1. Introduction

High‐speed synthesis with microwaves has attracted a considerable amount of attention in recent years.1 More than 2000 articles have been published in the area of microwave‐assisted organic synthesis (MAOS) since the first reports on the use of microwave heating to accelerate organic chemical transformations by the groups of Gedye and Giguere/Majetich in 1986.2, 3 The initial slow uptake of the technology in the late 1980s and early 1990s has been attributed to its lack of controllability and reproducibility, coupled with a general lack of understanding of the basics of microwave dielectric heating. The risks associated with the flammability of organic solvents in a microwave field and the lack of available systems for adequate temperature and pressure controls were major concerns.

Although most of the early pioneering experiments in MAOS were performed in domestic, sometimes modified, kitchen microwave ovens, the current trend is to use dedicated instruments which have only become available in the last few years for chemical synthesis. The number of publications related to MAOS has therefore increased dramatically since the late 1990s to a point where it might be assumed that, in a few years, most chemists will probably use microwave energy to heat chemical reactions on a laboratory scale. Not only is direct microwave heating able to reduce chemical reaction times from hours to minutes, but it is also known to reduce side reactions, increase yields, and improve reproducibility. Therefore, many academic and industrial research groups are already using MAOS as a forefront technology for rapid optimization of reactions, for the efficient synthesis of new chemical entities, and for discovering and probing new chemical reactivity. A large number of review articles4–13 and several books14–16 provide extensive coverage of the subject. The aim of this Review is to highlight some of the most recent applications and trends in microwave synthesis, and to discuss the impact and future potential of this technology.

1.1. Microwave Theory Microwave irradiation is electromagnetic irradiation in the frequency range of 0.3 to 300 GHz. All domestic “kitchen” microwave ovens and all dedicated microwave reactors for chemical synthesis operate at a frequency of 2.45 GHz (which corresponds to a wavelength of 12.24 cm) to avoid interference with telecommunication and cellular phone frequencies. The energy of the microwave photon in this frequency region (0.0016 eV) is too low to break chemical bonds and is also lower than the energy of Brownian motion. It is therefore clear that microwaves cannot induce chemical reactions.17–19 Microwave‐enhanced chemistry is based on the efficient heating of materials by “microwave dielectric heating” effects. This phenomenon is dependent on the ability of a specific material (solvent or reagent) to absorb microwave energy and convert it into heat. The electric component20 of an electromagnetic field causes heating by two main mechanisms: dipolar polarization and ionic conduction. Irradiation of the sample at microwave frequencies results in the dipoles or ions aligning in the applied electric field. As the applied field oscillates, the dipole or ion field attempts to realign itself with the alternating electric field and, in the process, energy is lost in the form of heat through molecular friction and dielectric loss. The amount of heat generated by this process is directly related to the ability of the matrix to align itself with the frequency of the applied field. If the dipole does not have enough time to realign, or reorients too quickly with the applied field, no heating occurs. The allocated frequency of 2.45 GHz used in all commercial systems lies between these two extremes and gives the molecular dipole time to align in the field, but not to follow the alternating field precisely.18, 19 The heating characteristics of a particular material (for example, a solvent) under microwave irradiation conditions are dependent on its dielectric properties. The ability of a specific substance to convert electromagnetic energy into heat at a given frequency and temperature is determined by the so‐called loss factor tanδ. This loss factor is expressed as the quotient tanδ=ε′′/ε′, where ε′′ is the dielectric loss, which is indicative of the efficiency with which electromagnetic radiation is converted into heat, and ε′ is the dielectric constant describing the ability of molecules to be polarized by the electric field. A reaction medium with a high tanδ value is required for efficient absorption and, consequently, for rapid heating. The loss factors for some common organic solvents are summarized in Table 1. In general, solvents can be classified as high (tanδ>0.5), medium (tanδ 0.1–0.5), and low microwave absorbing (tanδ<0.1). Table 1. Loss factors (tanδ) of different solvents.[a] Solvent tanδ Solvent tanδ ethylene glycol 1.350 DMF 0.161 ethanol 0.941 1,2‐dichloroethane 0.127 DMSO 0.825 water 0.123 2‐propanol 0.799 chlorobenzene 0.101 formic acid 0.722 chloroform 0.091 methanol 0.659 acetonitrile 0.062 nitrobenzene 0.589 ethyl acetate 0.059 1‐butanol 0.571 acetone 0.054 2‐butanol 0.447 tetrahydrofuran 0.047 1,2‐dichlorobenzene 0.280 dichloromethane 0.042 NMP 0.275 toluene 0.040 acetic acid 0.174 hexane 0.020 Other common solvents without a permanent dipole moment such as carbon tetrachloride, benzene, and dioxane are more or less microwave transparent. It has to be emphasized that a low tanδ value does not preclude a particular solvent from being used in a microwave‐heated reaction. Since either the substrates or some of the reagents/catalysts are likely to be polar, the overall dielectric properties of the reaction medium will in most cases allow sufficient heating by microwaves (see Section 1.2). Furthermore, polar additives such as ionic liquids, for example, can be added to otherwise low‐absorbing reaction mixtures to increase the absorbance level of the medium (see Section 2.2.1). Traditionally, organic synthesis is carried out by conductive heating with an external heat source (for example, an oil bath). This is a comparatively slow and inefficient method for transferring energy into the system, since it depends on the thermal conductivity of the various materials that must be penetrated, and results in the temperature of the reaction vessel being higher than that of the reaction mixture. In contrast, microwave irradiation produces efficient internal heating (in‐core volumetric heating) by direct coupling of microwave energy with the molecules (solvents, reagents, catalysts) that are present in the reaction mixture. Since the reaction vessels employed are typically made out of (nearly) microwave‐transparent materials, such as borosilicate glass, quartz, or teflon, an inverted temperature gradient results compared to conventional thermal heating (Figure 1). The very efficient internal heat transfer results in minimized wall effects (no hot vessel surface) which may lead to the observation of so‐called specific microwave effects (see Section 1.2), for example, in the context of diminished catalyst deactivation. Figure 1 Open in figure viewer PowerPoint Inverted temperature gradients in microwave versus oil‐bath heating: Difference in the temperature profiles (finite element modeling) after 1 min of microwave irradiation (left) and treatment in an oil‐bath (right). Microwave irradiation raises the temperature of the whole volume simultaneously (bulk heating) whereas in the oil‐heated tube, the reaction mixture in contact with the vessel wall is heated first.38

1.2. Microwave Effects Since the early days of microwave synthesis, the observed rate accelerations and sometimes altered product distributions compared to oil‐bath experiments have led to speculation on the existence of so‐called “specific” or “nonthermal” microwave effects.21–23 Historically, such effects were claimed when the outcome of a synthesis performed under microwave conditions was different from the conventionally heated counterpart carried out at the same apparent temperature. Today most scientists agree that in the majority of cases the reason for the observed rate enhancements is a purely thermal/kinetic effect, that is, a consequence of the high reaction temperatures that can rapidly be attained when irradiating polar materials in a microwave field. As shown in Figure 2, a high microwave absorbing solvent such as methanol (tanδ=0.659) can be rapidly superheated to temperatures >100 °C above its boiling point when irradiated under microwave conditions in a sealed vessel. The rapid increase in temperature can be even more pronounced for media with extreme loss factors, such as ionic liquids (see Section 2.2.1), where temperature jumps of 200 °C within a few seconds are not uncommon. Naturally, such temperature profiles are very difficult if not impossible to reproduce by standard thermal heating. Therefore, comparisons with conventionally heated processes are inherently troublesome. Figure 2 Open in figure viewer PowerPoint Temperature (T), pressure (p), and power (P) profile for a sample of methanol (3 mL) heated under sealed‐vessel microwave irradiation conditions (single‐mode heating, 250 W, 0–30 s), temperature control using the feedback from IR thermography (40–300 s), and active gas‐jet cooling (300–360 s). The maximum pressure in the reaction vessel was ca. 16 bar. After the set temperature of 160 °C is reached, the power regulates itself down to ca. 50 W. Dramatic rate enhancements between reactions performed at room temperature or under standard oil‐bath conditions (heating under reflux) and high‐temperature microwave‐heated processes have frequently been observed. As Baghurst and Mingos have pointed out on the basis of simply applying the Arrhenius law [k=A exp(−E a /RT)], a transformation that requires 68 days to reach 90 % conversion at 27 °C, will show the same degree of conversion within 1.61 seconds (!) when performed at 227 °C (Table 2).18 The very rapid heating and extreme temperatures observable in microwave chemistry means that many of the reported rate enhancements can be rationalized by simple thermal/kinetic effects. Table 2. Relationship between temperature and time for a typical first‐order reaction.[a] T [°C] k [s−1] t (90 % conversion) 27 1.55×10−7 68 days 77 4.76×10−5 13.4 h 127 3.49×10−3 11.4 min 177 9.86×10−2 23.4 s 227 1.43 1.61 s In addition to the above mentioned thermal/kinetic effects, microwave effects that are caused by the uniqueness of the microwave dielectric heating mechanisms (see Section 1.1) must also be considered. These effects should be termed “specific microwave effects” and shall be defined as accelerations that can not be achieved or duplicated by conventional heating, but essentially are still thermal effects. In this category fall, for example 1) the superheating effect of solvents at atmospheric pressure,24 2) the selective heating of, for example, strongly microwave absorbing heterogeneous catalysts or reagents in a less polar reaction medium,25–27 3) the formation of “molecular radiators” by direct coupling of microwave energy to specific reagents in homogeneous solution (microscopic hotspots),26 and 4) the elimination of wall effects caused by inverted temperature gradients (Figure 1).28 It should be emphasized that rate enhancements falling under this category are essentially still a result of a thermal effect (that is, a change in temperature compared to heating by standard convection methods), although it may be difficult to experimentally determine the exact reaction temperature. Some authors have suggested the possibility of “nonthermal microwave effects” (also referred to as athermal effects). These should be classified as accelerations that can not be rationalized by either purely thermal/kinetic or specific microwave effects. Nonthermal effects essentially result from a direct interaction of the electric field with specific molecules in the reaction medium. It has been argued that the presence of an electric field leads to orientation effects of dipolar molecules and hence changes the pre‐exponential factor A or the activation energy (entropy term) in the Arrhenius equation.21, 22 A similar effect should be observed for polar reaction mechanisms, where the polarity is increased going from the ground state to the transition state, thus resulting in an enhancement of reactivity by lowering the activation energy.22 Microwave effects are the subject of considerable current debate and controversy,21–23 and it is evident that extensive research efforts will be necessary to truly understand these and related phenomena.29 Since the issue of microwave effects is not the primary focus of this Review, the interested reader is referred to more detailed surveys and essays covering this topic.21–23

1.3. Processing Techniques Frequently used processing techniques employed in microwave‐assisted organic synthesis involve solventless (“dry‐media”) procedures where the reagents are preadsorbed onto either a more or less microwave transparent (silica, alumina, or clay)32 or strongly absorbing (graphite)33 inorganic support, which can additionally be doped with a catalyst or reagent. The solvent‐free approach was very popular particularly in the early days of MAOS since it allowed the safe use of domestic household microwave ovens and standard open‐vessel technology. Although a large number of interesting transformations with “dry‐media” reactions have been published in the literature,32 technical difficulties relating to non‐uniform heating, mixing, and the precise determination of the reaction temperature remain unsolved, in particular when scale‐up issues need to be addressed. In addition, phase‐transfer catalysis (PTC) has also been widely employed as a processing technique in MAOS.34 Alternatively, microwave‐assisted synthesis can be carried out in standard organic solvents either under open‐ or sealed‐vessel conditions. If solvents are heated by microwave irradiation at atmospheric pressure in an open vessel, the boiling point of the solvent (as in an oil‐bath experiment) typically limits the reaction temperature that can be achieved. In the absence of any specific or nonthermal microwave effects (such as the superheating effect at atmospheric pressure which has been reported to be up to 40 °C)24 the expected rate enhancements would be comparatively small. To nonetheless achieve high reaction rates, high‐boiling microwave‐absorbing solvents such as DMSO, N‐methyl‐2‐pyrrolidone (NMP), 1,2‐dichlorobenzene (DCB), or ethylene glycol (see Table 1) have been frequently used in open‐vessel microwave synthesis.6 However, the use of these solvents presents serious challenges during product isolation. The recent availability of modern microwave reactors with on‐line monitoring of both temperature and pressure has meant that MAOS in sealed vessels—a technique pioneered by Strauss in the mid 1990s35—has been celebrating a comeback in recent years. This is clearly evident from surveying the recently published literature in the area of MAOS (see Section 2), and it appears that the combination of rapid dielectric heating by microwaves with sealed‐vessel technology (autoclaves) will most likely be the method of choice for performing MAOS in the future.