Abstract

Homosalate, systematically named 3,3,5-trimethylcyclohexyl 2-hydroxybenzoate (C₁₆H₂₂O₃), represents an organic ester compound belonging to the salicylate chemical class. This compound exhibits a molecular weight of 262.35 g·mol⁻¹ and manifests as a colorless to pale yellow liquid with a characteristic mild odor at standard temperature and pressure. Homosalate demonstrates limited aqueous solubility of 0.4 mg·L⁻¹ but excellent solubility in most organic solvents including ethanol, isopropanol, and various oils. The compound possesses a density of 1.05 g·cm⁻³ at 20 °C and shows a boiling point range of 181-185 °C at atmospheric pressure. Its primary industrial significance stems from its ultraviolet absorption properties, particularly in the 295-315 nm wavelength range, making it valuable as a chemical UV filter in various formulations.

Introduction

Homosalate constitutes an important organic compound within the broader class of salicylate esters, characterized by the esterification product of salicylic acid and 3,3,5-trimethylcyclohexanol. This compound belongs to the category of organic UV filters and finds extensive application in photoprotective formulations. The trimethylcyclohexyl moiety provides enhanced hydrophobicity compared to simpler salicylate esters, contributing to its persistence in topical applications. First developed in the mid-20th century, homosalate has undergone extensive characterization regarding its physicochemical properties and photochemical behavior. The compound's molecular architecture combines aromatic character with alicyclic structural elements, creating unique electronic properties that govern its ultraviolet absorption characteristics.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The homosalate molecule exhibits a distinctive molecular architecture comprising two principal domains: the salicylate aromatic system and the trimethylcyclohexyl alicyclic system. The salicylate portion consists of a benzene ring with hydroxyl and ester functional groups in ortho relationship, creating potential for intramolecular hydrogen bonding. The cyclohexyl ring adopts a chair conformation with equatorial orientation of the ester linkage. Molecular geometry analysis indicates bond angles of approximately 120° for sp² hybridized carbon atoms in the aromatic system and 109.5° for sp³ hybridized carbon atoms in the cyclohexyl system. The ester carbonyl carbon demonstrates trigonal planar geometry with bond angles of 120°.

Electronic structure analysis reveals that the highest occupied molecular orbital (HOMO) primarily resides on the phenolic oxygen and aromatic π-system, while the lowest unoccupied molecular orbital (LUMO) shows significant density on the carbonyl group and associated π* system. This electronic distribution facilitates ultraviolet absorption through π→π* transitions. The intramolecular hydrogen bond between the phenolic hydroxyl and carbonyl oxygen creates a six-membered chelate ring, influencing both electronic properties and molecular conformation. This interaction results in a bond length of approximately 1.85 Å between the hydroxyl hydrogen and carbonyl oxygen, significantly shorter than typical intermolecular hydrogen bonds.

Chemical Bonding and Intermolecular Forces

Covalent bonding in homosalate follows typical patterns for organic esters, with carbon-oxygen bond lengths of 1.36 Å for the phenolic C-O bond and 1.23 Å for the carbonyl C=O bond. The ester C-O bond linking the salicylate and cyclohexyl moieties measures approximately 1.44 Å. Bond dissociation energies for these bonds range from 85-90 kcal·mol⁻¹ for C-O single bonds and 175-180 kcal·mol⁻¹ for the carbonyl π bond. The molecule exhibits significant dipole moment due to the polar carbonyl group and hydroxyl functionality, with experimental measurements indicating a dipole moment of approximately 2.5 Debye in nonpolar solvents.

Intermolecular forces dominate the physical behavior of homosalate, with van der Waals interactions arising from the hydrophobic trimethylcyclohexyl group and dipole-dipole interactions originating from the polar ester functionality. The molecule demonstrates limited capacity for conventional hydrogen bonding due to intramolecular hydrogen bond formation, which reduces availability of the hydroxyl group for intermolecular interactions. London dispersion forces contribute significantly to cohesion in the liquid state, particularly from the alicyclic portion of the molecule. These collective intermolecular forces result in a viscosity of approximately 25 mPa·s at 25 °C.

Physical Properties

Phase Behavior and Thermodynamic Properties

Homosalate exists as a liquid under standard conditions with a melting point below -20 °C, indicating considerable molecular disorder even at reduced temperatures. The boiling point occurs between 181-185 °C at atmospheric pressure (101.3 kPa), with vapor pressure measurements showing 0.01 mmHg at 25 °C. The compound exhibits a glass transition temperature of approximately -65 °C, below which it forms an amorphous solid. Enthalpy of vaporization measures 65.2 kJ·mol⁻¹, while the heat of fusion remains undetermined due to the compound's low melting characteristics. Specific heat capacity measurements yield values of 1.8 J·g⁻¹·K⁻¹ for the liquid state.

Density measurements show temperature dependence following the relationship ρ = 1.068 - 0.00078T g·cm⁻³, where T represents temperature in Celsius. The refractive index measures 1.516 at 20 °C using the sodium D-line, with temperature coefficient of -4.5×10⁻⁴ K⁻¹. Surface tension measurements indicate 35.2 mN·m⁻¹ at 25 °C, consistent with moderately polar organic liquids. The compound demonstrates limited miscibility with water but complete miscibility with most organic solvents including ethanol, acetone, ethyl acetate, and hydrocarbon solvents.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at 3250 cm⁻¹ (broad, O-H stretch), 1680 cm⁻¹ (C=O stretch), 1600 cm⁻¹ and 1580 cm⁻¹ (aromatic C=C stretches), and 1280 cm⁻¹ (C-O stretch). The broad hydroxyl stretching frequency indicates strong intramolecular hydrogen bonding. Nuclear magnetic resonance spectroscopy shows proton chemical shifts at δ 10.8 ppm (phenolic OH, concentration-dependent), δ 6.8-7.8 ppm (aromatic protons), δ 4.7 ppm (methine proton of cyclohexyl ring), and δ 0.9-2.2 ppm (aliphatic protons). Carbon-13 NMR displays signals at δ 170 ppm (carbonyl carbon), δ 160 ppm (phenolic carbon), δ 120-140 ppm (aromatic carbons), and δ 20-50 ppm (aliphatic carbons).

Ultraviolet-visible spectroscopy demonstrates maximum absorption at 306 nm with molar absorptivity of 4,200 L·mol⁻¹·cm⁻¹ in ethanol solution. This absorption corresponds to the π→π* transition of the salicylate system. Mass spectrometric analysis shows molecular ion peak at m/z 262 with characteristic fragmentation patterns including loss of the cyclohexyl moiety (m/z 138, salicylic acid fragment) and decarboxylation products. The base peak appears at m/z 120 corresponding to the protonated salicylic acid fragment.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Homosalate demonstrates typical ester reactivity including hydrolysis, transesterification, and aminolysis. Acid-catalyzed hydrolysis follows first-order kinetics with rate constant of 3.2×10⁻⁶ s⁻¹ in 0.1 M HCl at 25 °C. Base-catalyzed hydrolysis proceeds more rapidly with second-order rate constant of 0.15 L·mol⁻¹·s⁻¹ in 0.1 M NaOH at 25 °C. The presence of the ortho-hydroxy group facilitates intramolecular catalysis of hydrolysis through formation of a cyclic intermediate. Photochemical degradation occurs under ultraviolet irradiation through radical mechanisms, with quantum yield of 0.03 for degradation at 310 nm in ethanol solution.

Thermal stability studies indicate decomposition onset at 180 °C through retro-esterification pathways. The compound demonstrates resistance to oxidation under ambient conditions but undergoes photoxidative degradation in the presence of singlet oxygen with rate constant of 2.1×10⁸ L·mol⁻¹·s⁻¹. Reduction with lithium aluminum hydride yields the corresponding diol, 3,3,5-trimethylcyclohexanol and salicyl alcohol, with quantitative yield under appropriate conditions. Ester exchange reactions proceed readily with catalytic amounts of acid or base.

Acid-Base and Redox Properties

The phenolic hydroxyl group exhibits acidic character with pKₐ of 9.2 in aqueous ethanol, slightly lower than typical phenols due to intramolecular hydrogen bonding and electron-withdrawing effects of the ortho ester group. Protonation occurs exclusively at the carbonyl oxygen with pKₐ of -2.3 for the conjugate acid. Redox properties show irreversible oxidation wave at +1.2 V versus standard hydrogen electrode corresponding to phenol oxidation. Reduction potentials occur at -1.8 V for carbonyl reduction and -2.4 V for aromatic ring reduction.

The compound demonstrates stability across pH range 3-9 with maximum stability at pH 5-6. Outside this range, hydrolysis accelerates significantly. Redox stability maintains under ambient atmospheric conditions but deteriorates in strong oxidizing environments. The presence of transition metal ions catalyzes oxidative degradation, particularly copper(II) and iron(III) ions. Chelation with metal ions occurs through the salicylate moiety with formation constants of log K = 5.2 for copper(II) and log K = 4.8 for iron(III).

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Laboratory synthesis of homosalate typically employs Fischer-Speier esterification between salicylic acid and 3,3,5-trimethylcyclohexanol. The reaction proceeds with catalytic sulfuric acid (0.5-1.0% by weight) in toluene solvent under reflux conditions with azeotropic water removal. Typical reaction conditions involve equimolar quantities of reactants at 110 °C for 4-6 hours, yielding 85-90% conversion. Purification involves washing with sodium bicarbonate solution to remove unreacted salicylic acid, followed by distillation under reduced pressure (0.5 mmHg, 150 °C). Alternative catalysts include p-toluenesulfonic acid and acidic ion exchange resins.

More recent methodologies utilize Steglich esterification with dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) catalyst in dichloromethane solvent at room temperature. This method affords higher yields (92-95%) and milder conditions but requires additional purification steps to remove urea byproducts. Enzymatic catalysis using lipases from Candida antarctica provides enantioselective esterification when using resolved 3,3,5-trimethylcyclohexanol, though this approach remains primarily of academic interest due to economic considerations.

Industrial Production Methods

Industrial production scales the Fischer-Speier esterification process using continuous flow reactors with integrated water separation systems. Typical production employs excess 3,3,5-trimethylcyclohexanol (1.2:1 molar ratio) to drive conversion and facilitate purification. Reaction conditions optimize at 120-130 °C with heterogeneous acid catalysis using sulfonated polystyrene resins. Process yields reach 93-95% with production capacities exceeding 1000 metric tons annually worldwide. The final product specification requires minimum 99% purity by gas chromatography with limits on free salicylic acid (≤0.5%) and residual alcohol (≤1.0%).

Economic analysis indicates raw material costs dominate production economics, with salicylic acid and 3,3,5-trimethylcyclohexanol comprising approximately 75% of variable costs. Energy requirements focus primarily on distillation separation and solvent recovery. Environmental considerations include wastewater treatment for acidic wash streams and recovery of organic solvents through distillation. Modern facilities implement closed-loop systems with greater than 95% solvent recovery and neutralization of acid streams with lime followed by biological treatment.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with flame ionization detection provides the primary method for homosalate quantification, using non-polar stationary phases (5% phenyl methylpolysiloxane) and temperature programming from 100 °C to 280 °C at 10 °C·min⁻¹. Retention indices measure 2150 on methylsilicon stationary phases. High-performance liquid chromatography utilizes reversed-phase C18 columns with methanol-water mobile phases (80:20 v/v) and ultraviolet detection at 306 nm. Limit of quantification reaches 0.1 mg·L⁻¹ with linear range extending to 1000 mg·L⁻¹.

Spectroscopic identification employs infrared spectroscopy with matching of characteristic bands at 1680 cm⁻¹ and 3250 cm⁻¹. Nuclear magnetic resonance spectroscopy provides definitive structural confirmation through comparison of chemical shifts and coupling patterns. Mass spectrometric analysis confirms molecular weight through electron impact ionization with characteristic fragments at m/z 262, 138, and 120. X-ray diffraction analysis of crystalline derivatives provides absolute structural confirmation, though the compound itself does not crystallize readily.

Purity Assessment and Quality Control

Quality control specifications for industrial homosalate require minimum 99.0% purity by area normalization in gas chromatography. Common impurities include unreacted 3,3,5-trimethylcyclohexanol (≤1.0%), salicylic acid (≤0.5%), and dehydration products of the alcohol. Color specification typically requires APHA value less than 50. Moisture content limits to 0.1% by Karl Fischer titration. Residual acid catalysts measure by potentiometric titration with detection limit of 10 ppm. Heavy metal contamination limits to 10 ppm total by atomic absorption spectroscopy.

Stability testing under accelerated conditions (40 °C, 75% relative humidity) shows no significant degradation over six months when protected from light. Photostability testing under ultraviolet irradiation (310 nm, 500 W·m⁻²) demonstrates 5% degradation after 24 hours. Packaging typically employs amber glass or polyethylene containers with nitrogen atmosphere to prevent oxidative degradation during storage. Shelf life specifications generally allow two years from manufacture date when stored under recommended conditions.

Applications and Uses

Industrial and Commercial Applications

Homosalate serves primarily as an ultraviolet absorbing compound in sunscreen formulations, providing protection in the UV-B range (295-315 nm). Commercial sunscreen products typically contain 4-15% homosalate by weight, often in combination with other UV filters to achieve broad-spectrum protection. The compound's lipophilic character enhances substantivity on skin and improves water resistance in formulations. Additional applications include ultraviolet stabilization for polymers and coatings, particularly for materials requiring protection against UV-B radiation. Industrial formulations incorporate homosalate at 0.1-0.5% concentration as a light stabilizer.

The global market for homosalate exceeds 5000 metric tons annually, with primary consumption in personal care products. Production occurs predominantly in China, Germany, and the United States, with major manufacturers including BASF, Symrise, and Jiangsu Jiayuan Chemical. Economic analysis indicates stable demand growth of 3-4% annually, tracking overall sunscreen market expansion. Regulatory approvals exist in most major markets including the United States, European Union, and Japan, though concentration limits vary by jurisdiction.

Research Applications and Emerging Uses

Research applications utilize homosalate as a model compound for studying intramolecular hydrogen bonding effects on photophysical properties. Recent investigations explore its potential as a molecular probe for studying microenvironments in organized assemblies such as micelles and liposomes. The compound's fluorescence properties, though weak, provide information about local polarity and hydrogen bonding environments. Emerging applications include use as a ultraviolet tracer in environmental studies and as a photolabile protecting group in synthetic chemistry due to its clean photodegradation pathways.

Patent literature describes novel derivatives of homosalate with enhanced photostability and altered absorption characteristics. These structural modifications include halogenation of the aromatic ring and incorporation of additional chromophores. Research continues into polymeric derivatives where homosalate units attach to polymer backbones, creating ultraviolet-absorbing materials with reduced mobility and increased environmental compatibility. The compound's relatively simple structure makes it an attractive starting point for development of new ultraviolet filters with improved safety and efficacy profiles.

Historical Development and Discovery

Homosalate development originated in the 1950s as part of broader research into salicylate derivatives for ultraviolet protection. Initial patent literature from this period describes the compound's synthesis and ultraviolet absorption properties. Commercial introduction occurred in the 1960s as sunscreen formulations evolved from simple physical blockers to more sophisticated chemical ultraviolet filters. The 1970s saw expanded use following regulatory approval in major markets and growing awareness of ultraviolet radiation health effects.

Structural characterization advanced significantly in the 1980s with application of modern spectroscopic techniques, particularly two-dimensional NMR methods that elucidated conformational preferences. The 1990s brought increased attention to photostability and environmental fate, leading to process improvements that enhanced purity and performance. Recent decades have focused on understanding degradation pathways and potential environmental impacts, though the compound remains widely used due to its favorable efficacy and safety profile established through decades of use.

Conclusion

Homosalate represents a well-characterized organic ultraviolet filter with established applications in photoprotection and polymer stabilization. Its molecular structure combines salicylate chromophore characteristics with alicyclic hydrophobicity, creating favorable balance between ultraviolet absorption and material compatibility. The compound demonstrates good photostability and appropriate physicochemical properties for formulation into various product types. Ongoing research continues to explore structural modifications and novel applications while maintaining the fundamental characteristics that make homosalate valuable for ultraviolet protection. Future developments will likely focus on enhanced environmental compatibility and expanded utility in materials science applications.