Responsive Molecular Systems through Dynamic Covalent Chemistry Antanas Karalius Doctoral Thesis LIC OR DOC Thesis Stockholm 2020 Stockholm year Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 21 februari kl 14.30 i sal F3, KTH, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är Professor Stefan Matile, Université de Genève (UNIGE), Schweiz. I ISBN 978-91-7873-435-1 ISSN 1654-1081 TRITA-CBH-FOU-2020:9 © Antanas Karalius, 2020 Universitetsservice US AB, Stockholm II Tėčiui III Antanas Karalius, 2020: “Responsive Molecular Systems through Dynamic Covalent Chemistry”, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH – Royal Institute of Technology, SE-100 44 Stockholm, Sweden. Abstract Nature tends to inspire research in chemistry. Systems that emerge from molecules interacting via reaction networks is something that life has mastered over the course of evolution in order to produce complexity. Dynamic reactions are key in systems chemistry, where reaction networks give rise to complex, emergent behavior. This thesis aims to harness a special feature of selected dynamic reaction systems – responsiveness. The first chapter of this thesis introduces dynamic covalent chemistry and a general approach to create simple reaction networks by connecting dynamic covalent reactions. Concepts in systems chemistry are introduced in terms of network topology, responsiveness and non-equilibrium processes, while drawing parallels to natural systems. The second chapter explores the potential of the nitroaldol reaction for dynamic systems. Nitroaldol reactions are demonstrated for dynamic polymerization as well as formaldehyde-responsive breakdown of dynamic polymers. The simultaneous formation and breakdown of polymers create emergent non- equilibrium behavior. Furthermore, nitroaldol produced-diols are used in boronate ester formation. This reactivity produces interdependence over two reactions. Combining nitroaldol and boronate building blocks enabled boronate dynamers of different topology. The third chapter explores metal coordination effects in dynamic reaction networks. Novel base-free nitroaldol reactivity is exploited in reaction networks with hemiacetals. A systemic response to metals is demonstrated by hemiacetal- metal coordination. In the second half of the chapter, a biomimetic dynamic imine complex is shown to produce emergent, π-π-interactions resembling a “draw-bridge”. Variation of metal charge, effective electrostatic character of substituent and ligands gives control over the system and its emergent π-π- interactions. Keywords: stimuli-responsiveness, dynamic covalent reactions, systems chemistry, constitutional dynamics, non-equilibrium systems, nitroaldol reaction, dynamers, reversible polymerization, boronate ester, imine ligand, metal coordination, self–assembly, emergent properties, network topology. IV Sammanfattning på svenska Naturen tenderar att inspirera forskning inom kemi. System uppkommer från molekyler som interagerar i reaktionsnätverk, något som levande system genom hundratusentals år av evolution har utnyttjat för att producera ständigt växande komplexitet. Dynamiska reaktioner är en nyckelkomponent i systemkemi, där reaktionsnätverk ger upphov till komplexa, emergenta beteenden. Denna avhandling syftar till att utnyttja en speciell egenskap hos dynamiska reaktionssystem - responsivitet. Det första kapitlet i denna avhandling introducerar dynamisk kovalent kemi och en allmän metod för att skapa enkla reaktionsnätverk genom att sammankoppla olika dynamiska kovalenta reaktioner. Begrepp inom systemkemi introduceras i termer av nätverkstopologi, responsivitet och reaktionssystem långt ifrån jämvikt, samtidigt som paralleller dras till naturliga system. Det andra kapitlet undersöker potentialen för nitroaldolreaktioner för dynamiska system. Nitroaldol-reaktioner används här för dynamisk polymerisation såväl som formaldehyd-responsiv nedbrytning av dynamiska polymerer. Simultan bildning och nedbrytning av polymer skapar ett emergent icke- jämviktsbeteende. Vidare används nitroaldol-producerade dioler i boronatesterbildning. Denna reaktivitet skapar en sammankoppling av två reaktioner som därmed influerar varandra. Genom att kombinera nitroaldol- och boronat-system öppnas möjligheterna att skapa boronatdynamerer av olika topologi. Det tredje kapitlet utforskar metallkoordinationseffekter i dynamiska reaktionsnätverk. Den nya basfria nitroaldolreaktionen beskriven i kapitel två utnyttjas här i ett reaktionsnätverk med hemiacetaler. Ett systemiskt svar på addition av metaller uppkommer således genom hemiacetal-metall- koordination. Under andra hälften av kapitlet demonstreras ett naturinspirerat dynamiskt iminkomplex som ger emergenta π-π-interaktioner som liknar en så kallad ”klaff-bro”. Variation av metallernas laddning samt den effektiva elektrostatiska karaktären hos substitutuenterna och liganderna ger kontroll över systemet och dess emergenta π-π-interaktioner. Nyckelord: stimuli-responsivitet, dynamiska kovalenta reaktioner, systemkemi, konstitutionell dynamik, icke-jämviktssystem, nitroaldolreaktion, dynamerer, reversibel polymerisation, boronester, iminligand, metallkoordination, själv- organisation, emergenta egenskaper, nätverkstopologi. V Abbreviations d Day d Deuterated Da Dalton DCC N,N′-Dicyclohexylcarbodiimide DFT Density Functional Theory DMSO Dimethyl Sulfoxide DNA Deoxyribonucleic Acid DOSY Diffusion Ordered Spectroscopy EDG Electron-Donating Group equiv. Equivalent Et Ethyl EWG Electron-Withdrawing Group EXSY Exchange Spectroscopy Gb Giga-Base Pairs h Hours kb Kilo-Base Pairs MALDI-TOF Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry MeOD Deuterated Methanol min Minute(s) NMR Nuclear Magnetic Resonance NOE Nuclear Overhauser Effect NOESY Nuclear Overhauser Effect Spectroscopy ppm Parts Per Million RNA Ribonucleic Acid TEA Triethylamine THF Tetrahydrofuran VI List of Publications This thesis is based on the following papers, referred to in the text by their Roman numerals I–IV: I. Formation and Out-of-Equilibrium, High/Low State Switching of a Nitroaldol Dynamer in Neutral Aqueous Media Karalius, A., Zhang, Y., Kravchenko, O., Elofsson, U., Szabó, Z., Yan, M. and Ramström, O. Angew. Chem. Int. Ed., 2020, DOI:10.1002/anie.201911706 II. Rapidly Exchanging, Double-Dynamic, Catalyst-Free Nitroaldol-Hemiacetal Systems for Metal-Responsive Reversible Polymerization Karalius, A., Kravchenko, O., Elofsson, U., Szabó, Z., Yan, M. and Ramström, O. Manuscript III. Control Over Emergent π-π-Interactions in Double-Dynamic Coordination Complexes Through a Nature-Inspired Coordination-Triggered System Karalius A., Grape, E. S., Inge, K., Kravchenko, O., Szabó, Z., Yan, M. and Ramström, O. Manuscript IV. Interdependent, Dynamic Nitroaldol and Stereoselective Boronic Ester Reactions for Complex Dynamers of Different Topologies Karalius A., Szabó, Z. and Ramström, O. Manuscript VII Table of Contents Abstract.................................................................................................. IV Sammanfattning på svenska .................................................................. V Abbreviations ......................................................................................... VI List of Publications ................................................................................ VII Table of Contents ................................................................................. VIII 1. Introduction .................................................................................. 1 1.1 Dynamic chemistry ............................................................................. 2 1.2 Systems chemistry .............................................................................. 7 1.3 Dynamic-kinetic coupled systems ....................................................... 8 1.4 Multi-dynamic covalent systems ......................................................... 9 1.5 Dynamic covalent polymers ................................................................ 9 1.6 Stimuli-responsiveness of dynamic covalent systems ...................... 17 1.7 Non-equilibrium systems .................................................................. 22 1.8 The aim of this thesis ........................................................................ 23 2. Nitroaldol-coupled dynamic systems ......................................... 25 2.1 Introduction ....................................................................................... 25 2.2 Aqueous nitroaldol systems .............................................................. 27 2.3 Boronate-nitroaldol systems ............................................................. 36 3. Metal coordination-coupled multi-dynamic systems .................. 43 3.1 Introduction ....................................................................................... 43 3.2 Metal coordination in nitroaldol-hemiacetal double dynamic system 44 3.3 Metal coordination-triggered emergence of π-π interactions ............ 55 4. Concluding remarks ................................................................... 67 Acknowledgements .............................................................................. 69 Appendix ............................................................................................... 71 References