Design and operation of microchemical systems for multistep chemical syntheses

Abstract

This thesis focused on advancing the microchemical field from single device based demonstrations to systems that can perform multi-step series and parallel synthesis. Few examples of micro-separators and micro-pumps suited for miniaturized lab-on-a-chip systems for organic syntheses exist, so the first half of this thesis developed systems for these micro-unit-operations, while the second half demonstrated multistep microchemical operations enabled by these systems. In-line continuous separation devices are developed that enabled removal of unreacted reagents/byproducts, making it possible to realize a series of reactions without leaving the microreactor environment. Differences in surface forces and preferential wettability characteristics of fluoropolymers are used for phase separation. Such microseparators are used to demonstrate 100% separation of two phase flows of hexane and water, toluene and water, dichloromethane and water, and hexane and methanol. Integrated liquid-liquid extraction devices are microfabricated that performed two -phase contacting by segmented flow, followed by separation - resulting in single stage extraction. Single stage extraction of N,N-dimethylformamide from dichloromethane to water, and from diethyl ether to water is demonstrated. The development of separators allows microreactors to be connected to microseparators to form microreactor networks enabling reactions and separations in succession. The starting reagents are loaded in syringes and syringe pumps push fluid through the train of microdevices. However, this pumping scheme is limited by pressure constraints at the pump drives as well as the microseparators. Therefore, there is a need to develop in-line pumps to sustain the microdevice network. Pressure-driven flow is employed for the operation of micropumps. An enclosure with the liquid is pressurized with helium gas, causing the liquid to flow. The dynamics of pressurizing and de-pressurizing an enclosure are modeled and confirmed by experiments. Active and passive control schemes to provide constant flowrate of the liquid are developed and implemented. Different schemes are developed to use the gas pressure to manipulate the flow path of liquids.

(cont.) In one scheme, two enclosures are used together to perform as an in-line pump. The in-line pumps also acted as a buffer to prevent any disturbance propagation, and allowed the upstream and downstream to operate at different flowrates. The pump concept is demonstrated at two scales - 1) microfabricated silicon chips of 40 microliter volume and 2) using glass shell vials of 10000 microliter volume. These pumps are used along with two microseparators to demonstrate two-stage countercurrent and cross-flow liquid-liquid extraction of N,Ndimethylformamide from dichloromethane to water starting with 4.4 mole percent mixture. The in-line pumps also allowed recirculation with a constant flowrate that enabled long residence time reactions. As an example, peptide synthesis from amino acids, using the Merrifield technique is implemented. Specifically, the pentapeptide, Leuenkephalin is synthesized on different resins simultaneously as an example. A new design for the silicon microreactor for packed bed reactions is developed to enable larger catalyst loadings and offer manageable pressure drops across the packed bed even when the solid loading increased in volume during operation, as is the case with the peptide synthesis experiments. These microchips are also used to study "click chemistry" reactions to synthesize drug-candidate molecules. The packed bed microreactor experiments give higher conversions and better selectivities than batch experiments after the same amount of reaction time as the microreactor experiments provide increased relative catalyst concentration, and reduce side reactions that otherwise reduce selectivity. As an example of multi -step synthesis involving reactions and separations, the synthesis of carbamates starting from azoyl chloride and sodium azide, using the Curtius rearrangement of isocyanates is performed. This example also demonstrates parallel synthesis of analogous carbamates by introducing branching in the synthesis sequence after the isocyanate production to form microreactor networks. The second reaction involved heat decomposition of the organic azide, and performs faster when catalyzed using solid acid zeolite catalyst in a packed bed microreactor.

(cont.) Continuous operation of the microdevice network for ~ 7-10 days at flowrates of 1-5 [mu]l/min show no change in performance. The microreactor based synthesis is run at higher temperatures than conventional batch scale reactions due to the inherent safety in microreactor based production. The multiple-carbamate-synthesis microreactor network consists of five microreactors and two separators. This demonstration is the first multi-step organic synthesis involving reactions and separations, and showcased the major contributions from this thesis. The development of micro-unit-operations in this thesis has advanced the microchemical field from single device based demonstrations to systems that can perform continuous-flow multi-step series and parallel chemical synthesis.