A consistent setup of experiments has been conducted to demonstrate an enhanced reaction rate under microwave irradiation as compared to conventional heating, i.e. a real microwave effect. It was found that addition of a cosolvent, diminishing the heterogeneous character of the reaction mixture, greatly reduced the microwave effect. This was demonstrated by two examples; selective mono-urea formation and racemization of an N-acetylamino acid. Furthermore, formation of a Grignard reagent was accelerated under MW irradiation by electrostatic etching of the metal surface. The microwave effect observed in these reactions seems to rely on heterogeneity and specific interactions on the solid-liquid interface. Basic understanding of these findings is crucial for scaling up microwave assisted processes.

A detailed study regarding the influence of microwave irradiation on the formation of a series of Grignard reagents in terms of rates and selectivities has revealed that these heterogeneous reactions may display a beneficial microwave effect. The interaction between microwaves and magnesium turnings generates violent electrostatic discharges. These discharges on magnesium lead to melting of the magnesium surface, thus generating highly active magnesium particles. As compared to conventional operation the microwave-induced discharges on the magnesium surface lead to considerably shorter initiation times for the insertion of magnesium in selected substrates (i.e. halothiophenes, halopyridines, octyl halides, and halobenzenes). Thermographic imaging and surface characterization by scanning electron microscopy showed that neither selective heating nor a "specific" microwave effect was causing the reduction in initiation times. This novel and straightforward initiation method eliminates the use of toxic and environmentally adverse initiators. Thus, this initiation method limits the formation of by-products. We clearly demonstrated that microwave irradiation enables fast Grignard reagent formation. Therefore, microwave technology is promising for process intensification of Grignard based coupling reactions.

A commercially available continuous-flow reactor was adapted to run three organic reactions, e.g. two heterogeneous and one homogeneous mixture under microwave heating. The setup was operated either as a batch-loop reactor for running a biocatalyzed esterification of (R,S)-1-phenylethanol with vinyl acetate and the esterification of (S)-pyroglutamic acid with n-decanol (i.e., Laurydone process) or in a single pass for the aspirin synthesis as a homogeneous mixture. The tubular reactor has been characterized to perform a series of three equally sized, continuously operated stirred tank reactors on average. Although the (operational) costs of the microwave-heated tubular reactor are higher than conventionally heated processes in fine chemical operations, it was demonstrated that the experimental data can be used for process design. Plugging remains an important obstacle to be dealt with. However, benefits with respect to safety and scalability are expected to enable a fair compensation for the costs when implementing this novel technique.

The racemization of N-acetylindoline-2-carboxylic acid in p-xylene revealed beneficial rate enhancements due to microwave effects, by comparing conventional and microwave heating. The magnitude of this effect was governed by the degree of heterogeneity of the reaction system. The amount of catalyst, the temperature and the amount of cosolvent played a decisive role. The microwave effect completely vanished when a homogeneous solution was heated. During the microwave-assisted heterogeneous racemization of N-acetylphenylalanine in p-xylene a comparable microwave effect was observed. The microwave effects could be rationalized by adapting selective heating in the phase boundary region of solid and liquid. Additionally, a straightforward translation was achieved from batchwise operation in a stirred reactor to a batch-loop reactor. The (heterogeneous) racemization of N-acetylindoline-2carboxylic acid retained its microwave effect in the loop reactor. Our results demonstrated that avoiding plugging of the tubular reactor is a severe challenge in scaling up.

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