Toxic metals extracted with supercritical carbon dioxide 211th ACS National Meeting
NewOrleans Elizabeth K. Wilson C&EN West Coast Bureau
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upercritical carbon dioxide has received much attention lately for its tantalizing solvating properties. Many a research lab is searching for ways to exploit its potential as an inexpensive, innocuous substitute for many noxious solvents. Billed as the nonpolar counterpart to water, supercritical C0 2 has for some time been used to decaffeinate coffee, and could be used as a dry-cleaning agent or even as a solvent for washing engine parts. "The major reason to use it is that it's environmentally friendly, and it's cheaper than dirt," according to Steven B. Hawthorne, research chemist with the Energy & Environmental Research Center at the University of North Dakota in Grand Forks. Now a group of researchers at the University of Idaho, Moscow, are touting supercritical C0 2 as a novel way to solvate toxic heavy metals. These elements, from mercury to plutonium, are a major environmental problem, currently dealt with by complicated procedures that themselves generate voluminous, sometimes toxic, waste. By itself, the nonpolar supercritical C0 2 is almost useless for solvating positively charged heavy-metal ions. However, researchers have discovered that metals can be solvated if they are first neutralized by chelating agents and, furthermore, that the solvency increases dramatically when the chelating agents are fluorinated. At a symposium sponsored by the Division of Analytical Chemistry, chemistry professor Chien M. Wai presented an overview of his group's methods for extracting heavy metals with fluorinated ligand-spiked supercritical C0 2 . Their efforts, which span half a de-
rinated macrocycles that might act as good chelating agents. The Idaho collaboration has produced compounds tailored to specific metals— for example, terf-butyl-substituted dibenzobistriazolo crown ether in supercritical C0 2 selectively removes mercury and, to a lesser extent, gold from filter paper [Anal Chem., 67,919 (1995)]. The solubility of metal complexes in fluorinated macrocycles "is always two to three orders of magnitude higher than nonfluorinated complexes," Wai said. The group now has a patent on their methods of supercritical fluid extraction. The mechanisms by which the highly electronegative fluorinated groups in-
cade, are now garnering interest from researchers around the world—from the U.K/s British Nuclear Fuels to companies in Japan. In addition, Wai's colleagues, including research associate Sadik Elshani, presented several other papers in the Division of Fluorine Chemistry detailing their work with fluorinated macrocycles, particularly crown ethers and porphyrins. Researchers have been exploring supercritical C0 2 as a way to extract toxic wastes for years. Although a polar solvent such as water might appear to be more suited to positively charged heavymetal ions, "once extracted, you have a huge volume of contaminated wastewater," Hawthorne said. However, with supercritical C0 2 , one can simply release the pressure and vent the C0 2 gas, leaving behind the contaminated waste, he explained. Another benefit of C 0 2 is its versatility. Many extractions work perfectly well near, yet not exactly at, supercritical conditions. The transition from an ordinary fluid to a supercritical one "is gradual," said Robert E. Sievers, chemistry professor at the University of Colorado, Boulder. "It isn't just an enormous jump—it sort of eases through." Elshani: developing fluorinated macrocycles For example, supercritical C0 2 has a critical temperature of 31 °C and a critical pressure of 1,075 psi—but plenty of extractions can proceed effectively at room temperature or at pressures below 1,000 psi. The Idaho group has explored many avenues of metal extraction, including removal of heavy metals from vegetation (C&EN, Sept. 11, 1995, page 44). Wai's specific interest in the potential of fluorinated ligands in supercritical C 0 2 stems from his collaboration with University of Idaho fluorine chemists Jean'ne M. Shreeve, Robert L. Kirchmeier, and colleagues. Shreeve and colleagues are developing syntheses of fluoWai: fluorinated groups increase solvency in C02 APRIL 15,1996 C&EN 27
SCIENCE/TECHNOLOGY crease solvency in supercritical C0 2 are still not ironed out, Wai said. ''Fluorine One route to crown ethers starts with fluorinated catechols chemists have different theories—nobody yet has [agreed on a] solution." Fluorinated macrocycles have been .OH HOv (CICH2CH2)2Q ^ " Y ^ developed and studied by other groups as well for various uses. For example, a ^O O' ^OH group headed by Richard J. Lagow at the University of Texas, Austin, has pioneered the synthesis and chemistry of OH perfluoro macrocycles [/. Am. Chem. Soc, 116, 5172 (1994)]. ci Researchers at the University of R S> 0 ^ |Y^ Pennsylvania and the University of NeBrCH2C02H braska, Lincoln, have synthesized highNaOH NaH ly electron-deficient perfluoroalkylated porphyrins (C&EN, Nov. 28, 1994, page 39). Wai and colleagues have since demonstrated these porphyrins' OCH 2 C0 2 H solubility in supercritical C0 2 , which they described at the meeting. Other groups are also looking at fluoR o rinated chelates for extracting heavy R = F,SCF2CHFCF3 metals. Emeritus chemistry professor -o o^ Reed M. Izatt, at Brigham Young University, Provo, Utah, is doing work with solid-phase extraction, putting macrocycles on solid phases such as silica gel. The macrocycles can then extract metal ions from solutions. ity of porphyrins in supercritical C022 increases with pressure Solubility Where Wai's method comes in handy, Izatt Solubility, moles per L says, is in situations deal400 atm 200 atm R 100 atm Compound ing with contaminated 4 5 8.7 x K T 4 3.4 x K T 1.2 x10" THFPP C3F7 soil, where fluid needs to seep through pores. 3.8 x K T 4 2.3x10^ TTFMP 8.5 x1CT5 CF3 One of the most pro8 vocative such uses of x10" 7 1.3 x1CT 8.7 2.2 x K T 7 TPP 8 . 7x K 1 0T* CeHs &^s Wai's extraction method is the area of actinide 2.0 x10" 5 7.6 x10" 5 4.6 x K T 6 TPFPP C6F5 wastes, which include ra1.9x10* 1.1 x K T 4 4.4 x10" 5 THFPP-Zn C6F5 dioactive elements such as uranium and plutonium. "The work on actinides is significant because [the U.S.] spent nuclear fuels. Scientists there are it would have worked as well as it aphas an enormous problem with mixed acutely interested in more environmen- pears to be working. It's not a fluke, wastes," according to Sievers. Radioac- tally safe and economic alternatives to he's really doing it." tive substances—themselves intractable current techniques. But in general, while fluorine is vital enough—must be dissolved in acid, Supported in part by British Nuclear to making these species soluble, it is also then extracted into an organic solvent, Fuels, the Idaho group has found that costly, Sievers cautioned. He believes the which then itself becomes a waste. thorium and uranium can be extracted "fluorinated species may likely be too The chlorinated solvents that contain from nitric acid solutions or from solid expensive to be used on a large scale." actinides often destroy liners and other materials using supercritical C 0 2 with But Wai hopes that once developed, the holding vessels made of materials such tributylphosphate either alone or chelating agents can be mass produced as neoprene. "So it's a really big step to mixed with a fluorinated (3-diketone, a much more inexpensively. "We want to make people more intechnique for which the group has apjust separate them," Sievers said. terested in this research," Wai said. Particularly affected by such wastes plied for a patent. "It's just amazing that C 0 2 will ex- "For the next century, we have got to are facilities such as Rocky Flats in Colorado, and the Hanford nuclear waste tract these things," said Sievers, who is consider environmental factors. We site in Washington. And unlike in the also a regent of the University of Colo- cannot use the old solvent extraction • U.S., in Europe it is legal to reprocess rado. "You never would have dreamed methods any more."
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Cobalt catalysts improve amine selectivity 211th ACS National Meeting
NewOrleans A procedure for producing primary aliphatic amines from synthesis gas (syngas, a mixture of carbon monoxide and hydrogen), olefins, and ammonia has been developed at Huntsman Corp., Austin, Texas. Research chemists John F. Knifton and J. J. Lin have used cobalt octacarbonyltriphenylphosphine catalysts to improve the selectivity for primary amines over that obtained with current processes. The products, mostly C7-C27 primary amines, are useful intermediates and are in commercial demand as softeners for synthetic fibers, anticorrosion agents, and paint dispersants. In his presentation to the Division of Petroleum Chemistry, Knifton said the new synthesis of primary amines was a continuation of previous work that was directed toward using syngas as a building block to produce various amine and amidocarboxylic acid products using oxoamination and amidocarbonylation chemistry. Knifton noted that aliphatic amines of lower molecular weight than the range the Huntsman chemists targeted already are available via four commercial amination processes. Although the principle of making amines from syngas, olefins, and ammonia is known, these syntheses usually lead to tertiary
amines. Selectivity to primary amines is poor. The most promising work to date seems to be that of chemists at Mitsubishi Petrochemical, who have reported primary amines in yields of about 30% from olefins, syngas, and ammonia using a homogeneous cobalt-phosphine catalyst in ethanol solvents. The work at Huntsman has been focused on using combinations of cobalt catalysts, phosphine ligands, and ether/ acetamide mixed solvent systems. The syntheses involve reacting the olefin, syngas, and ammonia in the presence of cobalt octacarbonyl and a tertiary phosphine ligand [(C6H5)3P or (n-C4H?)3P] in a mixed solvent composed of p-dioxane, tetraglyme, and acetamide. The reactions run at a pressure between 500 psi and 2,000 psi and an operating temperature between 150 and 250 °C The major products are the desired primary amines, particularly the aliphatic amines having a carbon number either one greater (Cn+1) than the starting olefin (Cn) or larger molecules resulting from aldol condensation of the intermediate aldehydes. Those larger primary amine products have carbon numbers either two greater than twice the original olefin (C2n+2) or three greater than three times the size of the starting olefin (C3n+3). The principal byproducts are alkanols. "The linear and branched primary amines formed in the reactions are probably formed by a combination of aldol condensation of linear and branched aldehydes followed by reductive ami-
Primary amines derivedfromolefins, syngas, and ammonia CH 3
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Knifton: using syngas as a building block nation and by Schiff-base condensation/' Knifton said. "Finally, there is probably imine reduction of a variety of linear and branched amine-aldehyde combinations/' Knifton cited a particular example using n-hexene as the starting olefin. The major products are heptyl and tetradecyl primary amines. The heptylamine fraction usually consists of both primary and secondary amines with the linear amine predominating. The corresponding by-products are C7 and C14 alcohols, with traces of hydrocarbons detected on occasion. In the case of the dicobalt octacarbonyltriphenylphosphine catalyst, the total selectivity to primary amines in the n-hexene system is slightly above 57%. The reaction paths to these products include initial olefin oxonation followed by parallel reactions of reductive amination, hydrogenation, and basecatalyzed aldol condensation. Varying the operating parameters of the system indicates that there is some olefin isomerization. A large excess of ammonia may halt any oxo and oxonation activity in addition to limiting double bond isomerization. Oxoamination and oxoalcohol product formation rates are comparable only when the initial ammonia charge is stoichiometric with respect to the olefin. Knifton concluded that to achieve selective oxoamination of olefins to primary amines, the ammonia, syngas, olefin, and homogeneous catalyst must achieve a very delicate balance of initial molar ratios. The molar ratios must be such that there is sufficient ammonia present at all times to aminate a substantial portion of the intermediate aliphatic aldehyde, but not so much that the ammonia interferes with the initial APRIL 15,1996 C&EN
29
SCIENCE/TECHNOLOGY hydroformylation or with the forma- zyme, according to Anna tion of the required quantities of the ac- M. Tempczyk of Agouron tive cobalt carbonyl-tertiary phosphine Pharmaceuticals. catalyst. Tempczyk is part of a Homogeneous rhodium, ruthenium, team of computational and cobalt catalysts are all effective in chemists and biophysicists this chemistry, but Knifton believes at the San Diego-based company that solved the that cobalt is the best found thus far. Joseph Haggin structure of the enzyme, both in its native form and bound to a complex that inhibits it. She described Calcineurin structure the work in a symposium on computer-assisted drug reveals active site discovery, cosponsored by the Divisions of Comput211th ACS National Meeting ers in Chemistry and of Chemical Information. Calcineurin is the target of two natural products used as immunosuppressive drugs, cyclosporin and The crystal structure of human cal- FK506. Both drugs work by cineurin—a key enzyme in the signal- first binding to a druging pathway that activates the immune specific protein from a class system's T cells—is providing a basis known as immunophilins. for designing drugs to inhibit the en- The complex between the
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[email protected] 30 APRIL 15,1996 C&EN
In native human calcineurin (top), the tail segment of the enzyme, shown in red, wraps around and blocks the enzyme's active site, located in the A subunit shown in yellow. Iron (red) and zinc (green) metal atoms, located at the active site, play key roles in the enzyme's hydrolyzing activity. Calcineurin's B subunit is shown in blue. The enzyme can be inhibited by binding to FK506 and FK binding protein (bottom). Here the immunosuppressive drugFK506 is the ball-and-stick structure, the FK binding protein is purple, and the A subunit of calcineurin is orange. Regions of the FK binding protein that are homologous to A kinase anchoring protein are shown in yellow.
drug and the protein then binds and inhibits calcineurin. The X-ray crystal structures reveal, however, that the FK506-binding protein complex does not bind to calcineurin at its enzymatically active site, but rather at a site about 20 A away. This site is probably where the enzyme would ordinarily bind to an anchoring protein. Tempczyk used computer modeling to predict where the FK506-binding protein complex would bind to calcineurin before the crystal structure of the ternary complex was resolved. Based on information from the crystal structures of calcineurin alone and the drug-immunophilin complex, she calculated the solvent-accessible surfaces of each of these units. She mapped
onto these surfaces the electrostatic po- carbocation or its equivatential for different regions of the two lent, and coupling that Monosaccharide diacetylthione proteins and then manipulated the atom to a nucleophilic porbuilding block •.. model until she found the best docking tion of the aglycone. The accomplishment of the arrangement for the two units. The model predicted most of the in- chemists from Hunter Coltermolecular interactions that occur in lege of the City University SNPhth PhthNsCI the ternary complex, Tempczyk said. It of New York and the Unialso helped to identify key regions of the versity of Florence thus anH3C HaC crystallographic data where the group swers a challenge from other sugar chemists to needed to pin down electron densities. In its native form, calcineurin is actu- find a way out of the nuPyridine ally autoinhibited, Tempczyk explained. cleophile-electrophile rut. That is, one of its subunits has a tail segSpecifically, in "Modern H,C ment that wraps around and blocks the Synthetic Methods 1995," enzyme's active site. That interaction organic chemistry profesprovides useful clues to designing drugs sor Ole Hindsgaul and •.. couples by cycloaddition to a that will directly inhibit the enzyme's ac- postdoctoral fellow Frank glycal building block •.. tivity, rather than indirectly, as FK506 Barresi of the University of Alberta, Edmonton, stated: and cyclosporin do. CH2OBn "That tail segment is really the key," "It is extremely regrettable CH2OBn project leader J. Ernest Villafranca tells that so few researchers in O this field document their C&EN. Using the information from the crys- failed synthetic schemes, BnO tal structure, the team has designed because therein lies the inH3C^O^O compounds to mimic both the sub- centive to invent truly new strate and the transition state of the en- and different glycosylation zyme-catalyzed reaction, which is the strategies that will not rehydrolysis of a phosphate group from quire a bimolecular reacphosphorylated serines or threonines. tion to occur between a deCH3 They have synthesized some of these veloping oxocarbonium potential inhibitors and are investigat- ion and a sterically hin•.. and yields a disaccharide after dered, lowly, nucleophilic ing their properties. alcohol. sulfur removal Rebecca Rawls "We are, in our opinion, approaching the limits of CH2OBn what this classical strategy Glycosylation route uses will yield, and this is very Raney Ni clearly evidenced from the Diels-Alder reaction wide variation of yields BnoH—f\ Bn = CH2C6H5 within any of the glyco211th ACS National Meeting sylation methods currently Phth = in use." Postdoctoral fellow Cecilia Marzabadi of Hunter College described the new method to the Division of An international team of investigators Organic Chemistry. Her coworkers are team treated commercially available from the U.S. and Italy has devised a organic chemistry professor Richard 5,6-dihydro-4-hydroxy-6-methyl-2Hmethod for coupling a monosaccharide W. Franck and graduate students An- pyran-2-one with phthalimidosulfenyl building block either to another such geles Dios, Aloma Geer, and Maria chloride, producing a 3-phthalimidosugar derivative or to the aglycone por- Tamarez at Hunter College, and organ- thio derivative of the pyran. This reacts tion of a glycosylated natural product ic chemistry professor Giuseppe Ca- with bases such as pyridine to form during total synthesis. Their approach pozzi and research associates Stefano 2,4-dioxo-6-methyltetrahydropyran-3is the first to join the two units by a Menichetti and Cristina Nativi at Flor- thione. An 0=C>C=S sequence of the Diels-Alder cycloaddition, which is fol- ence. Their work also will appear dioxothione undergoes cycloaddition with tri-O-benzylglucal to form a 1,4lowed by the breaking of one of the shortly in Angewandte Chemie, International Edition in English [35, 777 (1996)].oxathiine. Raney nickel desulfurizes bonds in the cycloadduct. Such an approach is in striking conTheir method uses a diacylthione as the oxathiine, leaving only the desired trast to the century-old techniques that the diene, and the carbon-carbon dou- C-O-C link between the two sugarlike depend on somehow making the "front ble bond of a glycal as the dienophile. pyran rings. Stephen Stinson end" carbon atom of one sugar into a In one example, the Hunter-Florence
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