Microwave-matter effects in metal(oxide)-mediated chemistry and in drying

Abstract

Microwave irradiation is a well-accepted heating technique for lab-scale organic synthesis but its application for large-scale operation is still limited. To determine the potential of microwave heating in producing fine chemicals beyond the kg-scale, the added value of this heating technique, compared to conventional heating, has been evaluated at accurately controlled conditions on lab-scale. The research described in this thesis focuses on comparing microwave heating with conventional heating for a series of heterogeneous reactions and for purification, i.e. drying. This enabled to elucidate factors determining the benefits of microwave-mediated technology. In Chapter 1 the state of the art in the application of microwave technology is discussed and the outline of the thesis is presented. In Chapter 2 the Grignard reagent formation, involving a heterogeneous metal, i.e. magnesium, is discussed. Microwave irradiation of magnesium turnings led to electrical discharges, which modify the surface and, therefore, the reactivity of magnesium. The influence of modifying the magnesium surface on the reactivity of the metal in the Grignard reagent synthesis was determined for a series of halo-compounds. The initiation time significantly shortened upon irradiating the reaction mixtures of relatively reactive (2-bromothiophene, 2-bromopyridine, bromobenzene, iodobenzene and n-octyl bromide) and moderately reactive (2-chlorothiophene and 2-chloropyridine) halo-substrates. In contrast, irradiating the reaction mixtures of non-reactive halogenated compounds (3-bromopyridine and n-octyl chloride) led to major magnesium carbide formation causing a reduced reactivity of the metal and prolonged initiation times. In Chapter 3 the influence of microwave heating on another heterogeneous organometallic reaction, the Reformatsky reaction, involving metallic zinc, is discussed. In this system microwave-induced electrical discharges caused major zinc carbide formation, irrespective of the presence of a species reactive towards zinc. The zinc carbide formation coated the zinc surface, which was responsible for inhibition of zinc insertion in acetate, propionate and isobutyrate esters. This zinc carbide formation limited the beneficial use of microwave heating in the Reformatsky reaction to such an extent that conventional heating has to be preferred. Information on the influence of microwave energy on a heterogeneous organometallic reaction involving metallic copper, the Ullmann coupling of 2-chloro-3-nitropyridine, is given in Chapter 4. In this case, microwaves did not seem to interact with the copper directly, limiting the impact of this heating mode. The reaction was optimized in terms of temperature, copper source, stoichiometry and solvent. Surprisingly, fine copper powder (45 µm) is a better metal source than traditional copper-bronze for this Ullmann carbon-carbon coupling. A ratio of 1:1 of copper to 2-chloro-3-nitropyridine resulted in reaction profiles similar to those resulting from an excess of copper. Switching solvent from N,N-dimethylformamide (DMF) to N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidone (NMP) diminished reaction rates, prolonged initiation times, lowered yields and gave rise to the formation of 2,2'-oxybis(3-nitropyridine) as byproduct. Therefore, DMF is the preferred solvent for this Ullmann coupling. Comparison of microwave heating with conventional heating for the reactions performed at optimized conditions (in DMF at 110 °C), as well as under less ideal conditions (in DMA and NMP at various temperatures) revealed identical time-conversion histories, yields and selectivities. The results with magnesium, zinc and copper reveal that, although, the Grignard reagent formation, the Reformatsky reaction and the Ullmann coupling are very similar processes, the influence of microwave irradiation on the outcome of the process is not. In Chapter 5 the influence of microwave irradiation on a freshly prepared zirconium-based heterogeneous catalyst for the amide formation from a nitrile and an amine is presented. The ZrO2-based catalyst not only efficiently catalyzes the formation of N-hexylpentamide from valeronitrile and n-hexylamine but also the polymerization of 6-aminocapronitrile and ?-caprolactam and does so with conventional as well as microwave heating. Microwave energy, however, heats the catalyst substantially, inducing selective heating that enhances the catalytic activity, compared to conventional heating. The drying behavior of (S)-N-acetylindoline-2-carboxylic acid with various moisture contents and of N-acetyl-(S)-phenylalanine, in a straightforward microwave-mediated drying setup, is presented in Chapter 6. The way energy is supplied to the system has a profound influence on the drying rate and on the internal temperature of the samples during drying. To achieve similar drying times with conventional heating as reached under microwave irradiation, extremely high energy inputs are required, causing extremely large temperature differences between the heating source and the sample. These results demonstrate that microwave energy is particularly useful for drying thermally unstable materials in short periods of time. Microwave heating is not a universally beneficial technique applicable to all reactions. The results we gathered suggest that every reaction has to be evaluated separately to judge whether microwave heating is a suitable upscaling tool and whether microwave heating is to be preferred over conventional heating.