Single-mode reactors

A number of microwave-assisted multicomponent methods for the synthesis of imidazoles have been reported [68-71 ]. The irradiation of a 1,2-diketone and aldehyde with ammonium acetate in acetic acid for 5 min at 180 °C in a single-mode reactor provides alkyl-, aryl-, and heteroaryl-substituted imidazoles 39 in excellent yield (Scheme 14) and this method has been used for the rapid and efficient preparation of two biologically active imidazoles, lepidiline B and trifenagrel [68]. 

Fig. 2.9 Microwave heating (single-mode reactor) of ethanol under open-vessel conditions. Initially, the temperature rises during the heating phase (AB), above the normal boiling point of ethanol (78 °C), to a point C at which the solvent bumps and starts to boil at the vapor/liquid interface. At this point, the...

Scheme 4.26 Direct scalability of microwave synthesis from small-scale single-mode reactors (1—4 mmol) to large-scale multimode batch reactors (40-640 mmol).

Greater reproducibility The homogeneous microwave field present in dedicated single-mode reactors promises comparable results in every experimental run. 

Microwave heating is often applied to already known conventional thermal reactions in order to accelerate the reaction and therefore to reduce the overall process time. When developing completely new reactions, the initial experiments should preferably be performed only on a small scale applying moderately enhanced temperatures to avoid exceeding the operational limits of the instrument (temperature, pressure). Thus, single-mode reactors are highly applicable for method development and reaction optimization. 

Decomposition of H2S over MoS2 [92]. The rate enhancement, quantitatively unspecified, was attributed to the creation of hot spots with temperatures 100-200 K above that of the bulk. Reaction conditions a flow fixed-bed single-mode reactor. 

Cyclization of citronellal in the presence of KSF catalyst [93]. Reaction conditions reflux, CC14 as solvent, single-mode reactor,... 

Lately, a number of papers have dealt with microwave-assisted reactions on palladium-doped A1203. Villemin reported on Stifle, Suzuki, Heck and Trost—Tsuji reactions where potassium fluoride on alumina was used as the base26. The reactions were carried out without solvent or stabilising phosphine ligands in single-mode reactors. The Stifle reactions were noteworthy as the toxic organotin residue remained adsorbed on the solid support, thus allowing a simplified work-up procedure for the otherwise unpleasant, and toxic, stannous by-products. Both the Stifle and the Suzuki reactions could be performed under air. Furthermore, it was noted that with experiments where the... 

Hydro acylation of alkenes was achieved in the presence of Wilkinson s catalyst and microwave irradiation under solvent-free conditions. As an example, benzaldehyde was reacted with dec- 1-ene to give 1-phenylundecan- 1-one in 83%yield within 30 min. Both domestic microwave ovens and single-mode reactors have been used for this reaction. The presence of an amine such as 2-amino-3-picoline or aniline and a carboxylic acid is crucial for the success of the reaction, showing that the formation of an imine plays an important role as an intermediate in the mechanism of this reaction29. 

The incorporation of turntables and mode mixers to the domestic oven have been employed to reduce non-uniformity within the cavity and consequently reduce the number of hot and cold spots. On scale-up it is important that homogeneity is maintained and the temperature within the bulk medium is consistent. With a single mode reactor, the sample can be located precisely within the cavity where the electric field strength will be maximal. This in turn allows tuning of the power input into the sample and very high internal heat transfer. 

Specialized microwave reactors for chemical synthesis are commercially available from several companies Anthon-Paar [41], Biotage [42], CEM [43], Ertec [44], Lambda Technologies [45], Microwave Materials Technologies (MMT), Milestone [46], and Plazmatron-ika [47]. They offer a number of multi-mode and single-mode reactors which are mostly... 

For reactions that are planned to be carried out in single-mode reactors there is available a great number of differently shaped vessels usually provided by the producers of microwave equipments (see Section 3.4). These vessels, which can be also made of borosili-cate glass as was mentioned in the previous paragraph, have different diameters depending on their intended volume (Fig. 4.2). 

Figure 4.3. Volume of reaction mixtures during experiments in single-mode reactors (a) -volume of the reaction vessel is too big, (b) - volume of the reaction vessel is to small, (c) - volume of the reaction vessel is correct.

In conclusion, there are three different approaches for microwave synthesis on a large scale (>100 mL volume). While some groups have employed larger batch-type multimode or single-mode reactors (< 1000 mL processing volume), others have used CF or SF techniques (multi- and single-mode cavities) to overcome the inherent problems associated with MAOS scale-up. 

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). 

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-... 

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... 

With those single-mode reactors that do not require a minimum filling volume (CEM Discover platform temperature measurement is performed from the bottom and not from the side by an external IR sensor) even volumes as low as 50 xL can be processed [57]. With the commercially available singlemode cavities of today, the largest volumes that can be processed under sealed vessel conditions are ca 50 mL, with different vessel types being available to upscale in a linear fashion from 0.05 to 50 mL. Under open vessel conditions higher volumes (> 1000 mL) have been processed under microwave irradiation conditions, without presenting any technical difficulties as, e.g., described for the synthesis of various ionic liquids on a 2 mol scale [35]. 

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. 

Scheme 4 Scale-up synthesis of thiocarbamates and quinazolines in single-mode reactors...

Not surprisingly, the final temperature of the solvent relies on the volume used, especially if experiments are performed at constant power. In such experiments, a decrease of the final temperature was observed with increased volume. Obviously, it is not possible to directly compare single-mode experiments with multimode experiments at an identical output power. Due to the significantly higher power density, the heat transfer of single-mode reactors is substantially higher. 

A more recently published example of organic microwave synthesis under CF conditions is the 1,3-dipolar cycloaddition chemistry in the CEM CF Voyager system (Fig. 11). Savin and coworkers presented the cycloaddition of dimethyl acetylene dicarboxylate with benzyl azide in toluene, which was first carefully optimized with respect to solvent, temperature, and time under batch conditions. The best protocol was then translated to a CF procedure where a 0.33 M solution of both building blocks was pumped through a Kevlar-enforced Teflon coil (10 mL total capacity) heated in the single-mode reactor at 110 °C (10 min residence time) [66]. This method provided a 91% conversion to the desired triazole product (Scheme 12). 

Most of the single-mode reactors commercially available have been designed for small to medium scale reactions (250 L-120 mL). Single mode and multi-mode batch reactors that allow for microwave-assisted synthesis up to 500 mL have been recently introduced. Importantly, reactions optimized in smaller cavities can be directly reproduced in these larger reactors. 

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