To date the manufacturing of ionic liquids on a large scale is limited by ineffective batch procedures employed for the alkylation step. Here we present a way to intensify the synthesis of 1-butyl-3-methylimidazolium bromide ([BMIM]Br) by using a continuously operating microreactor system. It consists of a microstructured mixer of 450 mm channel width and reaction tubes with inner diameter ranging from 2 to 6 mm allowing a production rate of 9.3 kg [BMIM]Br per day. In this reactor system the strongly exothermic alkylation can be thermally controlled even at elevated temperatures leading to high reaction rates in a solvent-free modus. Inspite of temperatures up to 85 uC the product purity achieved was above 99%. The degree of process intensification achieved results in a more than twentyfold increase of the space-time-yield compared to a conventional batch process. The measured conversion data could be modelled successfully using a second order reaction kinetic. With the generated kinetic parameters the time course of temperature and conversion was also simulated for batch synthesis. Based on these data the performance of the continuous micro-reactor and the conventional batch process was compared. The simulation shows the potential of process intensification as an improvement of space-time-yield in the range of two orders of magnitude. Materials and methodsAs a representative of the reactions of interest, the butylation of methylimidazole, an example of a strongly exothermic

Random peptide ligands displayed on viral capsids are emerging tools for selection of targeted gene transfer vectors even without prior knowledge of the potential target cell receptor. We have previously introduced adeno-associated viral (AAV)-displayed peptide libraries that ensure encoding of displayed peptides by the packaged AAV genome. A major limitation of these libraries is their contamination with wild-type (wt) AAV. Here we describe a novel and improved library production system that reliably avoids generation of wt AAV by use of a synthetic cap gene. Selection of targeted AAV vectors from wt-containing and the novel wt-free libraries on cell types with different permissivity for wt AAV2 replication suggested the superiority of the wt-free library. However, from both libraries highly specific peptide sequence motifs were selected which improved transduction of cells with moderate or low permissivity for AAV2 replication. Strong reduction of HeLa cell transduction compared to wt AAV2 and only low level transduction of non-target cells by some selected clones showed that not only the efficiency but also the specificity of gene transfer was improved. In conclusion, our study validates and improves the unique potential of virus display libraries for the development of targeted gene transfer vectors.

In this work, the high-temperature production of the imidazolium-based ionic liquid 1-butyl-3-methylimidazolium bromide ([BMIM]Br) by means of micro reaction technology was investigated. This reaction is strongly exothermic and a two-phase liquid/liquid system is formed. Heat and mass transfer limitations can, therefore, have a negative effect on product quality and reaction rate. Here we demonstrate that, even at harsh thermal conditions, the ionic liquid, [BMIM]Br, can be produced at high quality. Side product formation, which usually occurs at elevated temperatures, leading to strong discolorization, can be avoided by enhancing mass transfer in a capillary slug flow. This was done by adjusting the flow rate so that the reaction regime shifted from strongly mass transfer limited to kinetically controlled. Here, the Hatta-number had been shown to be a suitable measure for defining the minimal flow rate. . This successful approach for continuous ionic liquid production with up to a thousand-fold space time yield compared to batch processes could be easily transferred to other imidazolium-based ionic liquids.

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