98% p-Chlorophenethyl Bromide (CAS 6529-53-9)

IUPAC Name:​ 1-(4-Chlorophenyl)-2-bromoethane

Other Common Names:​ 2-(4-Chlorophenyl)ethyl bromide; 4-Chlorophenethyl bromide

Chemical Formula:​ C₈H₈BrCl

Molecular Weight:​ 219.51 g/mol

Structure:​ 4-Cl-C₆H₄-CH₂-CH₂-Br

Appearance:​ Typically a clear, colorless to pale yellow liquid. May darken upon storage due to light exposure and potential decomposition.

Boiling Point:​ ~ 125-130 °C at 10 mmHg (decomposes at atmospheric pressure)

Density:​ ~1.52 g/cm³ at 25°C

Refractive Index:​ ~1.563 - 1.565 (n²⁰/D)

Solubility:​ Soluble in most common organic solvents (ether, acetone, chloroform, DMF, THF). Insoluble in water.

Stability:​ Moisture-sensitive and light-sensitive.​ Can decompose upon prolonged exposure to air/light, releasing HBr. The bromide is a good leaving group, making the compound highly reactive as an electrophile. Incompatible with strong bases, strong oxidizing agents, and strong nucleophiles.

Key Reactivity:​ Primarily undergoes Sɴ2 nucleophilic substitution reactions​ where the bromine is displaced by a nucleophile (e.g., amines, alkoxides, thiols, cyanide, stabilized carbanions) to form new C-N, C-O, C-S, C-C, etc., bonds. The aromatic chlorine is relatively inert under these conditions but can be further functionalized via metal-catalyzed cross-coupling (e.g., Suzuki, Buchwald-Hartwig reactions).

Toxicity:​ Expected to be toxic and corrosive.​ It is a potent alkylating agent​ and can alkylate biological macromolecules like DNA and proteins, leading to cellular damage. Details on chronic toxicity are limited.

Irritancy:​ Severely irritating​ to eyes, skin, and mucous membranes. It is a lachrymator​ (causes tearing).

No Known Therapeutic Activity:​ Its value is purely as a synthetic intermediate. Any biological activity in assays would likely be non-specific and related to its alkylating properties.

Natural Occurrence:​ This compound is not known to occur naturally.

Industrial Synthesis:​ It is produced synthetically via several routes:

Free Radical Bromination:​ The most common method involves the bromination of 4-chlorophenethyl alcohol​ using phosphorus tribromide (PBr₃) or hydrobromic acid (HBr) under controlled conditions.

From 4-Chlorostyrene:​ Via anti-Markovnikov hydrobromination (radical addition of HBr) to the double bond.

From 4-Chlorophenylacetic Acid:​ Via a Hell–Volhard–Zelinsky reaction followed by decarboxylation, or via reduction to the alcohol and subsequent bromination.

1. Dual-Functionality for Sequential Modular Synthesis

Benefit:​ Enables a "divergent synthesis" strategy​ where one inexpensive starting material can be rapidly elaborated into a library of complex molecules through selective reactions at each site.

Application Scenario:​ In medicinal chemistry lead optimization, a researcher can first perform a high-yield Sᴺ2 reaction of the bromide with a piperazine scaffold to install a basic amine side chain, then in a subsequent step use palladium-catalyzed Suzuki coupling on the aryl chloride to introduce a diverse array of boronic acids, rapidly generating dozens of analogs for structure-activity relationship (SAR) testing.

2. Superior Bromide Reactivity for Efficient Alkylation

Benefit:​ The primary benzylic-type bromide is an excellent electrophile, facilitating rapid and high-yield alkylation reactions under milder conditions compared to chlorides or mesylates.

Application Scenario:​ In the scale-up synthesis of an agrochemical intermediate, reacting p-chlorophenethyl bromide with a sodium thiolate in acetone proceeds cleanly and quickly at 0-25°C to form the thioether linkage, minimizing side-product formation and reducing process time versus using the less reactive chloride analog.

3. Chemoselective Control for Unparalleled Synthetic Flexibility

Benefit:​ The significant reactivity gap between the aliphatic C-Br bond and the aromatic C-Cl bond allows for perfectly selective modification of one site in the presence of the other, a critical feature for complex synthesis.

Application Scenario:​ When synthesizing a functionalized liquid crystal material, a chemist can first use the bromide to attach a flexible alkyl chain via a nucleophile, then employ a Buchwald-Hartwig amination on the preserved aryl chloride to install a specific aromatic amine group, all without protecting group chemistry.

4. Cost-Effective Introduction of Key Pharmacophore

Benefit:​ Provides an economical route to incorporate the 4-chlorophenethyl moiety, a common lipophilic aromatic group found in numerous bioactive molecules, enhancing binding affinity and metabolic stability.

p-Chlorophenethyl Bromide (CAS 6529-53-9)​ is a strategically superior synthetic intermediate​ prized for its perfectly tuned dual reactivity. It solves a fundamental challenge in organic synthesis by providing a highly reactive "first click" site (the bromide) and a stable, yet versatile "second click" site (the aryl chloride). This makes it an indispensable tool for efficient parallel library synthesis in pharmaceutical R&D​ and for the streamlined, cost-effective production of complex active ingredients. For chemists, it represents a reliable and flexible building block that accelerates innovation and simplifies route design compared to less differentiated analogs.

Q1: What is the main value of p-Chlorophenethyl Bromide for a synthetic chemist?

A:​ Its core value lies in its dual functionality and reactivity profile. The primary bromide is a highly reactive handle for Sɴ2 alkylation​ to install the 2-arylethyl group onto a nucleophile. The para-chlorine is an orthogonal reactive site for subsequent palladium-catalyzed cross-coupling reactions​ (e.g., Suzuki, amination). This allows for efficient, sequential diversification to build complex molecules from a single, readily available starting point.

Q2: How critical is handling and storage? What are the specific risks?

A: Extremely critical.​ This compound is moisture-sensitive, light-sensitive, and corrosive.​ It can decompose, releasing hydrogen bromide (HBr) gas, which is toxic and corrosive. It is also a potent lachrymator and skin irritant.

Handling:​ Must be handled in a fume hood​ with appropriate PPE: nitrile or neoprene gloves, chemical splash goggles, and a lab coat. Avoid inhalation and contact.

Storage:​ Store under an inert atmosphere (N₂ or Argon)​ in a tightly sealed, dark container​ in a freezer (e.g., 2-8°C or below 0°C for long-term storage).​ Regularly check container integrity.

Q3: What purity grade should I request for my application, and how is stability assured?

A:​ For synthetic applications, ≥97% purity (by GC or HPLC)​ is standard. For critical steps (e.g., final API stage), ≥99%​ may be required.

Stability:​ Reputable suppliers ship the compound under inert gas, in amber vials or bottles, and with cold packs.​ Upon receipt, transfer it to a proper storage environment immediately. Acid scavengers like molecular sieves are NOT recommended​ in the primary container as they may cause localized reactions.

Q4: What are common impurity profiles, and how do they affect reactions?

A:​ Common impurities include:

4-Chlorophenethyl alcohol​ (from incomplete bromination or hydrolysis).

1,2-Bis(4-chlorophenyl)ethane​ (from Wurtz-type coupling side reactions).

Discoloration products​ (from decomposition).

Impurities can act as inhibitors, poisons for catalysts (especially in cross-coupling), or lead to low yields and difficult purifications. Always assess purity by NMR or GC before critical steps.

Q5: Can the bromine be selectively displaced in the presence of the chlorine?

A: Yes, absolutely.​ This is a key advantage. The primary alkyl bromide (benzylic/allylic type activation)​ is vastly more reactive toward Sɴ2 conditions​ (soft nucleophiles) than the aryl chloride. The aryl chloride requires transition metal catalysis​ (Pd, Ni, Cu) or very harsh conditions for displacement, allowing for excellent chemoselectivity in sequential functionalization.

Q6: Is it regulated under controlled substance or precursor laws?

A:​ Generally, it is not​ listed as a controlled substance or drug precursor. However, it is classified as a hazardous chemical​ (Acute Tox., Skin Corr., Eye Damage). Always check local and destination country regulations​ (e.g., REACH, TSCA) for specific reporting or restrictions related to its transportation, use, and disposal.

Q7: What are its main competitors or alternatives in synthesis?

A:​ Alternatives depend on the target.

p-Chlorophenethyl Chloride:​ Less reactive and cheaper, but reactions are slower and may require catalysts/phase-transfer agents.

p-Chlorophenethyl Methanesulfonate (Mesylate) or Tosylate:​ Similar reactivity, often crystalline solids (easier to handle), but more expensive to produce.

p-Chlorobenzyl Bromide:​ More reactive (benzylic vs. primary alkyl), but yields a different linker (one-carbon vs. two-carbon spacer), which changes the pharmacology and properties of the final molecule significantly.