Abstract

Chloroxylenol (IUPAC name: 4-chloro-3,5-dimethylphenol, molecular formula: C₈H₉ClO) is a chlorinated phenolic compound characterized by its white to off-white crystalline appearance and distinctive phenolic odor. The compound exhibits a melting point of 115.0 °C and boiling point of 246.0 °C at atmospheric pressure. With moderate aqueous solubility of 300 mg/L at 25 °C, chloroxylenol demonstrates significantly higher solubility in organic solvents including alcohols, ethers, and benzene. The compound displays a partition coefficient (log P) of 3.377, indicating substantial lipophilicity, and a pK_a value of 9.76, classifying it as a weak acid. First synthesized in 1923, chloroxylenol represents an important development in substituted phenol chemistry, offering reduced toxicity and irritation compared to simpler phenolic compounds while maintaining effective chemical properties for various industrial applications.

Introduction

Chloroxylenol belongs to the class of organic compounds known as chlorophenols, specifically a disubstituted derivative featuring both chlorine and methyl functional groups on an aromatic phenol ring. The compound emerged from systematic investigations into phenol derivatives that commenced in the late 19th century, when researchers recognized that increased substitution and lipophilicity in phenolic compounds correlated with reduced toxicity and irritation while enhancing antimicrobial efficacy. The structural modification of phenol through chloro and methyl substituents at specific positions produces a compound with optimized physicochemical properties for various chemical applications. The synthesis of chloroxylenol in 1923 in Germany represented a significant advancement in the development of specialized phenolic compounds derived from coal tar components. The compound's molecular structure, characterized by strategic positioning of substituents on the aromatic ring, confers unique electronic and steric properties that distinguish it from related chlorophenols and contribute to its specific chemical behavior.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Chloroxylenol possesses a molecular structure based on a phenolic ring system with substituents at the 3, 4, and 5 positions. The hydroxyl group occupies position 1, while methyl groups are located at positions 3 and 5, and a chlorine atom at position 4. This substitution pattern creates a symmetric 1,3,5-trisubstituted benzene derivative with C_2v molecular symmetry. The aromatic ring exhibits typical benzene geometry with bond angles of approximately 120° and carbon-carbon bond lengths ranging from 138 to 142 pm. The chlorine substituent, with an electronegativity of 3.16 on the Pauling scale, induces significant electron-withdrawing effects through inductive mechanisms, while the methyl groups (electronegativity: 2.55) exert electron-donating effects through hyperconjugation. The hydroxyl group participates in hydrogen bonding and contributes to the compound's acidic character through resonance stabilization of the phenolate anion.

Molecular orbital analysis reveals that the highest occupied molecular orbital (HOMO) primarily consists of π orbitals from the aromatic system with contributions from oxygen p orbitals, while the lowest unoccupied molecular orbital (LUMO) contains significant antibonding character between the aromatic ring and substituents. The chlorine atom's p orbitals interact with the π system through resonance effects, though to a lesser extent than in ortho or para positions relative to hydroxyl. The methyl groups adopt sp³ hybridization with nearly tetrahedral geometry (bond angles: 109.5°), while the aromatic carbons exhibit sp² hybridization. Spectroscopic evidence confirms the electronic structure, with characteristic UV-Vis absorption maxima at 282 nm (ε = 2300 M^-1cm^-1) corresponding to π→π* transitions in the aromatic system.

Chemical Bonding and Intermolecular Forces

The covalent bonding in chloroxylenol follows established patterns for substituted benzenes. Carbon-carbon bonds within the aromatic ring demonstrate bond energies of approximately 518 kJ/mol, while carbon-hydrogen bonds exhibit energies around 413 kJ/mol. The carbon-chlorine bond measures 177 pm in length with a bond energy of 339 kJ/mol, typical for aryl chlorides. Carbon-oxygen bond length in the phenolic group is 136 pm with a bond energy of 385 kJ/mol, slightly longer than in aliphatic alcohols due to resonance effects. The carbon-methyl bonds measure 150 pm with bond energies of 435 kJ/mol.

Intermolecular forces in chloroxylenol include strong hydrogen bonding capabilities due to the phenolic hydroxyl group, with hydrogen bond donor capacity of one and acceptor capacity of one. The compound exhibits a measured dipole moment of 2.8 Debye, resulting from the vector sum of individual bond dipoles: C-Cl (1.7 D), O-H (1.5 D), and C-CH₃ (0.4 D). Van der Waals forces contribute significantly to intermolecular interactions, particularly due to the chlorine atom's polarizability and the methyl groups' hydrophobic character. The calculated polar surface area is 20.2 Ų, while the molecular volume is approximately 130 ų. Comparative analysis with related compounds shows that chloroxylenol exhibits stronger intermolecular forces than phenol itself due to increased molecular weight and polarity, but weaker than more highly substituted phenolic compounds.

Physical Properties

Phase Behavior and Thermodynamic Properties

Chloroxylenol appears as white to off-white crystalline solid at room temperature with a characteristic phenolic odor detectable at concentrations as low as 0.01 ppm. The compound crystallizes in the monoclinic crystal system with space group P2₁/c and unit cell parameters a = 8.42 Å, b = 11.36 Å, c = 7.89 Å, and β = 98.7°. The melting point occurs at 115.0 ± 0.5 °C with a heat of fusion of 22.8 kJ/mol. The boiling point at atmospheric pressure is 246.0 ± 2.0 °C, with heat of vaporization measuring 48.5 kJ/mol. The compound sublimes appreciably at temperatures above 80 °C under reduced pressure.

The density of crystalline chloroxylenol is 1.265 g/cm³ at 20 °C, while the liquid density at the melting point is 1.102 g/cm³. The refractive index of the molten compound is 1.542 at 120 °C and 589 nm wavelength. Specific heat capacity measures 1.32 J/g·K for the solid phase and 1.89 J/g·K for the liquid phase. The thermal conductivity is 0.18 W/m·K for the solid form. The compound exhibits limited polymorphism, with only one stable crystalline form identified under ambient conditions. Phase transitions show minimal hysteresis upon cooling, with supercooling of up to 15 °C observed before crystallization occurs.

Spectroscopic Characteristics

Infrared spectroscopy of chloroxylenol reveals characteristic absorption bands including O-H stretch at 3200-3600 cm^-1 (broad), aromatic C-H stretch at 3020 cm^-1, methyl C-H stretches at 2960 and 2870 cm^-1, aromatic C=C stretches at 1600, 1580, and 1490 cm^-1, C-O stretch at 1230 cm^-1, and C-Cl stretch at 1090 cm^-1. The fingerprint region below 1000 cm^-1 shows distinctive patterns at 860, 820, and 750 cm^-1 corresponding to aromatic C-H out-of-plane bending vibrations.

Proton nuclear magnetic resonance (¹H NMR, CDCl₃) displays signals at δ 2.27 ppm (singlet, 6H, two methyl groups), δ 5.20 ppm (broad singlet, 1H, phenolic OH), and δ 6.70 ppm (singlet, 2H, aromatic protons). Carbon-13 NMR shows signals at δ 20.7 ppm (methyl carbons), δ 117.4 ppm (aromatic CH carbons), δ 129.8 ppm (quaternary carbon attached to chlorine), δ 136.2 ppm (quaternary carbons attached to methyl groups), and δ 153.0 ppm (carbon attached to oxygen). Mass spectral analysis reveals a molecular ion peak at m/z 156/158 (3:1 ratio due to chlorine isotopes) with major fragmentation peaks at m/z 141 (loss of CH₃), m/z 113 (loss of CH₃ and CO), and m/z 77 (C₆H₅⁺).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Chloroxylenol demonstrates reactivity characteristic of phenolic compounds with additional influence from the chlorine and methyl substituents. Electrophilic aromatic substitution occurs preferentially at the positions ortho to the hydroxyl group, though these positions are blocked by methyl groups, resulting in decreased reactivity compared to phenol. The compound undergoes O-alkylation with alkyl halides to form ethers, with second-order rate constants of approximately 0.015 M^-1s^-1 for methyl iodide in acetone at 25 °C. Esterification with acid chlorides or anhydrides proceeds with rate constants of 0.008 M^-1s^-1 for acetic anhydride in pyridine.

The chlorine substituent exhibits moderate reactivity in nucleophilic aromatic substitution reactions. Displacement occurs with strong nucleophiles such as hydroxide (k = 1.2 × 10^-4 M^-1s^-1 at 80 °C in water) or alkoxides (k = 3.8 × 10^-3 M^-1s^-1 for methoxide in methanol at 60 °C). The methyl groups undergo free radical bromination at the benzylic position with N-bromosuccinimide (activation energy: 85 kJ/mol), followed by oxidation to aldehyde or carboxylic acid derivatives. The compound demonstrates stability under normal storage conditions, with decomposition occurring only above 300 °C through cleavage of the C-Cl bond (activation energy: 190 kJ/mol) and subsequent radical reactions.

Acid-Base and Redox Properties

Chloroxylenol behaves as a weak acid with pK_a = 9.76 ± 0.05 in water at 25 °C, making it approximately 100 times less acidic than phenol (pK_a = 9.99) due to the electron-donating effects of the methyl groups. The acid dissociation constant shows temperature dependence following the equation pK_a = 10.12 - 0.021(T-25) where T is temperature in °C. The compound forms stable salts with strong bases, with sodium chloroxylenolate exhibiting solubility exceeding 500 g/L in water. Buffer solutions containing chloroxylenol and its conjugate base maintain effective pH control between 8.5 and 10.5.

Redox properties include oxidation potential of +0.95 V versus standard hydrogen electrode for one-electron oxidation to the phenoxyl radical. The compound undergoes electrochemical oxidation at glassy carbon electrodes with E_1/2 = +1.05 V in acetonitrile. Reduction of the chlorine substituent occurs at mercury electrodes with E_1/2 = -1.35 V versus saturated calomel electrode. Chloroxylenol demonstrates stability in reducing environments but undergoes gradual oxidation in the presence of strong oxidizing agents such as chromic acid or peroxide. The compound exhibits antioxidant properties through radical scavenging mechanisms, with measured rate constant for reaction with peroxyl radicals of 1.8 × 10⁴ M^-1s^-1.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The primary laboratory synthesis of chloroxylenol involves direct chlorination of 3,5-dimethylphenol. The reaction proceeds with chlorine gas in inert solvents such as carbon tetrachloride or chloroform at temperatures between 0-5 °C to control substitution pattern. The reaction follows electrophilic aromatic substitution mechanisms with the chlorine electrophile attacking the aromatic ring. The para position to the hydroxyl group is favored due to directing effects, yielding predominantly the 4-chloro derivative. Typical reaction conditions employ 1.05 equivalents of chlorine gas relative to 3,5-dimethylphenol to minimize polychlorination. The reaction achieves yields of 85-90% with purification through recrystallization from hexane or toluene.

Alternative synthetic routes include the reaction of 3,5-dimethylphenol with sulfuryl chloride (SO₂Cl₂) in dichloromethane at -10 °C, which provides improved regioselectivity and reduced byproduct formation. This method yields chloroxylenol with 92-95% purity after simple filtration. Another approach utilizes the Dakin-West reaction modifications starting from 4-hydroxybenzoic acid derivatives, though this route is less efficient for large-scale preparation. Laboratory characterization of synthesized chloroxylenol includes melting point determination, thin-layer chromatography (R_f = 0.45 in 3:1 hexane:ethyl acetate), and spectroscopic verification through IR and NMR comparison with authentic samples.

Industrial Production Methods

Industrial production of chloroxylenol employs continuous chlorination processes in reactor systems designed for handling corrosive and toxic materials. The manufacturing process typically utilizes 3,5-dimethylphenol as feedstock with chlorine gas introduction under carefully controlled conditions. Large-scale reactors constructed from glass-lined steel or Hastelloy C-276 maintain temperature control through external cooling jackets. The reaction occurs in the liquid phase with efficient mixing to ensure homogeneous chlorine distribution and minimize hot spots that could lead to polychlorination.

Process optimization includes real-time monitoring of chlorine consumption and reaction progress through UV-Vis spectroscopy or gas chromatography. Typical production scales reach 500-1000 kg per batch with cycle times of 4-6 hours. The crude product undergoes purification through fractional distillation under reduced pressure (20 mmHg) with collection of the fraction boiling at 140-145 °C, followed by recrystallization from hydrocarbon solvents. Industrial purity specifications require minimum 98.5% chloroxylenol content with limits of 0.5% for 3,5-dimethylphenol and 0.1% for dichloro derivatives. Production waste streams primarily consist of hydrochloric acid gas, which is scrubbed and converted to calcium chloride for commercial sale, and solvent vapors, which are recovered through condensation systems with greater than 95% efficiency.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of chloroxylenol employs multiple complementary techniques. Gas chromatography with flame ionization detection provides separation on 5% phenyl-methyl polysiloxane columns (30 m × 0.32 mm × 0.25 μm) with typical retention time of 8.2 minutes at 180 °C isothermal conditions. High-performance liquid chromatography utilizes reversed-phase C18 columns with mobile phase consisting of acetonitrile:water (70:30) acidified with 0.1% phosphoric acid, yielding retention time of 4.5 minutes at 1.0 mL/min flow rate. Detection occurs at 282 nm with molar absorptivity of 2300 M^-1cm^-1.

Quantitative analysis employs external standard calibration with linear response ranges from 0.1 to 100 μg/mL for HPLC methods and 1 to 1000 μg/mL for GC methods. Method validation parameters demonstrate excellent precision with relative standard deviations less than 1.5% for retention time and less than 2.5% for peak area. Accuracy, determined through spike recovery experiments, ranges from 98% to 102% across the validated concentration range. The limit of detection measures 0.05 μg/mL for HPLC-UV and 0.5 μg/mL for GC-FID, while the limit of quantification is 0.15 μg/mL and 1.5 μg/mL respectively. Sample preparation typically involves dissolution in methanol or acetonitrile followed by appropriate dilution.

Purity Assessment and Quality Control

Purity assessment of chloroxylenol requires determination of organic impurities, residual solvents, and inorganic contaminants. Common organic impurities include starting material 3,5-dimethylphenol (typically <0.5%), dichloro derivatives such as 4,6-dichloro-3,5-dimethylphenol (<0.2%), and oxidation products including quinone derivatives (<0.1%). Residual solvents from manufacturing or purification processes are limited to 500 ppm for chlorinated solvents and 3000 ppm for hydrocarbon solvents according to industrial specifications.

Quality control parameters include assay determination by differential scanning calorimetry for melting point and purity, requiring onset temperature of 114.5-115.5 °C with purity >98.5%. Karl Fischer titration measures water content with specification <0.2% w/w. Heavy metal contamination, determined by atomic absorption spectroscopy, must not exceed 10 ppm for lead, 5 ppm for cadmium, and 15 ppm for total heavy metals. Ash content after combustion at 550 °C is specified at <0.1%. Stability testing under accelerated conditions (40 °C, 75% relative humidity) demonstrates no significant degradation over 6 months, supporting a recommended shelf life of 36 months when stored in airtight containers protected from light.

Applications and Uses

Industrial and Commercial Applications

Chloroxylenol serves as a key intermediate in the synthesis of more complex chemical compounds, particularly in the production of specialized phenolic resins and polymers. The compound's molecular structure, featuring both reactive hydroxyl and chlorine functional groups, enables incorporation into epoxy resins and other cross-linked polymer systems. In adhesive formulations, chloroxylenol acts as a modifying agent that enhances thermal stability and chemical resistance. The compound finds application in sealant products where it contributes to improved durability and resistance to microbial degradation.

In coating and paint formulations, chloroxylenol functions as a biostabilizer that prevents microbial growth in water-based products during storage and application. Lubricant and grease products incorporate chloroxylenol as an antioxidant and extreme pressure additive that enhances performance under demanding conditions. Plastic and polymer products utilize the compound as a processing stabilizer that minimizes degradation during high-temperature extrusion and molding operations. Industrial wash tanks employ chloroxylenol solutions for equipment sanitation, particularly in food processing and pharmaceutical manufacturing where effective cleaning is critical. The compound's stability under various pH conditions and compatibility with diverse materials contributes to its utility across multiple industrial sectors.

Research Applications and Emerging Uses

Research applications of chloroxylenol focus on its potential as a building block for novel materials with tailored properties. Investigations explore its incorporation into metal-organic frameworks (MOFs) where the phenolic and chloro functionalities serve as coordination sites for metal ions. Studies examine chloroxylenol derivatives as ligands in catalytic systems for oxidation reactions, leveraging the electronic effects of substituents on catalytic activity. Research into supramolecular chemistry utilizes chloroxylenol as a hydrogen-bonding component in molecular recognition systems.

Emerging applications include development of chloroxylenol-based ionic liquids for specialized separation processes, where the compound's amphiphilic character provides unique solvation properties. Investigations explore its use in photolithographic processes as a photoacid generator precursor for microfabrication applications. Research continues into modified chloroxylenol derivatives with enhanced selectivity for specific chemical transformations. The compound serves as a model system for studying substituent effects on aromatic systems, particularly the interplay between electron-donating methyl groups and electron-withdrawing chlorine atoms on chemical reactivity and physical properties.

Historical Development and Discovery

The development of chloroxylenol emerged from systematic investigations of phenol derivatives that commenced in the late 19th century. Early research into coal tar components revealed that phenolic compounds exhibited varying biological activity depending on their substitution patterns. Scientists observed that increased substitution and lipophilicity in phenolic compounds correlated with reduced toxicity and irritation while maintaining or enhancing efficacy. This structure-activity relationship guided the development of improved phenolic compounds for various applications.

The specific synthesis of chloroxylenol was accomplished in Germany in 1923 as part of broader efforts to develop chlorinated phenolic compounds with optimized properties. The compound represented a significant advancement over simpler phenols, offering improved handling characteristics and reduced corrosivity. The manufacturing processes evolved throughout the mid-20th century, with improvements in chlorination methodology and purification techniques that enabled larger-scale production. Analytical methods for characterization advanced significantly with the development of modern spectroscopic techniques in the 1950s-1970s, allowing precise determination of molecular structure and purity. The understanding of chloroxylenol's chemical behavior expanded through mechanistic studies conducted in the 1960s-1980s, which elucidated its reaction pathways and stability characteristics. Ongoing research continues to explore new applications and derivatives of this historically significant compound.

Conclusion

Chloroxylenol represents a chemically significant compound that demonstrates how strategic molecular modification can optimize the properties of basic chemical scaffolds. The compound's specific substitution pattern on the phenolic ring confers unique physicochemical characteristics including moderate acidity, significant lipophilicity, and stability under various conditions. The interplay between electron-donating methyl groups and electron-withdrawing chlorine substituent creates a balanced electronic environment that influences both reactivity and intermolecular interactions. The well-established synthesis routes and thorough characterization provide a solid foundation for both industrial applications and research investigations.

Future research directions include further exploration of chloroxylenol derivatives with additional functional groups that could enhance specific properties or enable new applications. Investigations into the compound's behavior under extreme conditions of temperature and pressure may reveal previously unobserved phases or reactivity patterns. Development of more sustainable manufacturing processes that reduce environmental impact represents another important area for continued improvement. The fundamental understanding of chloroxylenol's chemical behavior contributes broadly to the field of substituted aromatic chemistry and provides insights applicable to related compound classes.