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CATALYTIC REACTION ACTIVATES ALKANES Organometallic catalyst converts alkanes into versatile terminal organoboranes

L ate last year, when chemistry professor John F. Hartwig's group at Yale University re­

ported the discovery of a way to selectively functionalize alkanes using catalytic photochemistry, Angewandte Chemie suggested the researchers were "approach­ing a Holy Grail" [Angew. Chemie. Int. Ed., 3 8 , 3391 (1999)]. The chemists are even closer now, hav­ing uncovered an organometallic catalyst that lets them accomplish the same feat thermally [Science, 287,1995(2000)].

The Holy Grail in question is a method for directly converting the unreactive sat­urated hydrocarbons that nature pro­vides in petroleum and natural gas into compounds with useful functional groups tacked onto the ends. Current industrial processes like cracking and free-radical halogenation create mixtures of prod­ucts. Selective activation of carbon-hydro­gen bonds on a laboratory scale through transition-metal complexes was devel­oped in the 1980s by chemistry profes­sors Robert G. Bergman at the University of California, Berkeley; William D. Jones II at the University of Rochester; and Wil­liam A. G. Graham at the University of Al­berta, Edmonton. But those reactions re­quire stoichiometric amounts of expen­sive reagents.

Now Hartwig, Yale postdocs Huiyuan

Aikane to alkylborane in one step

Λ-Α

Catalyst Heat

Ha

Yale postdocs Schlecht (loft) and Chen.

Chen and Sabine Schlecht, and Thomas C. Semple of Shell Chemicals' Westhol-low Technology Center in Houston re­port they can catalytically couple linear al­kanes with commercially available bo-rane reagents to give good yields of linear alkylboranes. (Shell Chemicals provides support for the research.) The borane products can be easily converted to alco­hols, amines, alkenes, and other types of functionalized molecules using textbook organic chemistry.

"This is a real breakthrough," com­ments Bergman, who notes that Hartwig is a former student of his. "Peo­ple have been trying to do this kind of chemistry catalytically for years. It turns simple alkanes into molecules that can be used synthetically. "

Identifying just the right catalyst to make the coupling proceed thermally was a challenge, according to Chen and Schlecht. "We needed to put a thermally labile ligand onto a metal known to acti­vate C-H bonds," Chen says. After trying various li-gand/metal combinations, the researchers hit upon a little-known metal complex that sandwiches rhodium between hexamethylben-zene and pentamethylcy-clopentadienyl ligands. They believe the active cat­

alytic species is actually a metal-hydride-boryl complex.

"It was really Huiyuan's selection of catalyst that made it work," Hartwig says.

If the new Yale chemistry is to be used to make commodity chemicals, the cata­lyst must be made more robust—a goal the Hartwig group is currently pursuing. And because the borane reagents them­selves are expensive, the team hopes to find a method that would allow the re­

agents to be recycled. "It is easier — · to imagine," Schlecht says, that the

reaction in its current state of devel­opment "might be used for the pro­duction of specialty chemicals."

The Yale group's success un­derscores the importance of fund­ing basic research even when a utilitarian application isn't obvious, Bergman points out. "All of this work was stimulated by people's basic understanding of the under­lying chemistry," he says. "John thought about how a catalytic re­action could work mechanistically and put together a system that is

really practical." Pamela Zurer

Palladium Catalyst Activates Aromatics Although aromatic hydrocarbons are not as tough to functionalize as alkanes, they are still a challenge. Only a few catalytic systems that can activate aromatic car­bon-hydrogen bonds are known. But now professor of chemistry Yuzo Fujiwara and coworkers at Kyushu University in Fukuoka, Japan, have found a remark­ably efficient catalytic method for regio-selectively adding aromatic compounds to acetylenes [Science, 287,1992 (2000)].

Even sterically bulky arènes add to alkynes when catalyzed by palladium ace­tate in trifluoroacetic acid (JFA), the group reports. The addition occurs in a trans fash­ion, so the products are cis alkenes, which can be hard to prepare by other methods. The active catalytic species is a Pd(D) cat-ionic species—[Pd02CCF3]

+—formed from TFA, the researchers suggest

Fujiwara, who has been investigating CH activation by palladium for more than 30 years, asked research fellow Chengguo Jia to investigate the cou­pling of acetylenes with aromatic com­pounds. Unexpectedly, Jia discovered that with TFA as solvent the aromatics add to acetylenes instead.

MARCH 20,2000 C&EN 9

'φ

Intramolecular reaction gives high yield of a coumarin

CH3O^^Y CH3O

Catalyst CH3O

CH3O

Catalyst = Pd(OCCH3)2

"It is surprising that the reaction oc­curs under mild conditions such as room temperature," Fujiwara says, "and that not only inter- but also intramolecular re­actions take place. More surprising, we found that heteroaryls such as methyl-furane, pyrroles, and indoles can under­go this reaction in acetic acid in lieu of TFA at room temperature." Heteroaro-

95% yield

1 matic compounds, such as the couma-rins, are of special interest to the phar­maceutical indus­try, he notes.

"I can see imme­diate synthetic ap­plications for this work," says William D. Jones II, chemis­try professor at the University of Roch­ester. A commen­tary by Jones on both Fujiwara's pa­

per and the work of Yale chemistry pro­fessor John F. Hartwig's group on alkane activation appears in the same issue of Science (page 1942).

"Fujiwara uses methodology that or­ganic chemists are already familiar with," Jones tells C&EN. "They're not afraid to pick up a jar of palladium acetate."

Pamela Zurer

Biotech Woes Tied To An As the U.S. and Britain pledged last week that data from the international Human Genome Project would be freely available to scientists worldwide, the SNP Consortium announced that it in­tends to speed up its own efforts to make genetic information freely avail­able to researchers.

The announcements caused biotech stock markets to fall sharply as investors reacted to the news. The American Stock Exchange biotech index fell more than 20% early last week. Some analysts de­scribed die situation as a "bloodbath" af­fecting nearly every biotech company. As panic set in, stocks of leading genomics firms—such as Affymetrix, Cèlera Genomics, Incyte, Millennium Pharma­ceuticals, and Human Genome Scienc­es —lost anywhere from 10 to 30% of their market value. Early Wednesday, biotech stocks rebounded slightly, but only tem­porarily, and many, including Cèlera and Incyte, ended the day lower.

The biotech sell-off was triggered by a joint statement from President Bill Clinton and British Prime Minister Tony Blair to the effect that information about the human genome should be made "freely" available.

The market collapse stunned U.S. offi­cials who insisted, as presidential science adviser Neal F. Lane said at a White House briefing, that this "statement is not

about patents or what should or should not be patentable. Patent law dictates cri­teria for patentability, and nothing in the statement supersedes these criteria." The U.S. Patent & Trademark Office has

received around 10,000 genome-related patent applications.

All the statement does, Lane said, is encourage "everyone in the public and private sector to do everything they can to make the raw, fundamental genome data as available as possible and as accessible as possible, as fast as possible." Further­more, he said, "I want to make it absolute­ly clear that this statement has nothing to do with any ongoing discussions between the public and private sector."

Those assurances did not stop indus­try observers from speculating that the Clinton-Blair statement had something to do with joint talks between the govern­ment-backed Human Genome Project and Cèlera that had collapsed two weeks earli­er (C&EN, March 13, page 29). The groups were discussing a collaboration to assist each other in sequencing the human genome. However, they disagreed on is­sues regarding public access to the data.

'The deal-breaking issue is that the Human Genome Project is insisting that the data be made available for free," says a source, speaking on condition of anonymi­ty. "Cèlera saw that as an irreconcilable difference of opinion." Celera's business model is to sell sequence information and to sign contracts that allow pharmaceuti­cal companies early access to its data be­fore making them publicly available.

'The negotiations ended with the

The diplomatic statement that roiled the market On March 14, U.S. President Bill Clin­ton and British Prime Minister Tony Blair issued a joint statement that said:

"In the last decade of the 20th centu­ry, scientists from around the world ini­tiated one of the most significant scien­tific projects of all time: to determine the DNA sequence of the entire hu­man genome, the human genetic blueprint. Pro­gressing ahead of schedule, hu­man genome re­search is rapidly advancing our understanding of the causes of hu­man disease and will serve as the foundation for development of a new generation of effective treatments, preventions, and cures.

To realize the full promise of this re­search, raw fundamental data on the human genome, including the human

Blair

DNA sequence and its variations, should be made freely available to sci­entists everywhere. Unencumbered ac­

cess to this infor­mation will pro­mote discoveries that will reduce the burden of disease, improve health around the world, and enhance the qual­ity of life for all humankind. In­tellectual proper­ty protection for gene-based in­ventions will also

play an important role in stimulating the development of important new health care products.

"We applaud the decision by scientists working on the Human Genome Project to release raw fundamental information about the human DNA sequence and its variants rapidly into the public domain, and we commend other scientists around the world to adopt this policy."

Clinton

1 0 MARCH 20,2000 C&EN

Biotech Woes Tied To Announcements

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