Microwave Heating in Organic Synthesis and Drug Discovery

Microwave dielectric heating was firstly reported on the use in organic chemistry by Gedye (Gedye, R. et al., 1986) and Giguere/Majetich (Giguere, R. J. et al., 1986) in the mid-1980s. However, it takes a long time before the wide application of this technology in the late 1980s and early 1990s. This has been principally attributed to the lack of controllability and reproducibility of the initial domestic microwave ovens implemented in organic chemistry, and partly due to a general lack of understanding of the basics of microwave dielectric heating. Since the year 2000, dedicated commercial microwave reactors for chemical synthesis have become available, promoting the wide spread of microwave energy in academic and industry to heat various chemical transformations. Nowadays, this enabling technology has been considerably exploited in organic synthesis and drug discovery. Microwave technology triggers heating into the reacting system by either dipolar polarization or ionic conduction. When irradiated at microwave frequencies, electromagnetic waves pass through the dipoles or ions of the sample and cause the molecules to oscillate. In this process, energy is lost in the form of heat through molecular friction and dielectric loss. Because microwave radiation is introduced into the reaction system remotely without direct physical contact with reaction materials, this can lead to a rapid temperature increase throughout the sample causing less by-products or decomposition products. In contrast, conventional heating of organic reactions such as oil baths, sand baths or heating mantles are rather slow and create an inward temperature gradient, which may result in localized overheating and reagent decomposition when heated for prolonged periods. The most prominent advantage of controlled microwave dielectric heating for chemical synthesis is the dramatic reduction in reaction time from days and hours to minutes. Moreover, microwave heating is able to reduce side reactions, increase yields, improve reproducibility, allow control of temperature and pressure, and even realize impossible reactions by conventional heating. Since a large number of articles have been published in the area of microwave synthesis, including a number of general and specific review articles (Caddick, S. & Fitzmaurice, R., 2009; Mavandadi, F. & Lidström, P., 2004; Mavandadi, F. & Pilotti, Å., 2006; Kappe, C. O., 2004, 2008; Kappe, C. O. & Dallinger, D., 2006; Wathey, B. et al., 2002) and several books (Hayes, B. L., 2002; Kappe, C. O. et al., 2009; Kappe, C. O. & Stadler, A., 2005; Leadbeater, N.