1-Bromo-4-(2-ethoxyethoxy)benzene: Properties & Lab Uses

1-Bromo-4-(2-ethoxyethoxy)benzene is a para-substituted aryl bromide featuring an ethoxyethoxy ether side chain that serves as a versatile electrophilic building block in palladium-catalyzed cross-coupling reactions and pharmaceutical intermediate synthesis.

IUPAC Name

1-Bromo-4-(2-ethoxyethoxy)benzene

Molecular Formula

C10H13BrO2

Molecular Weight

245.11 g/mol

Functional Class

Aryl bromide; aliphatic ether

Primary Use

Electrophilic coupling partner in Pd- and Ni-catalyzed cross-coupling reactions

Storage Recommendation

Store in a cool, dry place away from light and moisture; seal tightly

CAS Number

Not confirmed in source material — needs review

Chemical Structure and Properties

1-Bromo-4-(2-ethoxyethoxy)benzene consists of a benzene ring bearing a bromine atom at the 1-position and a 2-ethoxyethoxy (–OCH₂CH₂OC₂H₅) substituent at the para (4-) position. The molecular formula is C₁₀H₁₃BrO₂, giving a molecular weight of approximately 245.11 g/mol.

The ethoxyethoxy side chain introduces a flexible, polar ether linkage that improves the compound's solubility in common organic solvents such as tetrahydrofuran (THF), dichloromethane, and dimethylformamide (DMF). The C–Br bond on the aromatic ring is the primary reactive site, lending itself to oxidative addition into low-valent transition-metal catalysts.

The compound is expected to be a colorless to pale-yellow liquid or low-melting solid at room temperature, typical of para-substituted bromobenzene ethers. Precise physical constants (boiling point, melting point, density, refractive index) should be verified against the certificate of analysis supplied with the product lot.

Synthesis and Key Reactions

1-Bromo-4-(2-ethoxyethoxy)benzene is most commonly prepared by O-alkylation of 4-bromophenol with 2-chloroethyl ethyl ether (or equivalent electrophile) under basic conditions, typically using potassium carbonate in an aprotic solvent such as acetone or DMF. The para-bromophenol precursor is commercially available, making this a practical and scalable route.

Cross-Coupling Reactions: The aryl bromide functionality makes this compound a suitable electrophilic partner in a range of transition-metal-catalyzed transformations:

• Suzuki–Miyaura coupling: Reaction with aryl or vinyl boronic acids/esters in the presence of a Pd catalyst and base yields biaryl or styryl products bearing the 2-ethoxyethoxy substituent.
• Buchwald–Hartwig amination: Pd-catalyzed coupling with primary or secondary amines provides diarylamine or aryl alkylamine products.
• Negishi and Kumada couplings: Reaction with organozinc or organomagnesium reagents extends the accessible product space.
• Miyaura borylation: Conversion to the corresponding arylboronic acid pinacol ester using bis(pinacolato)diboron (B₂pin₂) enables further downstream coupling.

The ether side chain is generally inert under standard cross-coupling conditions, making this compound a clean building block for library synthesis and target-directed campaigns.

Applications in Research and Drug Discovery

The combination of an electrophilic aryl bromide and a hydrophilic ethoxyethoxy ether appendage makes 1-Bromo-4-(2-ethoxyethoxy)benzene particularly valuable in medicinal chemistry and materials science contexts.

Medicinal Chemistry: The 2-ethoxyethoxy group is a bioisostere-compatible fragment that can mimic polyethylene glycol (PEG)-like motifs, improving aqueous solubility and membrane permeability of drug candidates. Building blocks of this type are frequently incorporated into lead optimization campaigns targeting CNS, oncology, and infectious disease indications, where modulating lipophilicity and metabolic stability is paramount.

Liquid Crystal and OLED Materials: Para-substituted bromobenzene ethers serve as precursors to liquid-crystalline monomers and hole-transport materials. The ethoxyethoxy chain acts as a flexible spacer that lowers melting points and modulates mesophase behavior.

Polymer Chemistry: Aryl bromides with ether side chains are monomers or chain-end functionalization reagents in controlled radical and step-growth polymerizations, including those targeting amphiphilic block copolymers.

Agrochemical Synthesis: The structural motif is found in several agrochemical scaffolds; this building block may serve as an advanced intermediate in herbicide or fungicide development.

Handling, Safety, and Storage

As with all organobromine compounds, 1-Bromo-4-(2-ethoxyethoxy)benzene should be handled with standard laboratory precautions. Users should consult the Safety Data Sheet (SDS) supplied with the product prior to use.

Personal Protective Equipment (PPE): Chemical-resistant gloves (nitrile or neoprene), safety glasses or goggles, and a laboratory coat are recommended. Work in a well-ventilated fume hood to minimize inhalation of vapors.

Storage: Store in a tightly sealed container in a cool (≤25 °C), dry, and well-ventilated area away from direct sunlight, oxidizing agents, and strong bases. Long-term storage under inert atmosphere (nitrogen or argon) is advisable to prevent slow hydrolysis or oxidation of the ether linkage.

Waste Disposal: Dispose of waste material in accordance with local, national, and institutional regulations governing halogenated organic waste. Do not pour down the drain.

Stability: The compound is expected to be stable under recommended storage conditions for an extended period. Purity should be confirmed by GC or NMR before use in sensitive synthetic applications. Check the certificate of analysis for lot-specific purity data.

Frequently asked questions

What transition-metal-catalyzed reactions is 1-Bromo-4-(2-ethoxyethoxy)benzene suitable for?

This compound is suitable as an electrophilic coupling partner in Suzuki–Miyaura, Buchwald–Hartwig, Negishi, and Kumada cross-coupling reactions, as well as Miyaura borylation. The aryl C–Br bond undergoes facile oxidative addition into Pd(0) and Ni(0) catalysts under standard conditions.

Why is the 2-ethoxyethoxy substituent useful in medicinal chemistry applications?

The 2-ethoxyethoxy group provides a short, flexible PEG-like ether chain that can improve aqueous solubility and modulate the lipophilicity (log P) of resulting drug candidates. This substituent can also act as a metabolic handle and bioisosteric replacement for longer polyether chains, making it valuable in lead optimization workflows.

How should 1-Bromo-4-(2-ethoxyethoxy)benzene be stored to maintain purity?

Store the compound in a tightly sealed container at or below 25 °C in a cool, dry location away from light and moisture. For long-term storage, an inert atmosphere of nitrogen or argon is recommended to prevent oxidation or hydrolysis. Verify purity by GC or NMR prior to use.

Can the ethoxyethoxy ether group interfere with cross-coupling reaction conditions?

Under the mild to moderate conditions typically used for Pd-catalyzed cross-coupling reactions (aqueous base, temperatures up to ~100 °C), the aliphatic ether linkage is generally stable and non-interfering. However, strongly Lewis-acidic or protic conditions should be avoided to prevent ether cleavage.

References

1. Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
2. Hartwig, J. F. Evolution of a Fourth Generation Catalyst for the Amination and Thioetherification of Aryl Halides. Acc. Chem. Res. 2008, 41, 1534–1544. doi:10.1021/ar800098p
3. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-Catalyzed Cross-Coupling Reaction of Alkoxydiboron with Haloarenes: A Direct Procedure for Arylboronic Esters. J. Org. Chem. 1995, 60, 7508–7510. doi:10.1021/jo00128a024

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