Synthesis and Chemistry of Agrochemicals III - ACS Publications

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Progress in a Time of Change 1

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Don R. Baker , Joseph G. Fenyes , and James J . Steffens 1

ICI Americas Inc., 1200 South 47th Street, Richmond, CA 94804 Buckman Laboratories International, Inc., 1256 North McLean Boulevard, Memphis, TN 38108 E. I. du Pont de Nemours and Company, Stine-Haskell Research Center, Newark, D E 19714

Downloaded by WASHINGTON UNIV ST LOUIS on October 10, 2014 | http://pubs.acs.org Publication Date: September 22, 1992 | doi: 10.1021/bk-1992-0504.ch001

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Agrochemicals continue to be the prime method for controlling insects, plant diseases, and weeds throughout the world and will continue as such for the foreseeable future. The increasing world population will require increased crop production and this will require the use of new environmentally safe and efficacious agrochemicals. Increasing costs of registration and re-registration are causing organizations to reevaluate their products and to discontinue those which are less profitable or have safety difficulties. Increasing pressures for greater product safety provide opportunities for new materials which are safer and more effective. Increasing knowledge about vital enzyme structures are providing greater understanding of interactions with control agents. This is being used in the design of new materials for agriculture. Resistance to agrochemicals by plants, insects, fungi, etc. continues to be a challenge to scientists. More is being learned about the molecular causes of this resistance and in the case of plants this is being used to prepare crop plants which are resistant to certain herbicides. These forces and how they present challenges for those working in the development of new agrochemicals are discussed in this chapter.

A chemist, like a painter or poet, is a maker of concepts. If these concepts are more permanent than theirs, it is because they are made with ideas. Ideas are the core of the chemist's creation. No discussion here can be more than a reflection of each individual undertaking. Moreover, only by studying how the road was traveled in the past can we gain an understanding of the future. The case histories we present here, commercially successful or not, provide that insight into that process which lies behind that creative leap from the old to the new. These considerations have inspired our previous volumes on this subject (7,2) and our ongoing ACS Agrochemicals Division Symposium series on which these volumes are based.

0097-6156/92/0504-O001S06.00/0 © 1992 American Chemical Society In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS III

We seem to be always in a period of change. However, only with change is progress possible. Concern for man himself and his fate must be the chief interest of all technical endeavors. The solutions to these unsolved problems coming from the creations of our minds must be a blessing to mankind and not a curse. The memory of the Silent Spring should be a reminder of our responsibility to future generations.


The Environment for New Agrochemicals In our lifetime we have seen a tremendous change in how science is perceived in the community (5). In the middle decades of the twentieth century science was a major vitality in our society. Scientists ranked high in our community and what they said was believed. Scientific knowledge expanded at a tremendous rate. The world's problems were finding solution through the application of scientific principles. This knowledge was making life easier and better than ever before for many groups in the industrialized world. Even in the developing nations, science in the form of medicine and agriculture was steadily increasing the life span. Hunger was being conquered. Everyone had a conviction that even the most difficult problems were solvable. This was the time of the start of the space and electronic age. For the average person there was more and more time to enjoy life. Still the same business goes on today, however, many do not have that confidence and conviction that we will continue to find solutions to the world's problems. Today the scientist has lost that stature that he once enjoyed. At the same time various groups in society have developed which are poorly informed about a variety of technical issues. Major decisions are often not made according to rational principles, but by vague intuition or political expediency. The basis of our society is an informed electorate. And with the vast expansion of knowledge most of society today is very poorly informed. To many, the scientist appears to be the foe of both nature and mankind. This view (5) is fostered by a media portrayal of everyone being opposed to anything nuclear, chemical or genetically engineered. Any chemical, no matter how safe, is labeled as toxic. If it is not natural it is somehow bad. The media seems to be asking for a risk free society which is just not possible. Risk versus Benefit Mankind has always been faced with a changing variety of risks. Science and technology have contributed toward the reduction of many of the historic major risks. Modern medicine has minimized many of the old health risks. Life expectancy has greatly increased to the point that aging processes are now the major cause of death. Counteracting the effects of aging is the new medical challenge. Modern transportation has made mankind much more mobile. However, the increase in speed has generated a variety of new risks. Technology associated with warfare has brought its own group of risks. Relations between nations are now much more critical for an increasing variety of reasons. There is an expanding list of economic and social risks. The steadily increasing population creates another group of risks. As society becomes more and more complex and interdependent, new risks and

In Synthesis and Chemistry of Agrochemicals III; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1992.


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problems are created. The benefits of modern civilization are many, however, this has created its own challenges for the future. Increasingly, society seems to be unwilling to accept many of these new risks, however small, even if the benefit is great. With this seems to come an ever increasing resistance to change. The media has fostered a disproportionate awareness of risks in those areas that create headlines. As an example, if an airliner crashes and kills 100 people, within a few hours most of the world has heard about it. This increased public awareness has contributed toward making air travel by far the safest form of transportation in terms of deaths per mile traveled. The death of a single individual on the highways receives almost no publicity unless the death is unusual for other reasons. And yet there are over 100 deaths each day on the U. S. highways without any apparent recognition. Everyone has heard about Chernobyl and the disaster resulting from that nuclear power plant. However, nuclear power is still the safest form of electric power generation in terms of deaths or injury per megawatt of electric power generated. But what does the public think about the risks of nuclear power? The politicians of the world in general lean in the direction to which most of their constituencies belong. In the area of risk versus benefit the public is willing to accept large risks in certain areas, and in other areas there is great public reaction to very small risks. In general where the risk involves life style choices much greater risk is accepted by the public. The public knows that hundreds of thousands die each year due to smoking but does very little about it. Alcohol is almost as bad and even less is done by the public. However, in the case of agrochemical food contamination, there is public concern for a risk that is relatively minor. Only relatively recently has the public's attention been focused on the influence of diet and exercise on long term health and well being. This food risk (4) is far greater than from agrochemical contamination of our food. The agrochemical industry responds to these increasing public demands for risk free materials by developing products that meet or exceed these requirements. However, the costs are great to discover and develop these new alternative products. Because of these increased costs in registration and re-registration, only those superior products which are expected to have large markets have sufficient potential for profit to warrant the costs necessary for their development. In the light of these increased costs in the registration and re-registration of products, many organizations are dropping the registrations on those materials that are less profitable. For farmers growing so-called minor crops, this usually means that there are fewer and fewer materials that are available and registered for use on these crops. In any risk benefit analysis dealing with these major issues of society such as nuclear power, genetic manipulation, and use of agrochemicals the question becomes "What is the acceptable risk?" In the light of other risks that everyone faces each day, the risks inherent with agrochemicals must be evaluated (4-7). As an example, consider the risk of cancer which is many times greater when eating broiled meat once a week as compared to eating an apple each week with a certain pesticide residue. What level of risk is perceived as acceptable?


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Agrochemical Safety In our previous volume we referred to the changing picture concerned with agrochemical safety. Earlier we have discussed risk-benefit as it relates to development of new products. This situation has come about by the changing standards; new laws and regulations at both the federal and state level. Even local governments are making their own regulations. These new laws and regulations have greatly increased the costs associated with the registration and manufacture of agrochemicals in the U. S. Manufacturers are forced to consider which products to support in light of the time and effort needed for continued registration of the product. Some new tests cost millions of dollars for just one environmental investigation. Only those products worthy of such costs continue to be registered. For the development of new materials these new environmental requirements such as leaching, soil persistence, volatility, and soil surface loss are important considerations. These structure-environmental fate and structure-toxicity relationships now enter very early in the development of new products. Modes of action that are peculiar to a pest are the major choice for materials which are safe from a toxicity standpoint. The prime targets are those systems which require small amounts of compounds so as to reduce the environmental impact on other systems. The cause of these increasing regulatory expenses is the public perception of a suspected problem. Is our food safe? Is the environment safe? Education is clearly needed so that the public understands just what the food and environmental risks are and can put them into perspective. The agrochemical industry needs to abandon its traditional reserve and put safety issues to the public in a form that can be understood. Resistance Pest resistance to chemicals has long been known. No class of agrochemical is unaffected. More and more resistance is coming to be understood (8,9), even - in some cases — its biochemical and molecular genetic basis. Single site compounds which interact with an enzyme noncompetitively, or uncompetitively with respect to substrate are potentially very troublesome, since a resistant species may be as fit as the susceptible form (10). A similar concern applies to forms which owe their resistance to enhanced metabolism (11,12). On the other hand, evidence has shown that, at least with Photosystem II herbicides, strains resistant by virtue of mutation at the site of binding of competitive inhibitors may be less fit in the environment in the absence of selection pressure (13). Compounds, which have as their mode of action an effect at multiple sites in the organism, develop resistance much more slowly. The major problem with this type compound is the fact that it may also effect sites in non-target species and there is then the potential for toxicology problems. Historically, most of the broad spectrum foliar fungicides were types which effect multiple sites in the fungi. Resistance is slow to develop for these materials. However, most of these compounds have toxicology problems of one type or another. Resistance management strategies are evolving to accommodate these various types.


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This knowledge about the molecular changes occurring in resistant organisms is an aid to the molecular biologists to develop crop plants which are resistant to a particular herbicide. (14,15)


Discovery Designs Making new compounds is at the heart of the discovery process for the agricultural chemist. In our last volume we describe the four basic approaches for compound design. These approaches have changed little in the intervening time. The approach involving the synthesis of enzyme target site directed inhibitors inhibitors has yet to yield a commercial success in agricultural chemistry, although several classes of potent herbicides have been shown after the fact to be target site directed (16). In spite of this lack of commercial success, we can nevertheless be encouraged by a growing number of comparable successes in the field of pharmaceutical chemistry (17), and thus inhibitors of specific enzymes are now receiving increasing attention from crop protection chemists (18). The chapter by Basarab et al. in this volume discusses some recent progress in designing inhibitors of a fungal sterol reductase. The chapter by Yamaki et al. is an example of an effort to better understand an important enzyme, and what is involved in enzyme binding in order to design more effective control agents of potential agrochemical utility. The number of cases in which natural products have provided leads to commercially successful crop protection chemicals have, in the past, been few in number but significant in scope ~ most notably the development of modern synthetic pyrethroids from pyrethrin and more recently the avermectin family of compounds. This use of natural products as models appears to be gaining momentum as numerous leads of biological origin are uncovered (19,20), and several papers in this volume attest to the success of this approach. Conclusions We continue to be optimistic about the future of agricultural chemistry. With the resistance problem in all areas of interest there is the continuing need to find highly active materials which also control resistant species. Understanding the molecular biology of resistant species offers the hope of devising materials which overcome the resistance problem. Also, the search goes on for new biological systems which can be affected at low levels by control compounds. Environmental concerns too are creating the need for new materials which have little environmental impact. This is adding a new dimension to what is needed for an acceptable profitable new material. As these chapters show, the search has truly become international. Agrochemistry continues to attract creative chemists to the adventure so necessary to our civilization.

Acknowledgments We express our appreciation to the ACS Agrochemical Division Executive Committee and Program Committee for their continued support of our efforts for the Symposium Series which forms the basis for this book. Also we are grateful for the ACS Books


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Department for their timely publication of the efforts resulting from these symposia. Particularly thanks are due Anne Wilson of ACS Books for her help throughout the whole editorial process. And above all, we express our thanks to those scientists the world over who have generously shared their experiences with the agricultural community in this volume.


Literature Cited 1. Synthesis and Chemistry of Agrochemicals; Baker, D . R.; Fenyes, J. G . ; Moberg, W . K . ; Cross, B . , Eds.; ACS Symposium Series No. 355; American Chemical Society: Washington, D C , 1987. 2. Synthesis and Chemistry of Agrochemicals II; Baker, D . R.; Fenyes, J. G . ; Moberg, W . K., Eds.; ACS Symposium Series No. 443; American Chemical Society: Washington, D C , 1991. 3. Mohr, H . In Pesticide Chemistry: Advances in International Research, Development, and Legislation; Proceedings of the Seventh International Congress of Pesticide Chemistry (IUPAC), Hamburg 1990; Frehse, H., Ed.; V C H Publisher Inc., New York, 1991; pp 21-33. 4. Ames, B. N . ; Magaw, R.; Gold, L . S.; Science 1987, 236, 271-280. 5. LeBaron, H . M. Weed Technology 1990, 4, 671-689. 6. Bidinotto, R. J. Readers Digest October 1990, 53-58. 7. Brookes, W . T . The High Costs of "Political Science." American Industrial Health Council, 1991 Annual Meeting, December 5, 1991, A N A Hotel, Washington D C . 8. Managing Resistance to Agrochemicals; Green, M . B., LeBaron, H . M., Moberg, W. K . , Eds.; A C S Symposium Series No. 421;American Chemical Society: Washington, D C , 1990. 9. Herbicide Resistance in Weeds and Crops; Caseley, J. C.; Cussans, G . W . ; Atkin, R. K . , Eds.; Long Ashton International Symposium; ButterworthHeineman: Oxford, 1991. 10. Schloss, J. V . In Target Sites for Herbicide Action; Boeger, P.; Sandmann, G., Eds.; C R C Press: Boca Raton, 1989, pp 221-223. 11. Brattsten, L . B. In Managing Resistance to Agrochemicals; Green, M . B . ; LeBaron, H . M.; Moberg, W. K . , Eds.; ACS Symposium Series No. 421; American Chemical Society: Washington, D C , pp 42-60. 12. Powles, S. B . ; Holtum, J. A . M.; Matthews, J. M.; Liljegren, D . R. In Managing Resistance to Agrochemicals; M . B. Green, LeBaron, H . M.; Moberg, W . K . , Eds.; ACS Symposium Series No. 421; American Chemical Society: Washington, D C , pp 394-406. 13. Holt, J. S. In Managing Resistance to Agrochemicals; Green, M . B.; LeBaron, H . M . ; Moberg, W . K., Eds.; ACS Symposium Series No. 421; American Chemical Society: Washington, D C , pp 419-429. 14. Mazur, B. J.; Falco, S. C . Ann. Rev. Plant Physiol. Plant Mol. Biol. 1989, 40, 441. 15. Stalker, D . M. In Target Sites for Herbicide Action; Boeger, P.; Sandmann, G., Eds.; C R C Press: Boca Raton, 1989, pp 147-164.



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16. Schloss, J. V . In Target Sites for Herbicide Action; Boeger, P.; Sandmann, G., Eds.; C R C Press: Boca Raton, 1989, pp 165-245. 17. Design of Enzyme Inhibitors as Drugs; Sandler, M.; Smith, H . J., Eds.; Oxford University Press: Oxford, 1989. 18. Prospects for Amino Acid Biosynthesis Inhibitors in Crop Protection and Pharmaceutical Chemistry; Copping, L . G . ; Dalziel, J . ; Dodge, A . D . , Eds.; B C P C Monograph No. 42; British Crop Protection Council: Farnham, Surrey, U K , 1989. 19. Boeger, P. In Target Sites for Herbicide Action; Boeger, P.; Sandmann, G., Eds.; C R C Press: Boca Raton, 1989, pp 247-282. 20. Cremlyn, R. J. Agrochemicals. Preparation and Mode of Action; John Wiley & Sons: Chichester, U K , 1991, pp 53-78. RECEIVED May 13, 1992


Synthesis and Chemistry of Agrochemicals III - ACS Publications

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