment, away from moisture, strong oxidants, and incompatible chemical classes. Users should refer to the current Aladdin Scientific product label and Safety Data Sheet for confirmed storage temperature recommendations and shelf-life information, as batch-specific data may vary.

Can 1-Bromo-4-chloro-2-morpholinobenzene be used in Buchwald–Hartwig amination reactions?

Yes, the aryl bromide functionality makes this compound a viable electrophilic partner in Buchwald–Hartwig C–N cross-coupling reactions. The ortho-morpholine group may introduce steric effects that slow oxidative addition or reductive elimination steps, so careful selection of palladium catalyst and ancillary ligand—such as bulky biaryl phosphines—is advisable to achieve good yields.

References

1. Negishi, E. (Ed.). Handbook of Organopalladium Chemistry for Organic Synthesis. Wiley-Interscience, 2002. (General reference for palladium-catalyzed cross-coupling reactions involving aryl halides.)
2. Roughley, S. D.; Jordan, A. M. The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451–3479. (Documents morpholine as a key pharmacophore and the prevalence of cross-coupling in drug synthesis.) doi:10.1021/jm200187y
3. Aladdin Scientific. Product Specification Sheet: 1-Bromo-4-chloro-2-morpholinobenzene, SKU B180738. (Primary source for purity, physical data, and storage conditions.)

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