Monomode cavity

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively, deserves special comment. While the parallel set-up allows for a considerably higher throughput achievable in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature/pressure is limited. In the parallel mode, all reaction vessels are exposed to the same irradiation conditions. In order to ensure similar temperatures in each vessel, the same volume of the identical solvent should be used in each reaction vessel because of the dielectric properties involved [86]. As an alternative to parallel processing, the automated sequential synthesis of libraries can be a viable strategy if small focused libraries (20-200 compounds) need to be prepared. Irradiating each individual reaction vessel separately gives better control over the reaction parameters and allows for the rapid optimization of reaction conditions. For the preparation of relatively small libraries, where delicate chemistries are to be performed, the sequential format may be preferable. This is discussed in more detail in Chapter 5. 

It was found that the first step was rate determining. When, moreover, the reaction was run with the same reaction-temperature profiles under both conventional (oil) and microwave (monomode cavity) conditions, different distributions of the intermediate (1) and final (2) products were obtained (Tab. 5.10). Indeed, the product distribution was strongly affected by microwaves when the reaction was run at 85 °C rather than 110 °C, and addition of a small amount of a polar or nonpolar solvent also affected the product distribution. In this work two solvents capable of extensive coupling (i.e. ethanol) and not coupling (i.e. cyclohexane) with microwaves were used. Addition of ethanol strongly shifted the product distribution towards the final product (2), whereas addition of cyclohexane resulted in much lower yield of 2 [34]. 

Another metal-catalyzed microwave-assisted transformation performed on a polymer support involves the asymmetric allylic malonate alkylation reaction shown in Scheme 12.4. The rapid molybdenum(0)-catalyzed process involving thermostable chiral ligands proceeded with 99% ee on a solid support. When TentaGel was used as as support, however, the yields after cleavage were low (8-34%) compared with the corresponding solution phase microwave-assisted process (monomode cavity) which generally proceeded in high yields (>85%) [30],... 

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively deserves special comment. While the parallel setup allows for considerable throughput that can be achieved in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature and/or pressure is limited. In the parallel... 

Microwave irradiation, in contrast to thermal heating, produces very efficient heat transfer resulting in even heating throughout the sample. The process can be optimized by giving careful thought to the dimensions of the reaction vessel and volume of reactants [9] it is fortunate that radiochemical syntheses are usually performed on a very small scale (< 5 cm3) where a high and stable E-field intensity is easier to maintain, especially if a monomodal cavity, rather than a multimodal mode, is adopted. 

Several workers have employed monomodal cavities for microwave chemistry on the sub-gram scale. In some cases in which monomodal cavities have been used7, special benefits of so-called focussed microwaves have been claimed. As mentioned earlier, the dielectric properties of a sample can alter substantially with temperature and/or with changing chemical composition. Hence, regardless of whether multi-modal or unimodal cavities are employed, frequent tuning may be necessary if heating efficiency is to be retained. This aspect has often been overlooked by proponents of focussed microwaves. The nett result is that transfer of microwave conditions between monomodal to multi-modal cavities is usually facile. With the MBR (which had a tunable multimodal cavity), Cablewski et al. performed five reactions that had been conducted earlier on the gram scale or below with focussed microwaves (T. Cablewski, B. Heilman, P. Pilotti, J. Thorn, and C.R. Strauss, personal communication see also Ref. 117 for conference poster). These were scaled-up between 40- and 60-fold and reaction conditions... 

The CMR and MBRs provided the basis for modern commercial microwave reactors, including robotically operated automated systems that are now widely employed in synthetic research and pilot-scale laboratories in academia and industry [13]. Since 2000, commercial microwave reactors have become available. Batch systems, produced by three major companies in Italy and Germany, Sweden and the United States, typically operate on a scale from 0.5 mL up to 2 L. Other companies based in Austria, Poland and Japan have also recently entered the market. Systems possessing either multimodal or monomodal cavities are produced with one recent addition being a single unit capable of performing in either mode as required. Microwave reactors are employed extensively in chemical discovery where successive reactions can be performed rapidly in parallel or sequentially. One manufacturer recently estimated that about 10000 reactions per week were performed in its systems alone. This indicates the extent to which microwave chemistry in closed vessels has dramatically influenced approaches to synthesis. 

As mentioned above, monomodal cavities have been used for microwave chemistry on the sub-gram scale. Occasionally special benefits have been claimed for so-... 

It was found that the first step was rate-determining. When, moreover, the reaction was performed with the same reaction temperature profiles under both conventional heating (oil bath) and MW (monomode cavity) conditions, different dis-... 

As already mentioned above, a different strategy to achieve high throughput in microwave-assisted reactions can be realized by performing automated sequential microwave synthesis in monomode microwave reactors. Since it is currently not feasible to have more than one reaction vessel in a monomode microwave cavity, a robotic system has been integrated into a platform that moves individual reaction... 

In a faster, selective and cleaner applications of the microwave-accelerated reactions, Stone-Elander et al. have synthesized a variety of radiolabeled (with 3H, 11C, and 19F) organic compounds via the nucleophilic aromatic and aliphatic substitution reactions, esterifications, condensations, hydrolysis and complexation reactions using monomodal MW cavities on microscale [121]. A substantially reduced level of radioactive waste is generated in these procedures that are discussed, at length, in Chapt. 13 [122]. 

Fig. 12.6 Monomode microwave reactor with integrated robotics interface for automated use (left). Details of the cavity/gripper (top right)...

Chemat and his coworkers [92] have proposed an innovative MW-UV combined reactor (Fig. 14.7) based on the construction of a commercially available MW reactor, the Synthewave 402 (Prolabo) [9[. It is a monomode microwave oven cavity operating at 2.45 GHz designed for both solvent and dry media reactions. A sample in the quartz reaction vessel could be magnetically stirred and its temperature was monitored by means of an IR pyrometer. The reaction systems were irradiated from an external source of UV radiation (a 240-W medium-pressure mercury lamp). Similar photochemical applications in a Synthewave reactor using either an external or internal UV source have been reported by Louerat and Loupy [93],... 

The former French company Prolabo developed two microwave systems for synthesis7. The machines were employed in several research laboratories mainly for solvent-free organic chemistry. They had monomodal rectangular waveguide sections that also served as microwave cavities. Cylindrical tubes could be inserted and rotated to increase thermal homogeneity and if required condensers could be fitted. Temperature measurement was by infrared pyrometry. Computer control enabled reaction monitoring with respect to temperature or power. 

Fig. 4. Monomode microwave reactor with integrated robotic platform for automated use (left). A liquid handler allows dispensing of reagents into Teflon-sealed reaction vials, while a gripper moves each vial in and out of the microwave cavity after irradiation. The instrument processes up to 120 reactions per run with a maximum throughput of 12-15 reactions/h. The temperature is measured by an IR sensor on the outside of the reaction vessel. Details of the cavity/gripper (top right) and reaction vials (bottom right) are also displayed (Emrys Synthesizer, Personal Chemistry AB). Reprinted with permission from Wiley-VCH.41 (See color insert.)...

Batch synthesis in single-mode reactors is definitely limited in scale as the size of the utilized microwave cavities is restricted to being monomodal. However, the Biotage Initiator EXP series allows a 100-fold linear scale-up when employing the different available vessel sizes, going from 0.2 mL to 20 mL operation volume (Fig. 1). Repetitive reaction cycles using the au-... 

Both CEM and Biotage have developed automated vessel handlers that can be interfaced with their monomode units. These allow chemists to run a number of reactions sequentially in an automated manner. A robotic arm loads a reaction from a queue into the microwave cavity the sample is heated for a predetermined time, cooled, returned to the holding area and the cycle started again with the next sample. Biotage has two commercially available units (Figure 1.9), and CEM has an Explorer line with variants that can accommodate 12, 24,48,72, or 96 preloaded reaction vials. 

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