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Recent steps in that direction have been taken by several groups. In one study, postdoc Melanie S. Sanford (now assistant professor of chemistry at the University of Michigan, Ann Arbor) and chemistry professor John T. Groves at Princeton University used a tetraphenylporphyrin rhodium(III) hydride reagent to convert olefins intramolecularly to anti-Markovnikov products. The reactions produce cyclic ethers, cyclic amines, and other heterocyclic products with greater than 97% anti-Markovnikov regioselectivity [Angew. Chem. Int. Ed., 43, 588 (2004)]. Sanford and Groves also determined the mechanism of the reaction, which involves reactive Rh(II) radicals as intermediates. "A key advantage of the radical process is its wide tolerance for other reactive functional groups," Groves says. "At the end of the cycle, we get the cyclic organic product and the rhodium(I) anion in quantitative yield," he says. "To get back the starting hydride, we protonate the rhodium(I) anion with a mild acid to remake the rhodium(III) hydride. While what we have achieved here is a formal catalytic cycle, a truly catalytic system returns spontaneously to the active form to start another cycle. That is the goal for us now--to find a single set of conditions that will allow this protonation and still be compatible with the rest of the cycle. We have every reason to believe that such conditions can be found." PHOTO BY ADAM MATZGER PHOTO BY SHELLEY WESTER RADICALS Sanford (left) and Groves developed an intramolecular anti-Markovnikov reaction. Its mechanism--generation of a rhodium(II) radical and its anti-Markovnikov addition to a terminal olefin--is shown on the blackboard. -------------------------------------------------------------------------------- The technique currently doesn't produce the type of terminally functionalized addition products that are favored by industry. Instead, it uses an intramolecular nucleophilic displacement in the product-forming step, yielding cyclic products. Such a reaction is easier to carry out because it's favored entropically--that is, the nucleophile and substrate are favorably positioned to react with each other. Groves says he hopes to make the process work intermolecularly as well. Such intermolecular transfers have been shown to be feasible in previous work with another rhodium-based complex; those studies were carried out independently by associate professor of chemistry Stephen G. DiMagno of the University of Nebraska, Lincoln; Stanford professor of chemistry James P. Collman; and their coworkers. "So we have reason to be optimistic," Groves says. Groves points out that the reaction builds on several key precedents. One of these is work by Halpern's group and that of chemistry professor Bradford B. Wayland at the University of Pennsylvania showing that this type of reaction proceeds by an unusual free-radical chain mechanism involving rhodium(II). Another precedent is research by chemistry professor Richard Eisenberg of the University of Rochester and coworkers demonstrating the delocalized radical nature of the Rh(II)-olefin adduct that forms in the reaction. The Sanford-Groves study is "a significant advance," according to Halpern. The need to regenerate the rhodium complex detracts from the utility of the reaction, but "the work is a proof of principle that it's possible to achieve anti-Markovnikov functionalization, which is a long-sought goal," he says. |
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