Water-Soluble Rotaxanes: Identifying Suitable Building Blocks for Molecular Daisy Chains Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Sylvie Carolin Drayss-Orth aus Lorsch, Deutschland Basel, 2016 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Marcel Mayor Prof. Dr. Thomas R. Ward Basel, den 20. September 2016 Prof. Dr. Jörg Schibler Dekan Die Naturforschung lehrt uns die Geschichte der Allmacht, der unergründlichen Weisheit eines unendlich höheren Wesens in seinen Werken und Taten erkennen; unbekannt mit dieser Geschichte kann die Vervollkommung des menschlichen Geistes nicht gedacht werden, ohne sie gelangt seine unsterbliche Seele nicht zum Bewusstsein ihrer Würde und des Ranges, den sie im Weltall einnimmt. Justus Freiherr von Liebig (1803 – 1873) Abstract Structurally diverse rotaxane-based systems have been investigated extensively for applications as molecular machines and functional nanomaterials. Although the vast majority of functional molecules were assembled and function in organic solvents, to date the most efficient and sophisticated molecular machines are biomolecules which function in aqueous media. Many vital processes, such as protein folding and assembly, rely on hydrophobic interactions and are only possible in aqueous environment. From a supramolecular chemistry perspective, the hydrophobic effect is an appealing driving force for host-guest association as it potentially leads to high complexation affinities and no extra binding sites need to be installed into the respective components. Appealing macrocyclic candidates for the preparation of mechanically interlocked molecules in aqueous media are the synthetically modifiable, water-soluble cyclophanes developed and comprehensively studied by Diederich et al.. The focus of this doctoral thesis was to identify suitable guest molecules for Diederich-type cyclophanes, allowing for the assembly of rotaxanes and also molecular daisy chains. The first part of the thesis describes the investigation of the aggregation behavior of amphiphiles based on OPE guests which are potentially capable of forming molecular daisy chains (Chapter 2). A deeper insight into the system was obtained through a series of rotaxane model compounds, basically relying on the main components of the previously examined amphiphiles (Chapter 3). The investigation of an extended scope of potential guest molecules via 1H NMR complexation studies resulted in an optimization of the molecular guest design and revealed some important features of suitable candidates (Chapter 4). Based on these results a water-soluble 2,6-disubstituted naphthalene derivative was found to function as (pseudo)rotaxane axle and enabled the isolation and characterization of a [2]rotaxane (Chapter 5). The results obtained throughout this doctoral thesis allow to obtain guidelines for the successful preparation of interlocked molecular daisy chains. Chapter 1 provides a general introduction to mechanically interlocked molecules and explains basic conceptual and synthetic principles of rotaxanes and molecular daisy chains by means of introducing the most common recognition motifs, classified by different types of macrocycles, in particular Diederich-type cyclophanes. Chapter 2 describes the design, synthesis and aggregation studies of a series of amphiphilic molecules potentially capable of assembling to molecular daisy chains and to function as nanoscale potentiometer. Furthermore, the chapter contains MCBJ conductance measurements of a thiol-terminated amphiphile and attempts to obtain mechanically interlocked aggregates by reaction with bulky stopper molecules. Chapter 3 describes the design, synthesis and investigation of the threading behavior of different monostoppered OPE molecules in presence of Diederich cyclophanes via rotaxanation as well as 1H NMR-based complexation studies. Chapter 4 describes the design, synthesis and 1H NMR spectroscopy-based complexation studies of a series of potential guest molecules for mechanically interlocked molecules, comprising different solubilizing functionalities. Chapter 5 describes the assembly, isolation and characterization of a water-soluble rotaxane comprising a 2,6-disubsituted naphthalene axle moiety. Furthermore, a series of naphthalene axle derivatives, differing in their length of solubilizing oligoethylene glycol chains, were investigated in their propensity to react to rotaxanes by applying a modular proof-of-principle analysis strategy. Chapter 6 gives a summary of the obtained results of this thesis and provides on outlook. Chapter 7 provides the experimental details, including the characterization of all compounds described throughout the thesis. Table of Contents 1 Introduction .......................................................................................................................................... 1 1.1 Mechanically Interlocked Molecules ............................................................................................. 1 1.2 Rotaxanes and Molecular Daisy Chains ......................................................................................... 3 1.2.1 Molecular Daisy Chains .......................................................................................................... 3 1.2.2 General Approaches to the Construction of Rotaxanes and Molecular Daisy Chains ........... 5 1.3 Recognition Motifs in Rotaxanes and Molecular Daisy Chains ..................................................... 7 1.3.1 Crown Ether ............................................................................................................................ 8 1.3.2 Cyclodextrins ........................................................................................................................ 15 1.3.3 Cucurbiturils ......................................................................................................................... 19 1.3.4 Pillar[ n]arenes ...................................................................................................................... 21 1.3.5 Calix[ n]arene ........................................................................................................................ 25 1.3.6 Tetralactam based Macrocycles ........................................................................................... 28 1.3.7 Metal-ligand based Macrocycles .......................................................................................... 31 1.3. 8 Tetracationic Cyclophanes ................................................................................................... 34 1.3.9 Diederich Cyclophanes ......................................................................................................... 37 2 Towards Molecular [c2]Daisy Chains as Functional Materials ........................................................... 45 2.1 General Molecular Design of Amphiphiles 91-95 ........................................................................ 46 2.2 General Synthetic Approach for Amphiphiles 91-95 ................................................................... 47 2.3 General Approach for the Aggregation Studies .......................................................................... 49 2.3.1 1H NMR Dilution Studies ....................................................................................................... 49 2.3.2 DOSY Analysis ....................................................................................................................... 51 2.3.3 Fluorescence Spectroscopy .................................................................................................. 52 2.4 Synthesis and Aggregation Studies of Hydroxyl-substituted Amphiphile 92 .............................. 53 2.4.1 Synthesis of Monomer 92 .................................................................................................... 53 2.4.2 1H NMR Dilution Studies ....................................................................................................... 55 2.4.3 DOSY Analysis ....................................................................................................................... 57 2.4.4 Fluorescence Spectroscopy .................................................................................................. 58 2.5 Synthesis and Aggregation Studies of Acetylene-substituted Amphiphile 93 ............................ 59 2.5.1 Synthesis of Monomer 93 .................................................................................................... 59 2.5.2 1H NMR Dilution Studies ....................................................................................................... 60 2.5.3 DOSY Analysis ....................................................................................................................... 62 2.5.4 Fluorescence Spectroscopy .................................................................................................. 62 2.6 Synthesis and Aggregation Studies of Anthracene-substituted Amphiphile 94 ......................... 63 2.6.1 Synthesis of Monomer 94 .................................................................................................... 63 2.6.2 1H NMR Dilution Studies ......................................................................................................