Microwave-assisted synthesis

Dedicated microwave reactors allow fast heating of reaction mixtures to high pressures and temperatures – far above the boiling point of the used solvent(s). Employing closed vessel conditions dramatically reduces reaction times from several hours down to only a few minutes! This rate acceleration is based on the Arrhenius Law, which states as a rule of thumb that the reaction rate is doubled when increasing the reaction temperature by 10 °C.

Example:
a reaction which is performed in boiling ethanol (approx. 80 °C) within 8 hours can be performed at 160 °C within only 2 min.

Reaction Temperature80 ℃90 ℃100 ℃110 ℃120 ℃130 ℃140 ℃150 ℃160 ℃
Reaction Time8 h4 h2 h1 h30 min15 min8 min4 min2 min

General Aspects

The bottleneck of conventional synthesis is typically the optimization, i.e. finding the optimum conditions for a specific reaction to obtain the desired products in good yields and purities. Since many synthesis reactions require at least one or more heating steps for long time periods, these optimizations are often difficult and time-consuming. Microwave-assisted heating under controlled conditions has been shown to be a valuable technology for any application that requires heating of a reaction mixture, since it often dramatically reduces reaction times – typically from days or hours to minutes or even seconds. Compounds can therefore be rapidly synthesized in either a parallel or (automated) sequential way using this new promising technology.

The speed at which multiple variations of reaction conditions can be performed allows a morning discussion of “What should we try?” to become an after-lunch discussion of “What were the results?”. As a consequence – not surprisingly – most pharmaceutical, agrochemical, biotechnology and material science companies are already heavily using microwave synthesis as major methodology in their chemical laboratories. They have realized the ability of microwave technology to speed up chemical reactions and therefore their whole production process.[1]

 

“Microwaves do have the potential to become the Bunsen burners of the 21st century.”
Prof. C. Oliver Kappe, University of Graz

 

History

While fire is nowadays rarely used in order to perform chemical synthesis it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by oil baths or hot plates, while in the 21st century reactions by microwave energy has been an increasingly popular topic in the scientific community.[2]

Microwave energy was originally applied for heating food. It was used for the first time by Percy Spencer in the 1940s and it was not until the mid-1980s, when the first reports on the use of microwave heating to accelerate chemical synthesis were published.[3] In those early days, experiments were typically carried out in sealed Teflon or glass vessels in a domestic household microwave oven without any temperature or pressure measurement. The results were often violent explosions due to the rapid uncontrolled heating of organic solvents under closed-vessel conditions. Nevertheless, in the first 15 years of microwave synthesis, domestic microwave ovens were increasingly used for chemical synthesis.

Number of publications on microwave-assisted organic synthesis
Figure 1: Number of publications on microwave-assisted organic synthesis (1986-2013).[1] Gray bars: Number of articles involving microwave-assisted organic synthesis (keyword search).[4] Black bars represent the number of publications (2001-2008) reporting microwave synthesis experiments performed in scientific reactors with adequate process control (full text search).[5]
Courtesy of Prof. C. O. Kappe, University of Graz.

 

Figure 1 shows two different graphs. The first one (gray bars) shows that the number of publications using “microwave” as a keyword was significantly increasing over the first 20 years of microwave chemistry. The second graph (black bars) shows the result of a full text search for publications in which dedicated reactors (= reactors which have exclusively been developed for scientific use) have been used for chemical synthesis.[4] Obviously, as expressed by the exponential growth of the number of publications, there was a dramatic increase of interest in microwave chemistry since dedicated reactors were introduced into the market. This was for obvious reasons: the lack of safety and insufficiently accurate measurement of reaction parameters in domestic microwave ovens and the resulting fact that most of the respected scientific journals (e.g. journals of the American Chemical Society) will not consider manuscripts describing the use of kitchen microwave ovens any more.[6] As a consequence, the number of users of dedicated microwave reactors is still growing at a rapid rate, and from this trend it appears only to be a question of time until most chemical laboratories will be equipped with suitable microwave instrumentation.[1] A clear indication for that is the significant drop of the publications mentioning “microwave” as a keyword since 2008 (Figure 1, gray bars) while a full text search reveals an annual increase of 1000-1200 publications.[5] Consequently, microwave heating is no longer considered a curiosity worth mentioning, but a completely established standard method for heating reaction mixtures, such as other usual laboratory equipment like hotplates or rotary evaporators.[1]

Principles of Microwave Heating

The Electromagnetic Spectrum

The spectrum of electromagnetic waves
Figure 2: The spectrum of electromagnetic waves

Microwave irradiation is electromagnetic irradiation in the frequency range 0.3 to 300 GHz, corresponding to wavelengths between 1 mm to 1 m (see Figure 2). All domestic “kitchen” microwave ovens as well as commercially available dedicated microwave reactors for chemical synthesis operate at a frequency of 2.45 GHz (corresponding to a wavelength of 12.25 cm).

As can be precisely calculated, the energy of microwave irradiation is too low to cleave molecular bonds.[7] It is therefore clear that microwaves cannot “induce” chemical reactions by direct absorption of microwave power. However, microwave irradiation provides unique thermal effects, which are highly beneficial for chemical synthesis.
Cleaving molecular bonds and therefore inducing chemical reactions is only possible employing irradiation with higher energy (e.g. UV or visible light => photochemistry).

Microwave Dielectric Heating

Microwave chemistry is based on the efficient heating of materials (in most cases solvents) by dielectric heating effects. Dielectric heating works by two major mechanisms:

  • Dipolar polarization (see Figure 3)
    For a substance to be able to generate heat when irradiated with microwaves it must be a dipole, i.e. its molecular structure must be partly negatively and partly positively charged. Since the microwave field is oscillating, the dipoles in the field align to the oscillating field. This alignment causes rotation, which results in friction and ultimately in heat energy.
  • Ionic conduction (see Figure 3)
    During ionic conduction, dissolved (completely) charged particles (usually ions) oscillate back and forth under the influence of microwave irradiation. This oscillation causes collisions of the charged particles with neighboring molecules or atoms, which are ultimately responsible for creating heat energy.
    As an example: if equal amounts of distilled water and tap water are heated by microwave irradiation, more rapid heating will occur for the tap water because of its ionic content in addition to the dipolar rotation of water molecules.

Microwave heating of gases and solids…
… is hardly possible! Gases cannot be heated under microwave irradiation, since the distance between the rotating molecules is too wide. Similarly, solid materials like ice are (nearly) microwave transparent, since the water dipoles are bound in the crystal lattice and cannot move as freely as in the liquid state. However, some conductive solid materials, like silicon carbide, where electrons can move freely, are excellent microwave absorbers and therefore heat very quickly.

Dielectric heating mechanisms
Figure 3: Schematic illustration of the two main dielectric heating mechanisms: dipolar polarization (dipoles align in the microwave field) and ionic conduction (ions move in the microwave field).

 

With dielectric heating, electric energy is converted into kinetic energy
which is ultimately converted into heat.

Dielectric Properties

As the term “dielectric heating” suggests, a material must possess certain dielectric properties in order to be efficiently heated in the microwave field. The heating characteristics of a particular material (e.g. a solvent) under microwave irradiation conditions are dependent on the ability of a specific substance to convert electromagnetic energy into heat. This ability is determined by the so-called loss tangent, tan δ (Figure 4).

Definition dielectric loss and dielectric constant
Figure 4: Definition of the loss factor tan δ and of the components that determine this factor (dielectric loss and dielectric constant).

 

The tan δ values for some commonly used organic solvents are summarized in Table 2. This table shows the classification of solvents into high (tan δ > 0.5), medium (tan δ 0.1-0.5), and low microwave absorbing (tan δ < 0.1). Solvents without a dipole moment, such as benzene and dioxane, are more or less microwave transparent (tan δ < 0.01).
A solvent with a high tan δ (see Table 1) is required for rapid heating in the microwave field. However, this does not mean that solvents with low tan δ values cannot be used for microwave synthesis. Since either substrates or reagents/catalysts are likely to be polar, the overall dielectric properties of a reaction mixture will in most cases allow sufficient heating by microwaves, even with non-polar solvents. If, however, the mixture is non-polar, passive heating elements can be added to aid the heating process.

High (> 0.5)Medium (0.1 - 0.5)Low (< 0.1)
Solventtan δSolventtan δSolventtan δ
Ethylene glycol1.3502-Butanol0.447Chloroform0.091
Ethanol0.941Dichlorobenzene0.280Acetonitrile0.062
DMSO0.825NMP0.275Ethyl acetate0.059
2-Propanol0.799Acetic acid0.174Acetone0.054
Formic acid0.722DMF0.161THF0.047
Methanol0.659Dichloroethane0.127Dichloromethane0.042
Nitrobenzene0.589Water0.123Toluene0.040
1-Butanol0.571Chlorobenzene0.101Hexane0.020
Table 1: Commonly used organic solvents classified according to their heating efficiency (tan δ) in the microwave field.[1]

 

Polar mixtures are needed for efficient microwave heating.

In general, the interaction of microwave irradiation with matter is characterized by three different processes: absorption, transmission and reflection (Figure 5). While highly dielectric materials, like polar organic solvents, lead to strong absorption of microwaves and consequently to a rapid heating of the medium, non-polar (microwave transparent) materials show only small interactions with microwaves (transmission). Microwaves pass through such materials. This makes them suitable as construction materials for reactors. If microwave radiation is reflected by the material surface, there is almost no introduction of energy into the system.

Microwave interaction
Figure 5: Interaction of different materials with microwaves: electrical conductors (e.g. metals), absorbing materials (e.g. solvents) and insulation materials (e.g. Teflon, glass, quartz).

Benefits of Microwave Synthesis

Microwave vs. Conventional Heating

Traditionally, organic synthesis is carried out by refluxing a reaction mixture using a hot oil bath as a heat source. However, this way of heating a reaction mixture is comparatively slow and energy inefficient, since first the heat energy is transferred from the hot oil bath to the surface of the reaction vessel, and then the hot surface heats the content of the reaction vessel (see Figure 6, entry a). Furthermore, the hot surface can lead to local overheating and to decomposition of sensitive material.
In contrast, microwave irradiation results in energy efficient internal heating by direct coupling of microwave energy with dipoles and/or ions that are present in the reaction mixture. Microwaves pass through the (almost) microwave-transparent vessel wall (see Figure 5, transmission) and heat the reaction mixture on a molecular basis – by direct interaction with the molecules (solvents, reagents, catalysts, etc., see Figure 5, absorption). Due to this direct “in-core” heating (no initial heating of the vessel surface), microwave irradiation results in inverted temperature gradients as compared to a conventionally heated system (Figure 6, entry b).
Furthermore, the conversion of electromagnetic energy into heat energy works highly efficiently and results in extremely fast heating rates – not reproducible with conventional heating. Due to the rapid heating to the target temperature, the formation of byproducts is suppressed. This is another huge advantage of microwave heating, since it means that higher product yields can be achieved and the work-up is simplified.

Microwave heat introduction
Figure 6: Graphical illustration of heat introduction and temperature distribution in(to) a reaction mixture for (a) conventional heating and (b) microwave heating. While conventionally the heat comes from the outside and goes into the reaction mixture by convection currents (resulting in a very hot vessel wall), microwaves go through the almost microwave-transparent vessel wall and directly heat the reaction mixture on a molecular basis.

 

Microwaves…
… help to minimize wall effects since the vessel wall is not directly heated.
… provide a more energy efficient way of heating (direct “in-core” heating).
… allow faster heating of a reaction mixture.=> less byproducts, higher yields and simplified work-up!

Domestic Microwave Ovens vs. Dedicated Instrumentation

In the early days of microwave synthesis, household microwave ovens were extensively used in chemical laboratories. Although nowadays dedicated instrumentation is available, there are still chemists who use kitchen microwave ovens for scientific purposes.
However, most major scientific journals no longer accept manuscripts wherein domestic ovens have been described as a heating source,[6] since there are serious scientific and also practical reasons why dedicated instrumentation should be preferred:

Safety
Domestic microwave ovens have exclusively been developed for household purposes. Therefore, such ovens do not provide any active safety features for chemical synthesis. If nevertheless used for chemical reactions, household ovens will not protect the chemist in case of unexpected reaction behavior.
As it is the highest priority of an instrument manufacturer to provide the utmost safety for the user, dedicated instrumentation has numerous safety features implemented in order to allow safe processing, even under extreme temperature and pressure conditions. At 300 °C and 80 bar, safe processing is still guaranteed!

Possibility of Superheating
Superheating of solvents in sealed vessels is the key advantage in microwaves synthesis, since due to the Arrhenius law, the reaction times can be shortened considerably!
In open vessel systems, the potential time-saving benefit is limited. Therefore, microwave synthesis in sealed vessels gives access to a much wider range, applying temperatures far above the boiling point of the used solvent(s). Dedicated microwave reactors allow the reaction vessels to remain completely sealed throughout the whole experiment process and therefore act as highly convenient autoclaves, which can quickly and efficiently heat reaction mixtures up to 300 °C and 80 bar.

Excellent Parameter Control
Domestic microwave ovens do not allow reaction parameter control, since this is not necessary for simply heating food to eatable temperatures. A kitchen microwave oven therefore does not provide any possibility to measure the temperature of the reaction mixture. However, this is the key parameter for chemical synthesis!
In contrast to domestic microwave ovens, dedicated microwave reactors are usually equipped with IR sensors for reaction temperature control, pressure sensors to monitor the reaction pressure in the closed vessels and a magnetic stirrer to enable proper agitation. Often optional immersing temperature probes for more accurate internal measurement of the reaction temperature are available. Figure 7 shows an example heating profile of a typical microwave experiment, in which the parameters are accurately measured and recorded throughout the whole experiment process.

Microwave heating profile
Figure 7: Heating profile of a reaction mixture heated to 300 °C for 10 minutes. The instrument records temperature, pressure and power during the whole experiment. A typical experiment process consists of three steps: (a) heating to a certain temperature, (b) holding the temperature for a certain time and (c) cooling down.

 

Automation and Parallel Synthesis
Since time equals money, tools for improving the economic efficiency are always highly appreciated. Besides the great advantages that result from microwave heating per se, dedicated microwave instrumentation allows for an additional efficiency improvement, since in contrast to domestic microwave ovens they enable you to adapt two valuable approaches for your laboratory workflow:

a. Automated sequential processing, where reactions are processed one-by-one overnight in a completely unattended way, employing an autosampler unit which is compatible with the microwave reactor.

b. Performing reactions in parallel, where up to almost 200 reactions can be performed within one single microwave experiment.

Parallel techniques from high-throughput reaction screening to parallel scale-up as well as exploiting the economic advantages of automated sampling units are well-established methods nowadays. These techniques cannot be served by domestic ovens in such a convenient and efficient way.

Stirring
In contrast to domestic ovens, dedicated microwave reactors feature an in-built magnetic stirrer, which is of great importance since without proper agitation the temperature distribution within the reaction mixture will not be uniform and the measured temperature will be dependent on the position of the temperature sensor, as clearly demonstrated in Figure 8.

Microwave temperature profiles
Figure 8: (a) Sealed reaction vial filled with 5 mL NMP and with 3 fiber optic probe thermometers immersed at different heights. (b) Temperature profiles (three internal fiber optic probes and one external IR sensor) when irradiating setup A at const. 50 W magnetron output power. Magnetic stirring reduces the temperature differences between the individual fiber-optic probes from max 36 °C to less than 6 °C (adapted from Ref. [8]). Reprinted with permission from: J. Org. Chem. 2008, 73 (1), 36-47. Copyright 2016 American Chemical Society.

As a consequence, even completely homogeneous solutions need to be stirred when employing microwave heating, since otherwise efficient agitation cannot be ensured and temperature gradients may develop. In cases of e.g. solvent-free or dry-media reactions and for very viscous or biphasic reaction mixtures where standard magnetic stirring is not effective, extreme care must be taken in determining the proper reaction temperature since adequate mixing cannot be assured.

Continuous Power Output
Domestic microwave ovens usually provide a pulsed irradiation mode for heating. This means that a setting of e.g. 500 W will result in pulsed 1000 W power peaks, so that an average of 500 W is applied (Figure 8a). This way of heating is sufficient for household applications. However, it can be very dangerous when used for chemical synthesis, since such power peaks force the formation of hot spots and the risk of spontaneous non-controllable exotherms.
In order to reduce the occurrence of hot spots as well as to minimize the risk of thermal runaways, dedicated reactors provide continuous power output (Figure 8b). This allows you to apply exactly the amount of microwave power which is needed in order to reach or hold the set reaction temperature.

Applied microwave power profile
Figure 9: Applied microwave power profile for an experiment at 500 W (a) in a pulsed mode application (domestic microwave oven), and (b) in a reactor providing the possibility of continuous power output.

 

Software Control
Besides scientifically and economically important advantages, dedicated instruments also provide advantages in terms of handling and programming. They are usually equipped with an intuitive user interface that is operated via touchscreen, where the software supports on-screen monitoring and editing of running experiments, automatic data recording as well as data management on the instrument or on a PC.

 

Benefits of microwave synthesis in dedicated microwave reactors

=> possibility of convenient superheating of solvents

  • achieve higher temperatures
  • dramatically shorten your overall process time
  • obtain higher yields and purer compounds

=> excellent parameter control

  • improved reproducibility
  • utmost handling convenience

=> access to automated setups and parallel synthesis

  • improves your efficiency
  • time equals money!

=> possibility of stirring

  • improve the temperature homogeneity
  • increase the scientific validity of your results

=> continuous power output

  • sophisticated reaction control
  • safe and smooth processing

=> intuitive user interface via touchscreen

  • convenient programming and data management
  • automatic data recording

=> utmost safety even under high temperature/pressure conditions

References

[1] C. O. Kappe, A. Stadler, D. Dallinger, Microwaves in Organic and Medicinal Chemistry, 2nd Edition, 2012, Wiley-VCH, Weinheim.
[2] (a) N. Leadbeater, Chemistry World 2004, 1, 38; (b) D. Adam, Nature 2003, 421, 571; (c) V. Marx, Chem. & Eng. News 2004, 82, 14; (d) A. Yarnell, Chem. & Eng. News 2007, 85, 32.
[3] (a) R. Gedye et al., Tetrahedron Lett. 1986, 27, 279; (b) R. J. Giguere et al., Tetrahedron Lett. 1986, 27, 4945.
[4] SciFinder scholar search (keyword search: “microwave”) for seven selected synthetic organic chemistry journals: J. Org. Chem., Org. Lett., Tetrahedron, Tetrahedron Lett., Synth. Commun., Synthesis, Synlett.
[5] SciFinder scholar search (full text search: “microwave”) for approx. 50 journals. Data for recent years are not available but are estimated to be far higher than for 2008 (in the range of approx. 1000 to 1200 publications per year).
[6] J. Org. Chem. 2015, Author Guidelines.
[7] E. Neas, M. Collins, in Introduction to Microwave Sample Preparation: Theory and Practice (Eds.: H. M. Kingston, L. B. Jassie) 1988, American Chemical Society, Washington, DC.
[8] M. A. Herrero, J. M. Kremsner, C. O. Kappe, J. Org. Chem. 2008, 73, 36.

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