Abstract

Chloroacetophenone oxime, systematically named (1Z)-2-chloro-N-hydroxy-1-phenylethan-1-imine (CAS: 21572-32-7), represents an organochlorine oxime compound with molecular formula C₈H₈ClNO. This crystalline solid exhibits a melting point of 88.5-89.0°C and demonstrates significant lachrymatory and irritant properties. The compound features a distinctive molecular architecture combining aromatic phenyl ring character with an oxime functional group adjacent to a chloromethyl substituent. Its chemical behavior is characterized by both oxime reactivity patterns and the enhanced electrophilicity imparted by the chlorine atom. Chloroacetophenone oxime serves as an intermediate in organic synthesis and finds application in specialized chemical formulations requiring controlled irritant effects. The compound's structural features and chemical properties position it within the broader family of α-halogenated ketoximes with modified reactivity profiles compared to non-halogenated analogs.

Introduction

Chloroacetophenone oxime belongs to the class of organic compounds known as ketoximes, specifically α-halogenated aromatic ketoximes. This compound derives from chloroacetophenone through oxime formation, resulting in a molecule that exhibits unique chemical properties distinct from its parent ketone. The presence of both oxime functionality and chlorine substituent creates a molecular system with interesting electronic and steric characteristics. Historically, compounds in this structural class have attracted attention due to their modified reactivity patterns compared to non-halogenated oximes, particularly in cyclization reactions and as precursors to heterocyclic systems. The combination of aromatic character, hydrogen bonding capability through the oxime group, and the reactive chlorine center provides multiple sites for chemical transformation, making chloroacetophenone oxime a versatile intermediate in synthetic organic chemistry.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular geometry of chloroacetophenone oxime exhibits several distinctive features arising from its constituent functional groups. The phenyl ring maintains typical aromatic character with bond lengths of approximately 1.395 Å for C-C bonds and 1.085 Å for C-H bonds. The oxime functionality adopts a (Z)-configuration about the C=N bond, with the hydroxyl hydrogen positioned syn to the phenyl ring. This configuration results from intramolecular hydrogen bonding considerations and steric factors. The C=N bond length measures approximately 1.28 Å, characteristic of carbon-nitrogen double bonds, while the N-O bond length is approximately 1.42 Å, indicating partial double bond character due to resonance with the nitrogen lone pair.

The chloromethyl group exhibits bond lengths of 1.79 Å for the C-Cl bond and 1.50 Å for the adjacent C-C bond. Molecular orbital analysis reveals that the highest occupied molecular orbital (HOMO) primarily resides on the oxime oxygen and nitrogen atoms, while the lowest unoccupied molecular orbital (LUMO) shows significant density on the carbon atoms of the imine and chloromethyl groups. This electronic distribution accounts for the compound's nucleophilic character at the oxygen center and electrophilic reactivity at the carbon centers.

Chemical Bonding and Intermolecular Forces

Covalent bonding in chloroacetophenone oxime follows expected patterns for aromatic oxime systems. The carbon atoms of the phenyl ring exhibit sp² hybridization with bond angles of approximately 120°. The imine carbon shows sp² hybridization with bond angles deviating slightly from ideal due to steric constraints. The chlorine atom maintains typical bonding characteristics with a carbon-chlorine bond dissociation energy of approximately 339 kJ·mol^-1.

Intermolecular forces include significant hydrogen bonding capability through the oxime hydroxyl group, with typical O-H···N hydrogen bond energies of 20-30 kJ·mol^-1. The compound exhibits a molecular dipole moment of approximately 3.2 Debye, oriented from the chloromethyl group toward the oxime functionality. Van der Waals interactions contribute significantly to crystal packing, with the chlorine atom participating in weak chlorine-based interactions. The compound demonstrates moderate polarity with an estimated log P value of 1.8, indicating balanced hydrophobic-hydrophilic character.

Physical Properties

Phase Behavior and Thermodynamic Properties

Chloroacetophenone oxime presents as a crystalline solid at room temperature with a characteristic melting point range of 88.5-89.0°C. The compound exhibits polymorphism with at least two crystalline forms identified, though the α-form represents the most stable modification under standard conditions. The density of the crystalline material measures 1.35 g·cm^-3 at 20°C. The heat of fusion is determined as 28.5 kJ·mol^-1 with entropy of fusion of 78.9 J·mol^-1·K^-1.

Sublimation characteristics show the compound begins significant vaporization at temperatures above 70°C under reduced pressure. The boiling point under atmospheric pressure is estimated at 285°C with decomposition. The specific heat capacity of the solid phase measures 1.2 J·g^-1·K^-1 at 25°C. The refractive index of crystalline material is 1.58 at 589 nm wavelength. Solubility characteristics demonstrate moderate solubility in polar organic solvents including ethanol (45 g·L^-1), acetone (68 g·L^-1), and ethyl acetate (32 g·L^-1), with lower solubility in water (1.2 g·L^-1) and non-polar solvents.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrations including O-H stretch at 3220 cm^-1, C-H aromatic stretches between 3000-3100 cm^-1, C=N stretch at 1620 cm^-1, and C-Cl stretch at 730 cm^-1. The spectrum also shows aromatic C=C vibrations at 1580 cm^-1 and 1490 cm^-1, along with N-O stretch at 950 cm^-1.

Proton NMR spectroscopy displays aromatic protons as a multiplet centered at δ 7.45 ppm, the methylene protons as a singlet at δ 4.35 ppm, and the oxime proton as a broad singlet at δ 11.2 ppm. Carbon-13 NMR shows the imine carbon at δ 150.5 ppm, aromatic carbons between δ 128-135 ppm, and the chloromethyl carbon at δ 45.8 ppm. UV-Vis spectroscopy demonstrates absorption maxima at 245 nm (ε = 12,500 M^-1·cm^-1) and 290 nm (ε = 850 M^-1·cm^-1) corresponding to π→π* and n→π* transitions respectively. Mass spectrometry exhibits a molecular ion peak at m/z 169 (M⁺) with characteristic fragment ions at m/z 134 (M⁺-Cl), m/z 117 (M⁺-C₂H₄NO), and m/z 77 (C₆H₅⁺).

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Chloroacetophenone oxime demonstrates diverse reactivity patterns stemming from its functional group arrangement. The oxime functionality undergoes typical reactions including O-alkylation with rate constants of approximately 2.3×10^-3 L·mol^-1·s^-1 for methylation with dimethyl sulfate in acetone at 25°C. The Beckmann rearrangement proceeds with activation energy of 85 kJ·mol^-1 when catalyzed by phosphorus pentachloride, yielding N-chloroacetyl aniline derivatives.

The chloromethyl group exhibits enhanced electrophilicity due to the electron-withdrawing effect of the adjacent oxime function. Nucleophilic substitution reactions proceed with second-order rate constants of 1.8×10^-4 L·mol^-1·s^-1 for reaction with sodium iodide in acetone at 50°C. The compound undergoes dehydrohalogenation under basic conditions with elimination rate constant of 4.2×10^-5 s^-1 in 0.1 M NaOH at 25°C, producing the corresponding nitrile oxide intermediate. Thermal stability studies indicate decomposition onset at 150°C with activation energy for decomposition of 120 kJ·mol^-1.

Acid-Base and Redox Properties

The oxime hydroxyl group exhibits acidic character with pK_a of 10.2 in aqueous solution at 25°C, making it significantly more acidic than typical alcohols but less acidic than phenols. Protonation occurs at the nitrogen atom with pK_a of -2.1 for the conjugate acid, indicating weak basicity. The compound demonstrates stability across pH range 4-9, with hydrolysis occurring under strongly acidic (pH < 2) or basic (pH > 11) conditions.

Redox properties include oxidation potential of +1.15 V versus standard hydrogen electrode for one-electron oxidation, primarily involving the oxime functionality. Reduction proceeds at -0.85 V for cleavage of the carbon-chlorine bond. The compound does not undergo significant autoxidation under atmospheric oxygen but can be oxidized by strong oxidizing agents such as potassium permanganate or chromium trioxide. Electrochemical studies reveal irreversible reduction waves corresponding to chlorine loss and reversible oxidation waves associated with oxime redox chemistry.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The primary laboratory synthesis of chloroacetophenone oxime involves condensation of chloroacetophenone with hydroxylamine hydrochloride. The reaction typically employs aqueous ethanol or methanol as solvent with sodium acetate or carbonate as base to liberate free hydroxylamine. Standard conditions involve refluxing equimolar quantities of chloroacetophenone and hydroxylamine hydrochloride (1.2 equivalents) in 75% ethanol with sodium acetate (1.5 equivalents) for 2-3 hours. The reaction proceeds with yield of 85-90% after recrystallization from ethanol-water mixtures.

Purification typically involves recrystallization from ethyl acetate/hexane mixtures, yielding colorless crystals with purity exceeding 98% by HPLC analysis. The (Z)-isomer predominates under standard reaction conditions due to thermodynamic stability considerations. Alternative synthetic routes include reaction of acetophenone oxime with chlorinating agents such as sulfuryl chloride or N-chlorosuccinimide, though these methods generally provide lower yields and require careful control of reaction conditions to avoid over-chlorination.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of chloroacetophenone oxime employs complementary techniques including chromatography, spectroscopy, and crystallography. Reverse-phase HPLC utilizing C18 columns with acetonitrile-water mobile phases (60:40 v/v) provides retention time of 7.2 minutes with UV detection at 245 nm. Gas chromatography with mass spectrometric detection shows retention index of 1450 on DB-5 columns with characteristic mass fragments providing definitive identification.

Quantitative analysis typically employs HPLC with external standard calibration, demonstrating linear response range of 0.1-100 mg·L^-1 and detection limit of 0.05 mg·L^-1. Precision studies show relative standard deviation of 1.2% for repeatability and 2.8% for intermediate precision. Titrimetric methods based on the acidic nature of the oxime hydroxyl group provide alternative quantification with precision of ±2% using potentiometric end-point detection.

Purity Assessment and Quality Control

Purity assessment typically identifies common impurities including unreacted chloroacetophenone (typically <0.5%), isomeric impurities, and decomposition products. Chromatographic methods resolve these impurities with separation factors exceeding 1.5 for all significant contaminants. Karl Fischer titration determines water content, typically less than 0.2% in properly stored material. Residual solvent analysis by headspace gas chromatography shows ethanol content below 0.1% in recrystallized material.

Quality control specifications for technical grade material typically require minimum purity of 97% by HPLC, melting point range of 88.0-90.0°C, and ash content less than 0.1%. Stability studies indicate shelf life exceeding three years when stored in airtight containers protected from light at room temperature. Accelerated stability testing at 40°C and 75% relative humidity shows no significant decomposition over six months.

Applications and Uses

Industrial and Commercial Applications

Chloroacetophenone oxime serves primarily as a chemical intermediate in organic synthesis, particularly for the preparation of heterocyclic compounds including isoxazoles and oxadiazoles. Its application in the synthesis of these nitrogen-oxygen heterocycles leverages both the oxime functionality and the reactive chlorine center in cyclocondensation reactions. The compound finds use in specialty chemical formulations where controlled irritant properties are required, though applications in this area remain limited compared to related compounds.

Additional industrial applications include use as a stabilizer in certain polymer systems where it functions as a radical scavenger and acid acceptor. The compound's ability to complex metal ions finds application in extraction processes and as a component in metal deactivation formulations. Production volumes remain relatively small with global production estimated at 10-20 metric tons annually, primarily manufactured by specialty chemical producers.

Conclusion

Chloroacetophenone oxime represents a structurally interesting compound combining aromatic character, oxime functionality, and reactive chlorine substitution. Its physical properties, including well-defined melting characteristics and moderate solubility parameters, make it handleable for laboratory and industrial applications. The compound's chemical reactivity demonstrates the interplay between its functional groups, with enhanced electrophilicity at the chloromethyl position and both acidic and nucleophilic character at the oxime functionality. Synthetic utility primarily derives from its use as a building block for nitrogen-containing heterocycles and as a specialty intermediate in organic synthesis. Further research opportunities exist in exploring its coordination chemistry with metals and developing novel synthetic methodologies utilizing its unique combination of functional groups.