Victoria Skelton

The use of a novel microreactor for high throughput continuous flow organic synthesis

Abstract The aim of this study was to investigate the performance characteristics of a flow injection microreactor with reference to both the chemistry and reactor design using a model system, the established synthesis of 4-cyanobiphenyl based on a modified Suzuki coupling of an aryl halide and an organoboron compound. The catalytic reaction was carried out in micro-channels (300 μm wide and 115 μm deep) etched into glass and sealed with a top plate. The mobility of the reagent solutions was achieved using electroosmotic flow (EOF) assisted by the incorporation of a microporous silica structure within the microreactor channels, which acted as both a micro-pump and an immobilisation technique for the catalyst bed (1.8% palladium on silica). The yield of 4-cyanobiphenyl was determined by GC–MS. The synthesis of 4-cyanobiphenyl at room temperature in a flow injection microreactor, using a supported catalyst, without the addition of a base gave a product yield of 67±7% ( n =6). This was achieved by injecting 4-bromobenzonitrile for 5 s, with a 25-s injection interval, into a continuous stream of phenylboronic acid. A series of injections were performed over a 25-min period and the product collected for analysis. Palladium contamination in the crude product was found to be in the range of 1.2–1.6 ppb, determined using ICP–MS, indicating a low leach rate from the immobilised catalyst. A conventional laboratory batch scale method was also performed for the same synthesis using the identical conditions as those used in the flow injection microreactor, with and without the addition of a base, at both room and elevated temperatures (75–80°C) in an inert atmosphere under reflux for 8 h. The product yield for the non-optimised bulk reaction was 10% (determined by GC–MS), significantly lower than with the flow injection microreactor illustrating the potential of microreactors for clean efficient synthesis.

Chemical and biochemical microreactors

Abstract Research into the fundamental and practical advantages of using micrometre scale reactors for chemical and biochemical applications is now growing at a considerable rate. This review tracks such developments, illustrating their inherent strengths and identifying areas where further development of a technology is poised to revolutionise significant areas of synthetic chemistry and biochemistry.

The application of micro reactors to synthetic chemistry

A feature article describing the fundamental characteristics and emerging applications of micro technology in the field of synthetic chemistry.

The generation of concentration gradients usingelectroosmotic flow in micro reactors allowing stereoselective chemicalsynthesis

The stereoselective control of chemical reactions has been achieved by applying electrical fields in a micro reactor generating controlled concentration gradients of the reagent streams. The chemistry based upon well-established Wittig synthesis was carried out in a micro reactor device fabricated in borosilicate glass using photolithographic and wet etching techniques. The selectivity of the cis (Z) to trans (E) isomeric ratio in the product synthesised was controlled by varying the applied voltages to the reagent reservoirs within the micro reactor. This subsequently altered the relative reagent concentrations within the device resulting in Z/E ratios in the range 0.57-5.21. By comparison, a traditional batch method based on the same reaction length, concentration, solvent and stoichiometry (i.e., 1.0:1.5:1.0 reagent ratios) gave a Z/E in the range 2.8-3.0. However, when the stoichiometric ratios were varied up to ten times as much, the Z/E ratios varied in accordance to the micro reactor i.e., when the aldehyde is in excess, the Z isomer predominates whereas when the aldehyde is in low concentrations, the E isomer is the more favourable form. Thus indicating that localised concentration gradients generated by careful flow control due to the diffusion limited non-turbulent mixing regime within a micro reactor, leads to the observed stereo selectivity for the cis and trans isomers.

Micro-reactor synthesis: synthesis of cyanobiphenyls using a modified Suzuki coupling of an aryl halide and aryl boronic acid

The synthesis of cyanobiphenyls using a modified Suzuki coupling was performed in a micro-reactor system (channel geometries of 300 μm wide and 115 μm deep) etched in borosilicate glass, using a photolithographic patterning technique [1]. The organic starting reagents were moved by electro-osmotic flow (EOF). A micro-porous silica structure [2] was used within the channels, to act as a micro-pump and also assist in the immobilisation process for the heterogeneous catalyst bed.

The Design of a Continuous Flow Combinatorial Screening Micro Reactor System with On-Chip Detection

A micro reactor device has been developed which enables the synthesis of a number of nitro stilbene esters to be carried out using electroosmotic flow (EOF) as the mobilisation mechanism. The micro reactor was fabricated from borosilicate glass using photolithography and wet etching techniques generating an array of interconnecting channels. The micro reactor device was optimised using Wittig chemistry that allowed analogue synthesis of a number of aldehydes generating a generic methodology. Currently, work is continuing to automate and develop the micro reactor allowing in-situ detection to be coupled to the system, thus increasing the drug development and screening flexibility.

A Micro Reactor Device for the Ugi Four Component Condensation (4CC) Reaction

This paper describes a micro reactor system, in which the solution phase Ugi four-component condensation (4CC) reaction was investigated. The micro reactor is the first of its kind to perform the Ugi reaction on-chip using electro osmotic flow (EOF) producing the reaction intermediate in-situ. Currently, the reaction intermediate (an imine) can be synthesised successfully to a maximum yield of 94.3±4.4% (n=12) with a conversion to the final product of 60%. However, research is continuing into the final stage of the reaction to improve the reactions reproducibility.