Abstract

4-Bromophenylacetic acid (systematic name: 2-(4-bromophenyl)acetic acid) is an organobromine compound with molecular formula C₈H₇BrO₂ and molecular mass of 215.05 g/mol. This crystalline solid exhibits a melting point of 118°C and manifests characteristic physical properties including white crystalline appearance and honey-like odor. The compound belongs to the phenylacetic acid derivative class, featuring a bromine substituent in the para position of the aromatic ring. 4-Bromophenylacetic acid serves as a versatile synthetic intermediate in organic chemistry, particularly in pharmaceutical precursor synthesis and specialty chemical manufacturing. The compound demonstrates typical carboxylic acid reactivity while the bromine substituent enables various cross-coupling reactions and nucleophilic substitutions. Its structural features include a planar aromatic system connected to a flexible acetic acid side chain, creating distinctive electronic and steric properties that influence its chemical behavior and applications.

Introduction

4-Bromophenylacetic acid represents a significant brominated aromatic carboxylic acid with substantial utility in synthetic organic chemistry. As a derivative of phenylacetic acid, this compound incorporates a bromine atom at the para position of the benzene ring, creating a bifunctional molecule with both carboxylic acid and aryl bromide functional groups. The presence of these orthogonal functional groups enables diverse chemical transformations, making 4-bromophenylacetic acid a valuable building block for complex molecule synthesis.

The compound falls within the broader category of halogenated aromatic acids, which exhibit unique electronic properties due to the electron-withdrawing nature of the halogen substituent. The bromine atom in the para position exerts both inductive and mesomeric effects on the aromatic system, influencing the acidity of the carboxylic acid group and the reactivity of the aromatic ring toward electrophilic substitution. These electronic characteristics distinguish 4-bromophenylacetic acid from its non-halogenated analog and other positional isomers.

Industrial interest in 4-bromophenylacetic acid stems from its role as a precursor to various pharmaceuticals, agrochemicals, and fine chemicals. The compound's commercial availability and well-characterized reactivity profile have established it as a standard reagent in synthetic laboratories worldwide. Its stability under normal storage conditions and predictable chemical behavior contribute to its widespread application across multiple chemical disciplines.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of 4-bromophenylacetic acid consists of a benzene ring substituted at the 1-position with a bromine atom and at the 4-position with an acetic acid group (-CH₂COOH). X-ray crystallographic studies reveal that the compound crystallizes in the monoclinic space group P2₁/c with unit cell parameters a = 7.892 Å, b = 5.648 Å, c = 17.321 Å, and β = 93.47°. The aromatic ring maintains perfect planarity with carbon-carbon bond lengths ranging from 1.385 Å to 1.395 Å, consistent with typical aromatic systems.

The bromine-carbon bond length measures 1.903 Å, characteristic of aryl-bromine bonds. The acetic acid side chain adopts a conformation where the methylene group lies approximately 35° out of the aromatic plane, while the carboxylic acid group rotates freely around the C-C bond. The carboxylic acid functionality displays typical bond parameters: C=O bond length of 1.211 Å, C-O bond length of 1.316 Å, and O-H bond length of 0.972 Å.

Electronic structure analysis using density functional theory calculations indicates highest occupied molecular orbital (HOMO) localization on the aromatic system and bromine atom, while the lowest unoccupied molecular orbital (LUMO) shows significant density on the carboxylic acid group and the ring position ortho to bromine. The HOMO-LUMO gap calculates to approximately 5.2 eV, indicating moderate stability toward electronic excitation. Natural bond orbital analysis reveals partial charge distribution with bromine carrying a partial negative charge of -0.32 e, while the carboxylic acid hydrogen exhibits a partial positive charge of +0.42 e.

Chemical Bonding and Intermolecular Forces

4-Bromophenylacetic acid exhibits covalent bonding typical of aromatic carboxylic acids with carbon-carbon bonds in the aromatic ring demonstrating complete delocalization. The carbon-bromine bond displays covalent character with a bond dissociation energy of approximately 72 kcal/mol, slightly lower than typical aryl-chlorine bonds due to larger atomic size and reduced bond strength. The carboxylic acid group features polar covalent bonds with oxygen atoms exhibiting significant electronegativity, resulting in bond dipole moments of 2.4 D for the C=O bond and 1.7 D for the O-H bond.

Intermolecular forces in solid-state 4-bromophenylacetic acid primarily involve hydrogen bonding between carboxylic acid groups, forming characteristic dimeric structures common to carboxylic acids. The O-H···O hydrogen bond distance measures 2.632 Å with an angle of 176°, indicating strong, nearly linear hydrogen bonding. Additional weaker C-H···O interactions occur between methylene groups and carbonyl oxygen atoms with distances of 2.813 Å. Van der Waals interactions between bromine atoms and aromatic systems contribute to crystal packing with Br···Br contacts of 3.892 Å and Br···π interactions at 3.567 Å.

The compound exhibits significant molecular polarity with a calculated dipole moment of 4.3 D oriented along the bromine-to-carboxylic acid axis. This polarity influences solubility behavior, with 4-bromophenylacetic acid demonstrating higher solubility in polar organic solvents compared to non-polar media. The bromine substituent increases molecular polarizability, enhancing London dispersion forces and contributing to higher melting point compared to non-halogenated phenylacetic acid.

Physical Properties

Phase Behavior and Thermodynamic Properties

4-Bromophenylacetic acid exists as a white crystalline solid at room temperature with characteristic plate-like crystal habit. The compound melts sharply at 118°C with enthalpy of fusion measuring 28.5 kJ/mol. Boiling point occurs at 315°C with decomposition, accompanied by decarboxylation and release of carbon dioxide. Sublimation begins at temperatures above 85°C under reduced pressure (0.1 mmHg), with sublimation enthalpy of 89.3 kJ/mol.

The solid-state density measures 1.65 g/cm³ at 25°C, with linear thermal expansion coefficient of 7.8 × 10⁻⁵ K⁻¹ along the a-axis and 9.2 × 10⁻⁵ K⁻¹ along the c-axis. Heat capacity at constant pressure (C_p) measures 195 J/mol·K at 25°C, increasing to 245 J/mol·K at the melting point. The compound exhibits negligible vapor pressure at room temperature (2.3 × 10⁻⁷ mmHg at 25°C), increasing to 0.8 mmHg at the melting point.

Solubility characteristics show marked dependence on solvent polarity. In water, solubility measures 0.45 g/L at 25°C, increasing to 1.2 g/L at 100°C. Organic solvent solubility follows the order: ethanol (125 g/L) > acetone (98 g/L) > ethyl acetate (67 g/L) > toluene (8.5 g/L) > hexane (0.8 g/L). The refractive index of crystalline material measures 1.623 at 589 nm, while solution refractive index increment (dn/dc) in ethanol is 0.145 mL/g at 25°C.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrational modes: O-H stretch at 3000-2500 cm⁻¹ (broad), C=O stretch at 1695 cm⁻¹, aromatic C=C stretches at 1600 cm⁻¹ and 1580 cm⁻¹, C-Br stretch at 1075 cm⁻¹, and out-of-plane C-H bends at 830 cm⁻¹ and 750 cm⁻¹. The carboxylic acid dimerization manifests as broad feature between 3000-2500 cm⁻¹ with distinct hydrogen-bonded pattern.

Proton nuclear magnetic resonance (¹H NMR, 400 MHz, DMSO-d₆) displays the following signals: aromatic protons appear as double doublet at δ 7.45 (2H, J = 8.4 Hz, ortho to Br) and double doublet at δ 7.15 (2H, J = 8.4 Hz, ortho to CH₂), methylene protons singlet at δ 3.55 (2H), and carboxylic acid proton broad singlet at δ 12.3 (1H). Carbon-13 NMR (100 MHz, DMSO-d₆) shows signals at δ 174.2 (COOH), 131.8 (C-Br), 131.2 (C-CO), 130.5 (CH ortho to Br), 119.8 (CH ortho to CH₂), and 40.5 (CH₂).

Ultraviolet-visible spectroscopy in ethanol solution exhibits absorption maxima at 205 nm (ε = 12,400 M⁻¹cm⁻¹) and 245 nm (ε = 1,850 M⁻¹cm⁻¹), corresponding to π→π* transitions of the aromatic system. Mass spectral analysis shows molecular ion peak at m/z 214/216 with characteristic 1:1 isotope pattern due to bromine. Major fragmentation peaks occur at m/z 195/197 (M⁺-H₂O-CO), m/z 171/173 (M⁺-CO₂H), and m/z 91 (C₇H₇⁺).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

4-Bromophenylacetic acid demonstrates characteristic reactivity of both carboxylic acids and aryl bromides. The carboxylic acid group undergoes typical acid-base reactions with pK_a of 4.2 in water at 25°C, indicating moderate acidity enhanced by the electron-withdrawing bromine substituent. Esterification reactions proceed with second-order rate constants of 2.8 × 10⁻⁴ L/mol·s for methanol and 3.1 × 10⁻⁴ L/mol·s for ethanol under acid-catalyzed conditions at 60°C.

The aryl bromide functionality participates in various cross-coupling reactions including Suzuki, Heck, and Sonogashira couplings. Palladium-catalyzed Suzuki coupling with phenylboronic acid proceeds with second-order rate constant of 0.18 L/mol·s at 80°C in toluene/water mixture. Nucleophilic aromatic substitution occurs with strong nucleophiles such as alkoxides and amines, with second-order rate constants ranging from 10⁻⁶ to 10⁻⁴ L/mol·s depending on nucleophile strength and reaction conditions.

Thermal decomposition begins at 180°C with decarboxylation as the primary pathway, yielding 4-bromotoluene as major product with activation energy of 125 kJ/mol. Oxidation with potassium permanganate cleaves the aromatic ring, producing 4-bromobenzoic acid as intermediate followed by further oxidation to carbon dioxide and inorganic bromine compounds. Reduction with lithium aluminum hydride converts both functional groups to yield 4-bromophenethyl alcohol.

Acid-Base and Redox Properties

The acid-base behavior of 4-Bromophenylacetic acid follows typical carboxylic acid dissociation with pK_a = 4.2 ± 0.1 in aqueous solution at 25°C. The Hammett substituent constant for the 4-bromo group correlates with this acidity enhancement, with σ_p = +0.23 contributing to increased acid strength compared to unsubstituted phenylacetic acid (pK_a = 4.3). Buffer capacity maximizes at pH 4.2 with buffer value β = 0.025 mol/L·pH unit.

Redox properties indicate reduction potential of -1.35 V vs. SCE for the aryl bromide reduction in acetonitrile, while the carboxylic acid group shows oxidation potential of +1.85 V vs. SCE for one-electron oxidation. Polarographic reduction in aqueous solution exhibits half-wave potential of -0.95 V at pH 7, corresponding to two-electron reduction of the carboxylic acid group. The compound demonstrates stability in reducing environments up to -1.2 V but undergoes debromination at more negative potentials.

Electrochemical behavior shows irreversible oxidation at glassy carbon electrode with peak potential of +1.28 V vs. Ag/AgCl in acetonitrile. Cyclic voltammetry reveals reduction wave at -1.05 V corresponding to bromine elimination followed by further reduction at -1.45 V associated with carboxylic acid reduction. The compound exhibits good stability in acidic media (pH 2-6) but undergoes gradual hydrolysis in strongly basic conditions (pH > 10) with half-life of 45 minutes at pH 12 and 25°C.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Traditional laboratory synthesis involves electrophilic bromination of phenylacetic acid using elemental bromine in the presence of mercury(II) oxide catalyst. This method produces a mixture of ortho and para isomers (approximately 15:85 ratio) due to directing effects of the acetic acid side chain. The reaction proceeds in acetic acid solvent at 60-70°C with reaction time of 4-6 hours. Isolation of the para isomer employs fractional crystallization from ethanol/water mixture, yielding pure 4-bromophenylacetic acid with overall yield of 65-70%.

Alternative synthesis routes begin with 4-bromotoluene, which undergoes free radical bromination to form 4-bromobenzyl bromide. Subsequent displacement with sodium cyanide in ethanol solvent at reflux temperature produces 4-bromophenylacetonitrile with yield of 85-90%. Acidic or basic hydrolysis of the nitrile group then affords 4-bromophenylacetic acid. Hydrolysis with concentrated hydrochloric acid at reflux for 8 hours provides the acid in 90-95% yield, while alkaline hydrolysis with sodium hydroxide proceeds at 120°C for 4 hours with comparable yield.

Modern synthetic approaches employ palladium-catalyzed carbonylation of 4-bromobenzyl halides using carbon monoxide pressure (5-10 atm) in methanol solvent with palladium(II) acetate catalyst and triethylamine base. This method produces methyl 4-bromophenylacetate directly, which subsequently hydrolyzes to the free acid under mild basic conditions. Yields exceed 80% with excellent regioselectivity and minimal byproduct formation.

Industrial Production Methods

Commercial production of 4-bromophenylacetic acid typically employs the nitrile hydrolysis route starting from 4-bromotoluene. Large-scale bromination of 4-bromotoluene uses bromine vapor in the presence of light initiators or peroxide catalysts at 120-140°C, producing 4-bromobenzyl bromide with conversion exceeding 95% and selectivity of 88-92%. The reaction occurs in continuous flow reactors with residence time of 30-45 minutes and automatic removal of hydrogen bromide byproduct.

Cyanide displacement operates in stainless steel reactors with sodium cyanide in aqueous ethanol at 80°C for 2 hours, achieving 95% conversion to 4-bromophenylacetonitrile. Hydrolysis employs concentrated hydrochloric acid in pressurized reactors at 150°C for 6 hours, followed by crystallization and purification through activated carbon treatment. Overall process yield reaches 80-85% with final purity exceeding 99.5%.

Economic considerations favor this route due to availability of raw materials and established process technology. Production costs primarily derive from 4-bromotoluene (60%), bromine (15%), and energy consumption (20%). Environmental management focuses on hydrogen bromide recovery from bromination steps and cyanide waste treatment through alkaline chlorination. Major manufacturers produce 100-500 metric tons annually worldwide, with market price fluctuating between $80-120 per kilogram depending on purity and quantity.

Analytical Methods and Characterization

Identification and Quantification

Standard identification of 4-bromophenylacetic acid employs a combination of spectroscopic techniques including Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. Infrared spectroscopy provides characteristic fingerprint region between 1800-600 cm⁻¹ with specific peaks at 1695 cm⁻¹ (C=O stretch) and 1075 cm⁻¹ (C-Br stretch). Proton NMR confirms the substitution pattern through characteristic AA'BB' splitting pattern of aromatic protons with coupling constant J = 8.4 Hz.

Quantitative analysis typically utilizes reversed-phase high performance liquid chromatography with C18 column and UV detection at 245 nm. Mobile phase composition of acetonitrile/water (55:45 v/v) with 0.1% trifluoroacetic acid provides adequate separation with retention time of 6.3 minutes. Calibration curves show linear response from 0.1 μg/mL to 100 μg/mL with detection limit of 0.05 μg/mL and quantification limit of 0.15 μg/mL. Gas chromatography with flame ionization detection also serves for quantification using DB-5 column with temperature programming from 100°C to 280°C at 10°C/min.

Titrimetric methods employ standard sodium hydroxide solution (0.1 M) with phenolphthalein indicator for determination of acid content. Potentiometric titration provides more precise results with accuracy of ±0.2% and precision of ±0.5%. Bromine content determination uses oxygen flask combustion followed by ion chromatography or potentiometric titration with silver nitrate, achieving accuracy of ±0.3% for bromine quantification.

Purity Assessment and Quality Control

Purity assessment focuses on determination of organic impurities including starting materials, isomeric contaminants, and decomposition products. Common impurities include 2-bromophenylacetic acid (typically <0.5%), phenylacetic acid (<0.1%), and 4-bromobenzoic acid (<0.2%). Chromatographic methods achieve separation of these impurities with detection limits below 0.05%. Residual solvent content, particularly ethanol from crystallization processes, monitors by headspace gas chromatography with flame ionization detection, requiring levels below 500 ppm.

Quality control specifications for technical grade material require minimum assay of 99.0% by HPLC, melting point range of 116-119°C, and loss on drying below 0.5% at 105°C. Heavy metal content limits to <10 ppm, sulfated ash below 0.1%, and chloride content <100 ppm. Pharmaceutical grade material imposes stricter requirements with assay >99.5%, individual unknown impurities <0.1%, and total impurities <0.5%.

Stability testing indicates that 4-bromophenylacetic acid remains stable for at least 36 months when stored in sealed containers protected from light at room temperature. Accelerated stability studies at 40°C and 75% relative humidity show no significant degradation over 6 months. Packaging typically employs polyethylene-lined drums or foil bags with desiccant packets to prevent moisture absorption, which can cause caking and handling difficulties.

Applications and Uses

Industrial and Commercial Applications

4-Bromophenylacetic acid serves primarily as a synthetic intermediate in pharmaceutical industry for production of non-steroidal anti-inflammatory drugs and analgesic agents. The compound functions as key building block for fenbufen synthesis through Friedel-Crafts acylation followed by reduction. Additional pharmaceutical applications include synthesis of xenbucin and felbinac, both possessing anti-inflammatory properties. Production volumes for pharmaceutical applications exceed 50 metric tons annually worldwide.

Agrochemical applications utilize 4-bromophenylacetic acid as precursor for herbicide and fungicide synthesis. The compound undergoes conversion to various esters and amides that exhibit plant growth regulation properties. Specific derivatives show activity against fungal pathogens in cereal crops, with structure-activity relationships indicating optimal activity when the acid functionality remains unconverted while the bromine position allows specific spatial orientation.

Specialty chemical applications include use as ligand in metal complex catalysis, particularly for palladium-catalyzed cross-coupling reactions where the carboxylic acid group provides coordination sites while the bromine serves as reactive handle. The compound also functions as monomer for synthesis of specialty polymers with incorporated bromine atoms for flame retardancy applications. Market size for these non-pharmaceutical applications approximates 20-30 metric tons annually with growth rate of 5-7% per year.

Research Applications and Emerging Uses

Research applications of 4-bromophenylacetic acid span multiple disciplines including organic synthesis methodology, materials science, and coordination chemistry. In synthetic methodology, the compound serves as standard substrate for developing new cross-coupling reactions due to its well-defined reactivity and ease of product characterization. Recent developments include photoredox-catalyzed reactions, electrochemical transformations, and flow chemistry applications using 4-bromophenylacetic acid as model compound.

Materials science research employs 4-bromophenylacetic acid as building block for metal-organic frameworks and coordination polymers. The bifunctional nature allows connection through both carboxylic acid coordination and bromine interactions, creating diverse structural motifs. Emerging applications include design of porous materials for gas storage and separation, with specific interest in carbon dioxide capture capabilities.

Coordination chemistry utilizes 4-bromophenylacetic acid as ligand for various metal ions, particularly lanthanides and transition metals. The resulting complexes exhibit interesting magnetic and luminescent properties, with potential applications in molecular electronics and sensing technologies. Recent patent literature indicates growing interest in these advanced applications, with several patents filed covering specific metal complexes and their uses in electronic devices.

Historical Development and Discovery

The initial preparation of 4-bromophenylacetic acid dates to late 19th century when electrophilic bromination methods for aromatic compounds became established. Early literature references appear in German chemical journals around 1890, describing bromination of phenylacetic acid using bromine in the presence of various catalysts. The para selectivity of this reaction was recognized early, with researchers noting the predominance of the 4-bromo isomer over the ortho isomer due to steric and electronic factors.

Significant methodological advances occurred in the 1920s with development of alternative synthesis routes starting from 4-bromotoluene. The discovery of free radical bromination conditions for side-chain substitution provided more direct access to 4-bromobenzyl bromide, which could be converted to the target acid through cyanide displacement and hydrolysis. This route offered improved regioselectivity and higher overall yields compared to direct electrophilic bromination.

Modern understanding of the compound's reactivity emerged during the development of cross-coupling chemistry in the 1970s and 1980s. The discovery of palladium-catalyzed coupling reactions revealed the exceptional utility of 4-bromophenylacetic acid as a versatile building block, leading to increased research interest and commercial production. Recent developments focus on greener synthesis methods and applications in materials science, expanding the compound's utility beyond traditional organic synthesis.

Conclusion

4-Bromophenylacetic acid represents a chemically significant compound that bridges traditional organic chemistry with modern synthetic applications. Its well-characterized physical properties, predictable reactivity patterns, and commercial availability have established it as a valuable reagent in both academic and industrial settings. The bifunctional nature combining carboxylic acid and aryl bromide functionalities enables diverse chemical transformations, making this compound particularly useful for complex molecule synthesis.

The compound's structural features, including the electron-withdrawing bromine substituent and flexible acetic acid side chain, create unique electronic and steric properties that influence its chemical behavior. These characteristics distinguish it from both non-halogenated phenylacetic acids and other positional isomers, providing specific advantages in synthetic applications requiring regioselectivity and functional group compatibility.

Future research directions likely include development of more sustainable production methods, exploration of new catalytic applications, and expansion into materials science applications. The continuing importance of aryl bromide compounds in cross-coupling chemistry ensures ongoing relevance of 4-bromophenylacetic acid as a fundamental building block in synthetic organic chemistry. Its established role in pharmaceutical synthesis and emerging applications in advanced materials suggest continued scientific and commercial interest in this versatile compound.