The nuke's the thing for synthesis
In combinatorial chemistry, the new wave is micro.
Once, chemists might have spent days sweating over a Bunsen burner, pleading with a reactive brew to release its product. But with the arrival of combinatorial chemistry, those heady days are long gone, and vast arrays of molecules are generated in a trice. Recently, though, huge libraries have become passé, and software now allows chemists to focus on predicted chemical and physiological properties, which means that smaller libraries can do the job. Mats Larhed of Uppsala University in Sweden points out that, these days, medicinal chemists are homing in on targeted and designed libraries of only 25100 compounds in lead optimization.
Even with compound libraries coming into sharper focus, the rate-determining step, especially in the pharmaceutical industry, remains the speed at which usable quantities of materials can be synthesized. Optimization can take one only so far. A less subtle approach, which owes more to defrosting pizza than to retrosynthetic analysis, might, however, allow chemists to come up with a recipe for new products in half the time. As with dinner, so with chemistry. Why not blast the reactants with microwaves to speed things up?
Microwave chemistry has been around for decades. In the 1960s, physical chemists used domestic microwave ovens to give their reaction systems a temperature kick, and microwave-generated polymers were all the rage in 1967. By the early 1980s, several chemists were bringing domestic ovens into the laboratory, and since the mid-1980s, groups led by Richard Gedye (Laurentian University, Sudbury, ON), George Majetich (University of Georgia, Atlanta), Raymond Giguere (Mercer University, Atlanta, GA), Rajender Varma (Sam Houston State University, Huntsville, TX), and others have found that microwaves can accelerate, boost the yields of, and initiate otherwise impossible reactions. To date, ~1300 microwave chemistry papers have been published.
But as Pino Pilotti of Personal Chemistry (Uppsala, Sweden) points out, many would-be microwavers were put off by spurious results. There is no way one can get reproducible results using a normal domestic microwave oven, because you get interferences between the microwaves, he explains. Parts of the plate are heated very much, others at the temperature you are hoping for, while other regions are not heated at all. The occasional excellent results were tarred by the explosions and lack of reproducibility.
Most reaction rates are accelerated by increasing the reaction temperature. For every 10° increase in temperature, the rate is approximately doubled. The maximum temperature of a reaction is usually the boiling point of the solvent. But in a closed microwave vessel, the temperature of the mixture can be raised further, so the reaction rate increases accordingly (Table 1).
Early research was carried out in a conventional domestic microwave oven, but the development of more controllable machines tailored to chemistry with flow reactors and pressure vessels were more suited to synthesis. After all, whether a single- or multimode machine is used, molecules see microwaves the same way and are coupled just as well to the oscillating electromagnetic field. Problems arise when the microwave units cavity is close to the wavelength of the microwaves, because standing waves can be inadvertently set up, resulting in hot and cold spots. Designers can go some way to avoid this by building in a rotating metal propeller that breaks up standing waves or by continuously moving the sample on a platter to ensure homogeneous exposure to the microwave field.
Multimode machines waste some of the microwave energy, but they are often more flexible in terms of the range of vessel types, sizes, and volumes, according to Kenneth Borowski of Milestone, Inc. (Bergamo, Italy). Single-mode machines have a smaller cavity, so they are limited to smaller vessels that must be inserted one way and with specific volumes to reduce microwave reflections and energy loss.
To provide a more consistent menu, companies such as Milestone, Personal Chemistry, and CEM Corp. (Matthews, NC), are cooking up state-of-the-art microwave machines with reaction parameter monitoring and control (i.e., time, temperature, pressure, applied power, and stirring rate), advanced vessel technologies, and process control software that could make microwave methods the haute cuisine of chemistry (see box, World Wide microWave).
With these machines becoming more common in industry and academia, the number of microwave reactions is growing. Christopher Strauss and colleagues at the Commonwealth Scientific and Industrial Research Organisation Division of Chemicals and Polymers in Clayton, Australia, have found that they can carry out reactions of allyl phenyl ether at 200 ºC in water simply by applying a little pressure to keep the water under control. This not only allows them to generate interesting products and to demonstrate that it is possible to use microwave heating to interconvert alcohols and alkenes, but it also allows them to avoid volatile organic solvents and acid catalysts, adding to microwavings green credentials.
Controlling the stereochemical outcome of a drug synthesis is crucial because many materials either have hazardous isomers or are less effective medicines as isomeric mixtures. Nikolai Kuhnert and Timothy Danks of Surrey University (U.K.) have demonstrated, for the first time, stereoselective synthesis under thermodynamic control for an important group of reactionsthe synthesis of 1,3-oxazolidines. Condensation reactions between enantiomerically pure amino alcohols, such as ephedrine and pseudoephedrine, and aldehydes occur with high yields and without the formation of unwanted diastereoisomers. No further workup is needed, explains Kuhnert, because the equilibrium is shifted to the thermodynamically more stable diastereoisomer.
Ajay Bose and colleagues at the Stevens Institute of Technology (Hoboken, NJ) found that microwaves allowed them to perform catalytic transfer hydrogenations in open vessels with high-boiling solvents such as ethylene glycol. Reactions are performed in minutes, and the researchers have made various -lactam synthons by reducing ring substituents containing alkene and alkylidene groups or conjugated unsaturated esters. One critical aspect of Boses work is that he neatly sidesteps the need for increased pressures, the bugbear of industrial scale-up for synthetic hydrogenation reactions.
Qian Cheng and colleagues of the Laboratory of Applied Bioorganic Chemistry at Tohoku University (Sendai, Japan) found that microwaves allowed them to quickly carry out highly stereoselective intramolecular cycloadditions of unsaturated N-substituted oximes, nitrones, and azomethine ylides on the surface of silica gel without solvent. The reactions resulted in good yields of a range of functionalized tricyclic isoxazolidines that are fused with a pyrrolidine or piperidine ring. The isoxazolidines manipulable NO bond makes it useful in producing various compounds, including antimicrobial agents.
Larhed and colleague Anders Hallberg reported the first examples of microwave flash-heated, palladium-catalyzed CC bond formation. Using Personal Chemistrys single-mode cavity in sealed vessels, they performed the reactions both in solution and with polymer-supported starting materials. We were astonished that we could reduce the reaction times for these highly stereoselective metal-catalyzed reactions from hours and days to minutes and seconds, says Larhed. Such results are typical with the new-generation chemistry microwaves. And as with many novel approaches to synthesis, there are other beneficial side effects, such as fewer reagents wasted.
So, how does this microwave diversity fit into the combinatorial picture? The development of solid-phase organic synthesis based on the original Merrifield method of peptide preparation has been one of the mainstays of combinatorial chemistry. Insoluble polymer supports enable reactions to be driven to completion and products to be readily separated. But nonlinear kinetic behavior, slow reactions, solvation problems, and degradation of the polymer support during long reaction times have presented serious problems, according to Alexander Stadler and Oliver Kappe of Karl Franzens University (Graz, Austria).
They recently reported an interesting fusion of microwave and combinatorial chemistry with the development of a fast and effective method for attaching aromatic and aliphatic carboxylic acids to chloromethylated polystyrene resins using cesium salts. Such attachment procedures are common requirements in the initial stage of a combinatorial synthesis, in which the starting material must first be supported on a bead. The microwave version of the process is not only significantly faster than the standardfrom days to minutesbut Stadler and Kappe get much higher capacity.
They used a custom-built microwave to carry out the transformations with controllable on-line temperature, pressure, and microwave power. The kinetics of the process led them to believe that the rate enhancement boils downs to a rapid direct heating effect on the solventin this case, N-methyl-2-pyrrolidone. Others, including Larhed, have suggested that many reactions amenable to microwaves might be incorporated into library production.
Baked potatoes were always the big no-no in the kitchen microwave, generally yielding a tasteless, albeit hot inner mush with none of the ovens crusty coat. Then came the embellishments, such as browners and grills, to help the chef in a hurry. So too with chemistry. The early microwaving pioneers also had problems with consistency. But greater control is standard in robotic machines and is putting microwaves back on the menu. Fifty years ago, an overheated clamp-stand might have told you the reaction was complete. These days, it is more likely to be a ping from a machine.
|A micro aside
|There is nothing mysterious about the action of microwaves on chemical reactions. Microwaves are simply electromagnetic radiation of wavelength between 1 mm and 0.1 m (300 to 3 GHz). Chemists found early on that many slow or impossible reactions were suddenly fast and easy in a microwave oven. Certain DielsAlder and ene reactions were much faster than would be expected from simple heating. For years, researchers speculated that there was more to microwaves than was apparent.
Many researchers were convinced, on the basis of some unusual reactions, that there were effects other than the well-known twisting back and forth of polar molecules, such as water, and the subsequent heating that took place. It was suggested, for instance, that the incident microwaves might lower the Gibbs energy of activation of a reaction. If reactant molecules lined up under microwave irradiation, this might somehow reduce a reactions free energy requirements.
The speculation turned out to be unfounded, according to Michael Mingos of Imperial College (London), who demonstrated that all the effects of microwaves on chemical reactions were nothing more than heating effects. These effects caused some spectacularly sharp rises in temperature but without solvents boiling, because the microwaves heated the whole contents of the flask rather than just the edges. Water, for example, reaches 105 ºC before boiling, and acetonitrile makes it to 120 ºC, 38º above its normal boiling point. Mats Larhed of Uppsala University in Sweden was relieved to see Mingoss results. In my opinion, it is very important to remove all magic from this research area, he said.
There still is no consensus in the literature regarding the so-called microwave effect, says Kenneth Borowski of Milestone, Inc. (Monroe, CT), who believes that physical organic chemists have not promulgated the theoretical framework to keep pace with the efforts of synthetic chemists. Although the idea of activating or tweaking individual bonds or functional groups is taboo, microwave energy transfer, when used as a heating technique, does impart certain characteristics that are unlike anything that can be produced with resistive heating thermal techniques. Microwave lab stations are nevertheless one more tool for the advanced synthetic chemist to use, he suggests.
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David Bradley is a freelance science writer living in Cambridge, U.K. Send your comments or questions regarding this article to firstname.lastname@example.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.
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