NEWS OF THE WEEK
DIOXYGEN BOND CLEAVAGE Reaction reversible in model copper complex leavage and formation of the O-O bond in molecular oxygen occurs reversibly in a copper complex that is a model for metalloenzymes, a team of U.S. and Swiss scientists has discovered. Their finding has potentially major implications for understanding a variety of critical biological systems, including photosynthesis. Chemistry professor William B. Tolman and colleagues at the University of Minnesota, Minneapolis, and at the University of Basel, Switzerland, studied a synthetic copper complex and showed existence of an equilibrium between a dicopper-dioxygen adduct and its isomer having two oxo bridges and lacking an O-O bond [Science, 271,1397 (1996)]. This second isomer, characterized by X-ray crystallography, is the first of its kind to be identified unequivocally in copper chemistry. "We can actually see reversible O-O bond formation and cleavage within a dinuclear system," Tolman says. "This implies that this type of equilibration is possible in many biological systems." Molecular oxygen is a ubiquitous oxidant in biology, and metalloenzymes are the agents that organisms use to harness it. Enzymes such as cytochrome P450, which contains a mononuclear heme center, and methane monooxygenase, which contains a nonheme diiron center, cleave 0 2 in the process of oxidizing an alkane to an alcohol. Such cleavage reactions occur at a variety of copper and iron centers in enzymes that catalyze these organic oxidations. The reverse reaction, the oxidative coupling of water molecules to form 0 2 during photosynthesis, involves formation of O-O bonds at a tetranuclear manganese cluster. Tolman and coworkers first characterized the adduct of a copper(I) complex and 0 2 in the solvent CH2C12. The spectroscopic properties of the adduct suggest it contains a peroxo dicopper(II) core in which the O-O bond remains intact. However, when the
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Researchers at the University of Minnesota who studied copper complex included (from left) Lawrence Que Jr., Jason A. Half en, Elizabeth C. Wilkinson, Samiran Mahapatra, and Tolman.
chemists carried out oxygenation of the copper® complex using tetrahydrofuran as the solvent, a different isomer formed that contained a cleaved O-O bond. "It really was serendipitous," Tolman says. "Just by changing the solvent, we can go from one compound to the other." Additionally, he notes, kinetic evidence shows that in at least one solvent—acetone—the two species are in rapid equilibrium. "We observed both species formed at identical rates at a range of different temperatures." The scientists say the solvent dependence on bond cleavage and formation remains a mystery. The research "is an unexpected but exciting new insight in copper chemistry," comments Kenneth D. Karlin, a chemistry professor at Johns Hopkins University. "In this case, the copper analogy suggests similar things may be occurring in other metal systems, including photosynthesis." The work is hailed as "a tremendously important result" by Stephen J. Lippard, a chemistry professor at Massachusetts Institute of Technology. "The
Oxygen atoms (red) at core ofdicopper complex can be nonbonded, as in tetrahydrofuran (left), or form 0-0 bond, as in CH2Cl2 (right). Copper atoms in the complex are green, nitrogen atoms are blue, and carbon atoms are not shown.
reversible cleavage of the O-O bond in a peroxy compound is unprecedented and possibly relevant to a much wider number of transition-metal peroxides," he points out. The reversibility of O-O cleavage and formation in the complex indicates the complex has "a very peculiar electronic situation," notes Richard H. Holm, a chemistry professor at Harvard University. The complex does not
Ciba will spin off within 12 months its seem to have a classical electronic dis tribution, he says. Rather, the electrons specialty chemicals division, which will are delocalized over the dioxygen and become a separate publicly traded com two copper units. "I must say it is not pany. Sandoz—which spun off its spe a result I would have anticipated. If it cialty chemicals business last year to turns out this peculiar electronic struc form Clariant—will also sell or spin off ture occurs in other binuclear bridged its construction chemicals operation. To systems, it will be very interesting," gether, the operations to be spun off had sales of $8.34 billion last year. After the Holm comments. "I'm fascinated by the idea that sol demergers, Novartis' business mix will vent changes can break or form [the ox be health care, 59%; agribusiness, 27%; ygen bonds]," adds Edward I. Solo and nutrition, 14%. mon, a chemistry professor at Stanford Ciba Chairman Alex Krauer will be University who studies tyrosinase, a chairman of Novartis. Daniel Vasella, binuclear copper enzyme. "I don't chief executive officer of Sandoz Pharma, think it's understood how that works Sandoz's pharmaceuticals division, will be yet," he says, but chemists will no Novartis president and head its executive doubt soon be pursuing answers to committee. There will be 16 directors on those questions. the board, eight from each partner. The "It's a step that must be happening headquarters will be in Basel, the base for in a number of different areas," notes both Ciba and Sandoz. Joan S. Valentine, a professor of chem In the pharmaceuticals field, Novar istry and biochemistry at the Universi tis will focus on several areas: immu ty of California, Los Angeles. "As we nology/inflammatory diseases; disor understand more about it, we'll under ders of the central nervous system; car stand more about some very important diovascular, endocrine, and metabolic enzymatic steps in oxygen activation diseases; and oncology, asthma, and with metalloenzymes, so it provides a dermatology. The company will also system you can actually study." maintain its markets in vision care— with contact lenses, lens care products, Elizabeth Wilson and Rudy Baum and ophthalmic products—and in a va riety of over-the-counter products. also will continue research Ciba, Sandoz merge to in Novartis gene-, cell-, and organ-based thera pies. Included is work on gene map form giant Novartis ping and sequencing in more than a Consolidation of the global pharma dozen collaborations with research in ceutical industry continued last week stitutions, such as the Stanford Human with announcement of one of the larg Genome Center—to which Sandoz last est mergers in corporate history. Swiss week contributed $1 million—the Max drug finns Ciba-Geigy and Sandoz will Planck Institute, and the Johns Hop form a new company, Novartis, that kins Consortium. they say will be the second largest The two firms also complement each drugmaker in the world. It will have other in nutrition products, including 4.4% of the global market, behind only health foods, medical nutritionals, and Glaxo-Wellcome's 4.7%. The merger of the Gerber line of foods, which Sandoz Ciba and Sandoz, which had combined acquired in August 1994. And in agri sales of nearly $30 billion last year, business, Novartis will play a major will become effective upon sharehold global role in agrochemicals for weed, er approval. disease, and insect control; in seeds; and in animal health. According to the merg er announcement, "Rapid 1995 was healthy for Sandoz, Ciba integration and comple Sandoz Ciba mentarity of the business % change 1995 % change 1995 areas will realize estimat $ Million results from 1994 results from 1994 ed synergies of [$1.5 bil Sales $12,705 - 4 % $17,252 -3% lion] over three years," Operating profits 2,258 11 2,539 12 with half the savings com 8 Net profits 1,717 19 1,797 13 ing in the first 18 months. a After taxes and unusual items. Some of the savings will come in worldwide job re-
ductions, although their extent is not yet clear. The partners say the deal is structured as a merger of equals based on an ex change of shares. Sandoz shareholders will get 55% of the shares and Ciba shareholders will get the remaining 45%. Sandoz shareholders will receive one Novartis share for each Sandoz share. Ciba shareholders will receive Wis No vartis shares for each Ciba share. Patricia Layman
Regulatory reform bill put off indefinitely A regulatory reform bill, scheduled to be brought to the House floor for a vote on March 5, was dropped from the sched ule at the last minute. Its abrupt with drawal dims the chances that Congress will pass this year any kind of major reg ulatory reform legislation, as promised in the House Republican "Contract With America." The bill, H.R. 994, is generally sup ported by industry and opposed by the Administration and most environmen tal groups. It consists of three titles, or major sections. Title I would allow small businesses and local governments to legally chal lenge federal agency assessments of the impact of proposed federal rules on the businesses and governments. Current law does not allow for such legal chal lenges. Title III would give Congress the power to veto any major regulation issued after November 1994. However, most of the attention has fo cused on the highly controversial Title Π. That section would require federal agen cies to conduct periodic reviews of new and existing major rules to determine whether to amend, terminate, or contin ue them. A major rule is defined as one having an annual impact on the econo my of $100 million or more. Existing rules would be reviewed over a period of nine years; new rules would be re viewed during seven years from their adoption. If a federal agency missed a review deadline, interested parties could seek a court-ordered deadline, and the rule could be suspended until that review was complete. Also, adversely affected persons could petition for review of mi nor rules. If the petition were denied, the petitioner could sue the agency. MARCH 11,1996 C&EN 7
