Immobilized catalysts get moving

03 October 2005 00:01  [Source: ICB Americas]

Although chemists have been experimenting with immobilized catalysts for decades, few are known to have been used at commercial scale. That may soon change. Powerful and flexible, homogeneous catalysts fit well with the complex chemistry of today’s pharmaceutical pipelines, while immobilization might address their major shortcomings. Just as importantly, commercial immobilization technologies are now available from major catalyst suppliers Johnson Matthey and Engelhard, as well as Reaxa, the recent Avecia spin-off.

Homogeneous catalysis offers several advantages over heterogeneous catalysis. Because homogeneous catalysts are soluble, all of the catalytically active species is equally available to the reactants; the process can employ multiple metal oxidation states and ligands; the rate of reaction is usually controlled by kinetics rather than mass transfer; and exotherms are easily controlled. Homogeneous catalysis is thus typically faster, more selective and more flexible than heterogeneous catalysis. Homogeneous catalysis for cross-coupling, asymmetric synthesis and other transformations has accordingly burgeoned in the last decade or two.

“These reactions achieve things you cannot easily do by conventional methods,” observes Steven Ley, a professor of organic chemistry at the University of Cambridge and one of the founders of UK-based Reaxa, which develops new platforms for easier, faster and cleaner chemistry in pharmaceutical and specialty chemical production.

Still, homogeneous catalysts do have disadvantages. “Where possible, you would like the catalysts to be heterogeneous so that they do not contaminate the final goods. Furthermore, it gives you an opportunity, by direct filtration, of removing any of the spent catalyst. And you can then much more easily recycle or reuse,” says Ley. “Many of the catalysts that we use today are also associated with a ligand. A chiral ligand is often as expensive as the metal itself, so it is equally important to recover the ligand.”

To address these shortcomings, immobilization attempts to create a sort of hybrid heterogeneous catalyst by attaching the homogeneous catalyst to a solid support in such a way that its performance is only minimally affected. The concept is straightforward, but success has not come easily.

“The first report of heterogenizing homogeneous catalysts was over 30 years ago,” points out Robert Augustine, executive director of the Center for Applied Catalysis (CAC) at Seton Hall University. Unfortunately, early examples failed to live up to their billing. “As a result, there has been 30 years of skepticism built up.”

For example, the misconception is widely held that immobilized catalysts are always slower than homogeneous catalysts, says Ley. “That’s just not true. It depends very much on the linkage, the binding, on whether you’re using a polymer or silica gel or carbon support. It’s really all about how it is presented, and it cannot be generalized that homogeneous catalysis is always faster.” Additionally, many first-time users of immobilized catalysts misunderstand them because of their dual nature, suggests Augustine.

Marketing Immobilization

But each immobilized catalyst is a new species, a simple truth that plays an essential role not only in the application but also in development, notes Ramesh Subramanian, regional sales manager, US, pharma and fine chemicals industry, at Johnson Matthey. “The trick is to take the knowledge you have on the homogeneous side, and know-how you have on the anchoring side, and then go to the next step, to find the right anchored homogeneous catalysts,” he says. “So it’s not as if you could take a coupling catalyst that works very well in the homogeneous realm and then simply anchor it and think it’s going to work well for the same system.”

There are many ways to immobilize homogeneous catalysts, says Peter Berben, research scientist at Engelhard Corp. “The first is to anchor the active phase, including the ligand, by a covalent bond to the support. Another approach is to make use of ionic interaction between the support and the active phase.”

Typical supports include polymers, carbon, silica, alumina and zeolites.

“Generally, to obtain covalent bonds requires a synthesis method that is more difficult,” Berben says. “Also the active site is influenced by the generation of this bond, thereby influencing the performance of the catalyst. The advantage is that the bond is strong and that leaching of the immobilized homogeneous catalyst is minimized. The advantage of an ionic bond is the more simple synthesis. A disadvantage is the potential leaching of the active compounds.”

The CAC’s Augustine divides immobilization into two broad categories, tethering and anchoring. “Tethering” is the term he prefers when the catalyst is covalently attached to the support by way of the ligand. The tether, typically a carbon chain, is built into the ligand at one end and attached to the support at the other. “The disadvantage of the tethering technique, where you have to modify the ligand, is if you are dealing with a chiral ligand, you have to do some extensive synthetic chemistry to make the ligand amenable to tethering,” he says. “Then when you’re done with it, you have no guarantee that you haven’t distorted the chirality effect.”

FORGING LINKS

Augustine uses “anchoring” to refer to attachment by way of the metal. In the early 1990s, his colleague at the CAC, Setrek Tanielyan, hit upon the idea of linking the metal to the support by way of a heteropoly acid such as phosphotungstic acid. “It’s a three component system—a catalyst, a heteropoly acid, and a support, usually alumina,” he says. A key advantage of the technology, patented in 1999, is that it leaves the ligand untouched. “So chances are, if you have a good homogeneous catalyst, we can anchor it,” says Augustine. In some cases, enantioselectivity is even enhanced using the anchored catalyst.

The anchored Wilkinson catalyst is particularly promising, and it suggests how anchoring can improve stability and minimize leaching of metal. “There are a few processes that use [the Wilkinson catalyst industrially], and from what I understand, they can’t go more than 1000 to 2000 turnovers, substrate-to-catalyst ratio,” Augustine says. “We have used anchored Wilkinsons at 200,000 to 1. Sometimes by repeating 50,000 turnovers four or five times, using the same catalyst, or simply in one reaction with 200,000 to 1 substrate-to-catalyst ratio. In both instances, we’ve found less than 1 ppm of rhodium in the final product.”

Augustine and his colleagues at the CAC have worked with Eastman Chemical Company to adapt the technology to Eastman’s chiral BoPhoz catalysts, research described in a patent application filed last year. Eastman is now considering its options, according to Neil Boaz, senior research associate at Eastman and inventor of BoPhoz. “The anchored homogeneous catalyst technology is promising, particularly as it is applied to the BoPhoz catalyst family,” he says.

Both Engelhard and Johnson Matthey have non-exclusive licenses for the anchoring technology. Johnson Matthey has made it the foundation of its Cataxa line of anchored chiral and achiral catalysts and continues to develop it at labs in the UK.

Johnson Matthey also has a line of immobilized catalysts called FibreCat. “When we wanted to design a catalyst, the first thing we had in mind was, it had to fit into a batch process,” says Subramanian. “And at the end of the chemistry, you should be able to filter these fibers right out—they had to clean up well. Third, we wanted to come up with a way by which these fibers would not make the reaction slow, because chemists love the reaction rates they get with homogeneous catalysts.”

The result is an immobilized catalyst in which the support is a fine polyethylene or polypropylene fiber, about 300 microns long, onto which ligands have been attached through a combination of graft co-polymerization and wet chemistry. The best developed FibreCats are the 1000 series, based on palladium, for cross-coupling reactions.

The fibers provide greater functional group accessibility than polystyrene beads, says Thomas Colacot, senior scientist in the Catalysis and Chiral Technologies Division at Johnson Matthey. “In beads, the substrate must go through the beads by diffusion. If the molecule is big, it may not be able do the chemistry.” He also points to the high mechanical stability and solvent compatibility of polyethylene and polypropylene fibers.

But one of the greatest advantages of the Fibrecat system is its adaptability, he says, noting that there are three ways the catalyst can be tuned. First, different catalyst precursors can be used—for example, Pd(OAc)2 or Pd(COD)Cl2. Second, the ligands in the fiber can be varied. And third, the ligands can also be varied on the metal. This last option led Colacot to the development of the most successful FibreCat so far, Fibrecat 1032. “That is a big selling point for us,” he says. “And in that way I think we get the best advantage. Even then, I’m not going to say we’ve reached all we want to accomplish.”

The reaction rates obtained from FibreCat are totally dependent on the substrate and the chemistry, Subramanian says. “But it is slower than the homogeneous catalyst. Fifty to 100 percent would be a nice number to gun towards.” In some cases, when rates were lower, he adds, customers still worked with FibreCat to avoid the high levels of metal they otherwise obtained.

The problem of leaching

“An important problem with immobilization is leaching of the metal,” notes Reaxa’s Ley. “If the products that you are making are better ligands than the immobilizing ligand, leaching can occur, which will mean that metal will desorb from the solid phase and go into solution and contaminate the products. So just because we lock things onto immobilized supports doesn’t mean they always stay there.”

Ley’s research group at the University of Cambridge has been heavily involved in the study of leaching from heterogeneous catalysts. That work led to the development, with Avecia, and now Reaxa, of EnCat, a polyurea encapsulation technology for catalysts. Polyurea encapsulation had already been developed for the slow release of fungicides in agricultural settings. Palladium EnCat is the lead product. The Pd EnCat beads, 100 to 350 microns in diameter, form a cage that traps the catalyst complex while allowing the substrate in and the product out. When the reaction is complete, the beads are filtered off. The levels of free palladium are very low, and the beads can be reused up to 10 or 20 times, depending on the process.

Reaxa has also developed metal scavengers, the Quadrapure range, for removing free metal. “Now we are able to use one of our absorbing scavengers, which will essentially hunt down those impurities, bind to them selectively, and we can then filter that away and recover, say, palladium metal,” says Ley. “It leaves behind the API, and we can by one recrystallization generate material that has less than 10 ppm palladium in it.”

Engelhard and Johnson Matthey also have scavenging products. “Engelhard has invented special scavenging materials for the removal of dissolved metals and catalyst remains in case leaching of these compounds occur. The materials are known as Metals Scavenging Agents and are commercially applied and available,” says Berben.

Johnson Matthey’s scavengers, the Smopex line, are based on essentially the same technology as FibreCat, but the functionality attached to the fibers is optimized for removing metals rather than supporting catalysts. Additionally, viscose fiber is an option that might be chosen for its wettability in polar solvents. Twelve Smopex products are on the market, and 60 or 70 in development, says Mark Dank, technical specialist at Johnson Matthey. Four products have proven especially valuable to the pharmaceutical industry, he says: Smopex 102, 105, 111 and 234. These scavengers are able to achieve particularly low levels of metals, both precious and base. Johnson Matthey is submitting Drug Master Files with the FDA for the four scavengers, so that customers will be able to use them under GMP conditions. Smopex 111 and 102 have already been filed.

Close to success?

Smopex products are used on plant scale in a number of industries, says Dank, but its use in pharmaceuticals is still developmental. The same is true of FibreCat. “It’s been on the market for about 3 years. The pharma cycle is five to six years, so there it’s presently used in phase I/II projects,” says Subramanian. “A lot depends on whether these products go to the next stage.” But the day when immobilized homogeneous catalysts are used to manufacture commercial pharmaceutical actives seems not far off. “We feel that the future for catalysts and scavenging materials in the fine chemicals market is healthy,” says Engelhard’s Berben. “Immobilized catalysts will be a part of this market.”

“Anchor technology is almost a no-brainer,” says Subramanian. “The trick is to come with the right catalyst for the specific substrate or specific conditions. There is no doubt that we will continue to focus on this area, trying to either fine tune or [develop] offsprings from this area.” Ultimately, catalysts and scavengers are enabling tools, he adds. “We are trying to give a variety of options to the chemist,” he notes. “We have anchored catalysts, homogeneous catalysts, metal scavengers—so among this plethora of options, we hope he’s going to hit a home run with one of them or a combination.”

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