Pd/C-Catalyzed Suzuki Cross- and Self- Couplings &
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PD/C-CATALYZED SUZUKI CROSS- AND SELF- COUPLINGS & THE DEVELOPMENT OF A LAB-SCALE HYDROGENATION SYSTEM by JENG-SHIOU CHEN A Dissertation submitted to the Graduate School-New Brunswick Rutgers, The State University of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Chemical and Biochemical Engineering Written under the direction of Professor Johannes G. Khinast And approved by ________________________ ________________________ ________________________ ________________________ New Brunswick, New Jersey Jan. 2008 ABSTRACT OF THE DISSERTATION PD/C-CATALYZED SUZUKI CROSS- AND SELF- COUPLINGS & THE DEVELOPMENT OF A LAB-SCALE HYDROGENATION SYSTEM By JENG-SHIOU CHEN Dissertation Directors: Professor Johannes G. Khinast Suzuki couplings have become an efficient and clean strategy for the preparation of biologically active functionalized biphenyls, which are important building blocks for pharmaceutical and agricultural compounds. Among all catalysts of choice for Suzuki couplings, palladium on carbon (Pd/C) is most frequently used for industrial applications due to its high catalytic activity, low cost and easy removal from the reaction mixture. Using a model coupling reaction of biphenylacetic acid, we intended to provide a thorough understanding of Pd/C-catalyzed Suzuki couplings for a straightforward industrial implementation. A detailed investigation of the reaction parameters was carried out in Chapter 2. The experimental observations indicate that excess amount of the borate is helpful to accelerate the reaction and 2 moles eq. of a strong base is the best choice for the reaction. Furthermore, our results suggest that transmetalation is the rate-limiting step of the Pd/C-catalyzed Suzuki couplings and also show that [OH-] is a critical factor affecting the reaction rate. ii In Chapter 3, the mechanism of Pd-leaching from Pd/C was investigated. The filtration test was used to prove that oxidative addition of aryl-bromides is the main cause for Pd-leaching, which is independent of the reaction solvent and temperature. In addition, the oxidative addition of aryl-borates is another cause for Pd-leaching. PVPy adsorption studies suggest that the activity of Pd/C is mainly due to leached Pd. Furthermore, PVPy was proven to be a good reagent for complete removal of Pd-residuals from the reaction mixture. In Chapter 4, homocoupling of arylboronic acids was successfully carried out with Pd/C in water/2-propanol (9:1 in volume ratio) under air, to obtain symmetric biaryls in good yield. This novel system was discovered during Pd-leaching studies and optimized in our work. The experimental observations suggest that higher water fractions in the co-solvent and higher reaction temperature are beneficial for the reaction. DFT calculations suggest that the overall reactivity of the different arylboronic acids is independent of the oxidative addition of Pd to the arylboronic acid. Lastly, we successfully established a lab-scale hydrogenation system at Rutgers University to carry out chiral hydrogenation, which is presented in Chapter 5. The system allows reactions operated under 120 bars at a wide range of reaction temperatures (-80~350 oC). iii ACKNOWLEDGEMENT First of all, I wish to thank my advisor, Dr. Johannes Khinast, not only for his guidance and support in the academic work but also for the friendship we developed over the last four years. I really appreciate and treasure this opportunity to work with you. It is always joyful to talk to you. You are patient, always listen to me, and allow me to try all kinds of ideas. No matter if I obtained good or bad results, you provided me with the positive thinking all the times and guided me to go forward in the correct, optimistic direction. Moreover, thank you so much for your time on instructing my writing and speaking. I learned a lot from our discussions and communications through hundreds of emails. Although you are not in New Jersey for two years, I always feel that you are with me and support me. I really appreciate it. To my committee member, Dr. Henrik Pedersen, thanks for your advice and help to operate and maintain HPLC, which is an important tool for me to obtain experimental results. Thanks to Dr. Marianthi Ierapetritou for your help and consideration. You always gave me your best smiles and encouraged me to look forward in research. To Dr. Karsten Krogh-Jespersen, thanks for your guidance and help in computational chemistry. This work could not have been accomplished without your assistance. It is very pleasant to discuss with you at all times. A special thank to Dr. Yee Chiew and Anne. You not only guided me in the academic path but also helped me to root my life in New Jersey. With your help, I could adapt myself quickly to this new place and love everything happening in this beautiful place. Furthermore, I would like to thank my parents and my sisters for always supporting me to do anything that interested me. Without your support, it is iv impossible for me to fully concentrate on pursuing a Ph.D. degree in the most distant place from Taiwan. Thank you so much for listening to my complaints, giving me positive opinions, and for encouraging me to look forward. Although you cannot be close to me, it is always my most wonderful time to have your calls and emails. I feel as if I were still in that warm and cozy home. I love you!! I-Ling, thank you for sharing my happiness and sadness for more than 12 years. Before or after the wedding, you always put a smile on my face and give me your best support. Thank you for establishing a new family with me in this new place. Although I cannot provide you with attractive and expensive things, I will always love you! For Shang-Jiun, I am so happy to have you in the family although you do not understand anything yet. Another special thanks to Anthony Panarello. You’re just like my big brother. Thank you for teaching me everything in the lab and for getting me acquainted with American life. I am glad that we had great times in the lab, in the bar, at the BBQs and at the football games. Last but not the least: thanks to my fellow co-workers: Oleksiy, Natalia, Athanas, and Jane, as well as the many departmental friends: Zhenya, Marggret, Yangyang, Marcos, Eric, Eddie, Alan, Steve, Hong, Patty, and Frank. You all have taught me more than you can imagine. I will miss the many interesting conversations. Thank you so much! v TABLE OF CONTENTS ABSTRACT..................................................................................................... ii AKNOWLEGDEMENT................................................................................ iv TABLE OF CONTENTS .............................................................................. vi LIST OF TABLES ...........................................................................................x LIST OF FIGURES AND SCHEMES......................................................... xi 1. INTRODUCTION............................................................................................1 1.1 HETEROGENEOUS CATALYSIS.................................................................1 1.2 COUPLING REACTIONS............................................................................2 1.3 SUZUKI COUPLINGS ................................................................................3 1.4 HOMOCOUPLING OF ARYLBORONIC ACIDS .............................................6 1.5 COMPUTATIONAL CHEMISTRY BY DFT METHOD.....................................7 1.6 BIMETALLIC CATALYSTS CATALYZED ENANTIOSELECTIVE HYDROGENATION ...................................................................................8 1.7 RESEARCH OBJECTIVES ........................................................................10 2. INVESTIGATION OF PD/C-CATALALYZED SUZUKI COUPLINGS ..........................................................................................................................14 2.1 EXPERIMENTAL.....................................................................................14 2.1.1 MATERIALS............................................................................14 2.1.2 MODEL REACTIONS FOR SUZUKI COUPLINGS ........................15 2.1.3 RC1 CALORIMETRIC ASSAY ..................................................15 2.1.4 HPLC ANALYSES ..................................................................16 2.1.5 EXPERIMENTAL VALIDATION.................................................17 vi 2.2 INVESTIGATION OF REACTION PARAMETERS ........................................18 2.2.1 INFLUENCE OF AGITATION .....................................................18 2.2.2 INFLUENCE OF CATALYST LOADING ......................................18 2.2.3 INFLUENCE OF BASE LOADING...............................................19 2.2.4 INFLUENCE OF BASE LOADING...............................................20 2.2.5 INFLUENCE OF REACTION TEMPERATURE ..............................20 2.3 DERIVATION OF THEORETICAL RATE EXPRESSIONS..............................22 2.3.1 SEVEN ELEMENTARY REACTIONS ..........................................22 2.3.2 RATE EXPRESSIONS OF THE ASSUMED RATE-LIMITING STEPS23 2.4 PH-EFFECTS ON PD/C-CATALYZED SUZUKI COUPLINGS.......................25 2.4.1 INFLUENCE OF BASE SPECIES .................................................25 2.4.2 INFLUENCE OF REACTION CO-SOLVENT .................................26 2.5 CONCLUSION.........................................................................................27 3. PD-LEACHING & PD-REMOVAL IN