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SYNTHETIC PYRETHROIDS A seminar by Meet Patel - 13DYE1001

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Page 1: Synthetic Pyrethroids

SYNTHETIC PYRETHROIDSA seminar by Meet Patel - 13DYE1001

Page 2: Synthetic Pyrethroids

TABLE OF CONTENTS Synthetic Pyrethroids – Discovery, Classification and Structureso Novelty of synthetic pyrethroids Synthesis Process o Application of synthetic pyrethroids Mode of actiono Mechanism of metabolism Recent developmentso Current market

Page 3: Synthetic Pyrethroids

1. SYNTHETIC PYRETHROIDS – DISCOVERY, CLASSIFICATION AND STRUCTURES

Page 4: Synthetic Pyrethroids

DISCOVERY Pyrethroids insecticides are synthetic analogues of the naturally occurring insecticidal

pyrethrins found in extract of Chrysanthemum cinerariaefolium.

J. J. Schleier & R. K. Peterson, Green Trends in Insect Control, Ch. 3, Royal Society of Chemistry, 2011, 94-13

R

OO

OX

Page 5: Synthetic Pyrethroids

TIMELINE AND CLASSIFICATION

• Hermann Staudinger and Leopold Ruzicka in the 1920sPyrethrins

• Schechter in 1949 • First non-natural pyrethroids, Allenthrin1st Generation

• Further classified as Type1- Permethrin, 1973 Type2- Cypermethrin, 1974

2nd Generation

Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

Page 6: Synthetic Pyrethroids

STRUCTURES

O

O

O

O

O

O

OO

OClCl

OO

OClCl

C

N

Allenthrin Resmethrin

Permethrin Cypermethrin

1st generation synthetic pyrethroids

2nd generation synthetic pyrethroids

Type I Type II

Page 7: Synthetic Pyrethroids

STRUCTURAL CHANGES

Etofenprox

Kadethrin Protriefenbute

Fenvalerate

Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

OO

OCl

C

N

OO

O

O

O

O

S

O

O

F

O

Page 8: Synthetic Pyrethroids

STEREOCHEMISTRY- TYPE I

The 1R conformations about the cyclopropane ring are considerably more toxic than the 1S isomers.

(S)

(S) H

H

RO

OR'

(S)

(R) H

H

RO

OR'

(R)

(R) H

H

RO

OR'

(S)

(S) H

H

RO

OR'

Cis isomers

Trans isomers

Page 9: Synthetic Pyrethroids

STEREOCHEMISTRY- TYPE II

Pyrethroid Product Isomers Stereo-chemistry

Cypermethrin Alpha 2 (1R)-cis, αS(1S)-cis, αR

Beta 4 (1R)-cis, αS(1S)-cis, αR(1R)-trans, αS(1S)-trans, αR

Cyhalothrin Lambda 2 (1R)-cis, αS(1S)-cis, αR

Super 1 (1R)-cis, αS

R1

O

O

R2

CN

Type II

All type II pyrethroids possess an additional chiral center at the α-C with the α S conformation considerably more toxic towards insects when compared to the α R conformation.

**

*

Table: Examples of commercial product based on isomers

i. Pyrethroids, Agrochemicals Analysis Technical Note, Coresta March 2014ii. Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

Page 10: Synthetic Pyrethroids

2 . NOVELTY OF SYNTHETIC PYRETHROIDS

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TOXICITY PROFILE

Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1

InsecticidesLD50 (mg /kg)

Mammal (rat) Insects

Ratio of selectivity

Carbamate 45(15) 2.8(27) 16

Organophosphorus 67(83) 2.0(50) 33

Organochlorine 230(21) 2.6(26) 91

Pyrethroids 2000(27) 0.45(35) 4500*Number of pesticides tested in parenthesis

Page 12: Synthetic Pyrethroids

TOXICITY DATA

The Pesticides Manual, Twelfth edition

Insecticide Oral LD50 (rats)

(mg/kg)

Dermal LD50 (rats)

(mg/kg)Chlorpyrifos 135-163 2000 (rabbit)

Diazinon 300-400 >2150

Deltamethrin 531-5000 >2000

Cypermethrin 251-4123 >2400 (rabbit)

Bioresmethrin 7070-8000 >10000 (female)

Allenthrin 1100 (male) >2300

Page 13: Synthetic Pyrethroids

TOXICITY TO NON-TARGET INSECTSFish Bee

i. Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1i. F. Antwi, V. P. Reddy, Toxicology effects of pyrethroids on non-target aquatic insects, Environmental Toxicology and Pharmacology, September 2015

PyrethroidsLC50 Value

Carp(ppm/48 h) Daphnid(ppm/3 h)

Silafluofen >100 7.66Etofenprox 5 40

Cycloprothrin 8 >10Fenvalerate 0.00075 0.3Permethrin 0.043 >10Cyfluthrin 0.012 0.94

Tralomethrin 0.008 0.22Fluvalinate 0.00048 0.298

Pyrethroid

Acute Oral LD50 (μg a.i./bee )

Acute Contact LD50 (μg a.i./bee )

Bifenthrin 0.01 0.002

Cypermethrin

0.03 0.02

Deltamethrin 0.08 0.001

Permethrin 0.03 0.1

Page 14: Synthetic Pyrethroids

TOXICITY TO HUMANS

Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016

Acute toxicity Chronic toxicityEye irritation Change in immunity

Mouth Ulcer Potential carcinogenicity

Irritation in nasal cavity Non-specific symptoms

Tremors Thyroid inactivity

Paraesthesia & Cutaneous reactions

Estrogenic & anti-androgenic activities

Coma, convulsions & Death Neurotoxicity

Page 15: Synthetic Pyrethroids

TOXICITY TO HUMANS – CASE STUDIESCase study 1 In a single case report, a 28-

year-old man who applied some 1.5g permethrin in cream from neck to toe and did not wash for about 10 hours developed severe torticollis and inability to tilt his head to the left. This persisted unchanged for 24 hours and no cause other than the pesticide was identified.

Case study 2 Of 12 workers who

sprayed lambda Cyhalothrin indoors,11 complained of nasal irritation and six of throat irritation.

Case study 3 A 45-year-old man died 3 hours

after eating beans and cheese prepared using Cypermethrin 10% instead of oil. He developed symptoms within a few minutes, including prolonged vomiting, tenesmus, diarrhea, convulsions, coma. Death followed respiratory arrest.

A. Vale, Poisoning due to Pyrethroids, Toxicological Reviews, February, 2005

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TOXICITY TO ENVIRONMENT

Noritada Matsuo & Tatsuya Mori, Pyrethroids:From Chrysanthemumto Modern Industrial Insecticide, 2012, Ch.1

Isomerization

Homolytic cleavage

Page 17: Synthetic Pyrethroids

SYNERGISTS Synergists are typically non toxic compounds at the dosage applied, but which

enhance the toxicity of the active pesticide ingredients. Methylenedioxyphenyl synergists, such as piperonyl butoxide, are thought to suppress

primarily oxidative detoxification by inhibiting enzymatic action of CYP enzyme within the insect.

C. Pasa, L. Arlian, M. Morgan, R. Gunning, L. Rossiter, D. Holt, S. Walton, S. Beckham, J. McCarthy, Synergists in Pyrethroid-Resistant Scabies Mites, PLOS journal of neglected tropical diseases, January 2009, Volume 3, Issue 1

Treatment Sensitive mites Resistant mitesPermethrin 4 15

Permethrin + PBO 4 4Permethrin + DEF 3.5 6Permethrin + DEM 2 3

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3 . SYNTHESIS PROCESS

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SYNTHESIS OF CHRYSANTHEMIC ACID

Trans-chrysanthemic acid

Cu - catalyst

N2

OEt

O

OEtO

First industrial process and its still used with better catalysts giving specifically 1R isomer which has more insecticidal activity.

Professor Dr. Bernd Schaefer, Natural Products in the Chemical Industry, Springer-Verlag Berlin Heidelberg 2014, 704-723

Page 20: Synthetic Pyrethroids

ISOMERIZATION OF CHRYSANTHEMIC ACID

O

OH

Thionyl chlorideLewis acid,150° to 170° C

Cis : Trans = 45:55

Cis : Trans = 18.8:81.2

Cis : Trans ratio in the product depends on Lewis acid we use.

Process for isomerization of a cyclopropane carboxylic acid, US 4008268 A, Sumitomo Chemical Company, 15 Feb 1977

Page 21: Synthetic Pyrethroids

MECHANISM OF ISOMERIZATION

Dr. Klaus Naumann, Chemistry of Plant Protection, Ch. - Synthetic Pyrethroid Insecticides: Chemistry and Patents, 1990

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GETTING 1R ISOMER

(S)

NH2

(S) (R)HH

OH

O (Z)

Cl

CF3

H

(R) (S)HH

OH

O (Z)

Cl

CF3

H

i. MeOH, H2Oii. Acid hydrolysis

A process for the production of 1r pyrethroid esters,  WO 2003053905 A1, Syngenta Limited, Jul 3, 2003

H

F

F

FCl

OH

O Major product

Page 23: Synthetic Pyrethroids

SYNTHESIS OF GAMMA CYHALOTHRIN

Three step synthesis:-

Chlorinating acid derivative Esterification Epimerizing the diastereoisomeric mixture

PRODUCTION PROCESS OF GAMMA-CYHALOTHRIN, Indian Patents: 219118, SYNGENTA LIMITED, Publication Date 06-Jun-2008 http://www.allindianpatents.com/patents/219118-production-process-of-gamma-cyhalothrin

(R)

(R)

(Z)

F3C Cl

O

O

(S)O

CN

(S)- α -cyano-3-phenoxybenzyl (Z)-(1R,3R)-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate

Page 24: Synthetic Pyrethroids

CHLORINATION

Chlorinating agentSolvent, Tb of solvent(R)

(R)

(Z)

F3C Cl

OH

O

(R)

(R)

(Z)

F3C Cl

Cl

O

Page 25: Synthetic Pyrethroids

ESTERIFICATION

OHC

O Cyanide source SolventOrganic base 0°C and 20°C.

Diastereoisomeric mixture of Cyhalothrin isomers

(R)

(R)

(Z)

F3C Cl

Cl

O

(R)

(R)

(Z)

F3C Cl

O

O

(S)O

CN

(R)

(R)

(Z)

F3C Cl

O

O

(R)O

CN

Page 26: Synthetic Pyrethroids

EPIMERIZING THE DIASTEREOISOMERIC MIXTUREDiastereoisomeric mixture of Cyhalothrin isomers

Solvent, -10°C to 10°C  

Source of cyanide / tertiary amine / a seed of gamma-Cyhalothrin

gamma-Cyhalothrin and a diastereomer ratio of 95:5.

Second and third step can be done in a single reactor without any isolation but we need to compromise with yield.

PRODUCTION PROCESS OF GAMMA-CYHALOTHRIN, Indian Patents: 219118, SYNGENTA LIMITED, Publication Date 06-Jun-2008 http://www.allindianpatents.com/patents/219118-production-process-of-gamma-cyhalothrin

Page 27: Synthetic Pyrethroids

FORMULATIONSPyrethroid Formulation

PermethrinEmulsifiable concentrate (100-500 g a.i/l)

Wettable powders (100-500 g/kg)Aerosol conc. & Fumigants ( household use)

Cypermethrin Emulsifiable concentrate (25-200 g/l)ULV concentrates (10-50 g/l)

DeltamethrinEmulsifiable concentrate (25 g a.i/l)

Granules (0.5 g/kg)Wettable powders (25 g/l)

Bioresmethrin Aerosol concentrates (1 g/l)Ready to use liquid (for oil/water based sprays, 2.5 g/l)

The Pesticides Manual, Twelfth edition

Page 28: Synthetic Pyrethroids

4 . APPLICATIONS OF SYNTHETIC PYRETHROIDS

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AGRICULTURAL APPLICATIONS

Pyrethroids Insects Crops

Bifenthrin Beetles, aphids, moths, locust, lice, houseflies

Beans, cereals, corn, cotton, melons

Cypermethrin Cockroaches, flies, moths, mosquitoes

Cotton, onions, pears, peaches

Deltamethrin Aphids, bollworms, caterpillars, cicadas

Alfalfa, beet, maize, cotton potatoes, soyabean

Fluvalinate Leafhoppers, thrips spider mites, moths

Cereals, cotton, tobacco, apples

Permethrin Ants, termites, lice, weevils, Cotton, lettuce, wheat, tomatoes

Page 30: Synthetic Pyrethroids

OTHER APPLICATIONS

Pyrethroids

Households

Medical uses

Veterinary uses

OrnamentalsPlants

i. A.J. Thatheyus, A.Deborah Gnana Selvam, Synthetic Pyrethroids: Toxicity and Biodegradation, App. Eco. & Env. Sci., 2013, Vol. 1, 33-36 ii http://www.anapsid.org/pyrethroids.html

Page 31: Synthetic Pyrethroids

5 . MODE OF ACTION

Page 32: Synthetic Pyrethroids

MODE OF ACTION

Page 33: Synthetic Pyrethroids

SYMPTOMS Mammalian intoxication by type I pyrethroids causes symptoms characterized by tremor

i.e. T-class, exaggerated startle response, and hyperexcitability. Intoxication by type II pyrethroids results in burrowing and pawing behavior, followed by

salivation and coarse tremor, which evolves into choreoathetosis (involuntary movement and writhing). This second type of poisoning is referred to as CS-class.

Some pyrethroids, such as fenpropathrin and cyphenothrin can result in symptoms from both T and CS-class, thus are called TS-class.

i. E. Wakeling, A. Neal & W. Atchison, Pesticides-Advances in Chemical and Botanical Pesticides, Ch. 3 ii. Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016

Page 34: Synthetic Pyrethroids

RESISTANCE TO PYRETHROIDS A major contributory factor is that pyrethroids exhibit cross-resistance to DDT,

which is thought to act at the same binding site on the voltage-gated sodium channel.

Resistance

Increased detoxification Target site Insensitivity

Dr. Bhupinder Khambay, Pyrethroids Insecticides, Pesticide Outlook,13,2002,49-54

Page 35: Synthetic Pyrethroids

6 . MECHANISM OF METABOLISM

Page 36: Synthetic Pyrethroids

METABOLIC PATHWAYS

Phase 1 reaction

• Ester hydrolysis• Oxidation

Phase 2 reaction

• Hydrophilic conjugate• Lipophilic conjugate

Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791

Page 37: Synthetic Pyrethroids

ESTER HYDROLYSIS

Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791

H

COOR2

H

R1

R1

COOR2

H

HR1

R1

H

R

R

H COOCH2

O

H

R

R

H COOCH

O

C

N

Trans isomer Cis isomer

Page 38: Synthetic Pyrethroids

OXIDATION

i. Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791 ii. Junshi Miyamoto, Degradation, Metabolism and Toxicity of Synthetic Pyrethroids, EHP, 1976, vol. 14,15-28

N

O

O

O

O

O

C

O

N

OBrBr

O

O

O

OO

O

(1RS, trans)- tetramethrin

Deltamethrin

(1R, trans)- resmethrin

(1R, tans)- phenothrin

Page 39: Synthetic Pyrethroids

HYDROPHILIC CONJUGATION

Thiocynates conjugates

Sulfonic acid conjugates

Kaneko, H. Pyrethroid chemistry and metabolism, Hayes’ Handbook of Pesticide Toxicology, 3rd ed., 2010; Ch.76.

Hydrophilic conjugates are often found as glucuronides, sulfates, or amino acid conjugates. But in few pyrethroids other conjugates are also formed like

Page 40: Synthetic Pyrethroids

LIPOPHILIC CONJUGATES

Hideo Kaneko, Pyrethroids: Mammalian Metabolism and Toxicity, J. Agric. Food Chem. 2011,59,2786–2791

Page 41: Synthetic Pyrethroids

METABOLISM OF CYHALOTHRIN

OHC

O

C

N

OCF3Cl

COOHCl

F3C

O

CN

HO

OHOOC

OHOOC

OH

COOHCl

F3C

HO

Glucuronide

Glucuronide Glycerides

Sulfate

Kaneko, H. Pyrethroid chemistry and metabolism, Hayes’ Handbook of Pesticide Toxicology, 3rd ed., 2010; Ch.76.

Page 42: Synthetic Pyrethroids

7 . RECENT DEVELOPMENTS

Page 43: Synthetic Pyrethroids

DISCOVERY OF SILAFLUOFEN High insecticidal activity and low mammalian toxicity, this compound features low fish

toxicity, chemical stability under sunlight, in the soil and under alkaline environments.

F

OSi

O

Acute oral toxicity for rat (LD50): >5,000 mg/kg Acute dermal toxicity for rat (LD50): >5,000 mg/kg Fish toxicity for carp (LC50 after 48 hours): >100

ppm

Y. Katsuda, Y. Minamite, and C. Vongkaluang, Development of Silafluofen-Based Termiticides in Japan and Thailand, December 2011

Page 44: Synthetic Pyrethroids

DISCOVERY OF METOFLUTHRIN

N. MATSUO, K. UJIHARA, Y. SHONO, T. IWASAKI, M. SUGANO, Discovery and Development of a Novel Pyrethroid Insecticide Metofluthrin (SumiOne®, Eminence®), SUMITOMO KAGAKU, vol. 2005-II.

F

F

F

F

O

O

O

Compound Recovery rate(%)Metofluthrin 98.2Empenthrin 82.7d - Allenthrin 6.9Prallenthrin 11.2

Photo stability Compound Culex pipiens Adese albopictus

Metofluthrin 0.0015 0.00047d - Allenthrin 0.038 0.023Prallenthrin 0.0056 0.0050

D-tetramethrin 0.0096 0.0036permethrin 0.0028 0.0012

LD50 (μg/ female adult)

Page 45: Synthetic Pyrethroids

PROPERTIES OF METOFLUTHRIN

N. MATSUO, K. UJIHARA, Y. SHONO, T. IWASAKI, M. SUGANO, Discovery and Development of a Novel Pyrethroid Insecticide Metofluthrin (SumiOne®, Eminence®), SUMITOMO KAGAKU, vol. 2005-II.

Efficacy

Acute toxicity to mammals

Species Route Lethal doseRat Oral >2000 mg/kgRat Dermal >2000 mg/kg

Rat Inhalation Male: 1960 mg/m3

Female: 1080 mg/m3

Dog Oral >2000 mg/kg

Compound

Conc. (%w/w)

No. of mosquitoesPretreatment After

treatment

Reduction%

Metofluthrin 0.005 210 18 93Transfluthrin 0.03 187 26 88d - Allenthrin 0.3 188 27 88

Page 46: Synthetic Pyrethroids

7 . CURRENT MARKET & FUTURE SCOPE

Page 47: Synthetic Pyrethroids

CURRENT MARKET Pyrethroids account for up to 17% of global insecticide sales – a market worth more than

$7Bn each year.

Extermination

Vegetal Farming

Domestic

Animal Farming

Technical Report, Louise Hénault-Ethier, Canadian Association of Physicians for the Environment, 2016 http://www.foodsecurity.ac.uk/research/impact/pyrethroids.html

Page 48: Synthetic Pyrethroids

PROBLEMS FACED BY PYRETHROIDS

• Cancellation of Fenvalerate and EsfenvalerateProblem 1

• Increase in resistanceProblem 2

• Least commercial researchProblem 3

J. J. Schleier & R. K. Peterson, Green Trends in Insect Control, Ch. 3, Royal Society of Chemistry, 2011, 94-13

Page 49: Synthetic Pyrethroids

ALTERNATIVES TO PYRETHROIDS

Silicon dioxide provides an effective and safer control against household and pet animal pests.

Bollcure – a biopesticides can be used on cotton. Biopesticides derived from vegetable oil can be used in

grain protection.

Alternative to Pyrethroids are Biopesticides

A. Singh, A. Khare, A. P. Singh, Use of Vegetable Oils as Biopesticide in Grain Protection, J. of Fertilizers & Pesticides, January 25, 2012

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THANK YOU