DOI: 10.1002/chem.201104059 Gas–Liquid Segmented Flow Microfluidics for Screening Pd-Catalyzed Carbonylation Reactions Xiuqing Gong, [a] Philip W. Miller, [a] Antony D. Gee, [b] Nicholas J. Long, [a] Andrew J. de Mello,* [c] and Ramon Vilar* [a] Chemical reactions that occur within nanoliter to microli- ter volumes demonstrate many advantages over traditional batch synthetic methods. [1–4] On the microscale, the inherent high surface area-to-volume ratios facilitate highly efficient heat transfer processes and rapid and controllable mixing re- gimes enhancing mass transport. Both factors act to signifi- cantly enhance product quality, reaction yields and analyti- cal throughput. Reactions performed under continuous flow within microfluidic channels also offer the advantages of im- proved safety under extreme conditions, enhanced processa- bility, facile in-line detection, and reagent economy. [5–12] Gas–liquid phase reactions are particularly amenable to processing within small volumes under continuous flow con- ditions. The increased contact areas generated within such devices are ideal for enhancing mass transport of gaseous re- agents into the liquid phase, and the safety benefits associat- ed with pressuring small gas volumes is clear. A diversity of gas–liquid phase reactions are key components of many in- dustrial processes. For example, hydrogenations, hydrofor- mylations, carbonylations, chlorinations, and oxidations all require a gaseous reagent to enter a liquid phase before a reaction can occur. Typically, these gas–liquid reactions are performed in pressurized containers under batch conditions, however in many cases the reactions are amenable to flow processing. [13–17] Gas–liquid flow within channels can be broadly catego- rized as being either annular or segmented. Annular flow is characterized by a rapid gas flow through the center of a channel resulting in a thin film of liquid coating the internal surface of the channel, whilst segmented flow describes the regular and alternating formation of segments of gas and liquid. The flow regime obtained is dependent on volumetric flow rates, channel geometries, and the physical properties of the liquid phase. Flow regime maps can be generated by plotting the superficial gas velocity against liquid velocity. [18] Although an annular flow regime will generate high surface area contact between the gaseous and liquid phases within a microchannel the high gas flow rates typically result in un- desirably short residence times (few minutes) for the liquid reagents. Our group and others have previously used various gas– liquid flow regimes to study the palladium-catalyzed carbon- ylations of aryl halides. [19–22] This is a versatile and widely used approach for synthesizing organic molecules containing a carbonyl functional group. [23–25] In previous studies, using annular flow conditions, we found that reaction yields were improved compared to macroscale reactions, however, the short reaction times imposed by the flow regime precluded studies over longer timescales. Additionally, undesirable traces of metallic palladium were found to accumulate on channel surfaces, which occasionally resulted in channel blockage. To study carbonylation reactions over longer time periods and to prevent Pd aggregation we have developed a microfluidic system for rapidly generating and incubating segmented gas–liquid flows and used it to screen Pd-cata- lyzed carbonylation reactions. Importantly, this has allowed us to study the scope of the palladium(I) dimer [Pd 2 ACHTUNGTRENNUNG(m-I) 2 - ACHTUNGTRENNUNG(PtBu 3 ) 2 ] as pre-catalyst for carbonylative coupling reactions using a range of different substrates. The microfluidic reaction system contains two parts, a glass chip for segment generation and a fluorinated ethylene propylene (FEP) tube for incubation (Figure 1a and Fig- ure S1 in the Supporting Information). To study flow gener- ation within our device, the CO gas flow rate was fixed at 5 sccm and the liquid flow (toluene) rate was increased steadily. By gradually raising the liquid flow rate the transi- tion between annular and segmented flow could be visual- ized by injecting markers into the flow. Flow regimes were plotted as gas flow rate versus liquid flow rate (Figure S2 in the Supporting Information). The transition between annular and segmented flow is known to be dependent on both the channel size and the fluid properties, with smaller channel sizes favoring the for- mation of segmented flows. [26–28] Accordingly, the glass seg- ment generation chip has a small internal diameter (ID = [a] Dr. X. Gong, Dr. P.W. Miller, Prof. N.J. Long, Prof. R. Vilar Department of Chemistry, Imperial College London Exhibition Road, South Kensington, London SW7 2AZ (UK) E-mail : r.vilar@imperial.ac.uk [b] Prof. A. D. Gee Division of Imaging Sciences and Biomedical Engineering Kings College, St Thomas Hospital, London, SE1 7EH (UK) [c] Prof. A. J. d. Mello Institute for Chemical and Bioengineering Department of Chemistry and Applied Biosciences ETH Zurich (Switzerland) E-mail: andrew.demello@chem.ethz.ch Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201104059.  2012 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. 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