This electronic thesis or dissertation has been downloaded from Explore Bristol Research, http://research-information.bristol.ac.uk Author: Hernandez Fajardo, Oscar Title: Mechanistic and Reactivity Studies of First-Row Complexes as Catalysts in Cross- Coupling Reactions. General rights Access to the thesis is subject to the Creative Commons Attribution - NonCommercial-No Derivatives 4.0 International Public License. A copy of this may be found at https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode This license sets out your rights and the restrictions that apply to your access to the thesis so it is important you read this before proceeding. Take down policy Some pages of this thesis may have been removed for copyright restrictions prior to having it been deposited in Explore Bristol Research. However, if you have discovered material within the thesis that you consider to be unlawful e.g. breaches of copyright (either yours or that of a third party) or any other law, including but not limited to those relating to patent, trademark, confidentiality, data protection, obscenity, defamation, libel, then please contact [email protected] and include the following information in your message: •Your contact details •Bibliographic details for the item, including a URL •An outline nature of the complaint Your claim will be investigated and, where appropriate, the item in question will be removed from public view as soon as possible. Mechanistic and Reactivity Studies of First-Row Complexes as Catalysts in Cross-Coupling Reactions. Oscar Hernández Fajardo A thesis submitted to the University of Bristol in accordance with the requirements of the degree of Doctor of Philosophy in the School of Chemistry, Faculty of Science. November 2018 1 Abstract Iron(II) complexes show activity in Negishi cross-coupling reactions. A series of mechanistic studies were conducted using spectroscopic techniques in order to improve the understanding of this reaction. It has been observed that Fe(II) is reduced to Fe(I) species when it interacts with the nucleophilic reagent in the reaction mixture. These reduced species show excellent catalytic activity. A kinetic study was conducted using UV-vis spectroscopy which demonstrates that the presence of Lewis acids and Lewis bases influence the speed of reaction. A free-energy relationship using the Hammett equation suggests a free radical mechanism. Activation parameters provided evidence for an associative transition step. The data obtained revealed a complex system of reactions. With the experimental results obtained in these studies, mechanisms for the iron(I) catalysed cross-coupling reaction were proposed. An X-ray absorbance spectroscopy study was conducted in iron complexes in order to illuminate the role of iron of the species. Reaction mixtures of typical cross-coupling reactions were examined at the end of the reaction in order to detect iron complexes and characterise them. A reaction time-dependent study was undertaken to determine the iron complexes in the reaction mixture. A kinetic study on the Negishi cross-coupling using iron(II) was conducted. The experimental results from the kinetic study on iron(I) and the kinetic study on iron(II) were used to propose a mechanism of reaction for the iron catalysed Negishi cross- coupling. The development of a new cross-coupling system using manganese as pre-catalyst was explored. The use of different ligands, additives and conditions of the reaction was tested. 2 Acknowledgements A massive thanks to my supervisor Professor Robin Bedford for giving the opportunity to work with him and for the help provided. I will always admire your enthusiasm and creativity. Thanks to all my friends in the Bedford group: Starting with Michelle, Paul, Johnny and Dom who introduced me to everything in the laboratory and to the life in the UK. Thanks to Sanita, Stephen, Harry, Mattia and Soneela for all the good chats, for enjoying my great taste in music and making a fun work environment in the lab. I thank the postdocs in the Bedford group: Antonis, David, Peter and Carolina, who were always helpful and taught me a lot. I appreciate the willingness to share your expertise. I thank all my friends in Bristol, particularly to the Mexican community in Bristol which gave a little piece of my country abroad. I am so grateful to my parents, who have always been rooting for me and cheering me up. A massive thanks to my brother, who is always someone I could talk without judgment. I am grateful to my grandfather, who helps me and cares about me. Thanks to the Consejo Nacional de Ciencia y Tecnología (CONACyT) for its financial support throughout my doctoral studies. 3 I declare that the work in this dissertation was carried out in accordance with the requirements of the University's Regulations and Code of Practice for Research Degree Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, the work is the candidate's own work. Work done in collaboration with, or with the assistance of, others, is indicated as such. Any views expressed in the dissertation are those of the author. SIGNED: ............................................................. DATE:.......................... 4 Abbreviations Ac Acetyl EPR Electron Paramagnetic Ots Tosylate Resonance acac Acetylacetonate PEG Polyethylene glycol eq Equivalents Ar Aryl Piv Pivalate EXAFS Extended X-ray B(Arf)4 Tetrakis[3,5- absorption fine structure PPh3 Triphenylphosphine bis(trifluoromethyl)phenyl]borate Py Pyridine Feact Active Iron Catalyst Bn Benzyl RE Reductive elimination Feoff Iron off-cycle species cat. Catalyst RT Room Temperature Feon Iron on-cycle species COD Cyclooctadiene s Seconds Feout Stable iron species Cy Tricyclohexylphosphine SALEN N,N'- Fepre Iron pre-catalyst DABCO 1,4- bis(salicylidene)ethylenediamine diazabicyclo[2.2.2]octane h Hour sBu Secbutyl dba Dibenzylideneacetone HMPA Hexamethylphosphorami SET Single electron transfer dbm Dibenzoylmethane de SET Single electron transfer depe Diethylenephosphine iBu isobutyl T Temperature DFT Density functional theory IMes 1,3-Dimesitylimidazol-2- tBu tertbutyl DIBAL ylidene, 1,3-bis(2,4,6- Diisobutylaluminum hydri trimethylphenyl)-imidazolium Tf Triflate de iPr Isopropyl TFA Trifluoroacetic acid DMA Dimethylacetamide M Metal THF Tetrahydrofuran DME Dimethoxyethane Mes Mesitylene TM Transition metal dpbz 1,2- min Minutes TMEDA N,N,N',N'- bis(diphenylphosphino)benzene tetramethylethylenediamine NHC N-heterocyclic dppe 1,2- TMS Tetramethylsilane bis(diphenylphosphino)ethane NMP N-Methyl-2-pyrrolidone XANES X-ray absorption near dppm NMR Nuclear Magnetic edge structure Bis(diphenylphosphino)m Resonance ethane XAS X-ray absorption OA Oxidative addition spectroscopy dppp 1,2- bis(diphenylphosphino)propane Otf Triflate 5 Table of contents Chapter 1 Introduction ................................................................................................................... 7 1.1 Metal-catalysed cross-coupling reactions ................................................................................. 8 1.2 First row transition metal catalysed cross-coupling reactions ................................................... 9 1.3 Palladium Cross-coupling reactions ........................................................................................ 11 1.4. Use of softer nucleophiles ..................................................................................................... 13 1.5 Iron as a catalyst .................................................................................................................... 23 Chapter 2. Exploring Fe(I) reactivity in Negishi Cross-Coupling ......................................................... 44 2.1 Introduction ........................................................................................................................... 45 2.2 General Considerations .......................................................................................................... 71 2.3 Preliminary UV-Vis studies in Fe catalysed cross-coupling. ..................................................... 72 2.4 Kinetic studies on the oxidation of Fe(I) ................................................................................. 76 2.5 Order of reaction ................................................................................................................... 88 2.6 Linear free energy relationship analysis using the Hammett equation. ................................... 97 2.7 Activation parameters of the reaction of [FeBr(dpbz)2] and BnBr in the presence of ZnBr2 ... 102 2.8 Mechanism of reaction. ....................................................................................................... 105 2.9 Conclusions and Future Work .............................................................................................. 109 Chapter 3. Further studies on the iron-catalysed cross-coupling .................................................... 111 3.1 Introduction ......................................................................................................................... 112 3.2 Results and discussion ......................................................................................................... 114 3.3 Monitoring the catalysis using FeBr2(dpbz)2 ......................................................................... 122 Chapter 4. Developing a novel Manganese-catalysed Negishi cross-coupling