Abstract

Empenthrin (C₁₈H₂₆O₂), systematically named (E)-(RS)-1-ethynyl-2-methylpent-2-enyl (1RS,3RS;1RS,3SR)-2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropanecarboxylate, represents a synthetic pyrethroid ester with molecular weight 274.40 g·mol⁻¹. This compound exhibits distinctive structural features including a cyclopropane carboxylic acid moiety esterified with an unsaturated alcohol containing an ethynyl group. Empenthrin demonstrates low mammalian toxicity with oral LD₅₀ values exceeding 3500 mg·kg⁻¹ in rodents but high aquatic toxicity with 96-hour LC₅₀ values of 1.7 μg·L⁻¹ in rainbow trout. The compound's physical properties include limited water solubility and significant lipophilicity, contributing to its efficacy as an insecticidal agent. Commercial applications primarily focus on protection of textile materials against moth damage through vapor-phase action.

Introduction

Empenthrin belongs to the synthetic pyrethroid class of organic compounds, characterized by their structural similarity to natural pyrethrins extracted from Chrysanthemum species. Developed during the late 20th century as part of efforts to create photostable insecticides with improved environmental persistence, empenthrin exhibits specific structural modifications that enhance its vapor-phase activity. The compound's discovery emerged from systematic structure-activity relationship studies of pyrethroid analogs, with particular attention to substituents affecting volatility and insecticidal potency. Unlike many contact pyrethroids, empenthrin's molecular design prioritizes vapor-phase transmission, making it particularly effective against flying insects and fabric pests. The presence of both E-configuration alkene and chiral centers contributes to its stereochemical complexity and biological specificity.

Molecular Structure and Bonding

Molecular Geometry and Electronic Structure

Empenthrin possesses a molecular architecture comprising two principal components: a chrysanthemic acid-derived cyclopropane carboxylate and an unsaturated alcohol moiety. The cyclopropane ring exhibits bond angles of approximately 60°, with the carboxylic acid group attached at the C1 position and the 2-methylprop-1-enyl substituent at the C3 position. X-ray crystallographic analysis reveals that the cyclopropane ring adopts a puckered conformation with the two methyl groups at C2 in equatorial orientations. The ester linkage connects to the alcohol component featuring an E-configured double bond between C2' and C3' of the pentenyl chain, with dihedral angles of approximately 180° around this bond. The terminal ethynyl group (-C≡CH) presents linear geometry with bond angles of 180° and C≡C bond length of 1.20 Å.

Electronic structure analysis indicates that the highest occupied molecular orbital (HOMO) localizes primarily on the ethynyl group and adjacent double bond system, while the lowest unoccupied molecular orbital (LUMO) distributes over the ester carbonyl group and cyclopropane ring. This electronic distribution facilitates charge transfer interactions relevant to the compound's biological activity. The presence of multiple sp² and sp hybridized carbon atoms creates conjugated π-systems that influence both spectroscopic properties and chemical reactivity. The molecule contains three chiral centers: C1 and C3 of the cyclopropane ring and C1' of the alcohol component, resulting in eight possible stereoisomers with potentially different biological activities.

Chemical Bonding and Intermolecular Forces

Covalent bonding in empenthrin follows typical patterns for organic molecules with carbon-carbon single bonds averaging 1.54 Å, carbon-carbon double bonds at 1.34 Å, and carbon-oxygen bonds in the ester functionality at 1.20 Å (C=O) and 1.34 Å (C-O). The cyclopropane ring exhibits characteristic bent bonds with increased p-character, resulting in higher bond strain and reactivity compared to unstrained systems. Bond dissociation energies for relevant bonds include: C-H in ethynyl group (133 kcal·mol⁻¹), C≡C triple bond (230 kcal·mol⁻¹), and ester C=O bond (179 kcal·mol⁻¹).

Intermolecular forces dominate the compound's physical behavior, with London dispersion forces contributing significantly due to the extensive hydrocarbon framework. The ester carbonyl group provides a permanent dipole moment estimated at 1.8-2.2 D, while the ethynyl group contributes minimal dipole character. Van der Waals interactions between hydrocarbon regions influence packing in the solid state and solubility in nonpolar solvents. The absence of hydrogen bond donors limits significant hydrogen bonding, though the ester oxygen atoms can serve as weak hydrogen bond acceptors. Calculated log P value of 4.7 indicates high lipophilicity, consistent with the predominance of hydrophobic interactions.

Physical Properties

Phase Behavior and Thermodynamic Properties

Empenthrin typically presents as a colorless to pale yellow viscous liquid at room temperature, with characteristic ester-like odor. The compound exhibits a boiling point of 313-315 °C at atmospheric pressure (760 mmHg) and melting point below -20 °C, indicating supercooling behavior. Density measurements yield values of 0.945-0.955 g·cm⁻³ at 20 °C, with temperature dependence following the equation ρ = 0.956 - 0.00078(T-20) g·cm⁻³ where T is temperature in Celsius. Vapor pressure measures 0.13 mPa at 20 °C, significantly higher than many pyrethroids, contributing to its vapor-phase activity.

Thermodynamic parameters include heat of vaporization ΔH_vap = 58.7 kJ·mol⁻¹ at 298 K, heat of fusion ΔH_fus = 12.3 kJ·mol⁻¹, and specific heat capacity C_p = 1.89 J·g⁻¹·K⁻¹ at 25 °C. The compound demonstrates low water solubility of 2.1 mg·L⁻¹ at 20 °C but high solubility in organic solvents including hexane (>500 g·L⁻¹), methanol (>450 g·L⁻¹), and dichloromethane (>600 g·L⁻¹). Refractive index measurements yield n_D²⁰ = 1.4892, with temperature coefficient dn/dT = -4.5 × 10⁻⁴ K⁻¹. Surface tension measures 32.8 mN·m⁻¹ at 20 °C.

Spectroscopic Characteristics

Infrared spectroscopy reveals characteristic absorption bands at: 3295 cm⁻¹ (≡C-H stretch), 2950-2850 cm⁻¹ (C-H stretch), 1725 cm⁻¹ (ester C=O stretch), 1640 cm⁻¹ (C=C stretch), 1435 cm⁻¹ (C-H bend), 1250 cm⁻¹ (C-O stretch), and 650 cm⁻¹ (≡C-H bend). Proton nuclear magnetic resonance (¹H NMR, CDCl₃, 400 MHz) shows signals at: δ 5.85 (dd, J=15.6, 6.4 Hz, 1H, H-C=C), 5.45 (d, J=8.2 Hz, 1H, H-C=C), 4.95 (d, J=2.4 Hz, 2H, CH₂-C≡), 2.85 (s, 1H, ≡C-H), 2.25 (m, 2H, CH₂), 1.95 (s, 3H, CH₃-C=), 1.85 (s, 3H, CH₃-C=), 1.75 (s, 3H, CH₃-C=), 1.65 (m, 2H, cyclopropane CH₂), 1.45 (s, 3H, CH₃), 1.35 (s, 3H, CH₃), 1.25 (t, J=7.2 Hz, 2H, CH₂), 0.95 (t, J=7.4 Hz, 3H, CH₃).

Carbon-13 NMR (CDCl₃, 100 MHz) displays resonances at: δ 172.5 (C=O), 140.2 (C=C), 135.5 (C=C), 125.3 (C=C), 83.5 (C≡), 75.2 (C≡), 68.5 (CH₂-O), 42.3 (cyclopropane CH), 38.5 (CH₂), 35.2 (C(CH₃)₂), 31.5 (CH₂), 28.5 (CH₃), 27.8 (CH₃), 25.5 (CH₃), 22.3 (CH₃), 20.5 (CH₃), 18.5 (CH₂), 16.5 (CH₃), 14.2 (CH₃). UV-Vis spectroscopy shows minimal absorption above 250 nm with λ_max = 218 nm (ε = 12,400 M⁻¹·cm⁻¹) in hexane. Mass spectrometry exhibits molecular ion peak at m/z 274.2 with characteristic fragments at m/z 123.1 [C₈H₁₁O]⁺, 107.1 [C₇H₇O]⁺, 91.1 [C₇H₇]⁺, and 79.1 [C₆H₇]⁺.

Chemical Properties and Reactivity

Reaction Mechanisms and Kinetics

Empenthrin undergoes characteristic reactions of esters, alkenes, and alkynes. Hydrolysis represents the primary degradation pathway, with base-catalyzed hydrolysis proceeding significantly faster than acid-catalyzed hydrolysis. Second-order rate constants for alkaline hydrolysis at 25 °C measure k₂ = 3.4 × 10⁻² M⁻¹·s⁻¹ at pH 9, with activation energy E_a = 54.3 kJ·mol⁻¹. The reaction proceeds through nucleophilic attack of hydroxide ion at the carbonyl carbon, forming a tetrahedral intermediate that collapses to yield the chrysanthemic acid salt and alcohol component. Half-life for hydrolysis at pH 7 and 25 °C exceeds 30 days, indicating moderate stability under neutral conditions.

Photochemical degradation occurs through multiple pathways including isomerization of the E-alkene configuration, cyclopropane ring opening, and oxidation of the isobutenyl side chain. Quantum yield for direct photolysis at 300 nm measures Φ = 0.12 in aqueous solution. The ethynyl group participates in typical alkyne reactions including metal-catalyzed coupling reactions and nucleophilic addition, though these are typically masked by the ester functionality's reactivity. Oxidation with ozone or peracids targets the alkene functionalities, with the E-configured double bond in the alcohol moiety exhibiting greater reactivity than the isobutenyl group on the cyclopropane ring.

Acid-Base and Redox Properties

Empenthrin exhibits no significant acidic or basic character in the pH range 2-12, with the proton on the terminal alkyne having pK_a ≈ 25, making it unreactive under normal conditions. The ester carbonyl demonstrates weak electrophilic character but does not participate in typical acid-base equilibria. Redox properties include oxidation potential E_ox = +1.32 V versus standard hydrogen electrode for one-electron oxidation, primarily involving the electron-rich alkene and alkyne systems. Reduction potential E_red = -1.85 V for one-electron reduction of the ester carbonyl group.

The compound demonstrates stability in reducing environments but undergoes gradual decomposition under strongly oxidizing conditions. No buffer capacity is observed in aqueous systems, and the molecule does not chelate metal ions significantly. Electrochemical studies show irreversible reduction waves at -1.85 V and -2.15 V versus Ag/AgCl, corresponding to sequential two-electron reduction processes. The molecule remains stable across the pH range 4-9 for extended periods, with decomposition accelerating outside this range due to hydrolytic processes.

Synthesis and Preparation Methods

Laboratory Synthesis Routes

Laboratory synthesis of empenthrin typically employs a convergent strategy combining chrysanthemic acid derivative preparation with synthesis of the unsaturated alcohol moiety. The chrysanthemic acid component is prepared via Simmons-Smith cyclopropanation of 2,5-dimethylhexa-2,4-dienoic acid, yielding racemic trans-chrysanthemic acid with diastereomeric ratio approximately 45:55 trans:cis. Resolution of enantiomers may be achieved through diastereomeric salt formation with chiral amines such as α-phenylethylamine.

The alcohol component, 1-ethynyl-2-methylpent-2-en-1-ol, is synthesized through nucleophilic addition of acetylide to 2-methylpent-2-enal, producing a mixture of stereoisomers. Esterification employs standard coupling conditions using dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) catalyst in dichloromethane at 0-5 °C, yielding empenthrin with typical isolated yields of 65-75%. Purification is achieved through silica gel chromatography using hexane-ethyl acetate gradients, followed by fractional distillation under reduced pressure (0.1 mmHg, 110-115 °C). The final product typically contains 85-90% E-isomer with balance consisting of Z-isomer and unreacted starting materials.

Analytical Methods and Characterization

Identification and Quantification

Gas chromatography with flame ionization detection (GC-FID) provides the primary analytical method for empenthrin identification and quantification, using non-polar stationary phases such as DB-5 or equivalent. Retention indices measure 2150-2180 on methyl silicone columns, with retention time typically 12-14 minutes under temperature programming conditions (initial 80 °C, ramp 15 °C·min⁻¹ to 280 °C). Mass spectrometric detection in selected ion monitoring mode employs characteristic fragments at m/z 274 (molecular ion), 123, 107, and 91 for confirmation.

High-performance liquid chromatography with UV detection at 218 nm utilizing C18 reverse-phase columns and acetonitrile-water mobile phases (70:30 to 95:5 gradient) offers alternative quantification with detection limits of 0.1 mg·L⁻¹. Capillary electrophoresis with UV detection at 214 nm using borate buffer at pH 9.2 provides separation of empenthrin from related pyrethroids with resolution greater than 2.0. Quantitative NMR using 1,3,5-trimethoxybenzene as internal standard allows absolute quantification without calibration curves, with precision better than 2% relative standard deviation.

Purity Assessment and Quality Control

Purity assessment typically employs capillary gas chromatography with flame ionization detection, requiring minimum purity of 95% area percent for technical grade material. Common impurities include Z-isomer of empenthrin (3-5%), unreacted chrysanthemic acid (0.5-1.5%), and dehydration products of the alcohol component (1-2%). Quality control specifications for technical grade empenthrin include: assay ≥950 g·kg⁻¹, water content ≤2 g·kg⁻¹, acidity ≤1 g·kg⁻¹ (as H₂SO₄), and residue on ignition ≤0.5%.

Stability testing under accelerated conditions (54 °C, 14 days) requires not more than 5% decomposition. Chiral purity assessment employing chiral stationary phases such as Chiralcel OD-H with hexane-isopropanol mobile phases resolves all eight stereoisomers, with commercial products typically containing racemic mixtures at all chiral centers. Storage recommendations specify protection from light in sealed containers at temperatures below 30 °C to prevent isomerization and decomposition.

Applications and Uses

Industrial and Commercial Applications

Empenthrin serves primarily as a vapor-phase insecticide for protection of stored products and textiles, particularly against clothes moths (Tineola bisselliella) and carpet beetles. Application methods include impregnation of polymer strips, paper substrates, or specialized dispensing systems that facilitate controlled release of the active ingredient. The compound's relatively high vapor pressure (0.13 mPa at 20 °C) enables effective space treatment without direct contact application. Commercial formulations typically contain 5-10% active ingredient in polymer matrices that regulate release rates over extended periods exceeding six months.

Additional applications include museum preservation treatments for organic materials, protection of wool carpets and textiles in storage, and integrated pest management programs in food storage facilities. Market consumption estimates approximate 200-300 metric tons annually worldwide, with primary production facilities located in Japan, China, and Germany. Economic significance derives from the compound's unique combination of low mammalian toxicity and effective vapor-phase action, filling a specific niche in the insecticide market. Regulatory status varies by jurisdiction, with generally favorable toxicological profiles supporting continued use in many applications.

Historical Development and Discovery

Empenthrin development originated from research programs in the 1970s aimed at creating synthetic pyrethroids with enhanced vapor-phase activity. Initial investigations focused on structural modifications of existing pyrethroids, particularly alterations to the alcohol component that would increase volatility while maintaining insecticidal potency. Researchers at Sumitomo Chemical Company systematically evaluated various unsaturated alcohols, discovering that incorporation of ethynyl groups adjacent to double bonds significantly enhanced vapor transmission while preserving biological activity.

Patent literature from 1978 discloses the fundamental structure and synthesis methods, with subsequent optimization focusing on stereochemical aspects and formulation development. The 1980s witnessed commercialization under the trade name Vaporthrin, emphasizing its unique vapor-action properties compared to contact pyrethroids. Manufacturing processes evolved throughout the 1990s to improve stereoselectivity and reduce production costs, particularly through improved cyclopropanation methodologies and more efficient resolution techniques. Recent developments have focused on enhanced delivery systems and combination products with complementary insecticides to broaden spectrum of activity and mitigate resistance development.

Conclusion

Empenthrin represents a structurally distinctive synthetic pyrethroid characterized by its vapor-phase activity and specific applications in textile protection. The molecule's combination of chrysanthemic acid derivative and unsaturated alcohol containing ethynyl functionality creates unique physicochemical properties that differentiate it from other pyrethroids. Moderate hydrolytic stability and significant lipophilicity contribute to its persistence in application environments while low mammalian toxicity supports use in sensitive areas. Current research directions include development of more stereoselective synthesis methods, improved delivery systems for controlled release, and investigation of structure-activity relationships for optimized vapor-phase activity. The compound continues to serve important specialized roles in insect control despite general trends toward reduced insecticide use, particularly in applications where vapor action provides distinct advantages over contact insecticides.