Continuous-Flow Study and Scale-up of Conventionally Difficult Chemical Processes

Microfluidic systems provide valuable tools for exploring, studying, and optimizing organic syntheses. The small scales and fast transport rates allow for faster experiments and lower amounts of chemicals to be used, reducing costs and increasing safety. Additionally, continuous flow processes allow for a large number of experiments to be performed after a single setup. These advantages were exploited to enable continuousflow study of chemical syntheses that are hazardous or difficult to perform by conventional methods and of applying the acquired knowledge toward improvement of industrial processes at large scales. Using silicon semiconductor microfabrication techniques, microdevices have designed and produced to address various challenges in continuous-flow reaction study and synthesis, enabling operation at reaction conditions not easily obtained in batch setups or on macroscopic scale. Several model reactions and systems were selected for study and/or augmentation. Silicon micromixers were designed and microfabricated to ensure low-pressure-drop millisecond-scale mixing of liquid streams. The micromixers were used to perform a quantitative kinetics and scale-up study of the direct two-step synthesis of sodium nitrotetrazolate by a Sandmeyer type reaction via a reactive diazonium intermediate. The use of continuous-flow microsystems significantly reduced the typically high explosion hazard associated with the energetic product and intermediate. An epoxide ring opening reaction was augmented and kinetics of the reaction were rapidly obtained using a silicon microreactor at high temperatures and pressures, demonstrating microreactor utility for rapid reaction space profiling, as well as the use of continuous flow to easily study and sample reaction conditions not readily accessible in batch. Scale-up was demonstrated using obtained kinetics. Synthesis steps of two pharmaceutical APIs were thus studied and greatly accelerated, which may be useful for considerations of continuous manufacturing. Finally, a system has been designed and studied to enable microfluidic study of solids-forming reactions such as an organic coupling reaction with inorganic salt byproduct precipitate. Conventionally, these solids render such reactions difficult to study in microreactors, which limits the types of chemistries that could be investigated and improved using microfluidic technology. To minimize these constraints, the formation of solids in flow was systematically studied, and a combination of reactor design and application of acoustic forces to effect solid agglomerate disruption was used to allow slurries with relatively large amounts of solids to flow through microchannels. Thesis Supervisor: Klavs F. Jensen Title: Warren K. Lewis Professor of Chemical Engineering