ALKYLATION STRATEGIES USING 5-BROMOVALERIC ACID AS AN ALKYLATING AGENT

Alkylation Strategies Using 5-Bromovaleric Acid as an Alkylating Agent

Alkylation Strategies Using 5-Bromovaleric Acid as an Alkylating Agent

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5-Bromovaleric Acid: An In-Depth Study of a Multifunctional Synthetic Intermediate

 

 Overview

5-Bromovaleric acid (5-bromopentanoic acid) is a five-carbon, straight-chain haloalkanoic acid with dual reactive centers—an alkyl bromide and a terminal carboxylic acid. This unique bifunctionality makes it exceptionally valuable in organic synthesis, polymer chemistry, pharmaceutical manufacturing, and bioorganic compound design.

Its reactivity stems from the electrophilic carbon bearing bromine, and the acidic carboxyl group, both of which can be independently modified to yield a wide array of products including amines, amides, esters, lactams, azides, and organometallic derivatives.

 Chemical Identity

  • Common Name: 5-Bromovaleric acid

  • IUPAC Name: 5-Bromopentanoic acid

  • CAS Number: 2067-33-6

  • Molecular Formula: C₅H₉BrO₂

  • Molecular Weight: 181.03 g/mol

  • Chemical Structure:
    Br–CH₂–CH₂–CH₂–CH₂–COOH

The molecule can be thought of as valeric acid (pentanoic acid) with a bromine substituent at the ω-position (fifth carbon from the carboxyl end), making it an ω-bromo acid—a key class in polymer and medicinal chemistry.

 Physical and Chemical Properties

  • Appearance: White to off-white crystalline powder or solid

  • Odor: Slight, acrid, somewhat similar to fatty acids

  • Melting Point: 32–35°C

  • Boiling Point: Decomposes before boiling (not suitable for distillation)

  • Solubility:

    • Water: Moderate

    • Ethanol, acetone, THF: Soluble

    • Non-polar solvents (hexane, toluene): Sparingly soluble

  • pKa: ~4.8 (carboxyl group)

  • Refractive Index (20°C): ~1.47 (in solution)

  • Stability: Stable under dry, ambient conditions. Hydrolysis of the bromo group may occur in aqueous alkaline conditions.

 Synthesis Pathways

1. From Valeric Acid Derivatives

One common route is the radical bromination of valeric acid or valeric acid esters, using N-bromosuccinimide (NBS) under light or peroxide initiation.

Example:

CH3(CH2)3COOH + NBS → BrCH2(CH2)3COOH + Succinimide

2. From 5-Hydroxyvaleric Acid

A two-step transformation:

  1. Convert 5-hydroxyvaleric acid to its mesylate or tosylate.

  2. Perform nucleophilic substitution with NaBr in acetone (SN2) to yield 5-bromovaleric acid.

3. From γ-Butyrolactone

Using γ-butyrolactone as a precursor:

  1. Ring-opening with HBr gives 4-bromobutyric acid.

  2. Chain extension via cyanide addition and hydrolysis yields 5-bromovaleric acid.

This multistep process is used industrially where control over chirality or substitution position is critical.

 Reactivity and Functional Group Transformations

1. Nucleophilic Substitution at the Bromine

The terminal bromide is an excellent leaving group, allowing for a wide variety of SN2-type reactions:

  • Amines → 5-Aminovaleric acid

  • Azide → 5-Azidovaleric acid (a precursor to click chemistry)

  • Thiolates → Thiol-functionalized acids

  • Cyanide → Nitrile derivatives (5-cyanovaleric acid)

  • Alcohols → Ethers (via Williamson ether synthesis)

These reactions are typically performed in polar aprotic solvents like DMF or DMSO to favor substitution over elimination.

2. Carboxylic Acid Functionalization

The carboxyl group can undergo standard transformations:

  • Amide formation (with amines, using coupling agents like DCC, EDC)

  • Esterification (with alcohols under acidic or catalytic conditions)

  • Conversion to acyl chloride (with SOCl₂ or oxalyl chloride)

  • Lactamization: Intramolecular cyclization under heating can form δ-valerolactam, a five-membered ring important in bioactive molecules.

 Applications

Pharmaceutical Chemistry

Used as a synthetic intermediate in:

  • Peptidomimetic synthesis

  • Prodrug design, especially when chain length and terminal reactivity are critical

  • Formation of N-substituted or O-substituted analogs via clean derivatization

Common transformations yield:

  • CNS-active drugs

  • Antiviral intermediates

  • Inhibitors of amino acid transporters

Polymer and Material Science

5-Bromovaleric acid is used as a monomer or functional chain terminator in:

  • Polyamides and polyesters

  • Graft copolymers

  • Surface modifiers (especially for PEGylation or nanoparticle functionalization)

The carboxylic acid offers adhesion or solubility, while the bromo group allows post-polymerization modification.

Chemical Linkers and Spacers

Its linear 5-carbon chain is ideal as a molecular spacer in drug delivery systems, solid-phase synthesis, or bioconjugation. The terminal functionalities allow for precise linking to:

  • Dyes

  • Drug payloads

  • Affinity tags

  • Biopolymers

 Safety and Toxicology

Hazards

  • Irritant to skin, eyes, and mucous membranes

  • Harmful if inhaled or ingested in large amounts

  • Corrosive in concentrated form

  • May release toxic hydrogen bromide on decomposition

GHS Classification

  • Signal Word: Warning

  • Hazard Statements: H315 (skin irritation), H319 (eye irritation), H302 (harmful if swallowed)

  • Precautionary Measures: Use protective gloves, goggles, and operate in a fume hood

First Aid

  • Skin/eye contact: Rinse thoroughly with water for 15 minutes

  • Inhalation: Move to fresh air; seek medical attention if symptoms persist

  • Ingestion: Rinse mouth; do not induce vomiting; seek medical advice

 Storage and Handling

  • Store in airtight containers

  • Keep in cool (room temperature or below), dry environments

  • Protect from moisture, strong bases, and nucleophilic agents

  • Avoid storing near oxidizing substances or reactive halide scavengers

 Analytical Methods

Identification and Purity Assessment

  • NMR (¹H, ¹³C): Distinct triplets and multiplets in alkyl chain; carboxylic proton as a broad singlet; α-CH₂-Br appears as deshielded

  • IR Spectroscopy: Strong C=O stretch near 1700 cm⁻¹; O–H stretch broad 2500–3300 cm⁻¹

  • GC-MS: M⁺ = 181 with characteristic isotopic Br pattern (M+2 peak)

  • HPLC: Suitable for purity assay and stability studies

 Conclusion

5-Bromovaleric acid is a compact yet powerful synthetic intermediate. It offers a balance of stability and reactivity, allowing chemists to efficiently build complex structures through simple, well-understood reactions. Its dual-functional nature enables diverse transformations, making it an essential reagent in:

  • Advanced organic synthesis

  • Pharmaceutical development

  • Functional material design

  • Bioconjugation and linker chemistry

Whether you're forming heterocycles, elongating carbon chains, or developing bioactive derivatives, 5-Bromovaleric acid provides the reactive handle you need—with the flexibility and performance that modern synthetic challenges demand.

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