'Dialyzable' Carbosilane Dendrimers as Soluble Supports in Organic Synthesis: Proof of principle, application and diafiltration performance

Abstract

Since the development of polystyrene as (insoluble) support for the synthesis of peptides by Merrifield in the 1960s, the application of supported synthesis in both industrial and academic research has increased. The introduction of dendrimers as supports solved many of the problems arising from the inhomogeneous nature of the solid supports. Dendrimers are highly soluble in various reaction media and standard spectroscopic analysis in solution phase is well applicable. Carbosilane dendrimers take a special position due to their chemical robustness and stability. Initially, these dendrimers were used as support for homogeneous catalysts, and could easily be removed from the reaction mixture by nano- or diafiltration. The application of carbosilane dendrimers as support in organic synthesis and optimization of the filtration steps in this procedure are subject of this thesis. Carbosilane dendrimers can be functionalized with various substrates, like 2-bromopyridines, which can be attached via lithiation chemistry. The complete attach-modify-release sequence was optimized using model reactions. It appeared that the conditions used for the model reactions could not always be directly translated to the dendrimer-supported syntheses. A new method for the loading of the dendrimers with bromopyridines was developed, which makes use of a hydrosilylation reaction. The supported bromopyridines were converted into a series ofcompounds and the products were released from the dendrimers. During the filtration experiments with membranes of various pore sizes, it appeared that the dendrimers are also retained by membranes that have a theoretical pore size larger than the dimensions of the dendrimer, and that the speed of filtration increases with increasing pore size. Since the applied dendrimers are flexible, especially under the ‘shear flow’ conditions of the filtration, it is expected that more rigid dendrimers will be retained better by membranes, and that even higher filtration speeds will be achieved. Two rigid core molecules and two dendritic wedges were synthesized and used for the formation of several new rigid dendrimers. The dendrimers were loaded with different dye molecules to detect them during the filtration experiments. The rigid dendrimers are retained somewhat better by membranes with larger pore sizes, but generally the difference with the ‘flexible’ dendrimers is not big. The results obtained from UV/Vis spectroscopy, GPC and modeling studies generally correspond to the results of the diafiltration experiments, showing a correlation between the dimensions and the molecular weights of the dendrimers. Some exceptions suggest that besides structural parameters of the dendrimers also other effects, like the presence of solvent molecules, play a role in determining the dimensions of the dendrimers in solution. In order to compare the results obtained with the dendrimers directly to the results of SPOS, one dendrimer is loaded with three typical SPOS linker groupings: benzylbromide-, DEAM- and REM-linkers. SPOS methodologies were used to investigate the application of these dendritic supports. For all three linkers the yields and purities of the products appeared not to be as high as for comparable SPOS results. This was partly due to the incompatibility of the used purification method (passive dialysis) with water-labile and water-soluble products.