Science
Electron transfer more common than believed Many reactions of alkoxides, dialkylamides, metal hydrides, Grignard reagents go through radical-ion intermediates rather than polar mechanisms
,ét
ATLANTA ACS National Meeting
Reagents like alkoxides, dialkylamides, metal hydrides, and Grignard reagents always react with such substrates as carbonyl compounds, alkyl halides, polynuclear aromatic hydrocarbons, and alcohols by polar mechanisms. Right? Wrong. A considerable chunk of organic chemical theory was rewritten during the time chemistry professor Eugene C. Ashby of Georgia Institute of Technology, Atlanta, was speaking to the Division of Organic Chemistry. Working with postdoctoral student Anil Goel and graduate student Robert DePriest, Ashby has amassed a large number of examples demonstrating that many such additions or reductions begin with single-electron transfer from reagent to substrate with formation of radical cations and radical anions, followed by transfer of hydride or another group from reagent radical cation to substrate radical anion. Ashby is cautious about overinterpreting his results, however. He says that single-electron transfer occurs only when the oxidation potential of the reagent and the reduction potential of the substrate are favorable. When potentials are unfavorable, such reactions probably proceed by the nucleophilic, polar mechanisms usually written in organic chemistry texts. Nevertheless, the prevalence of single-electron transfer is probably more general than the list he has cataloged to date. This is because single-electron transfer can be verified only with reagents and substrates that yield intermediates detectable by 26
C&EN April 13, 1981
electron spin resonance (ESR) spectroscopy or products that require stable radicals to explain them. There may be other cases that have not been detected by available methods. The implications reach as far as introductory courses in organic chemistry. Discussions of these reactions in college sophomore texts will have to be a little longer. In his research, supported by the National Science Foundation, Ashby has developed three techniques for detecting reactions that proceed by single-electron transfer. One method is to choose reagents and substrates that form stable radicals and allow enough time to detect them by ESR before they react in the second step to form products. He uses both ESR and ultraviolet-visible spectroscopy to gauge relative reactivities of reagents and substrates by single-electron transfer according to concentrations of radical ions formed as well as to verify that the concentrations of radical ions decrease as those of products increase. His second method is to use such alkyl halides as l-iodo-5-hexene or l-bromo-2,2-dimethyl-5-hexene as substrates. Radical anions formed from these partly cyclize to give products derived from cyclopentylmethyl or 3,3-dimethylcyclopentylmethyl radicals. A third method is to verify that the amounts of radical anions formed from polynuclear aromatic hydrocarbons are proportional to the known reduction potentials of these. In reactions with lithium aluminum hydride, for example, the highest concentration of radical anions is formed from perylene, whose reduction potential is -1.64 eV, and the lowest concentration from naphthalene, with a potential of —2.56 eV. In studies on ketone reduction, Ashby treated dimesityl ketone with aluminum hydride, diborane, magnesium hydride, chloromagnesium hydride, and cyclopentadienylmagnesium hydride in tetrahydrofuran (THF). In all these cases, Ashby observed colored solutions that showed evidence of paramagnetic species— radicals—in ESR. For reaction of dimesityl ketone with aluminum hydride, for example, he found that the rise in intensity of
the radical anion/radical cation visible absorption peak at 579 nm rose as the UV peak at 269 nm for ketone fell off. Thereafter, decay of the radical anion/radical cation absorption matched increasing formation of dimesitylcarbinol product. Ashby also has studied reduction of naphthalene, anthracene, phenanthrene, 2,3-benzanthracene, chrysene, benzo[a]pyrene, and perylene with lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, chloromagnesium hydride, and cyclopentadienylmagnesium hydride. These reactions give colored solutions in T H F that are also ESR-active. Rates of color development depend on reduction potentials of hydrocarbons and reactivities of hydrides. At 10~ 4 M concentrations, 80% of perylene is converted to radical anion in two days by lithium or sodium aluminum hydride, and the color slowly fades thereafter. By contrast, only a trace of radical anion forms from naphthalene at higher concentrations after 10 days. The least reactive hydride, chloromagnesium hydride, converts only 20% of perylene to radical anion after 15 days. ESR and UV-visible spectra of reaction mixtures of any one hydrocarbon with a series of metal hydrides were identical, regardless of hydride used. Ashby adduces this as further evidence that only one radical anion intermediate forms in all cases. He has used lithium aluminum deuteride as well as hydride, and deuterium oxide as well as water quench, to show that part of the reduction of anthracene goes by abstraction of a hydrogen atom from lithium aluminum hydride radical cation to form 9hydroanthryl anion, followed by reaction with a second proton from quenching solvent to yield 9,10dihydroanthracene product. A greater part of the reaction goes, however, by disproportionation of anthracene radical anion to anthracene and anthracene dianion, which takes both protons from quenching solvent to give product. In the case of alcohols, reaction of lithium aluminum hydride with benzhydrol, di-o -tolylcarbinol, dimesitylcarbinol, triphenylcarbinol, and isopropyldi-ieri-butylcarbinol in T H F occurred with initial evolution
Single-electron transfer processes can be detected by isolation of isomerized products...
13%
10%
16%
59%
, or ESR detection of radicals
LiAIH4
of hydrogen gas, followed by development of colored, ESR-active solutions in the next few days. When Ashby reduced the alcohols with lithium aluminum deuteride, 90% of the substituted methane products were substituted with deuterium and 10% with hydrogen. He concluded that radical anions abstract hydrogen atoms from solvent to form product. Ashby's study of the reaction of l-iodo-2,2-dimethyl-5-hexene with lithium diisopropylamide is an example of his use of the cyclizing 5hexenyl group as a diagnostic marker for radical formation. Of the products, 10% was 1,1,3-trimethylcyclopentane and 16% was 3,3-dimethyl1-methylenecyclopentane in addition to 13% of 5,5-dimethyl-l-hexene and 59% of recovered starting material. He concludes that 1,1,3-trimethylcyclopentane could form only by reaction of 3,3-dimethylcyclopentylmethyl radical with quenching solvent or by disproportionation. 3,3Dimethyl -1 - methylenecyclopentane could arise either by disproportionation or by dehydrohalogenation of intermediate l-iodomethyl-3,3-dimethylcyclopentane. Lithium diisopropylamide or lithium or potassium ieri-butoxide all reacted with trityl chloride or bromide to give colored, ESR-active solutions. Lithium diisopropylamide
and trityl bromide gave triphenylmethane, which is consistent with a radical mechanism. Potassium tertbutoxide and trityl bromide gave ieri-butyltrityl ether, plus a small amount of 3-£er£-butoxy-6-diphenylmethylene - 1,4 - cyclohexadiene. Thus, he says, it is possible that some Williamson ether syntheses go by single-electron transfer mechanisms. The 5-hexenyl system also provided evidence of single-electron transfer mechanisms in reduction of alkyl halides by hydrides. Again, the extent of single-electron transfer was governed by the reduction potential of the halide and the reactivity of the hydride. l-Bromo-2,2-dimethyl-5hexene yields more 1,1,3-trimethylcyclopentane than the chloro compound, and the iodo derivative gives most of all. On the other hand, lithium aluminum hydride produces up to 96% of cyclized product, whereas the relatively less reactive chloromagnesium hydride gives hardly any. Even before Ashby's detailed studies, there were indications that hydrides might reduce some halides by single-electron transfer processes. Chemistry professor Sung-Kee Chung of Texas A&M University, College Station, recently showed that lithium aluminum deuteride produces about equal amounts of cisand trans -/3-deuterostyrene with ei-
ther cis- or trans -/3-bromostyrene. This product distribution would be expected from a radical but not from a polar mechanism. Chung earlier reported that lithium aluminum hydride reductions of aryl bromides also go by single-electron transfer. Many Grignard reactions of ketones also probably occur by singleelectron transfer, Ashby says. For example, following rates of reactions, Ashby finds that methylmagnesium Grignard reagents react with acetone faster than ieri-butylmagnesium reagents do. This is expected, he says, because the reduction potential of acetone is unfavorable (-2.56 eV) for single-electron transfer. On the other hand, the tert- butyl reagent reacts faster than the methyl one in the case of benzophenone. The reduction potential of benzophenone is only —1.88 eV, and the mechanism probably has switched from a polar to a radical one. tert- Butyl radicals are more stable than methyl radicals. Similarly, Ashby says, 2,2-dimethyl-5-hexen-l-ylmagnesium reagents give some cyclized products in reactions with benzophenone and 2-methyl- and 2,2 / -dimethylbenzophenones. Again, there have been indications in previous years that some Grignard reactions proceed through radical intermediates. Chemistry professors Harry S. Mosher of Stanford University and Cornelius Blomberg, then a visiting scholar at Stanford, found that 20% of the products from reaction of neopentylmagnesium reagents with benzophenone were neopentane and benzopinacol. These products could arise from dimerization of radicals from benzophenone and proton abstraction from the solvent by neopentyl radicals. Chemistry professor Jean Fouvarque of the University of Paris XIII, France, reached similar conclusions on observing ESR-active solutions on reaction of dibenzylmagnesium with fluorenone. Chemistry professor Torkel Holm of the University of Copenhagen, Denmark, has reported evidence that tert- butylmagnesium reagents react with hindered benzophenones by radical mechanisms but primary reagents do not. Ashby has since extended the single-electron transfer mechanism to primary Grignard reagents as well. Chemistry professor Masao Okubo of Saga University, Japan, also has suggested a singleelectron transfer mechanism for reactions of Grignard reagents with hindered ketones on the basis of ESR studies of reaction mixtures. D April 13, 1981 C&EN
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Science
Reactions tested for concerted mechanisms
ATLANTA ACS National Meeting
An experimental test of whether re actions occur in a concerted or step wise fashion has been developed by chemistry professor Laren M. Tolbert and graduate student Mahfuza B. Ali of the University of Kentucky, Lex ington. Their method also may guide chemists to maximize yields of de sired optical isomers during syn thesis. All concerted reactions—those that occur in one step—proceed so that symmetries of the molecular orbitals involved are conserved. Rules con cerning conservation of orbital sym metry, first laid down in their fullest form in 1965 by Roald Hoffmann of Cornell University and the late Rob ert B. Woodward of Harvard Uni versity, have helped chemists ever since to predict stereochemistries of products from concerted reactions. In fact, some chemists have tried to turn the rules around. Stereochem istries of products have been used as evidence that reactions are concerted. There are doubts as to whether this converse of the rules is valid. Semiempirical quantum mechanics cal culations of Michael J. Dewar at the University of Texas, Austin, have even cast doubt on the Diels-Alder reaction as a concerted one. He argues that a two-step mechanism via diradical intermediates is a lower en ergy pathway. Tolbert told the Division of Or ganic Chemistry that two identical asymmetric substituents induce op tical purity in one Diels-Alder reac tion that is twice as great as that in duced by one such group alone. He concluded the Diels-Alder reaction is a concerted one, because the effect of asymmetric substituents would be multiplicative if there were only one transition state. By contrast, he and Ali find no such cooperation in a photocycloaddition they studied that is known to occur stepwise. To study the Diels-Alder reaction, the Kentucky chemists used the re action between 1,3-diphenylisobenzofuran and dimethyl, methyl bornyl, and dibornyl fumarates. Dibornyl fumarate yields two diastereomers. Methyl bornyl fumarate gives four disastereomers—two with exo and 28
C&EN April 13, 1981
two with endo carbobornyloxy groups. The trans geometry of fumarates separates bornyl groups from one another so that they exert indepen dent asymmetric inductive effects. Tolbert reasoned that two such bor nyl groups would exert twice the ef fect on enthalpies and entropies of activation as one. This additive effect of bornyl groups on these components of free energy of activation becomes a multiplicative effect on the rate constants leading to one or another diastereomeric product. The Lexington team did not know absolute configurations of any of the diastereomers. They called the two from dibornyl fumarate a and β. They then used nuclear magnetic resonance (NMR) spectra to relate one pair of methyl bornyl diastereo mers to the α-dibornyl and the other pair to the β. They calculated relative amounts of each formed by intensities of exo and endo protons. They cal culated unknown chemical shifts for
protons on the same carbons as the carbobornyloxy groups of dibornyl adduct by taking the chemical shift of carbomethoxy protons and adding increments for geminal and vicinal carbobornyloxy groups. For their nonconcerted photo cycloaddition, Tolbert and Ali chose the reaction of trans- stilbene with the same fumarates. On analyzing ratios of diastereomers of various δ-truxinate esters produced, they found no such cooperation between two bornyl groups compared with one. δ-Truxinic acid is one of the isomeric 3,4diphenyl-1,2-cyclobutanedicarboxylic acids. Tolbert predicted that chemists may be able to use the cooperative effect in the future to maximize op tical purities of products from con certed reactions. By studying effects of single, asymmetric groups attached at various places on substrate mole cules, chemists might predict which combination would give the highest optical purity. D
Unexpected roles for lipids surfacing
£5- 'ή
ATLANTA ACS National Meeting
Molecules belonging to the general family of lipids are being found to have important and sometimes unexpected roles in controlling physiology. One of the more unusual recent findings was described to the Division of Medicinal Chemistry by Donald J. Hanahan of the University of Texas Health Science Center, San Antonio. He and his colleagues have identified what they call "the first biologically active phospholipid," meaning the molecule acts as a bio logical effector instead of in some structural capacity, which is more typical of phospholipids. The molecule, acetyl glyceryl ether phosphorylcholine (AGEPC), is the same as the scarce and elusive plate let-activating factor that resides in blood and that was first noted about 10 years ago. "We had worked on these compounds years ago/' Han ahan says. "So their recent discovery was not the result of the blinding ge nius that one might have over a mar tini." AGEPC exhibits several biological activities, according to Hanahan. In troducing it into the bloodstream of rabbits, for example, elicits a sharp
drop in platelet, neutrophil, and ba sophil cells in the blood. Also, the rabbits show a reaction like anaphy lactic shock when they are appro priately sensitized. The molecule is highly potent, exerting such activity when given in concentrations of about 20 nanomolar, Hanahan notes. Figuring out the structure of AGEPC was not easy, Hanahan says, and full understanding of the natural compound's stereochemistry still is lacking. Also, he and his colleagues know that AGEPC is probably a mixture of at least two compounds with fatty-acid chain lengths differing by one two-carbon unit. Other parts of the molecule cannot be varied without sacrificing biologi cal activity, Hanahan continues. For instance, the acetyl group on the second carbon position of glycerol is vital for biological activity, although
Acetylated phospholipid is biological effector ο
CH20(CH2)15CH3
II
CH 2 -0-P-CH 2 CH 2 N(CH 3 ) 3
oAcetyl glyceryl ether phosphorylcholine Note: The natural compound also can contain a fatty-acid chain having 18 instead of 16 carbons.
surprisingly the stereochemistry at that carbon so far does not appear to be so crucial, he says. Activity is highest when the nitrogen atom of the molecule is fully methylated. But the dropoff in biological activity when the first methyl group is left off is not precipitous. Another family of lipid molecules, called the leukotrienes (C&EN, Feb. 18, 1980, page 28), is under intense study and continues to provide biochemical surprises, according to K. Frank Austen of Harvard University medical school, who has collaborated extensively with Harvard chemist Elias J. Corey in studying these compounds. For example, one of the leukotrienes, called LTB4, is perhaps the most potent natural chemotactic factor identified to date, he says. Another unusual aspect of leukotrienes may be their place of origin among cells of the body. For instance, some of the leukotrienes may be released from cells responding directly to others called mast cells. The mast cells are well known for their role in delivering and releasing histamine molecules in the body as part of the inflammatory reaction. One of the leukotrienes also can be involved in such reactions—it is called the slowreacting substance of anaphylaxis (SRS). e Medical researchers generally have thought that histamine release represents the early phase of anaphylaxis, and SRS release (thus its name) the slower phases. However, Austen says, the biological potency of the leukotrienes is so high that when their synthesis is begun—within seconds after histamine release—they also go very quickly into action. "I don't know what the mechanism is for turning on cells to make leukotrienes," he says, "but it's no 'secondary' action." The high biological potency of the leukotrienes helps to confound ordinary studies of molecular structureactivity relationships. Thus, for instance, changing the location of polar groups, eliminating certain double bonds, and the like can result in considerable losses in biological activity for the leukotrienes, Austen says. "But the response curve stays the same. That's very unusual in biology, but these molecules are so potent that several logs' [orders of magnitude] loss makes them still about as potent as histamines." What sorts of leukotriene analogs might make useful drugs is not yet known. No leukotriene antagonists yet have been identified, according to Austen. D
Computers: diverse uses, mixed success
ATLANTA ACS National Meeting
Computers steadfastly are worming their way more deeply into the chemical world. Though they are no substitute for intellectual ingenuity, they sometimes can offer helpful insights into chemical problems. Currently computers can directly provide chemists with two principal benefits: First, computers have the ability to cough up near-exhaustive lists of molecular candidates, depending on the nature of the analysis being performed. And second, when tied into appropriate visual-display equipment, computers offer a useful and efficient means for thinking spatially about molecular problems. On the analytic side of things, computers so far have been given mixed reviews for the help they provide. G. William A. Milne of the National Institutes of Health, Bethesda, Md., brought members of the Division of Analytical Chemistry up to date on efforts to identify chemical samples with the aid of computers. Several such systems work well when substances within the sample being analyzed already have been logged into the computer's data base. One system is used extensively by NIH and the Environmental Protection Agency, Milne says, and it's similar to another one that was developed by Cornell University chemist Fred W. McLafferty. The routine for such analysis is straightforward enough, with the computer searching through its library of data as it scans mass spectral information about an unknown sample, one peak at a time. Where this approach tends to break down and fail is in cases when it's needed most—namely, when the analytic sample contains previously undescribed materials. Of course, this is just the situation when a computer's infinite patience ought to be most useful; unfortunately so far it hasn't been so successful as its developers promised it to be, Milne says. The basis for such programs rests on the computer searching through structural data information and then working by means of logical induction to draw inferences about the structure of a compound (or mixture of compounds) being analyzed. Jargon, such
as Self Training Induction Retrieval System (STIRS) and Probability Based Matching search (PBM), gives some idea of the logic being programed into various systems. Despite the logical sound to such terminology, computers simply don't score so well on all the analytic tasks they're given. For example, the NIH/EPA system succeeds in only about 30% of the cases, Milne says. And presented with a challenge such as analyzing the contents of Love Canal waste dumps, the success rate was even lower, or about 9%, he adds. Another way to use the computer is to have it list all the structural formulas that a particular empirical chemical formula makes possible. Several chemistry research groups, including ones at Stanford University, Arizona State University, and in Japan, have developed more or less similar computer programs for dealing with this problem. Perhaps the best known of these systems is Congene, developed by Carl Djerassi at Stanford University in California. Given an empirical chemical formula, that program will generate "positively huge numbers" of structural possibilities, according to Milne. When the empirical formula gets moderately large, those numbers quickly can get into the hundreds of millions. Thus it immediately becomes essential to apply constraints and thereby cut the list down to a more reasonable size. At this point all of the current computer programs fall short, usually requiring direct human intervention.
Long: trying for quantifiable judgments April 13, 1981 C&EN
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Science thrusts—one devised by Elias J. Corey and his colleagues at Harvard University and the other by William L. Jorgensen at Purdue University. Corey's collaborator at Harvard Alan K. Long summarized that frustration succinctly in Atlanta: "I'd like to report we have had more success than we actually have had," he said. One curious but still theoretical advantage a computer has is that it lacks the prejudices of a typical organic chemist, Long says. "We have been directing the program to look at strategies and techniques instead of keeping the data base up. So it still can't come up with syntheses that a good organic chemist can come up with." The program now contains information for about 450 organic reacPensak: computer gets closer to nature tions, some in great detail. The general strategy is to begin with the Such intervention goes by various structure of an end-product molecule names, but no matter how fanciful the and work backwards by having the name it inevitably amounts to computer generate structures that throwing in fudge factors that require could be intermediates in a synthetic the presence of a well-educated pathway. Recent work on the prochemist to direct the computer gram has been devoted to making search. "It may be entirely valid, but that search go in both directions, the caveat is that the human intellect Long says. "We're trying to get has done well without going through quantifiable judgments put into the this exhaustive approach," Milne computer program. The 'look-ahead' says. "Maybe the methods won't work capability can provide all possible until we have better means of prun- ways to construct a target molecule. ing." The saving grace is that, by The program compares which sebeing exhaustive, the computer pre- quences [of reactions] seem most sumably does not overlook any rea- feasible in the lab and which would sonable possibilities. A weary chem- take the fewest steps and have the ist, on the other hand, might omit highest reliability," he adds. "But the something from consideration. final judgment rests on the fickle If computers sometimes frustrate forces of nature in the lab." analytical chemists, they also have Computers are proving a great deal frustrated organic chemists seeking less frustrating when used to portray to use computers to help design novel molecular shape. That use not only syntheses. There are two major provides instant visible proof of success, it's also leading to design of drug candidates and to analysis of complex biological molecules. "We tend to forget that molecules have size and shape," says David Pensak of Du Pont. "The computer is a good tool to get closer to nature." For instance, computer-assisted analysis enabled Du Pont chemists to realize that four seemingly separate classes of pharmaceutical^ active compounds actually were similar in the way they bound to a particular receptor. "The computer allowed us to focus to produce many more compounds that have biological activity in a shorter time," Pensak says. This same utility of computers is showing up increasingly for scientists eyeing the large molecules that make up the biochemical world. For most macromolecules, x-ray crystallograFeldmann: must hit the lock's tumblers phy is the "rate-limiting process" in 30
C&EN April 13, 1981
figuring out their structures, according to Richard Feldmann of NIH. But recently, biochemists are doing macromolecular structure analysis that "extends beyond the crystal data. The reliability varies," he says, "but it gives the biochemist insight." Feldmann cites as an example his work in collaboration with a hematologist studying blood-clotting factors. Many of those factors are scarce proteins whose biological activities include self-destruction. "It's almost impossible to get enough of these molecules to do crystallography," he says. But computer programs tied into visual display systems now can "imagine" the structures of such proteins fairly rigorously. The programs work by extending information obtained from analysis of other proteolytic enzymes. All of these proteins work as lock-and-key combinations, Feldmann says, adding: "The lock is a tumbler lock, and the specificity occurs around the periphery of the active site. "The implication for drug design is that you can't block the blood-clotting factor specifically unless you design something that can hit the tumblers," he continues. "That's a useful insight." D
Root of nitrosamines' carcinogenicity sought
ATLANTA ACS National Meeting
Since the revelation some 14 years ago that nitrosamines could cause cancer in rats, the widely found compounds have provided a fertile field for research. Some recent findings were discussed at a symposium on nitrosamines organized jointly by the Division of Agricultural & Food Chemistry and the Division of Pesticide Chemistry. For example, Christopher J. Michejda, of the National Cancer Institute's Frederick Cancer Research Center, Frederick, Md., noted that nitrosamines, like many other organic carcinogens, have to be metabolized to express their carcinogenic potential. In the case of nitrosamines, they must be metabolically converted to electrophilic alkylating agents. One of the commonly accepted mechanisms for this conversion involves an enzyme-mediated hydrox-
ylation of the α-carbon of nitrosa mines, leading to an alkyldiazonium ion as the alkylating species. How ever, Michejda says, although the α-hydroxylation route is an impor tant one, it isn't the only one. Recent experiments by Michejda and asso ciates have shown that the iV-nitroso group exerts a powerful anchimeric (neighboring group) effect on leaving groups on the /3-carbon and that ap propriate derivatives of these /3-hydroxylated nitrosamines are very good biological alkylating agents. The most recent studies, Michejda adds, suggest that /3-hydroxylation of nitrosamines, followed by appropriate conjugation, should be considered an activation process leading to directacting carcinogens. This is important, he says, because /3-hydroxylated ni trosamines (for example, diethanolnitrosamine) are found in significant quantities in nature and are also formed metabolically. In any event, the chemistry of ni trosamines is far from simple, ac cording to William Lijinsky, also of the Frederick center. He notes that some 150 iV-nitroso compounds have been tested for mutagenicity to bac teria and carcinogenicity to animals, but that the results haven't led to any simple concept of the mechanisms of either phenomenon. For example, there are "notable exceptions" to the rule that carcinogens are mutagens. Also, small changes in structure can lead to large changes in carcinoge nicity; sometimes the target organ also changes. α-Oxidation seems to be a usual mechanism of activation, Lijinsky says, since α-deuterium substitution generally lowers carcinogenic poten cy, at least in rats. However, in the case of nitroso-2,6-dimethylmorpholine, α-deuterium substitution increases carcinogenicity to hamsters, indicating an activation pathway different from that in rats. The rela tive potencies of cis and trans isomers are also opposite in rats and ham sters. Lijinsky offers more evidence of the importance of structure: In rats, he says, smaller nitrosomethylalkylamines induce tumors of the esopha gus and also some liver tumors; even-numbered long-chain com pounds induce bladder tumors; oddnumbered long-chain compounds induce liver tumors; the Cs compound induces both. This suggests, he says, that /3-oxidation might be involved in activation of the even-numbered compounds to bladder-active agents, but is not important in liver carcino genesis.
U.S. and Japan have found that fish of a type frequently eaten in Japan, when reacted with nitrite at pH 3, yielded an extract that in Ames tests was "powerfully mutagenic." Ad ministered to rats, the extract caused gastric cancers of a type also seen in humans. The group also found that addition of vitamin C (ascorbic acid) to the fish before pickling prevented formation of the mutagen. Weisburger notes that this confirms earlier studies by Sidney Mirvish at the University of Nebraska, Omaha. He concludes that the trend to greater year-round con sumption of vitamin C-containing fresh foods may have contributed to the decline of stomach cancer in the U.S. Meanwhile, another American Lijinsky: competition among pathways Health Foundation team, led by Dietrich Hoffmann and Stephen S. Except for the simplest com Hecht, has been investigating the pounds, Lijinsky says, "It seems presence and significance of volatile probable that the metabolic pathways nitrosamines in tobacco and tobacco leading to carcinogenesis comprise smoke. Hoffmann notes that the several steps." The major routes of agents aren't present in fresh tobacco nitrosamine metabolism are probably but are formed during aging, fer detoxification pathways. But other mentation, and processing. The AHF "minor pathways" may be more rel scientists also are concerned about evant to carcinogenesis. In addition, high levels of nitrosamines in chewing "there seems to be competition be tobacco and snuff. D tween the various pathways," so that small differences in chemical struc ture can result in large changes in Plant extracts disturb carcinogenicity. And "while consid erable metabolism of nitrosamines insect pests' molting occurs in the liver, it is likely that specific activating enzymes exist in various organs. These may be re sponsible for the pronounced organ specificity of many nitrosamines." ACS National Meeting The relationships between diet and cancer continue to be studied and debated. In another presentation, John H. Weisburger of the American In the search by scientists for safe, Health Foundation commented that nonpolluting ways to control insect no human cancers have yet been un pests, one approach—disturbance of ambiguously attributed to nitro hormonal systems—can lead to some samines. However, it's certainly been bizarre, if effective, results. A case in shown that nitrosamines can induce point is the disturbance of the molt cancers in animals. Specifically, ing process of two major cotton pests Weisburger says, it's been shown that that leads to their starvation. stomach cancers can be induced in The work was described to the Di animals by alkylnitrosoureido com vision of Pesticide Chemistry by Isao pounds formed by reaction of nitrile Kubo, assistant professor of natural with suitable substrates. products chemistry in the depart In the U.S., Weisburger says, can ment of entomology and parasitology cer of the stomach isn't nearly so at the University of California, common as it was 50 to 70 years ago, Berkeley. He worked with entomol when it was "a major killer." But in ogy doctoral candidate James Klocke some parts of the world—Japan, for and entomology research associate example—the incidence of gastric Shoji Asano on the university-sup cancer is still high. One reason may be ported research. that the Japanese eat significant The researchers have isolated ecamounts of foods pickled with salt dysis (molting) inhibitors—phyand nitrite. toecdysones—from an East African Weisburger and coworkers in the medicinal plant, Ajuga remota (La-
ATLANTA
April 13, 1981 C&EN
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Science could continue feeding because of impaired mandibular function due to restricted expansion of the new head capsule. Those unmasked larvae that could feed, again experienced mask ing at the next molt. The phytoecdysones also were fed to two other troublesome pests, the corn earworm and tobacco budworm. But they molted without difficulty. Silkworms, however, respond like the cotton pests. Kubo points out that it's important to know more about the compounds to prevent any harm they might do to Three head capsules ( as big as pinhead)silkworms as well as to use them in mask mouth parts of starving army wormpest control. Eventually the Berkeley scientists hope to test the compounds biatae), and fed them to several in the field by breeding them into species of insects. The effect, when plants that the pests feed on or by they were fed to larvae of the pink spraying the plants. bollworm and fall armyworm, was to To get greater quantities than are prevent the larvae from shedding now available, the researchers are their head moltings, leading to their experimenting with cheap ways to death. synthesize simpler phytoecdysonelike D Kubo notes that the bitter tasting compounds in large amounts. leaves and roots of A. remota are well known to be naturally resistant to insect attack. In fact, he says, four X-ray method clarifies diterpenes have been chemically identified from the ether extract as zeolite structure having antifeedant activity against a major East African pest, Spodoptera exempta. The phytoecdysones came from a methanol extract of the leaves and roots. ACS National Meeting Biological assay and purification of the methanol extract were used to isolate two active principles, which were then identified by spectroscopic A more detailed examination of the data as cyasterone and ecdysterone. structure of metal-exchanged zeolites It has long been known, Kubo says, is possible using extended x-ray ab t h a t ecdysteroids have marked sorption fine structure (EXAFS) physiological effects. What the cur techniques, according to a team of rent work establishes, he says, is that researchers from Sandia National the compounds act through ecdysis Laboratories, Argonne National inhibition in successive molts until Laboratory, and the University of death is the result. Connecticut. Cyasterone and ecdysterone, Kubo Timothy I. Morrison of Argonne explains, apparently upset the time explained some of the capabilities of pattern of the molting cycle because this technique to a symposium on the hardening of newly synthesized cu surface properties of inorganic com ticle occurs before its expansion, so pounds at elevated temperatures and that the previous cuticle remains ad their relation to catalysis. The sym hering to and masking the new cuti posium was sponsored jointly by the cle. The process, he says, repeats itself divisions of Inorganic and Petroleum until individual larvae have up to Chemistry. three cuticular head capsules, all of Zeolites are highly structured aluabout equal size and all adhering to minosilicate compounds with an open one another. The larvae are unable to anionic polycrystalline network in continue feeding because their mouth which large cavities are joined by parts are masked by unshed head channels. Large ions or water mole capsules. cules can occupy these cavities and If the old capsules weren't removed move fairly freely from one cavity to from the insects artificially, death another. occurred within 72 to 96 hours after Because they have a large internal the onset of the abortive molt. Kubo surface area and an acidic framework, says that even when affected larvae zeolites are often excellent catalysts were artificially unmasked, only some for petrochemical reactions. Their
rr
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C&EN April 13, 1981
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ATLANTA
definite pore structure gives them a high degree of shape selectivity as catalysts; thus, they can be tailored to select for a particular desired product. However, the very importance of precise structure in a zeolite makes detailed information about the structure of these compounds par ticularly significant both for under standing how existing zeolites work and for engineering new ones. X-ray diffraction studies can give much information on the zeolite framework, Morrison says, but for zeolites that contain exchanged cat ions—and many of the better cata lytic ones do—x-ray diffraction can not pinpoint the precise location of individual cations unless they are placed uniformly within the zeolite framework. EXAFS is an obvious tool for lo cating such cations, Morrison says, because it probes the local environ ment around a particular absorbing atom. Since the oscillations that EXAFS measures occur with nearly all elements, the technique can be used to pinpoint the location of any cation within the zeolite. One example of the kind of infor mation EXAFS can provide is the structure of hydrated cation-ex changed zeolites. Single-crystal x-ray diffraction studies on these com pounds give surprising distances for the spacing between the absorbed ions and framework oxygens. EXAFS studies of the environments around absorbed cobalt or manganese ions, however, show that these cations are essentially solutionlike and are highly disordered. They move about much as if they were in aqueous solution. Thus, the unusual cation-oxygen distances found in x-ray diffraction studies are probably average dis tances for many atom pairs and do not represent any real spatial ar rangement within the zeolite. EXAFS studies can be supple mented by a newer technique which Morrison calls x-ray absorption near-edge structure, or XANES. Whereas EXAFS is sensitive to the arrangement of atoms around an ab sorbing atom, XANES gives infor mation about the symmetry and chemical bonding of the complex. The two techniques provide comple mentary information about cations in zeolites, Morrison says. XANES studies of copper ion complexes in aqueous solution and in a large-pore zeolite, for example, give virtually identical spectra, helping to confirm that cations of this type are essen tially in solution within zeolites. Π
