How Insecticides Are Developed

R. C. Roark.

New insecticides are developed in two ways.

The first is by determining the structure of the active principles of plants recognized as toxic to insects. Then the principles or other compounds closely related to them are synthesized put together again to make the whole.

The second is by testing compounds of known structure and unknown toxicity upon several species of insects and selecting the ones that are effective.

The first method starts with a material of known toxicity but unknown structure. The second starts with a compound of known structure but unknown toxic value.

The insecticidal principles parts or elements of plants have a complicated make-up. Even after their formulas are known it may be impossible to reconstruct them : The structural formulas of rotenone and deguelin have been known since 1932, but the chemist does not know how to attempt their synthesis.

An example of the first method is the synthesis of anabasine. For that, nicotine, a compound of known structure isolated from a plant, was used as a model.

The chief insecticidal principle of tobacco, the liquid alkaloid nicotine, 1-methyl-2-(3-pyridyl) pyrrolidine, kills many kinds of insects. When a systematic search for new synthetic insecticides was undertaken in the Depart of Agriculture in 1922 by C. R. Smith, he naturally turned to nicotine as the first model of compounds to be synthesized. Its structure was determined a half century ago, but no commercially feasible process of making it synthetically on a large scale is known.

Many derivatives of pyridine and pyrrolidine, the two rings of carbon and nitrogen atoms that are found in the nicotine molecule, then were prepared. The derivatives were tested on the bean aphid, a species highly susceptible to nicotine, but none approached nicotine in insecticidal effectiveness.

Finally in 1928 Smith, by the action of sodium on pyridine, prepared 243- pyridyl) piperidine, a compound containing the same number of carbon, hydrogen, and nitrogen atoms as nicotine but arranged differently. This isomer of nicotine proved even more effective than nicotine for killing aphids. Because of its resemblance to nicotine, Smith named the new compound neonicotine. Shortly after its synthesis was announced, Russian chemists found the alkaloid in Anabasis aphylla, a weed belonging to the goose-foot family, and named it anabasine.

Another example is the synthesis of allethrin. For nearly 30 years chemists sought to learn the nature of the insecticidal constituents of the pyrethrum flowers. Two Swiss chemists, H. Staudinger and L. Ruzicka, in 1924 announced that two compounds containing carbon, hydrogen, and oxygen in pyrethrum flowers were responsible for the insecticidal value of the flowers. They explained the structure of the compounds, called pyrethrin I and pyrethrin II, and described their unsuccessful efforts to synthesize them. F. B. LaForge and associates in the Department of Agriculture reexamined pyrethrum in 1934 and discovered two additional insecticidal esters in the flowers. They named them cinerin I and cinerin II.

Of the four active principles in pyrethrum flowers, cinerin I has the simplest structure. It was taken as the pattern when synthetic work was undertaken. Compounds closely related to cinerin I were made. One of them, called the allyl homolog of cinerin I, was found to equal the natural compound in killing house flies. About a dozen steps are required in synthesizing it. The large-scale manufacture of the ester has been accomplished, and 10,000 pounds of it were used in 1951 in liquefied-gas aerosol bombs. To avoid the cumbersome "allyl homolog of cinerin I," the name allethrin was coined for the compound.

Allethrin is a light-yellow, viscous liquid. It has a slight but pleasant odor. It is insoluble in water but readily soluble in the solvents used in fly sprays and in Freons 11 and 12, used in aerosol bombs. It is more stable than pyrethrum extract and is free from the Freon-insoluble material present in the natural product. Allethrin has been tested by pharmacologists and pronounced to be as safe as pyrethrum to man; pyrethrum is regarded as the least objectional of all insecticides in toxicity to people. Its many desirable properties should mean a wide use of allethrin in aerosol bombs, fly sprays, and agricultural insecticides. The development of allethrin is a vindication of the thesis that it is possible to develop synthetic insecticides that rival the constituents of insecticidal plants, but this achievement is possible only when the structure of the plant insecticide is known.

Another insecticide of plant origin is scabrin, a constituent of the root of Heliopsis scabra. An account of the work leading to the discovery of this toxicant illustrates the method of developing new insecticidal chemicals through research on insecticidal plants.

In 1943 the division of insecticide investigations of the Bureau of Entomology and Plant Quarantine received from Mexico City the roots of a plant reported to be used by Mexicans as an insecticide. The plant was incorrectly labeled Erigeron affinis, but Department botanists later identified it as Heliopsis longipes. The active principle was isolated and was identified as n-isobutyl-2, 6, 8-decatrienamide. Three other species of the genus Heliopsis were collected in several parts of the United States and tested for insecticidal value. Laboratory tests disclosed that all the species, particularly their roots, were toxic to house flies.

From the most toxic of the species, Heliopsis scabra, there was isolated an amide C₂₂H₃₅NO, called scabrin, which proved to be nearly three times as toxic as the pyrethrins to house flies.

THE FIRST SYNTHETIC organic compounds used to kill insects were employed as fumigants. Carbon disulfide, made by the direct combination of carbon and sulfur, may be regarded as one of the simplest organic compounds. It was first used as an insecticide nearly 100 years ago in France. Paradichlorobenzene, originally a byproduct in the manufacture of chlorobenzene, was used as a substitute for naphthalene in combating clothes moths in Germany in 1911. Chloropicrin emulsified in water was proposed as an insecticide in Austria in 1907 and was tested as a fumigant in the United States about 1917.

In 1922 a systematic search for new fumigants was undertaken by Department chemists and entomologists with the object of finding substitutes for the dangerously inflammable carbon disulfide widely used for fumigating weevily grain. The search resulted in the discovery of several new fumigants, all synthetic organic compounds. Among those that have come into commercial use are ethylene dichloride; propylene dichloride; dichloroethyl ether; ethylene dibromide; the methyl, ethyl, and isopropyl esters of formic acid; and ethylene oxide. About 10 years later methyl bromide was first used as an insecticidal fumigant in France. D-D mixture (containing 1,3-dichloropropene, 1,2-dichloropropane, and other chlorides) has come into use in California and the Hawaiian Islands as a soil fumigant.

As I mentioned, the early synthetic work in the Department of Agriculture to develop new contact and stomach poisons for insects was based on nicotine as a model. Later the empirical method of approach was used synthetic organic compounds were tested irrespective of their structure. The work led to the development of phenothiazine as a pesticide. First it was tested against mosquito larvae and found to be highly toxic to them. It was then tested against a variety of agricultural pests and found to be amazingly effective in controlling codling moth on apple. More than 3 million pounds were used as an intestinal worm remedy in 1951.

The modern synthetic chlorinated organic insecticides DDT and benzene hexachloride were discovered in the same way that phenothiazine was discovered that is, by screening thousands of compounds of known structure but unknown toxic value. As yet too little is known of the relationship between the chemical structure of compounds and their insecticidal value to serve as a guide to the synthesis of new insecticides. Every candidate insecticide must be tested against the insect it is designed to control.

Often compounds closely related chemically differ widely in insecticidal value. As more compounds are tested, the chemist should be able to find a relationship between the chemical structure and insecticidal value of organic compounds. Eventually he will be able to synthesize a compound for the control of a specific insect pest. Meanwhile the study of the constituents of insecticidal plants will help enlarge our knowledge of how chemical structure affects toxicity.

R. C. ROARK is in charge of the division of insecticide investigations, Bureau of Entomology and Plant Quarantine. He has been engaged in research on insecticides since 1910. He is a native of Kentucky and holds degrees from the University of Cincinnati, University of Illinois, and George Washington University. In 1948 his division received an award for Distinguished Service from the Secretary of Agriculture for chemical research that discovered new insecticidal chemicals, new means of increasing the usefulness of insecticides, new methods of chemical analysis, and new ways of applying insecticides.