Suzuki–Miyaura coupling reactions in aqueous microdroplets with catalytically active fluorous interfacesw Ashleigh B. Theberge,* a Graeme Whyte, a Max Frenzel, a Luis M. Fidalgo, a Robert C. R. Wootton b and Wilhelm T. S. Huck* a Received (in Cambridge, UK) 12th June 2009, Accepted 12th August 2009 First published as an Advance Article on the web 28th August 2009 DOI: 10.1039/b911594c 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. In the drive towards miniaturizing and automating chemical and biological experiments, droplet-based microfluidics has emerged as a powerful research platform. 1 Generating discrete droplets in an immiscible continuous (carrier) phase allows reactions to be compartmentalized into femtolitre to nanolitre volumes. In essence, each droplet reactor is analogous to the traditional chemist’s flask, with the added advantages of reduced reagent consumption, rapid mixing, automated handling, and continuous processing. 1 Building on advances in continuous flow chemistry, 2 droplet-based microfluidics has been used to conduct a variety of organic reactions. 3–7 This platform provides opportunities for handling precious reagents that are not possible with conventional synthetic techniques and has been used to screen reaction conditions using microgram amounts of starting material. 3 Moreover, the encapsulation provided by microdroplets enables their application to precipitate-forming reactions that cannot be conducted in conventional continuous flow microreactors due to channel clogging. 4 It is well known that the high surface-to-volume ratio inherent to the dimensions of the droplets and the internal flow circulations in droplets in microfluidic channels can significantly enhance mass transfer between the dispersed and continuous phases. 8–12 O ¨ nal et al. reported a triphasic hydrogenation using organic reagent droplets and hydrogen gas bubbles dispersed in an aqueous catalytic stream. 9 Phase-transfer mediated nitration, 10 Claisen–Schmidt, 11 and hydrolysis 12 reactions have also been carried out using droplet-based microfluidics. In this work we aimed to use the multiphase nature of microdroplets to facilitate biphasic catalytic reactions. We envisioned anchoring a catalyst in the carrier phase such that it could assemble at the droplet ‘wall,’ catalyzing reactions inside each droplet microreactor. To this end we sought a continuous phase immiscible with both organic and aqueous phases. Fluorous solvents are immiscible with organic and aqueous phases and have been used extensively in droplet-based microfluidics. 1 Such a system with a fluorous continuous phase and aqueous or organic dispersed phase draws parallels with existing techniques in the field of fluorous biphasic catalysis (FBC) conducted in bulk reaction vessels. 13 While most of the described applications of FBC involve elevated temperatures to create a monophasic reaction mixture, FBC can also be used at room temperature when the reaction is designed to proceed at the fluorous–organic interface. 13 Droplet-based microfluidics provides an opportunity for controlling such interfaces. Here, we present a method for biphasic catalysis that incorporates the efficiency and control of droplet-based microfluidics with emerging fluorous phase chemistry. We generated droplet reactors with catalytically active walls by using a fluorous ligand which both solubilized a transition metal catalyst in fluorous solvents while also acting as a surfactant and hence accumulating at the fluorous–water interface (Fig. 1). Moreover, our fluorous ligand allowed for reactivity under ambient, aqueous conditions inside the droplet reactors. Fig. 1 Cartoon representation of microdroplets with catalytically active interfaces. Fluorous-tagged palladium catalyst (a) and aqueous reagents (b) were pumped into the T-junction, forming monodisperse aqueous droplets surrounded by the fluorous continuous phase. Product is formed as the droplets flow through the channel (c and d). Reaction time is linearly proportional to distance along the tubing and the controllable flow rates. a Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW. E-mail: abt30@cam.ac.uk, wtsh2@cam.ac.uk; Fax: +44 (0)1223-334-866; Tel: +44 (0)1223-331-797 b School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, UK L3 3AF w Electronic supplementary information (ESI) available: Reaction conditions for fluidic experiments and the synthesis of the fluorinated ligand (1). See DOI: 10.1039/b911594c This journal is  c The Royal Society of Chemistry 2009 Chem. Commun., 2009, 6225–6227 | 6225 COMMUNICATION www.rsc.org/chemcomm | ChemComm