Suzuki-Miyaura cross couplings in a continuous flow system
Researchers at the Massachusetts Institute of Technology (MIT) reported on the development of a Suzuki–Miyaura cross-coupling
reaction in a continuous-flow microreactor system. Specifically, the researchers reported on a continuous-flow Suzuki–Miyaura
cross-coupling reaction that started from phenols and produced various biaryls in good yield using a microfluidic-extraction
operation and a packed-bed reactor. The project used a multidisciplinary approach with the research on microreactor technology
developed by a team led by Klaus F. Jensen, department head, Warren K. Lewis professor of chemical engineering, and professor
of materials science and engineering at MIT. The organic synthesis portion of the project was developed by a group led by
Stephen Buchwald, Camille Dreyfus professor of chemistry at MIT (4, 5).
Suzuki coupling is a palladium-catalyzed coupling between organoboron compounds and organohalides and is an important reaction
in organic chemistry in general and in the development of pharmaceutical compounds specifically. Akira Suzuki, distinguished
professor emeritus at Hokkaido University in Sapporo, Japan, was a corecipient of the 2010 Nobel Prize in Chemistry for the
development of palladium-catalyzed cross coupling (6).
Although batch manufacturing is the predominant form of manufacturing in the pharmaceutical industry, there is growing interest
in microreactor technology. In general, microstructured devices with small internal volumes and high surface-to-volume ratios
offer transport capabilities for rapid mixing, enhanced heat transfer for good temperature control, and intensified mass transfer.
Microstructured devices operate in continuous-flow environment, which can offer certain advantages, such as controlled process
conditions, high flow rates, and high mass throughput. Continuous operations also may allow bulk-chemistry processes to have
high production capacities. Fluid dynamics determine the characteristics of continuous-flow equipment such as pressure loss,
residence time, heat-transfer characteristics, and mixing time (7).
Buchwald is engaged in various research projects involving catalysis, including the creation and study of new ligands, the
design of new methods to form carbon–nitrogen bonds through the use of metal catalysts, such as palladium or copper, new methods
for the formation of carbon–carbon bonds, including asymmetric transformations, as well as continuous flow chemistry using
microreactors and capillary tubing. Buchwald recently reported on the continuous-flow synthesis of 3,3-disubstituted oxindoles
by a palladium-catalyzed a-arylation/alkylation sequence. Specifically, he reported on the pallidum-catalyzed a-arylation
of oxindoles in continuous flow involving a biphasic system, a precatalyst, and a packed-bed microreactor. The reaction was
integrated into a two-step continuous-flow sequence for rapid, modular, and efficient syntheses of 3,3-disubstituted oxindoles
Jensen's research is focused on understanding and controlling the interaction of reaction and transport processes in realizing
and testing functional microstructured and nanostructured materials and devices for chemical, biological, optical, electronic,
and energy applications, including the use of microfabricated systems. He recently reported on research using an automated
microfluidic system for online optimization in chemical synthesis. He reported that the time and material required for an
optimization trial were minimized by performing reactions in an integrated silicon microreactor and incorporating high-performance
liquid chromatography for in-line monitoring of the reaction performance. The system was used to optimize two different reactions
to understand the potential impact of the system for reaction development. The two reactions studied were a Knoevenagel condensation
reaction and a mulitparameter optimization to maximize the yield of benzaldehyde in the oxidation pathway of benzyl alcohol
to benzaldehyde to benzoic acid (9).
In other work, Jensen's team reported on the design and use of a high-pressure and high-temperature microsystem. Key parameters
for the fabrication of the microreactors and modular fluidic packaging were to withstand high pressure and temperature conditions
(i.e., 30MPa and 400 °C). The researchers reported on various applications of the high-pressure/high-temperature plug and
play microsystems. These applications included multiphase follow visualization through the transition of liquid–liquid immiscible
hexane–water segmented flow to homogeneous supercritical flow, on-chip supercritical water oxidation, and synthesis of iron
oxide nanoparticles (10).