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Cubane and Triptycene As Scaffolds in the Synthesis of Porphyrin Arrays

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Cubane and Triptycene As Scaffolds in the Synthesis of Porphyrin Arrays Cubane and Triptycene as Scaffolds in the Synthesis of Porphyrin Arrays Submitted by Gemma M. Locke B.A. (Mod.) Medicinal Chemistry Trinity College Dublin, Ireland A thesis submitted to the University of Dublin, Trinity College for the degree of Doctor of Philosophy Under the Supervision of Prof. Dr. Mathias O. Senge University of Dublin, Trinity College September 2020 Declaration I declare that this thesis has not been submitted as an exercise for a degree at this or any other university and it is entirely my own work. I agree to deposit this thesis in the University’s open access institutional repository or allow the Library to do so on my behalf, subject to Irish Copyright Legislation and Trinity College Library conditions of use and acknowledgement. I consent to the examiner retaining a copy of the thesis beyond the examining period, should they so wish. Furthermore, unpublished and/or published work of others, is duly acknowledged in the text wherever included. Signed: ____________________________________________ March 2020 Trinity College Dublin ii Summary The primary aim of this research was to synthesise multichromophoric arrays that are linked through rigid isolating units with the capacity to arrange the chromophores in a linear and fixed orientation. The electronically isolated multichromophoric systems could then ultimately be tested in electron transfer studies for their applicability as photosynthesis mimics. Initially, 1,4-diethynylcubane was employed as the rigid isolating scaffold and one to two porphyrins were reacted with it in order to obtain the coupled product(s). Pd-catalysed Sonogashira cross-coupling reactions were used to try and achieve these bisporphyrin complexes. After extensive optimisation attempts, of both copper and copper-free Sonogashira reaction conditions, the desired alkynylcubane-linked bisporphyrin was detected, but unfortunately not isolated. The instability of the alkynylcubane-linked systems prevented efficient purification and inhibited further reactions, and while the cubane porphyrin dimer was identified, its insolubility prevented further analysis. Overall, five new alkynylcubane-linked monoporphyrin compounds were synthesised, albeit in very low yields. 1,4-Bis(phenylethynyl)cubane was obtained suggesting that coupling with the large porphyrin systems may have been the issue rather than solely the instability of 1,4- diethynylcubane. Following on from the work with 1,4-diethynylcubane, 9,10-diethynyltriptycene was investigated for its uses as a rigid isolating unit. Initially, Sonogashira cross-coupling conditions that were developed from the previous work with cubane, were utilised with various porphyrins and boron dipyrromethenes (BODIPYs) and worked seamlessly. Although there are previous examples of triptycene porphyrin complexes, this was the first example of a linear porphyrin dimer that was connected to triptycene through the bridgehead carbons. Symmetric and unsymmetric examples of these complexes were obtained. The unsymmetric porphyrin dimer proved more difficult to access, owing to the unreliability of the Diels–Alder reaction of benzyne with 9-[(triisopropylsilane)ethynyl]-10- [(trimethylsilane)ethynyl]-anthracene to access the triptycene starting material. In a slightly different vein, a series of porphyrin-cubane/bicyclo[1.1.1]pentane-porphyrin arrays were synthesised via amide coupling reactions. The utilisation of semi-rigid amide bonds to attach the porphyrin skeletons to a rigid scaffold introduced a controlled conformational flexibility into porphyrin dyad/s. This allowed significant modulation of the photophysical properties in the porphyrin dyad/s through the coordination of transition metal(II) ions. These reversible photophysical changes suggest that the dimeric systems are acting like switchable porphyrin tweezers. The (1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium iii 3-oxid hexafluorophosphate) (HATU) amide coupling procedure employed was robust and versatile, allowing access to the very first porphyrin-cubane/ bicyclo[1.1.1]pentane- porphyrin arrays, representing the largest non-polymeric structures available for cubane/bicyclo[1.1.1]pentane derivatives. These reactions demonstrated considerable substrate scope, from utilisation of small phenyl moieties to large porphyrin rings, with varying lengths and different angles. Depending on the orientation of the substituents around the amide bond of the cubane/bicyclo[1.1.1]pentane units different intermolecular interactions were identified through single crystal X-ray analysis. Moreover, X-ray structural analysis revealed non-covalent interactions that are the first-of-their-kind, including a unique iodine-oxygen interaction between cubane molecules. Lastly on a different note, a cationic dimer with a phenylene linker and an anionic porphyrin dimer with a conjugated butadiene linker were synthesised. The central aim of this work was to introduce water-soluble moieties into porphyrin dimers as there are very limited examples in the literature of porphyrin dimers with application in photodynamic therapy. It was hoped that by introducing cation/anionic moieties to a dimer that these water-soluble moieties would allow it to be suitable for biological application. The porphyrin dimer was successfully obtained, but tests to see its efficiency as a photodynamic therapy agent are still underway. iv Publications G. M. Locke, M. O. Senge, “Towards Electron Transfer Compounds with Rigid Resistor Units” ECS Trans. 2016, 16, 1–11. doi:10.1149/07216.0001ecst S. S. R. Bernhard, G. M. Locke, S. Plunkett, A. Meindl, K. J. Flanagan, M. O. Senge, “Cubane Cross-Coupling and Cubane-Porphyrin Arrays” Chem. Eur. J. 2018, 24, 1026– 1030. doi:10.1002/chem.201704344 Front Cover: Cubane Cross‐Coupling and Cubane– Porphyrin Arrays (Chem. Eur. J. 2018, 24, 997). doi:10.1002/chem.201705227 Invited review: G. M. Locke, S. S. R. Bernhard, M. O. Senge, “Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry” Chem. Eur. J. 2019, 25, 4590–4647. doi:10.1002/chem.201804225 N. Grover‡, G. M. Locke‡, K. J. Flanagan, M. H. R. Beh, A. Thompson, M. O. Senge, “Bridging and Conformational Control of Porphyrin Units through Non-Traditional Rigid Scaffolds” submitted for publication. Conference Abstracts G. M. Locke, M. Roucan, S.Plunkett, M. O. Senge. “Functionalisation of cubane scaffolds- Towards the use of cubane as a rigid linker in energy transfer compounds” in the Centre for Synthesis and Chemical Biology (CSCB) Recent Advances in Synthesis and Chemical Biology XVI, (04.12.15), Dublin, Ireland. This poster won one of three prizes for the best poster award. G. M. Locke, S. S. R. Bernhard, S. Plunkett and M. O. Senge “Advances in the Functionalisation of Cubane, for Use as a Scaffold in the Synthesis of Multiporphyrin Arrays” in the Tetrapyrrole Discussion Group Meeting (21.03.16–22.03.16), Liverpool John Moores University, Liverpool, England. Abstract book page 17. v G. M. Locke, S. S. R. Bernhard, S. Plunkett and M. O. Senge “Advances in the Functionalisation of Cubane, for Use as a Scaffold in the Synthesis of Multiporphyrin Arrays” in the ORCHEM 2016 conference (05.09.16–07.09.16), Weimar, Germany. Abstract-ID: 6243_15208. G. M. Locke, S. S. R. Bernhard, S. Plunkett and M. O. Senge “Advances in the Functionalisation of Cubane, for Use as a Scaffold in the Synthesis of Multiporphyrin Arrays” in the CSCB conference (09.12.16) Trinity College Dublin, Dublin, Ireland. Abstract P023. G. M. Locke, S. S. R. Bernhard, S. Plunkett, K. J. Flanagan and M. O. Senge “The Synthesis of Multiporphyrin Arrays with non-Heteroatom Linkers” in the GDCh Scientific Forum Chemistry 2017 (10.09.17–14.09.17), Berlin, Germany. Abstract-ID: 7210-14218. G. M. Locke, S. S. R. Bernhard and M. O. Senge, “Rolling the Die for Dyes” in 16th Belgian Organic Synthesis Symposium, (08.07.18–13.07.18), Brussels, Belgium, Abstract book P152. G. M. Locke, A. F. Syeda and M. O. Senge, “Triptycene and its use as a scaffold in the synthesis of multiporphyrin arrays” in Centre for Synthesis and Chemical Biology (CSCB) Recent Advances in Synthesis and Chemical Biology XVI, (07.12.18), Dublin, Ireland. vi Acknowledgements First of all, I would like to thank Prof. Dr. Mathias O. Senge for giving me the opportunity to pursue this research and offering me a position in his research group. Also for his encouragement, belief in my capabilities and supervision which encourages self-thought and the constant pursuit of new knowledge. I would also like to thank the Irish Research Council for their funding support. A big thank you goes out to my valued colleagues Alina, Bhavya, Elisabeth, Harry, Ganapathi, Jess, Karolis, Keith, Marc, Marie, Mikhail, Nitika, Stefan, Susan, Piotr and Zoi who helped make our workplace a safe, fun and encouraging environment. A place where laughter was a part of everyday life and there was never a shortage of advice or people who wanted a coffee break. All the brave international souls must also be noted who were always up for an after work swim in the Irish sea, sometimes regardless of the weather. I want to additionally thank Keith for his X-ray crystallography work, Ganapathi and Alina for supplying some of the starting materials for my work and for everyone’s help proof-reading this thesis. I especially want to thank our two brilliant post-Docs Dr. Stefan Bernard and Dr. Nitika Grover (the referencing Queen) for their unwavering patience and consistent help in all things chemistry and for being a part of team cubane/BCP. I am also indebted to Dr. Gary Hessman, Dr. Martin Feeney, Dr. John O’Brien and Dr. Manuel Rüther for their help in analytical questions and I would like to express my gratitude to everyone working behind the curtains at Trinity College Dublin. Finally, I want to thank my family and friends, who have listened to my failures, cheered me up when I was down, consistently prayed for me and my chemistry and celebrated with me in my successes. I want to thank God who is my constant strength and encouragement, who gave me hope at times when I could have despaired and who has taught me what “His mercies are new every morning” truly means over the past four years.
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