Palladium's Hidden Talent

PALLADIUM CATALYSTS are widely used for making carbon-carbon, carbon-nitrogen, and carbon-oxygen bonds for agrochemicals, pharmaceuticals, and materials. But new research is revealing that chemists can do a lot more than that with Pd. New structural evidence indicates that Pd can build carbon-fluorine bonds by a versatile mechanism that could open the way to many new synthetic pathways valuable to materials scientists, medicinal chemists, and others.

In the key mechanistic finding, chemist Tobias Ritter and graduate student Takeru Furuya of Harvard University observed an elusive intermediate in a Pd-mediated C–F bond-forming reaction (J. Am. Chem. Soc. 2008, 130, 10060). The intermediate breaks down to yield fluorinated products by a pathway called reductive elimination. Reductive elimination is the last step in Pd-mediated reactions that form many other bonds. Although chemists have suspected involvement of this important intermediate in this type of fluorination, until now no one has conclusively demonstrated its presence.

The pharmaceutical industry uses reductive elimination chemistry on a multiton scale, says chemist Melanie S. Sanford of the University of Michigan, Ann Arbor. The Ritter team's results, she says, build on efforts by several other groups to exploit Pd species different from those used conventionally in commercial reductive eliminations.

Large-scale Pd-mediated syntheses rely on a catalytic cycle that switches between a Pd species with an oxidation state of zero and an oxidized Pd(II) species. The cycle begins with Pd(0) and progresses to Pd(II) after the Pd metal center inserts into a covalent bond on one of the reactants. This process, called oxidative addition, creates a Pd–C bond that is activated for further transformation. At the end of the catalytic cycle, reductive elimination releases the reaction product from the transient Pd complex, regenerating the Pd(0) oxidation state.

"This has been unbelievably useful chemistry, but there are still real limitations to it," Sanford says. She says that decades of pioneering work, particularly that of DuPont chemist Vladimir V. Grushin, have shown that "forming C–F bonds with the Pd(0)-Pd(II) system is extremely difficult."

Although routes to C–F bonds already exist (C&EN, June 5, 2006, page 15), developing robust catalytic alternatives to the established chemistry is a major goal. Reactions that swap hydrogen atoms for fluorine, for example, can dramatically affect the products' properties, including their bioactivity.

Ritter, Sanford, and others already had shown that harnessing Pd in a higher oxidation state than that used in typical large-scale syntheses can form C–F bonds, but they lacked direct evidence for reductive elimination. "Generally, transition metals in higher oxidation states are more prone to doing reductive elimination chemistry," comments Arkadi Vigalok, an organometallic chemist at Tel Aviv University, in Israel, who also works in this area.

IN 2006, Sanford's group developed a Pd-catalyzed C???F bond-forming reaction (J. Am. Chem. Soc. 2006, 128, 7134). In that work the team inferred the presence of reductive elimination intermediates on the basis of observations in their previous work on related reactions, Sanford says.

In his own fluorination chemistry work, Vigalok also was unable to pin down a reductive elimination pathway (J. Am.Chem. Soc. 2003, 125, 13634; Inorg. Chem. 2008, 47, 5). "We didn't see the intermediates," Vigalok says, although he believed they might have been around because his team had previously observed analogous intermediates with platinum complexes (Inorg. Chem. 2005, 44, 1547).

Ritter and Furuya finally found evidence for the reductive elimination step while working on a new fluorination reaction, which the team recently published (Angew. Chem. Int. Ed. 2008, 47, 5993). Furuya saw a color change consistent with an oxidation state change that led him to believe reductive elimination might have been taking place. However, this observation alone was not enough evidence to confirm the pathway.

According to Vigalok, at least one other process could have been at play. "The reaction might undergo a simpler mechanism that doesn't involve a change in Pd's oxidation state," he says.

To distinguish between those options, the researchers needed to observe a Pd species with the right structure and oxidation state to undergo reductive elimination—in this case, Pd(IV).

Ritter's group at last captured the fleeting intermediate by designing a Pd(II) complex that included rigid aromatic ligands and subjecting it to their fluorination reaction conditions. That's a well-known strategy for stabilizing metals in high oxidation states, Ritter says. Sanford's team had used a similar strategy to stabilize the Pd(IV) intermediate in a closely related carbon-chlorine bond-forming reductive elimination (J. Am. Chem. Soc. 2007, 129, 15142). "Our team has been inspired by Sanford's mechanistic work, especially in the area of Pd(IV) chemistry," Ritter says.

THE APPROACH gave the Harvard team a complex that could be analyzed by 19F NMR. Adding a second fluorine ligand, another stabilizing tactic, led to a complex stable enough to be observed by X-ray crystallography.

In the X-ray structure one fluorine ligand and the aromatic substrate are suitably positioned to undergo reductive elimination. Together with the NMR data, the structure provides a convincing case for a reductive elimination pathway, Vigalok says. "This is a major mechanistic breakthrough."

Dmitry V. Yandulov of Stanford University, who has also explored Pd-mediated fluorination, calls Ritter's work "a spectacular and fundamentally significant advance."

"You can propose any intermediate you want, but at the end of the day, you have to show that it's the right one," Sanford says. The new work, she says, is the first to show that the intermediate exists, and it suggests that the reductive elimination process that she and other researchers in this area have proposed is plausible.

At last month's American Chemical Society national meeting in Philadelphia, Sanford disclosed that she and graduate student Nicholas D. Ball have observed a related Pd(IV) intermediate in action. Using ¹⁹F NMR, the Michigan team watched their complex undergo reductive elimination to form a C–F bond at an aromatic carbon. This complex differs from Ritter's, Sanford tells C&EN, in that the aromatic substrate doesn't have any additional stabilization in its interaction with the Pd metal center. "We think this intermediate is directly relevant to the kinds of catalytic processes we want to develop," Sanford says. "Knowing how things work is at the core of developing new reactions."

The researchers agree that a routine method for Pd-catalyzed C–F bond formation is still a long way off, but the payoff for such a reaction for medicinal or materials chemistry could be great. "We're excited to have fundamental organometallic chemistry that might have a direct impact on medicine," Ritter says.

"Carbon-fluorine bond formation is very difficult chemistry, but it can be very rewarding chemistry," Vigalok adds.