The Development of Simplified Microreactors for Use in Multi-Step Reaction Sequences
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THE DEVELOPMENT OF SIMPLIFIED MICROREACTORS FOR USE IN MULTI-STEP REACTION SEQUENCES A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Andrew R. Bogdan August 2009 © 2009 Andrew R. Bogdan THE DEVELOPMENT OF SIMPLIFIED MICROREACTORS FOR USE IN MULTI-STEP REACTION SEQUENCES Andrew R. Bogdan, Ph. D. Cornell University 2009 This dissertation describes the development of simplified microreactors to be used in multi-step reaction sequences. Microreactors are a developing technology with numerous benefits and whose modular design permits multi-step reaction sequences to be performed in a continuous flow process. The first chapter discusses the physical properties of microreactors and describes how performing reactions in these miniaturized reactors leads to safer, more efficient and more selective chemical transformations. A brief discussion of multi-step reaction sequences already performed in flow will also be presented. These multi-step reaction sequences, however, rarely rely on catalysis to facilitate chemical transformations. This area therefore has room for great improvement. The next two chapters discuss the development and application of solid-supported catalysts to be used in flow. In the first of these two chapters, two catalysts are immobilized on a solid-support and used in a simplified flow reactor. These reactions proved to be more efficient than similar batch reaction and the catalysts were highly recyclable. The next chapter presents a supported TEMPO catalyst used to oxidize alcohols to carbonyl species. These three catalysts set the foundation for multi-step flow reaction to be potentially performed in the group. The ensuing chapter uses a flow reactor to facilitate a two-step click reaction starting from an alkyl halide, sodium azide and a terminal acetylene. This process proved to be high throughput and rapidly synthesized vast libraries of compounds to be submitted for biological testing. The next two chapters discuss the synthesis of the ibuprofen and atropine in flow. Initial studies were carried out to synthesize both of these drugs in flow as part of a project geared toward synthesizing drugs on-demand. Later, a continuous flow synthesis of ibuprofen was realized using a series of reactions in which excess reagents and byproducts were compatible with downstream reactions. Finally, on-going work to develop asymmetric, multi-step reaction sequences in flow will be discussed in which the majority of reaction steps utilize solid-supported catalysts. BIOGRAPHICAL SKETCH Andrew Robert Bogdan (known as Drew to everybody who knows him) was born in State College, PA in 1982. He spent the next 18 years growing up in the shadows of Penn State University, but despite his love for Nittany Lion football, he pledged that he would never be a student there. During his senior year in high school, Drew applied to only one college, Franklin & Marshall, and thankfully they let him in. Knowing from the start that he was going to be a chemistry major, Drew immersed himself in the chemistry department and became close to various faculty members. After his sophomore year, Drew was granted the opportunity to perform undergraduate research at Syracuse University under the supervision of Dr. John E. Baldwin. Upon returning to Franklin and Marshall in August of 2002, Drew continued to collaborate with Dr. Baldwin while working in Dr. Phyllis A. Leber’s laboratory, ultimately continuing this research until graduation. Drew graduated cum laude from Franklin and Marshall in May of 2004, having achieved various departmental chemistry awards during his time in school. Drew decided to head to New York state for graduate school, where he joined the group of Dr. D. Tyler McQuade at Cornell University in late 2004. Soon thereafter he started working with microcapsules and microreactors, in efforts to develop multi-step reaction sequences. In September of 2007, Drew joined the group during its move to Florida State University, where he would complete his doctorate. Friends back in Ithaca were jealous of Drew for living in the Sunshine State. Unfortunately for Drew, he remained as pasty as ever during his time in Tallahassee, rarely venturing outside during the daylight hours. Drew focused on completing his degree and instead of getting a tan. iii To my family. iv ACKNOWLEDGMENTS Graduate school was anything but typical for me. At one point, I was a Florida resident living in California who was enrolled at a school in New York State. That being said, I cannot imagine going through graduate school without the constant support of numerous people. My family and friends were always there, serving as perpetual sources of advice and laughter, helping me through complicated times. Thanks to my advisor D. Tyler McQuade, who provided me with the guidance and knowledge necessary to help me complete this degree. Furthermore, his confidence in me helped me develop as an independent scientist and made me realize that no matter what challenges I am confronted with, I have the ability to overcome them. I would also like to thank Phyllis Leber, who provided constant support and advice throughout both my undergraduate and graduate careers. I am deeply grateful for my parents. Throughout my life, they have always been supportive of the decisions I have made, and made it possible to be in places that I never thought I would be. Thanks to my big brother, Matt, who finally stopped abusing me as a child, having finally realized that sending me to the hospital repeatedly was not in anybody’s best interest. Steve Broadwater showed me the ropes in graduate school and helped set the foundation for my graduate career. He has always been the source of valuable insight and I cannot thank him enough. I would also like to thank Sarah Poe who was with me since the first day in the group. She has always been there when I needed advice, a laugh, cookies, or somebody to annoy (despite the fact she graduated months before I did). I cannot imagine graduate school without these two, and thankfully the memories go beyond lab, ranging from tire fires to the more traditional barbeques. To everybody else who has helped me along the way, in both Ithaca and Tallahassee, thank you. v TABLE OF CONTENTS Biographical Sketch…………………………………………………………………...iii Dedication……………………………………………………………………………..iv Acknowledgements…………………………………………………………………….v Table of Contents……………………………………………………………………...vi List of Figures………………………………………………………………………...vii List of Schemes………………………………………………………………………...x List of Tables…………………………………………………………………………xii List of Equations……………………………………………………………………..xiii Chapter 1: The Application of Microreactors to Organic Synthesis……………....1 Chapter 2: Improving Solid-Supported Catalyst Productivity by Using a Simplified Packed-Bed Microreactor………………………………....17 Chapter 3: A Biphasic Oxidation of Alcohols to Aldehydes and Ketones Using a Simplified Packed-Bed Microreactor………………………..42 Chapter 4: The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4-Disubstituted 1,2,3-Triazoles…………..61 Chapter 5: The Flow Syntheses of Active Pharmaceutical Ingredients…………..87 Chapter 6: The Continuous Flow Synthesis of Ibuprofen………….………...…113 Chapter 7: Progress Toward Multi-Step Reaction Sequences Using Solid-Supported Catalysis……………………………………137 Appendix 1: Supporting Information for Chapter 2………………………………165 Appendix 2: Supporting Information for Chapter 3………………………………168 Appendix 3: Supporting Information for Chapter 4………………………………171 Appendix 4: Supporting Information for Chapter 6………………………………173 vi LIST OF FIGURES 1.1 Surface area-to-volume ratios of two 1 mL reactors………………………….2 1.2 Temperature profiles for batch and flow reactors…………………………….3 1.3 Mixing profiles for batch and flow reactors…………………………………..5 1.4 Retrosynthetic analysis of the drug naproxcinod……………………………..6 1.5 Ley’s continuous flow synthesis of oxomaritidine……………………………8 1.6 Ley’s continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles…………9 1.7 Experimental setup for Jensen’s carbamate synthesis in flow………………10 1.8 Cosford’s three-step continuous flow synthesis of 1,2,4-oxadiazoles………12 2.1 Flow reactions with a packed-bed microreactor……………………………..18 2.2 The simplified microreactor setup…………………………………………...22 2.3 Conversion of Knoevenagel condensation vs. residence time………………23 2.4 Conversion of acylation vs. residence time………………………………….26 2.5 Yield from a single-channel AO-TBD packed-bed microreactor…………...27 2.6 Long-term activity of single-channel AO-TBD microreactor……………….28 2.7 Yield from an eight-channel AO-TBD packed-bed microreactor…………...28 2.8 Long-term activity of eight-channel AO-TBD microreactor…………….….29 2.9 Heat exchanger………………………………………………………………30 2.10 Packed-bed microreactor regeneration………………………………………31 3.1 Catalytic cycle of the TEMPO-catalyzed oxidation of alcohols…………….44 3.2 Redox reactions for the generation of the oxoammonium cation……………44 3.3 The simplified microreactor setup…………………………………………...47 3.4 Plug flow and coalescence…………………………………………………...47 3.5 The long-term activity of AO-TEMPO packed-bed microreactors………….52 4.1 Drug derivative synthesis using click chemistry…………………………….62 vii 4.2 Catalytic cycle of the click reaction…………………………………………64 4.3 Conjure Flow Reactor schematic…………………………………………….65 4.4 Copper reactor diskette………………………………………………………66 4.5 Contour plot for the click reaction at 100 ˚C………………………………...68 4.6 Contour plot for the click reaction