Chemical Aerobics

In a "green" academic-industry collaboration, Shannon S. Stahl and coworkers of the University of Wisconsin, Madison, and Martin D. Johnson and colleagues at Eli Lilly & Co. teamed up to create a safe and scalable continuous-flow reactor system for palladium-catalyzed aerobic oxidation reactions. The development should enable broader use of molecular oxygen in place of environmentally undesirable chromate and permanganate oxidizing reagents currently used for oxidations in pharmaceutical production (Green Chem., DOI: 10.1039/c0gc00106f).

The synthetic scope and utility of palladium-catalyzed oxidations for pharmaceutical process chemistry has increased substantially over the past decade, Stahl notes. Because O₂ is inexpensive and readily available, it's commonly used as an oxidant in large-scale commodity chemical production, he says. But aerobic oxidations have been avoided in the pharmaceutical industry primarily because most companies lack process chemists specializing in O₂ safety engineering, Stahl adds.

In 2007, Stahl and Lilly's Matthew H. Yates connected at a conference and began discussing possible solutions. The researchers realized they could address the safety challenge if they could combine Stahl's "organometallic oxidase" palladium reaction chemistry, which mimics the two-step catalytic cycle of oxidase enzymes, with Lilly's process engineering.

The outcome is a modular flow reactor system with a small footprint—easily transported on a truck between Stahl's lab in Wisconsin and Lilly's facility in Indianapolis—in which stainless steel tube reactors of different diameters and lengths can be interchanged to accommodate gram- to 1 kg-scale reactions.

The researchers used oxidations of alcohols to aldehydes and ketones to demonstrate the functionality of the reactor. The system consists of reservoirs for the substrate and homogeneous palladium pyridine catalyst solution, as well as O₂ and N₂ tanks. The O₂ is diluted in the inert N₂ (8% O₂ in N₂), ensuring that the combination of O₂ and flammable organic reagents doesn't become explosive.

The Wisconsin-Lilly team typically carried out reactions at 100 °C at 30 psi of O₂. Reactions lasting up to about five hours provided better than 90% yield, generating only water as a by-product and permitting catalyst recovery.

"This work shows the possibilities for transferring lab-scale results of catalytic reactions in a straightforward manner to production scale," comments Norbert Kockmann, who is responsible for continuous-flow processes and microreactor technology at Swiss specialty chemical firm Lonza. "This type of closed handling of a potentially explosive mixture can dramatically increase process safety," Kockmann adds.

Green oxidations are one of the goals of the ACS Green Chemistry Institute's Pharmaceutical Roundtable, a group of pharmaceutical industry representatives with a mission to identify and overcome common drug discovery and process chemistry challenges. GlaxoSmithKline's Conchita Jimenez-Gonzalez, who cochairs the roundtable, says the Wisconsin-Lilly aerobic oxidation represents "a very good piece of work" that responds to one of the roundtable's key strategic areas. "This type of research expands the available options of synthetic chemistry by leveraging engineering and chemistry in an integrated fashion," she says.