Abstract

Chlormephos (IUPAC name: S-(chloromethyl) O,O-diethyl phosphorodithioate) is an organothiophosphate compound with the molecular formula C₅H₁₂ClO₂PS₂ and molecular mass of 234.70 g·mol⁻¹. This organophosphorus compound exhibits significant insecticidal properties through inhibition of acetylcholinesterase enzymes. The compound manifests as a colorless to pale yellow liquid with characteristic organophosphorus odor and demonstrates limited water solubility while maintaining high solubility in most organic solvents. Chlormephos possesses a density of approximately 1.30 g·cm⁻³ at 20 °C and boiling point around 120 °C at 0.1 mmHg. The compound's chemical behavior is dominated by the electrophilic phosphorus center and nucleophilic sulfur atoms, enabling various substitution reactions. Industrial applications primarily focus on agricultural pest control, though its extreme toxicity necessitates careful handling and regulated use.

Introduction

Chlormephos represents a significant member of the organothiophosphate class of compounds, first developed during the mid-20th century as part of intensive research into organophosphorus insecticides. This compound belongs specifically to the phosphorodithioate subclass, characterized by the presence of two sulfur atoms bonded to phosphorus. The systematic IUPAC nomenclature identifies the compound as S-(chloromethyl) O,O-diethyl phosphorodithioate, reflecting its structural features including ethyl ester groups and a chloromethyl substituent on the sulfur atom. Chlormephos is classified as an extremely hazardous substance under United States regulations (42 U.S.C. 11002) due to its high toxicity profile. The compound's chemical significance lies in its mechanism of action as a potent acetylcholinesterase inhibitor, sharing this property with certain chemical warfare agents though developed for agricultural applications.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

The molecular structure of chlormephos centers around a tetrahedral phosphorus atom coordinated to two oxygen atoms, two sulfur atoms, and connected to the chloromethyl group through one sulfur atom. The phosphorus atom exhibits sp³ hybridization with bond angles approximating 109.5° as predicted by VSEPR theory, though slight distortions occur due to differing electronegativities of substituents. The P=S bond length measures approximately 1.93 Å, while P-O bond lengths range from 1.60 to 1.65 Å. The P-S-CH₂Cl bond angle is approximately 115° due to the larger atomic radius of sulfur compared to oxygen. Electronic structure analysis reveals highest occupied molecular orbitals localized primarily on sulfur atoms and phosphorus, with the lowest unoccupied molecular orbitals predominantly antibonding orbitals associated with phosphorus-chlorine interactions. The chloromethyl group exhibits C-Cl bond polarization with partial positive charge on the carbon atom (δ+ = 0.18) and negative charge on chlorine (δ- = -0.32), facilitating nucleophilic substitution reactions.

Chemical Bonding and Intermolecular Forces

Covalent bonding in chlormephos involves significant polarity differences across various bonds. The P=O bond demonstrates a dipole moment of approximately 2.5 D directed toward oxygen, while P-S bonds exhibit dipoles of 1.8 D directed toward sulfur. The C-Cl bond possesses a dipole moment of 1.6 D toward chlorine. The molecular dipole moment measures 4.2 D, oriented along the P-S-CH₂Cl vector. Intermolecular forces include London dispersion forces due to the relatively large molecular surface area, with additional dipole-dipole interactions contributing to cohesion in the liquid state. The compound does not form significant hydrogen bonds due to absence of hydrogen bond donors, though weak C-H···O interactions may occur between ethyl groups and phosphoryl oxygen. Van der Waals radius calculations indicate molecular dimensions of approximately 7.8 Å × 5.2 Å × 4.3 Å based on space-filling models.

Physical Properties

Phase Behavior and Thermodynamic Properties

Chlormephos exists as a colorless to pale yellow liquid at room temperature with a characteristic organophosphorus odor. The compound demonstrates a boiling point of 120 °C at 0.1 mmHg and decomposes before reaching its atmospheric pressure boiling point. Melting point determination shows solidification occurs at -15 °C to form a glassy amorphous solid rather than a crystalline phase. Density measurements yield 1.30 g·cm⁻³ at 20 °C with temperature dependence of -0.0009 g·cm⁻³·°C⁻¹. The refractive index is 1.558 at 20 °C using sodium D-line. Vapor pressure measures 0.0012 mmHg at 25 °C with enthalpy of vaporization 45.2 kJ·mol⁻¹. Heat capacity determinations show Cp = 298 J·mol⁻¹·K⁻¹ at 25 °C. The compound exhibits limited water solubility of 60 mg·L⁻¹ at 20 °C but demonstrates complete miscibility with most organic solvents including acetone, ethanol, benzene, and hexane.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic vibrations including P=O stretching at 1260 cm⁻¹, P-O-C stretching at 1030 cm⁻¹ and 970 cm⁻¹, P-S stretching at 750 cm⁻¹, and C-Cl stretching at 680 cm⁻¹. Proton NMR spectroscopy (CDCl₃, 300 MHz) shows triplets at δ 1.35 ppm (3H, J = 7.1 Hz) and δ 1.38 ppm (3H, J = 7.1 Hz) for methyl groups, quartets at δ 4.15 ppm (2H, J = 7.1 Hz) and δ 4.18 ppm (2H, J = 7.1 Hz) for methylene groups adjacent to oxygen, and a singlet at δ 3.85 ppm (2H) for the chloromethyl group. Phosphorus-31 NMR exhibits a singlet at δ 75 ppm relative to 85% H₃PO₄. Carbon-13 NMR displays signals at δ 16.1 ppm and δ 16.3 ppm (CH₃), δ 63.2 ppm and δ 63.5 ppm (O-CH₂), δ 41.8 ppm (Cl-CH₂), and the phosphorus-coupled carbon signals show characteristic coupling patterns. Mass spectrometry demonstrates molecular ion peak at m/z 234 with major fragments at m/z 199 [M-Cl]⁺, m/z 143 [C₂H₅O)₂PS₂]⁺, m/z 125 [C₂H₅O)₂PS]⁺, and m/z 97 [C₂H₅O)₂P]⁺.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Chlormephos demonstrates reactivity typical of organothiophosphate esters with particular sensitivity to nucleophilic attack at phosphorus and electrophilic attack at sulfur. Hydrolysis follows pseudo-first order kinetics with rate constants of 2.3 × 10⁻⁶ s⁻¹ at pH 7 and 25 °C, increasing to 8.7 × 10⁻⁴ s⁻¹ at pH 12. The hydrolysis mechanism involves nucleophilic attack by hydroxide ion at phosphorus with simultaneous P-S bond cleavage, yielding O,O-diethyl phosphorothioate and chloromethanol which rapidly decomposes to formaldehyde and hydrochloric acid. Reaction with nucleophiles such as thiols proceeds with second-order rate constants of approximately 0.15 M⁻¹·s⁻¹ for reaction with glutathione at pH 7.4 and 37 °C. Thermal decomposition occurs above 150 °C with activation energy 105 kJ·mol⁻¹, producing ethylene, chloromethane, and various phosphorus-containing fragments. Oxidation with peracids converts the P=S group to P=O, yielding the corresponding oxon compound which exhibits enhanced acetylcholinesterase inhibition.

Acid-Base and Redox Properties

Chlormephos exhibits minimal acid-base character in aqueous solution with no protonatable groups having pKa values in the physiological range. The phosphorus center demonstrates weak Lewis acidity with formation constants for complexation with fluoride ion of Kf = 120 M⁻¹. Redox properties include irreversible oxidation at +1.35 V versus standard hydrogen electrode due to sulfur oxidation, and reduction at -1.82 V corresponding to cleavage of the C-Cl bond. The compound demonstrates stability in reducing environments but undergoes rapid oxidation in the presence of strong oxidizing agents such as hydrogen peroxide or hypochlorite. Electrochemical studies indicate a one-electron transfer process for both oxidation and reduction steps with diffusion coefficients of 6.7 × 10⁻⁶ cm²·s⁻¹ for the oxidized species and 7.2 × 10⁻⁶ cm²·s⁻¹ for the reduced species.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Laboratory synthesis of chlormephos typically proceeds through a two-step sequence beginning with preparation of O,O-diethyl phosphorodithioic acid. This intermediate is generated by reaction of phosphorus pentasulfide with ethanol in molar ratio 1:4 at 40-50 °C for 4 hours, yielding the dithioic acid with liberation of hydrogen sulfide. The second step involves alkylation with chloromethyl chloride in the presence of base, typically sodium hydroxide or triethylamine. Reaction conditions employ dichloromethane or benzene as solvent at 0-5 °C with gradual addition of chloromethyl chloride to the dithioic acid solution. The reaction proceeds with 75-80% yield after purification by vacuum distillation. Alternative routes include reaction of O,O-diethyl phosphorochloridothioate with sodium mercaptide derived from chloromethanethiol, though this method gives lower yields due to competing side reactions. Purification typically involves washing with sodium bicarbonate solution followed by drying over anhydrous sodium sulfate and fractional distillation under reduced pressure.

Analytical Methods and Characterization

Identification and Quantification

Analytical identification of chlormephos employs gas chromatography with mass spectrometric detection (GC-MS) using capillary columns with non-polar stationary phases such as DB-5 or equivalent. Retention indices measure 1850 on methylsilicone stationary phases at 200 °C. High-performance liquid chromatography with UV detection at 220 nm provides alternative determination with C18 reverse-phase columns and acetonitrile-water mobile phases. Limit of detection measures 0.01 μg·mL⁻¹ by GC with electron capture detection and 0.05 μg·mL⁻¹ by HPLC with UV detection. Quantitative analysis typically employs internal standardization with compounds such as triphenyl phosphate or deuterated analogs when using mass spectrometric detection. Calibration curves demonstrate linearity from 0.1 to 100 μg·mL⁻¹ with correlation coefficients exceeding 0.999. Recovery studies show 85-95% recovery from various matrices including water, soil, and plant materials.

Purity Assessment and Quality Control

Purity assessment of technical-grade chlormephos typically reveals 90-95% active ingredient with major impurities including O,O,O-triethyl phosphorothioate (2-3%), bis(S-chloromethyl) O,O-diethyl phosphorodithioate (1-2%), and various oxidation products. Quality control specifications require absence of the corresponding oxon compound (O-analog) above 0.1% due to enhanced toxicity. Determination of water content by Karl Fischer titration must not exceed 0.2% w/w. Acid content as hydrochloric acid equivalents must remain below 0.1% w/w determined by titration with standard alkali. Storage stability testing indicates 95% retention of active ingredient after 12 months at 25 °C when protected from light and moisture. Accelerated stability testing at 54 °C for 14 days demonstrates less than 5% decomposition when properly formulated.

Applications and Uses

Industrial and Commercial Applications

Chlormephos finds application primarily as a soil insecticide for control of various agricultural pests including rootworms, cutworms, and soil-dwelling insects in crops such as corn, potatoes, and vegetables. Application rates typically range from 1.0 to 2.0 kg active ingredient per hectare, incorporated into soil to a depth of 5-10 cm. The compound acts through both contact and stomach poisoning mechanisms, with residual activity persisting for 4-8 weeks depending on soil type and environmental conditions. Formulations include emulsifiable concentrates (500 g·L⁻¹), granules (5-10%), and dusts (2-5%). Commercial production reached maximum capacity in the 1980s with annual global production estimated at 500-1000 metric tons, though production has declined significantly due to regulatory restrictions and development of alternative compounds. The compound's mechanism of action involves irreversible inhibition of acetylcholinesterase in insect nervous systems, leading to accumulation of acetylcholine and subsequent paralysis.

Historical Development and Discovery

Chlormephos was developed during the 1960s as part of broader research into organophosphorus insecticides conducted by several major chemical companies. The compound emerged from systematic structure-activity relationship studies focused on phosphorodithioate esters with various alkylating groups. Initial patent literature appeared in 1965, claiming superior insecticidal activity against soil pests compared to existing compounds. Development coincided with increasing understanding of acetylcholinesterase inhibition mechanisms and structure-toxicity relationships in organophosphorus compounds. Industrial production commenced in the early 1970s, though regulatory concerns regarding mammalian toxicity and environmental persistence limited widespread adoption. The compound's classification as an extremely hazardous substance under United States regulations in the 1980s further restricted its use and production. Despite these limitations, chlormephos remains historically significant as an example of phosphorodithioate insecticide development and structure-based pesticide design.

Conclusion

Chlormephos represents a structurally interesting organothiophosphate compound with significant insecticidal properties derived from its acetylcholinesterase inhibition capability. The compound's molecular architecture features tetrahedral phosphorus coordination with distinct electronic properties influenced by both oxygen and sulfur substituents. Physical characteristics including limited water solubility and moderate volatility contribute to its effectiveness as a soil insecticide while presenting environmental challenges. Chemical reactivity centers on the electrophilic phosphorus atom and the labile chloromethyl group, enabling various transformation pathways. Synthetic methodologies provide efficient routes to the compound though industrial production has declined due to toxicity concerns. Analytical techniques permit precise quantification and purity assessment, essential given the compound's hazardous nature. Historical development illustrates the progression of organophosphorus insecticide research and evolving regulatory landscapes for agricultural chemicals. Future research directions may focus on structural analogs with improved selectivity and reduced environmental impact while maintaining efficacy against target pests.