Pyrethroid
Pyrethroids are a class of synthetic insecticides chemically derived from the natural pyrethrins, which are neurotoxic esters extracted from the flowers of Chrysanthemum cinerariaefolium (also known as Tanacetum cinerariifolium).[1] These compounds mimic the structure of pyrethrins but are modified for enhanced stability, potency against insects, and resistance to environmental degradation, such as photodegradation in sunlight.[2] Pyrethroids target the nervous systems of insects by binding to voltage-gated sodium channels, prolonging their opening and causing repetitive nerve firing, paralysis, and death, while exhibiting lower toxicity to mammals due to differences in body temperature and detoxification mechanisms.[3] Developed in the mid-20th century to overcome the limitations of natural pyrethrins—such as rapid breakdown in light and air—pyrethroids emerged commercially in the 1970s, with key innovations like the synthesis of allethrin in 1949 and permethrin in 1973.[4] By the 1980s, they accounted for approximately 25% of the global insecticide market, covering over 33 million hectares of agricultural land annually.[4] They are classified into two main types based on chemical structure: Type I pyrethroids (e.g., permethrin, allethrin), which lack an α-cyano group and typically induce repetitive tremors in exposed organisms; and Type II pyrethroids (e.g., deltamethrin, cypermethrin), which include the α-cyano group and cause more severe symptoms like choreoathetosis with salivation.[3] This classification influences their potency and toxicological profiles, with Type II variants often being more effective against a broader range of pests.[2] Pyrethroids are extensively used in agriculture for crop protection against insects, in public health programs for vector control (such as malaria and Zika prevention via insecticide-treated mosquito nets recommended by the World Health Organization), and in household products for pest management, including lice shampoos and pet treatments.[1][2] Over 1,000 pyrethroid compounds have been synthesized, though fewer than a dozen are commonly registered for use in the United States, often formulated as emulsifiable concentrates, aerosols, or dusts.[1] Their lipophilic nature allows them to penetrate insect cuticles effectively, and they are frequently combined with synergists like piperonyl butoxide to enhance efficacy by inhibiting detoxification enzymes.[3] Despite their benefits, concerns include environmental persistence in sediments, bioaccumulation in aquatic organisms, and emerging insect resistance, prompting ongoing research into sustainable alternatives.[4]Chemical Properties
Structure and Stereochemistry
Pyrethroids are synthetic esters structurally analogous to natural pyrethrins, consisting of a cyclopropanecarboxylic acid moiety esterified to an alcohol moiety. The acid component typically features a 2,2-dimethylcyclopropane ring substituted at the 3-position with groups such as a 2,2-dichlorovinyl (as in permethrin) or isobutenyl chain. The alcohol moiety varies by type: Type I pyrethroids often use primary or secondary alcohols like 3-phenoxybenzyl alcohol or allethrolone (a cyclopentenolone), while Type II incorporate an α-cyano group on the alcohol, such as in 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid esterified with α-cyano-3-phenoxybenzyl alcohol (as in deltamethrin). These structural modifications enhance stability and potency compared to pyrethrins.[5][6] Pyrethroids exhibit complex stereochemistry due to multiple chiral centers. The cyclopropane ring introduces cis/trans isomerism at the 3-substituent, with trans isomers generally more bioactive. Most pyrethroids have at least two chiral centers: the 1- and 3-positions of the cyclopropane (configuring as 1R,3R or 1S,3S for active forms). Type I compounds like permethrin have two centers (four stereoisomers), while Type II like cypermethrin have three (including the α-carbon, yielding eight stereoisomers). Insecticidal activity is highly stereospecific, with the (1R,trans)-acid and specific alcohol configurations (e.g., (S)-α-cyano for Type II) being most potent; commercial products are often mixtures enriched for active isomers.[6][7]Synthesis
The extraction of natural pyrethrins from the dried flowers of Chrysanthemum cinerariaefolium (also known as Tanacetum cinerariifolium) provided the basis for early insecticides, where flowers are harvested, dried, and subjected to solvent extraction using organic solvents like petroleum ether or ethanol to isolate the crude pyrethrin mixture, followed by purification steps such as chromatography or distillation to obtain the active esters.[8][9] This natural extraction method, while effective for small-scale production, was limited by seasonal availability and low yields (typically 1-2% pyrethrins content), prompting the development of synthetic pyrethroid analogs.[8] Modern pyrethroid synthesis primarily involves the esterification of cyclopropanecarboxylic acid derivatives, such as halomethyl-substituted chrysanthemic acids, with specific alcohols to mimic the ester linkage in natural pyrethrins.[10] A key route entails reacting the acid chloride of the carboxylic acid component with an alcohol under basic conditions; for instance, the reaction of (S)-allethrolone with chrysanthemoyl chloride in the presence of a base like pyridine yields bioallethrin, a first-generation synthetic pyrethroid, with the stereochemistry of the alcohol ensuring high insecticidal activity.[11] Similarly, 3-phenoxybenzyl alcohol is esterified with 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid to form permethrin, often using coupling agents like dicyclohexylcarbodiimide to facilitate the reaction.[12] These esterifications typically occur in aprotic solvents at controlled temperatures to minimize side reactions and preserve stereoisomers.[10] Industrial-scale production of pyrethroids like permethrin employs multi-step processes starting from readily available precursors, including the synthesis of the cyclopropane ring via carbene addition to dienes and the introduction of double bonds using the Wittig reaction on aldehydes to form the vinyl substituent.[13][14] Stereoselective steps, such as asymmetric cyclopropanation with chiral catalysts, are incorporated to favor the bioactive trans-isomers, followed by purification via crystallization or chromatography to achieve high enantiomeric purity.[15] These processes are optimized for large-scale reactors, enabling continuous production with yields exceeding 80% for key intermediates.[14] Synthetic pyrethroids offer significant advantages over natural pyrethrins, including greater scalability through chemical manufacturing that bypasses agricultural dependencies and reduced production costs, as well as enhanced stability via modifications like the addition of an alpha-cyano group to the alcohol moiety, which prolongs insecticidal efficacy in sunlight and heat.[4] The cyclopropane ring motif in these synthetics is often derived from natural precursors but adapted for efficient laboratory assembly.[10]Classification and Examples
Types of Pyrethroids
Pyrethroids are primarily classified into two categories based on the presence or absence of an α-cyano group in their molecular structure: Type I pyrethroids, which lack this group and typically induce rapid knockdown through repetitive neuronal firing, and Type II pyrethroids, which contain the α-cyano group and cause prolonged paralysis via modification of sodium tail currents.[16][17] This distinction arises from differences in their chemical makeup and resulting toxicological effects, with Type I compounds often producing shorter-lived symptoms compared to the more persistent actions of Type II.[18] Pyrethroids can also be categorized by generations, reflecting advancements in their development for improved stability and efficacy. First-generation pyrethroids, such as simple esters like allethrin, were developed in the 1940s and 1950s but suffered from photolability, limiting their outdoor use.[4] Second-generation pyrethroids, exemplified by photostable compounds like permethrin, emerged in the 1970s and addressed this issue through structural modifications that enhanced resistance to light degradation.[4] Some sources refer to more advanced Type II compounds like cyfluthrin, introduced in the 1980s, as third-generation pyrethroids due to their enhanced potency and environmental persistence.[19] Functionally, pyrethroids are distinguished as knockdown agents, which immobilize pests quickly but may allow recovery without lethality, versus lethal agents that ensure higher mortality rates through sustained effects.[20] Formulation types further differentiate them, with oil-soluble variants suitable for solvent-based applications and water-dispersible forms, such as emulsions or granules, enabling easier mixing and application in aqueous systems despite their inherent low water solubility.[21] At a group level, structure-activity relationships highlight the α-cyano group's pivotal role, as its addition to Type I scaffolds increases insecticidal potency by 10- to 100-fold, primarily by prolonging the duration of neuronal disruption.[22][20] This enhancement underscores the evolution from earlier, less potent designs to more effective modern pyrethroids, guiding their selection for diverse pest control needs.[23]Specific Compounds
Permethrin is a broad-spectrum Type I pyrethroid insecticide, notable for its mixture of cis and trans isomers, with the cis form exhibiting greater potency and persistence.[24] It has a molecular formula of C₂₁H₂₀Cl₂O₃ and a molecular weight of 391.3 g/mol, appearing as a viscous yellow-brown liquid with a melting point around 34 °C (ranging 34-39 °C for the mixture, higher for pure isomers).[24] Its solubility in water is very low at 0.006 mg/L at 20 °C, and it possesses a logP of 6.5, indicating high lipophilicity; it remains stable under heat for over two years at 50 °C but undergoes some photochemical degradation upon exposure to light.[24] Commercially available under trade names such as Ambush and Dragnet, permethrin was produced and used globally at approximately 600 tonnes per year in the 1980s.[25] Cypermethrin, a Type II pyrethroid distinguished by its α-cyano group, offers high potency particularly against lepidopteran pests and exists as a mixture of eight stereoisomers, with alpha-cypermethrin being one of the most active forms.[17] Its molecular formula is C₂₂H₁₉Cl₂NO₃ with a molecular weight of 416.3 g/mol; it is a viscous beige to brown liquid or crystalline solid with a melting point of 60-80 °C for technical grade.[26] Water solubility is minimal at 0.004 mg/L at 20 °C, and its logP is 6.60, reflecting strong partitioning into organic phases; it is stable in neutral to weakly acidic conditions (optimal at pH 4) and shows good photostability in field applications, though it hydrolyzes in alkaline media.[26] Trade names include Cymbush and Ripcord, and it is widely formulated for agricultural and structural pest control.[27] Deltamethrin represents one of the most potent Type II pyrethroids, featuring an α-cyano group and resolved primarily to its active (1R)-cis enantiomer for enhanced efficacy.[17] With a molecular formula of C₂₂H₁₉Br₂NO₃ and molecular weight of 505.2 g/mol, it forms colorless to white odorless crystals with a melting point of 98 °C and a density of 1.5 g/cm³.[28] It exhibits negligible water solubility (<0.0001 mg/L at 20 °C) and a high logP around 6.4, contributing to its low mobility; notably, deltamethrin demonstrates excellent UV stability, resisting photodegradation better than earlier pyrethroids.[29] Commercial products bear names like Decis and K-Othrine, reflecting its broad adoption in pest management.[30] Allethrin, the first synthetic pyrethroid developed in 1949, is a Type I compound primarily suited for indoor applications due to its rapid knockdown effect on flying insects.[31] Its molecular formula is C₁₉H₂₆O₃ with a molecular weight of 302.4 g/mol, existing as a clear to pale yellow viscous liquid with a low melting point near 4 °C and boiling point of 140 °C at 0.1 mm Hg.[32] Insoluble in water and with a logP of 4.78, it is more stable to UV light than natural pyrethrins but still decomposes under direct sunlight and in alkaline conditions.[32] It is marketed under trade names such as Pynamin and is often used in aerosol formulations.[33] Among minor variants, tetramethrin is a Type I pyrethroid with a phthalimide structure, appearing as white crystals (melting point 65-80 °C) that are insoluble in water and volatile, making it effective for space sprays against household pests; it is commercially available as Neo-Pynamin. Resmethrin, another early Type I compound, features a furan ring and was noted for its low mammalian toxicity but limited by instability to light and air (melting point ~62 °C, low water solubility); its registrations were voluntarily canceled in 2010, leading to discontinuation of sales by 2015 due to these stability issues.[34][35]| Compound | Type | Key Physical Properties | Notable Stability | Trade Names |
|---|---|---|---|---|
| Permethrin | I | MW: 391.3 g/mol; MP: 34 °C; Water sol.: 0.006 mg/L; logP: 6.5 | Heat-stable; moderate photodegradation | Ambush, Dragnet |
| Cypermethrin | II | MW: 416.3 g/mol; MP: 60-80 °C; Water sol.: 0.004 mg/L; logP: 6.60 | pH-stable (acidic); good photostability | Cymbush, Ripcord |
| Deltamethrin | II | MW: 505.2 g/mol; MP: 98 °C; Water sol.: <0.0001 mg/L; logP: ~6.4 | Excellent UV stability | Decis, K-Othrine |
| Allethrin | I | MW: 302.4 g/mol; MP: ~4 °C; Water sol.: Insoluble; logP: 4.78 | Better than pyrethrins but UV-sensitive | Pynamin |
| Tetramethrin | I | MW: 331.4 g/mol; MP: 65-80 °C; Water sol.: Low | Volatile; light-unstable | Neo-Pynamin |
| Resmethrin | I (discontinued) | MW: 338.4 g/mol; MP: ~62 °C; Water sol.: Low | Unstable to light/air | (Former: SBP-1382) |