Multimode instruments

The development of multimode reactors for organic synthesis occurred mainly from already available microwave acid-digestion/solvent-extraction systems. Instruments for this purpose were first designed in the 1980s and with the growing demand for 

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Based on their microwave digestion system, Milestone offers the MicroSYNTH labstation (also known as ETHOS series) multimode instrument (Fig. 3.4 and Table 3.1), which is available with various accessories. Two magnetrons deliver 1000 W microwave output power and a patented pyramid-shaped microwave diffuser ensures homogeneous microwave distribution within the cavity [12]. 

Consequently, which strategy is utilized in reaction optimization experiments is highly dependent on the type of instrument used. Whilst multimode reactors employ powerful magnetrons with up to 1500 W microwave output power, monomode reactors apply a maximum of only 300 W. This is due to the high density microwave field in a single-mode set-up and the smaller sample volumes that need to be heated. In principle, it is possible to translate optimized protocols from monomode to multimode instruments and to increase the scale by a factor of 100 without a loss of efficiency (see Section 4.5). 

Multimode instruments with an IR sensor mounted in the cavity side wall (see Section 3.4) certainly need larger volumes for precise temperature monitoring. Immersion temperature probes require a well-defined minimum volume for accurate measurement, depending on the total vessel volume. It must be ensured that the temperature probe has extensive contact with the reaction mixture, even when the mixture is stirred, in order to obtain reliable, reproducible results. 

For general solid-phase reactions in a dedicated multimode instrument, an adaptable filtration unit is available from Anton Paar (see Fig. 3.18). This tool is connected to the appropriate reaction vessel by a simple screw cap and after turning over the vessel, the resin is filtered by applying a slight pressure of up to 5 bar. The resin can then be used for further reaction sequences or cleavage steps in the same reaction vessel without any material loss. However, at the time of writing, no applications of this system for solid-phase synthesis had been reported. 

In addition to the aforementioned microwave-assisted reactions on solid supports, several publications also describe microwave-assisted resin cleavage. In this context it has been demonstrated that carboxylic acids could be cleaved from conventional Merrifield resin, using the standard TFA-DCM 1 1 mixture, by exposure of the polymer-bound ester and the cleavage reagent to microwave irradiation in a dedicated Teflon autoclave (multimode instrument). After 30 min at 120 °C, complete recovery of the carboxylic acid was achieved (Scheme 12.9) [26]. At room temperature, however, virtually no cleavage was detected after 2 h in 1 1 TFA-DCM. 

Laboratory scale-up in single-mode reactors to produce gram amounts of material can be performed either by the above-mentioned sequential batch processing using various vessel sizes (up to 50 mL) or by employing CF or SF reaction cells (5-50 mL). Conversely, multimode instruments allow for parallel synthesis or applications in large batches up to 1 L total volume and even CF and SF approaches utilizing > 300 mL cells (see below). 

In contrast to single-mode reactors, dedicated multimode instruments allow scale-up to be performed in multivessel rotor systems utilizing various types of sealed vessels. In these systems, reactions can be carried out in batch to synthesize multiple gram quantities (< 250 g) of material in typically up to 1 L processing volume. Most of the multimode instruments available for organic synthesis have been derived from closely related sample preparation equipment [39-41]. The MARS Microwave Synthesis System (Fig. 4) is based... 

A comprehensive study on the scalability of optimized small-scale microwave protocols in single-mode reactors to large-scale experiments in a multimode instrument has been presented by Kappe and coworkers [26]. As a model reaction, the classical Biginelli reaction in acetic acid/ethanol (3 1) as solvent was rim in parallel in an eight-vessel rotor system of the Anton Paar Synthos 3000 synthesis platform (Fig. 8) on a 8 x 80 mmol scale [26]. Here, the temperature in one reference vessel was monitored with the aid of a suitable probe, while the surface temperature of all eight quartz reaction vessels was also monitored (deviation less than 10 °C, see Fig. 16). The yield in all eight vessels after 20 min hold-time at 120 °C was nearly identical, resulting in an overall amount of approximately 130 g of the desired dihydropyrimidine. 

To investigate these findings further the authors determined heating rates of the employed multimode instruments and the Discover unit, once again using toluene as solvent. After 10 min irradiation at a constant maximum power output for each microwave reactor, different final temperatures were measured (Fig. 17). Furthermore, it could be shown that the observed differences in temperature are not only related to the different heating efficiencies of the instruments but also to the specific vessel material [27]. Usually the vessel material itself is not completely microwave-transparent and therefore it is at least partially responsible for heating of the irradiated solvent via conventional thermal conduction [42]. 

Working on larger scales in sealed-vessel mode will probably require the use of a multimode instrument such as the MARS, the MicroSYNTH, or the Synthos 3000, which can provide typically 50-250 g quantities per cycle (about 1 h) in sealed-vessel operation at typical concentrations. These are also ideal for preparing in a single cycle... 

Monomode and Multimode Instruments for large-scale Preparations... 

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