Importance of Electrostatically Driven Non-Covalent
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IMPORTANCE OF ELECTROSTATICALLY DRIVEN NON-COVALENT INTERACTIONS IN ASYMMETRIC CATALYSIS A Dissertation by RAJAT MAJI Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Steven E. Wheeler Co-Chair of Committee, Daniel A Singleton Committee Members, David C Powers Lei Fang Head of Department, Simon W. North August 2018 Major Subject: Chemistry Copyright 2018 Rajat Maji ABSTRACT Computational chemistry has become a powerful tool for understanding the principles of physical organic chemistry and rationalizing and even predicting the outcome of catalytic and non-catalytic organic reactions. Non-covalent interactions are prevalent in organic systems and accurately capturing their impact is vital for the reliable description of myriad chemical phenomena. These interactions impact everything from molecular conformations and stability to the outcome of stereoselective organic reactions and the function of biological macromolecules. Driven by the emergence of density functional theory (DFT) methods that can account for dispersion-driven noncovalent interactions, there has been a renaissance in terms of computational chemistry shaping modern organic chemistry. DFT Studies of the origins of stereoselectivity in asymmetric organocatalytic reactions can not only provide key information on the mode of asymmetric induction, but can also guide future rational catalyst design. We start with an overview of weak intermolecular interactions and aromatic interactions. Special emphasis is given to the methods that one can use to study these ephemeral interactions. We next provide a brief account how computational chemistry has aided our understanding of chiral phosphoric acid (CPA) catalyzed reactions. Thereafter, three case studies showcasing the importance of non-covalent interactions in chiral NHC catalysis, CPA catalysis, and chiral nucleophilic catalysis has been elaborated. Each of these studies highlights the importance of electrostatically-driven non-covalent interactions in controlling reactivity and selectivity. Moreover, ii unprecedented activation modes are identified and new predictive selectivity models developed that can be used to rationalize the outcome of future reactions. Studying these reactions using state of art DFT methods, we aimed not only to contribute to the understanding of their selectivity and the importance of noncovalent interactions in catalysis, but also to bring a sound understanding that will enable the design of new reactions and better catalysts. Overall, this dissertation highlights the underappreciated role of electrostatic interactions in controlling reactivity and selectivity in asymmetric catalysis. iii DEDICATION To my parents, family, teachers, friends! iv ACKNOWLEDGEMENTS I would like to take this opportunity to thank everyone who had left a memorable mark in my journey. First and foremost, I would like to thank my advisor, Prof. Steven Wheeler, for giving me the opportunity to work in his group. He knew I had no formal exposure to computational chemistry and was still kind enough to welcome me in his group when I decided to switch in my 3rd year of grad school. In retrospect, I can proudly say that this was certainly the best decision I have taken to date. Steven spent an enormous amount of time working with me, teaching me how to run calculations. There are far too many things to enumerate in this page, for which I owe him this gratitude. His attention to promote students’ scientific and career development via custom-tailored research topics contributes a lot to creating a well-rounded experience and preparing for life after graduation. He was more than a research advisor to me. Not only he is an excellent guide and a nice and approachable person whom I really I enjoyed working with but also he has provided me a terrific role model of what an advisor should be. If you are reading this, Boss, I hope you know how grateful I am to you. Although I am sad to be leaving, I am looking forward to see exciting science from our lab in future. I also want to thank his wife Margaret for her friendly presence and discussions during my time in the Wheeler group. I owe a great debt to Prof. Daniel A Singleton, who is also my co-supervisor. DAS is a stalwart in this area and it has been a privilege to have him in my committee. I am extremely grateful for the time and effort he has put into scrutinizing my work with a fine-toothed comb for the last four years! I have also thoroughly enjoyed countless v stimulating conversation with him and his insightful comments have been useful over the years in helping me develop my intuition as a chemist. Most of all, I value his highly interactive teaching style and the philosophical discussions that he promotes! Although Prof. Powers and Prof. Fang are new to my committee, I have already gotten to know them quite well, thanks to several departmental events and some close friends. They agreed to serve on my committee within a very short notice and I really appreciate them devoting valuable time. Special thanks to my previous committee members Prof. David Bergbeiter and Prof. W. Liu for all their help. The Wheeler group members, past and present, made every day of research in the lab a happy and exciting experience. It was a pleasure to be a part of a dynamic, supportive and friendly research group. I would like to thank Yi, Trevor, Yanfei, Sharath, Andrea, Drew, Bryan, Stephen, Victoria, Aarya, and Juni for being awesome lab mates…you guys are amazing and I wish you all the best in your respective career. I will treasure the moments that I spent with you all during my time in the Wheeler group. A special shout out goes to Stephen for providing me shelter during my visits to Athens, which meant a lot to me. Thank you! I have to single out Sharath for a second. Not only because he is the only person in the group with whom I have been working in multiple projects but also his excitement about chemistry and eagerness to learn is what I admire the most. This research would not have been possible without a number of other very enthusiastic collaborators like Pier Alexander Champagne and Heena Ugale. I also consider myself lucky to have had a chance to closely work with Prof. Ken Houk’s group at UCLA. vi I was fortunate to have supportive departmental staff during my tenure as a grad student at Texas A & M. I am extremely grateful to Sandy Manning and Julie Zercher in particular for their constant support. I am also thankful to Dr. Amber Schafer for her numerous advice related to teaching. I would like to thank my teachers without whose influence I could have been anything except a chemist. I am grateful to late Dr. Arunava Sen for squandering life- long dream of my parents’ to send their only child in medical school. I can’t thank him ever enough for all his teaching, motivation and of course ruining my parents plans! I also must thank Dr. Chandan Saha and Dr. Atanu Bhattacharya for their passionate teaching in organic chemistry that left an indelible impression in my mind. My roots as a researcher come from working in the labs of Prof. Tanmaya Pathak and Prof. Saumen Hajra at IIT Kharagpur. They not only taught me different synthetic chemistry skills but also the importance of rigorous work in a lab that helped me in my perseverance and consistency in grad school. Life in College Station would not have been nearly as enjoyable as it was without all of my friends. Every time when I found myself lost in the trenches of grad school, their inspiration and support kept me going. I am fortunate to have several great friends in the department whom I had the pleasure of working with in different student organizations: Trang, Courtney, Tan, Peerada, Ryan, Zhengyang to name a few. Brateen and Bibaswan deserve special mention for hosting me when I first arrived in College Station. Yindrila will remain forever one of the most influential people in my life. She was truly a great mentor and this journey would have been a little less interesting if I had vii missed out those opportunities to bully her! Her friendship and compassion is something that I will cherish forever. Shyamalendu was a fantastic roommate over the years in grad school and I really enjoyed discussing politics, making travel plans, and engaging in wild gossip mostly after 3 AM when we finally got a chance to see each other! Arghya, Srobona, Deepika and Vangmayee were great batch mates and we had a lot of fun in our first year. “Parar Maye” Isita epitomizes the art of culinary skills in College Station and fed us numerous times. It was wonderful to have people like Sanjoy, Asim, Anuvab, Indra da who are always willing to engage in scientific discussions and offer some great insights. I am thankful to my surrogate family here at College Station: Sayan Saha, Bacha Sayan, Anushree, Nandini, Nairita, Sagnika, Raka, Sajal, Sougata and the list goes on. I am also fortunate to have several great friends outside chemistry courtesy to Riad, Shahina, Piyali, Farida for their warm friendship. Thank you all for accepting me with open arms and making College Station a home away from home. I could not more proud to have someone like Bakwas in my life. She stood by my side firmly during my darkest time and believed in me. Her patience, love, trust and support means the world to me. I am looking forward to have many more travels, flights and disagreements in rest of our life! Finally, I am eternally thankful to my family and close relatives for their constant love and support and that’s why this work is dedicated to them.