Abstract

Vedaprofen, systematically named 2-(4-cyclohexyl-1-naphthyl)propanoic acid, is an organic compound with molecular formula C₁₉H₂₂O₂ and molecular mass 282.38 g·mol⁻¹. This chiral carboxylic acid belongs to the 2-arylpropanoic acid class of compounds, characterized by a naphthalene ring system substituted at the 4-position with a cyclohexyl group and at the 1-position with a propanoic acid moiety. The compound exhibits typical properties of aromatic carboxylic acids including moderate water solubility (approximately 0.1 mg·mL⁻¹ at 25 °C) and significant lipophilicity with calculated log P value of 4.2. Vedaprofen demonstrates characteristic UV absorption maxima at 226 nm and 278 nm in methanol solution. The compound's chemical behavior is dominated by its carboxylic acid functionality (pKa 4.2) and extended π-conjugated system, making it suitable for various synthetic modifications and analytical applications in organic chemistry.

Introduction

Vedaprofen represents a structurally interesting member of the 2-arylpropanoic acid family, distinguished by its unique combination of naphthalene and cyclohexyl ring systems. First synthesized in the late 20th century, this compound has attracted attention primarily for its structural features rather than biological activity in chemical literature. The molecular architecture incorporates both planar aromatic and non-planar alicyclic components, creating a distinctive electronic environment that influences its physical and chemical properties. With CAS registry number 71109-09-6, vedaprofen serves as a model compound for studying steric and electronic effects in substituted naphthalene systems. The presence of a chiral center at the carbon alpha to the carboxylic acid group adds stereochemical complexity to this system, making it relevant to studies of asymmetric synthesis and chiral recognition phenomena.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Vedaprofen possesses a well-defined molecular structure with bond lengths and angles consistent with its hybrid aromatic-alicyclic character. The naphthalene ring system maintains planarity with typical carbon-carbon bond lengths of 1.40 Å in the aromatic rings and 1.46 Å for the bond connecting the two rings. The cyclohexyl substituent adopts the chair conformation with carbon-carbon bond lengths of 1.54 Å and bond angles of 111°. The propanoic acid side chain exhibits bond lengths of 1.50 Å for the C-C bond and 1.21 Å for the C=O bond, with the carboxylic acid group twisted approximately 35° from the plane of the naphthalene ring due to steric interactions.

Electronic structure analysis reveals significant electron delocalization throughout the molecule. The highest occupied molecular orbital (HOMO) primarily resides on the naphthalene π-system with some contribution from the carboxylic oxygen lone pairs, while the lowest unoccupied molecular orbital (LUMO) shows antibonding character between the naphthalene system and the carboxylic acid group. The ionization potential is calculated at 8.3 eV, and electron affinity measures 0.7 eV. The chiral center at C2 of the propanoic acid chain creates two enantiomers with identical physical properties but potentially different chemical behavior in chiral environments.

Chemical Bonding and Intermolecular Forces

Covalent bonding in vedaprofen follows typical patterns for aromatic carboxylic acids. The carbon-carbon bonds in the naphthalene system exhibit bond energies of approximately 518 kJ·mol⁻¹ for aromatic C-C bonds and 364 kJ·mol⁻¹ for the C-C bond connecting the naphthalene to the cyclohexyl group. The carboxylic acid functionality displays characteristic C=O bond energy of 799 kJ·mol⁻¹ and C-O bond energy of 358 kJ·mol⁻¹.

Intermolecular forces dominate the solid-state structure and solution behavior. The compound exhibits strong hydrogen bonding capability through its carboxylic acid group, with hydrogen bond donor and acceptor capacities calculated at 1 and 2 respectively. The molecular dipole moment measures 2.1 Debye, oriented from the cyclohexyl group toward the carboxylic acid functionality. Van der Waals forces contribute significantly to molecular packing, particularly through interactions between the hydrophobic cyclohexyl and naphthalene systems. The calculated polar surface area is 37.3 Ų, while the non-polar surface area measures 245.2 Ų, reflecting the compound's amphiphilic character.

Physical Properties

Phase Behavior and Thermodynamic Properties

Vedaprofen exists as a white to off-white crystalline solid at room temperature. The compound melts at 126-128 °C with enthalpy of fusion measuring 28.4 kJ·mol⁻¹. Crystalline forms exhibit orthorhombic crystal symmetry with space group P2₁2₁2₁ and unit cell parameters a = 8.92 Å, b = 11.34 Å, c = 16.78 Å. Density measures 1.18 g·cm⁻³ at 20 °C. The compound sublimes at reduced pressure with sublimation temperature of 95 °C at 0.1 mmHg.

Thermodynamic parameters include heat capacity of 312 J·mol⁻¹·K⁻¹ at 25 °C, entropy of formation ΔfS° = 392 J·mol⁻¹·K⁻¹, and enthalpy of formation ΔfH° = -412 kJ·mol⁻¹. The compound demonstrates moderate thermal stability with decomposition onset at 210 °C under nitrogen atmosphere. Solubility parameters include water solubility of 0.1 mg·mL⁻¹ at 25 °C, ethanol solubility of 45 mg·mL⁻¹, and chloroform solubility exceeding 100 mg·mL⁻¹. The octanol-water partition coefficient log P measures 4.2, indicating significant lipophilicity.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrations including O-H stretch at 3000 cm⁻¹, C=O stretch at 1715 cm⁻¹, aromatic C=C stretches between 1600-1450 cm⁻¹, and C-H stretches at 2950 cm⁻¹ for cyclohexyl and 3050 cm⁻¹ for aromatic hydrogens. The fingerprint region shows distinctive patterns at 750 cm⁻¹ and 810 cm⁻¹ corresponding to naphthalene ring vibrations.

Proton NMR spectroscopy (400 MHz, CDCl₃) displays chemical shifts at δ 0.9-2.1 (m, 11H, cyclohexyl), δ 1.55 (d, 3H, J = 7.2 Hz, CH₃), δ 3.75 (q, 1H, J = 7.2 Hz, CH), δ 7.4-8.2 (m, 6H, naphthalene), and δ 11.2 (s, 1H, COOH). Carbon-13 NMR shows signals at δ 18.5 (CH₃), δ 26.1, 26.8, 34.5, 45.2 (cyclohexyl carbons), δ 45.8 (CH), δ 125.8, 126.2, 127.5, 128.1, 129.4, 131.2, 133.5, 134.8, 141.5 (aromatic carbons), and δ 181.2 (COOH). UV-Vis spectroscopy in methanol solution shows absorption maxima at λmax = 226 nm (ε = 12,400 M⁻¹·cm⁻¹) and λmax = 278 nm (ε = 4,800 M⁻¹·cm⁻¹).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Vedaprofen exhibits chemical reactivity typical of carboxylic acids with additional influences from its aromatic system. Esterification reactions proceed with second-order kinetics, rate constant k = 2.3 × 10⁻³ L·mol⁻¹·s⁻¹ in methanol at 25 °C. Nucleophilic substitution at the carboxylic carbon follows standard addition-elimination mechanisms with activation energy ΔG‡ = 85 kJ·mol⁻¹ for reaction with ethanol. The compound undergoes electrophilic aromatic substitution preferentially at the 5 and 8 positions of the naphthalene ring, with relative rates compared to benzene of 0.3 for nitration and 0.5 for halogenation.

Decarboxylation occurs at elevated temperatures (above 200 °C) with activation energy Ea = 120 kJ·mol⁻¹. Oxidation reactions primarily affect the cyclohexyl ring, with potassium permanganate oxidation yielding the corresponding dicarboxylic acid. Photochemical reactivity includes naphthalene ring photodimerization with quantum yield Φ = 0.05 in concentrated solutions. The compound demonstrates stability in air at room temperature but undergoes slow oxidation upon prolonged exposure to light.

Acid-Base and Redox Properties

Vedaprofen functions as a monoprotic acid with pKa = 4.2 ± 0.1 in aqueous solution at 25 °C. The acid dissociation constant shows slight solvent dependence, measuring pKa = 5.8 in ethanol and pKa = 8.2 in DMSO. Buffer capacity peaks at pH 4.2 with maximum buffer index β = 0.025 mol·L⁻¹·pH⁻¹. The compound forms stable salts with inorganic bases, including sodium vedaprofenate which exhibits water solubility of 85 mg·mL⁻¹.

Redox properties include oxidation potential E° = +1.23 V versus SCE for one-electron oxidation of the naphthalene system. Reduction potential measures E° = -1.85 V for reduction of the carboxylic acid group. The compound demonstrates stability in reducing environments but undergoes gradual decomposition under strongly oxidizing conditions. Cyclic voltammetry shows irreversible oxidation wave at +1.35 V and reduction wave at -1.90 V in acetonitrile solution.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of vedaprofen follows a multi-step route beginning with 1-cyclohexylnaphthalene. Chloromethylation using paraformaldehyde and hydrochloric acid in acetic acid solution introduces the chloromethyl group at the 4-position of the naphthalene ring. This intermediate undergoes conversion to the corresponding cyanide through reaction with sodium cyanide in DMSO at 80 °C for 6 hours, yielding 4-cyclohexyl-1-naphthaleneacetonitrile.

The nitrile group is subsequently hydrolyzed to the carboxylic acid using concentrated hydrochloric acid under reflux conditions for 12 hours, producing 2-(4-cyclohexyl-1-naphthyl)acetic acid. The critical step involves introduction of the methyl group through alkylation using methyl iodide and sodium hydride in tetrahydrofuran at 0 °C. This reaction proceeds with complete racemization at the chiral center. Final purification employs recrystallization from hexane-ethyl acetate mixture, yielding vedaprofen with overall yield of 42% and purity exceeding 98% by HPLC analysis.

Analytical Methods and Characterization

Identification and Quantification

Vedaprofen is routinely characterized by chromatographic and spectroscopic methods. High-performance liquid chromatography employing C18 reverse-phase column with mobile phase acetonitrile:water:acetic acid (65:34:1) provides retention time of 7.2 minutes at flow rate 1.0 mL·min⁻¹. Detection utilizes UV absorption at 226 nm with limit of detection 0.1 μg·mL⁻¹ and limit of quantification 0.3 μg·mL⁻¹.

Gas chromatography-mass spectrometry shows molecular ion peak at m/z = 282 with characteristic fragmentation patterns including loss of COOH (m/z 237), loss of cyclohexyl (m/z 185), and naphthalene-related fragments at m/z 141 and 115. Thin-layer chromatography on silica gel with toluene:ethyl acetate:formic acid (80:18:2) mobile phase yields Rf value of 0.45. Quantitative analysis by UV spectrophotometry utilizes the absorption maximum at 226 nm with molar absorptivity ε = 12,400 M⁻¹·cm⁻¹.

Purity Assessment and Quality Control

Purity assessment typically identifies several common impurities including the des-methyl analog (2-(4-cyclohexyl-1-naphthyl)acetic acid), the cyclohexyl oxidation product, and naphthalene dimerization byproducts. Specification limits require vedaprofen content ≥98.0%, with individual impurities limited to ≤0.5% and total impurities ≤1.5%. Residual solvent content is controlled with limits of 5000 ppm for ethyl acetate and 3000 ppm for hexane.

Stability testing indicates that vedaprofen remains stable for至少 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. The compound is sensitive to strong light, undergoing photochemical degradation with half-life of 120 days under ambient light conditions.

Applications and Uses

Industrial and Commercial Applications

Vedaprofen serves primarily as a chemical intermediate in organic synthesis rather than as an end-product in industrial applications. The compound's structure makes it valuable for preparing more complex molecules containing the 2-arylpropanoic acid motif. Its chiral center provides a template for studies of asymmetric induction and stereoselective reactions. The naphthalene system offers opportunities for developing fluorescent probes and molecular sensors when coupled with appropriate reporter groups.

In materials science, vedaprofen derivatives have been explored as building blocks for liquid crystalline compounds due to the combination of rigid aromatic and flexible alicyclic components. The carboxylic acid functionality allows for incorporation into metal-organic frameworks and coordination polymers, with potential applications in heterogeneous catalysis and gas storage materials. Production volumes remain relatively small, typically measured in kilogram quantities for research purposes.

Historical Development and Discovery

Vedaprofen was first synthesized in the 1970s during structure-activity relationship studies of anti-inflammatory compounds. Initial synthetic work focused on modifying the structure of existing 2-arylpropanoic acids by incorporating larger aromatic systems. The compound gained attention primarily as a structural analog of better-known profen drugs rather than as a therapeutic agent itself. Patent literature from this period describes the synthesis and basic characterization without extensive development of applications.

The 1980s saw improved synthetic routes developed, particularly methods for introducing the cyclohexyl substituent and controlling the stereochemistry at the chiral center. Analytical methodology advanced significantly during the 1990s with the application of modern chromatographic and spectroscopic techniques for complete characterization. Recent research has focused on using vedaprofen as a model compound for studying crystal engineering principles and supramolecular chemistry of carboxylic acid dimers.

Conclusion

Vedaprofen represents a chemically interesting member of the 2-arylpropanoic acid family with distinctive structural features arising from its naphthalene ring system and cyclohexyl substituent. The compound exhibits physical and chemical properties characteristic of aromatic carboxylic acids while demonstrating unique aspects due to its particular molecular architecture. Its well-defined synthesis, comprehensive characterization, and stability make it valuable for fundamental studies in organic chemistry and materials science. Future research directions may include development of enantioselective synthesis methods, exploration of supramolecular applications, and investigation of its potential as a building block for advanced materials with tailored properties.