Issue Date: March 15, 2004
PIN THE TAIL ON THE OLEFIN
Chemists have been trying for some time to find a practical synthetic method that the chemical industry could use to add terminal functional groups such as alcohols, ethers, and amines to olefins. Several research teams have now progressed toward that goal by developing anti-Markovnikov reactions that add such functional groups to alkene double bonds.
In an anti-Markovnikov reaction, a nucleophilic group, such as an alcohol or amine, adds to the less substituted of the two double-bonded carbons in an alkene. In most alkenes with terminal double bonds, the end carbon is less substituted than the adjacent internal carbon. So an anti-Markovnikov reaction adds an alcohol, amine, or other group to the terminus of such an alkene, where the added functionality is often most desirable.
"The conversion of olefins to addition products is a very important process," says professor of chemistry emeritus Jack Halpern of the University of Chicago. "Olefins are typically derived from petroleum and tend to be cheap. Addition products such as alcohols, on the other hand--and particularly terminal alcohols--are much more valuable to industry.
"It's easy to convert olefins to internal [nonterminal] alcohols," Halpern continues. "But for various applications, such as plasticizers, it's the terminal alcohols that you want, and that's been a challenge because almost all additions to terminal double bonds give you the internal product--the Markovnikov product. So finding a practical way to add to olefins in an anti-Markovnikov fashion is an important goal."
Matthias Beller, director of the Leibniz Institute for Organic Catalysis at the University of Rostock, in Germany, points out that "olefins are among the most important feedstocks for the chemical and pharmaceutical industry. In general, olefins are further functionalized to alcohols, amines, aldehydes, carboxylic acid derivatives, ethers, etcetera, by various catalytic reactions. For the production of bulk chemicals on a multi-million-ton scale, the linear isomers are especially important. In order to produce linear alcohols and amines, multistep processes, such as hydroformylation and reductive amination, currently have to be applied. Obviously, a shorter, direct anti-Markovnikov functionalization of olefins will provide the basis for a significant environmental and economical benefit."
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."
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.
Halpern explains that alkenes can also be terminally functionalized to alcohols noncatalytically using hydrozirconation, a technique devised by Princeton chemistry professor Jeffrey Schwartz and coworkers. Schwartz notes that hydrozirconation is used to synthesize fine chemicals such as pharmaceuticals. Hydrozirconation and other zirconium reagent-based addition processes that can be used for anti-Markovnikov additions will be spotlighted in a symposium, "Half a Century of Organozirconium Chemistry," at the American Chemical Society's national meeting in Anaheim, Calif., later this month.
In another study, visiting scholar Masaru Utsunomiya and chemistry professor John F. Hartwig at Yale University achieved the first ruthenium-catalyzed anti-Markovnikov hydroaminations, with anti-Markovnikov regioselectivities of over 99% [J. Am. Chem. Soc., 126, 2702 (2004)]. It's a truly catalytic process in that the catalysts are recoverable and reusable, making it potentially useful industrially. However, the starting materials were styrene and other vinylarenes and do not currently include aliphatic alkenes. The efficiency of the ruthenium catalysts could be better, but Hartwig says he hopes to improve that over time.
A similar anti-Markovnikov hydroamination of styrene was developed by Beller's group in 1999, but the yield was low and most of the reactions were oxidative, yielding enamines instead of amines. The Utsunomiya-Hartwig technique offers improved yields and does not form competing enamines.
The ruthenium-based technique is complementary to an earlier approach--the use of organolanthanides to catalyze the anti-Markovnikov hydroamination of vinylarenes with primary amines, also with no competing oxidative enamine formation. Chemistry professor Tobin J. Marks of Northwestern University and coworkers, including grad student Jae-Sang Ryu, developed the organolanthanide method, analyzed its synthetic scope, and determined its unique mechanism of action [J. Am. Chem. Soc., 125, 12584 (2003)].
Like the ruthenium-based methods, the organolanthanide-based reactions have potential industrial applications. "What is unique about the lanthanide catalysts is the capability to couple C–N with C–C bond-forming reactions in cascade processes, thus forming complex heterocyclic structures with high regioselectivity," Marks says. Hartwig comments that the organolanthanide approach is "pioneering and overall outstanding chemistry."
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