that mouse fit with how that control element works under ordinary cir cumstances in mice, Brinster notes. What made this mouse's gene so much more responsive than those of any of its experimental litter mates is unknown, thus raising the possibility that its apparent high degree of con trol may have been fortuitous. The injected genes go into different animals at vastly different chromo somal locations, usually even on dif ferent chromosomes, Brinster and other scientists, including Columbia University's Frank Constantini, are finding. Nonetheless, those genes can take a stable place there, so that they can be passed through the germ line to successive generations of mice. The next big step will be to introduce those genes into specific sites sys tematically. As Brinster sums it up, "There's still a long way to go to get proper regulation." Jeffrey Fox, Washington
CHEMICAL SAFETY
Molten salt baths cited as lab hazards A University of California, Berkeley, lab has been rebuilt and is ready for use again after being demolished in late July by the explosion of a molten salt bath. Berkeley chemistry and chemical engineering faculty mem bers are concerned that many re searchers are unaware of the potential dangers of these commonly used heat-transfer media. The explosion involved a glass polymer-synthesis apparatus im mersed in a fused salt bath containing 3 lb of sodium nitrite and 1 lb of po tassium thiocyanate. The bath had been heated above 270 °C using a hot plate. The experiment was being conducted in a closed fume hood. The explosion, which Berkeley faculty members estimate had the force of about 1 lb of dynamite, caused more than $200,000 damage to the new lab. The doors of the fume hood were imbedded in a wall 20 feet from the point of explosion and the interior walls of the lab were bulged outward. The chemical engineering graduate student conducting the ex periment escaped probable death only because he was bending over to work on a floor vacuum pump at the time of the explosion. Book references to molten salts imply that they may be used freely, according to C. Judson King, dean of Berkeley's College of Chemistry.
Berkeley lab was demolished when a heated nitrite/thiocyanate mixture exploded
"Molten salts are safe—that's the message," he says. Some may be, but others clearly are not. Mixtures of salts for heat transfer are common and are marketed com mercially. Such commercial mixtures contain, for example, potassium ni trate, sodium nitrate, and sodium nitrite. King points out that, in the com mercial mixtures, all of the compo nents are oxidizers. In the mixture that exploded at Berkeley, thiocy anate, a reducer, was included and seems to have triggered the explosion. Mixtures that contain only nitrate and thiocyanate do not seem to ex plode. The explosive reaction in volved nitrite and thiocyanate.
The literature is not of much help in elucidating the problem. The dangers of the mixture are not men tioned in the molten salt safety review in the Journal of Hazardous Mate rials, King says. An extensive litera ture review carried out by King un earthed a 1945 Soviet publication that reported that some mixtures of potassium nitrite and potassium thiocyanate exploded when heated above 370 °C. "A small community of industrial chemists is aware of the dangers of molten salt baths," King says. "However, the information does not seem to have filtered down to the rest of the chemical community." Rudy Baum, San Francisco
Electrocyclic biosynthetic reactions probed Spontaneous formation of a series off thesized seven compounds in the setetracyclic compounds from acyclic,, ries. A sample of one of these led unsaturated precursors in the labo Australian chemists to find their ratory has given support to a theory/ fourth acid. The story that led to discovery of that these compounds arise from aι series of electrocyclic reactions inι this novel electrocyclic biosynthesis nature. If so, this would be one of aι began 25 years ago at the University very few electrocyclic mechanismss of New England, Armidale, New that occur in biosynthesis of natural1 South Wales, Australia. Organic products. The theory itself would1 chemist James E. Banfield received a explain why living organisms makeΒ shipment of stems and leaves of the complex molecules with eight asym Dorrigo plum tree for investigation. metric atoms in racemic form. The Dorrigo plum, which is EndianIt was organic chemistry professorr dra introrsa, is a rare tree that grows K. C. Nicolaou of the University off in the rain forests of New South Pennsylvania, Philadelphia, who re Wales. Banfield was plagued with a lack of ported that generation in situ of theι suspected biogenetic precursors leads5 adequate instruments to investigate to isolation of endiandric acids [J. the structure, and by the very lack of Am. Chem. Soc, 104, 5560 (1982)]. optical activity in the first compound He calls the spontaneous sequence off isolated. Likely structures contained three electrocyclic reactions thatt asymmetric atoms, but it seemed ensue the endiandric acid cascade. improbable that such compounds Four such acids have been isolated to3 from natural sources would be optidate from an Australian tree called1 cally inactive. Banfield enlisted the the Dorrigo plum. Nicolaou has syn- help of organic chemistry professor Oct. 11, 1982 C&EN
29
Science
Nicolaou: mimicking an Australian tree
David Black of Monash University, Clayton, Victoria, Australia, who studied acid A by single-crystal x-ray crystallography. Meanwhile, Banfield isolated acids Β and C from a second stand of the Dorrigo plum, 200 miles north of the first. Black deduced the complete structures of the three acids. He ver ified the lack of optical activity by measurement at different wave
lengths of light. The centrosymmetric x-ray structure also confirmed the racemic nature of the acids. Black went on to propose that nonenzymic, electrocyclic reactions could produce racemic compounds from precursors with symmetrical molecules. Nicolaou became interested in the problem independently. Working with graduate students Nicos A. Petasis and Robert E. Zipkin, and postdoctoral fellow Jun-Ichi Uenishi, Nicolaou synthesized acids now called A, B, C, D, E, F, and G. The work was supported by Merck Sharp & Dohme, the Alfred P. Sloane Foundation, and the Camille & Henry Dreyfus Foun dation. Using a sample of Nicolaou's acid D, Black was able to find this com pound in extracts of the Dorrigo plum. The Australian chemists have found no evidence for acids E, F, and G, however, despite the expectation that an electrocyclic endiandric acid cascade would produce these also. But a question remained as to whether Black's postulated acyclic, polyunsaturated precursors would yield endiandric acids spontaneously. Nicolaou demonstrated that they could, by making these precursors. The Philadelphia group generated methyl esters of 15-phenylpentadeca-3,5,7,9,12,14-hexaenoic and 17-
phenylheptadeca - 2,5,7,9,11,14,16heptaenoic acids in situ by hydrogénation of diacetylene intermediates. For example, hydrogénation of methyl 15-phenylpentadeca-3,9,12,14-tetraene-5,7-diynoate at 25 °C yielded endiandric acids D and E. Heating the hydrogénation mixture to 100 °C before workup gave acid A. Also, hydrogénation of methyl 17phenylheptadeca-2,5,ll,14,16-pentaene-7,9-diynoate at 25 °C led to isolation of acids F and G, whereas prior heating to 100 °C produced acids Β and C. In addition to total syntheses of seven known and unknown endian dric acids and studies of their acyclic precursors, Nicolaou also has followed events at the end of the endiandric acid cascade with kinetics work. For example, he followed the nuclear magnetic resonance signal for methoxy protons of methyl ester Ε in deuterated toluene at 70 °C. He ob served disappearance of ester Ε with reversible formation of ester D and irreversible formation of ester A. Similarly, beginning with ester D, he saw reversible formation of ester E, which converted irreversibly to ester A. Again, beginning with ester F or G, Nicolaou found that they were inter convertible, but that the final prod ucts from each were esters Β and C.
Acyclic precursors cascade to polycyclic acids
COOCK
COOCf-k
zzzz
COOCH3
COOCH, Ph'
H3COOC"^
.COOCH, HXOOC
J.
J , HXOOC
COOCI-L Ph = phenyl
30
C&ENOct. 11, 1982
H'*
COOCH,
Education Extrapolating these results to lower temperatures, Nicolaou calculated that all these reactions could occur at ambient temperatures, as might be the case in nature. Indeed, some esters did become contaminated with others on long standing at 25 °C. Although Nicolaou has shown that endiandric acids can form nonenzymically and spontaneously from polyene acids in the laboratory, he cautions that there is as yet no evidence that the reactions are nonenz y m e in nature. An additional problem is the uncertainty about which geometrical isomers of polyene acids might be used in the Dorrigo plum. In his work to date, Nicolaou has used phenyl-Ci5 ester with the 3,4-, 5,6-, 7,8-, and 9,10-double bonds arranged transcis-cis-trans (EZZE). Similarly, his phenyl-Civ ester has the 5,6-, 7,8-, 9,10-, and 11,12-double bonds likewise arranged trans-cis-cis-trans. But he calculates that polyene acids that have an all-cis arrangement (ZZZZ) at these double bonds would give the same endiandric acids, and at a slower rate. Nicolaou presently is working on generation of all-cis esters. The geometrical isomerism of endiandric acid precursors is important to a complete solution of the problem. An additional significance would arise if the Dorrigo plum does make all-cis precursors. In that case, the fact would provide encouragement that relatively slower reaction rates would allow isolation of missing acids E, F, and G from plant materials. Having made great progress in demonstrating that the Dorrigo plum makes elaborate preparations for three consecutive spontaneous electrocyclic reactions to make these complex structures, chemists have begun to ask why. Preliminary screening indicates no pharmacological activity. But it has been suggested that endiandric acid secretions may inhibit germination of competing Dorrigo plum trees. Questions of phytochemistry and taxonomy of the once plentiful Dorrigo plum take on a certain poignancy in light of the fact that the tree is virtually extinct. Between the two stands in New South Wales, observers count only about 20 trees. Since collection of the first botanic materials 25 years ago, the Australian government has set aside these rain forest areas as national parks. Logging operations there in the past, however, may have altered the environment in such a way as to endanger the trees' existence. Steve Stinson, New York
Chemical research council gains solid financial footing Conceived at a gathering of industrial and academic scientists convened in Midland, Mich., just three years ago and delivered after a 14-month gestation, the Council for Chemical Research (CCR) held its second annual meeting at the end of last month in Houston. In less than two years, CCR clearly has grown into a lusty stripling. "We are now at a point where we can really go to work," says Malcolm E. (Mac) Pruitt, former vice president for R&D at Dow Chemical and CCR's first chairman. It is Pruitt, more than anyone else, who is credited with fathering the council. At the 1979 Midland conference, sponsored by Dow, he proposed forming an organization to provide a forum in which chemists and chemical engineers from both industry and academia could talk with one another and compare notes. Such an organization, he envisioned, could serve as a conduit for piping a steady stream of sorely needed funds from chemical producers into university chemistry and chemical engineering departments. Considerable skepticism was apparent, especially among academic scientists, at both the Midland meeting and an organizational conference held a year later in Bethlehem, Pa., regarding the need for such an organization and the motives of its industrial backers. Academic scien-
Pruitt: promoting mutual understanding
tists, however, have flocked to CCR. The initial membership goal of 100 university departments, each paying basic annual dues of $1000, has been exceeded; at present, 128 universities belong to CCR. Council officials figure that the academic membership likely will reach a maximum of 150. The 37 present members from industry, on the other hand, fall just a bit short of CCR's initial goal of 40, although included are a majority of the major companies in the chemical and petroleum industries, as well as a scattering of firms from other lines of business, such as GTE, Westinghouse, and Xerox. A few big chemical producers have not been enticed into CCR's fold, however; among them are Union Carbide, American Cyanamid, Olin, and Ethyl. Also still absent are almost all of the big drug houses. CCR officials hope the council eventually will attract at least 50 members from industry, each paying basic dues of $5000 a year. As a source of money for academic research, CCR also has fallen a bit short of what its backers initially had hoped for. They tend to blame the current recession for the shortfall, as well as the council's tardiness in getting its fund drive under way. The council has two channels for pumping industrial dollars into academia. It encourages—but does not require—member firms to increase their own direct grants to chemistry and chemical engineering departments, using guidelines established by the council. To date, just nine companies have done so, to the tune of $3.3 million to be divvied up between 1982 and 1984. Eastman Kodak's $1.3 million and Dow's $700,000 are the largest increases so far. In addition, industrial members can contribute to the Chemical Sciences and Engineering Fund, which is administered by CCR. Six companies provided nearly $560,000 this year, which has been divided among the 120 universities that were CCR members as of last April on the basis of the number of their Ph.D. graduates in chemistry and chemical engineering during the past three years. Each school received at least $1000 and grants ranged up to $22,000. Although the distribution this year was only about a fourth as much as what CCR officials had hoped to have at Oct. 11, 1982 C&EN
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