Pharma Voice

New frontiers in microwave synthesis

For almost two decades, the use of microwave energy to perform efficient organic synthesis has attracted considerable interest. The possibility to drastically shorten reaction times by employing sealed vessels in microwave cavities established this modern technique as a sophisticated procedure in chemical research [1]. The development of so-called ‘dedicated’ microwave instruments, especially for synthesis applications, allowed to elaborate new methods and protocols for chemical reactions leading to significantly reduced reaction times, increased yield and purer products [2].

Exploring the limits

Although the available instruments with either multi-mode or single-mode technology fulfil the demands of preparative chemists for precise reaction control by accurate temperature measurement, pressure sensing and software-aided experiment monitoring, these microwave reactors show several limits, for instance, vessel and cavity size (especially when working with single-mode instruments) as well as limitations in temperature and pressure range. Usually, the monomode instruments operate at a maximum of 300 W output power within a performance range of up to 250 °C and 20 bars. The powerful multi-mode instruments offer some special vessels capable of higher temperatures (280°C), but usually decrease pressure stability (7-14 bar). However, one of the commercial instruments allow not only for scale up towards microwave-assisted multi-gram synthesis, but also represents equipment, which enables to run reactions at maximum temperature and pressure at the same time. For that purpose, high performance eight-position rotor serving 80 mL quartz vessels especially designed for reaction conditions of 300 °C AND 80 bar (Figure 1) are employed. This setup enables to perform organic reactions even under microwave-mediated near critical water conditions (>260 °C, > 60 bar) as well as the applications of alcohols in the supercritical stage. Organic synthesis has shown remarkable interest in both applications. These special features are under current investigation and have been presented in recent scientific publications. [3], [4], [5]

Simplified handling of the accessories makes it easy to prepare the equipment for such high-pressure applications. Laborious set-up of thick-walled autoclave systems to reach these conditions is not needed. Just sealing the quartz vessels with lip-type seals and placing them into the rotor make the system ready to start. The hydraulic system integrated in the rotor top plate of the eight-position rotor allows simultaneous pressure sensing of all eight reaction vessels, additional temperature control is achieved by an IR sensor measuring the surface temperature of the vessels from the bottom.

For the extreme pressure reactions a volume range of 15 to 30 mL should not be applied for optimised performance of the system. The powerful dual magnetron set-up (2x 850 W, delivering 1400 W output power) enables to acquire the desired near critical conditions within approximately 15 minutes. If more rapid heating up to such extreme conditions is required, special inserts to carry silicon carbide heating elements can be applied in each vessel as well [5]. Once the reaction conditions are reached, the instrument requires only 300-500 W to maintain the high pressure and temperature. Reaction cooling is achieved by forced air cooling using the unique vessel. The rotor is designed to withdraw the heat with maximum efficiency.

With this high-performance configuration beneficial transformations can be conducted, such as the rapid one-step direct conversion of aryl halides to its corresponding phenols (Scheme 1) [4].

Scheme 1 is direct conversion of aryl halides to phenol in near critical water.

Figure 1. Multimode microwave instrument and its high-performance with quartz vessels

Summary

Microwave synthesis far beyond usual operation limits enables the development of completely new reaction pathways using appropriate instrumentation. Rotor systems, especially designed for extreme reaction conditions, guarantee a maximum of user safety when working at high temperatures and high pressure.

References

[1] C O Kappe, Angew. Chem. Int. Ed. 2004, 6250-6284
[2] C O Kappe, A. Stadler, Microwaves in Organic and Medicinal Chemistry, 2005, Wiley-VCh, Weinheim
[3] J Kremsner, C O Kappe, Eur. J. Org. Chem. 2005, 3672-3679
[4] C M Kormos, N E Leadbeater, Tetrahedron 2006, 4728-4732
[5] J Geuens et al, Energy Fuels, 2008, 643-645.

(The article was contributed by Dr Alexander Stadler, Anton Paar GmbH, Austria. He can be contacted at alexander.stadler@anton-spaar.com)