A nanoparticle catalyst containing far less palladium than catalysts generally used for Suzuki-Miyaura cross-coupling reactions for making pharmaceuticals promises economic and environmental advantages, say its developers at the University of California Santa Barbara, Santa Barbara, Calif. Reactions take place under mild conditions and with minimal need for organic solvents, they note. Moreover, such nanoparticles may suit other palladium-catalyzed reactions, such as Sonogashira couplings and nitro-group reductions, and may offer benefits for making some agricultural chemicals and polymers, believes Bruce Lipshutz, a professor of chemistry who led the research team.
Figure 1. Team led by Bruce Lipshutz (center) includes Sachin Handa (left) and Ye Wang (right). Source: Sonia Fernandez, University of California Santa Barbara.
“Our patent-pending chemistry virtually removes the normally high cost of palladium by substantially reducing the amount required for this key type of reaction,” notes Lipshutz. “We used about 100 times less palladium than is generally needed in pharmaceutical applications.”
“…Dropping the amount of catalyst by itself is not the only factor that comes with this chemistry. That is, use of these nanoparticles is tied to use of water as the medium, and the associated milder conditions.”
The researchers discovered that some commercially available ferric chloride (FeCl3) naturally contains enough palladium to catalyze the cross-coupling reaction. “We hit upon this magic composite, but if you don’t have all of the key ingredients nothing works,” he explains. “So, it’s not just about having palladium; it’s about having the right components in the right proportions.”
The process offers several environmental advantages, he emphasizes. “It eliminates organic solvents from the reaction medium, requires little to no energy input — and now reduces the cost and extends the lifetime of an endangered precious metal, palladium.” Moreover, the nanoparticles are recyclable, and show little susceptibility to poisoning, Lipshutz adds.
Dragonfly Technologies, Palo Alto, Calif., will offer the technology for license; Novartis, Basel, Switzerland, funded the work and will be able to use the process. “Novartis sees substantial economic savings both from savings on materials used and on operational cost, and even greater savings from the environmental footprint perspective… Taken together, the savings are quite significant,” says Lipshutz.
To prepare the catalyst, inexpensive 97%-purity FeCl3 containing palladium is admixed with a ligand and dissolved in tetrahydrofuran (THF). Treatment of this solution at room temperature with a Grignard reagent in THF yields nanoparticles. These, after solvent removal and addition of a commercially available surfactant and a base, can be used directly in Suzuki-Miyaura reactions. More details appear in an article in the journal Science.
“The next step is to find a different ligand that will function in a similar capacity to SPhos, which is the ligand initially discovered that leads to the best results. SPhos is relatively expensive and proprietary (MIT). We have already identified such a species and we are working to fully develop the next generation of nanoparticles of this type,” says Lipshutz.
