151ISSN 1756-8919Future Med. Chem. (2010) 2(2), 151–15510.4155/FMC.09.133 © 2010 Future Science Ltd

Commentary

The beginning of microwaves in synthetic chemistryMicrowave energy began to be applied to organic chemistry reactions in the mid-1980s [1,2]. The initial work was performed in kitchen microwaves or in multiple-mode systems with 50–100-ml pressure vessels, which were designed for acid-digestion applications. The problems with performing chemistry in a kitchen microwave are reproducibility and safety; there is no temperature control or stir-ring, there are limitations to the power that can be applied and the placement of the reaction vessel in the cavity is critically important. The multimode systems, although capable of tem-perature measurement, stirring and running at elevated pressures, struggle with sample size. Typically, you need to run a total sample size of 20 ml or more in these systems. It was not until around 2000 that single-mode reactors, which were designed for smaller samples, began to emerge in the market. A single-mode cavity is a smaller cavity design that allows a standing wave to be propagated in the cavity, resulting in a single mode of high microwave intensity. These cavities must be designed specifically to stay in tune with the load in the microwave cavity. One of the tricks of microwave cavity design is that, as the sample in the microwave cavity changes, so does the field. So, the cavity has to be allowed to adjust to different samples in order to ensure that the sample is in the region of high microwave intensity. This also addresses the issue of reproducibility. It ensures that if the same reaction is run in a single-mode cavity multiple times, the reaction yield will remain fairly consistent. An additional benefit of the smaller, single-mode cavities is that the footprint of the entire system is much smaller

and weighs less than a multimode system, which is more amenable to a synthetic chemistry labo-ratory, even allowing the microwave to reside in the fume hood.

Initially, the main advantage of microwaves was thought to be in combination with pres-sure vessels, where microwave energy was used to quickly drive a reaction mixture to elevated tem-peratures and hold it at these temperatures; how-ever, it appears that microwaves actually offer an advantage beyond that, in the application of the energy itself. Applying energy to the system directly and instantaneously provides the mol-ecules in the reaction mixture with the energy needed to react and form chemical bonds, thus, the bulk temperature is a side product involving the entire reaction mixture rising to an elevated energy level. More microwave users have begun to think of the technology as an efficient way to apply energy directly into a system instead of simply a way to heat things rapidly. This shows benefits for chemistries performed at reflux, as well as chemistries carried out in pressure vessels. The advantage of being able to run an open ves-sel is that it applies to a broader range of chem-istries for the medicinal chemist and is less of a change from what they are doing conventionally. It also allows the evolution of gaseous products and operation at larger scales.

�� Microwaves explainedAn important topic to address here is how microwave energy works, because that has a bearing on the future direction of the tech-nology. Microwave energy is spectrum in the same way as visible light, infrared irradiation and UV irradiation. Microwaves occupy the region of the spectrum from approximately 300–300,000 MHz, just lower in quantum

Future trends in microwave synthesis

This article discusses the current status of microwave organic chemistry and briefly explains how the technology evolved to this point. Several trends in the technology and where it is likely to go in the future are also discussed. These trends include the way in which chemists think about microwave energy, the current method of use and the hardware presently available. Some of the future trends explored are microwave use in relation to materials synthesis, bioscience applications, scale up and flow chemistry.

Michael J Collins JrCEM Corporation, PO Box 200, Matthews, NC, USA Tel.: +1 704 821 7015 Fax: +1 704 821 8710 E-mail: michael.collins_jr@ cem.com

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energy than infrared irradiation. This means that microwave energy does not have the quan-tum energy necessary to make or break chemi-cal bonds. There is not even sufficient quan-tum energy in microwaves to rotate or vibrate chemical bonds, the energy simply causes mol-ecules to attempt to orient along their dipole moment with the electric field. Since the elec-tric field oscillates billions of times per second, the molecule is in constant motion, attempting to align with the field. This motion causes fric-tion, which translates into heat or an increase in temperature around this molecule that is quickly dissipated in the bulk solution. In the case of ions, any ions present in solution will move through the solution based on the orienta-tion of the electric field and, again, since this is in constant fluctuation, the ion is moving in constantly changing directions through the solution, causing a local temperature rise due to friction. Another interesting phenomenon is that microwave energy induces electron move-ment in metals, which causes rapid heating. Traditionally, metals are thought to be incom-patible with microwave energy; however, this is not true of all cases. This electron movement in metals is what causes arcing in some cases when the electrons jump a gap from one metal surface to another. There are ways to prevent the arcing of metals in a microwave cavity, such as ensuring that the metals are in solution – the liquid provides an insulator between the metal surfaces making it less likely that electrons will jump the gap. Using these unique properties of metals can actually be to a chemist’s advantage in microwave chemistry. For metal-catalyzed reactions, a metal catalyst can be used in a sol-uble form or as an insoluble metal to drastically enhance reaction rates and product yields. This is due to the fact that the surface of the catalyst, where the reaction occurs, is superheated, thus, essentially, you have supercharged your cata-lyst. This is one of the main reasons why pal-ladium-catalyzed coupling reactions have been explored so extensively in the microwave. These mechanisms help illustrate that the advantages seen when using microwave synthesizers really boil down to the fact that microwaves allow energy to be transferred rapidly and specifi-cally and that the application of the energy can be turned on and off instantaneously (Figures 1 & 2). The reasons for the speculation that microwave energy is doing something other than what is achievable conventionally are that the reactions seem to follow unusual kinetics or

the results of the chemistry are different. This is likely because the measured bulk tempera-ture of the reaction mixture is not indicative of the instantaneous molecular temperatures that are driving the reaction. If you use these instantaneous temperatures as the temperatures driving the reaction, the kinetics of the reaction can usually be shown to be the same for both conventional and microwave methods. The rea-son for unusual results likely occurs because the bulk reaction mixture is not exposed to the elevated temperatures for extended amounts of time. Essentially, with microwave energy you can achieve the temperatures needed to cause chemical conversion without the condi-tions that cause molecular degradation. This can allow chemistries to take place that will not react or will only occur minimally under conventional conditions.

�� Where is microwave acceptance today?A reasonable estimate is that microwave synthe-sizers can be found in 15–20% of organic chem-istry laboratories and they are usually a shared resource for everyone in that laboratory. Of the chemists who actually use the microwave, there is a dichotomy: those who use microwave as a last resort to see if they can make impossible reactions happen and those who use it on a daily basis for a large percentage of the reactions they attempt. We have seen, and are seeing, a move-ment of chemists from the first category to the latter, which is encouraging for the acceptance of microwaves into the everyday workflow of the organic chemist. In addition to this trend, a higher percentage of microwave users are using laboratory-grade instruments, which improves the repeatability of their results, as evidenced by the increasing number of microwave pub-lications each year. In addition, there is quite a number of books and review articles on the topic of microwave chemistry [3–17].

�� Where are things going?The presence of microwaves in chemistry laboratories is increasing, but there are still a few roadblocks preventing the dramatic expansion usage.

The first of these is ease of use. Part of this is the perception many chemists have of micro-waves as being difficult to use and requiring a specialist; part of this is that the systems themselves must become easier to operate. Microwave systems will never find themselves in every fume hood or even every laboratory if

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Vessel wall istransparent tomicrowave energy

Localizedsuperheating

Reactant–solventmixture (absorbsmicrowave energy)

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they require a microwave specialist to use them. They must be easy enough to operate that any chemist in the laboratory, even if he or she has never used a microwave before, can work out how to run the system and what parameters to enter for a reaction, within 5 min of walking up to the system. Really, using microwaves is no more difficult than that. It is very similar to using a hotplate, only it is a more efficient way to apply the energy. The chemistry follows the same basic rules as on a hotplate. It just may be that the temperatures and the times are different because, at a molecular level, the reactants are exposed instantaneously to higher temperatures.

The second factor that will determine the future success of microwave systems is the hard-ware. Although there are currently good systems available for laboratory work, the price of these instruments is anywhere from US$10,000 to US$50,000. In order to make systems avail-able for every fume hood, the US$5000 barrier must be broken, meaning that a system must be developed costing the user less than US$5000 to put in his or her laboratory. The footprint of this system would have to be approximately the same as a hotplate with temperature control and it would have to be as simple to use as a hotplate. The availability of a system like this, which has been talked about in the industry for quite some time, would increase the use of microwaves dramatically.

A third factor in the acceptance of the tech-nology is the comfort level chemists have with microwave energy. One trend that is occurring is a dramatic increase in the usage of microwave energy at the graduate research level, which creates familiarity with the technology that extends into their professional career. Over the past decade, we have seen researchers who are starting their careers at pharmaceutical or bio-technology companies or as young professors, telling their new employers that they need a microwave for their research just as they would a rotary evaporator. To them, it is no more dif-ficult to use than a hotplate, and provides many more possibilities. We see them use it as a first resource in their chemistry and without any hesitation or uncertainty, due to their familiar-ity with the technology. An extension of this is that, now, universities and colleges have begun to incorporate microwaves into their under graduate organic chemistry teaching laboratories. To assist teaching, there are now manuals available that contain preconstructed and tested microwave

experiments. By being exposed to a technology at this early stage in their careers, young chemists develop a real understanding of the technology and become comfortable with it. In some cases, they help to remind us how uncomplicated the technology really is. In addition to the expo-sure they are getting to a new technology, there is an additional benefit for young chemists in using microwaves in their teaching laboratories. Since the reactions are so fast (5–30 min even

Figure 1. Conventional heating. The temperature on the outside surface is greater than the internal temperature. Energy is transferred via thermal conduction.

Figure 2. Microwave heating. The vessel wall is transparent to microwave energy. Since the energy is transferred kinetically, localized superheating occurs and the reactant mixture absorbs microwave energy.

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for difficult reactions), they can perform reac-tions that were previously too difficult and there-fore required too much time to run in a 2–3-h laboratory period. Who would have thought of running Diels–Alder reactions, multistep reac-tions, S

NArs or Suzuki couplings in Organic

Laboratory 101? But are these not the reactions we run in the real world?

�� Areas of future explorationThere are a few things that are likely to occur with microwave technology in the next few years. First is the advancement of microwaves into new areas such as materials science and bio-chemistry. Second is the future role of micro-wave in flow and scale-up chemistries. Third, and finally, is the evolution of the ways in which microwaves are used.

Microwaves offer some unique advantages to materials synthesis. Owing to the ability of microwaves to interact directly with the sam-ple and to turn on and off quickly, the particle growth of these materials is much more con-trolled and uniform, which results in an improve-ment in the desired property of these materials. There is only a small number of researchers using microwave synthesizers in this field currently, but they are seeing remarkable results. This will most likely lead to an increased adoption rate of the technology over the next few years.

Another trend that is occurring is the use of microwaves in biochemistry. This helps illustrate the real advantage of the technology. Most bio-molecules are fairly temperature-sensitive and will lose their biological function if exposed to elevated temperatures for extended periods of time; however, there are a lot of biochemical interactions that are slow or difficult to occur. For temperature-stable small molecules, the solution would typically be to apply heat to promote the reaction, but this is less feasible in the ‘bio’ world. Microwaves, however, fit this need perfectly. They are able to push biochemical interactions to occur without the high bulk temperatures that would cause loss of activity or degradation. This helps to show that the great advantage of microwave energy is efficient energy transfer rather than a method to rapidly heat a solution to elevated temperatures. Think of a microwave as a scalpel compared with a sledgehammer. This property is what has caused a tremendous amount of accep-tance in areas including peptides and proteomics. The challenge in this field is on the instrument providers to deliver the right hardware to the market for these different applications.

Flow chemistry is now emerging as an area of interest and with it is the desire to couple flow with microwave energy. Although it is an interesting field and there are many examples of very good chemistries being performed in a flow microwave, it remains to be seen whether flow will be adopted more broadly in the medicinal chemistry world. Organic chemists have been mixing things in pots for over 100 years, and moving from batch to flow, although techni-cally feasible, would require a significant con-certed movement. The eventual role of flow in a field where the chemistries are varied and constantly changing is unclear, so it remains to be seen where microwaves will fit in this area.

One of the main questions asked about micro-waves is related to scale up; when will scale-up systems be available for microwaves? Currently, there are microwave systems to address scale up to the kilogram level, but ‘off-the-shelf ’ sys-tems are not available for larger scales. There are several industrial microwave companies that specialize in large-scale microwave systems, but most of these systems are developed for appli-cations other than bulk chemical processing, such as curing, drying and food processing, for example. The problem with developing a scale-up microwave system for bulk chemical processing is that you start to question the advantage of microwave. In some of the cur-rent applications where scale-up microwaves are applied, there are clear advantages to using a microwave; however, for bulk heating of a large vat of chemicals to drive a reaction, microwave energy may not be the way to go. Even continu-ous flow on that scale has its issues, such as the handling of solids, residence time in the micro-wave field versus throughput and dealing with elevated pressures. The application of micro-wave energy on the research scale demonstrates clear advantages to conventional heating, but it is unclear whether microwaves will ever find their way into the manufacturing facilities. As more chemical reactions are run in a micro-wave as a primary method, this will push the microwave scale-up discussion to the forefront and solutions will have to be found. It may be that microwave energy is only the solution in certain cases and, in these cases, the solution may be a custom design versus an off-the-shelf system that will find broad acceptance across the board in manufacturing plants.

A decade from now, a microwave will not be uncommon or unique in a chemistry laboratory. It will be much like having a hotplate or a

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Executive summary

�� Microwave energy is a safe and efficient method of rapidly performing organic synthesis.

�� Microwave energy enables chemists to instantaneously heat their reactants, allowing chemistries to proceed much more rapidly and with fewer side reactions than conventional methods.

�� Acceptance of microwave technology for the laboratory is growing.

�� The perception of microwave energy as difficult to work with must be overcome in order for the technology to grow, but with the use of microwave synthesis in undergraduate teaching laboratories, many chemists are becoming familiar with the equipment early on.

�� The use of microwave energy in materials synthesis and biochemistry will grow, but it remains to be seen if it is the right technology for scale-up or flow chemistry.

rotary evaporator in your laboratory. The units will be small, almost unnoticeable, but they will be used every day for a majority of the chemistry performed in order to allow rapid reactions and push the boundaries of chemis-tries that will afford good results. The technol-ogy will open up new synthetic pathways and allow the use of more environmentally friendly solvents. It will yield cleaner products that will not require as much purification. In addi-tion, the scientists using this equipment will understand how to apply this technology to their workflow, but they will not be microwave

specialists. Microwaves will simply be another tool in their standard toolkit, much like thin layer chromatography.

Financial & competing interests disclosureThe author has no relevant affiliations or financial involve-ment with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert t estimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Bibliography1 Gedye R, Smith F, Westaway K et al. The use

of microwave-ovens for rapid organic-synthesis. Tetrahedron Lett. 27(3), 279–282 (1986).

2 Giguere RJ, Bray TL, Duncan SM, Majetich G. Application of commercial microwave-ovens to organic-synthesis. Tetrahedron Lett. 27(41), 4945–4948 (1986).

3 Hayes BL. Microwave Synthesis: Chemistry at the Speed of Light. CEM Publishing, Matthews, NC, USA (2002).

4 Loupy A (Ed.). Microwaves in Organic Synthesis. Wiley-VCH, Weinheim, Germany (2002).

5 Kappe CO, Stadler A. Microwaves in Organic and Medicinal Chemistry. Wiley-VCH, Weinheim, Germany (2005).

6 B Lidström P, Tierney JP (Eds). Microwave-Assisted Organic Synthesis. Lackwell, Oxford, UK (2005).

7 Loupy A (Ed.). Microwaves in Organic Synthesis. Wiley-VCH, Weinheim, Germany (2006).

8 Kappe CO, Dallinger D, Murphee SS. Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols. Wiley-VCH, Weinheim, Germany (2009).

9 Larhed M, Moberg C, Hallberg A. Microwave-accelerated homogeneous catalysis in organic chemistry. Acc. Chem. Res. 35(9), 717–727 (2002).

10 Lew A, Krutzik PO, Hart ME, Chamberlin AR. Increasing rates of reaction: microwave-assisted organic synthesis for combinatorial chemistry. J. Comb. Chem. 4(2), 95–105 (2002).

11 Wathey B, Tierney J, Lidstrom P, Westman J. The impact of microwave-assisted organic chemistry on drug discovery. Drug Discov. Today 7(6), 373–380 (2002).

12 Kappe CO. Controlled microwave heating in modern organic synthesis. Angew. Chem. Int. Ed. Engl. 43(46), 6250–6284 (2004).

13 Man AK, Shahidan R. Microwave-assisted chemical reactions. J. Macromol. Sci. A 44(4–6), 651–657 (2007).

14 Kappe CO. Microwave dielectric heating in synthetic organic chemistry. Chem. Soc. Rev. 37(6), 1127–1139, 2008.

15 Caddick S, Fitzmaurice R. Microwave enhanced synthesis. Tetrahedron 65(17), 3325–3355 (2009).

16 Kappe CO, Dallinger D. Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature. Mol. Diversity 13(2), 71–193 (2009).

17 Santagada V, Frecentese F, Perissutti E, Fiorino, F, Severino, B, Caliendo G. Microwave assisted synthesis: a new technology in drug discovery. Mini-Rev. Med. Chem. 9(3), 340–358 (2009).