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Opportunities in Chemistry: Today and Tomorrow (1987)

Chapter: III. Human Needs Through Chemistry

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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Suggested Citation:"III. Human Needs Through Chemistry." National Research Council. 1987. Opportunities in Chemistry: Today and Tomorrow. Washington, DC: The National Academies Press. doi: 10.17226/1884.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

CHAPTER III Human Needs Through Chemistry In this chapter, we will see how chem- istry is essential in our eternal struggle for survival, freedom from toil, and, finally, for comfort. All of the tangible human needs will be considered: food, energy, materials, health, products that raise the quality of life, and economic vitality. We will begin with the most fundamental of these needs, adequate food supply for an ever-increasing world population. 2

1 Whipping a Wicked Weed The plant Stnga asiatica is one of the most devastating destroyers of grain crops in the world. This wicked weed restricts the food supply of more than 400 million people in Asia and Africa. It is a parasite that nourishes itself by latching onto and draining the vitality of a nearby grain plant. The results are stunted grain, a meager harvest, and hungry people. Basic research on Striga asiatica by chemists and biologists has revealed one of the plant world's incredible host-parasite adaptations. The parasite seed lies in wait until it detects the proximity of the host plant by using an uncanny chemical radar. ED ~0 The give-away is provided by specific chemical compounds exuded by the host.~` Striga asiatica can recognize the exuded compounds and use them to trigger its own growth cycle. Then the parasite has an independent growth period of 4 days, ding which it must locate the nearby host. Researchers trying to solve the mystery of this recognition system faced forrn~dable obstacles; they were seeking unknown, complex molecules produced only in tiny amounts. But, by extending the sensitivity of the most modern instruments, chemists have been able to deduce the chemical structures of these host-recognition substances, even though the agricultural scientist could accumulate the active chemicals in amounts no larger than a few bits of dust (a few micrograms). One method used, nuclear magnetic resonance (NMR), depends upon the fact that the nuclei of many atoms have magnetic fields that respond measurably to the presence of other such nuclei nearby. Thus precise NMR measurements reveal molecular geometries, even of ornate molecules. A second, equally sophisticated approach is high-resoluiion mass a/ (:JA IT spectometry. In a high vacuum, molecules are given an electric charge, then acceler- ated with a known energy. By measuring the velocities at which these molecules and fragments from them are traveling (or their curved paths in magnetic fields), chemists can measure the masses and decide the atomic groupings present. These He critical clues to the molecular identities. Now, the complex host-recogli~tion (xenogistic) substances have been identified and their detailed structures are known. With this information in hand, we may be able to beat this wicked weed at its own game. Chemists can now synthesize the substances and give agricultural scientists enough material for field tests designed to tnck the parasite into begging its today growth cycle. It will die out never having found its host. A few days later, grain can be planted safely. With this success for guidance, similar host-parasite relationships are being sought and foun~here In the United States. In addition to grains, bean crops have similar parasite enemies. Thus in collaboration with agricultural and biological scientists, chemists play a crucial role in our efforts to increase the world's food supply and eliminate hunger. ~ 4~ HO ~ At. ~

III-A. MORE FOOD IlI-A. More Food Agriculture, discovered 12,000 years ago, was the beginning of man's attempt to enhance survival by increasing the food supply. The human population at that time was about 15 million, but agriculture helped it rise to 250 million 2,000 years ago. By 1650, it had doubled to 500 million. But then it took only 200 years, until 1850, for the world population to double again, to one billion. Eighty years later, in 1930, the 2 billion level was passed. The acceleration has not abated: by 1985, the number of humans to be fed had reached 5 billion. If the growth were to continue at the 1985 level of 2 percent per year, the world population in 2020 would be about 10 billion. The rate of natural increase in population seems to be slowing worldwide (Table IlI-A-1), with the industnal countries adding only 80 million up to the year 2000. This is not the case for Africa, however, where population Table III-A-1 Population Growth-Rate, 1960-1980 growth has been accelerating at an alarming pace. In 1983, about 20 million hu- man beings starved to death- about 0.5 percent of the worId's population. Moreover, an additional 500 million were severely malnourished. Esti- mates indicate that by the end of the century, the number of severely undernourished people will reach 650 million. Plainly, one of the major and increasing problems facing the human race will be providing itself with adequate food and nourishment and, ultimately, to limit its own population growth. And whose problem is this? In the most elemental way, it is the problem of those who are hungry, those who are undernourished, those who are least able to change the course of events on more than a personal and momentary scale. But human hunger is also the problem, indeed, the responsibility, of those who can affect the course of events. Any attempt to fulfill that responsibility will surely need the options that can come from science, and among the sciences that can generate options, chemistry is seen to be one of the foremost. It can do so, first, by increasing food supply and, second, by providing safe methods by which individuals can limit population growth (see Section ITI-E). Food production cannot be significantly increased simply by cultivating new land. In most countries, the farmable land is already in use. In the heavily populated developing countries, expansion of cultivated areas requires huge capital investments and endangers the local ecology and wildlife. To increase the world food supply, we need improvements in food production; food preservation; conservation of soil nutnents, water, and fuel; and better use of solar energy through photosynthesis. Science is providing such improvements and chemistry is playing a central role by clarifying the actual chemistry involved in biological life cycles. We are developing an understanding at the molecular level of the factors Annual Percent Increase Area 1960-1965 1975-1980 World 1.99 1.81 Industrialized 1.19 0.67 Asia 2.06 1.31 Latin America 2.77 2.66 -4.0 Africa 2.49 2.91 ~ 16.9 SOURCE: W.P. Mauldi. 1980. Science 209:148-157. Percent Change -9.0 —43.7 -33.5 23

24 HUMAN NEEDS THROUGH CHEMISTRY that can be controlled to aid in the fight for more food. These factors include the hormones, pheromones, self-defense structures, and nutrients at work in our animal and plant food crops and also those of their natural enemies. We can best address these problems by using our present understanding of living systems. Pest control, for example, is an essential element of efficient food production. The emphasis in this area has been on the use of chemicals that attempt to eliminate insects or other pests by killing them (biocidal agents). This method risks upsetting nature's balance and introduces foreign substances into the envi- ronment. But we want to control insect pests, not exterminate them. Then we can avoid the potentially devastating ejects that may accompany profound ecological disturbances. By understanding the biochemistry of the organisms themselves, we can limit the impact of pests on food production in ways that can be used indefinitely without harmful effects on nature. Increasingly, such fundamental questions about biological systems have become questions about molecular struc- tures and chemical reactions. The following examples vividly display the key role chemistry plays in our current attempts to expand the world food supply. PLANT HORMONES AND GROWTH REGULATORS Growth regulators are chemical compounds that work in small concentrations to regulate the size, appearance, and shape of plants and animals. They include natural compounds produced within the organism and also some natural products that come from the environment. However, many similar compounds (analogs) that have been synthesized in the laboratory have been found to function as growth regulators. They are usually patterned after compounds found in nature, and some of them work just as effectively but without undesired side effects. The chemicals already present in plants or animals that exert regulatory actions are called hormones (e.g., growth hormones and sex hormones). A hormone can be said to be a chemical message sent between cells. The so-called plant hormones include growth substances (e.g., auxins, gibberellins, and cytokinins) and growth inhibitors (e.g., abscisic acid and ethylene) that seem to be structurally unrelated. These growth regulators are surely of immense social (and economic) importance for the worId's future because they influence every phase of plant development. Unfortunately, even though we know the structures of many plant growth regulators, we have little insight concerning the molecular basis for their activity. Since chemical interactions and reactions are involved, chemistry must play a central and indispensable role in the development of this insight. Below are some typical growth regulators. Notice the variety of molecular structures nature has developed for this function. By establishing the exact makeup of these structures, scientists have taken an essential step toward understanding and controlling the growth processes being regulated. Indole Acetic Acid (lAA), an Auxin (1) This compound was the first plant hormone to be characterized. It promotes plant growth, the rooting of cuttings, and the formation of fruit without fertilization.

III-A. MORE FOOD The synthesis of numerous lAA analogs led to the first commercial herbicide, 2,4-dichiorophenoxya- cetic acid, or 2,4-D. Gibberellic Acid (GA) (2) COOH H INDOLE ACETIC ACID (IAA) Promotes plant growth More than 65 compounds related to gibberedic acid have been characterized from plants and lower orga- n~sms since their landmark discovery in the fungus Gibberella fujikuroi. Commercially produced by large-scale cultures of this fungus, GA has extensive use in agnculture. Its applications range from trigger- ing formation of flower buds to growing seedless GIBBERELLIC ACID(GA) grapes and manufacturing malt in the beer industry. Triggers flowenng (I) o A ~ HO go OH COOH Cytokinins (3) The first cytokinin that was isolated is a compound that enhances cell division. Many analogs, including trans-zeatin, have since been isolated from DNA, transfer RNA, and other sources, and quite a number have been synthesized. They promote cell division, en- hance flowering and seed germination, and inhibit aging. H ~ CH2 OH C=C NH—CH2 ACHE Nit NO H Ethylene (4) This simple gas behaves like a hormone since it encourages fruit ripening, leaf-drop, and gelmina- lion, as well as growth of roots and seedlings. TRANS-ZEATIN Currently, a substance that generates ethylene Promotes seed germination above pH 4 is used widely as a fruit ripener. It is suggested that ethylene regulates the action of the growth hormones auxin, GA, and cytokinin. Strigol (5) The seeds of witchweed (Striga) lie in the soil for years and will only sprout when a particular chemical substance is released by the root of another plant. The weed then attaches itself to the root of the plant and lives off of it (as a parasite). The active substance stngol now has been isolated from the root area of the cotton plant and its structure identified. Now it has been synthesized. Strigol and its synthetic analogs are proving effective in removing these parasitic weeds by causing them to sprout and die off before a crop is planted. HA OH C=C H' 'H ETHYLENE Ripens fruit G2 Factor or Trigonelline (6) H o o STRIGOL Initiates weed growth This compound was discovered to be involved in one stage of a four-step cycle in plant cell reproduction. This stage, called G2 or "gapZ," is characterized by a 25 (2) (3) (4) (5)

26 (6) AN} CH3 HUMAN NEEDS THROUGH CHEMISTRY pause in growth activity. In isolating this compound, the "first leaves" or cotyledons of 15,000 garden pea seedlings provided r~~ only one quarter of a milligram of the G2 factor. This compound may be of particular importance because of a link between the G2 stage and the formation of root bumps (caDed nitrogen nodules) that have the power to convert elemental nitrogen from the soil to nitrate, which enriches the soil. TRIGONELLINE G2 FACTOR Influences nitrogen fixation Glycinoeclepin A (7) Nematodes are tiny worms that inflict huge damage on such crops as soybean and potato. The nematode eggs can rest unchanged in the soil for many years until H ' t~ (7) I It ~L~ COOH GLYCINOECLEPIN A Promotes worm egg hatching the root of a nearby host plant releases a substance that will promote hatching. The first such hatching COOH initiator was isolated and understood recently. Dur- ing a span of 17 years, a total area corresponding to 500 football fields was planted with soybeans to give 1.5 mg of the active substance, glycinoeclepin A, which was then shown to have the unusual structure (7~. Synthetic analogs may someday be applied agriculturally to force nematode eggs to hatch be- fore a crop is planted. Hundreds of natural plant products are now known to exert growth regulatory activity of one sort or another. These compounds represent a surprising range of structural types. Recognition of these structures is the first step toward their systematic use to increase the worId's food supply. We are only at the beginning of this important process. INSECT HORMONES AND GROWTH REGULATORS Insects that attack food-beanng plants reduce crop yields and, thereby, limit food supplies. The ability to understand and control these natural enemies provides another dimension by which the worId's food supply can be increased. The desire to reduce maInourishment and starvation around the globe is not incompatible with the strong element of environmental concern in our society. Pests can be controlled without being exterminated. Furthermore, with the sensitivity of detection meth- ods constantly improving, we can be assured that pest control can eventually be monitored to give ample early warning of unexpected side effects. Certainly, knowledge of the basic chemistry involved in the growth and increase of insect populations should be extended to provide options that may be needed to save human lives. Molting Hormones (MH) (~) Two types of hormones are directly involved in the development of insects (known as metamo~phosisKmolting hormones and juvenile hormones. The molt- ing hormones cause insects to shed their skins; an example is 20-hydroxyec~ysone

III-A. MORE POOD all. Nine milligrams of this complex substance (a steroid) were painstakingly extracted from one ton of silkworm pu- pae (a cocoon-like stage of in- sect development). It was also shown to be the active molting hormone of crustaceans, using two milligrams isolated from one ton of crayfish waste. It was discovered that molting hormones are widely distnb- HO OH "% ~ HO, ~ HO ~ O 20-HYDROXYECI)YSONE INSECT MOLTING H-ORMO-NE Causes insects to shed their skins POOH uted in plants and are probably produced as a defense against insects. Approximately 50 such steroids with insect MH activity have been identified. Juvenile Hormone (JH) (9) These hormones tend to keep insects in the juvenile state. The first OH (9) was identified using 0.3 milligrams of sample isolated from the butterfly T.epidoptera. Several OH analogs are now known, the most universal be- ing ~H-~l with three methyl groups on carbons 3, 7, and 11. Their importance has stimu- lated syntheses of thousands of related compounds, one of which is methoprene (101. This biodegradable compound imi- tates (mimics) the natural hor- mone, and therefore, insects will not readily become resistant to it; it is widely used to kill the larval stage of fleas, flies, and mosquitoes. Because it produced oversized larvae and pupae by prolonging the juvenile stage in silkworm, it has been widely used in China to increase silk production. (a) o JUVENILE HORMONE JH-I Prolongs juvenile state COOCH3 (9) H3 CO~COO ~ (10) METHOPRENE Biodegradable insecticide Anti-Juvenile Hormones These are substances, both natural and man-made, that somehow interfere with normal juvenile development. Systematic screening of plants has led to the identification of a number of compounds with anti- ~H activities. They are called precocenes (111. MeO BOW Some insects develop prematurely into tiny sterile ~ ~! -I (~) adults when they are treated with precocenes. Natural Defense Compounds: Antifeedants R:4W PRECOCENES R=H OR OCH3 Causes early maturation Plants produce and store a number of chemical substances used in defense against insects, bacteria, fungi, and viruses. One 27

28 HUMAN NEEDS THROUGH CHEMISTRY category of such defense substances is made up of chemical compounds that interfere with feeding. Many antifeedants have been characterized and show a wide variety of structure. Among them, azadirachtin (12) is probably the most potent antifeedant isolated to date. It is found in the seeds of the neem tree Azadirachta indica, which is known for its use in folk medicine. An amount of only 2 ng/cm2 (2 x 10-9 g/cm2) is enough to stop the desert locust from eating. Although (12) is far too complex for commercial synthesis, it might be possible to isolate it in useful amounts from cultivated trees. It is known that (12) is not poisonous because twigs from the neem tree have been commonly used for brushing teeth, its leaves are used as an antimalarial agent, and the fruit is a favorite food of birds. H ~ ~` MeOOC ~ (12) (13) (14) ,C—C- C—O CH3COO' J~.,O H MeOOC '` O \ OH AZADIRACHTIN Causes locusts to stop eating ECHO /\ WARBURGANAL Causes worms to stop feeding H Warburganal (13) seems to be specifically active against the African army worm. An insect kept for 30 minutes on corn leaves sprayed with war- burganal will permanently lose its ability to feed. The plant from which warburganal has been isolated is also commonly used as a spice in East Africa and therefore cannot be highly poisonous to humans. Practically all antifeedants are isolated from plants that are resistant to insect attack. While no antifeedant has yet been developed commercially, they offer an intriguing new avenue for control of insect pests. INSECT PHEROMONES Pheromones are chemical compounds released by organisms in order to trigger specific behaviors from other individuals of the same species. Pheromones function as communication signals in mating, alarm, territonal display, raiding, nest mate recognition, and marking. They have attracted great interest as a means to monitor and perhaps control pest insects. The first insect pheromone to be identified was from the female silkworm, and it was shown to be an unbranched Cue alcohol containing two double bonds, structure (14~. Since then, hundreds of pheromones have been identified, including those for most major agIicultura1 and forest pests. The isolation and full identification always involve handling extremely small quan- tities. Characterization of the four pheromones for cotton boll weevil pheromones (1SA-D) required over 4 million weevils and 215 pounds of waste material (feces). It took over 30 years to cianfy the structure that SILKWORM PHEROMONE First insect attractant identified

III-A. MORE FOOD stimulates mating in the American cockroach (16~. It required processing of 75,000 female cockroaches, which fi- nally resulted in 0.2 mg of one compour~d and 0.02 mg of an- other. Special methods for collect- ing and analyzing these com- pounds had to be developed to cope with the tiny quantities being investigated. It is now possible to extract a single fe- male moth gland, remove the intestines of a single beetle, AMERICAN COCKROACH PHEROMONE collect airborne pheromones Stimulates mating on glass wool, and analyze the pheromone from a single insect. One of the most important developments in this area is the electroantennogram technique, in which a single sensory unit from an olfactory antenna hair (used for smell by the insect) is used by researchers to detect the presence of these compounds. In addition to natural pheromones, chemists continue to synthesize artificial pheromones. Pheromone-baited traps have been used worldwide to monitor and survey pest populations. They assist in precise timing of insecticide application, thus reducing the amount of spray, and in insect trapping operations. For example, more than one million traps have been recently deployed for a period of 4 years in the Norwegian and Swedish forests, resulting in spruce bark beetle captures of 4 billion a year. Another commercial use is pheromone distribution throughout an area to confuse the insects. In 1982, pheromones were used on 130,000 acres of cotton to control pink bollworms, on 2,000 acres of artichokes to control plume moths, and on 6,000 acres of tomato to fight pinworms. Many questions about the basic chemistry and biology of pheromones remain to be answered. In the long run, it is clear that research on pheromones will yield useful benefits to agnculture and to health. B H. ~ ~ CHO OHC ~ C H H D ~CH2OH Am,, POOH ': (15) FOUR COTTON BOLL WEEVIL PHEROMONES A tiny bit is enough ~0 PESTICIDES Pesticides insecticides, herbicides, and fungicides are essential to our at- tempts to improve food and fiber production and to control insect-transmitted diseases in humans and livestock. Although major changes have recently occurred in pesticide use, environmental concerns make it increasingly difficult to introduce better pesticides into practical use in this country. The time and cost of developing a new compound currently run about 10 years and $30 million. Over 10,000 new compounds normally have to be synthesized and tested before a single acceptably safe and therefore marketable—pesticide is found. 29 (16)

30 HUMAN NEEDS THROUGH CHEMISTRY Insecticides Most potent insecticides discovered recently are modeled on natural products and act on the nervous system of insects. They include deltamethrin (17) and cartap (18), which are based on compounds found in chrysanthemum flow- ers and marine worms. Another compound still on the drawing board is pipercide (19), which includes an unusual cyclic di- ether unit. Chemical synthesis aIld testing programs have led to other novel structures that act as nerve poisons, inhibitors of chitin synthesis, and growth dis- ruptors (e.g., (20~. This new range and vanely of insecticide classes has helped immensely in the pest control battle. Br (17) (18) (19) o_, (20) (21) '0 B: O H CN OELTAMETHRIN An insecticide from chrysanthemum CH3. o 11 rSCNH2 NO CH3 ~ ~ SCNH2 D o CARTAP An insecticide from marine worms W ~~'~ O / PIPERCIDE A synthetic insecticide o HN I H l Cl F IF A growth disrupter \ / Fungicides ~~ - so BUTY LATE A weed control agent Herbicides These are substances that work to control weed pests. Highly novel structures de- rived through chemical synthe- sis have provided a variety of new herbicides in recent years. The butylates (21) work on the weed before it emerges from the soil, while atrazine (22) blocks photosynthesis by the weed. Still others interfere with seed germination or block formation of chlorophyll. Her- bicide resistance in weeds is an increasingly impor- tant problem. Genetic research currently directed toward improved crop tolerance suggests that we should transfer to the crop the gene that a weed has developed to make itself herbicide resistant. Major advances have been made in fungicides and antibiotics to control plant diseases caused by fungal and bacterial microorganisms. Some fungicides, such as triadimefon (23), work by slowing RNA synthesis. Other compounds block cell division or formation of cell walls, as in benomyl (241. New fungicides are needed

Ill-A. MORE FOOD that are not only highly selective of their targets but that may also disrupt more than one biological function so that resistance is less likely to develop. Special Techniques Specialized techniques, instrumentation, and fa- cilities are required to solve the multidisciplinary problems encountered in pesticide chemistry. The quantities of pesticide that can be used on crops are restncted so that crops will be free of hazardous leftover chemicals. The chemical by-products of pesticide use are also being evaluated for environ- mental impact and safety levels. Some hazardous impurities have been placed under strict control, such as tetrachIorodibenzodioxin ("dioxin,~' an im- purity in the herbicide 2,4,5-T) and nitrosamines (25) that occur in some other useful herbicides. The fact that pesticide research involves many scientific disciplines requires increased cooperation on a lo- cal, national, and international basis between indus- tnal, government, and university scientists. Research into pesticide chemistry can provide farmers and public health officials with safe and effective means to control pests. The research per- mits replacement of compounds that may be highly toxic or that have unfavorable long-tenn effects with better and environmentally safe pesticides. Because pest control problems are complex, but of extreme importance to society's well-being, long-term commit- ments to pesticide research are necessary and will be rewarding. c] NOUN 1NJ:N4NJ (22) 1 ! H H ATRAZINE Blocks photosynthesis Cl~o~ /N: \'N 0~' TRIADIMEFON '\ Slows fungus growth \ - NHCOCH ~ O—CNH'— BENOMYL Blocks fungus cell division DIPROPYLNITROS~ INK A herbicide impurity FIXATION OF NITROGEN AND PHOTOSYNTHESIS All of our food supply ultimately depends upon the growth of plants. Hence, a fundamental aspect of increasing the worId's food supply is to deepen our knowledge of plant chemistry. Because of special promise, two frontiers deserve special mention nitrogen fixation and photosynthesis. Nitrogen Fixation Nitrogen is a crucial element in the chemistry of all living systems and one that can limit food production. Since nitrogen is drawn from the soil as the plant grows, restoring nitrogen to the soil is a primary concern in agriculture. This concern accounts for the centunes-old practice of crop rotation, and it figures importantly in the choice and amounts of fertilizers used by farmers. Ironically, nitrogen is abundant—air is 80 percent nitrogen but it is present in the elemental form that is difficult to convert into useful compounds. Some plants know how to convert this 31 (23) (24) (25)

32 HUMAN NEEDS THROUGH CHEMISTRY elemental nitrogen into compounds they can use; we'd like to know just how they do it. Certain bacteria and algae are able to reduce nitrogen in the air to ammonia (nitrogen fixation), which is then converted into amino acids, proteins, and other nitrogenous compounds by plants. A rather diverse group of organisms has the capability of reducing nitrogen. A group of plants called legumes, which includes soybeans, clover, and alfalfa, has the capability of fixing nitrogen, with the assistance of bacteria that live on their roots. About 170 species of nonIegum~nous plants also fix nitrogen in this manner. Additional nitrogen fixers in nature are certain free-living bacteria and the blue-green algae. Nitrogen fixation involves an enzyme called nitrogenase which consists of two proteins. One protein (dinitrogenase) has a molecular weight of approximately 220,000. It contains 2 molybdenum atoms and about 32 atoms each of iron and reactive sulfur atoms. The other protein (dinitrogenase reductase) is made up of two identical subunits of 29,000 molecular weight, each containing 4 iron and 4 sulfur atoms. The sequence of events involving this enzyme complex in the reduction of elemental nitrogen to ammonia has been partially resolved by spectroscopic and purification techniques. Many cntical aspects are not yet understood. Research with other compounds that can also be reduced with these enzymes (e.g., acetylene, cyanide, hydrogen ion, and cyclopropane) may provide clues. In another direction, a number of novel metal organic compounds are showing promise as soluble catalysts for nitrogen fixation. On another active frontier, genetic studies are being applied to nitrogen fixation in plants. Recombinant DNA techniques might permit control of a plar~t's aging to extend its penod of nitrogen fixation or development of more efficient nitrogen- fixing strains of bacteria. A still more adventurous goal would be to transfer genetically the nitrogen fixation ability to food-bearing plants so that they become self-fertilizing. Photosynthesis Photosynthesis will be discussed in Section IlI-C in its relevance to the worId's energy supply. Since all of our food supply ultimately depends upon the growth of plants, we see that photosynthesis is also the key to the world's food supply. Photosynthesis is the process in nature by which green plants, algae, and photosynthetic bacteria use the energy from sunlight to stimulate chemical reac- tions in plants. These reactions convert carbon dioxide and water into organic building block molecules used by the plant cells which act as chemical factories that satisfy the plant needs. Since 10~ tons of carbon are annually converted into organic compounds by photosynthesis, determination of the mechanisms of pho- tosynthesis remains an important goal. Despite the rapid progress described in Section IlI-C, we are still far from duplicating natural photosynthesis in the laboratory. Nevertheless, chemists hope and expect to add to the world's food supply (as well as its energy supply) by developing an artificial photosynthetic system that will use solar energy to produce safe and abundant animal feedstocks.

ill-A. MORE FOOD FOOD FROM THE SEA Seventy-one percent of the Earth's surface is covered by water, so more than two-thirds of the solar energy potentially available for photosynthesis is absorbed in our oceans and seas. Yet, on a global scale, food from the waters has not been as important as that from terrestrial sources. Of the total of 3.3 billion tons of food har- vested in 1975, only 2 percent came from the ocean and in- land waters. Moreover, the harvest of fish, mollusks, and crustaceans has leveled off in recent years. Significant advances can be made, for example, in aquaculture technology and in the cultivation of algae, fish, and crustaceans. Knowledge of the chemistry of biological life cycles in marine species is an important requirement for such R () \ art /0 CH3 l ~C~ CH2 CH2 I_ ~ H MACH 3$ —~ INN If ,CH 2/ ~ - ,Mg,` me, 'N4' CH' ~—~C,H3 CH3 CH LOROPHYLL -an- ~n Absorbs sunlight to power photosynthesis advances. ISOLATION AND CHARACTERIZATION TECHNIQUES OF BIOACTIVE MOLECULES All of the advances discussed above are the more remarkable in view of the tiny amount of quite complex molecular compounds that are available for isolation and identification. While a successful purification can take years of work, it is a necessary first step in explaining a biological behavior on the basis of molecular structure. In addition, new and unique methods are being developed to determine precisely how much and what kind of a chemical has been isolated. In the case of biologically active molecules, these methods themselves are often biological in nature and are allowing chemists to work effectively with extremely small amounts of matenal, in the range of a thousandth of a millionth of a gram (i.e., a nanogram, 10~9 g). These separation and isolation techniques have been a major factor responsible for the launching of genetic engineering. A key process in genetic engineering is the ability to cut the DNA strand at specific sites. This cutting is called "cleavage." Discovering what the cleavage products are requires that they be separated in reasonable purity. Chromatography and electrophoresis techniques fill this need. None of the molecular structures displayed in this section could have been determined without the use of the most modern spectroscopic methods. The instrument with the widest impact has undoubtedly been nuclear magnetic reso- nance (NMR), which permits clarification of the local molecular neighborhood of individual atoms in a large molecule. 33

34 HU1J!AN NEEDS THROUGH CHEMISTRY Mass spectrometry has also been extremely effective, as measured by our ability to identify larger and larger molecules. Currently, solids with molecular weights up to 23,000 and without noticeable vapor pressure can be measured, and under favorable conditions, as little as lo-~3 g of the solid is needed. Computer-aided infrared and Raman spectroscopy show the vibrational motions that characterize certain chemical groupings. Diffractive methods (X-ray, neutron, electron micro- scope) can now clarify structures and shapes of nonrigid biopolymers, including flexible proteins. These powerful instruments have played a central role in the advances already mentioned in this section; they are essential to our continued progress in the science that underlies modern methods of food production. CONCLUSION Food supply and efficient use of energy are rapidly emerging as major concerns for the wodd's future. The theme '`more food" requires understanding of the basic principles of nature so that wise choices can be made. The traditional disciplinary classifications of biology, chemistry, biochemistry, physics, physiology, and med- icine are becoming less distinct; and cooperative effort among scientists with broad and overlapping interests is becoming common as research moves into topics dealing with the nature of life. In these cross-disciplinary collaborations, chemists are essential because we need to know the structures and shapes of molecules, their reactivities, and how to synthesize molecules of biological importance. Chemistry will play a central role in the search for options that will help us feed and limit the worId's population in the decades ahead. SUPPLEMENTARY READING Chemical & Engineering News "First Tunichrome Isolated and Character- ized" by R.J. Seltzer (C.&E.N. staid, vol. 63, pp. 67-69, Sept. 16, 1985. "Plants Natural Defenses May Be Key to Better Pesticides" (C.&E.N. staid, vol. 63, pp. 46-51, May 27, 1985. "Proteinaceous Pheromones Found in Gold- en Hamsters" by R.J. Seltzer (C.&E.N. stab, vol. 62, pp. 21-23, Oct. 22, 1984. "Pesticide Chemists Are Shifting Emphasis from Kill to Control" by W. Worthy (C.& E.N. staff), vol. 62, pp. 22-26, July 23, 1984. "Cutting Carbonyl Group Stabilizes Weed- killer" (C.&E.N. stag), vol. 62, pp. 26-27, Apr. 23, 1984. "Lemon Odor Helps Identify Male Moth Pheromone'' (C.&E.N. staff), vol. 61, pp. 34-36, Sept. 19, 1983. "Ultraviolet-Active Compounds Kill Insect Pests" (C.&E.N. staff), vol. 61, p. 334, Apr. 11, 1983. "Allelopathic Chemicals, Nature's Herbi- cides in Action" by A.R. Putnam, vol. 61, pp. 34~5, Apr. 4, 1983. "Herbicides" by H.E. Sanders (C.&E.N. staff), vol. 59, pp. 20-35, Aug. 3, 1981. "Photosynthesis and Plant Productivity" by I. Zelitch, vol. 57, pp. 28-48, Feb. 5, 1979.

Beauty Is Only Skin Deep Ever think of going into the gold-beck business? Just take a big hunk of gold and a hacksaw and you've got a good-looking brick with a nice heft. Unfortunately, one such brick and you're talking $140-150,000! There's no room for mark-up. But suppose you get an ordinary brick (wholesale in South Jersey, 17¢!) and just coat the surface with gold- the cost win come down a lot. And you'll have a beautiful brick well, at least "skin~eep." So how much would such a surface coating cost? For openers, put a one-atom-thick layer of gold atoms over the entire surface of the beck. Let's see, 2 inches by 4 inches by ~ inches gold at $320 an ounce one atom thick that~ll be . . . 0.3¢ worth of gold. Wow! There, we've got an attractive product at a total material cost of 17.3¢ (not including packaging). That's pretty impressive. It means that the outermost layer (the surface) of a $150,000 piece of gold involves so few atoms that they would cost less than a _ cent. Yet that miniscule fraction of atoms on the surface of a piece of metal RAu controls the chemistry of that piece. For instance, these surface atoms are the ones that determine whether the metal surface acts as a catalyst or not. And catalysts account, one way or another, for about 20 percent of our gross national product. So what is a catalyst? It's a chemical substance that speeds up a chemical reaction without itself getting into the act (i.e., it is not consumed while doing its thing). A solid it, ,,, , I, ,; 1 ,, or= , .~_ I catalyst merely Ashes its surface as a meeting place tor gaseous molecules. For instance, when a molecule of methanol lands on a rhodium catalyst surface, it usually sticks for a while (becomes adsorbed). Now, if a carbon monoxide molecule happens to arrive, zingo, it reacts with the adsorbed methanol molecule and they leave the surface as acetic acid. When methanol and carbon monoxide meet in the gas phase, they won't even give each other the time of day. But because of the special environment provided by that thin layer of surface atoms on the rhodium catalyst, methanol and carbon monoxide react so rapidly that 500,000 tons of commercial acetic acid are made every year this way! This kind of speed-up might be anywere from a thousand- fold to a million-fold when things are working. Because of such successes, chemists care a lot about how these catalytic gold bricks do their job. What actually happens to that thin layer of adsorbed molecules as they come and go on a catalytic metal surface? Unfortunately, that's where the skin-deep principle works against us. If there isn't much on that surface, there isn't much to see. But nowadays, we have several powerful instruments with which we can learn about the special properties of the skin of a metal. These instruments also let us watch molecules as they lodge on the surfaces of catalysts like platinum and rhodium and many others. We can see how the molecules are chemically changed by the metallic skin to make them more reactive when a suitable reaction partner comes along. So chemists are beginning to understand how to design these catalytic gold bricks to do whatever we want. Right now, every gallon of your gasoline began as a bunch of molecules sure to make your engine knock and then some chemist catalytically converted them into other molecules that make your engine punt. But now we are looking ahead to new energy feedstocks with more sulfur and metallic contaminants that will require much better catalysts so that we can keep your engine purring and the air clean at the same time. We'll do it by learning how those catalytic gold bricks work so we can tailor them to our needs. This is a case where skin-deep beauty really pays off! 3s

36 HUMAN NEEDS THROUGH CHEMISTRY IlI-B. New Processes A prime reason for wishing to understand and control chemical reactions is so that we can convert abundant substances into useful substances. When this can be done on an economically significant scale, the reaction (or sequence of reactions) is called a chemical process. Many employed chemists are engaged in perfecting existing chemical processes and developing new ones. Their success is reflected in the present vitality and strength of the U.S. chemical industry. The indus- try makes billions of pounds of chemicals at low cost, in high yield, and with minimum waste prod- ucts. For example, every year we produce 9.8 billion pounds of synthetic fibers (such as polyes- ters), 28 billion pounds of plastics (such as polyeth- ylene), and 4.4 billion pounds of synthetic rubber. To sense the magnitudes of these annual production figures, imagine 10 Astrodome-size football stadi- ums 9.8 billion pounds of polyester would fill up all 10! Our current position of world leadership in this wide-rang~ng industry can be attributed to our strength in the field of chemical catalysis. The major role of catalysis in industry is indicated by estimates that 20 percent of the gross national product Is generated through the use of catalytic processes. On the horizon, new catalysts will help us tap new energy sources (the subject of Section IlI-C). A catalyst is a substance that speeds up chemi- cal reactions without being consumed. Some reac- tions can be speeded up by a factor as large as 10 billion (10~°~. A selective catalyst can have the same dramatic effect but working on only one of many competing reactions. A stereoselective catalyst not only controls the end product, it also favors a particular molecular shape, often with remarkable effects on the physical properties (such as tensile strength, stiffness, or plasticity) and, for biologically active substances, on the potency. Catalysis can be subdivided according to the physical and chemical nature of the catalytic substance. · In heterogeneous catalysis, the catalyzed reaction occurs at the surface interface between a solid and either a gaseous or a liquid mixture of the reactants. · In homogeneous catalysis, reaction occurs either in a gas mixture or in liquid solution in which both catalyst and reactants are dissolved. · In electrocatalysis, reaction occurs at an electrode surface in contact with a solution but assisted by a flow of current. Thus, electrocatalysis is like heteroge- neous catalysis, but it adds the opportunity to put in or take out electrical energy. · In photocatalysis, reaction can take place at a solid surface (including electrode surfaces) or in liquid solution, but in these reactions energy encourage- $ 20 0 ~ , ~ ~ J __~ _ An' l J Lo an or C, g20 B E 10B Us O J -20B _ ~ + L or ~ CHEMICALS: SECOND LARGEST POSITIVE TRADE BALANCE

III-B. NEW PROCESSES ment is provided by absorbed light. · In enzyme catalysis, some characteristics of both heterogeneous and homo- geneous catalysis appear. Enzymes are large protein structures that provide a surface, or interface, upon which a dissolved reactant molecule can be held to await reaction In addition, the enzyme provides a suitable chemical environment that . . . . . . . . . . will catalyze the desired reaction when an appropriate partner amves. We discuss below aspects of each of these catalytic situations that are related to the development of new chemical processes. Then they will be revisited in Section IlI-C because of their importance in the development of new energy sources. HETEROGENEOUS CATALYSIS A heterogeneous catalyst is a solid prepared with an extremely large surface area (~-500 m2/gram) upon which a chemical reaction can occur. To appreciate the magnitude of this surface area, consider that a one-gram cube of platinum catalyst would be 4 mm high and it would have a surface area of 1.0 cm2. If that one-gram cube were sliced into eight equal cubes, the surface area would be doubled. To reach an area per gram of 100 m2, this process would have to be continued until the one gram has been divided into 10~8 tiny cubes, each about 40 A on a side and containing only 2,750 platinum atoms. Table IlI-B-1 shows the fruitful commercial outcome of developments in TABLE lIl-B-1 New Processes Based on Heterogeneous Catalysis Feedstocks Catalyst Ethylene Silver, cesium chlo- ride salts Bismuth molybdates Product Used to Manufacture 1982 U.S. Production (metric tons)a b Ethylene oxide Polyesters, textiles, lubricants 2,300,000 Propylene, NH3, O2 Ethylene Propylene Acrylonitrile Chromium titanium Titanium, magne- . . slum OXlC es High-density polyethylene Polypropylene Plastics, fibers, resins 925,000 Molded products 2,200,000 Plastics, fibers, films 1,600,000 a Production by all processes, including the innovative process; U.S. Tariff Commission Report. b One metric ton = 1,000 kg. heterogeneous catalysis in recent years. The potential economic significance is displayed in the last column, the total U.S. production (in metric tons) by all processes. With the new measurement techniques of surface science, we can now begin to understand how such solid catalysts work. Because surface atoms have unused bonding capacity, they change the chemistry of molecules stuck on that surface. Hence, when two reactants A and B meet in this two-dimensional reaction zone, their chemistry can differ greatly from when they meet in solution or in the gas phase. To understand this different chemistry, we must know the molecular structures for A and B as they exist on the reactive catalyst surface. Fortunately, we now have laboratory 37

38 HUMAN NEEDS THROUGH CHEMISTRY ~£. ~.,`.~.~ 7x HOW DOES CARBON MONOX I DE BIND TO A METAL SURFACE? tools with which chemists can "see" what these molecular structures are. Then our knowledge of reactions in familiar settings can be applied and the door begins to open to understanding, control, and design of catalysts. Here are four examples of heterogeneous cataly- sis where the fruits of such understanding will have a major impact on new technologies that benefit our society. Molecular Sieve Synthesis and Catalysis Molecular sieves are natural or synthetic solids made of aluminum, silicon, and oxygen (aluminosil- icates). A special property of these solids is that they contain tiny holes or channels into which gaseous molecules can enter if they are not too large. Once caught inside such a channel, these molecules can undergo reactions that would require a much higher temperature outside. Thus, the sieve acts as a catalyst. Furthermore, the shape and size of the cavity both select which molecules can react and also limit the size of the product. This means that the sieve is a selective catalyst. They have been used with remarkable efficiencies both for the breakdown of crude of] into smaller, more combustible molecules ("cracking") and for converting methanol (from biological sources) into gasoline. Metal Catalysis It has long been known that extremely small metallic particles of certain elements can catalyze hydrocarbon conversions for fuels and catalyze ammonia synthesis from nitrogen for fertilizer production. These elements are from the middle of the Penodic Table; they include cobalt and nickel and elements below them: rhodium, palladium, and platinum. We have already noted that the catalyst particles may contain only a few thousand atoms. We need to know why these tiny particles are so effective and why these particular metals work while other, more abundant metals, do not. Unfortunately, many of these catalytically active metals are rare, and their ore deposits are not located in the United States: e.g., cobalt, manganese, nickel, rhodium, platinum, palladium, and ruthenium. When we understand why these metals work so well, we are on our way to finding more available substitutes. Among the candidates are metal oxides (including rust, iron oxide), carbides, sulfides, and nitndes. Conversion Catalysts We must find catalysts to convert abundant and cheap substances to more useful compounds. Thus, we would like to convert nitrogen to nitrates (for fertilizer use); coal to hydrocarbons (for fuels); and one-carbon compounds, like carbon monox- ide, carbon dioxide, methane, and methanol, to two-carbon compounds, like ethylene, ethanol, acetic acid, and ethylene glycol (for industnal feedstocks).

III-B. NEW PROCESSES Catalysts to Improve the Quality of Air and Water We have many environmental pollution problems that must and can be solved, the way the catalytic converter helped clean up automobile exhaust gases. Thus, we would like to have catalysts that remove sulfur oxides from the smokestacks of factories, purify water, and prevent acid rain. HOMOGENEOUS CATALYSIS Homogeneous catalysts act in the gas or liquid state in the absence of a surface. Important among these are the soluble catalysts that are active in a liquid solution. Often they are complex, metal-containing molecules whose structures serve to fine-tune reactivity and achieve highly selective end results. The largest industrial- scale process using homogeneous catalysis is the partial oxidation of para-xylene to terepEthalic acid, with U.S. production of 6.2 bil- lion pounds in 1981. The process uses salts of cobalt and manganese dissolved in acetic acid at 215°C as the catalyst system. Most of the product is then copolymerized with ethylene glycol to give us poly- ester clothing, tire cord, soda bottles, and a host of other useful articles. HUH 1 HE _ catalyst HUH Co, Mn salts PP/ I \H H The chemical industry in the United States has been repeatedly strengthened by the introduction of new processes based upon homogeneous catalysts. Para-xy~ene Table IlI-B-2 lists six such processes, whose 1982 production figures were valued at over one billion dollars. TABLE III-B-2 New Processes Based on Homogeneous Catalysis 39 7 °`c' H: AH IOI H:—H ,~C~ Terephthalic Acid U.S. PRODUCTION (1981), $2.3 BILLION! Start- 1982 U.S. · up Production Feedstocks Catalysta Product Used to Manufacture Date (metric tons)b Propylene, oxi- Move complexes Propylene oxide Polyurethanes (foams) 1969 303,000 dizer Polyesters (plastics) Methanol, CO [Rh(CO)2I2t Acetic acid Vinyl acetate (coatings) 1970 495,000 Polyvinyl alcohol Butadiene, HCN Ni(L~)4 Adiponitrile Nylon (fibers, plastics) 1971 220,000 a-Olefins RhH(CO)(L2)3 Aldehydes Plasticizers 1976 300,000-350,000 Lubricants Ethylene Ni(L3)2 a-Olefins Detergents 1977 150,000-200,000 CO, H2 (from [Rh(CO)2I2]- Acetic anhy- Cellulose acetate 1983 [225,000, Capacity] coal) dride (films) a L = Ligand, L' = Triaryl Phosphite, L2 = PPh3, L3 = 00CCH2PPh2, Ph = C6H5. b One metric ton = 1,000 kg. An important branch of homogeneous catalysis has developed from research in organometallic chemistry. For example, in the second reaction in Table IlI-B-2, rhodium dicarbony! diiodide catalyzes the commercial production of acetic acid

40 HUMAN NEEDS THROUGH CHEMISTRY from methanol and carbon monoxide. With this catalyst present, the reaction economically gives more than 99 percent preference for acetic acid over other products. Almost a billion pounds of acetic acid is so produced, a large part of which is used to manufacture such polymenc materials as viny! acetate coatings and polyvinyl alcohol polymers. Activation of Inert Molecules Several abundant substances are inviting as reaction feedstocks, including nitrogen, carbon monoxide, carbon dioxide, and methane. However, these are relatively inert molecules, so catalysts are needed to speed up their chemistry. Soluble organometallic compounds are showing promise here. For example, soluble compounds of molecular nitrogen, N2, with tungsten and molybdenum have been prepared that permit ammonia production under mild conditions. Addition- ally, carbon-hydrogen bonds in normally unreactive hydrocarbons like methane and ethane have been split by organorhodium, organorhenium, and organoindium complexes. Hope for the buildup of complex molecules from one-carbon mole- cules, such as carbon monoxide and carbon dioxide, is stimulated by recent demonstrations of carbon-carbon bond formation at metal centers bound in soluble metal-organic molecules. Synthesis of compounds with multiple bonds between carbon and metal atoms has been of special importance. These compounds catalyze the interconversion (metathesis) of venous ethylenes to make desired polymer starting matenals. Metal Cluster Chemistry An adventurous frontier of catalysis has been opened by the increasing capability of chemists to synthesize molecules built around several metal atoms bonded together. In size, these cluster compounds lie between the molecular- sized homogeneous catalysts and the particles of T L ~ ~~ . . ~ J L~rL Lip VAIL L A GOLD CLUSTER COMPOUND OU1K metal that are used in heterogeneous cata- lysts. It is intriguing that many of the metals that are most active as heterogeneous catalysts also form such cluster compounds (e.g., rhodium, plat- inum, osmium, ruthenium, and iridium). Now the chemistry of these elements can be studied as a function of cluster size. Are small clusters better catalysts than bulk metal? Can they improve on the action of metal-organic catalysts that contain L- LIGAND only one or two metal atoms? With our new preparative methods, we will be able to answer these questions. Many metal cluster compounds consist of several metal atoms bound to each other in the "core" of the molecule with carbon monoxide molecules chemically attached on the outside. These metal carbonyls have formulas MX(CO)Y' and x can be made very large. The worId's record as of this writing is a platinum compound with x = 38, Pt3~(CO)2-, which is actually approaching the smallest catalyst particle sizes that have been made from bulk

lll-B. NEW PROCESSES material. This closes the gap between molecular and bulk catalysts. At the same time, very low temperature techniques are revealing the structures and chemistry of small clusters containing only metal atoms ("naked clusters". These are of special interest because heterogeneous catalysts are presumed to consist only of metal atoms. Still other cluster compounds are called "cubanes." These are molecules built around a unit of four metal atoms and four sulfur atoms at the eight corners of a cube. Such "cubane" structures have been made for iron, nickel, tungsten, zinc, cobalt, manga- cyS-s _ nese, and chromium. The iron example, ferrodox- in, has been fourth to be the functional part of the iron proteins that catalyze electron-transfer reac- tions in biological systems. Here is a small cluster compound in use by nature as a biological enzyme. Stereoselective Catalysts S—Cys -F _ , ,/ ~ . ~ 7 ~ WFC IS Cys-S/ Many biological molecules can have either of two THE B CLOG CA ENZYME FERRODOX N. AN geometric structures, one being the mirror image of ~RO:-SU:FUR "CUBANE" STRUCTURE the other. These are called "chiral" structures. Generally, only one of these structures is functionally use- ful in the biological system. If a complex molecule has seven such chiral carbon atoms and a synthetic process produces all the mirror-image structures, there would be 27=128 struc- tures, 127 of which might have no activity or, worse, some un- desired effect. Thus, the ability to synthesize at every chiral center the desired structure with the desired geometry is essential. A catalyst that will do this is called a stereoselec- tive catalyst. An example is provided by c-dope, a particu- lar mirror-image structure of an amino acid that has revolu- tionized the treatment of Park- inson's disease. This molecule has been made using the ste- reoselective addition of hydro- gen to a carbon-carbon double bond. The catalyst that does this is a soluble rhodium phos- 41 _ <: CHIRAl RELATIONSHIPS ARE CRUCIAl TO BIOLOGICAL FUNCTION CH3 ~C\ car of H H CH 3 AH L- DORA TREATMENT FOR PARKINSON-S DISEASE REQUIRES THE CORRECT CHIRAL STRUCTURE

42 HUMAN NEEDS THROUGH CHEMISTRY phine compound that gives the correct structure in 96 percent yield. Stereospe- cific oxidations can also be carried out. The recent discovery of a titanium catalyst to add, in a specific geometry, an oxygen atom across a carbon-carbon double bond has lowered 10-fold the price of the synthetic sex attractant of the gypsy moth. The gypsy moths are ecstatic about this; there are commercial applications as well. PHOTO C ATALYSIS AND ELE C TRO CATALYSIS Significant advances have recently been made in controlling the chemistry that takes place at the surface boundaries between liquid solutions and electrochemical electrodes (electrocatalysis). In some applications, absorption of light by a semi- conductor electrode initiates the chemistry (photocatalysis). This rapidly moving field depends upon our knowledge of homogeneous catalysis, heterogeneous catalysis, and semiconductor behavior. Photocatalysis An electrochemical cell can be built with one or both electrodes made of semiconductor materials that absorb light. In such a cell, the light absorbed by the electrode can be used to promote catalytic oxidation-reduction chemistry at the electrode-solution interface. The same sort of chemistry can be induced in solutions containing small particle suspensions of semiconductor materials but now at the particle-solution interface. Such oxidation-reduction chemistry has signifi- cant scientific interest and, without doubt, practical importance as well. For example, photodestruction of toxic waste matenal, such as cyanide, has been demonstrated at titanium dioxide surfaces. A more popularized concept is that such photocatalytic chemistry, Unven by solar energy, could give a process for produc- ing massive amounts of hydrogen and oxygen from water. It is an interesting prospect: to convert from using the dwindling, polluting petroleum fuels to a renewable fuel hydrogen that burns to form water and that is made from water using energy from the sun. Electrocatalysis Even without light-initiated processes, electrode surfaces with catalytic activity offer new opportunities for chemical syntheses. Recent developments have shown that electrode surfaces can be chemically tailored to promote particular reactions. For example, this research area has benefited from techniques used by the semiconductor industry, such as deposition of chemical vapors on the electrode surface, by combining those techniques with imaginative synthetic chemical techniques for modifying surfaces. This is demonstrated by the group of electrocatalysts developed for use in making chlorine in chIor-alkali cells. One successful case is based upon a thin layer of ruthenium dioxide the catalyst~eposited on a common metal electrode. This electrocatalyst has dramatically improved energy efficiency and reduced cell maintenance in the chIor-alkali industry, an industry representing billions of dollars

III-B. NEW PROCESSES in sales. The savings are enormous because this crucial industry consumes up to 3 percent of all electrical energy produced in the United States. Chemistry at the Soli~iquid Interface Before the technological potentialities of any of the above can be fully realized, we must have a much better understanding of the chemistry going on at the semiconductor/liquid interface. Most of the extraordinary instrumentation so far developed for surface science studies can only be applied at solid/vacuum interfaces. We need similar capability at the solid/liquid boundary, and there is already reason for optimism. For example, when light is scattered by a molecule, it can leave behind energy to excite the vibrational motions of the molecule. Hence, the scattered light contains the "signature" of the molecule and gives us clues to its structure. This behavior, the Raman effect, has been found to be intensified a millionfold when the scattering molecule is adsorbed (held) on a silver metal surface. This intensification permits us to detect the tiny number of molecules at a solid/liquid interface. Other scattering methods that depend upon the very high power of laser light sources (e.g., "surface-enhanced harmonic generation") show that other such discoveries are to be expected. The possible gains from these areas are considerable. We would like to know how to catalyze multielectron transfer reactions at an electrode surface. That is the chemistry required, for example, to photogenerate a liquid fuel like methanol from carbon dioxide and water. Multielectron transfer catalytic electrodes for oxygen reduction in electrochemical cells would find a welcoming home in the fuel cell industry. It is also likely that research on semiconductor electrode surfaces will benefit the field of electronics. The integrated circuit technology based on the new material gallium-arsenide depends upon control of its surface chemistry. Al- ready, scientists concerned with design of the tiny chips used in computers are recognizing the importance of the chemistry involved. The crowded circuits on an electronic chip must be chemically etched with great precision and on a · . microscopic sca e. ARTIFICIAI`-ENZYME CATALYSIS A striking outcome of our expanding chemical knowledge has been the develop- ment or our ability to deal with molecular systems ot extreme complexity. Using such modern instrumentation as nuclear magnetic resonance, X-ray spectroscopy, and mass spectroscopy, we can now synthesize and control the structure of molecules that come close to the complexity of biological molecules. This control includes the ability to fix the molecular shape, even including the mirror-image properties so critical to biological function. One intriguing application of these capabilities is to combine them with our growing knowledge of catalysis in the synthesis of artificial enzymes. There are compelling reasons to do this. Without catalysts, many simple reactions are extremely slow under normal conditions. Raising the temperature speeds things up, but at risk of a variety of possible undesired outcomes such as acceleration ~ _ ~ 43

44 HUMAN NEEDS THROUGH CHEMISTRY of unwanted reactions, destruction of delicate products, and waste of energy. Unfortunately, natural enzymes do not exist for most of the chemical reactions in which we have interest. In the manufacture of polymers, synthetic fibers, medicines, and many industrial chemicals, few of the reactions used can be catalyzed by naturally occurring enzymes. Even where there are natural en- zymes, their properties are not ideal for chemical manufacture since they are proteins, sensitive substances that are easily broken down and destroyed. In industries that do use enzymes, major effort is devoted to modifying them to increase their stability. Controlled Molecular Topography and Designed Catalysts We have a pretty good idea of how enzymes work. Nature fashions a molecular surface shaped to recognize and bind to a specific reactant. This surface attracts the unique molecular type desired from a mixture and holds it in a distinct position that encourages reaction. When the reaction partner arrives, the scene is set for the desired reaction to take place in the desired geometry. Organic chemists who are trying to make artificial enzymes are making notable progress. Without special control, large molecules usually have convex outer surfaces (ball-like shapes). So a first step toward making shaped surfaces has been to learn to synthesize large molecules with concave surfaces and hollows. Cyclodextrins provide examples: they are shaped like a doughnut. The crown ethers, developed over the last 15 years, have a quite different surface topography. For instance, 18-crown-6 con- sists of 12 carbon atoms and 6 oxygen atoms evenly spaced in a cyclic arrangement. In the presence of potassium ions, this ether assumes a crown-like structure in which the 6 oxygen atoms point toward and bind a potassium ion. Lithium and sodium ions are too small, and rubidium ions Top View too large, to fit in the crown-shaped cavity; so this ether extracts the intermediate-sized potassium ions from a mixture. More complicated examples now exist. Chiral binaphthy! units can be coupled into cylindrical or egg-shaped cavities. With ben- zene rings, enforced cavities have been made with the shapes of bowls, pots, saucers, and vases. One Side View of the descriptive names for such compounds is cavitand~s. We are clearly moving toward the next step, which is to build into these shaped cavities a catalytic binding site. This will probably be a metal-organic compound already known to have catalytic activity in solution. The earliest successes are likely to be patterned after natural enzymes, but there is no doubt that, in time, artificial, enzyme-like catalysts will go beyond what we find in nature. Br Ll ~ ~ H B r~(()io;H .¢Br r - .. ~ --~.Y, my,, H - H Br H>:H CAVI TaNDS WHAT SHAPE DO YOU NEE D?

-B. NEW PROCESSES Biomimetic Enzymes A shortcut approach to improved catalysis is to pattern artificial enzymes closely after natural enzymes sometimes called "biom~metic chemistry." For example, biomimetics, or mimics, have been prepared for the enzymes that biological synthesize amino acids. Artificial enzymes that structurally resemble such natural enzymes as vitamin B6 have shown good selectivity and even the correct m~rror-image preferences in the product. Mimics have been prepared for several of the common enzymes involved in the digestion of proteins, and substances that catalyze the cleavage of RNA have been synthesized based upon the catalytic groups found in the enzyme ribonuclease. Mimics have also been synthesized that imitate the class of enzymes called cytochromes P-450, which catalyze many bio- log~cal oxidations, and another that imitates the oxy- gen cattier hemoglobin. The United States is a forerunner in this field, and the Japanese have specifically targeted biomimetic H~CH=CH2 HC~CH Ho)CCH2C: cH_cH2 H~CH2CH2 CH3 C 1- HEMIN: THE ACTIVE PART OF HEMOGLOBI N chemistry as an area of special opportunity. Such study is pointed toward a logical approach to catalyst design, an area ripe for development. CONCLUSION A significant share of our economy is built upon the chemical industry. The long-range health of this critical industry win depend upon our ability to develop new processes that increase energy and cost efficiency, and create new products for new markets, all the while strengthening our protection of the environment. Today's basic research in all aspects of catalysis will provide the source of such creative invention. It will also produce young scientists working at the frontiers of knowledge with the state-of-the-art instrumental skills needed to recognize and take advantage of the rich potentialities. SUPPLEMENTARY READING Chemical & Engineering News '~Stereospecific Routes to Silyl Enol Ethers" by S. Stinson (C.& E.N. staff), vol. 63, p. 22, July 15, 1985. "New Dow Acrylate Ester Processes Denve From Cat Efforts" by J. Haggin (C.& E.N. staff), vol. 63, pp. 25-26, Feb. 4, 1985. "Rice University Chemists Study Reactivity on Metal Clusters" (C.& E.N. sew, vol. 63, pp. 51-52, Jan. 21, 1985. "Catalysts Selectively Activate C-H, C-C Bonds" (C.& E.N. staff), vol. 63, pp. 53- 54, Jan. 14, 1985. "Organic Electrosynthesis" by R. Jannso, 45 vol. 62, pp. 43-58, Nov. 19, 1984. "Flame Synthesis of Fine Particles" by G.D. Ulrich, vol. 62, pp. 22-30, Aug. 6, 1984. "Low-Severity Route to Acrylic Acid Devel- oped" (C.& E.N. stab, vol. 62, p. 32, Apr. 30, 1984. "Dow Continues Fischer-Tropsch Develop- ment" by J. Haggin (C.& E.N. stab). vol. 62, pp. 24-25, Mar. 5, 1984. ,, "Chemists Detail Catalysis Work with C1 Systems" by J. Haggin (C.& E.N. stag), vol. 62, pp. 21-22, Feb. 27, 1984. "Surface Modification Gives Selectivity to

46 Poisoned Catalysts" (C.& E.N. staff), vol. 61, pp. 24-25, Sept. 5, 1983. -Aluminophosphates Broaden Shape Selec- tive Catalyst Types" by J. Haggin (C.& E.~. staff), vol. 61, pp. 36-37, June 20, 1983. "Shape Selectivity Key to Designed Cata- lysts" by J. Haggin (C.& E.N. staff), vol. 60, pp. 9-15, Dec. 13, 1982. "Metal Clusters: Bridges Between Molecu- lar and Solid State Chemistry" by E.L. HUMAN NEEDS THROUGH CHEMISTRY Muetterties, vol. 60, pp. 28-39, Aug. 30, 1982. Science "Enhanced Ethylene alla Ethane Production With Free-Radical Cracking Catalysts" by J.H. Kolts and G.A. Delger, vol. 232, pp. 744-746, May, 9, 1986. "The Zeolite Cage Structure'' by J.M. Newsom, vol. 231, pp. 1093-1099, Mar. 7, 1986.

A Lithium-Powered Heart The cardiac pacemaker is a modern miracle of science that many of us take for granted but not a person who owns one! These pacemakers operate on battery power, and the demands put on the tiny batteries that generate it are awesome! They must start the human machine every morning without fail, and the hyenas lights and radio are running all the time. Yet many, many people are adding healthy years to life by betting on the chemical reactions that occur In these batteries to generate~ay in, day out the electnc current that drives their pacemakers. These batteries have special requirements because they must be implanted in a human body. They must be rugged and leakproof, have long life and minimal weight, and, of course, they must be nontoxic. The first batteries used in pacemakers had a lifespan of only 2 years, and the periodic operations required for replacement meant additional risk and stress for the patient. Chemists began to tackle this problem, and research efforts in electrochemistry uncovered lithium metal, a new ingredient with the potential to give long life to battenes. Unfortunately, lithium is highly reactive it burns in air and reacts with water to produce flammable hydrogen gas. If lithium were to be used, it would be necessary to discover new, nonaque- ous electrolyte systems. Electrolytes are substances that dissolve in water to form conducting solutions. They dissolve to produce ions, panicles carrying electrical charge. The movement of these charges carries the current as the battery's chemistry releases its stored energy. Conventional batteries that draw on the chem- ical energy of zinc and mercuric oxide depend upon aqueous electrolytes. So the problem for the chemists to solve was defined to design a battery that would operate without water. Extensive investigations into new solvents and new materials for use in high-energy, long-life batteries eventually led to the discovery of a solid electrolyte for use with lithium metal. The solid electrolyte is iodine, and the lithium-iodine battery was born for biomedical applications. These revolutionary batteries are cur- rently in use, and they have an impressive lifespan of 10 years! The benefits to those who must depend upon cardiact pacemakers are incalculable. The lithium-iod~ne battery is not the end of the story. It is a vast improvement over its predecessors and extremely useful in pacemakers, but it has a lower power than would be optimum for other uses. On the horizon is the need for new, higher-power batteries for use in other implantable organs like artificial kidneys and hearts. But further electrochemical research will undoubtedly provide the answer. It has in the past, and it will again. \ \ 47

48 100 80 o a' IS m o 40 20 HUMAN NEEDS THROUGH CHEMISTRY III-C. More Energy This country's economic development is tied to the growth of its use of energy. For six decades, the Industrial Revolution was fueled primarily by coal. Then, petroleum energy use caught up with coal in 1948. Mean- while, throughout the twenti- eth century the 3-fold growth in population has been accom- panied by a 10-fold increase in energy use in all its forms. As we look ahead, there can be no doubt that the nation's wealth and quality of life will be strongly linked to continued access to energy in large amounts. Today, about 92 percent of the U.S. energy consumption is based upon chemical fuels. Because of societal concern about nuclear fission as an en- ergy source, this dependence upon chemical technologies will continue wed into the twentieth century. Meanwhile, every es- timate of future energy use emphasizes the need to con- serve and develop every en- ergy source at our disposal. The need is urgent because, first, the planet's petroleum supply is limited and will eventually be exhausted. Second, our desire to protect the environment will result in stiffer restraints on new energy technologies. Chemistry and chemical engineering will play central roles as we develop each of the following energy sources and emerging alternatives: · Petroleum · Natural Gas · Coal, Lignite, Peat HOW MUCH WILL ENERGYUSEGROW?~3: ~ an_ NUCLEAR + f ~ ? HYDROELECTRIC ~ P~E~rR~O~L~E~ 190t} 1925 1950 1975 2000 YEAR U.S. ENERGY USE: NEW SOURCES ARE NEEDED PETROLEUM Shale Oil, Tar Sands Biomass Solar Nuclear Fission Nuclear Fusion Conservation Petroleum use has increased steeply worldwide; as much petroleum was taken from the ground between 1968 and 1978 as was removed in the 110 years before that. Complex chemical processing is required to convert the raw natural product into chemical forms that meet the demands of modern, high-compression engines.

III-C. MORE ENERGY Challenging research opportunities for chemists and chemical engineers lie in such key areas as recovery (getting more oil from the known deposits), refining (converting the crude of] into the most useful chemical form), and combustion "getting the most energy from the finished fuel). Recovery Recovery refers to the amount of oil that is actually removed from a known oil deposit. About 4,000 billion barrels of oil have been discovered worldwide, with about 12 percent of it in the United States. Most of that oil, how- ever, is not recoverable by pres- ently known methods of re- moval. Primary recovery, based upon natural pressure, can usu- ally recover no more than 10 to 30 percent of the of] from its natural reservoir, a complex structure of porous rock. Sec- ondary recovery, in which wa- ter, gas, or steam is injected to force more oil from the deposit, can raise the recovery e~- ciency, but even then, only about 35 percent of the known U.S. oil deposits are classified as recoverable. Of that recover- able part, more than 80 percent has already been extracted and consumed. Tertiary recovery goes after .. . ~ . ~ . . ~~////~;lvc ~N ~ ~ I' ~ "~////////////z ~ ~ ~ ~ ~ ~ ~ ~ -/-: ~ _y - t_ ~~ ~ at, _< ~ ,~ rC'~~~/////////~ ///// \ ~ 7 L _~--~ ~ ~ roll ''//////// ~//~0~ i// ~10 ~ ~ ~ ~—~~lf3~2~ A At ` - /////~/< ~ _ [~ _ ~ ~~ ~~ 1 _ - \~ ~\~~ %.~ TV ~ ~ A////// ///// -Call PHASED ~0 ~ ////~°`v~;~^ ///// DETERGENT MICELLES AROUND OIL /,,,,H,,A,S,E,,~/~ DROPLETS CARRY THEM TO THE SURFACE //////////// ,~/ ^~ ~ ~//~,~,o, ~ ~ ~ ~ ~ ~ At_ ~ PHASE - ~~,~— the rest or this valuable resource; it requires new chemistry and new methods. Two of these methods are the use of detergents (called surfactants) and solution polymers to separate oil droplets from the surrounding water. If tertiary recovery could be made possible, it would have enormous economic significance because it would permit us to tap the remaining 350 billion barrels of U.S. of} already discovered but currently beyond economic reach. Refining Crude oil, as it is pumped out of a well, is a liquid solution containing mostly hydrocarbons. The largest component is made up of compounds containing only single bonds; these are called alkanes. Most of the alkanes have long carbon chains, but some are branched and some are cyclic. A smaller fraction of the hydrocarbons have one double bond; these are called alkenes. Then there are also some molecules containing benzene rings; these are called aromatics. The molecular weights range from those of natural gas (methane, CH4, 14; ethane, C2H6, 30; 49

so HUMAN NEEDS THROUGH CHEMISTRY propane, C3H8, 44; butane, C4Hlo' 58) all the way up to those of the waxes (a typical wax would have the formula C3OH62 and a molecular weight of 422~. The first purpose of refining is to extract from this complex solution those hydrocarbons that have the right volatility for use in an auto engine and that burn well. Octane, COHEN, is about optimum, so we "calibrate" gasolines on the basis of "octane number" (octane equivalent). As far as combustibility is concerned, branched and cyclic alkanes burn smoothly, alkenes and aromatics are fine, but extended alkalies (normal alkanes) tend to explode in the auto cylinder rather than burn (causing your car to "knocked. So the second purpose of refining is to convert molecules that are unsatisfactory into the best molecular weight range and combustibility. This is where the chemistry becomes sophisticated. Refinement of the crude of] begins with disi/7ation, in which different petroleum ingredients are separated from each other according to their boiling points. Then, sulfur may be removed to improve the quality of the product. After that, the large molecules must be broken down into smaller, lower-boiling molecules by catalytic cracking. Then, catalytic reforming can be used to change the molecular structures to forms that burn better (high octane number). Catalysis is the key. Chemistry on a Catalytic Surface The best petroleum catalysts are expensive and rare elements like platinum, palladium, rhodium, and iridium, and they work as catalysts in the metallic state. Metallic crystals can exhibit a variety of surfaces, depending upon the angle of the surface relative to the natural crystal axes. The most stable surfaces tend to be flat and close-packed, with each surface atom surrounded by a large number of nearest neigh- bors. These are the surfaces we see in a neatly packed tray of oranges in a grocery store. Looking carefully at these trays one can see a variety of packing arrangements. There may be steps in the surface, forming terraces several or- anges wide, with the terrace width depending on the tilt of the tray. It is the same for the surface of a metal. When there are terraces on a metal surface, the atoms at the ledges are even more exposed, thus more reactive, than surface atoms embedded in the smooth ter- races. Further, there may be kinks in the steps, or the surface may be "rough" with atomic-sized openings between surface atoms that, again, will display special reactivity because of FLAT ( t,0.0) TERRACED (7.7,5) FLAT(I,tel) KINKED: ~ 0,8,7) CHEMISTRY ON A PLATINUM SURFACE DEPENDS ON THE SURFACE EXPOSED

III-C. MORE ENERGY unsatisfied bonding capability. These special sites may be crucial in determining the catalytic activity of a metal surface. Fortunately, such chemically important surface irregulanties can now be identified by low-energy electron diffraction (LEED) (see Section V-C). Petroleum refining shows how important these surface structures are in catalysis. Platinum is one of the best catalysts to restructure alkane hydrocarbons to forms with better combustion properties (e.g., octane number, volatility). Now it is possible to determine which catalyst surfaces give the most of the desired products. Thus, n-hexane, a stretched-out chain structure alkane with a low oc- tane number, can be converted to forms with higher octane numbers, such as benzene and branched or cyclic alkanes, us- ing a platinum catalyst in the presence of hydrogen. We know now that benzene is fa- vored on the flat (1,1,1) surface or on stepped surfaces with terraces of (1,1,1) orientation, like (7,5,5~. In contrast, forma- tion of branched or cyclic alkanes is favored on the flat (1,0,0) surface or stepped surfaces with (1,0,0) terraces. Kinked surfaces, like (10,S,7), tend to produce less desirable products like propane and ethane. Knowing this, we can seek a reagent that will permanently bind to and block ("poison") these active kink sites to eliminate their less desirable products. You benefit from this understanding of catalysis every time you fill up your tank with the gasoline that is best for your car. Table ITI-C-1 lists four important 51 ~ 1 A RONS AT I ZAT I ON ) (1,1.1), (7 5 5) CTCLIZATION CH2 CH2 CH3 P LATI NUM / \ / ~ / CATALTST H3C CH2 CH2 H2 normal alkanes ( 1,0,0) I SOMER I EAT I ON ( 1,0,0) H7DROGENO LT S I S , 1E I NEED ( 1 0,8.7 ) ~ CHIC HC`~ ITCH 2 CH aromatic _ H2C`c J. CH3 ~ H2 2 cyclic alkane CH3 1 TIC ACHE ~2 H branched all~anes CH2 H3C CH3 CH CH2 propane DIFFERENT SURFACES FAVOR DIFFERENT PRODUCTS TABLE IlI-C-1 Heterogeneous Catalysis in the Petroleum Industry Feedstocks Catalyst Product Used for C~6-C24 oils Zeolite C7-Cg alkanes, alkenes "Cracking,' to high- molecular sieves octane fuels (aluminosilicates) C7-Cg unbranched Platinum - -rheniuml Aromatics, other hydra- "Reforming" to hydrocarbons platinurn-iridiurn carbons high-octane fuels CO, NO, NO2 Platinu~lpalladiumJ CO2, N2 Auto exhaust rhodium cleanup CH3OH Zeolite C7-Cg branched Gasoline produc- molecular sieves hydrocarbons, aromatics tion (aluminosilicates) catalytic processes recently introduced dunng a period when our concerns for the environment influenced researchers to develop high-octane lead-free gasoline and reduce hazardous by-products. The need for new discoveries is even greater today

52 HUMAN NEEDS THROUGH CHEMISTRY as we turn to lower quality petroleum sources (called feedstocks) with higher sulfur content, with higher molecular weights (Alaska oils), and containing impurities that interfere with catalysts (e.g., vanadium and nickel in California offshore oils). It is likely that future refining techniques will differ a great deal from those currently used. Petroleum refining technology is already undergoing an evolution as refineries are being adapted to feedstocks of lower quality. Future developments may be based upon combustion of the {ow-hydrogen and coke components of these low-quality feedstocks to drive energy-consuming processes. Some of the least desirable portions may be used as fuel for other refinery processes or to produce other useful reactants such as hydrogen. Combustion The United States annually spends about $30 billion (10 percent of its GNP) on materials that are burned as fuel. It seems ironic that much remains to be learned about the chemistry of combustion since it is one of the oldest technologies of mankind dating back to the discovery of fire. The need for more knowledge stems from an ever increasing dependence on combustion, from changes in the compo- sition of our fuel, and, most important, from the sudden awareness and concern about the environmental impacts of combustion. In the last 30 years, society has recognized, and begun to grapple with, the undesired side effects of careless combustion of fossil fuels. These side ejects include smog from nitrogen oxides, acid rain from sulfur impunties, dioxins from inefficient burning of chIonnated compounds, and a problem almost too unwieldy to deal with, the long-range effect on the global climate of accumulating CO2. The combustion process is a tightly coupled system involving fluid flow, diffusion processes, energy transfer, and chemical kinetics. This complexity is shown in an oxyacetylene torch flame and even in a Bunsen burner flame. After 60 years of intensive study, it is only in the last few years that this methane-air flame has been well descnbed in chemical and physical detail. Fortunately, the area of chemical kinetics cur- rently offers great promise. Such optimism comes because of an array of new, sophisticated instru- mental techniques that allows us to understand the basic chemical behaviors at work (see Section IV- A). These advances, as they occur, will be quickly taken up by chemical engineers and will mean more efficient combustion and decreased environmental pollution. To indicate their importance, an increase of only 5 percent in the efficiency with which we burn coal, oil, and gas would be worth $15 billion per year to the U.S. economy, and an immeasurable additional value if it also reduces the growing prob- lems of smog and acid rain. SOME ACETYLENE REACI~IONS IMPORTANT IN GASOLINE COMBUSTION THERMAL REACTIONS C2H2+M C2H+H+M + C2H2 ~ C4H3 + H +H+M ~ C2H3tM + C2H3 C4H4 + H + C2H - C4H2 + H COMBUSTION C2H,+O2 ~ HCCO+OH CH2 CO + O ~ HCO + HCO +0 ~ CH2+CO HCCO + H +OH+M - C2H2OH+M

III-C. MORE ENERGY NATURAL GAS Natural gas is a mixture of low-molecular-weight hydrocarbons, mostly methane, CH4. In North America, natural gas is typically 60 to 80 percent methane (the rest, ethane, C2H6; propane, C3H8; and butane, C4H~o, in varying percentages). It contains some sulfur- and nitrogen-containing impurities, but they can be removed to give a clean-burning fuel and a widely useful chemical feedstock. The ethane and propane can be catalytically changed to ethylene, C2H4; propylene, C3H6; and acetylene, C2H2, all valuable raw materials for products needed by our society. Natural gas is an important resource as it is easily transported in pipelines and has many applications. Its contribution to U.S. energy use has almost doubled since 1960. The U.S. natural gas reserves are about equivalent to our petroleum reserves, perhaps somewhat larger. However, like petroleum, there is a limited amount of natural gas both worldwide and in this country, and its production will undoubtedly peak one or two decades from now. COAL Coal is the most abundant of the fossil fuel energy sources. Estimates of recoverable supplies worldwide indicate 20 to 40 times more coal than crude oil. The contrast is even more dramatic here in the United States where the estimates indicate 50 to 100 times more coal than crude oil. There can be no doubt that dependence on coal must increase during the next two or three decades as petroleum reserves are used up. Fortunately, being aware of this gives us time for the basic research needed to use this valuable resource efficiently and cleanly. It must be noted, too, that petroleum is not only a fuel; it also provides us with many im- po~tant fine chemicals and chemical feedstocks. In fact some people hold the opinion that petroleum as a source of other chemicals ought to be classified as "too valuable to burn." If coal can be econom- ically converted on a huge scale into combustible fuels, then we gain the option to save petroleum for more sophisti- cated uses. Further ahead, we can predict that with creative advances in chemistry, coal it- self can provide its own variety of valuable feedstocks, includ- ing some that now come from petroleum. 53 : J ~ CATALYS" . 2L3.2] ., :, , ; ................................ _; . ; ~ ~ Rhea ~ ~ . ~ThO~ _ . ~., ' - ~ .. syn gas ...... .. ...... .... ...... i: CO + H? ~ ....... ~ ~ STEAM ~ ~ ~ HE T ~ 1 I........... ... , . . .. ...'....................... .. , .... . . CORL CHEM ICAL CORNUCOPI A

54 HUMAN NEEDS THROUGH CHEMISTRY Coal is a carbonaceous rock containing chemically bound oxygen, sulfur, and nitrogen as well as varying amounts of minerals and moisture. As a fuel, it has an undesirably low hydrogen-to-carbon ratio (its H/C ratio is near unity, about half that of gasoline), which makes it burn less efficiently. In order to use coal for anything more sophisticated than simple combustion, its molecular weight must be reduced; sulfur, nitrogen, and minerals must be removed; and its hydrogen content must be increased. These goals can be reached either through processes that convert coal to liquid products, which can then be refined (hydroliquefaction), or by converting coal to a gaseous form called "syn gas" (an abbreviation for "synthesis gas"), which is a mixture of carbon monoxide and hydrogen. The use of synthesis gas has enormous potential, but so far it is not economically competitive. Table IlI-C-2 shows some catalysts that are effective with syn gas, the products that result, and the useful applications of those products. TABLE III-C-2 Catalyst Specificity for Syn Gas Conversion to Useful Products Catalyst CO + H2 ~ Product Catalyst Product Useful for Nickel Copper/zinc oxide/aluminum ox- ide Irona/cobalt Molybdenum/cobalt Ruthenium complexes (in solu- tion) Thorium oxide Rhodium complexes (in solu- tion) Methane, CH4 Methanol, CH3OH Straight chain hydrocarbons, CH3 (CH2)NCH3, N - 0 to 30 Mixed alcohol Cat to C3 oxygenated compounds Low-molecular-weight branched chain hydrocarbons Ethylene glycol Fuel Fuels, via zeolite catalysts, chemical [eedstock Feedstock for petroleums refin- eries Octane booster Chemical feedstocks High-octane fuel Polyester feedstock a The catalyst developed by Hans Fischer and Franz Tropsch in the early 1920s. The details of catalytic conversion of CO and H2 to particular desired products present an active research area. The potentials for the liquefaction processes are equally promising, and more research in this area would clearly be fruitful. The importance of the things that can be learned from research on both types of coal conversion was stnkingly displayed during World War Il. Germany, denied easy access to petroleum, was able to produce 585,000 tons of fuel hydrocarbons from coal. While a good fraction came through gasification combined with cobalt catalysts (Fischer-Tropsch chemistry), the larger share was produced through catalytic liquefaction. In a current situation, the Republic of South Africa now produces 40 percent of its gasoline requirements by similarly converting coal into 1,750,000 tons of hydrocarbons annually (using iron catalysts). Its plants and refineries are literally built on top of large coal deposits, and the coal enters the chemical reactors via conveyor belts rising from the mines. However, these examples are economically unique because the countries involved were denied access to petroleum because of political events.

III-C. MORE ENERGY SHALE OIL AND TAR SANDS Shale is a form of sedimentary rock and is a major potential source of liquid hydrocarbons in Colorado, Utah, and Wyoming. It is estimated that 4,000 billion barrels of hydrocarbons are contained in the shale of these three states alone. If only a third of this enormous reserve could be recovered, it would give us almost 10 times as much fuel as has been removed so far from U.S. of! weds. Complicated new problems of chemistry, geochemistry, and petroleum engineering must be overcome to reach this end. Shale, which comes from ancient marine deposits of mud and plant life, contains varying amounts of kerogen, a mixture of insoluble organic polymers, and smaller amounts of bitumin, a mixture of organic compounds soluble in benzene. Formi- dable environmental questions relating to water sources and land reclamation are raised in the development of shale deposits, because a ton of shale may yield only 10 to 40 gallons of crude oil. Shale of! has a favorably high H/C rati~about 1.5- ~, ~ , ,, . _ ~ out it also contains undesired organic nitrogen and sulfur compounds that must be removed. Arsenic compounds can also present a special problem. In Utah, sands are found containing dense, thick petroleum. Such deposits (called tar sands) exist in amounts equivalent to about 25 billion barrels of petroleum. Problems similar to those discussed for of! shales must be faced, particularly the environmental aspects. Because of its potential impact on the environment, practical use of this potential energy reserve may depend upon whether the rather complicated chemical conversions needed can be handled underground. BIOMASS An estimated 500 to 800 million tons of methane (equivalent to about 4 to 7 million barrels of of! and with an H/C ratio equal to 4!) are released each year into the air through the action of bacteria that work without oxygen. This bacterial action, which results in methane gas, is called anaerobic respiration. The obvious possibility of using such anaerobic processes to produce methane from what is called biomass (agricultural by-products, garbage, or other organic wastes) is complicated by the slowness of the process and by its great sensitivity to solution acidity. A detailed understanding of the chemical mechanism of methane produc- tion and of the biochemistry of the organisms involved could suggest ways to overcome the problems. Concerning the chemical mechanism, the reduction of carbon dioxide is now believed to occur in a succession of two-electron steps catalyzed by enzymes. Nickel plays a key role in the active enzyme, but its specific action is not known. Research on both synthesis and catalytic activity of metal- organic compounds, artificial enzymes, and natural enzymes should help us weigh the potential of biomass as a source of hydrocarbon fuels or chemical feedstocks. Of course, there is tremendous appeal in the prospect of producing useful energy from garbage, sewage, and plant waste disposal. A particularly appealing aspect of biomass as a major fuel source is related to the amount of carbon dioxide in our atmosphere. Because carbon dioxide, CO2, is 55

56 HUMAN NEEDS THROUGH CHEMISTRY transparent to visible light but absorbs infrared light, it lets most of the normal solar radiation reach the ground but intercepts infrared light which is radiated from the cooler Earth's surface. Thus, CO2 "traps" the solar energy, tending to warm up the atmosphere (the "greenhouse" effect). The problem we face is that measurements from the beginning of this century indicate that the amount of CO2 in the atmosphere is rising, which raises concern that in time the atmospheric tempera- ture might rise enough to melt the polar ice caps and inundate coastal areas all over the world (an average global rise of only 5°C might be sufficient). It is likely that most of the increase in atmospheric carbon dioxide over the last 60 years has resulted from combustion of fossil fuels. To halt this trend, we should be seeking new energy sources that do not release CO2. Solar energy is such an alternative. Less widely recognized, however, is that new biomass is an ongoing solar energy use that does not add to the CO2 problem. While combustion of new biomass does produce CO2, its carbon content was all taken recently from the atmospheric CO2 reservoir dunng growth of the biomass. Hence there is no net change in the CO2 balance. As mentioned above, this desirable concept can only be put into practice when researchers discover economic chemical methods for converting massive amounts of biomass into combustible substances. Further, there are trade-offs to be considered, such as the need to divert agncultural land from food production to biomass production. With the prospects provided by genetic engineenng, even this conflict may be diminished or eliminated. Food and energy-producing biomass could possibly be produced by the same plant. Perhaps, as wed, we can learn to genetically "engineer" plants that tend to counteract any rise of carbon dioxide in the atmosphere by growing more efficiently when carbon dioxide availability goes up. SOLAR ENERGY By far the most important natural process that uses solar energy is photosyn- thesis- the process by which green plants use the energy of sunlight to manufac- ture organic (carbon) compounds from carbon dioxide and water, with the simultaneous release of molecular oxygen. To be able to duplicate this process in the laboratory would clearly be a major triumph with dramatic implications. Despite much progress in understanding photosynthesis, we are still far from this goal. The solar spectrum that Unves photosynthesis places about two-thirds of the radiant energy in the red and near-infrared spectral regions. Understanding the way nature manages to carry out photochemistry with these low-energy photons is one of the keys to understanding (and imitating) photosynthesis. In current explana- tions, the energy of one near-infrared photon sets off a series of electron-transfer reactions (oxidation-reduction steps). While each of these steps uses up some of the absorbed energy, a fraction is stored through the production of adenosine tnphos- phate (ATP). Further, the chemistry is set up for the absorption of a second infrared photon to produce still more ATP and to begin reduction of atmospheric CO2. This sequence of events gives the raw matenals from which the cellular factory

III-C. MORE ENERGY manufactures its high-energy carbohydrate products. This factory is run by the solar en- ergy that was stored in ATP. Thus, natural photosynthe- sis is energized by near-in- frared light through production of energy-stonng intermediate substances with long enough lifetimes to await amval of a second near-infrared photon. The second photon "stands on the shoulders" of the first, so that their combined energy is enough to make or break the chemical bonds of the plant molecules. Several of the steps in this sequence take place in much less than a millionth of a second, at rates that were, only 15 years ago, too fast to measure. Now we have picosecond laser and nanosecond electron spin resonance techniques with which to probe each successive reaction on its own characteristic time scale. Hence, we are in a period of rapid progress in clarifying the chemistry of the photosynthetic process. This type of spectroscopic study reveals photosynthesis to be a complex process involving the cooperative interaction of many chlorophyll molecules. The packing arrangement of neighboring chlorophyll molecules has been probed by X-ray spec- troscopy and by proton and ~3C nuclear magnetic resonance (NMR). Electron spin reso- nance experiments have shown that an electron is rapidly ejected or transferred from chlorophyll shortly after the light absorption (within nano- seconds). This leaves an un- paired electron shared by two chlorophyll molecules. This observation has led to the idea that the center of photoreac- tion is a pair of parallel chIoro- phyI} rings held closely together by hydrogen bonding between amino acid groups. Another promising approach to the use of solar energy is the direct conversion of sunlight to electrical or chemical energy with the aid of electrochemical devices. Recent advances in electrochemistry have brought us closer to this goal. In a photoelectrochemical cell, one or both electrodes are made of light-absorbing semiconductors. The light absorption results in oxidation-reduction chemistry at ~ ~ H ~ O2 ~ Chtoroplast Membrane J 2 H2O Chlorophyll Pigments P-680 and P-700 S Absorb Two Photons of Fred Lights ~~x to Power Photosynthesis CHIN ~ R o — ~c' CH2 2 C: ~ ~ ASH C H 5 ~`R' I tic H 3 ~3 CH LOROPHYLL: PACKING GEOMETRY AFFECTS ITS FUNCTION 57 R

58 HUMAN NEEDS THROUGH CHEMISTRY the electrode-electrolyte interface and, hence, current flow in the external circuit. Alternatively, with suitable control, the final products of the oxidation-reduction chemistry can be hydrogen and oxygen. Determination of the thermodynamics and kinetics of light-induced processes at interfaces has, over the past decade, led to a lO-fold increase in efficiency of conversion from light to electrical energy (from ~ percent to better than 10 percent). Development of thin, polycrystalline semicon- ductor films with high conversion efficiencies to replace the expensive single crystals currently used has been another important achievement. For example, efficiencies of nearly 10 percent have been reported with thin cadmium-selenide- telluride films. NUCLEAR ENERGY At the same time that physicists and chemists gave us the atomic bomb, they made available atomic energy, a new source of energy with seemingly unlimited capacity. However, the role of nuclear energy in man's energy future is clouded by long-term risks that are difficult to weigh. Chernobyl has shown plainly the essential need for caution. Whatever course society ultimately chooses, it will rely heavily upon the ingenuity of chemists and chemical engineers to reduce those risks. Indeed, chemical research is essential to practically all phases of nuclear energy generation and the subsequent management of radioactive waste. To begin with, geochemistry plays a lead role in locating uranium ore deposits. Then, chemical separations are centrally important in the nuclear fuel cycle from concentration steps at the uranium mill, through reactor fuel manufacture, to the highly automated, remote-controT reprocessing of fuel elements from nuclear reactors. This last step has controversial overtones. While recovery of plutonium from fission products puts an appealing "recycling" aspect into the use of nuclear energy, it also makes more widely available plutonium, from which atomic weapons can be made. Radioactive waste management is also largely based upon chemistry and geochemistry. If these wastes are to be stored underground, we must find appropriately stable ground sites from which dangerous substances will not spread; we must develop more efficient separations of particularly hazardous radioactive elements (e.g., the actinides that pose the major health hazard after a few hundred years); and we must understand fully the geochemistry of potential waste storage sites. If temporary, recoverable containers are used, the problem shifts to the possibility that those containers might corrode and weaken under intense irradiation. Next, our analytical techniques must be made more sensitive for a variety of uses that extend from exploring for new uranium deposits to environmental monitoring that is sufficiently sensitive to reveal potential prob- lems before real hazard has developed. Finally, we must extend our understand- ing of the unfamiliar chemistry that would accompany a catastrophic reactor accident. We must have useful estimates of release rates for fission products from a decomposing ceramic in the presence of high pressure (up to 150

ill-C. MORE ENERGY atmospheres), high-temperature steam (up to 3,000K), and an intense radiation field. The use of nuclear reactors to generate energy is plainly a controversial and emotionally charged issue. Nevertheless, the scientific setting must be fully understood so that political choices can be made among well-defined and well- informed options. It must be remembered, too, that the use of nuclear energy is a global issue. U.S. decisions about our nuclear future may influence, but they will not determine, the policies of other governments. Plainly, it would be unwise to stop the research efforts that will define these options more clearly. FUSION ENERGY Nuclear fusion is a process in which two nuclei join or "melt together" to form a larger nucleus. An example would be the joining of the nuclei of a deuterium atom and a tritium atom to form a helium nucleus (with ejection of a neutron). The product helium nucleus is much more stable than the reactant hydrogen isotopes, though it is not clearly understood why. An enormous energy release would result from this fusion- more than 100 million kilocalories of heat would be released for every gram of helium formed. Thus, nuclear fusion competes with nuclear fission as a possible future source of energy, but it does not produce the myriad of radioactive fission products that present such a troublesome radioactive waste problem. We know that it can work since this same principle is used in the hydrogen bomb. Very large research efforts have been devoted for the last quarter century to the development of nuclear fusion. (The federal investment for 1985 exceeded $400 million.) The difficulty lies in the need to find an appropriate "match" to light this nuclear fire. The match will have to raise the fuel temperature to about a thousand million degrees before it will ignite. To "light" a hydrogen bomb, an ordinary nuclear fission bomb is used as a match hardly a practical device at a neighborhood power plant. But even putting aside the question of what match to use (a chemical laser has been considered!), think of the container problem! What could an oven be made of to cook something at 109 degrees? The oven walls will be exposed to these solar furnace temperatures, intense ultraviolet radiation, and bombardment by neutrons and chemical ions. Studies of materials that might be suitable for nuclear reactor components have begun with coated, temperature-resistant solids (refractory and ceramic materi- als). There is much to be learned, however, about the chemical changes that will occur at the surface of reactor components exposed to the high-temperature gas (which is called a "plasmas. While it is not clear yet that controlled nuclear fusion will ever be practical, it is obvious that everyday application will require significant chemical breakthroughs in the development of high-temperature materials. CONCLUSION Nothing is more critical to the long-term health of our technological society than continued access to abundant and clean sources of energy. As we try to look ahead 59

60 HUMAN NEEDS THROUGH CHEMISTRY l to these needs, we must face these challenging expectations for the next three decades: · by the year 2000 the U.S. annual energy consumption will probably exceed today's use by 20 to 50 percent; · dunng the next three decades, growth in the use of nuclear power wild be severely restricted by social concerns already in evidence; · further increase in hydroelectric power has natural limits and is in conflict with widespread desire to minimize environmental change; · even those most optimistic about nuclear fusion do not see it providing a large fraction of our energy use before well into the twenty-first century; · dependence upon high-grade petroleum crudes and high-grade coal deposits must decline as worldwide reserves are used up and as access to foreign crude of} is restncted by political developments beyond our control. These depressing expectations surely point to the need for expanding the knowledge base upon which new energy technologies can be built. Chemical and electrochemical systems provide some of the most compact and efficient means of energy storage. And we can predict with confidence that foremost among the new energy sources will be low-grade chemical fuels, such as high-sulfur coal, shale oil, tar sands, peat, lignite, and biomass. For none of these alternatives does the technology yet exist that can economically meet the strict demand that environmental pollution be avoided. Enormous chemical challenges must be met for new catalysts, new processes, new fuels, new extraction techniques, more efficient combustion conditions, better emissions controls, more sensitive environmental monitoring, and many others. Biomass must be further developed to reduce the amount of fossil fuel burned and thus to help check the rate of increase in atmospheric carbon dioxide. Solar energy must be fully investigated and put to use. We must develop artificial photosynthetic and electrocatalytic techniques that completely avoid combustion by converting the light energy directly to electrical or chemical energy. Fortunately, chemistry is ready to respond to these challenges. SUPPLEMENTARY READING Chemical & Engineering News "Photovoltaic Cells" by K. Zweibel, vol. 64, pp. 34~8, July 7, 1986. "First Methanol-to-Gasoline Plant Nears Star- tup in New Zealand" by J. Haggin (C.& E.N. staff), vol. 63, pp. 3941, Mar. 25, 1985. "New Dow Acrylate Ester Processes Derive from C, Efforts" by J. Haggin (C.& E.N. staff), vol. 63, pp. 25-26, Feb. 4, 1985. `'Dow Develops Catalytic Method to Pro- duce Higher Mixed Alcohols" by J. Haggin (C.& E.N. staff), vol. 62, pp. 29-30, Nov. 12, 1984. "Surface Sites Defined on Synthesis Gas Catalysts" (C.& E.N. stab, vol. 62, pp. 38-39, Sept. 17,1984. "Chemical Microstructures of Electrodes" by L.R. Faulkner, vol. 62, pp. 28-42, Feb. 27, 1984. "New Processes Upgrade Heavy Hydrocar- bons" (C.& E.N. staff), vol. 61, pp. 4344, Apr. 11, 1983. "Two New Routes to Ethylene Glycol from Synthesis Gas" (C.& E.N. staff), vol. 61, pp. 41~2, Apr. 11, 1983. Scadence "Surface Functionalization of Electrodes

III-C. MORE ENERGY with Molecular Reagents" by M.S. Wrighton, vol. 231, pp. 32-37, Jan. 3, 1986. Scientific American "Molecular Mechanisms of Photosynthesis'' by D.C. Youvan and B.L. Marrs, vol. 256, pp. 42-48, June 1987. "Materials for Energy Utilization" by R.S. Claasen and L.A. Girifalco, vol. 255, pp. 102-107, October 1986. 61 "Photonic Materials" by J.M. Rowell, vol. 255, pp. 146-157, October 1986. Chem Matters "Hydrogen and Helium" pp. 4-7, October 1985. "Detergents" pp. 4-7, April 1985. "Soap" pp. 4-7, February 1985. "The Sun Worshippers" pp. 4-?, April 1984.

Stone Age, Iron Age' Polymer Age There was a time when everything from arrowheads to armchairs was made from stones. Other features of those good old days were a~r-conditioned caves and charbroiled saber-tooth tiger steaks (if you caught him instead of the other way around). Fortunately, this age ended when someone discovered how to reduce iron oxide to metallic iron using coke (carbon) as the reducing agent. That all happened several thousand years ago, so the caveperson chemist who got the patent rights to the Iron Age wasn't educated at MIT or the University of Chicano. But this NEXT TRAltd , ,, chemical discovery profoundly changed the way people lived. It led to I ~ ~'`00GA1 all sorts of new products like swords and plowshares and the I ~ I ~nner-spnug mattress. Can you Imagine how those stone-agers would - ~3. have reacted the first time they put on a suit of annor, or went up the Eiffel Tower, or took the train to Chattanooga? Well, brace yourself, because chemists are at it again! This time, we're about to enter the V/r ~ , En- ~ TV 62 Polymer Age. You may think we're already there, with your polyester shirt, polyethylene milk bottle, and polyvinylchlonde suitcase. We walk or polypropylene carpets, sit on polystyrene furniture, ride on polyiso- prene tires, and feed our personal computers a steady diet of polyvinyl- acetate floppy disks. In just the last 40 years, the volume of polymers produced in the United States has grown Unfold and, since 1980, actually exceeds the volume of iron we produce. But the best is yet to come. The structural materials with which we have been building bridges since even before the one to Brooklyn, and automobiles since the Mode! T. would seem to be the last stronghold of the iron age (pun intended). Would anyone dare to suggest that polymers could compete on this sacred ground? Well, no one perhaps except chemists. Right now, there's tank of an all-plastic automobile, and you're already flying in commercial airliners with substantial structure elements made of composite polymers. One of these, poly~para-phenylene terephthala- mide), has a tensile strength slightly higher than that of steel. But where this polymer really scores Is in applications where the strength-to-we~ght ratio matters a lot, as it does in airplanes. Even with its cumbersome name, this polymer has a strength-to- weight ratio s~x-fold higher than steel' To appreciate this advantage, you should know that a 1-pound reduction in the structural weight of an airplane reduces its take-off weight by 10 pounds (counting the fuel to lift the pound and the fuel to lift the extra fuel).~;No wonder this polymer, under the trade name Kevlar@, is used to build tail sections for the biggest airliners. Oh, and bullet-proof vests, too. So what about this all-plastic automobile? Of course, weight reduction is the name of the game In trying to build fuel-efflc~ent cars. Already there are automobile driveshafts made of polymers strengthened with sti~fibers, and similar composites are used for leaf springs (oops, there goes the inner-spnog mattress!~. Right now, U.S. cars contain about 500 pounds of plastics if you count, as well, the rubber and paint and sealants and lubricants and upholstery. But what about the engine and the electrical system? What will we do about these in this allegedly all-polymer car? Gee, I'm glad you asked.... _ _

III-L). NEW PRODUCTS AND MATERIALS m-D. New Products and Materials Webster: Material. noun Chemistry. noun The substance or substances out of which a thing is constructed. The science that deals with the composition, prop- erties, and changes of properties of substances. Expectations are universally high for advances in the materials sciences. What is a material? Webster's definition includes all of the substances from which one might construct autos and airplanes, bridges and buildings, dishes and doors, parachutes and pantyhose, raincoats and radios, spacecraft and sewer pipe, tires and transistors, windows and walls, shirts, sheets, and shoes. That incredible range of application is reason enough for the high hopes scientists have for finding new substances and new ways to tailor their properties to fit our changing and diverse needs. Chemists clearly have a role here, because chemistry is the central science for understanding and controlling what substances are composed of, their structure, and the manner in which those substances behave. When designing a substance to meet a particular need, the chemist's special talent for synthesis and control of com- position can play a key role. By no means does that exclude other disciplines. To make this point, we need only mention the remarkable advances made in solid-state physics over the last three decades charactenz- ing and developing semicon- ductor materials. Because of PHYS I CS Synthesis CHEMISTRY ~ LMATERIALS| Composition Physical Characterization Processing Fabrication ENGI NEERI NG MATERIALS SCIENCE IS INTERDISCIPLINARY this we can now fashion calculators as thin as credit cards, and pocket radios to carry along when you go jogging. The fields of ceramics and metallurgy, too, have provided substances to meet special needs, from heat shields on the space shuttle to cylinder heads in automobiles. Equally important are the contributions of engineers in the processing and fabrication of the products we wish to use. There is probably no scientific frontier that is more interdisciplinary. The following analysis will focus on the rich opportunities for chemists to advance materials science to benefit us all. However, realization of these oppor- tunities win often depend upon cooperative interactions with other scientists in the materials science community. PLASTICS AND POLYMERS We find natural polymeric materials all around us in proteins and cellulose, for example. Polymers are long molecules made up of the same chemical unit repeated 63

64 HUMAN NEEDS THROUGH CHEMISTRY H / ~ / H ~ H /~l / over and over, linked by covalent bonds into a chain. Chemists probably learned most about how to make polymers through their attempts to imitate nature in synthesizing natural rubber. Today, chemists have designed so many polymers for so many purposes it is difficult to picture a modern society without their benefits. This im- portance is dramatically dis- played in the 100-fold growth of U.S. production of plastics over the last 40 years. Its pro- duction, expressed on a vol- ume basis, now exceeds that of steel, whose growth has barely doubled over this same time period. The economic implica- tions of these comparisons are obvious. Furthermore, produc- tion of plastics continues up- ward. There are many dimensions to polymer chemistry~imen- sions that chemists are in- creasingly able to control. Ex- tremely careful choice of reac- tion conditions (temperature, pressure, polymerization initi- ator, concentration, solvent, emulsifiers, etc.) and reactant (monomer) structures can de- termine a variety of different qualities of a polymer. We can fix the average chain length (molecular weight), extent of chain branching, cross-linking between polymer strands, and, through the addition of care- fully chosen functional units, the physical and chemical properties of the final poly- mer. By clever manipulation of these factors, chemists can design polymers with tailored properties such as plasticity or hardness, tensile strength, flexibility or elasticity, thermal softening or thermal stability, chemical inertness or solubility, attraction or repulsion of solvents (wetting properties), permeability to water, responsiveness to light (photodegradability), responsiveness to organisms (biodegradability), and vis- B ~ ~a Cx/ \ / \ / Polyethylene: A Chemical Chain of Many Identical Units H doe to7 L G a: A - O to6 Cat o G Q in 105 104 _ in\| / PLASTICS f------- d...--- · — · . . 1 1 1 1 1 1 1 1910 1920 t 930 t 940 1950 1 960 1 970 1980 fit .: - ,.—— .. - ALUM NUM - - YEAR ~ US. PRODUCTION OF PLASTICS: 1 940 -1 980 1 00 - FOLD GROWTH

III-D. NEW PRODUCTS AND MATERIALS cosity variability under flow (thixotropy). All of these pos- sibilities account for the con- R R tinning growth of plastics pro- \ / ~ auction and their increasing , c \ presence in the things we use, \c/ wear, sit upon, ride in, eat R/ \R from, and otherwise find in our everyday environment. Polymers as Structural Materials The potentiality of polymers as structural materials is demon- strated in the hundreds of com- mercial auplanes flying today that have substantial structural elements made of a substance called breviary. This is a compos- ite material made up in part of the lightweight, ultrastrong or- ganic polymer poly~para-phen- ylene terephthalamide). The widely known Learjet is largely built of polymer composites. More down to earth, the efforts directed toward an as-plastic and ceramic automobile shows the high expectations for poly- mers' capacity to reduce weight, eliminate corrosion, and lower costs. In the past, differences in mechanical properties of poly- mers were only discussed em- *1982 Production pirically, that is, in terms of their observed behaviors. Nowadays, much is known about the molecular conformation of these polymeric molecules. Using primary molecular data and the basic principles of chemical bonding, chemists can now predict how each polymer will behave. The elasticity in the polymer chain direction can now be calculated from bond lengths, bond angles, and the vibrational spring constants derived from infrared spectroscopic measurements. The resulting progress is shown in Table IlI-D-1, which compares the tensile strengths of two organic polymer fibers to those of both aluminum alloy and drawn steel. The two polymers significantly outperform both of the conventional structural metals in a crucial measure, strength per unit weight. 65 A FEW SIMPLE POLYMERS SHOW THAT POLYMERS CAN BE TAILORED TO NEED R1 R. \ / l / \C/ / \ R3 Rat Rl,R2,R3,R4 H,H,H,H F,F,F,F H,H,H,CH3 H,H,H,Cl Polytetrafluoro- ethylene Polypropylene H,H,H,C6H5 Polystyrene H,H,H,CN Polyacrylonitrile H,H,H,OCOCH3 Polyvinyl acetate H,H,Cl,Cl Polyvinylidine chloride H,H,CH3,COOCH3 Polymethyl meth- acrylate R. R' \ / Name 'C' / \ R3 R4 1986 U.S. Production Product (tons/year) Polyethylene Plastic bags, toys, 8,100,000 bottles, wire & cable coverings Cooking utensils, insulation (e.g. Teflon) Carpeting (indoor, 2,700,000 outdoor), bottles Polyvinyl chloride Plastic wrap, pipe, 3,500,000 phonograph rec- ords, garden hose, indoor plumbing Insulation, furrli- 2,100,000 sure, packaging Yarns, fabrics, wigs (e.g., Or- lon~, Acrilon~) Adhesives, paints, 500,000* textile coatings, floppy disks Food wrap (e.g., Saran) Glass substitute, bowling balls, paint (e.g., Lu- cite~, Plexiglass) 920,000*

66 TABLE IlI-D-1 Polymer Fibers Compete as Structural Materials Tensile Strengtha Tensile Strength per Unit Weighta Aluminum alloy Steel (drawn) Poly~p-phenylene terephthalamide)b PolyethyleneC Ceramic whiskers (1.03 5.0 5.4 5.8 25 (1.0) 1.7 10.0 15.0 50 a Relative to aluminum alloy. b Kevlar@. c Highly oriented samples. HUMAN NEEDS THROUGH CHEMISTRY Further developments will surely flow from continued re- search. It is already known, for example, that the elasticity that can be obtained with a zig-zag polymer chain is far higher than with a helical (spiral) structure. Polyethylene has a strength-to-weight ratio that is 10-fold better than that of steel. Calculations show that, in theory, it could be im- proved by another factor of five. Research is needed to tell us how to take advantage of these possibilities. L.'qliid Crystals and Polymer Liquid Crystals Though known for over a century, liquid crystals flared into prominence only a decade ago. Now, liquid crystal display (L.CD) devices provide an industry second only to television cathode ray tubes in the world market of display technology. Nothing comes close to matching the LCDs in low-power consumption for small-area displays. Liquid crystals are organic molecules that have been constructed to possess geometric and/or polar characteristics that will encourage one- or two-dimensional order. Because at least one dimension remains disordered, the substance remains fluid, and thus appears to be a liquid. However, the optical properties of these compounds give proof of their degree of order on the molecular level. Long, slender molecules that are highly rigid line up like logs floating down a river (such one-dimensional order is called a "nematic phased. More complex shapes, such as large but flat molecules, can give layered structures, like the successive sheets in a piece of plywood (such two-dimensional order is called a "smectic phase''). The actual behavior is determined by a balance between the effects of molecular shape and electncal charge distribution as the molecule interacts with its local environ- ment. This balance can be affected by a small electnc field, which provides a ready means of switching from one optical behavior to another (e.g., from transparent to opaque). Plainly, design of liquid crystals is an exciting research area for chemists. Their ability to synthesize new molecules of sphencal, rod-like, or disc-like shape, containing functional groups placed as desired, is crucial to progress. In fact, one of the most promising frontiers of liquid crystal chemistry is the application of this knowledge to the preparation of polymers. Combining the molecular ordenng of a nematic liquid with polymenzation chemistry permits the order to be built into the polymer, with dramatic effects on physical (and optical) properties. It is just this control that lies behind the production of fibers of exceptionally high tensile strength which can replace steel in products ranging from airframe construction to bullet-proof vests.

111-D. NEW PRODUCTS AND MATERIALS Block Polymers and Self-Organized Solids Another area of research GRAPHITE (1.00) that is destined to lead to en- tirely new types of materials is connected with block poly- mers. These polymers exploit the fact that long molecules of suitable structure will organize themselves into clusters. These organized clusters can take the shape of spheres or alternating layers or rods in a continuous pattern. A "tnblock" polymer is constructed of two polymers, A and B. so that one polymer B is sandwiched between two segments of a different poly- mer A. The resulting matenal, A-B-A, has the properties of A at its ends and the properties of B at its middle. If A and B are chemically designed to be un- fnendly to each other, one polymer will try to reject the other. This chemical conflict can result in a molecule in which the A ends cur! up into a ball in order to avoid contact with B. The result is a polymer in which spheres of A molecules are found distnbuted fairly regularly in a continuous matrix of B molecules. The values Stiffness KEVLAR 0.66 poly-(p-phenylene terephthalamide) S~ >I n PBT poly-(p-phenylene benzobisthiazole) hi< >I n PBO poly-(p-phenylene benzobisoxazole) n AB - PBO Tensile Strength (1.00) 2.25 1.43 3.00 2.07 3.00 0.7 1 3.25 EXPERIMENTAL POLYMERS FROM LIQUID CRYSTALS STRONGER AND STRONGER! 1— .,,.,..f2.. . ·. . B ~ ..... I ....... , . . . BLOCK POLYMERS CAN SELF-ORGANIZE of such molecular design are shown dramatically by companug the tensile strengths of the two types of triblock polymers that can be made from butadiene (B) and styrene (A). With ~ chains containing 1,400 B molecules and A chains with 250 A 67

68 HUMAN NEEDS THROUGH CHEMISTRY molecules, the tnblock polymer A-~-A has a useful tensile strength. If the polymers are hooked together in the reverse tnblock arrangement, B-A-B, the polymer is a syrupy liquid, showing no real tensile strength at all. The first of these two, A-B-A, can be shaped to any desired form at high temperature. On cooling to room temperature, it becomes rigid and behaves like a cross-linked rubber. However, unlike conventional rubber, the A-~-A block polymer can be warmed again and reshaped. Such "thermoplastic" behavior has many useful applications. This is only the beginning, however. The ability of block polymers to self- organize into microdomains of 10 to 100 A size and of different shapes (spheres, rods, planes) is sure to provide new materials with novel combinations of properties. The self-organization can give directional properties (anisotropic be- havior) to mechanical, optical, electrical, magnetic, and flow characteristics. As research advances give us control of these various dimensions, new applications, new devices, and new industries will be seen. NOVEL OPTICAL MATERIALS Optical Fibers - Just as the vacuum tube has been replaced by the transistor in modern electronics, copper wires are being replaced by hair-like silica fibers to transmit telephone conversations and digital data from one place to another. Instead of a pulse of electrons in a copper wire, a pulse of light is sent through the transparent fiber to convey a bit of information. The critical development that made this optical technology possible was the production of highly transparent silica fibers through a new process known as chemical vapor deposition (CVD). Essentially, a silicon compound is burned in an oxygen stream to create a "soot" of pure silica that is deposited inside a glass tube. The tube and its silica deposit are melted and drawn out to give a glass-coated silica fiber about one-tenth the diameter of a human hair. The CVD process made it possible, in less than a decade, to vastly improve the performance of fiber optics, reducing fiber light losses 100-fold. A new class of materials, the fluoride glasses, may result in fibers that are even more transparent. In contrast to traditional glasses, which are mixtures of metal oxides, fluonde glasses are mixtures of metal fluorides. Although many practical problems remain to be resolved, these new glasses would, in principle, permit transmission of an optical signal across the Pacific Ocean without any need for relay stations. Optical Switches In addition to chemistry's role in development of new materials and processes for optical fibers, it also has a major part in synthesis of materials for optical devices that switch, amplify, and store light signals. The possibilities in this area are quite remarkable since an optical switch might be able to operate in a millionth of a millionth of a second (a picosecond). Current optical devices are based on lithium niobate and gallium aluminum arsenide, which are spin-offs from the electronics industry. In new directions, mirror-image organic molecules, liquid crystals, and polyacetylenes can display desirable optical effects greater than those of lithium niobate. The potential for discovery and practical applications in this field are great.

III-D. NEW PRODUCTS AND MATERIALS NOVEL ELECTRICAL CONDUCTORS Semiconductors The modern age of solids was launched during the 1950s by brilliant advances of solid-state physicists as they developed deep understanding of pure semiconductor materials. There were early challenges to chemists, too, as it became clear that elemental silicon and germanium were needed in single-crystal form with impurity levels as low as one part in 100 million. Thereafter, similar behaviors were found in compounds consisting of two elements, one from the third group of the Periodic Table (e.g., gallium) and one from the fifth group (e.g., arsenic). A typical "~-V" compound is the mixed semiconductor indium antimonide, which has for 15 years provided one of the most sensitive detectors known for near-infrared light. Lately much attention has been directed toward single crystals of the IlI-V compound gallium-arsenide grown on single-crystal substrates of indium phosphide, another ITI-V compound. There may be as many as half a dozen gallium-arsenide layers with differing impurity compositions and thicknesses. This class of materials forms the basis for lasers and laser display devices for long-wavelength optical commu- nications. As the range of materials used in semiconductor technologies has broadened, more and more chemists have joined the physicists in such work. This upswing of the chemist's participation came about the same time as the startling discovery that amorphous silicon (silicon that is not crystalline) also can demonstrate semiconductor behavior. Because the prevailing and extremely successful text- book theory of semiconductor behavior is based upon the properties of perfectly ordered solids, such amorphous semiconductors were neither predicted nor comfortably described by theory. The language and concepts of chemistry are now being used to explain this puzzle (e.g., "dangling bonds" in amorphous silicon). We are on the verge of a new era in the solid-state field, one in which physicists will continue to expand their success in characterizing new solids, but now chemists will play an increasingly important role. The reason is that entirely new families of electrically conducting solids are being discovered families susceptible to a chemist's ability to control local structures and molecular properties. As will be seen, some of these new families are inorganic solids and some are organics. Conducting Stacks The field of organic conductors had its beginning in the late 1960s-early 1970s with the synthesis of organic crystals that conducted electricity. The first examples were formed by the reaction of compounds such as tetrathiafuivalene (TTF) with tetracyanoquinodimethane (TCNQ). Both of these molecules are flat, and in their mixed crystal they are found alternately stacked like poker chips. The interaction between two neighbor molecules is a familiar one to chemists- a charge-transfer complex is formed. Such an interaction always includes an electron donor, a molecule from which electrons are readily removed, and an electron acceptor, a molecule that has a high electron amenity. These two roles 69

70 c- ~~ : HUMAN NEEDS THROUGH CHEMISTRY are filled, respectively, by TTF and TCNQ. The surprise is that this charge transfer between two neighbors in the crystalline stack provides a mechanism for current flow up and down the stack, the length of the crystal. The bright future for conducting stacks has re- o cently been assured by the imaginative synthesis of <~7 polymeric conductors with charge transfer proper- ~u I', / ties. Again large, flat molecules furnish the elements of the conducting stack (metallomacrocycles). The rim 7 clever innovation lies in lacing them together with a u ~ string of covalently bound oxygen atoms. The fact ~7 that this chemically designed molecule is, indeed, an electrical conductor is quite a breakthrough. Plainly, the metal atom and the surrounding groups PHTHA OCYAN NES LINKED IN A in the flat metallomacrocycle can be substituted and "CONDUCTINGSTACK" altered in great variety. Then these units can be connected by an intervening atom chosen to give the desired spacing. The result is a polymer in which carefully chosen macrocycles are held in a molecular stacking that is rigidly enforced by the covalent bonding and designed to fit the desired function. Organic Conductors Polyacetylene is one of the simplest organic polymers. It has a carbon skeleton of alternating single and double bonds. Chemists call this bonding situation "conjugation," which means that electric charge is especially mobile along the skeletal chain. Nevertheless, unusual electrical properties C~r. - ~ C / \ / i r CIS C C // ~ ~ C -- C TRANS POLYACETYLENE DIFFERENT STRUCTURES => DIFFERENT PROPERTIES chemical methods are under possible. Because response tc these polymers give us hope it came as a surprise, half a dozen years ago, when the of polyacetylenes were discovered. Such polymers, when exposed to suitable chemical agents such as bromine, iodine, and arsenic pentafluoride (which physicists call "dopants"), become shiny, like met- als, and they display electrical conductivities higher than those of many metals (though not yet as good as copper). Plainly, the gates are now open, and other con- ducting polymers are rapidly appearing. The poly- mer poly(para-phenylene) has been shown to be- come a conductor when exposed to the correct chemicals. The same is true of poly(para-phenylene sulfide) and poly-pyrrole. Organic chemists can use their creative skills to fashion compounds that com- bine electrical conductivity with the various bene- ficial properties of polymers, such as structural strength, thermoplasticity, or flexibility. Electro- study that make polyacetylene photovoltaic cells light can be designed to match the solar spectrum, for cheap organic photovoltaic cells with which to

III-D. NEW PRODUCTS AND MATERIALS convert solar energy to elec- tricity. Extensive research is in progress to develop light- weight, high-power density, re- chargeable batteries with poly- menc electrodes. Superconductors Another discovery as signif- icant as polyacetylene was the synthesis of pure, single crys- tals of the inorganic polymer poly~sulfur nitride), (sN)x. This material not only showed metallic conductivity, it was found to become supercon- ducting (having no detectable lo, ~ CONVENTIONAL MATER ~ At lob 104 1 1 ore -12 1 0 ,, 10 NOVEL CONDUCTORS SILVER, COPPER - 1£ - 's 1 .c o — -2 ~ 10 - 104 ~ o6 $ -8 10 lo2 _ _ BISMUTH MERCURY INDIUM ANTIMONIDE ~TTF · TCNQ ~ o ~ ~ 7 Z I ol6 - SULFUR ~ electrical resistance) at about QUARTZ ~ 0.3K! It was the first covalent IO ~ ~ a PARAFF] N ~ polymer with metallic conduc- tivity (ahead of polyacetylene PO LYAC ETY ~ E N E by 4 or 5 years), and also the AN INSULATOR BECOMES A METAL first covalent polymer com- pnsed of nonmetals to show superconductivity. To solid-state scientists, this opened a whole new world of possibilities of chemical candidates for electrical behavior. For example, chemists have used the conducting stack design involving tetrathiafuivalene (TTF), mentioned earlier, to develop a superconducting poly- mer. They synthesized an analogous compound by replacing the sulfur atom on each TTF molecule with a selenium atom. Like TTF, this selenium analog also forms conducting salts, but in addition it displays superconductivity and at much higher temperatures than polyLsulfur nitride), (SN)X Inorganic compounds involving three elements are also under systematic study, and materials with relatively high superconducting temperatures have been discovered among this family of ternary compounds known as Cheveral phases. An example is PbMO6Ss which can remain superconducting in the presence of magnetic fields of several thousand gauss. This is a crucial property because construction of compact, hinh-field magnets is one of the most important applications of superconductors. GERMAN I UM SILICON SODIUM CHLOR I DE IODINE GLASS Dl AMOND : —- ~ -~.r~ ~ - - Late in 1986, however, an enormous breakthrough was made when certain copper oxide solids were found to become superconducting at temperatures above 90K. These solids have layers of copper oxide with various metal atoms sand- wiched between in the so-called perovskite crystal structure. A typical composition is YBa2Cu3Ox where x is about 7.5, indicating an oxygen-deficient lattice. How- ever, the yttrium atom can be replaced by almost any other lanthanide atom, and the barium atom can be partially replaced by calcium or strontium. These many substitutions have little effect on Tc' the temperature at which the material becomes superconducting (all have TC in the range 85 to 9SK), so it seems that the electrical 71

72 HUMAN NEEDS THROUGH CHEMISTRY behavior is a property of the oxygen-deficient, hence strained, copper-oxygen layers. The implications of this landmark discovery are mind-boggling. It provides zero-Ioss electncal conductivity at temperatures easily maintained with inexpen- sive liquid nitrogen coolant (77K). This makes many applications practical, ranging from loss-free energy transmission over long distances, tinier computer integrated circuits that are not limited by heat generation, and trains levitated with supercon- ducting magnets to make them virtually friction-free. But most remarkable is the fact that after 75 years since the discovery of superconductivity, the highest Tc recorded was only 23K. Then, in a penod of a few months, this record reached NOOK. We are irresistibly drawn to the expectation that other materials will be discovered that raise superconductivity upward further toward room temperature. The impact of such a development would likely have as dramatic effect on our culture as that caused by the transistor. Solid-State Ionic Conductors Solid materials with ionic structures are now known with ionic charge mobilities approaching those in liquids. Investigations of such materials over the last decade have already led to their use in memory devices, display devices, chemical sensors, and as electrolytes and electrodes in batteries. Thus, sodium beta-alumina provides the conducting solid electrolyte in the sodiumJsulfur battery. ~3 . ~ IONS Graphite has a layer structure Ions can more between the layers Normally, an ionic solid like sodium chloride has a fixed composition and is an electrical insu- lator. The new solid electrolytes are produced by carefully manipulating defects in crystals and by deviating from integer chemical formulas. In a process called intercalation, charges are inserted between the weakly bound layers of a crystal lattice that encourages charge migration. The mo- bile charge carriers might be small ions like lithium ion or hydrogen ion. Substances with layered molecular structures like graphite provide excellent crystal hosts for such manipulations. This method places charges in a two- dimensional zone where movement can be exceptionally high. Many such layered structures are known, so significant opportunities for new discoveries lie ahead. In a practical example of this ionic conduction, zirconium dioxide is used as a sensing element in the oxygen analyzer of an automobile emission control system. The electrical conductivity of this solid changes with the oxygen content of the exhaust gases. Acentric Materials Materials with directional properties (such as magnets, ferroelectncs, and pyroelec- tncs) are under active development and include a wide variety of ionic crystals, semiconductors, and organic molecular crystals. Both electncal and optical applica- tions are probable: optical memory devices, display devices (for digital wrist watches), capacitors for use over wide temperature ranges, pyroelectnc detectors (for fire alarm

Ill-D. NEW PRODUCTS AND MATERIALS systems and inhered imaging), and nonlinear optics (second harmonic generation and optical mixing). To cite an example, the polymer of vinylidene chloride, (CH2CCI2), changes shape in an electnc field (it is piezoelectnc), and has found use in sonar detectors and microphones. Conducting Glasses Both metallic and semiconducting glasses can be prepared by rapidly freezing a liquid, by condensing gases on a very cold surface, or by ion-implantation in ordinary solids. Thus, noncrystalline, semiconducting silicon can be prepared by rapidly condensing the products from a glow discharge through gaseous silane, SiH4. Low-cost solar cells can be made of such material, and their performance depends critically upon hydrogen impurities chemically bound to the silicon atoms randomly lodged in the solid. Inorganic nonmetallic glasses are important for optical fiber communication and for packaging solid-state circuits. MATERIALS FOR EXTREME CONDITIONS Performance in many areas of modern technology is limited by the materials available for construction. Jet engines, automobile engines, nuclear reactors, magne- tohydrodynanuc generators, and spacecraft heat shields are contemporary examples. The hoped-for fusion reactor lies ahead. Engine performance provides a convincing case. Any thermal engine, be it steam, ~ntemal combustion, jet, or rocket engine, becomes more powerful and more efficient if the working temperature can be increased. Hence, new matenals that extend working temperatures to higher ranges have real economic importance. New Synthetic Techniques There are a number of promising synthetic techniques for producing new heat-resistant materials. Among these are ion implantation, combustion synthe- sis, levitation melting, molecular-beam deposition on crystalline surfaces (epi- taxy), and chemical vapor deposition from glow discharges (plasmas). Most recently, laser technology has provided unusual synthetic approaches. A high- power, pulsed laser beam focused on a solid surface can locally create a very high temperature (up to lO,OOOK) for a very short time (less than 100 nanosec- onds). Such a short-lived, high-temperature pulse can cause significant chemical and physical changes, modifying the surface, forming surface alloys, and promoting specific chemical reactions when coupled with vapor deposition. All of these techniques share the ability to form thermodynamically unstable compounds with special properties "frozen in." (Diamond is an example. This expensive gemstone is valued for its sparkling beauty and its extreme hardness even though it is thermodynamically unstable with respect to graphite under normal conditions.) Some Example~Real and Projected Two examples of "exotic" high-temperature materials recently developed are silicon nitride, Si3N4, and tungsten silicide, WSi2, both of technological importance in the semiconductor industry. The first, Si3N4, can be an effective insulating layer 73

74 HUMAN NEEDS TNROUGN CNEMlSTRY even at thicknesses below 0.2 microns. The second, WSi2, is a low-resistance connecting link in microcircuits. Plasma deposition synthetic techniques allow sufficient control to permit these high-temperature materials to be deposited upon a less-heat-resistant substrate held at much lower temperatures (usually below 700K). Thus, the temperature-resistant material can be deposited without damage to the desired electrical properties of the substrate. Polymers offer another promising route to new, "high-tech" ceramics. Silicon- containing polymers can be molded into any desired shape and then, on heating, converted to silicon carbide or silicon n~tnde solids that hold the desired shapes. These and other recent advances in the synthesis and fabrication of ceramics make it reasonable to anticipate the fixture construction of an ad-cemmic internal combustion engine. CONCLUSION The next two decades will bring many changes in the materials we use; the materials in which we are clothed, housed, transported; the materials of our daily lives. New industries will be founded just as polymers led to synthetic fabrics, as phosphors led to television, as semiconductors led to computers. Metals wiB be used less often as deliberately designed matenals outperform them in their traditional functions. Chemists' ability to carry out this design and, hence, to control the properties of new materials is leading to their increasing role in these fields. Ultimately, that control depends upon understanding the composition, bonding, and geometry of materials at the atom~c/molecular level the chemist's home temtory. What we can do with this understanding then depends on what we can make— and synthesis is again the chem~st's bag. That is why industnes dependent upon use of new materials are looking for bright young chemists to add to their scientific stabs. That is why more chemists are being attracted to research in the matenals sciences. SUPPLEMENTARY READING Chemical & Engineering News "The Organic Solid State" by D.O. Cowan and F.M. Wiygul, vol. 64, pp. 2845, July 21, 1986. `' Solid Ionic Conductors" by D.F. Shriver and G.C. Farrington, vol. 63, pp. 42-53, May 20, 1985. "Liquid Crystals, A Colorful State of Matter" by G.H. Brown and P.P. Crooker, vol. 61, pp. 24-37, Jan. 31, 1983. "Conducting Polymers R & D Continues to Grow" (C.& E.N. staid, vol. 60, pp. 29-33, Apr. 19, 1982. Science "A Chemical Route to Advanced Ceramics" Science staff article, vol. 233, pp. 1-132, July 4, 1986. "Optical Activity and Ferroelectricity in Liq- uid Crystals" by J.W. Goodby, vol. 231, pp. 35~355, Jan. 24, 1986. "Electroactive Polymers and Macromolecular Electronics" by C.E.D. Chidsey and R.W. Murray, vol. 231, pp. 2S-31, Jan. 3, 1986. Scientific American "Materials for Information and Communica- tion" by J.S. Mayo, vol. 255, pp. 58-65,

111-D. NEW PRODUCTS AND MATERIALS Oct. 1986. "Matenals for Aerospace" by M.A. Stein- berg, vol. 255, pp. 66-91, October 1986. "Matenals for Ground Transportation" by W.D. Compton and N.A. Gjostein, vol. 255, pp. 92-101, October 1986. "Advanced Metals" by B.H. Kear, vol. 255, pp. 158-167, October 1986. "Advanced Polymers" by E. Baer, vol. 255, pp. 178-91, October 1986. 75 Chem Matters "Polymers" pp. 4-7, April 1986. "Polysaccharides" pp. 12-14, April 1986. "Silly Putty" pp. 15-17, April 1986. "Liquid Crystal Displays" pp. 10-11, April 1984. "Liquid Crystals" pp. 8-11, December 1983.

Rx-Snake Bite High blood pressure anyone? Maybe you'd like a dose of snake venom? Yes, it's true! Hypertension sufferers may find their future treatment coming from this unlikely sourc~and from sustained research in chemistry and physiology. This story began 30 years ago when scientists discovered the chemical mechanisms by which blood pressure is elevated in humans. Chemical techniques isolated two closely related substances, angiotensin ~ and angiotensin II. In the human body chemistry, lI Is produced from ~ with the help of a specific enzyme, ''angiotensin- converting enzyme" (ACE). Though I has no physiologic effect, its reaction produced angiotensin lI, the most potent blood pressure-elevating substance known. Thus I provides a reservoir fro In which II can be made as needed to maintain a normal blood pressure level, a conversion controlled by the enzyme ACE. It is no surprise that there is also a substance provided by Nature to lower blood pressure this substance is called bradykinin, which, along with angiotensin II, seems to complete the control mechanism. To raise pressure when it Is too low, make some an~otensin lI using ACE. To lower blood pressure when it is too high, a dash of ~_N bradykinir~ will do the trick. Dunng the 1960s, a group of Brazilian scientists were bent upon learning ~ ~ how a deadly snake like the South American pit viper manages to immobilize _' ~ ~ its prey. It was recognized that this snake's venom contained Camp_ ; ~ some substances that could cause the victim's blood pressure to ~~ >] ~/ drop precipitously. Biochemical research showed that these `~? snake substances were acting by stimulating bradykinin, so they ~ ~ Of #/ ~ ~~ i' - 1 ,~<,ci __ /~ ~ _ ~ were named `'bradykinin potentiating factors" (BPF). Again, chemists did their part by purifying BPF from the pit viper venom and identifying several compounds that camed the activity. Chemical analysis showed them to be specific peptides. The next chapter in this story began when ACE had been purified and charactenzed. That opened the door to understanding how the scald venom BPF did its world. Some of the peptides in BPF block ACE to interfere with the production of ang~otensin II. There, as a bit of a surpnse, it was discovered that ACE derived part of its control function from an ability to inactivate bradykinin. Realizing this, the canny pit viper provides some pepiides in its venom to protect bradykinir1 from inactivation! Thus these BPF peptides deprive the body of its ability to use ACE, either to Wise blood pressure by producing ar~giotensin II or to moderate the lowering action of its own control substance, bradykinin. With this understanding, teams of biologists and chemists recently began a systematic attack on hypertension, one of the most insidious causes of death in our stressful world. They synthesized a series of peptides modeled on those found ~n snake venom but designed for therapeutic use. Success came with the synthesis of the compound captopril. It acts as an ACE inhibitor, and clinical trials have amply demonstrated its ability to lower abnonllally high blood pressure. No wonder that the medical profession has great expectations for ACE enzyme inhibitors in the treatment of our hypertensive population. 76

III-E. BETTER HEALTH HI-E. Better Health In the next decade chemistry will contribute to the solution of some of contemporary biology's most important problems. All life processes are regulated by chemical interactions between macromolecules and smaller molecules of diverse structural types. Ultimately, our ability to control complex biological events will depend upon our understanding at the molecular level, so chemistry is in a position to make far-reaching contributions to physiology and medicine. The following discussions illustrate how advances in chemical knowledge and technology have led to the discovery of new and improved medicines and therapeutic drugs in recent years, and indicate where rapid progress can be anticipated in the future. NOTABLE SCIENTIFIC ADVANCES DURING THE LAST 15 YEARS There have been significant changes in recent years in the methods used to discover new medicinal compounds. Remarkable progress has been made in understanding how chemical reactions control and regulate biological processes. Such understanding of the chemical mechanism of drug action permits a logical approach to the discovery of new medicines replacing the traditional trial and error screening procedures. Two important frontiers deserve special mention, those of enzyme inhibitors and of receptors. Enzyme Inhibitors Enzymes are powerful catalysts that work in highly specific ways. They assist in most of the chemical transformations of life, including the production of the chemical messengers that regulate body processes. These messengers are called hormones and neurotransmitters. Hormones, in animals, work in the bloodstream. Neurotransmitters work in the spaces between nerve cells. Both act to send messages throughout the body to trigger the chemistry of a multitude of bodily processes such as muscle contraction and adrenalin release. One way to affect these messengers, and hence the processes they control, is to affect the enzymes that produce them. A substance that interferes with the action of an enzyme is called an enzyme inhibitor. Because our understanding of enzymes is now reaching the molecular level, we are making great strides in designing compounds that inhibit enzymes. Of particular importance have been molecular structure determinations through com- puter-a~ded high-resolution X-ray crystallography. Combining knowledge about how enzymes accelerate chemical reactions with knowledge about the coiling of proteins (tertiary structure) has been fruitful. There are two approaches to the design of enzyme inhibitors now being pursued. One is based on the belief that enzymes act by stabilizing a transition or intermediate form of the reactant molecule. A compound is designed and synthe- sized to mimic this transition structure. Because the mimic compound resembles the transition structure, it can occupy the active region of the enzyme and thus block its normal action. These compounds are called "blockers." They work by 77

78 PEPT I DE T cH2 H R \ / ECU /0 1 11 H O ~ /C~~/ NC/ \H~ III~IRI~ ~ ENZYME ACTIVE SITE ~ 1~ C\2 AH ENS ~C/ \H H' 0 =C O. 'AH ENZYME HYDROLYZES PEPTIDE AND RELEASES PRODUCTS BLOCKER I CH2 H 113~ 1—CHUB ~c/ \H" BLOCKER CAN NOT BE HYDROLYZED AND BLOCKS ACTIVE SITE OF ENZYME TRANSITION STATE ENZYME INHIBITOR FOR PEPTIDE HYDROI,YSIS H ~)~(N H I H CH3 H CH2COOH HUMAN NEEDS THROUGH CHEMISTRY successfully competing with the transition molecule for at- tachment to the enzyme active site. A second approach again in- volves a compound designed to fit the enzyme active region. This time, the compound is planned so that it will react with the enzyme to inactivate it permanently. These are the so- called "suicide" or "mecha- nism-based" inhibitors and work by disabling the enzyme. As evidence of their success- ful use in therapy, enzyme in- hibitors have been designed and shown to be effective in treatment of hypertension, ath- eroscierosis, and asthma. As- pirin is a familiar example it is now known to work by in- hibiting the enzyme cyclooxy- genase. As a result of this understanding, a whole family of cyclooxygenase inhibitors, such as indo- methacin, have been synthesized and found to be medically effective in killing pain and reducing swelling. Indomett~acin: An Enzyme Inhibitor Receptors That Worlds Like Aspirin A related research field concerns the so-called "receptors." These macromolecules are involved in triggering biological pro- cesses. Apparently, they cannot function until they have been activated by their appropriate hormones. They then recognize and bind biologically active mole- cules. This has the effect of catalyzing and controlling reactions with these molecules, as they are "held" by the receptors in a strategic manner. Until recently, receptors were studied only indirectly. Various compounds were tested for their ability to either stimulate or block a biological process. Conclusions were then made about the structural features required by a molecule to fit a given receptor. Over the last 10 to 15 years, more powerful approaches have been developed using radioactive molecules which allow easier evaluation of the structural requirements for receptor binding. In addition, physiochemical means (NMR, spectroscopy) have been useful in isolating and characterizing receptor molecules. Two types of agents have been defined which bind to receptors they are called agonists and antagonists. Agonists are compounds which trigger a biological response and include naturally occurring hormones and

111-E. BE17ER HEALTH neurotransmitters as well as drugs generated by chemists. Antagonists, on the other hand, are compounds which block biological responses by binding to a receptor, thus preventing the agonist from binding and fulfilling its job. Some chemical messengers can bind to more than a single receptor type, and thus take part in more than one type of biological action. For example, histamine triggers allergic reactions by binding to a receptor designated Hi, but it also promotes gastric acid secretion in the stomach by activating the so-called Hz-receptor. Too much gastric acid causes severe damage to the stomach lining and results in an ulcer. But a drug has been discovered which works specifically as an Hz-receptor antagonist. This drug, called cimetidine, binds to the H2-re- ceptor and blocks it, resulting in less gastric acid and great relief for the patient. Norepinephrine, the chemical messenger for the part of the nervous system that controls adrenalin flow, has been shown to bind to at least four types of receptors assisting in several types of biological responses. Compounds that act as specific antago- nists have already proven their value in treating cardiovascular disease, cancer, disorders of the central nervous system, and endocrine disorders. 79 BIOCHEMICAL RESPOR SE ~ TO BI"HEMICAL ECSPOR" ~ _ AGONIST 2~N/H6 AH ~ C i_ _ 4- REC=~R ANTAGONIST J ~ ACHE N HI ~ - ~ Act - _~H WHY ~CH3, ___— __ _ A- RECEPTOR ANTAGONIST DOES NOT PRODUCE A R~N~ BUT BINDS TO RECEPTOR AND BLOCICS ACCESS OF AGONIST. TWO TYPES OF DRUG BINDING TO RECEPTORS H H N—CN ,N~ CH3—NH—C—NHCH2 CH2—S—CH2 N CIMETIDINE CONTROLS PEPI IC ULCERS These themes, enzyme inhibition and receptor function, have wide applicability. They will come up again and again as we turn, now, to examples that display the breadth of chemical progress that has been made in recent years in the development of new therapeutic agents. ANTIBIOTIC RESEARCH An ti b a cteri al s Prior to World War II, sulfonamides were the only effective antibactenal agents available. Dunng and after World War IT, antibiotic research had a major impact in decreasing disease in both humans and animals. During the period 1945 to 1965, penicillins had come into large-scale use, and the cephalosporins (a group of antibactenal fungi) had been discovered. The tetracyclines, chIoramphenicol, erythromycin, and aminoglycosides were being used to treat infec- tious diseases. In addition to antibiotics obtained by fermentation, man-made antibac- terial agents such as nalidix~c acid and nitrofurans were also being discovered. During the past 20 years, major efforts have been made to improve the range, potency, and safety of the antibiotics available. This has involved the identification of new fermentation products, and chemical alterations to improve less-than-ideal natural products (semisynthesis), as well as the introduction by synthesis of new structural

80 HUMAN NEEDS THROUGH CHEMISTRY types. The newer sem~synthetic penicillins include agents that are not only active against common bacteria but also that are elective against the Pseudomonas group of bactena, which are an increasing problem in the hospital environment. The early cephalosponns have been successfully altered to provide new compounds possessing remarkably broad usefulness and high potencies combined with increased safety. Much of the effort in antibiotic research has concentrated on the problem of resistance development, especially in the hospital environment. Unfortunately, antibiotics may become ineffective as bacteria develop a resistance to them over time. For example, certain bacteria can gain the ability to produce enzymes that inactivate the antibiotic. Progress has been made in the design and synthesis of inhibitors to disarm these bacterial enzymes. Other bacteria can become resistant to antibiotics by preventing the antibacterial agent from entering the bacterial cell. Here again, advances have been made by both semisynthetic alterations and the discovery of new agents. Antivirals Viruses are the smallest of the infectious organisms. While antiviral chemother- apy is in its infancy compared with antibacterial therapy, breakthroughs are being made. Viruses do not contain much genetic information, so they exhibit only a few unique biochemical steps that are possible targets for a chemical agent. Viruses take over and control the cells of the host in order to survive and multiply. This means, unfortunately, that most of the steps in viral biology are identical, or closely similar to, those of the mammalian host. It is therefore difficult to attack the virus by chemotherapy without also endangering the host. In order to discover a safe chemotherapeutic agent, it is necessary to identify a biochemical pathway that is unique to the virus-infected cell. Viral DNA poly- ° merase enzymes represent such a target. These N Jim hi IN enzymes are involved in the synthesis of viral nucleic acids. Examples of compounds that func- H2N KIN' '' tion as viral polymerase inhibitors are known, but cH2OCH2cH2OH often these compounds are suitable only for local ACYCLOVIR: AN EFFECTIVE application. The antiherpes drug acyclovir is effec- ANTIHERPES DRUG live either when locally applied or after oral or intravenous administration. Its relative safety is due to the fact that it is ignored by cellular enzymes under normal conditions. However, in the presence of certain viral enzymes, acyclovir is converted to a drug that blocks DNA synthesis by the virus. CARDIOVASCULAR DISEASE Diseases of the heart and blood vessels are presently the major cause of death in the United States. Therefore, high blood pressure (hypertension) and high blood cholesterol levels (hypercholesterolemia) have been the subject of extensive research.

III-E. BETTER HEALTH Hypertension Death rates for coronary heart disease in the United States fell 20.7 percent between 1968 and 1978. Improvements in the control of moderate and severe hypertension have undoubtedly contnbuted to this decline in coronary heart disease fatalities in the United States. The earliest drugs used for hypertension had such serious side effects that they were used only when blood pressure reached life-threatening levels. Now several types of antihypertensive agents are used extensively for the treatment of mild and moderate hypertension, and with few negative effects. Adrenalin is a hormone that stimulates automatic nerve action, including that which keeps the heart pumping. Its release is regulated by what is called the adrenergic nervous system. While the cause of recurring hypertension remains unknown, it has long been recognized that this adrenergic nervous system and its chemical messenger, norepinephrine, play a major role in regulating blood pressure and cardiac function. Over the years chemists have supplied clinicians with many useful antihypertensive agents which influence the activity of the adrenergic system. a-MethyIdopa, tremendously valuable in the treatment of hypertension, is known to act within the central nervous system by means of an adrenergic receptor. The recognition N'~'N that norepinephrine acts on several different O~N~o-cH2-c-c~z-NH-c-c subtypes of receptors has allowed compounds to be T'molo! H CH3 designed which lower blood pressure by different Good For Heart Attaclcs and Glaucoma mechanisms. Two widely used compounds that block the action of norepinephnne are timolo] and propranolol. They provide effective treatments for certain heart disorders and have also been shown to reduce the risk of death and recurrence of a heart attack. Timolo! has also become the primary treatment for glaucoma, a disease that affects the eyes. Two other classes of antihypertensive compounds include "calcium channel blockers" (also effective against angina and stroke), and the so-called angiotensin- converting enzyme inhibitors, typified by captopri} and enalapril. They also show much promise for the treatment of heart failure. Very recently, chemists working with biologists have discovered, identified, and synthesized a group of peptides released in the heart. These peptides have been named Streak natnuretic factors. Their biological properties are now being investi- gated to decide their possible usefulness in the creation of new therapeutic agents. We already know that these compounds tend to increase urine discharge, to relax blood vessels, and to lower blood pressure. Atherosclerosis The second major cardiovascular threat is an inappropriately high level of cholesterol in the blood, hypercholesterolemia. An intensive search has been under way for many years for safe and effective drugs that will lower cholesterol levels to the normal range either by blocking the synthesis of cholesterol or by encouraging its breakdown. HMGCoA reductase is a critical enzyme in the steps leading to the formation of cholesterol by the liver. Elective treatment for hypercholesterolemia 81

82 HUMAN NEEDS THROUGH CHEMISTRY CoA \ _ ~ ~ ~ 3 | o=c Ace echo CH2 CH2 3-Hydroxy-3-Methyl Glutaryl CoA HMGCoA: Critical Enzyme In Cholesterol Formation H H HOT CH2Cl}2NH2 HO H Dopamine H3~H CH3 Cafle~ne TO HELP A WEAKENED HEART may be provided for the first time by an exciting new enzyme inhibitor which works on HMGCoA reductase. Heart Failure For the last two centuries, digitalis has remained central in the management of heart failure in spite of its serious side ejects. The search has been under way to find less toxic agents which also work to help weak- ened heart muscle to function. The most thoroughly investi- gated alternative has been through increasing levels of cy- clic adenosine monophosphate (cAMP), which stimulates heart contractility. An increase in cAMP levels in the cells can be accomplished directly by agents such as prenalterol, dopamine, and dobutamine, or indirectly with caffeine or theophyIline, which block the enzyme responsible for inactivating cAMP, phosphodiesterase (POE). Within the last 10 years, the traditional treatment of congestive heart failure using digitalis and diuretics has been assisted or replaced by drugs that have no direct cardiac action but that increase the heart's pumping efficiency by dilating, or widening, blood vessels. These new vaso~iiators (such as the above-mentioned captopri! and enalapnI) can be expected to have a significant impact on the management of congestive heart failure over the next decade. H3C ° H N) o~(N' N CH3 Theophylline Arrhythmia Another common heart ailment is irregularity in the force and rhythm of the heartbeat. Two of today's widely used antiarrhythmic drugs, quinidine and digitalis, trace their origins back over 200 years. Since the eighteenth century, these OCH3 - ~> CH = CH2 N~H N') QUINIDINE H ~ Nan Channel OCH3 C—N cH3 OCH3 CH3O ~ C—CH2 ~ CH2—CH2—N—CH2—CH2 ~ OCH3 CH I VERAPAMIL HC(CH3)2 Ca2 ~ Channel Depressing ion Movement Can Control Cardiac Rhythm compounds have been used to treat this potentially deadly condition characterized by ab- normal cardiac rhythm. Now we are making progress in de- termining how these chemical agents work. The heart's pumping cycle is regularly trig- gered by electrical signals in- volving movement of sodium and calcium ions (Na~ and Camp. Drugs that inactivate the sodium ion channel (quini- dine, procainamide, lidocaine), depress the calcium ion channel (verapamil), inhibit sympathetic activity (propran- olol, timolol), or prolong the nerve impulse (amiodarone) have been discovered.

III-E. BETTER HEALTH They form the basis for current antiarrhythmic therapy and point toward a rational approach to treatment. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM (CNS) The cost of direct care for mental illness is estimated to be 15 percent of our total national health care expense. Approximately 2.5 percent of our population receives treatment for mental or emotional disorders each year. Antidepressants and tranquilizers have enabled men and women to live useful lives who would not Otherwise have functioned effectively. Early therapeutic agents for treating mental ill- ness were discovered through trial and error clinical testing. This permitted only slow advance as chem- ists synthesized related compounds with more de- sirable therapeutic effects. More recently, however, chemists working with neurobiolog~sts have begun to learn the biochemical mechanisms by which these drugs work. As a result, alternative ap- proaches for achieving therapeutic effects in psychosis, depression, and anxiety are now being discovered. Among the most important pain relievers (analgesics) that act on the central nervous system are those that come from the opium poppy. Morphine, a widely used opiate pain reliever, is being replaced by synthetic drugs that are not as addicting and carry fewer side effects. In addition, drugs which are useful in treating addiction to heroin, opium, and morphine are now available. Ten years ago, two peptides were isolated from the brain and found to have actions similar to that of morphine. These compounds, called enkephalins, were then chemically characterized and synthesized. This discovery has had a profound impact on CNS research. The treatment for Parkinson's disease is a typical example of a biochemical approach to CNS ther- apy. Parkinson's is characterized by muscle trem- ors and paralysis, and is caused by a shortage of the compound dopamine. It is treated with levodopa, which gains access to the brain and is converted there to dopamine by the enzyme dope decarboxylase. A further advance came when chemists combined carbidopa with levodopa. Car- bidopa prevents levodopa from being metabolized HO outside the brain, thus allowing the active agent to be formed only where it is wanted, within the brain. Side effects are thus minimized. Dunng the past decade we have made great ~CARBIDOPA FACILITATES L-DOPA sties in understanding the process of chemical TREATMENT OFPARK~NSON'S DISEASE signaling within the central nervous system of mam- mals. Ten years ago, only eight or nine monoamine or amino acid compounds were known that seemed to be neurotransmitters. Now over 40 more small peptides have been added to the list, each of which has a possible messenger function. The of - |~ N—CH3 HO Morphine An Addictive Pain Reliever Try Gay—Gly—Phe—Leu Leucine Enkephalin Pept~de Chain A New Pain Reliever CH3 ,~ if Am rid ~— NHNH2 83

84 HUMAN NEEDS THROUGH CHEMISTRY opportunities for important advances in therapy through combined chemical and biological research are quite promising. CANCER RESEARCH The group of diseases collectively known as cancer is second only to cardiovas- cular disease as a cause of death in the United States, where cancer will strike one out of four persons alive today. Cancer is characterized by uncontrolled cell growth in the body. It is gratifying that cancer research has entered a fruitful phase. New developments can be conveniently divided into those dealing with our understand- ing of the origin of cancer, carcinogenesis, and those relating to cancer treatment through chemotherapy. Carcinogenesis The discovery that organic compounds can act as carcinogens in experimental animals in the 1930s led eventually to the finding that, in high enough dosage, quite a number of compounds have the ability to cause cancer in tissues of mice, rats, and other mammals. Today, some naturally occurring and some synthetic chemicals in the environment are suspected of being capable of causing cancer in humans, so interest in the detection of these agents and how they work has increased greatly. Several important facts about cancer-causing compounds (carcinogens) were established before 1965. Several different chemical carcinogens were found to bond covalently with cellular macromolecules (proteins, RNA, DNA), and this was found to be related to the cancer process. These findings set the stage for much further research. The majority of known chemical carcinogens are actually "pro-carcinogens," in other words, they must be activated in the body to form chemically reactive molecules known as ultimate carcinogens. For example, benzoka~pyrene, a pro- carcinogen, reacts in a series of enzyme-catalyzed reactions to produce an ultimate carcinogen which then binds to DNA. This DNA molecule with carcinogen attached is called a DNA abduct. It is the ultimate carcinogens that react with the nucleic acids and proteins in cells to disrupt their normal functions in cell growth. The major enzyme systems that transform pro-carcinogens have been identified and studied. The chemical basis for the reactions forming carcinogen-DNA abducts is well understood, but how these abducts actually cause cancer in animals has not been demonstrated. It is known, however, that when carcinogens are chemically processed by the body, the end products can cause changes in the DNA (mutagenic effects) of bacterial and animal cells. There is a relationship between compounds which are mutagenic and those which are carcinogenic. If it can be demonstrated that a compound is a mutagen, it could possibly be a carcinogen. This evaluation is done routinely in the laboratory with the "Ames test," which uses a special strain of Salmonella culture. However, not all mutagens are carcinogens, and there are many natural mutagens present in a normal diet. When cells become malignant, they grow abnormally and are considered life threatening. Perhaps the most promising and certainly the most dramatic recent

111-E. BETTER HEALTH development in cancer re- search is the recognition that certain genes in normal cells are closely tied to the develop- ment of malignancy. Impor- tantly, these genes resemble or are identical to genes from cer- tain viruses (oncogenes) that transform normal cells to ma- lignant ones. Organic chemists can determine (1) the nucleo- tide sequence of the normal gene and of the oncogene and (2) the amino acid sequence of the proteins made from these genes. Changing only a single nucleotide in a gene from a bladder, colon, or lung cell can replace a particular amino acid by another in the gene product, and thereby make an otherwise normal cell malignant. The 85 ~i' BENZ() (a) PYRENE o N(N1NH DiA HOMES Ho..4C~ DNA ADDUCT HO I< OH + NADPH + O2 o \+ H2O OH —~~ ~PH + ULTI MATE CARC 1 NOGEN ENZYMATIC REACTIONS OF CARCINOGENESIS striking achievement is that we now understand on a molecular basis the difference between the protein of a normal cell and that of a malignant cell, at least for some transformations. That kind of understanding brings us closer to logical develop- ment of new therapies. Chemotherapy Compounds used for the treatment of cancer were originally poisonous substances extracted from natural sources or of synthetic origin. The role of the medicinal chemist has been to design and synthesize new drugs with improved therapeutic value. Many new and clinically important antitumor agents have been isolated from microorganisms in the last 15 years, and their chemical structure has been determined. In a number of classes of these compounds, it has been possible to prepare semisynthetic compounds with reduced toxic side effects. Some of these antibiotics interact with DNA in the malignant cell by interleaving in the helical DNA coils. This mechanism has furnished a model for the design of new synthetic compounds now in clinical trial. The first synthetic anticancer agent was given the name nitrogen mustard; it acts by alkylation of DNA. Similar compounds that work more selectively on only disease-affected DNA have since been synthesized, yielding more elective drugs like cytoxan. One group of widely used anticancer drugs known as the "antime- tabolites" are fashioned after natural substances that upset metabolic processes. Other compounds with high electron affinity, such as misonidazole, make tumor cells more sensitive to radiation therapy.

86 HUMAN NEEDS THROUGH CHEMISTRY About 40 anticancer agents have proven to be clinically useful. The most significant breakthroughs in treatment have resulted from combination therapy, using two or more drugs together. For example, in 1963 advanced Hodgkins's disease in adults was incurable, but today 81 percent of patients have their health restored with combination therapy. Complete cure can also be achieved in 97 percent of all children with acute lymphocytic leukemia. Over the last 30 years, the greatest progress in chemo- therapy has been made in the treatment of cancer in chil- dren. For several tumor types, the percentage survival for children so afflicted has risen from below 20 percent to above 60 percent. There remains a pressing need for more effective and less toxic anticancer drugs, in particular for treating siow- growing solid tumors, lung cancer, and brain tumors. Im- munologists and cell biologists are discovering differences be- tween the surfaces of normal cells and tumor cells which may provide new directions for drug design. In addition, chemists will play a critical role in the search for drugs which can stimulate the host's immune response. Too - ~o - is > 60- - i_ 40~ Ad LU UJ · Hodgken's Disease /^ W'lms. Tunor ~ /—E - ng's Sarcoma / //2 RtiabdomYosarcoma / / //1 Osteogenic Sarcoma : Non-Plodgkin's LyrnDhoma 20 - _ ~ ~ ~ Brain Boors . ~— n_~—O—ONeuroblastoma r~rnmUnOIO9Y i Chemothe ra by I Radlotherapy Surgery 1950 tg60 1 975 SURVIVAL OF CHILDREN WITH SOLID TUMORS INFLAMMATORY AND IMMUNOLOGICAL DISEASES AND DEFENSE SYSTEMS Inflammatory and immunological diseases such as arthntis and rheumatism are major medical problems; they affect 7 percent of the total population. The isolation, characterization, and partial synthesis of cortisone in the 1940s enabled clinicians to make the dramatic discovery of its potent anti-inflammatory effect. This era was followed by the discovery of a family of nonsteroidal anti-inflammatory/anaIgesic drugs, typified by indomethacin, which are in wide use today. The biochemical mechanism of action of these compounds, like that of aspinn, has been shown to be inhibition of the enzyme cycloaxygenase. The anti-inflammatory steroids and the cyclooxygenase inhibitors have provided great medical benefits, but they do not arrest the progress of diseases such as rheumatoid arthritis. Nevertheless, the recognition that many inflammatory diseases represent disorders of the immune system has been particularly important. Chemistry provides the opportunity for us to understand the chemical basis of these events. The immune system is that part of an organism's body that fights disease and invasion by foreign substances. In the last 20 years, much has been learned about

III-E. BETTER HEALTH the group of enzymes and other proteins that help our body decide when a foreign organism is present and that coordinate a response to its presence. The production of antibodies is one such response. Antibody molecules are produced in the bloodstream by plasma cells which in turn come from white blood cells. Antibodies work to neutralize foreign proteins or polysaccharides found in the blood that may cause illness. Chemists have made major contributions to understanding the nature of antibody molecules, first demonstrating that they are proteins, and then actually determining their chemical structures, as well as those of the genes that code for these proteins. From this has emerged a picture of nature's design of these molecules. They have a "variable region," in which the amino acid sequence varies according to which foreign substance the antibody is attacking, and a "constant region," which stays essentially the same for most antibodies. The variable region of the antibody molecule recognizes and binds specific intruders, whereas the constant region is concerned with the actual removal of the foreign substance. This knowledge opens promising new research avenues. The urgency of progress in this area is underscored by the need to develop effective therapies for Acquired Immune Deficiency Syndrome (AIDS). ADVANCES IN FERTILITY CONTROL ED FERTILITY INDUCTION Our understanding of the human reproductive cycle moved ahead rapidly when we discovered the role of the hypothalamus and pituitary glands, both deep inside the brain. These organs produce hormones and neurotransmitters to control the reproductive cycle. Other hormones are released elsewhere in the body, in response to these hypothalamic or pituitary chemical messengers. Thus, the body controls a wide range of responses, from causing an egg to be released from an ovary, to triggering the production of breast milk. When chemists determined the molecular structure of these hormones, it became possible to begin to influence fertility, the human body's ability to reproduce. Oral contraceptives, or birth control pills, have been used with enormous impact worldwide on population control. They are made up of two groups of compounds called estrogens and progestins, including many synthetic analogs. Unfortunately, multiple side effects, including blood clots, migraine headaches, stroke, and heart disorders have been associated with their early use. In the last several years, attention has been devoted to reducing the doses of estrogen and progestin as well as balancing the ratio of the two in order to achieve oral contraception with minimal side effects. Chemical methods have also been discovered to assist in reproduction. Clomi- phene blocks estrogen receptors in the hypothalamus and in the pituitary gland. When this hormone antagonist is administered with appropriate timing in the reproductive cycle in women, it interferes with the normal feedback by estrogen to the hypothalamus and pituitary glands. Interference results in the desired hormonal surge by the hypothalamus and pituitary gland, often producing ovulation and thus fertility. 87 C2H5 ~ cH2 , x2, ~ ~ i_ - C—C' C2H5 ~ Clom~phene: Stimulates Ovulation

88 HUMAN NEEDS THROUGH CHEMISTRY Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus. It stimulates the pituitary gland to release a wide range of hormones involved in the reproductive system. Many compounds similar to GnRH (a 10-amino acid polypeptide) have been chemically synthesized and tested. Certain side effects have decreased enthusiasm for use of these analogs in contraception, but they remain of interest and are receiving attention for treating certain cancers. Dramatic medical successes have been achieved using analogs of GnRH in patients who were born without the ability to produce GnRH, a rare disorder. An analog of GnRH is administered using small, sophisticated pumps which are worn by the patient, and the drug is released in a pulsing fashion to mimic its normal secretion pattern by the hypothalamus. Patients in their 20s who have never undergone puberty can be brought through all of the successive stages of puberty and even fertility. This combination of impressive drug design with advanced drug delivery systems is an indication of future advances in the reproductive field. Finally, there are major new directions which should also result in important therapeutic advances. Evidence from several laboratories indicates that we will soon know the molecular structure of inhibin, the key hormone involved in regulating sperm production. Synthesis of compounds similar in structure to inhibin should enable the medicinal chemist to develop a form of male birth control. It is possible that this kind of chemical influence would have fewer side effects than the use of oral contraceptives in females. The role of the brain in regulating reproductive function has been observed for a long time. Factors such as stress, exercise, and depression are known to change or halt menstrual cycles in adult women or delay the beginning of puberty in adolescents. Women athletes and women who suffer from an eating disorder called anorexia nervosa often temporanly lose their menstrual period. Compounds found in the brain such as endo~phins and enkephalins may prove useful in restoring normal menstrual cycles to these women. It is interesting to note that these compounds are naturally produced by the brain and work in the same manner as some of the drugs derived from the opium poppy. They may be involved in killing pain, causing pleasure, or changing emotions. Hopefully, the next decade will see great impact from chemical design of hormone analogs for treatment of sexual and reproductive disorders. VITAMINS Throughout mankind's history, vitamin deficiencies have been a major cause of death. In the eighteenth century it was found that small amounts of citrus fruit, which provides Vitamin C, could prevent a deadly disease called scurvy on long sea voyages. In 1912 the `'accessory food factors," which the human body needs to function properly, were given the name "vitamins." Since that time, many vitamins have been isolated and identified. Though these compounds are not themselves enzymes, they are found to be necessary for the functioning of many enzymes. Hence, they are called "coenzymes" or "cofactors." A few of the advances and discoveries in this area are described below.

III-E. BELTER HEALTH The isolation and characterization of Vitamin By as the dietary ingredient required to prevent a fatal form of blood disorder called anemia was reported in 1948. Determination of its molecular structure in 1956 by X-ray crystallographic and chemical studies showed it to be by far the most complex of any of the known vitamins. Its synthesis in 1976 was a landmark of organic chemistry. There have been major advances in our understanding of the functions and mechanisms of action of the coenzyme forms of Vitamin By. Considerable progress has been made in the understanding of the flavins, of which riboflavin, Vitamin B2, is an example. The flavins in various forms act as coenzymes for oxidation-reduction reactions required for normal metabolic processes. Over 100 flavoproteins are now known. It is of interest that a modified Gavin has recently been discovered to be a coenzyme in meth- ane-producing bactena, which may be of future inter- est in the development of methane as an energy source. H3C CH3 H~HH H H H ~ H N N—C—C—C—C—C—H ~ 1 1 1 1 ~ =C~N H OH OH OH OH N-C H O Robot laden (alla Vitamin B2 ) It has long been known that Vitamin D IS reqUlreti Keeps Our Metabolic Fires Burning for the prevention of a bone disorder calied rickets. Without enough Vitamin D a child's bones may grow in a deformed manner. By the use of advanced chemical and spectroscopic techniques, it has now been shown that Vitamin D is actually a precursor to the true active substance, a hormone. Vitamin D is changed in the body to a highly powerful dihydroxy} compound that regulates ab- sorption of calcium from the diet, its reabsorption in the kidney, and the metabolism of calcium in bone. It is not yet understood how this Vitamin D hor- mone carries out its functions, but research is in progress. It has been synthesized and shown to be effective in the treatment of a number of bone diseases. Trials are in progress to evaluate its use- fuiness in osteoporosis, a disease that causes brittle bones. New functions of Vitamin D hormones will undoubtedly be discovered, now that the compound is available for research. Another vitamin whose molecular structure is now known is K. Vitamin K is required as a coenzyme for the production of three or four pro- teins that help blood to clot. We still need to clarify how Vitamin K does this- knowing the structure is a key step toward that end. For some time, we have known that a compound that comes from Vitamin A is required for the detection of light as it strikes the eye. However, Vitamin A is now recognized to play an essential role in the growth of animals as well. It also plays an important role in the development of bone, the formation of sperm in the male, and the development of the placenta in a pregnant female. Vitamin A must be Il3C~ ACHE 't:H2~ ACHY CH3 HACK AH Vitamin D ~L~CH2 Prevents Rickets HO 89 ~XCH2N ~ ~ HUH a CH3 Vitamin K: Helps Blood To Clot tH3 ~ 1~;& ,CH ~ ~ ~ CHIN ,CI! ~ ~H2J2 CHz CIl3

9o HUMAN NEEDS THROUGH CHEMISTRY CH3 CH3 CH3 .~ CH3 CH3 VITAMIN A: ESSENTIAL TO VISION AND GROWTH converted into several related compounds before it CH.OH can satisfy all these functions, and much progress has been made in determining the chemical changes involved. For example, it appears to be converted to retinoic acids for use in skin tissues, and some of these acids and synthetic analogs are useful in the treatment of skin disorders such as acne. Another significant development is the observation that Vi- tamin A compounds can retard some chemical carcinogenesis. CONCLUSION In this section, many examples have been given in which we are developing chemical understandings of drug action at the molecular level. Such knowledge permits us to anticipate what kinds of molecular structures are needed to deal with a particular disease, or to achieve a desired clinical result. Thus, we are entering a period in which drugs can be logically and deliberately planned this is called "rational drug design." It is tempting to speculate in which disease categories the most dramatic discoveries will occur during this decade. It is likely that new directions in receptor-related research will have an impact on drug discovery in cardiovascular diseases, especially atherosclerosis and hypertension, as wed as on diseases of the endocrine system like diabetes. Recent research with the oncogenes of viruses has begun to Provide an ~ .. . . . . . . understanding on the molecular level or certain human cancers, opening promising new frontiers for drug discovery in cancer research. Progress in our ability to regulate the immune system should open up new approaches to the treatment of many inflammatory diseases, such as arthritis. Developments in neurobiology should lead to new drugs that act on the cent nervous system. Finally, the discovery of new enzyme inhibitors and of honnone and neurotransmitter antagonists win certainly lead to the discovery of important new drugs. But this win not be the end. Science is starred with examples of unanticipated breakthroughs that prove to be more important than the advances we can foresee. SUPPLEMENTARY READING Chemical & Engineering News "Synthetic Antiviral Agents" by R.K. Robbins, vol. 63, pp. 20-21, Dec. 16, 1985. "Designer Drugs" by R.M. Baum (C.& E.N. stay, vol. 63, pp. 7-16, Sept. 9, 1985. '~Platinum Complexes of Vitamin C Show Anticancer Potential" (C.& E.N. stay, vol. 62, pp. 29-30, Sept. 17, 1984. "New Drugs for Combatting Heart Disease" by H.J. Sanders (C.& E.N. staff), vol. 60, pp. 28-38, July 12, 1982. Scientific American "Materials for Medicine" by R.A. Fuller and J.H. Rosen, vol. 255, pp. 118-125, October 1986. Chem Matters "Penicillin" pp. 10-12, April 1987. "Smoking" pp. 4-8, February 1986. "Toothpaste" pp. 12-16, February 1986. "Nuclear Diagnosis" pp. 4-7, December 1985. "Lead Poisoning" pp. 4-7, December 1983.

A Pac-Man for Cholesterol Since the 1960s we've known that high levels of cholesterol correlate with heart ailments, the major cause of death in the United States. What we need is a Pac-Man to chomp up the cholesterol in the blood and reduce "hardening'' of the arteries that carry blood from the heart (atherosclerosis). Now a lowly fungus—not unlike the famous mold, penicilium may have shown us one. A normally functioning human cell uses a dual system for meeting its cholesterol needs. First, the celd has its own factory to manufacture cholesterol. In addition, the cell's exterior has a number of lipoprotein receptors that can grab onto cholesterol~ontaining lipopro- teins as they pass by in the blood stream and pull them inside. The cell fixes the number of these Pac-Man-like receptors so that just the right amount of imported cholesterol is added to the factory-made product. If the inner cell cholesterol level falls too low, more receptors are added to extract more from the blood stream. There's an idea! If the cell's cholesterol factory could be slowed down, would the cell produce more receptors to make up the difference from the blood stream supply? A chance to test this scenario came when a biochemist discovered that cell n fund produced something that inhibited cholesterol synthesis. Chemists joined in the plot, purified the elective compound, determined its structure, and named it COMPACTIN. Knowing this structure, chemists were able to synthesize close relatives of compaction that are even more potent. Chemical tests with these new chemicals indicate that the scheme works as planned. The inhibitor slows HO`:O CH3 0 1 11 CH C O ~ ; H H . _ , Am,, 0 CH 2 CH3 ~ ~'CH3 Down the cellular cholesterol factory, the cell produces more lipoprotein receptors, and the blood cholesterol level drops. The importance of this advance is shown by the fact that the average person with double the normal blood level of cholesterol can expect to live only 45 to 50 years. For the few unlucky people with triple the normal amount, life expectancy drops to ~( 30 to 35 years. To complicate matters, 1 in 500 Americans has the genetic disease 4~- ~~ .. :/R-I ~ . k r on ano ~? by' it' A/ ~ \ /r ~\~ / - / >~ - familial hypercholesterolemia (FH). Victims of FH don't produce enough receptors at their cell surfaces, so lipoproteins accumulate in the blood and eventually cause heart attacks. Thus clinical researchers are excited to find that the new cholesterol-inhibitors work with PH patients, bringing the blood levels of cholesterol all the way down to the normal level. Much research remains, but these moldy chemicals offer immediate hope to FH sufferers and, in the future, to all people with abnormally high blood cholesterol. 9

92 HUMAN NEEDS THROUGH CHEMISTRY IIl-F. Biotechnologies A living thing is a chemical factory that takes in raw materials (foods arid nutrients) and, with its chemical work force, converts those nutrients into the wide range of products needed for the maintenance and operation of the living organism. And what does this chemical factory make? Its primary function is to build other factories very much like itself. This property, called reproduction, means that the factory carries blueprints that tell how to assemble a new factory that can function independently. These blueprints carry all of the instructions needed to build the new factory (again from nutrients that must be available) and to fashion the new sets of chemical blueprints and a whole new work force to make it an independent, self-sufficient organism. Today, we have a basic understanding of the chemical structures and functions of the molecules and macromolecules that are involved in these chemical factones. The blueprints are called DNA molecules (DNA means a~eoxynbonucleic acid). These DNA molecules are designed to make it easy to copy themselves to make new sets of bluepnnts. In addition, they carry all of the instructions needed to create the work force of the new organisms, the proteins. By far the most important members of this protein work force are the enzymes. They are the engineers who guide the construction of virtually every part of the organism. Enzymes are highly selective catalysts for reactions needed in the chemical synthesis of the many substances used in the operation of the organism. Enzymes achieve their selectivity through pattern-like or mold-like surface structures that can recognize the correct reactants among the nutrients and then shape the product to the desired structure. Biotechnology can be described as our attempt to adapt a part of one of nature's factories to our own use, to manufacture a product we want. One way to do this is to locate and put to work a part of the factory that already does what we want. This is the kind of biotechnology that has been used for centuries when we use natural enzymes to ferment sugar to make vinegar and wine and when we ferment starch to make bread. But modern biotechnology is much more ambitious. Now scientists are learning how to alter the actual blueprints so nature's factory will make a new substance that was not in its product line before. To see how this is becoming possible, we will examine DNA and how it encodes the instructions it contains. Next, we will see how these instructions are used to construct specific proteins, including enzymes. Finally, we will see how new instructions are inserted into natural DNA to give the new set of blueprints, which will be called recombinant DNA. DNA WHAT IS IT? DNA is a fascinating chain-like structure made up of long strings of sugar and phosphate molecules. Attached to the sugar molecules of these long chains are heterocyclic amines (commonly called "bases") which form cross-links between two strings. When flattened out, a double-stranded DNA molecule resembles a ladder. It is truly a macromolecule its molecular weight may be as high as 109. Despite the complexity and size of a DNA molecule, it actually contains only four

Ill-F. BIOTECHNOLOGIES different amine bases: adenine, thymine, cytosine, and guanine (abbreviated, A, T. C, and G). Adenine and thymine have geometrically fixed capacities to form hydrogen bonds to each other. They match so well that an adenine base can "rec- ognize" a thymine base and bond to it in strong preference to the other bases. Cytosine and guanine match in a similar way. Thus, A always bonds to T and C always bonds to G. This recognition capability permits two such sugar-phos- phate strings to twist into the famous double-helix structure that was experimentally dis- covered using X-ray crystal- lography. Thus, the covalent strands of two complementary DNA molecules are held to- gether in the helix shape by the much weaker hydrogen bonds. Because the bonding between these amino bases is so specific, the helix can form only if the sequence of bases on the first string is perfectly matched to the sequence on the second string. O- 0—P=0 1 ,, cat H C / Of 0—P=0 o H2C L.: o —P=0 o He '~0\ o 0-—P=0 O'' H ~—H-—o CH; </ ~j---H—N A T H N H ----O IN --- H—~ ~ ~ C 'i G \ . CIt3 O-- H—~ IN—H-- N~: a/ T THE KEY TO NUCLEOTI1)E STRUCTURE: HYDROGEN BONDS OF MATCHING PAIRS A = adenine; C = cytosine; G = guanine; T= thymine 0 - o= P—o- \ 0 \~ CH o 0= P—O- o '.: CH: o 0= P—O o A \/J\ \0~ CH o 1 O=P—O- 1 o _FC.. . Get MA -it. F°T- Aim_ fit ~= A - :~ r 1T Am ~ _c. -_ A schematic d iagram of MA Hi_ the DNA double helix. ~ ~ Sugar phosphate Fin backbone A three-dimensional representation of the DNA double helix TWO VIEWS OF THE DNA DOUBLE HELIX .~ The sugar-phosphate units, each with an attached amine base (A,T, C, or G) can be thought of as labeled building blocks, called "nucleotides," from which a DNA macromolecule can be formed. The order in which these nucleotides line 93

94 HUMAN NEEDS THROUGH CHEMISTRY up creates an information code in the molecule. This code is how the DNA molecule carries the information to create the proteins needed by a living organism. This information can be copied to produce duplicate DNA molecules through enzymatic synthesis. The double strands unzip their hydrogen bonds to expose a single strand. This strand then serves as a sequence guide in enzymatic synthesis of an identical copy. This process involves making and breaking complementary hydrogen bonds which, because of the low bond energies, can be done without breaking the much stronger sugar-phosphate covalent bonds. Thus, the genetic coding in DNA and its duplication are accomplished through a delicate orchestration of chemical bond energies and molecular structures. PROTEINS-- WHAT DO THEY DO? Proteins, too, are macromolecules their molecular weights are in the range 104 to lO5. This time, the macromolecular skeleton is linked together by amide or "peptide" bonds. Each amide bond is formed by elimination of water to bind two a-amino acids through a covalent chemical bond. There are 20 different amino acid building blocks that go into making proteins. Each amino acid has its own particular R group attached. Thus, these 20 amino acids make up a molecular alphabet + H2O containing 20 letters. The order in which these amino acid letters link up "speDs out" and deter- mines the molecular structure of the protein and therefore its bi- Ological function. Proteins carry out an astonishing range of biological functions. Nearly all chemical reactions in organisms are catalyzed by a category of proteins called enzymes. The breakdown of foods to generate energy and the synthesis of new cell structures involve thousands of chemical reactions that are made possible by protein catalysis. Proteins also serve as carriers an example is giobin, which transports oxygen from the lungs to the tissues. Muscle contraction and move- ments within cells depend on the interplay of protein molecules designed to generate coordinated motion. Another group of protein molecules, called antibod- ies, protect us from foreign substances such as viruses, bacteria, and cells from other organisms. The operation of our nervous system depends on proteins that detect, transmit, and gather information from the wodd around us. Proteins also serve as hormones that control cell growth and coordinate cell activities. Thus, life depends on the interplay of two classes of large molecules, nucleic acids (DNA) and proteins. The genetic inheritance of an organism is stored in its DNA, which serves both as a pattern for the formation of identical copies of itself for the next generation, and as the blueprint for the formation of proteins, the controllers of nearly all biological processes. The arrangement of the bases in a DNA molecule is the code that tells the amino acids in what order they should link up to become a particular protein. In order to construct proteins, a third macromolecule is used to read the information coded in HE R1 ~0 HE 92 ~0 HE 1 IN—C—C ,.' _:,.... EN—C [ TIC—Con ' '0-H PROTEINS ARE KINKED BY AMIDE (PEPTIDE) BONDS

llI-F. BlOTECHNOLOGlES Dow MONA l at, ptote,n —- 1C-A-T:C-T-GtIC-C-G:A-T-G, -— —- ~G-T-A$G-A-CiG-G-C - T-A- Cal—- _ ~ ~ t ~ . . .. . —- ' C-A—URIC—U—G" C-C-G4A—U—GO—- — HISTADINE—LEUCINE—PROLINE—METHIONINE THE GENETIC CODE: THREE LETTERS IN EACH WORD DNA. This molecule is called ribonucleic acid (RNA). It reads only one chunk of a DNA molecule at a time. An enzyme separates the two strands of DNA, and RNA begins to make a copy of the code using nucleotides. As before, adenine (A), cytosine (C), and guanine (G) are used, but now uraci} (U) replaces thymine (T) in the sequence. Thus is generated the macromolecule RNA, some of which is called "messenger RNA" (mRNA). This mRNA is the information-carrying link between the gene DNA and the desired protein. It takes three nucleotides to identify a particular amino acid thus, CCG in sequence stands for the amino acid proline, while CAU is the word for histidine in the genetic dictionary. Figuring out this genetic code took decades of painstaking and Circuit research, most of it involving chemistry. Chemistry provided the methods for determining the sequence of amino acids in the protein chains (usually called polypeptide chains). Chemists also learned how to assemble amino acids in a desired sequence so they could make polypeptides in the laboratory and even small proteins identical in structure and function to those isolated from natural sources. More recently, chemists have developed rapid chemical means for deciding the order of nucleotides (called "sequencing") in single-stranded DNA. This break- through was of extreme importance because it allowed scientists to determine the primary molecular structure of a gene. Oddly enough, sequencing at the gene level is performed with less difficulty than sequencing of the encoded protein. As a result, the rapid sequencing of DNA has provided an immense expansion of our knowledge of protein structures. Of equal importance, and at the heart of modern biotechnology, has been the development of simple, rapid, chemical strategies for gene synthesis. Two chemical methods are now in use. In the first, phosphoryl esters are formed with the alcoholic OH groups of the sugars by dehydrating agents. In the second, a preformed intermediate molecule is synthesized (a phosphoramidite) that can be used to form the desired backbone phosphate linkage. The second method has been 95

96 HUMAN NEEDS THROUGH CHEMISTRY adapted to a solid-state support, thus permitting routine synthesis of nucleotide chains (oligonucleotides) of lengths up to 50 base pairs. All of these developments in chemistry provided tremendous leaps in our ability to understand biological molecules in chemical terms. Without these advances, biotechnology as it exists today would not be possible. RECOMBINANT DNA TECHNOLOGIES A recent development in biotechnology is caned recombinant DNA technology or genetic eng~neenng. It combines nucleic acid chemistry, protein chemistry, microbi- ology, genetics, and biochemistry. The first step in genetic engineering is to isolate and identify genetic matenal (DNA) from one organism. It is then modified so that it can be inserted into a new "host" organism. When this host organism reproduces itself, those that have accepted the insertion also reproduce the desired gene. Molecular biologists have discovered two classes of proteins which make it possible to manipulate pieces of DNA in a precise manner. Restriction enzymes catalyze the cutting of DNA at specific nucleotide sequences. Ligation enzymes catalyze the joining together of two fragments of DNA in a particular nucleotide order. For example, a restriction enzyme called Bam Hi recognizes the double- stranded sequence GGATCC, and cuts between the two G nucleotides to create fragments as follows: GGATCC - CCTAGG Bam Hi G CCTAG GATCC G ENZYME Bam H1 CUTS DNA AT A PARTICULAR PLACE Then the enzyme DNA ligase can take fragments like those created above and join them together to form a single continuous duplex chain as follows: G CCTAG DNA Iigase GGATCC CCTAGG GATCC G ENZYME DNA LIGASE REJOINS DNA CUT BY Bam HI

Ill-F. BlOTECHNOLOGIES Now suppose that a foreign segment of DNA from another organism is also cut with the same matching ends. The DNA ligase will then catalyze the insertion of this foreign sequence into the host DNA. The result is called recombinant DNA. - G GATCCAAAAAG CCTAG GT1~TTCCTAG DNA Ligase GGATCCAAAAAGGATCC r~T A rrTTT~T A ~~ - `_w 1 ~~J~J ~ 1 1 1 1 w~ 1 ^~w DNA LIGASE CAN INSERT FOREIGN SEGMENTS GATCC The foreign segment is cut out of a donor DNA. The host DNA is called a plasmid. It is a ring of DNA that can be independently reproduced within bacterial cells. If the construction works successfully, the cells can direct the synthesis of RESTRICTION ENZYME DONOR DNA ,~~/ OPLASM1D \ DNA ~ LIGASE >I RESTRICTION ENZYME RECOMBINANT DMA MOLECULE BIRD'S EYE VIEW OF GENETIC ENGINEERING BACTERIUM CONTAINING NEW DNA (o - 1 - - REPLICATION PRODUCES LARGE AIdOUNT OF NEW DNA mRNA, and finally, protein. The goal is to alter the DNA to encode it for a particular desired protein. The genetically engineered bacteria can then be grown as colonies of identical bacteria (clones), all of which will then produce the particular protein for which the synthesis information was encoded by the onginal DNA fragment. Specialized techniques have been developed in order to analyze and identify particular DNA fragments, including those containing specific genes. Separations technology has been developed to isolate such DNA fragments. Other analytical techniques have been developed to identify the genetically engineered cells in which the desired DNA has been introduced as wed as those within which the DNA (through the inte~ediary rnRNA) is directing the synthesis of proteins. Once again, the 97

98 HUMAN NEEDS THROUGH CHEMISTRY isolation of the protein molecules requires the application of separations technology. Thus, the application of chemical techniques to biological systems is at the very heart of recombinant DNA technology. BIOTECHNOLOGY APPLICATION TO MEDICINE Various genes have been chemically synthesized, cloned, and used to direct the synthesis of a desired protein through recombinant DNA technology. For example, insulin is a protein which is used to treat diabetes. The gene that led to the production of human insulin was synthesized by chemists in 1978 and was engineered into a plasmid and introduced into the common bacterium, E. coli. Another example is human growth hormone, a protein which is a sequence of 191 amino acids. A gene encoding this protein was created by joining together some naturally isolated DNA with some chemically synthesized DNA. This Protein was ~ , _ , , ~ produced In it. cold In 1979 and Is being tested as a potential medication tor dwarfism and similar conditions caused by a shortage of this hormone. The production of a hormone is not the only type of protein for which recombinant DNA technology is useful. Classical vaccines developed to protect against viral infections are often isolated from natural sources. A vaccine works by stimulating the body to produce antibodies when "killed" virus cells or fragments of a virus are injected into a person. The body can then resist that particular viral infection. Of course, there is a risk associated with introducing the active disease-causing portions of a virus into someone's body. Now, using recombinant DNA technology, the DNA which codes for the protein on the outside of a virus can be produced. Thus, we can stimulate immunity to a disease by injecting just the protein coat of the virus involved and thereby create a safer vaccine which cannot accidentally cause the disease or be contaminated by other viruses. These examples illustrate the great power of recombinant DNA technology to synthesize, on a potentially large scale, valuable protein materials which would be difficult or too expensive to produce by other means. They represent the combined efforts of chemists, biologists, and other scientists and are a prime example of the complete interdependence of the different disciplines. The potential of recombinant DNA technology, however, has barely been touched. Chemically prepared DNA sequences can be used to screen an individual in order to locate genetic defects that may indicate a special sensitivity to the appearance of disease. It is even foreseeable that genetic diseases could be corrected through the replacement of defective genes or through the addition of a genetically engineered gene. Perhaps the most important contribution that recombinant DNA technology can achieve will be the expansion of knowledge about the regulation of genes within ceils. Naturally occumng molecules are often found that are biologically active and thus medically useful. But these molecules are often not the ones chosen for a pharmaceutical product. A chemically similar molecule (an analog) or a fragment of the naturally occurring product may be used instead to lower the cost or to avoid undesirable side effects. Recombinant DNA techniques can produce these modified products. Polypeptide hormones have many types of useful biological activity, but suffer from the disadvantage of not being active when taken orally and of having a

Ill-F. BIOTECHNOLOGIES short time of effectiveness. Further progress in the chemical modification of proteins may remove these limitations. Often, a protein produced using recombi- nant DNA technology requires modification before its biological activity can be realized. This was true for the insulin described earlier. Chemical modification of the insulin protein produced by E. cold led to a biologically active compound, a new hormone. On the other hand, the desirable pharmaceutical may be a compound that blocks or is antagonistic to the biological activity of some naturally occurring biomolecule. In this case, recombinant DNA technology can provide a good source of the biomolecule which can then be used to test chemically (or biotechnologically) synthesized compounds in order to develop a useful pharmaceutical drug. BIOENGINEERING An increasingly important part of modern medicine is the development of safe and effective methods for delivering drugs as well as the creation of assemblies that can replace failed human parts. This involves chemical as well as engineer- ing development. Examples include cardiac pacemakers, heart valves (and now artificial hearts), tendon replacements, and heart-lung and kidney dialysis machines. Recent research into blood substitutes has led to some promising possibilities such as fluorocarbon chemical emulsions and serum constituents such as albumin and factor VIll (recently reported to be produced by recombi- nant DNA technology). Thin membranes used as artificial skin and cultured epithelial cells promise major advances in burn treatment. Materials for tooth implants and bone replacement are being developed. Insulin-releasing pumps that can be implanted in the body of someone suffering from diabetes can make insulin treatment more regular and controlled, thus reducing serious health threats. In the longer term, it may become possible to implant genetically engineered cells directly into an organism that will provide treatment for genetic and hormonal deficiencies. BIOCATALYSIS Enzymes, the proteins that act as catalysts in biochemical reactions, are the main focus of yet another branch of biotechnology and chemistry. The ability of recombinant DNA technology to control the synthesis of enzymes will surely extend the application of the microbe as a biocatalyst. First, it will be possible to produce almost any enzyme found in nature inexpensively. Second, and more exciting, is the possibility of perfecting pre- , ~' sent techniques for preparing biocatalysts that cur- Raw material Product rently do not exist in nature through careful DNA A MICROBIAL FACTORY synthesis. X-ray crystallographic techniques have provided the chemist with detailed understanding of the three-dimensional struc 99 Cell

100 HUMAN NEEDS THROUGH CHEMISTRY ture of some enzymes. Further chemical research to increase the understanding of the relationship between the chemical structure of enzymes and their catalytic activity will be needed before logical design of such biologically produced synthetic biocatalysts can be achieved. A recent aid in biocatalysis has been the development of a technique called enzyme immobilization. In this technique a solid support is used to actually hold the enzyme still. This stabilizes the enzyme and increases the amount of material that it converts to the desired product. It also simplifies purification of the product because the enzyme is more easily separated from the end product. One example of this technology is the use of the immobilized enzyme penicillin acylase to convert the naturally occurring antibiotic penicillin G into 6-aminopenicilianic acid (6-APA). The acylase enzyme removes the chain of atoms that are linked at the amino nitrogen (N) atom in penicillin G. Other chains of atoms are then chemically added at this nitrogen to produce various semisynthetic penicillins for medical use. o HO2C~ H O ~ N ~ ACHE (> CH2 C NH--~4 ~ S H H penicillin acylase HOW H2 N --a :` S CH3 H ~ CH3 Penicillin G 6-Aminopenicillanic acid ENZYME IMMOBILIZATION IMPROVES PENICILLIN In another example, corn starch can be enzymatically converted to glucose. An immobilized enzyme, glucose isomerase, is then used to convert some of the glucose to the sweeter fructose. Over 2 million metric tons of this high-fructose coin syrup are produced annually in the United States. Immobilization technology does not necessarily require the isolation of a particular enzyme. Whole cells containing the enzyme can be immobilized on a solid surface. For example, whole cells of the bacterium E. cold have been immobilized and used to catalyze the chemical conversion of fumaric acid and ammonia into aspartic acid, one of the amino acid building blocks of proteins. In addition, immobilized yeast cells can be used in the fermentation by which we produce alcohol (ethanol). This process has been demonstrated industrially in a large test plant facility. No discussion of biocatalysis would be complete without talking about biomass. At this point, a relatively small amount of the total available biomass in the United States is converted into useful chemicals through biotechnology. There is increas- ing interest in biomass conversion, as the Earth's supply of raw materials of fossil origin (like crude oil) is limited and nonrenewable. The potential volume of cellulosic materials (plant matter) that could be converted into industrial chemicals, however, is large. Large-scale conversion of biomass into industrial chemicals requires a relatively constant, low-cost source of biomass. From a technical point of view, molasses, starch from corn or wheat, and sugar are well suited for fermentation. They are readily converted into glucose, and additionally, microor-

III-F. BIOTECHNOLOGIES ganisms are known for converting glucose into many useful chemical products. These starting materials, however, are also needed for food and are subject to wide variations in price and supply depending upon crop success and trade policies. The potential biomass avail- able from agricultural and for- estry waste is estimated to be 10 times greater than the sources mentioned above. This biomass is less subject to the changes of both price and CH4 availability. Unfortunately, it METHANE is mostly made up of lignocel- lulose (lignin, cellulose, and hemicellulose). Lignin, a woody compound found in plants, resists biocatalytic breakdown and physically in- terferes with the fermentation of the cellulosic materials. Thus, lignocelluTose biomass must be chemically pretreated to remove the lignin. Except for use as a combustible fuel, no large-scale uses for lignin have been developed and it often becomes a waste. Biocatalysis of these abundant sources of biomass is therefore waiting for further development in the chemical modification of the raw materials. CH3CHOHCHOHCH3 2,3-BUTANEDIOL C2H5OH ETHANOL HOCH2CHOHCH2OH GLYCEROL CH3CHO~O2H LACTIC ACID CH3CHOHCH3 ISOPROPANOL 1 4,, ~ . ~ / ,.,:: ' ~.~ I;,,.,. :, - C6 H' 2O6 — GLUCOSE ~ _ CH3CO2H ACETIC ACID ' CH3cOcH3+ n-c4~9oH ACETONE n-BUTANOL CH2 CHCO2H GLU COSE ACRYLIC ACID A SOURCE OF USEFUL CHEMICALS CONCLUSION Over the past two decades, progress in biotechnology has been dramatic. It is now possible to program living cells to generate products ranging from relatively simple molecules to complex proteins. We have only begun to realize the immense potential of recombinant DNA technology as a means of obtaining protein materials that were previously very costly or unobtainable in large quantities. Biocatalysts have already established themselves in the large-scale production of venous industrial chemicals. Continued progress in biotechnology will require the cooper- ative efforts as well as the individual advances in several disciplines including chemistry, chemical engineering, molecular biology, microbiology, and cell biol- ogy. SUPPLEMENTARY READING Chemical & Engineering News "Biomaterials in Artificial Organs" by lI.E. Kambic, S. Murabayashi, and Y. Nose, vol. 64, pp. 3148, Apr. 14, 1986. "ACHEMA Features Biotechnology's Big- ger Role in Chemical Technology', by J.H. 101 Krieger and D.A. O'Sullivan (C.& E.N. stair, vol. 63, pp. 31~0, June 24, 1985. "Single Cell Protein Process Targeted for Licensing" by J.H. Krieger (C.& E.N. staid, vol. 61, p. 21, Aug. 1, 1983. " Mammalian Cell Culture Methods

102 HUMAN NEEDS THROUGH CHEMISTRY Improved" (C.& E.N. staff), vol. 61, p. 26, Jan. 10, 1983. S. clence "Solid State Synthesis" (Nobel Address, Chemistry, 1985) by B. Merrifield, vol. 232, pp. 341-347, Apr. 18, 1986. "Automated Chemical Synthesis of a Protein Growth Factor for Hemopoietic Cells, In- terleukin-3" by I. Clark-Lewis, et al. (5 co-authors), vol. 231, pp. 93-192, Jan. 10, 1986.

Magnetic Fluids Attractive Possibilities When we hear the word "magnet" most of us picture a horseshoe-shaped affair with nails and paperclips clinging to it, or one of those things we put on the refrigerator to hold up messages. But what images come to mind when we try to picture a magnetic liquid? The possibilities stretch the imagination. The first question is whether or not such liquids even exist. Are there vast deposits of magnetic fluids waiting in the depths of the earth for excavation? The answer is no. Can we make a magnetic fluid by melting iron or nickel — or cobalt or some other' ferromagnetic material? Sorry, won't work. ~ ~ - Every magnetic substance loses its magnetism when heated above its own characteristic temperature. Yet magnetic fluids do exist' but the tenn refers to a suspension of small particles of a ferromagnetic material in a liquid. Scientists have been trying to make magnetic fluids this way since the 1770s, when one of them mixed up a batch of iron filings and water. We've come a long way since then, and magnetic fluids are now a practical reality. One of the chief problems with a magnetic fluid is keeping the tiny particles from bunching up. Two forces are at work trying to get these particles to clump together. One is the attraction of the little magnets to each other, and the other, stronger force is the van der Waals attraction between the atoms that make up the particles. Chemists have discov- ered ways of dealing with these two forces. First, they use extremely small particles to prevent clumping from magnetic attractio~as small as 100 Angstroms in diameter! Then, they coat the particles with substances called `'surfactants," which blanket each particle with a layer one molecule thick. This combats the van der Waals force by keeping the particles at a distance from each other. One of the first practical magnetic fluids was made from a mixture of iron oxide particles (FeO and Fe2O3), called magnetite, in kerosene. The surfactant used was oleic acid, a long molecule with a carboxyl group for a "head'' and an 18-carbon chain for a "tail." Since that time many different particles, liquids, and surfactants have been used with success. Magnetic fluids possess many unusual and useful properties. On an iron part, they can "stick" magnetically right where they are put, or they can be manipulated and moved around with a magnetic field. They can provide a very tight sealant to prevent contamination of sensitive ~ equipment. As a lubricant, the fluid can be positioned exactly where ~t expected wear might occur. Ferrofluids, as they are called, are used in seals and bearings around rotating shafts in machinery. Several drops can create an impenetrable seal around a shaft while still minimizing friction. Ferrofluids are used in airtight seals in the Menaces used for growing silicon crystals; in seals for gas lasers, motors, and blowers; and in computer disc drives where seals operate at extremely high rpm and where a single particle of dust on the recording head can destroy its surface. Magnetic fluids are also used in loudspeaker systems, and in magnetic inks like those found on our bank checks. There is even tack of using them in medicine, to close off arteries temporarily without damage. The future of magnetic fluids stretches more than the imagination—this `'attractive" innovation stretches the magnet itself. ~5 lit ' -'~3 ~ 103

104 NUMAN NEEDS THROUGH CHEMISTRY IIl-G. Economic Benefits INTRODUCTION The chemical industry has enormous scope. It encompasses inorganic and organic chemicals used in industry, plastics, drugs and other biomedical products, rubber, fertilizers and pesticides, paints, soaps, cosmetics, adhesives, inks, explo- sives, and on and on. The value of U.S. chemical sales in recent years has been in the neighborhood of $175 billion-$~80 billion, with a favorable balance of exports over imports of about $8 billion-$12 billion. Employment in U.S. chemical and allied product industries is over a million people, includ- ing over 150,000 scientists and engineers. The numbers are large, and the effect on the economy is important. And even they do not adequately indicate the far-reaching pres- ence and impact of chemistry throughout our society. Chem- ical products are supplied to countless other industries to be processed and resold. Addi- tionally, chemical processes are abundant and growing in modern manufacturing. Me- chanical operations, such as cutting, bending, drilling, and riveting, are being replaced by etching, plating, polymenza- tion, cross-linking, sintering, etc. For example, electronic microcircuits are produced through a sequence of perhaps 100 chemical process steps. Finally, chemistry is the science on which our understanding of living systems is based. Heredity is now understood in terms of the chemical structure of genetic material. Disease and its treatment are chemical processes. Every medicine that a doctor prescribes is a chemical compound whose effectiveness depends upon the chemical reactions it stimulates or controls. The business climate of the chemical industry is complex and changing. Here in the United States the situation is particularly difficult due to many diverse factors that are unique to our society. Antitrust law in the United States strongly discourages cooperative actions on the part of U.S. corporations. Abroad, coop- erative partnerships between foreign corporations and the government are encour- aged. Governmental policies in regard to science-based industnes are frequently more favorable abroad than in the United States. International activity in the petrochemical arena is increasing as nations control- ling cheap and abundant feedstocks establish their own manufacturing complexes ~ 965 ~ 970 ~ 975 _ _ _ i,, AS IOB C: he J a: S OB a A: A: ~ - S lOB of o - He -S2 OB be - Cal As cD -S30B _ Chemicals ~ | art ~65 '70 \41~: - ~74 \~ ; ~76 All Merchandise f 1 980 1 985 _ _ 1 ~ 1 _ ~ 1 1 . ~ 1 .. ~ 1.... ~74 \~ 6 CHEM ~ CA LS: A MU CH N BED ED POSITIVE TRADE BALANCE

111~. ECONOMIC BENEFITS to refine crude of! and produce polymers and other products higher up the value scale. It seems probable that this foreign effort will be concentrated in commodities with the largest established markets (e.g., ethylene glycol, polyethylene). The chemical industry must also respond to an active public concern for health and safety connected with possible exposure to toxic chemicals. This movement is most advanced in the United States, where concerns range from sensibly prudent to panicky. Economically, these responses must lead to higher costs to achieve the desired environmental protection, worker safety, proof of safety and effectiveness of new products, and protection against product liability. Of course, these costs are always paid for by the consumer, but they are significantly affecting the ability of U.S. industry to compete when the same industnes abroad do not feel the fud impact of these pressures. It is not surprising that the viability of chemical companies in the United States has become a cause for national concern. The advanced standard of living in the United States owes a great deal to the innovations and productivity of the nation's chemical businesses. Preservation of this quality of life depends to no small extent upon whether the United States can remain a strong and leading participant in chemistry-based technologies. A key factor responsible for past success has been the strength of U.S. university research and the effective use of its new discoveries to develop new products needed by society. Vigorous support of this academic research community is a critical first requirement for maintaining the ongoing health of the U.S. chemical industry. ENERGY AND FEEDSTOCKS Energy and chemical feedstocks are tied together through their overwhelming dependence on petroleum. Energy uses account for most of the consumption of these organic materials. Burning of petroleum goes on at an ever-increasing pace, and the future supply crisis is directly related to this fact. Throughout much of the world, people take petroleum-denved heat and transportation for granted. Thus, the inevitable depletion of the earth's petroleum resources will strongly affect the style and standard of living of people everywhere. The effects of de- pletion should become evident within two decades and severe within four. Hubbert has estimated that 80 percent of the worId's ultimate production of of! and gas will be consumed between 1965 and 2025. This estimate, made in 1970, seems to be consistent with current discovery and consumption rates. Its alarming implications are not fully recognized by the public. Petrochemical uses of petroleum account for only a few percent of the total 3 to 5 percent by most estimates. Thus, the chemical industry is not the cause of the approaching era of depletion, but the effects will be felt within the industry as feedstocks and processes change. However, petrochem- ical uses are charactenzed by higher retail prices, and they can withstand the 105 - a 0 0` en: . 1 1 1 1 . it, ~ OOJSU~ED . u' 1965.... 2025 C , . ,,., .,., ,.,.,.- c Jo ~ 9 so 2000 2050 2 100 YEAR An Estimate: Worldwide Production of Gas and O i 1 =_. <__,

106 HUMAN NEEDS THROUGH CHEMISTRY coming price increases brought on by decreases in oil and gas reserves better than uses involving combustion. Further, processes are already known for the conversion of coal to suitable forms for use as feedstocks, and coal deposits are more abundant. Therefore, it is expected that the impact of petroleum depletion on chemical feedstocks will be much less damaging than its impact on energy production. RENEWING OUR INDUSTRIES International competition is a general problem for U.S. industry. Steel, automo- biles, communications, textiles, and machine tools are examples of industries that have encountered significant problems. It is instructive to consider the response to these pressures in the automobile industry. It shows the central role of chemistry in maintaining and improving the U.S. position. The U.S. automobile industry evolved into a gigantic business during the first half of this century. In the 1950s and 1960s American products enjoyed great success. The vehicles were large, heavy, and powerful. Fuel was abundant and inexpensive. There was no reason to conserve, so fuel economy of the American car was not considered by buyers. Furthermore, few foreign-built cars made their way to North America. By the mid-1960s, however, Volkswagen had entered the U.S. market with sales of more than half a million small economy cars per year. During the 1970s the market was further affected by cars manufactured in Japan. Pursuing an aggressive policy of collecting design, technology, engineering, and assembly information from other countries, the Japanese developed the most automated and efficient car-building facilities in the world. These facilities, and a commitment to quality, yielded the worId's most fuel-efficient and low-cost cars at a time when gasoline prices began to soar. At the same time, antismog legislation was passed in the United States that required better fuel economy and placed strict limits on air pollution from automobile emissions. The American car was required to change dramatically, and the investment required by the manufacturers was very high, approximately $80 billion. The antismog objectives are being achieved through many developments involving chemistry: new and lighter materials, better combustion control and engine efficiency, catalytic exhaust treatment, lowered corrosion, reduced size, . . . transmission Improvements, etc. Polymers, aluminum, and high-strength alloy steels are used to reduce the weight of the car. New chemicals for of! additives and improved rubber formulations for tubes and hoses are solving problems of engine compartment temperature brought on by aerodynamic designs featuring sloping hoods. The ride quality of the smaller cars is being improved through the use of vibration-damping busy} rubber. Tire tread compounds are being reformulated to reduce rolling resistance. New, high-solid paints are being developed to reduce air pollution from automobile painting. Chemically based rust-proofing systems are being introduced to prolong life. Contemporary U.S. cars each contain over 500 pounds of plastics, rubbers, fluids, coatings, sealants, and lubricants, all products of the chemical industry. Further uses of plastic materials are sure to come. Reaction injection molding is a recently introduced process for making large parts such as fenders and hoods.

III-G. ECONOMIC BENEFITS High-performance composite materials, i.e., stiff fibers in a polymer matrix, have already appeared as drive shafts and leaf springs. Some advanced models have frames and bodies made of composite polymers. For automobiles, the use of composite polymers may lead to new design-fabncation methods which will greatly reduce the number of parts that must be assembled. Furthermore, new designs for light aircraft have airframes that are almost entirely composites. Advances such as these will tend to reduce the problems faced by the automobile and other basic U.S.industries, problems that arise from a complex mixture of historical prefer- ences, social pressure, legislation, and vigorous outside competition. NEW HORIZONS The chemical industry is changing, and chemical science is becoming importantly intertwined with other areas of science and technology. To an increasing degree chemists must be skilled at dealing with subjects in interrelated technologies. Chemistry is critical in providing materials and processes for American industry, meeting their wide range of needs from established industries (new electrode materials for aluminum production, decaffeinated coffees, sweeteners for the food industry, etc.) to rapidly growing, high-technology areas (composites for aircraft, ceramics for electronics and engines, protein pharmaceuticals, etc.~. Each of these areas requires development of chemical products that respond to markets outside of chemistry. Representative examples are given below. Biotechnology Biotechnology is not new. The ancients knew how to bake arid brew thousands of years ago. The processes of fermentation, separation, and purification have long been familiar. But as the molecular structure and basic chemistry of genetic matenal became known, a new era of biotechnol- ogy has opened up. (See Section IlI-F.) It led to gene splicing procedures that allow biochem- ists to cause bacteria to produce complex molecules with biolog- ical activity. Enzymes have been found that wid break chemical bonds in DNA chains at specific points and allow for- eign DNA to be inserted with new chemical bonds. The al- tered DNA wiD then produce proteins according to its revised code. The protein products can be hormones, antibodies, or other desired complex chemical compounds with specific prop- e~ties and functions. Interferon, 107 ~ ._ <$~! A'' + ~ ~ t ~ BIOTEC~C ~ 1~--~ L4> J ~ BI OTECH I Nc \/ ANYONE FOR DESIGNER GENES?

108 . HUMAN NEEDS THROUGH CHEMISTRY produced by bacteria with a human gene spliced in place, is expected to be valuable in treating a variety of diseases. Human insulin produced through gene splicing tech- n~ques is already being marketed. Activity is intense and commercial enterprises are emerging rapidly. The area of biotechnology is an exciting and optimistic one for scientists, engineers, and investors. Although some of the expectations may be extravagant, there can be no doubt that this area win give us many important economic developments in the coming decades. The United States is at present the world leader, with basic chemical and molecular biological research feeding an effective commercial community. Europe has strong, relevant research, and Japan has a leading position in fermentation processes. The advances that win determine the future of this field win come through a deep understanding of biology at the molecular level. Basic research on the molecular structure and chemistry of biological molecules wid be a crucial ingredient as we bring biotechnology into practical use. High-Technology Ceramics Ceramics are materials with high-temperature stability and hardness; they tend to be brittle and therefore are difficult to shape in manufactunng. Ceramics are now of major commercial interest for components of electrical devices, engines, tools, and a wide range of other applications in which hardness, stiffness, and stability at high temperatures are essential. Major advances in their use can be anticipated because of new chemical compositions and novel fabrication techniques. For many, many centunes, ceramic pieces have been made from fine particles suspended in a liquid (a slurry) or a paste of a finely ground natural mineral. The slurry is formed or cast in the desired shape and then "fired," i.e., heated to a high enough temperature to burn away the added slurry components and to melt and join the mineral particles where they touch. We now know that the strength of the final object is cntically limited by small imperfections. A number of new chemical techniques are now being developed to synthesize new ceramic starting materials that will produce more defect-free final products. These techniques depend upon control of reaction kinetics and tailoring of molecular properties. For instance, controlled hydrolysis of organometallic com- pounds is used to generate highly uniform ceramic particles ("sol-ge! technology". Organometallic polymers can be spun into fibers, and then all but the polymer skeleton is burned away to produce high-temperature materials like silicon carbide. Highly uniform temperature-resistant coatings in desired shapes can be produced using high-temperature reactions of volatile compounds followed by controlled deposit of the products onto a preformed solid object. For example, jet engine parts might be made this way. Addition of suitable impurities ("doping agents,') can change properties dramatically. For example, alumina ceramics can be significantly toughened by the addition of zirconia, solid ZnO2. Advanced Composites and Engineering Plastics The discovery of ultra-high-strength fibers based upon graphite embedded in an organic polymer has led to development of a new class of materials now referred to as "advanced composites." A fiber, such as a graphitic carbon chain, a mineral

III-G. ECONOMIC BENEFITS fiber, or an extended hydrocarbon polymer, is suspended in a conventional high polymer such as epoxy. The resulting composite can exhibit tensile strength nearly equal to that of struc- tural steel but at a much lower density. Because of this high strength-to-weight ratio, such composites are finding abun- dant applications in the aero- space industry. Significant weight reductions are achieved in commercial and military a~r- craft that use airframes and other aircraft components made of composites. Other applica- tions include space hardware, sporting goods, automotive components (e.g., Unve shafts and leaf springs), and boat hubs. There has also been a rapid development in designing 5000 30 21 ~ o ! ill 20 I=` Hi ~1 ICI All I 1 0 1_3 1_ 1~ . , _ ~ : ADDITION OF -ElTRA5- MEETING REGULATIONS FOR SAFETY, POLLUTION r C^R WEIGHT/ it, J GA S M I LEAGEI V 1 INTRODUCTION OF LIGHT WEIGHT - hIATERIALS /- \ / . · , ~ ~ 950 1 960 1 970 1 960 1 990 YEAR HIGH STRENGTH-TO-WEIGHT MATERIALS DOUBLED AUTO MILEAGE- 1975 TO 1985 polymer mixtures to obtain particular properties or behavior. Success with these polymer "alloys'' or "blends" has required a high degree of chemical under- standing of the molecular interactions at phase boundaries between two polymers that are not soluble in each other. An example is the commercial polymer blend called Zyte! Y.T.@, a nylon toughened with an elastic hydrocarbon. The development of this high-performance plastic was based upon extensive studies of interactions at interfaces between different polymers. Plastics are also being developed for high-temperature applications such as engine blocks for automobiles. A prototype '~plastic engine'' based on reinforced polyamide and polyimide resins has been demonstrated in an actual racing car. An engine weight reduction of 200 pounds can be achieved, with obvious benefit to fuel economy. All of these technologies are moving forward rapidly around the world. Carbon fiber production has been well developed in Japan, while the United States is showing the way in high-strength polymeric fibers. The nature of the bonding region between the fiber and its composite environment is an important factor in structural performance but is poorly understood chemically. Research will figure importantly in the evolution of the field. sooo — :~ 3000 c: 5 2000 Photoimaging The aim of photography is to produce an accurate and lasting record of the image of an object or a scene. With a history of 150 years, the silver halide process has evolved from complex procedures conducted by specialists with a working knowledge of photochemistry into a pastime expertly pursued by a large chunk of the population. The camera owner presides over remarkable feats of optics and chemistry to produce pictures on the spot, usually without having the faintest 109

110 HUMAN NEEDS THROUGH CHEMISTRY appreciation of what goes on in the camera and on the film. The result brings lifelike communication and pleasure to people throughout the world. The chemistry of the photographic process can be usefully divided into the inorganic photochemistry of the silver halide and the organic chemistry of sensitization, development, and dye formation. When radiation strikes a microcrys- tal of a silver halide in the film emulsion, a faint image is formed that is believed to consist of a few atoms of metallic silver. The metallic silver functions as a catalyst for the reduction of the entire microcrystalline grain under the chemical action of an easily oxidized organic substance, the "developer." The silver halide grains in a photographic film are typically about one micron in size, and control of the size and shape of the particles is important. Although silver halides are sensitive only to light at the blue end of the spectrum, the grains can be activated at longer wavelengths with sensitizing dyes on the crystal surface. These molecules are coated onto the silver halide surface in layers less than one thousandth of a millimeter thick. Color is achieved when the oxidized form of the developer reacts with another organic compound to give a dye of the required hue. By combining the 3 color primaries, 11 colors can be achieved. Conventional color photography involves several carefully controlled chemical processes, including development, bleaching, fixing, and washing. In instant color photography these steps must be combined in a single sheet that can be processed under existing light without temperature control. A typical instant film contains over a dozen separate layers with thicknesses of about one micron each. Physical chemical factors such as solubility and diffusion are critical, as are the chemical reactions occurring in the various layers dunug processing. The sophistica- tion of the chemistry of instant color photography is difficult to comprehend consid- ering how simple the camera is to use. In this important area of our economy, new technological achievements continue to appear, ranging from amateur photography to such demanding and specialized uses as photoresists for semiconductor production (see below) and infrared mapping of the Earth's resources from satellites. The United States has been the world leader in photographic technology for many years in an industry in which the connection with our traditional research strength in photochemistry is clear. Microelectronic Devices The microelectronics revolution has already had an enormous impact on the industrialized world, and it is clear that there is a great deal more to come. The best- known device is the microprocessor, a remarkably intricate and functionally integrated electrical circuit built on a tiny bit of pure silicon, called a "chip." Some microprocessors and the latest high-capacity computer memory chips contain hundreds of thousands of individual transistors or other solid-state components squeezed onto a piece of silicon about one-quarter of an inch square. These chips are currently made from highly purified silicon which contains impurities that have been deliberately implanted to form individual devices with desired electronic functions, such as amplification, rectification, switching, or storage of on-off logic information. These minute devices are then interconnected by metal "wires" on a microscopic scale. The fabrication of these exquisitely

III-G. ECONOMIC BENEFITS complex devices depends cntically on thin (less than one micron thick) organic films that are sensitive to radiation. Their technology involves organic chemistry, photochemistry, and polymer chemistry. The purpose of these films is to allow impurities or "dopants" to be added selec- tively to the silicon forming the pattern of a desired electncal circuit. Because steps in the process involve high tempera- ture, a thin layer of silicon dioxide is used to mask the underlying silicon. This mask determines whether or not the silicon below is exposed for doping. Organic materials called photoresists are used to form the pattern that is trans- fe~Ted into this silicon dioxide layer. In photolithography, chemi- cal changes in the photoresist matenal are begun by exposure to light. In these changes, co- valent chemical bonds are bro- KEY STEPS IN THE ken (or formed) at light-sensi- FABRICATION OF SILICON INTEGRATED live chemical groups attached CIRCUITS USING PHOTORESISTS to the polymer structure. These chemical bond changes result in a local increase (or decrease) of the photoresist solubility in a suitable solvent. Thus, after exposure through a mask, an image of the mask can be developed merely by washing in the solvent. What is not generally appreciated is that this solubility is achieved through carefully designed polymer photochemistry. Existing organic photoresists were able to achieve the spacing between circuit elements needed in the early 1970s when individual circuit features were in the size range of 3-10 microns. However, the continued desire for smaller devices has demanded smaller and smaller features. A decade ago it became apparent that new photoresists would be needed because existing materials were not capable of defining the feature sizes (1-2 microns) soon to be required. The development of these materials has been made possible by the research in polymer chemistry, photochemistry, and radiation chemistry done in the last two decades. Because these circuit elements have dimensions close to the wavelength of light normally used for conventional photographic imaging (0.4 microns), diffraction effects caused by lines and marks on the mask become important. These effects can be reduced by using shorter-wavelength radiation. Hence, lots of effort is being spent on widespread development of resist matenals that are chemically sensitive to ILLUMINATED AREAS - NEGATIVE RESIST O RENDERED I NSOLUBLE LIGHT | ~ ~ ~ ~ ~ MASK 111 ~ 11/ ~ — — ~ ,PHOTORESIST ~ ~ . ~ ~ at, = .., .. .., , , _ ~ ~ —SILICON DIOXIDE POSITIVE RESIST ORENDERED SOl UBLE 1 rat ETCHED FILM PATTERNS RESIST REMOVED ~ E3 if, ~ 111

112 HUMAN NEEDS THROUGH CHEMISTRY exposure with short-wavelength ultraviolet light, X-rays, and even electron beams, instead of the near-ultraviolet light now used. The mask itself is now made by chemically etching the desired pattern into a thin chromium film deposited on glass. The pattern is "written" into a resist film by exposure to a computer-controlled electron beam. The development of the organic resist material that is used for defining the pattern on the metal rests on relatively recent research. Many new types of chemical reactions and polymers are involved, and the advances in integrated circuit complexity could not have occurred if these new materials had not been available. Virtually none of them existed in 1970. Examples of new electron beam resists are the polymers that result from copoly- merizing various alkenes and sulfur dioxide. Their synthesis and radiation sensi- tivity were only recently discovered. A present trend in semiconductor fabrication is to use reactive gas plasmas from a glow discharge instead of liquid solutions to etch the material under the photoresist mask. Most organic materials are not sufficiently resistant to these vigorous conditions, and it has taken much research to provide a few useful materials. It is difficult to design materials having the necessary combination of physical and chemical properties. Their development will draw on continued research advances in polymer chemistry and photochemistry (including laser- induced chemistry). Molecular-Scale Computers . Miniaturization of electrical devices has been one of the most significant factors in the astonishingly rapid advances that have made modern computers possible. Circuit elements in present silicon chips have dimensions near one micron, i.e., in the range of 10,000 A. However, it may be that fabrication of microscopic devices based upon silicon and other semiconductor methods is beginning to push against natural barriers that will limit movement toward even smaller devices. Thereafter, breakthroughs will be needed. Where will we turn when existing technologies are blocked by natural limits? Irresistibly, we must contemplate molecular circuit elements that will permit us to move well inside the 10,000-A limit. We are led to think about computer devices in which information is stored in or transformed by individual molecules or assemblies of molecules i.e., molecular-scale computers. In a three-dimensional architecture, use of molecular circuit elements with lOO-A spacing would provide packing a million times more dense than now possible. The materials under discussion range from entirely synthetic, electrically conducting polymers to natural proteins. Molecular switches, the basic memory elements of the proposed computer, might be based upon charge movement in polyacetylene, photochromism, or molecular orientation in solids. Ideas on connecting the molecular elements to the outside world are still vague. As is normal, adventurous concepts generate exciting, often emotional contro- versy. However, the arguments of even the most sophisticated detractors are disarmed (contradicted?) by the obvious fact that their intelligent opposition is being generated in the human brain, a working "computer" using exactly the structure under challenge! In an age of machine synthesis of DNA segments and , . . ..

III-G. ECONOMIC BENEFITS laboratory design of artificial enzymes, it would be timid to say that we will never be able to mimic the elegant circuits that each of us depends upon to read and consider these printed words. Only a few de- cades ago, some individuals might have classified as science fiction a proposal that someday there would be a man on the Moon, that fertility could be controlled by taking a pill, or that we could learn the structure of DNA. But since we know that molec- ular computers are routine accessories in all animals ~3 ~ - ~ on ^ TV ~.~ ~- ~''--"~ Molecular Computer at Worlc from Ants to Zebras, it would be prudent to change the question from whether there will be man-made counterparts to the questions of when they will come into existence and who will be leading in their development. The question When? will be answered on the basis of fundamental research in chemistry. The question Who? will depend on which countries commit the required resources and creativity to the search. CONCLUSION The field of chemistry in the United States has great industrial and economic importance. The consistent and significant positive balance of payments is an indication of considerable strength. The continuing flow of innovations that benefit society is encouraging. U.S. universities are among the best in the world and year by year draw students from throughout the world for graduate study. We have a lot going for us. The United States must work hard and be creative to maintain its leadership in view of social values that lead to antitrust regulation, environmental restrictions, health and safety requirements, and high wage rates, all of which tend to increase the cost of U.S. chemical products. Hence, we must insist upon logical and objective justification of any restraints imposed by legislation while maintaining a balanced concern for the important social values represented in current regulations. And we must continue to stimulate the academic and industrial research that maintains the impressive knowledge base that makes our progress possible. We must attract some of the finest young minds to the field of chemistry, as only a sustained and vigorous approach will be effective in keeping pace in the essential field of chemistry, so necessary for any high-technology society. SUPPLEMENTARY READING Chemical & Engineering News `'Engineering Plastics: More Products, More Competition" by David Webber (C.& E.N. stab, vol. 64, pp. 21~6, Aug. 18, 1986. Cat Chemistry: Growing Field Despite Crude Oil Drop" by J. Haggin (C.& E.N. staff), vol. 64, pp. 7-13, May 19, 1986. "Marine Mining to Improve its Organization, Direction and Financing" by J. Haggin (C.& E.N. staff), vol. 63, pp. 63-67, Nov. 18, 1985. "High Tech Ceramics" by H. Sanders (C.& E.N. staf0, vol. 62, pp. 26-40, July 9, 1984.

114 HUMAN NEEDS THROUGH CHEMISTRY Scientific American `'Advanced Materials and the Economy" by J.P. Clark and M.C. Flemings, vol. 255, pp. 50-57, October 1986. `'Composites" by T.-W. Chou, R.L. McCul- lough, and R.B. Pipes, vol. 255, pp. 192- 203, October 1986. "Electronic and Magnetic Materials" by P. Chaudhari, vol. 255, pp. 136-145, October 1986. ``Advanced Ceramics'' by H.K. Bowen, vol. 255, pp. 168-177, October 1986.

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Experts agree that the nation would benefit if more young people "turned on" to the sciences. This book is designed as a tool to do just that. It is based on Opportunities in Chemistry, a National Research Council publication that incorporated the contributions of 350 researchers working at the frontiers of the field. Chemistry educators Janice A. Coonrod and the late George C. Pimentel revised the material to capture the interest of today's student.

A broad and highly readable survey, the volume explores:

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  • Working with lasers, molecular beams, and other sophisticated measurement techniques and tools available to chemistry researchers.

The book concludes with a discussion of chemistry's role in society's risk-benefit decisions and a review of career and educational opportunities.

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