UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ The rate enhancement of multi-component reactions by high speed ball milling Maxwell Zeb Shumba M.S. Eastern Kentucky University. M.S University of Cincinnati DISSERTATION A dissertation submitted the University of Cincinnati In Partial Fulfillment of The Requirements of the Degree of Doctor of Philosophy In Chemistry November 2007 ABSTRACT Solventless high speed ball milling (HSBM) technique has over the years gained the attention of organic chemists in particular from the viewpoint of green chemistry, because harmful organic solvents are not involved in the reaction process. Moreover, some novel products can also be obtained only from solvent-free reactions under the HSBM conditions rather than from the liquid-phase reactions. We looked to apply the HSBM technique towards the improvement of multi-component reactions (MCR). Based on their usefulness in organic synthesis and in pharmaceutical industry, the Baylis-Hillman reaction, the Gewald, and the Ugi-4-component reaction (U-4CR) were chosen for investigation. For these three reactions we were able to observe a rate enhancement and an increase in the product yields. Herein, we report the utility of HSBM to provide a rate enhancement and increased yields for the following multi-component reactions: The Baylis- Hillman, the Gewald reactions and the U-4-CR. 2 ACKNOWLEDGEMENTS First and foremost I would to thank the Lord and vadzimu vekwangu vese for guiding me through the arduous road towards my PhD degree. I would like to thank my wife Kudakwashe for giving me undying support, love and encouragement when the road seemed bleak. Special mention goes to my two daughters; Mia-Karen and Lisa-Alma who had to endure the pain of growing up without adequate parental attention accorded to other children; ‘Lisa and Mia had to forego sports activities at their respective schools because their dad had commitments in the lab’. I would like to thank my brother-in-law, Shingirai Mhonda, my mother in law, my brothers Alford and Edmore and my sister Anna (mai Enock) for the moral support and encouragement they offered me. I would like also to take this opportunity to dedicate this work to my late mother and father; Angeline and Callisto, my late brother and sister, Maki and Itai; the two who were tragic victims of the AIDS scourge. They provided me with the needed spiritual guidance, notably my Great Uncle, the late Francis ‘Franco’ Mutandwa. I would like to thank my advisor Dr. James Mack who was there for me and my family in the hour of need. His patience with me as I juggled between being a full time graduate student, a father and freedom fighter in the struggle for a free and democratic Zimbabwe; my home country was inspirational. His guidance and advice certainly made this PhD degree a reality. I would like to thank the Chemistry Departments at the University of Cincinnati and Eastern Kentucky University for providing me with a platform to realize my potential. Noteworthy is Dr. Otieno at Eastern Kentucky University. I would like to thank the Chemistry Department staff especially Dr. Brooks at the NMR, the now retired Zelda and Betty at the chemistry office, John at the stock room, Cassandra and John at the Chemistry Business Office, all of whom offered me unparralled service. 3 I would like to thank the Mack group members for their support, in particular Dennis Fulmer, who has over the years come to be a ‘brother’ to me and my ‘sister’ Angela Hurst. I would also want to thank the past and current graduate students in the Department of Chemistry for sharing with me their experiences which helped me a lot on this journey. I would like to thank my fellow comrades-in-the-struggle for walking with me and providing me with moral support as I trod on this dual road; graduate school and the ‘Struggle’ for Zimbabwe. Special mention goes to Aaron Mhonda, Andrew Mudzingwa, Oswald ‘Kazie’ Chibanda, Dr. Douglas Magomo, Mr. Cornelius Msimbe, Dr. Machekano, Modern Makovere, Ronnie Muvirimi, James Charlie, Josphat Tafirenyika, Paul Shumbayaonda (Shingai Munhamo), Mr. Leonard Chizinga, Ms Clara Matonhodze, Engineer Elias Mudzuri and MDC President Mr. Morgan Tsvangirai and others not on this list. To all these dedicated soldiers, I say, your efforts for a Free Zimbabwe are not in vain. I would like to thank my old friends for giving me unwavering support; Farai Chaimiti, Musatya Bere, Yamkelani Moyo, Wilson Sangadza, Vincent Aduda, Gitahi Waiganjo, Justice Dube, John Moto, Cexton Musekiwa, Richard Manungo, Newton ‘Bombeo’ Chihava, Simba Gerald Parumba, and Jane Abey. Special mention goes to the late Tendai Chidemo and Mrs Magreth (Mai Chidemo) Chidemo for bringing me to Cincinnati. Lastly, I would like to thank the Department of Chemistry and National Foundation of Science (NSF) for providing funding for my research projects. 4 CONTENTS ABSTRACT ................................................................................................................... 1 ACKNOWLEDGEMENTS ........................................................................................... 3 CONTENTS................................................................................................................... 5 List of Tables ..................................................................................................... 7 List of Figures.................................................................................................... 8 1. Introduction............................................................................................ 11 1.1 Mechanochemistry: Historical perspective......................................... 11 1.1 Milling and Grinding........................................................................... 12 1.2 Milling and Grinding........................................................................... 13 1.3 High Speed Vibrational Milling/High Speed Ball Milling.................. 19 1.4 The high speed ball milling technique in organic chemistry.............. 20 A. THE BAYLIS-HILLMAN REACTION ............................................................... 34 Background ..................................................................................................... 34 Results and Discussion .................................................................................... 37 B. GEWALD MULTI-COMPONENT REACTION................................................. 62 Background ..................................................................................................... 62 Results and Discussion .................................................................................... 67 C. THE UGI-4-COMPONENT REACTION (U-4CR) ............................................. 73 2.3 Background.......................................................................................... 73 Results and Discussion .................................................................................... 76 CONCLUSION ............................................................................................... 80 EXPERIMENTAL SECTION ................................................................................... 81 General Methods............................................................................................. 81 Materials.......................................................................................................... 82 5 (a) Solvents .................................................................................................... 82 (b) Column Chromatography ....................................................................... 83 (c) Reagents................................................................................................... 84 (d) Instruments and accessories.................................................................... 86 (e) Synthesis. ................................................................................................. 87 Chapter 1. Baylis-Hillman .............................................................................. 98 Chapter2. The Gewald Multi-component Reaction......................................102 Chapter 3. Ugi-4-Component Reaction.........................................................113 6 List of Tables Table Page 1. Reaction time against percent yield for Baylis-Hillman reaction 44 2. The Baylis-Hillman reaction using methyl acrylate, p-nitrobenzaldehyde, and the quiniclidine family of catalysts 47 3. Reaction of p-nitrobenzaldehyde, DABCO, and methyl acrylate and various tertiary amine catalysts 48 4. Steric hindrance studies 52 5. Reaction of p-nitrobenzaldehyde, DABCO, and various activated alkenes 60 6. Percent yield obtained from the reaction of para substituted benzaldehyde, DABCO, and methyl acrylate 61 7. The Gewald reaction with cyclic ketones 71 8. The Gewald reaction with aromatic ketones 72 9. Percent yield of the reaction between substituted aniline, trans-cinnamaldehyde, chloroacetic acid and cyclohexyl isocyanide 80 7 List of Figures Figure Page 1. Mortar and Pestle 13 2. The 8000D Spex Mill. 60 Hz vibrational milling 14 3. Laboratory Planetary Mono mill. Pulverisette 6 15 4. A laboratory