Cyclodextrin-Based Rotaxanes for Material Science Applications A thesis submitted for admission to the degree of Doctor of Philosophy By Hwi Young Lee Australian INcUIUMcll University Research School of Chemistry Canberra, Australia April, 2014 Author’s Statement This is to declare that the work in this thesis represents original work that I have undertaken during my PhD degree at the Research School of Chemistry, the Australian National University from 2010 to 2014, except the synthesis and X-ray crystal analysis of the compounds 4.1 and 4.2, and the synthesis of compounds 4.4 and 4.5, which was carried out as part of my PhB Honours degree. To my best of knowledge, the thesis does not contain material that has been published or written by another person or accepted for the award of any other degree of diploma in any other university or tertiary institution, unless due reference has been made in the text. I give consent to this copy of my thesis, when deposited in the University library, being available for loan or photocopying. April 2014 l Acknowledgements I would like to express my most sincere gratitude to my supervisor, Prof. Christopher J. Easton. This work would not have been possible without his guidance, patience and understanding. I appreciate the time and energy you put into students' academic excellence and personal welfare. I am also grateful that you have never stopped providing me with challenges and inspiration. I am extremely grateful to Dr Hideki Onagi for introducing me to cyclodextrin chemistry. I appreciate your willingness to sacrifice your lunch breaks, late evenings and even weekends to share your expertise. 1 am fortunate to have gone through this journey with two very talented chemists, Shenglin and Kaheng. I feel that we make a great team and have learnt from each other throughout our PhDs. Your thoughts and suggestions are greatly appreciated and I have enjoyed attending conferences and traveling with you. I wish to thank Roger for getting me interested in cyclodextrin chemistry and Daniel for his technical support and friendship. I also wish to thank the past and present members of the Easton group, especially Ryan, Suba, Karen, Allan, Nicole, Hye- Kyung, Amy, Melissa, Dan, Alex, Zac, Karine, Mantas, Sue and Carol. Many thanks to Hideki, Ryan, Kaheng, Jeff, Jim, Melissa and Shenglin for being great office mates. I would like to acknowledge Dr Chris Blake for training and assistance with NMR spectroscopy, Dr Anthony C. Willis and Dr Rowan Young for collecting X-ray crystal data, Prof. Peter J. Steel for solving the crystal structures, Dr Frank Brink and Dr Hua Chen for training and assistance with SEM and Prof. Steven E. Bottle for valuable discussions. Special thanks to my friends Lisa, Gordon, Ben, Stef, Sangeeta and Vivek for making Canberra my second home. Your friendship means the world to me. Finally, I wish to thank my family for their unconditional love and support. Presentations LEE, H-Y.; Onagi, H.; Maniam, S.; Cieslinski, M. M.; Steel, P. J.; Lincoln, S. F.; Easton, C. J. ‘Crystal Engineering with Cyclodextrin Based Rotaxanes for Material Science Applications.’ • Poster presentation. 16'h International Cyclodextrin Symposium (ICS 16). May 2012. Tianjin, China. • Oral presentation. Gordon Research Conference on Physical Organic Chemistry (GRC). June 2011. New Hampshire, America. • Poster presentation. Gordon Research Conference on Physical Organic Chemistry (GRC). June 2011. New Hampshire, America. • Poster presentation. 6,h International Symposium on Macrocyclic and Supramolecular Chemistry (ISMSC). July 2011. Brighton, England. • Oral presentation. 6,h Asian Cyclodextrin Conference (ACC2011). Aug 2011. Canberra, Australia. LEE, H-Y.; Maniam, S.; Fairfull-Smith, K. E.; Bottle, S. E.; Easton, C. J. ‘Photostable Stilbenylnitroxide Rotaxanes’ • Poster presentation. Free Radical Carnival. Nov 2011. Wollongong, Australia. • Poster presentation. Free Radical Carnival. Oct 2011. Sydney, Australia. LEE, H-Y.; Onagi, H.; Maniam, S.; Noren, L.; Sterns, M.; Willis, T.; Steel, P. J.; Lincoln, S. F.; Easton, C. J. ‘Cyclodextrin Based Rotaxane Crystals, Amorphous Solids and Lyotropic Liquid Crystals in Aqueous Solution’ • Poster presentation. 15lh International Cyclodextrin Symposium (ICS 15). May 2010. Vienna, Austria. Abstract In the work described in this thesis, CD-based rotaxanes were prepared and their solid-state structures/packing, morphology and crystal growth behaviour were explored. Encapsulation o f profluorescent nitroxides through rotaxane formation demonstrated the use o f CD-based rotaxanes to change the reactivity o f CD guests and therefore preserve their properties. In Chapter 2, the rotaxane 1.17 having a stilbene-based axle and 3,5-dimethylaniline blocking groups, as well as the rotaxane 1.18 having an azobenzene-based axle and 2,6-dimethylaniline blocking groups were prepared to complete the set o f rotaxanes 1.9, 1.10, 1.17 and 1.18 with 2,6-dimethylaniline and 3,5-dimethylaniline blocking groups, with azobenzene- and stilbene-based axles. Chapter 3 describes the solid-state structures/packing, morphology and crystal growth o f the set o f rotaxanes 1.9, 1.10, 1.17 and 1.18. Observation o f crystal morphology using SEM and microscope images, suggests not only that crystal shape and size can be controlled depending on the choice o f blocking groups and varying the conditions of crystal growth, but also that crystal packing is reflected in the crystal growth and the final shape o f the crystals. Thus, crystal engineering can be bottomed-up to make nano-molecular architecture to micrometre scale or beyond. In Chapter 4, the unsymmetrically capped rotaxanes 4.1 and 4.2 were purposely designed and prepared using a crystal engineering approach such that they can be used to regulate the crystal growth o f the self-assembling rotaxane 1.9 through co- crystallisation. 2D NMR spectroscopy was used to determine the orientation o f the CDs with respect to the dumbbells and assign the structures o f the rotaxane isomers 4.1 and 4.2. Co-crystallisation experiments showed that the rotaxanes 4.1 and 4.2 act as crystal growth inhibitors o f the rotaxane 1.9. In addition, a method to prepare supersaturated solutions from a mixture o f amorphous and crystalline rotaxane was developed for crystal growth studies. The unsymmetrically capped rotaxane 5.5 with 3,5-dimethylaniline and trinitrophenyl blocking groups on either end that can form jt- ji interactions was prepared in Chapter 5. Co-crystallisation experiments with the rotaxanes 1.9 and 5.5 illustrate that blocking groups of rotaxanes can be used as synthons to guide intermolecular self- assembly to regulate the formation of fibrous structures. Therefore crystal engineering using CD-based rotaxanes is a versatile approach towards regulating self-assembly and understanding molecular level interactions in the solid-state. These interactions may be used to fine-tune physical, chemical, photochemical or electrical properties of the end product that is fabricated through a bottom-up approach. New paramagnetic profluorescent nitroxides, the rotaxanes 1.33, 1.35 and 1.36, as well as the previously reported rotaxane 1.34 were prepared and their photoisomerisation and decomposition behaviour in comparison to the corresponding dumbbells 1.37 and 1.38 were examined in Chapters 6 and 7. UV/visible spectroscopy and HPLC analysis illustrated that the profluorescent probes of the dumbbells 1.37 and 1.38 were preserved through formation of the CD-rotaxanes 1.33, 1.34, 1.35 and 1.36 making them advantageous for fluorescence detection. Glossary Ä angstrom Abs. absorbance ACN acetonitrile AU arbitary units Azo azobenzene BOP benzotiazol-1 -y loxy-tris(dimethylamino)phosphonium hexafluorophosphate (Castro's reagent) Br broad °C degrees Celcius CD cyclodextrin CDCI3 deuterated chloroform CD2C12 deuterated dichloromethane CD30D deuterated methanol CD-CX-H cyclodextrin protons, X=l-6 cm centimetre DCM dichloromethane dec. decomposition DMF N, N ’-dimethylformamide DMSO dimethylsulfoxide DMT-MM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride DQF-COSY double quantum filter correlation spectroscopy EI electron impact EPR electron paramagnetic resonance equiv. equivalence ESI electrospray ionisation et al. et alia Et20 diethyl either EtOAc ethyl acetate g gram h hour(s) HPLC high performance liquid chromatography HR high resolution H z hertz J coupling constant (Hz) lit. literature LR low resolution M moles per litre M +' molecular ion MALDI matrix assisted laser desorption ionisation M e m ethyl MeOH methanol m in m inute(s) m m m ilim etre m/z mass-to-charge ratio nm nanom etre NMR nuclear magnetic resonance NOE nuclear Overhauser effect ppm parts per million Rf retention factor ROESY rotating-frame Overhauser effect spectroscopy SEM scanning electron microscope STM scanning tunneling microscope TEA triethylamine TEM transmission electron microscope TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TOF time of flight tR retention time t-BuOH tertiary butanol UV ultraviolet V volum e b chemical shift (ppm) ^>ma\ wavelength absorption maximum CONTENTS Author’s Statement i Acknowledgments ii Presentations iii Abstract iv Glossary vi CHAPTER 1 - Introduction 1.1 Supramolecular Chemistry 1 1.2 Cyclodextrins 1 1.3 Rotaxanes 2 1.4 Cyclodextrin Based Rotaxanes 3 1.5 Crystal Engineering 10 1.6 Encapsulation Stability of 'Nitroxides 20 CHAPTER 2 - Results and Discussion Synthesis of a-Cyclodextrin [2]Rotaxanes with Aniline-based