Microwave-Assisted Combinatorial Chemistry

In 1986 the first pioneering studies on the use of microwave irradiation to enhance chemical reactions were reported. Microwaves generate rapid intense heating of polar substances with significant reductions in reaction times, cleaner reactions, and in many cases higher yields. The main advantage of microwave heating is the almost instanteneous "in core" heating of materials in an homogeneous and selective manner. Coupled with the significantly shorter reaction times that can be achieved this implies a considerable savings in energy. Parallel to these developments, combinatorial chemistry has revolutionized drug discovery and many other branches of chemistry and related fields in the last 5 years. Today there is an ever growing demand for new synthetic procedures and for large libraries of compounds that are being evaluated for their biological and other properties using high throughput screening protocols. In the framework of this project we wish to develop the potential of microwave technology toward the area of combinatorial chemistry, more specifically toward microwave-enhanced solid-phase organic synthesis which has been one of the cornerstones of combinatorial chemistry. We therefore plan to investigate the potential rate-enhancements of microwave activation in considerable detail. By carrying out a variety of experiments that are designed to differenciate between temperature effects ("superheating"), pressure effects, and so-called "non-thermal" or microwave effects we want to establish the nature of the observed rate- enhancements and therefore provide a more rational basis for carrying out microwave-enhanced solid phase synthesis. We will e.g. vary the nature of the solvents, resins, and linkers used in such transformations, and apply this technique to the development of a library of heterocyclic compounds. Importantly, in all the above experiments we will make use of recently developed, state-of-the-art commercially available microwave reactors, and compare the performance of the different existing technologies (e.g. multimode versus monomode reactors) with each other. Until today a significant proportion of the published work is carried out using domestic household microwave ovens which have several severe limitations when used in scientific experiments

The results obtained from this three year FWF project have contributed to the fact that today microwave-assisted chemistry under controlled conditions (i.e. in dedicated instruments) has become an accepted technology for performing organic synthesis on a laboratory scale. Only a few years ago - when this project was drafted in early 2000 - microwave chemistry was seen by many as a laboratory curiosity that would eventually fade away. Today, the number of researchers employing microwave synthesis in routine fashion is constantly growing and in a few years perhaps most chemical processes requiring heating will be run under microwave conditions. Within the framework of this project our group was able to demonstrate the advantages of using microwave technology such as faster reactions, cleaner processes, improved product yields etc. for a variety of different chemical processes. These involved methods for the preparation of biologically active molecules using so-called "combinatorial methods" that allow the synthesis of a large number of molecules in parallel/automated fashion. Coupled with the significantly shorter reaction times that can be achieved, this implies a considerable savings in energy, leading to "green chemistry" approaches. In several instances the reasons for the observed rate- enhancements were studied in more detail and it was concluded that in most cases the rapid heating of solvents much above their normal boiling point in sealed vessels was responsible for the observed effects, not the presence of the controversial so-called "non-thermal microwave effects". Most importantly research in our group was exclusively carried out in dedicated, commercially available microwave reactors for organic synthesis, not in kitchen microwave ovens. The results from the fundamental research carried out within this project also led to more applied research in the area of microwave chemistry, namely in the field of microwave scale-up. Active collaborations and federally funded projects of our research group exist with Austrian companies interested in this technology.