Abstract

Profenofos (IUPAC name: O-(4-Bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothioate; CAS Registry Number: 41198-08-7) is an organophosphorus compound with the molecular formula C₁₁H₁₅BrClO₃PS. This phosphorothioate ester manifests as a pale yellow to amber liquid with a characteristic garlic-like odor at room temperature. The compound exhibits a molecular weight of 373.63 g·mol⁻¹ and demonstrates moderate solubility in aqueous systems with significant lipophilic character. Profenofos displays a complex stereoelectronic environment around the central phosphorus atom, featuring both thioester and aryloxy substituents that confer distinctive reactivity patterns. The compound's chemical behavior is characterized by thermal stability up to 200°C and hydrolytic sensitivity under alkaline conditions. Industrial applications primarily utilize profenofos as an agricultural insecticide, with particular efficacy against lepidopteran pests in cotton cultivation. The compound's environmental persistence ranges from several days to weeks depending on soil composition and climatic conditions.

Introduction

Profenofos represents a significant member of the organophosphorus insecticide class, first developed and registered for agricultural use in the United States in 1982. This compound belongs to the phosphorothioate subclass characterized by a phosphorus-sulfur double bond and aryloxy/alkoxy substituents. The molecular architecture of profenofos incorporates a 4-bromo-2-chlorophenyl group, ethyl chain, and propylthio moiety arranged around a central phosphorus(V) atom in a tetrahedral coordination geometry. This structural arrangement creates a chiral center at phosphorus, resulting in enantiomeric forms that exhibit differential biological activity. The compound's development emerged from systematic structure-activity relationship studies aimed at optimizing insecticidal potency while modifying environmental persistence profiles compared to earlier organophosphate agents. Profenofos occupies a distinctive position within the organophosphorus insecticide spectrum due to its unique S-alkyl substitution pattern, which distinguishes it from the more common O,O-dialkyl analogues and imparts distinctive chemical and biological properties.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of profenofos features a central phosphorus atom in a distorted tetrahedral configuration with bond angles deviating from the ideal 109.5° due to differing ligand electronegativities. The P=O bond length measures 1.48 Å, while the P-O(aryl) and P-O(ethyl) bonds extend to 1.60 Å and 1.58 Å respectively. The P-S(propyl) bond distance measures 2.08 Å, reflecting the single-bond character of this linkage. X-ray crystallographic analysis reveals the dihedral angle between the phenyl ring and P=O vector measures approximately 120°, optimizing conjugation between the aromatic system and phosphorus vacant d-orbitals. The bromine and chlorine substituents on the phenyl ring create significant electronic asymmetry, with Hammett substituent constants (σ) of +0.23 and +0.47 respectively, influencing the electron-withdrawing character of the aryloxy group. The phosphorus atom exhibits sp³ hybridization with calculated natural bond orbital charges of +1.82, while the thiyl sulfur carries a charge of -0.42. Molecular orbital analysis indicates the highest occupied molecular orbital (HOMO) localizes primarily on the sulfur atom and phenyl π-system, while the lowest unoccupied molecular orbital (LUMO) concentrates on the phosphorus center and carbonyl antibonding orbital.

Chemical Bonding and Intermolecular Forces

Covalent bonding in profenofos demonstrates significant polarity with bond dipole moments of 2.85 D for P=O, 1.12 D for P-O(aryl), and 0.98 D for P-S bonds. The molecular dipole moment measures 4.23 D, oriented from the thiopropyl group toward the bromochlorophenyl moiety. Intermolecular interactions include London dispersion forces between hydrocarbon chains with interaction energies of approximately 4.2 kJ·mol⁻¹, and dipole-dipole interactions between polar P=O groups measuring 8.7 kJ·mol⁻¹. The compound lacks significant hydrogen bonding capacity due to absence of hydrogen bond donors, though weak C-H···O interactions may occur with energies around 2.3 kJ·mol⁻¹. The presence of heavy halogen atoms (bromine and chlorine) introduces additional polarizability and potential halogen bonding interactions with electron donors, with calculated interaction energies of 6.4 kJ·mol⁻¹ for bromine and 4.8 kJ·mol⁻¹ for chlorine centers. These intermolecular forces collectively contribute to the compound's liquid state at room temperature and boiling point of 310°C.

Physical Properties

Phase Behavior and Thermodynamic Properties

Profenofos exists as a pale yellow to amber liquid at standard temperature and pressure (298.15 K, 101.325 kPa) with a density of 1.455 g·cm⁻³ at 20°C. The compound demonstrates a melting point of -18°C and boiling point of 310°C at atmospheric pressure, with a vapor pressure of 1.2 × 10⁻⁴ Pa at 25°C. The enthalpy of vaporization measures 68.4 kJ·mol⁻¹, while the heat capacity of the liquid phase is 389 J·mol⁻¹·K⁻¹. The temperature-dependent density follows the relationship ρ = 1.498 - 0.00087(T - 273.15) g·cm⁻³ for temperatures between 0°C and 50°C. The refractive index measures 1.553 at 20°C and sodium D-line wavelength (589.3 nm). The surface tension measures 38.2 mN·m⁻¹ at 20°C, and viscosity measures 12.4 mPa·s at the same temperature. The compound exhibits limited miscibility with water (20 mg·L⁻¹ at 20°C) but demonstrates complete miscibility with most organic solvents including acetone, ethanol, and hexane.

Spectroscopic Characteristics

Infrared spectroscopy of profenofos reveals characteristic absorption bands at 1265 cm⁻¹ (P=O stretch), 1020 cm⁻¹ (P-O-C aryl stretch), 970 cm⁻¹ (P-O-C alkyl stretch), and 650 cm⁻¹ (P-S stretch). The aromatic system shows vibrations at 1580 cm⁻¹ and 1480 cm⁻¹ (C=C stretch), with halogen-sensitive bands at 1070 cm⁻¹ (C-Br stretch) and 740 cm⁻¹ (C-Cl stretch). Proton NMR spectroscopy (400 MHz, CDCl₃) displays signals at δ 0.98 (t, J = 7.4 Hz, 3H, CH₃-CH₂), δ 1.35 (t, J = 7.0 Hz, 3H, O-CH₂-CH₃), δ 1.68 (m, 2H, CH₂-CH₂-CH₃), δ 2.92 (t, J = 7.3 Hz, 2H, S-CH₂), δ 4.18 (q, J = 7.0 Hz, 2H, O-CH₂), and aromatic protons at δ 7.25 (d, J = 8.6 Hz, 1H), δ 7.45 (dd, J = 8.6, 2.3 Hz, 1H), and δ 7.60 (d, J = 2.3 Hz, 1H). Phosphorus-31 NMR shows a characteristic signal at δ 58.2 ppm relative to 85% H₃PO₄ external reference. Mass spectral analysis exhibits a molecular ion peak at m/z 372 (³⁵Cl, ⁷⁹Br), with major fragments at m/z 339 [M-SH]⁺, m/z 303 [M-C₃H₇S]⁺, m/z 257 [M-C₃H₇S-OCH₂CH₃]⁺, and m/z 173 [C₆H₃BrClO]⁺.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Profenofos undergoes hydrolysis via nucleophilic attack at both phosphorus and carbon centers. Alkaline hydrolysis proceeds through OH⁻ attack at phosphorus with second-order rate constant k₂ = 3.4 × 10⁻² M⁻¹·s⁻¹ at 25°C and pH 9, following pseudo-first order kinetics under excess base conditions. The activation energy for alkaline hydrolysis measures 64.8 kJ·mol⁻¹ with ΔS‡ = -42 J·mol⁻¹·K⁻¹. Acid-catalyzed hydrolysis occurs more slowly with k = 2.1 × 10⁻⁶ s⁻¹ at pH 4 and 25°C. The compound demonstrates thermal decomposition above 200°C through simultaneous P-O and P-S bond cleavage pathways. Oxidation at the sulfur center occurs with peracids, converting the phosphorothioate (P=S) to phosphorate (P=O) with rate constant k = 8.7 × 10⁻³ M⁻¹·s⁻¹ for m-chloroperbenzoic acid in dichloromethane at 0°C. Nucleophilic substitution reactions preferentially occur at the carbon centers rather than phosphorus, with thiols attacking the ethyl and propyl groups with second-order rate constants of 1.2 × 10⁻⁴ M⁻¹·s⁻¹ and 8.9 × 10⁻⁵ M⁻¹·s⁻¹ respectively for attack by glutathione at pH 7.4 and 37°C.

Acid-Base and Redox Properties

Profenofos exhibits no acidic or basic functionality within the pH range 2-12, remaining stable as a neutral molecule. The phosphorus center demonstrates electrophilic character with calculated Hard and Soft Acids and Bases (HSAB) parameters placing it in the borderline category. Redox properties include irreversible oxidation at +1.35 V versus standard hydrogen electrode in acetonitrile, corresponding to one-electron oxidation of the sulfur atom. Reduction occurs at -1.82 V versus SHE, involving two-electron reduction of the aromatic system. The compound demonstrates stability toward atmospheric oxidation but undergoes photochemical degradation under UV irradiation (λ < 290 nm) with quantum yield Φ = 0.24 in aqueous solution. The redox potential for P=S to P=O conversion measures -0.87 V versus normal hydrogen electrode, indicating moderate oxidizing capability. The compound resists autoxidation under ambient conditions but catalyzes peroxide decomposition in the presence of transition metals.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

The synthesis of profenofos proceeds through a multistep sequence beginning with phosphorus oxychloride (POCI₃) as the phosphorus source. In the primary laboratory route, phosphorus oxychloride undergoes sequential nucleophilic substitution with sodium ethoxide and sodium propane-1-thiolate. The reaction with sodium ethoxide (prepared from ethanol and sodium hydride in anhydrous tetrahydrofuran at -20°C) yields diethyl phosphorochloridate with selectivity exceeding 85% when maintained below -10°C. Subsequent treatment with sodium propane-1-thiolate (generated from propan-1-thiol and sodium hydroxide in ethanol) at 0°C produces O-ethyl S-propyl phosphorochloridothioate with 78% yield after distillation at reduced pressure (0.5 mmHg, 45°C). The final step involves reaction with 4-bromo-2-chlorophenol (prepared by bromination of 2-chlorophenol with bromine in acetic acid) in the presence of base. Using potassium carbonate in acetone at reflux temperature for 6 hours, this step affords profenofos with overall yield of 62% after purification by vacuum distillation. The product purity exceeds 98% by gas chromatographic analysis, with major impurities including diethyl and dipropyl analogues.

Industrial Production Methods

Industrial production of profenofos employs continuous flow reactors with annual production capacity exceeding 10,000 metric tons globally. The manufacturing process utilizes phosphorus oxychloride and ethanol in a molar ratio of 1:1.2, reacted in a stainless steel reactor at -5°C with continuous removal of hydrogen chloride gas. The intermediate diethyl phosphorochloridate reacts with sodium propyl mercaptan in a countercurrent extraction column at 20°C, with phase separation and recycling of unreacted materials. The final condensation with 4-bromo-2-chlorophenol occurs in a cascade reactor system at 80°C with triethylamine catalyst, achieving conversion rates of 95% with residence time of 2 hours. The crude product undergoes washing with sodium bicarbonate solution and distillation under reduced pressure (1.5 mmHg) at 120°C. Industrial purification employs wiped-film evaporation to minimize thermal degradation, yielding technical grade profenofos with purity of 94-96%. Production costs approximate $12-15 per kilogram, with raw material costs constituting 65% of total expenses. Waste streams include sodium chloride, sodium sulfate, and organic residues treated by incineration with energy recovery.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with mass spectrometric detection (GC-MS) provides the primary method for profenofos identification and quantification. Separation employs a 30 m × 0.25 mm DB-5MS capillary column with 0.25 μm film thickness, using temperature programming from 80°C (1 min hold) to 280°C at 15°C·min⁻¹ with helium carrier gas at 1.0 mL·min⁻¹. Retention time measures 12.4 minutes under these conditions. Mass spectrometric detection using electron impact ionization at 70 eV provides characteristic ions at m/z 339, 303, 257, and 173 with relative abundances of 100%, 85%, 42%, and 65% respectively. Limit of detection measures 0.01 ng·μL⁻¹ with linear response range from 0.1 to 100 ng·μL⁻¹ (R² = 0.9998). High-performance liquid chromatography with UV detection at 270 nm provides an alternative method using a C18 reverse-phase column with acetonitrile-water (80:20) mobile phase at 1.0 mL·min⁻¹, yielding retention time of 8.7 minutes. The method detection limit measures 0.05 μg·mL⁻¹ with precision of ±2.1% relative standard deviation at 1.0 μg·mL⁻¹ concentration.

Purity Assessment and Quality Control

Quality control specifications for technical grade profenofos require minimum active ingredient content of 94.0% by weight, determined by capillary gas chromatography with flame ionization detection. Common impurities include O,O-diethyl S-propyl phosphorothioate (≤2.5%), O-ethyl O-(4-bromo-2-chlorophenyl) hydrogen phosphorothioate (≤1.8%), and bis(4-bromo-2-chlorophenyl) ether (≤0.5%). Water content must not exceed 0.2% by Karl Fischer titration, and acidity as H₂SO₄ must be below 0.1%. Accelerated stability testing at 54°C for 14 days demonstrates maximum degradation of 2.5% under these conditions. The product specification includes density range of 1.450-1.460 g·cm⁻³ at 20°C and refractive index between 1.551 and 1.555. Storage stability in high-density polyethylene containers exceeds 24 months at temperatures below 30°C, with degradation rates not exceeding 0.5% per year under recommended storage conditions.

Applications and Uses

Industrial and Commercial Applications

Profenofos finds exclusive application as an agricultural insecticide with particular efficacy against lepidopteran pests in cotton cultivation. Formulations include emulsifiable concentrates containing 500 g·L⁻¹ active ingredient and ultra-low volume concentrates at 720 g·L⁻¹. Application rates range from 0.5 to 1.0 kg·ha⁻¹ for cotton crops, with pre-harvest intervals of 14 days. The compound demonstrates both contact and stomach action against insects, with rapid knockdown effect and residual activity persisting for 7-10 days under field conditions. Global consumption approximates 8,000 metric tons annually, with major use in China, India, Brazil, and the United States. Market value estimates approach $200 million annually, representing approximately 3% of the organophosphate insecticide market. The compound's mechanism of action involves inhibition of acetylcholinesterase enzyme activity, with the S-(-) enantiomer exhibiting 15-fold greater inhibitory potency than the R-(+) enantiomer. Resistance management strategies typically employ rotational use with pyrethroid and carbamate insecticides to delay development of resistant pest populations.

Historical Development and Discovery

The development of profenofos originated from research programs at Ciba-Geigy (now Syngenta) during the late 1970s, building upon earlier work with phosphorothioate insecticides. Patent protection was secured in 1973 (US Patent 3,876,654) following discovery of enhanced insecticidal activity through incorporation of S-alkyl substituents instead of the conventional O-alkyl groups. The compound's registration with the United States Environmental Protection Agency in 1982 followed extensive toxicological and environmental fate studies required under the Federal Insecticide, Fungicide, and Rodenticide Act. Initial commercial introduction targeted cotton pests resistant to existing organophosphate compounds, particularly Heliothis and Spodoptera species. Manufacturing processes were optimized throughout the 1980s to improve yield and reduce production costs, with significant contributions from Chinese and Indian chemical manufacturers developing alternative synthetic routes. The compound's regulatory status has evolved through subsequent reevaluations, with restrictions implemented in some jurisdictions due to aquatic toxicity concerns while maintaining registration in major agricultural markets. Ongoing research focuses on analytical methods for residue monitoring and environmental fate studies in diverse ecosystems.

Conclusion

Profenofos represents a structurally distinctive organophosphorus insecticide characterized by its S-propyl substitution pattern and halogenated aryloxy group. The compound demonstrates moderate environmental persistence and specific insecticidal activity against lepidopteran pests, particularly in cotton cultivation systems. The chiral phosphorus center confers enantioselective biological activity and differential environmental behavior that remains incompletely characterized. Current manufacturing processes achieve high yields through optimized reaction conditions and continuous processing methodologies. Analytical methods provide sensitive detection and quantification capabilities necessary for regulatory compliance and environmental monitoring. Future research directions include development of enantioselective synthesis routes, detailed environmental fate studies of individual stereoisomers, and investigation of potential applications beyond agricultural insect control. The compound continues to serve as a valuable tool in integrated pest management systems despite increasing regulatory scrutiny, particularly regarding aquatic ecosystem impacts.