Robert C. R. Wootton

The past, present and potential for microfluidic reactor technology in chemical synthesis

The past two decades have seen far-reaching progress in the development of microfluidic systems for use in the chemical and biological sciences. Here we assess the utility of microfluidic reactor technology as a tool in chemical synthesis in both academic research and industrial applications. We highlight the successes and failures of past research in the field and provide a catalogue of chemistries performed in a microfluidic reactor. We then assess the current roadblocks hindering the widespread use of microfluidic reactors from the perspectives of both synthetic chemistry and industrial application. Finally, we set out seven challenges that we hope will inspire future research in this field.

Continuous-Flow Polymerase Chain Reaction of Single-Copy DNA in Microfluidic Microdroplets

We present a high throughput microfluidic device for continuous-flow polymerase chain reaction (PCR) in water-in-oil droplets of nanoliter volumes. The circular design of this device allows droplets to pass through alternating temperature zones and complete 34 cycles of PCR in only 17 min, avoiding temperature cycling of the entire device. The temperatures for the applied two-temperature PCR protocol can be adjusted according to requirements of template and primers. These temperatures were determined with fluorescence lifetime imaging (FLIM) inside the droplets, exploiting the temperature-dependent fluorescence lifetime of rhodamine B. The successful amplification of an 85 base-pair long template from four different start concentrations was demonstrated. Analysis of the product by gel-electrophoresis, sequencing, and real-time PCR showed that the amplification is specific and the amplification factors of up to 5 x 10(6)-fold are comparable to amplification factors obtained in a benchtop PCR machine. The high efficiency allows amplification from a single molecule of DNA per droplet. This device holds promise for convenient integration with other microfluidic devices and adds a critical missing component to the laboratory-on-a-chip toolkit.

A method for rapid reaction optimisation in continuous-flow microfluidic reactors using online Raman spectroscopic detection

An extremely rapid tool for continuous flow synthetic process optimisation is described. A microfluidic reaction system operating in continuous flow is used in conjunction with confocal Raman microscopy to afford rapid molecule synthesis and product quantitation. Accordingly, the approach allows for rapid reaction optimisation within a continuous flow system. Specifically, the catalytic oxidation of isopropyl alcohol (IPA) to acetone using tetra-N-propylammonium perruthanate (TPAP)/N-methylmorpholine N-oxide (NMO) in a radial interdigitated micromixer is studied as a model reaction system. The composition of the reaction effluent can be determined with great facility and information relating to catalyst/co-oxidant ratios, catalyst turnovers and reaction endpoints extracted. Specifically, variation of catalyst and co-oxidant volumetric flow rates between 0 and 50 microL min(-1) is used to vary reactant concentrations, define reaction residence times and control product conversions between 0 and 100%. The rapid nature of the system allows chemical information to be gathered and utilised on a sub-minute timescale.

Precise temperature control in microfluidic devices using Joule heating of ionic liquids

Microfluidic devices for spatially localised heating of microchannel environments were designed, fabricated and tested. The devices are simple to implement, do not require complex manufacturing steps and enable intra-channel temperature control to within +/-0.2 degrees C. Ionic liquids held in co-running channels are Joule heated with an a.c. current. The nature of the devices means that the internal temperature can be directly assessed in a facile manner.

On-chip generation and reaction of unstable intermediates-monolithic nanoreactors for diazonium chemistry: azo dyes.

Monolithic nanoreactors for the safe and expedient continuous synthesis of products requiring unstable intermediates were fabricated and tested by the synthesis of azo dyes under hydrodynamic pumping regimes.

Suzuki–Miyaura coupling reactions in aqueous microdroplets with catalytically active fluorous interfaces

Using microfluidic techniques and a novel fluorous-tagged palladium catalyst, we generated droplet reactors with catalytically active walls and used these compartments for small molecule synthesis.

Droplet-Based Microfluidic Platform for High-Throughput, Multi-Parameter Screening of Photosensitizer Activity

We present a fully integrated droplet-based microfluidic platform for the high-throughput assessment of photodynamic therapy photosensitizer (PDT) efficacy on Escherichia coli. The described platform is able to controllably encapsulate cells and photosensitizer within pL-volume droplets, incubate the droplets over the course of several days, add predetermined concentrations of viability assay agents, expose droplets to varying doses of electromagnetic radiation, and detect both live and dead cells online to score cell viability. The viability of cells after encapsulation and incubation is assessed in a direct fashion, and the viability scoring method is compared to model live/dead systems for calibration. Final results are validated against conventional colony forming unit assays. In addition, we show that the platform can be used to perform concurrent measurements of light and dark toxicity of the PDT agents and that the platform allows simultaneous measurement of experimental parameters that include dark toxicity, photosensitizer concentration, light dose, and oxygenation levels for the development and testing of PDT agents.

Microfluidics: Exploiting elephants in the room

Microfluidic devices have many applications in chemistry and biology, but practical hitches associated with their use are often overlooked. One such device that optimizes catalysts tackles these issues head-on.

Conjugate addition to 3-arylsulfinylchromones as a synthetic route to homochiral 2-substituted chromanones: Scope and limitations

A route to homochiral 2-substituted chromanones via the diastereoselective conjugate addn. of organocopper reagents to 3-(p-tolylsulfinyl)chromones has been improved and used to prep. 2,6-dimethylchromanone and LL-D253a Me ether [i.e., (2R)-2,3-dihydro-8-(2-hydroxyethyl)-5,7-dimethoxy-2-methyl-4H-1-Benzopyran-4-one]. The attempted prepn. of a 2-phenylchromanone (flavanone) using this strategy was unsuccessful due to the lability of the intermediate 2-phenyl-3-(p-tolylsulfinyl)chromanone, which underwent sulfoxide elimination at room temp. to give the corresponding 2-phenylchromone (flavone).

Microfluidics: Analog-to-digital drug screening

Current methods for screening libraries of compounds for biological activity are rather cumbersome, slow and imprecise. A method that breaks up a continuous flow of a compounds solution into droplets offers radical improvements.