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Volume 90 Issue 39 | pp. 32-34
Issue Date: September 24, 2012

Chemists Crank Up Heat On Microwaves

No longer a lab curiosity, microwave-assisted reactions are making headway in pharma and nanomaterials labs
Department: Science & Technology | Collection: Green Chemistry, Safety, Sustainability
News Channels: Environmental SCENE, Materials SCENE, Nano SCENE, Organic SCENE
Keywords: microwave, organic synthesis, process chemisry, continuous flow, green chemistry
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HOT SPOT
CEM scientists work on developing undergraduate lab experiments that focus on safer, faster, and more efficient chemistry using microwave reactors.
Credit: CEM
CEM scientists are developing undergraduate lab experiments that focus on safer, faster, and efficient chemistry using microwave reactors.
 
HOT SPOT
CEM scientists work on developing undergraduate lab experiments that focus on safer, faster, and more efficient chemistry using microwave reactors.
Credit: CEM

The microwave oven has been a technological godsend. It plays an essential role in the kitchen by thawing or cooking food and popping popcorn. People have also found alternative uses for microwaves, including drying socks and underwear, softening cosmetics, and sterilizing all manner of objects.

Chemists can take credit for one of the more clever auxiliary uses for microwaves: taking advantage of rapid heating to accelerate chemical reactions.

Under the superheated and elevated pressure conditions possible with microwaves, reactions that take hours of refluxing in a flask sitting in a conventional oil bath or heating mantle can instead be completed in minutes. Side reactions are also often reduced, leading to improved yields and fewer product impurities. In addition, reactions can typically be carried out in water or sometimes with no solvent. And in the high-temperature and -pressure microwave regime, sometimes only a jot of catalyst or even no catalyst is required.

The ability to carry out hot, fast reactions has attracted dedicated practitioners in drug discovery and nanotechnology labs who have embraced microwave-assisted chemistry for organic synthesis, solid-phase peptide synthesis, polymer chemistry, and nanomaterials development.

But that acceptance took time. The first published report on using microwaves to accelerate organic reactions came in 1986. For the first few years, chemists used ordinary kitchen microwave ovens, and it was hard to monitor or control the temperature and pressure of a reaction. Occasionally, an exploding reaction vessel would blow the oven door off its hinges. The inconsistent results led chemists to debate the reasons for the observed reaction rate enhancements and wonder whether nonthermal microwave radiation effects were at play.

“There has always been some confusion about what is happening with microwaves,” says Grace S. Vanier, a senior scientist at CEM Corp., a producer of microwave reactors. “Some people are under the impression that microwave chemists are trying to preach that there is some crazy microwave effect. We always have to clarify that we aren’t doing that. It really is just an efficient way to heat reactions.”

In a nutshell, microwave heating occurs because microwave reactors generate an electromagnetic field that interacts with polarizable molecules or ions in materials. As the polarized species fight to align their dipoles with the oscillating field, they rotate, migrate, and rub against each other, causing them to heat up. This microwave effect differs from indirect heating by conduction achieved by using a hot plate.

Today, commercially available benchtop microwave reactors are quite sophisticated instruments, Vanier says, loaded with all of the safety and automation features that a chemist could want.

“Microwave chemistry has truly gone from a laboratory curiosity to standard practice in 25 years,” notes C. Oliver Kappe of the University of Graz, in Austria. Virtually all pharmaceutical, agrochemical, and biotech companies now use microwave technology for organic synthesis in the discovery and lead optimization stages, Kappe says. It’s still early days, but in process chemistry, larger companies are evaluating or already using microwave-assisted chemistry for their kilogram-scale labs, he adds. Materials scientists have also become fond of microwave reactors for speeding up nanoparticle preparation.

Kappe’s group has demonstrated that microwave-assisted methods work for many types of organic reactions, including Diels-Alder reactions, palladium-catalyzed cross-couplings, and aromatic substitutions. For example, in 2010, Kappe’s group carried out a set of experiments to compare microwave-assisted reactions with conventional reflux reactions. In one experiment, the researchers synthesized 2-methylbenzimidazole from o-phenylenediamine and acetic acid, a common synthesis in pharmaceutical process chemistry (Org. Process Res. Dev., DOI: 10.1021/op900297e).

They showed that in a 2-mL round-bottom flask at room temperature and pressure, the reaction takes nine weeks to complete. Heating the flask to 100 °C at atmospheric pressure using an oil bath speeds things up considerably—the reaction takes only five hours. But in a sealed tube in a microwave reactor, heated to 200 °C and reaching a pressure of about 9 atm, the reaction is done after three minutes.

“That process intensification at high temperature and pressure is the essence of microwave synthesis,” Kappe emphasizes. “That is why a microwave reactor can be a powerful tool in organic synthesis.”

Microwave-assisted chemistry has many intangible benefits beyond speed, observes Bimal K. Banik of the University of Texas, Pan American. For one, it helped launch his career.

In the early 1990s, Banik was a postdoctoral researcher in the group of Ajay K. Bose, a chemistry professor at Stevens Institute of Technology. Bose, who died in 2010, was a passionate proponent of microwave chemistry who used kitchen microwaves to synthesize β-lactam antibiotics. Banik organized a memorial symposium in Bose’s honor that was held at the American Chemical Society national meeting in Philadelphia last month.

In looking forward, Bose was quoted as saying, “The microwave oven is the Bunsen burner of the 21st century.”

Banik agrees. Like a Bunsen burner, a microwave is important from a student’s perspective, he says, “especially for undergraduates, because they don’t have all day or multiple days to work on experiments. The microwave helps them get their lab work done so they can move on to their other studies.”

Another benefit of microwave-assisted chemistry is its versatility—it can be applied to nearly any type of chemistry, Banik points out. For example, he worked on β-lactam antibiotic chemistry in Bose’s lab, and since that time, he has taken microwave β-lactam synthesis in a new direction by preparing the first β-lactam anticancer agents.

A β-lactam is a cyclic amide—a four-membered ring containing adjacent nitrogen and carbonyl groups. Most antibiotics, including penicillin, amoxicillin, and cephalosporins, contain a β-lactam unit in their molecular structures.

One of Banik’s successes is an acetoxy β-lactam substituted onto the steroidlike polyaromatic hydrocarbon group chrysene. This compound is proving to be highly effective against ovarian and colon cancers in mice. The cancer-killing ability of the acetoxy chrysene β-lactam is on par with that of the well-known anticancer drug cisplatin, he notes. Banik has patented some of the chemistry and is working with Frederick F. Becker and colleagues at M. D. Anderson Cancer Center, in Houston, on clinical testing.

For Banik’s β-lactam synthesis, the added benefit of microwave heating besides speed is stereocontrol. The cycloaddition of an imine with a ketene to form the β-lactam ring is sluggish under conventional heating, Banik says, because the polyaromatic imine is sterically hindered. The cycloaddition reaction typically leads to a cis isomer when using conventional heating, he says. But he has found that the rapid heating possible with microwaves allows him to control the stereochemistry to exclusively obtain trans isomers, which have potent anticancer activity. It’s a possibility that nonthermal radiation effects could be contributing to the stereocontrol, Banik adds, but that hasn’t been proved.

For 20-year microwave veteran Rajender S. Varma, a senior scientist in the Environmental Protection Agency’s Sustainable Technology Division, in Cincinnati, microwave-assisted chemistry provides a green alternative to classical chemistry. “The benefits of microwaves all point to more sustainable chemistry,” Varma says.

It may seem odd that, as an EPA scientist, Varma is involved in microwave research. But as part of EPA’s mandate, he is charged with developing green solutions for emerging fields, such as nanotechnology. “In the synthesis of metal nanoparticles, there are three areas of opportunity to engage in green chemistry: choice of solvent, the reducing agent employed, and the capping agent or dispersing agent used,” Varma says.

In one approach to making silver, gold, and other nanoparticles, a metal salt is dissolved and the metal ions are then reduced with brutish reagents such as sodium borohydride or hydrazine, Varma explains. As the metal nanoparticles form, they need to be capped by inert molecules, typically a polymeric species, such as polyvinylpyrrolidone, to prevent the budding particles from agglomerating.

“There’s a potpourri of nasty chemicals involved in making nanoparticles,” Varma tells C&EN. “Chemists need to be thinking more about greener alternatives. Our chemical universe is so diverse, so I asked myself, ‘How would nature do this chemistry?’ Then I tried to copy nature. Microwave heating is one of the tools that enable us to do that.”

To that end, Varma and others have uncovered an array of alternative nanoparticle-processing aids: sucrose, vitamin B-2 (riboflavin), vitamin C (ascorbic acid), coffee and tea extracts, beet juice, and even agricultural waste such as red wine grape pomace. “These natural materials function as both reducing and capping agents and provide extremely simple, fast, one-pot, green synthetic methods to generate bulk quantities of nanomaterials in water,” Varma says.

In the case of coffee and tea extracts, the polyphenol-coated nanoparticles have lower toxicity in mice than do uncoated nanoparticles made by traditional methods, he notes. Iron nanoparticles made with tea extracts have been commercialized by VeruTek Technologies through a federal Cooperative Research & Development Agreement and are being used to oxidize organic pollutants for environmental remediation of soil.

Although the nanomaterials can be made by conventional heating or sometimes even at room temperature within a few hours, microwave heating in general is more consistent in producing nanostructures with smaller sizes, narrower size distributions, and a higher degree of crystallization, Varma says. In addition, controlling metal salt concentration, chain length of surfactant polymers, solvent, and reaction temperature leads to an array of crystal shapes: polygonal plates, sheets, rods, wires, tubes, and dendrites.

“This is simple chemistry, nothing very complicated,” he says. “We are more like kids playing around. But it’s effective.”

One dark cloud hanging over nanoparticle applications is uncertainty about the fate of the nanoparticles in the environment and the concern that some versions of the materials could prove to be toxic down the road. “Currently, there is no technology that allows nanoparticles to be retrieved once they are out in the environment,” Varma notes. But with his microwave-assisted natural chemistry, Varma and his coworkers have come up with a possible solution: place magnetic iron oxide (Fe3O4) nanoparticles at the core of larger nanoparticles.

The researchers make the iron oxide nanoparticles, called nanoferrites, using a standard microwave-assisted method with glutathione as the reducing and capping agent. “Glutathione is a ubiquitous natural tripeptide and antioxidant found in all human and plant cells,” Varma says. “It’s the ultimate in environmentally benign molecules.”

Glutathione’s thiol group on the central cysteine amino acid binds well to the iron particles, he explains, leaving the flanking glycine and glutamate amino acids free. The free amino acids enable nanoferrites to function as an organocatalyst on their own, Varma says. The amino functional groups can also bind catalyst metals, such as copper or palladium, to create a heterogeneous nanocatalyst (Green Chem., DOI: 10.1039/c2gc16301b).

“These nanocatalyst materials provide a bridge between homogeneous and heterogeneous catalysis,” Varma points out. The nanocatalyst has an enormous surface area, so it functions more like a homogeneous catalyst, but with the magnetic iron core it has the ease of recovery and recyclability of a heterogeneous catalyst. “You have the best of both worlds,” he says.

Despite the success, microwave chemistry isn’t a panacea. Not all chemical transformations can be executed at the extreme reaction conditions of microwave reactors, CEM’s Vanier says. And when moving to larger batch reactors, the benefits of rapid microwave heating can’t easily be duplicated because the penetration depth of the irradiation into the reaction vessel diminishes, she explains. There’s also a safety risk with any type of chemical reaction if something were to go wrong: “The bigger the reactor, the bigger the boom,” she says. But chemists see yet another opportunity in skirting the volume and safety issues by doing more with microwaves using continuous-flow approaches.

For example, Kappe has been engaged in determining how to translate the benefits of the high temperature and pressure of batch microwave reactions to microwave-assisted continuous flow.

In collaboration with scientists at specialty chemical firm Clariant, Kappe recently used his model benzimidazole synthesis and carried out what he believes is the first reported description of microwave-assisted continuous-flow chemistry at the production scale (Green Process Synth., DOI: 10.1515/gps-2012-0032). The researchers used a flow reactor capable of operating at up to 310 °C and 60 atm pressure and at flow rates as high as 20 L per hour, which works out to about 1,000 metric tons per year. The reactants need to spend only about 30 seconds in the microwave-irradiated zone for the reaction to be complete.

“For many researchers in the lab, microwaves have become the first choice and not a last resort,” Kappe says. “Now, in moving to microwave flow chemistry, we may be seeing a new game-changer in sustainable process chemistry.”

 
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