Experimental and Computational Investigations into the Benzyl-Claisen Rearrangement Jed M. Burns B.Sc. (Hons I) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 School of Chemistry and Molecular Biosciences i Abstract Being a prime example of a [3,3]-sigmatropic process, the Claisen rearrangement is an essential reaction at the core of modern organic chemistry. Its undisputed value is derived not only from its reliable and predictable application to the synthesis of complex molecules but, also, in being a reaction of longstanding interest in the field of computational organic chemistry, contributing to our theoretical understanding of pericyclic reactions. A long-standing shortcoming of the Claisen rearrangement is that while allyl-vinyl and allyl-phenyl ethers are viable substrates for the reaction, applications to benzyl-vinyl ethers have rarely been reported. To date, a very limited number of benzylic substrates have been investigated, with the few successful reactions typically requiring harsh conditions. Herein, we report the optimisation of a procedure for Claisen rearrangements of benzyl- vinyl ethers (referred to here as the “Benzyl-Claisen” rearrangement) based on a previous literature procedure and, for the first time, investigate the scope of such a process. Benzyl ketene acetals were generated in a short two-step procedure by bromoacetalisation of the requisite benzyl alcohol followed by elimination of HBr. Heating the ketene acetals in refluxing DMF smoothly converted the substrates to the product tolylacetates, which were saponified and isolated as their carboxylic acid derivatives. In the course of the reaction optimisation, a pronounced solvent effect was observed: DMF led to the [3,3]-rearranged product, whereas conducting the reaction in xylene led to a mixture of radical dissociation-recombination products. Electron-donating and electron-neutral substituents (–Me, –Ph, –Cl, –Br, –OMe and –SMe) gave the highest yields in the Benzyl-Claisen rearrangement (24–50%) whereas substrates derived from electron-poor aromatic systems (–NO2, – CN, –COOBn, –SO2Me or –CF3) tended to decompose under the reaction conditions. Claisen rearrangements conducted on meta-substituted systems were observed, unexpectedly, to preferentially generate products via rearrangement “towards” the meta substituent, leading to sterically crowded 1,2,3-trisubstituted tolylacetates. By analogy to the aromatic Claisen rearrangement, it was expected that the Benzyl-Claisen rearrangement should proceed through a dearomatised isotoluene intermediate. A benzyl ketene acetal possessing a terminal alkene was observed to form a ring-closed product via a facile Alder- ene reaction when submitted to the standard reaction conditions. This supports the formation of a dearomatised isotoluene intermediate along the reaction pathway and therefore the operation of the [3,3]-sigmatropic rearrangement. ii The mechanism of the Benzyl-Claisen rearrangement was investigated using computational methods. The activation free energy for rearrangement of benzyl vinyl ether calculated with the high-accuracy CBS-QB3 method was 40.1 kcal/mol, which is 10.2 kcal/mol higher than that of the aliphatic Claisen rearrangement of allyl vinyl ether at the same level of theory. The C-2 alkoxy substituent on the ketene acetal was shown to be essential in making the process both thermodynamically and kinetically favourable, lowering the barrier by 10.2 kcal/mol and stabilising the intermediate isotoluene by 18.0 kcal/mol. As a general rule, substitution of the aromatic systems with an electron-donor group was calculated to lower the barrier for the reaction whilst electron- withdrawing substituents were calculated to raise it. The para-OMe substituent was calculated to lower the activation free energy by 1.4 kcal/mol whereas the para-CN substituent raised the barrier by 0.9 kcal/mol. The regiochemical preference for rearrangement “towards” existing meta- substituents was confirmed in silico with 1,2,3-substituted product being favoured by 0.7 kcal/mol for the cyano substituent and 0.6 kcal/mol for the methoxy substituent. The results were rationalised as being due to the interaction of the frontier molecular orbitals of the system, with the preferred site on the aromatic ring possessing larger orbital coefficients. The computational results support the operation of a [3,3]-sigmatropic process and provide direction for the further development of the Benzyl-Claisen rearrangement. iii Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. Publications during candidature No publications. Publications included in this thesis No publications included. Contributions by others to the thesis Dr Ross McGeary and Dr Elizabeth Krenske have both had significant input into the conception and design of the project, as well as editing of the thesis iv Statement of parts of the thesis submitted to qualify for the award of another degree None. v Acknowledgements Firstly, I would like to thank Dr Ross McGeary for being my supervisor over the course of the PhD. For the ideas, helpful conversations and endless support, thank you. Synthetic methodology is my dream, and for the past 3 years I have been able to wake up every day and do what I love. I appreciate that at times I’ve been given an enviable degree of freedom in choosing the direction of my research (more than enough rope to hang myself) and for that I am truly grateful. To my second supervisor, Dr Elizabeth Krenske, thank you for introducing me to the strange and magical world that is computational chemistry. Chemistry, for me, has always been about trying to uncover “the rules” that govern the dim and murky realm of atoms and molecules. The knowledge you have given me (over many patient hours, thoroughly complicated by my confusion) means that that other-world is now in sharper relief. I have you to blame for the “superpower” that is the ability to do chemistry at 1 o’clock in the morning. I would also like to thank all the people in the SCMB who have made up the colourful fabric of our research community. My fellow group members for the short witticisms and long conversations (and free food!). Dr Tri Le and Graham MacFarlane for help with characterisation data, which was totally superfluous to the news and gossip I could catch up on. The tutors, staff and students on level 5 who allowed me to take a holiday, once a week, to teach. The other honours and PhD students for the opportunities to shoot the breeze, complain bitterly about the state of the art and, of course, drink coffee (or beer). Finally, to my family (Ma and Jess), and my beautiful soon-to-be wife Raichelle, thank you so much for providing me with the love and support that I needed throughout my PhD experience. I know deep in my heart that without the comfort, conversation and care that you offer I wouldn’t have made it. This thesis is for you. I love you all. P.S. To my dear colour-blind readers, I apologise in advance for the HSQC/HMBC spectra present in the experimental section and the free energy and HOMO/LUMO diagrams present in the computational section. Unfortunately, there are only a limited number of pigments which work on white backgrounds. vi Keywords Claisen rearrangement, Benzyl-Claisen, ketene acetal, computational chemistry, density functional theory Australian and New Zealand Standard Research Classifications (ANZSRC) ANZSRC code: 030503, Organic Chemical Synthesis, 70% ANZSRC code: 030701, Quantum Chemistry, 30% Fields of Research (FoR) Classification FoR code: 0305, Organic Chemistry, 70% FoR code: 0307, Theoretical and Computational Chemistry, 30% vii Table of Contents Abstract ..................................................................................................................................... ii Declaration by author ................................................................................................................iv Publications during candidature ................................................................................................iv