Continuous‐Flow Chemical Processing in Three‐Dimensional Microchannel Network for On‐Chip Integration of Multiple Reactions in a Combinatorial Mode

Abstract

Chemical syntheses using microchemical chips have been intensively investigated in recent years, but they have still not fully reached the stage of practical use. Combinatorial synthesis has been expected to be one of their useful applications. Benefits of using microchips, such as reduction in quantity of reagents and wastes, are thought to be suited for combinatorial syntheses, where numerous variations of products have to be synthesized each in small amounts. There are two modes of combinatorial syntheses using microchemical chips. One is sequential synthesis, in which reactant solutions are introduced sequentially in various combinations to a reaction microchannel. The other is parallel synthesis, where the number of reaction channels is the same as the number of final products, and starting materials are distributed to all the reaction channels in different combinations. Sequential synthesis has been considered as the more favorable way, because, especially when libraries of starting materials are large, numerous microchannels and complicated pipings for distribution of reagents to the channels are required for the parallel mode. Therefore, research on parallel microcombinatorial syntheses has been done only rarely, whereas there have been many reports of sequential microcombinatorial syntheses. Against this trend, our research group has taken an alternative path and tried to integrate both parallel reaction microchannels onto a glass microchip and channels for distributing reactant solutions to each reaction channel in a combinatorial mode. Microchips fabricated by laminating multiple layers of glass substrates have been used to construct three-dimensional microchannel networks necessary for mixing reagent flows in different combinations. We utilized low Reynolds number multi-phase laminar flow and developed micro-unit operations (MUOs). By combining MUOs in the multi-phase continuous laminar flows, microchemical systems were constructed. We called this micro-integration methodology "continuous-flow chemical processing (CFCP)", and by using it, a sequence of various operations in chemical syntheses could be integrated on a microchemical chip. Not just simple mixing of two reagents, which was most commonly done in microreactors, but also multi-step processes including other chemical operations, such as extraction and separation, could be carried out via CFCP. In the first part of this short review article, we explain CFCP with an example. Then, a microchemical chip with a three-dimensional microchannel network for a parallel reaction system is introduced. Finally, we present a case in which CFCP was realized in a three-dimensional microchannel network. 742

Parallel combinatorial chemical synthesis using single-layer poly(dimethylsiloxane) microfluidic devices

“…For instance, it would be possible to run the entire combinatorial series of reactions reported by Garcia-Egido et al in 210 s using one of the scaled up single-layer chips proposed above compared to the 4410 s needed using the sequential chip of Garcia-Egido et al, reducing the total time required to perform the reactions by a factor of 21. 4 The performance of our device compared favorably with that of the chip developed by Kikutani et al;7 using the chip, we succeeded in producing pure products at a throughput comparable to that achieved using the multilayer glass device. However, our device exhibits the additional major advantage of fabrication simplicity compared to that of Kikutani et al…”

“…As is typical in microfluidic organic chemistry experiments, the solution-phase reactants were driven hydrodynamically using a syringe pump. 7,10 Reactants were introduced into the chip by connecting the syringes to the inflow ports using the tubing. The syringe pump drove all of the reactants at an identical rate, ensuring approximately uniform flow and mixing of compounds.…”

“…6 In light of these limitations, a handful of studies have investigated developing microfluidic devices for parallel combinatorial chemical synthesis. 7 In such devices, the constituent reactions are run simultaneously in separate reaction channels, improving throughput as compared to sequential methods. Parallel combinatorial synthesis of organic compounds has been demonstrated using multiple microreactors on different microfluidic chips; 8 however, such an approach sacrifices the advantages and simplicity of having all reactions integrated onto a single device.…”

“…Only one major study has been published on parallel microfluidic combinatorial chemistry in which the reactions are run using a single microfluidic device: Kikutani et al recently reported the use of a multilayer glass microfluidic chip to perform a 2 ϫ 2 combinatorial series of phase-transfer amideformation reactions. 7 The design they developed for the 2 ϫ 2 synthesis required that the reaction channels cross at multiple locations, necessitating the use of a multilayer glass microfluidic chip. Their device required only four chemical inputs ͑one for each of the reactants involved in the 2 ϫ 2 synthesis͒ and was demonstrated to be an effective platform for genuinely parallel combinatorial chemical synthesis.…”

Comparison of Performance Parameters of Photothermal Procedures in Homogeneous and Heterogeneous Systems

“…The molar absorptivity of water-insoluble Co(III) tris(2-nitroso-1-naphtholate) is much higher in its PEG-or surfactant-containing solutions than its alkaline aqueous solutions (4 × 10 3 L/(mol cm)) due to micellar solubilization of the chelate in these solutions. 9 The following procedures were described previously: Co with diethyldithiocarbaminate; 39 Co and Fe with 4-(2-pyridylazo)resorcinol (PAR), 40 4-(2-thiazolylazo)resorcinol (TAR) and Xylenol Orange, 41 and dithizone; 42 Co with 2-nitroso-5-dimethylaminophenol, 29 2-nitroso-5-(N-propyl-3-sulfopropylamino)phenol (Nitroso-PSAP), 43 chiral Co complex with triethylenediamine; 31 and Fe with 1,10-phenanthroline, 32 bathophenanthroline, 44 and bathophenanthroline disulfonic acid. 45 Below, we briefly describe newly developed procedures.…”