Science, Faculty of
Chemistry, Department of
DSpace
UBCV
Le, Debbie
Master of Science - MSc
University of British Columbia
Motivated by the pursuit of shape-persistent macrocycles that could act as hosts for metal ions or clusters, we set out to construct arylene-ethynylene macrocycles with functionalized interiors. A step-wise synthesis using Sonogashira cross-coupling and deprotection reactions was used to make a series of arylene-ethynylene molecules. These compounds included a macrocycle with interior methoxy functional groups and trimers with methoxy or amine functionalities. These molecules were characterized using NMR spectroscopy as well as ESI-TOF mass spectrometry. The synthesis of these molecules provides the groundwork for the development of new aryleneethynylene based receptors to be used in host-guest chemistry.
Towards arylene-ethynylene based supramolecular hosts by Debbie Le B.Sc., Simon Fraser University, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2019 © Debbie Le, 2019 ii Abstract Motivated by the pursuit of shape-persistent macrocycles that could act as hosts for metal ions or clusters, we set out to construct arylene-ethynylene macrocycles with functionalized interiors. A step-wise synthesis using Sonogashira cross-coupling and deprotection reactions was used to make a series of arylene-ethynylene molecules. These compounds included a macrocycle with interior methoxy functional groups and trimers with methoxy or amine functionalities. These molecules were characterized using NMR spectroscopy as well as ESI-TOF mass spectrometry. The synthesis of these molecules provides the groundwork for the development of new arylene-ethynylene based receptors to be used in host-guest chemistry. iii Lay Summary Nature relies on enzymes to facilitate important processes such as photosynthesis and cellular metabolism. Inspired by the many enzymes that contain both molecular and metallic subunits, we sought to design and produce chemical complexes with organic and inorganic components. Here, we describe the synthesis of new molecules that can be used to form structures with metal atoms. Such complexes may act as minimalist models of the many metal-containing proteins found in nature to provide insight into how these proteins or enzymes work. These compounds may also have valuable applications in improving the efficiency of chemical reactions that are already used in industry. iv Preface This dissertation is my original, unpublished work. I conducted all the experiments for this thesis and all my work was carried out under the guidance of my supervisor, Prof. Mark J. MacLachlan. v Table of Contents Abstract .......................................................................................................................................... ii Lay Summary ............................................................................................................................... iii Preface ........................................................................................................................................... iv Table of Contents ...........................................................................................................................v List of Figures .............................................................................................................................. vii List of Schemes ...............................................................................................................................x List of Symbols and Abbreviations ........................................................................................... xii Acknowledgements .................................................................................................................... xiv Chapter 1: Introduction ................................................................................................................1 1.1 Historical Context ........................................................................................................... 1 1.2 Supramolecular Chemistry.............................................................................................. 3 Self-Assembly ......................................................................................................................... 6 Host-Guest Chemistry ........................................................................................................... 10 1.3 Macrocyclic hosts ......................................................................................................... 13 Shape-Persistent Macrocycles .............................................................................................. 19 Schiff-Base Macrocycles ...................................................................................................... 23 Arylene-Ethynylene Macrocycles ......................................................................................... 25 Synthesis of Macrocycles ..................................................................................................... 28 1.4 Goals and Scope of this Thesis ..................................................................................... 31 Chapter 2: Synthesis of a Novel Arylene-Ethynylene Macrocycle ..........................................32 2.1 Introduction ................................................................................................................... 32 2.2 Results and Discussion ................................................................................................. 36 vi Initial Attempts with Phenol Derivatives .............................................................................. 37 Syntheses with Methoxybenzene Derivatives ...................................................................... 42 2.3 Conclusion .................................................................................................................... 49 2.4 Experimental ................................................................................................................. 50 Chapter 3: Functionalizing Arylene-Ethynylene Hosts............................................................61 3.1 Introduction ................................................................................................................... 61 3.2 Results and Discussion ................................................................................................. 62 Demethylation attempts ........................................................................................................ 62 Towards amine-functionalized macrocycles ......................................................................... 64 Amine protection .................................................................................................................. 68 Amine-functionalized crescent ............................................................................................. 71 3.3 Conclusion .................................................................................................................... 74 3.4 Experimental ................................................................................................................. 75 Chapter 4: Conclusion .................................................................................................................82 4.1 Overview ....................................................................................................................... 82 4.2 Significance of findings ................................................................................................ 82 4.3 Future directions ........................................................................................................... 83 Bibliography .................................................................................................................................86 vii List of Figures Figure 1.1 Complexation of sodium ion with dibenzo-[18]-crown-6 ............................................. 2 Figure 1.2 Relative strengths of intermolecular interactions .......................................................... 3 Figure 1.3 Intermolecular forces: (a) ion-ion interactions (b) van der Waals interaction caused by a transient dipole (c) ion-dipole interactions with directional alignment of dipole, (d) hydrogen bonding due to permanent dipoles, and (e) different orientations of π-π stacking interactions...... 5 Figure 1.4 Representative binding geometries of common transition metals ................................. 7 Figure 1.5 Self-assembly of a square structure using square planar metal ions and a rigid ligand 8 Figure 1.6 Hydrogen bonding of DNA base pairs and the DNA double helix ............................... 9 Figure 1.7 Protein folding from (a) primary structure to (b) secondary and (c) tertiary structure . 9 Figure 1.8 Schematic representation of the formation of a host-guest complex .......................... 10 Figure 1.9 Model of selectivity between hosts and guests............................................................ 12 Figure 1.10 Schematic representations of (a) a rotaxane and (b) a catenane ................................ 13 Figure 1.11 Examples of (a) a crown ether, (b) a cryptand, and (c) a spherand ........................... 15 Figure 1.12 (a) A simplified representation of the calixarene cone shape and (b) different conformers of calixarenes ............................................................................................................. 16 Figure 1.13 Example of (a) a pillararene and (b) a cucurbituril ................................................... 17 Figure 1.14 Structures and three-dimensional representations of α- β- and γ-cyclodextrin ......... 18 Figure 1.15 Some examples of shape-persistent macrocycles ...................................................... 20 Figure 1.16 Macrocycle with endo-annular (R1, blue), exo-annular (R2, red), and adaptable (R3, green) functional group positions ................................................................................................. 22 Figure 1.17 AEMs with ortho- meta- and para-connectivity (respectively) ................................ 28 viii Figure 1.18 Schematic of intramolecular cyclization of an oligomer (top) and intermolecular cyclization between two oligomers (bottom) ................................................................................ 29 Figure 1.19 Schematic of single-step self-assembly of building blocks into a macrocycle (top) and template-assisted self-assembly of a macrocycle followed by removal of template (bottom)....................................................................................................................................................... 29 Figure 2.1 Some examples of previously reported AEMs ............................................................ 33 Figure 2.2 Examples of host-guest complexes with AEMs .......................................................... 34 Figure 2.3 Target arylene-ethynylene macrocycle with interior functional groups, R ................. 35 Figure 2.4 Position of different functional groups on the starting monomers and target macrocycle .................................................................................................................................... 36 Figure 2.5 1H NMR spectra (300 MHz in CDCl3) of 4 (top), 2 (middle), and reaction product (bottom)......................................................................................................................................... 39 Figure 2.6 1H NMR spectra (300 MHz in CDCl3) of 7 (top), 5 (middle), and reaction product (bottom)......................................................................................................................................... 41 Figure 2.7 1H NMR spectra (300 MHz in CDCl3) of 10 (top), 8 (middle) and product 11 (bottom) with enlarged partial spectrum of the aromatic region of 11 ........................................................ 44 Figure 2.8 1H NMR spectra (300 MHz in CDCl3) of 12 (top), 11 (middle), and their reaction product (bottom) ........................................................................................................................... 46 Figure 2.9 1H NMR spectra (300 MHz in CDCl3) of compound 12 and macrocycle 13 with enlarged partial spectra of the aromatic regions ........................................................................... 48 Figure 3.1 1H NMR spectra (300 MHz in CDCl3) of 16 (top), 14 (middle), and 17 (bottom) ..... 66 Figure 3.2 1H NMR spectra (300 MHz in CDCl3) of diacetylated monomers 19 (top) and 18 (bottom)......................................................................................................................................... 70 ix Figure 3.3 1H NMR spectra (300 MHz in CDCl3) of 16 (top), 20 (middle) and trimer product 21 (bottom)......................................................................................................................................... 72 Figure 3.4 Amine-functionalized arylene-ethynylene molecules of varying shapes and sizes .... 74 Figure 4.1 Arylene-ethynylene groups that can be incorporated into ligand backbone by coupling reactions ........................................................................................................................................ 84 x List of Schemes Scheme 1-1 Pedersen's ligand synthesis with dibenzo-[18]-crown-6 as a side product ................. 1 Scheme 1-2 Schiff base condensation to form salen (top) and salphen (bottom) compounds ..... 23 Scheme 1-3 Schiff base condensation to produce [3+3] macrocycle ........................................... 24 Scheme 1-4 Staab’s initial synthesis of an AEM .......................................................................... 26 Scheme 1-5 Moore's step-wise AEM synthesis ............................................................................ 27 Scheme 2-1 Synthesis of phenol-derived monomers .................................................................... 37 Scheme 2-2 Attempted coupling of phenol-derived monomers ................................................... 38 Scheme 2-3 Synthesis of ester-capped monomers ........................................................................ 40 Scheme 2-4 Attempted coupling of ester-capped monomers ....................................................... 41 Scheme 2-5 Synthesis of methoxy-capped monomers ................................................................. 42 Scheme 2-6 Synthesis of methoxy-capped trimers ....................................................................... 43 Scheme 2-7 Attempted intermolecular coupling of methoxy-capped trimers .............................. 45 Scheme 2-8 Synthesis of macrocycle 13 via intermolecular coupling of methoxy-capped trimers....................................................................................................................................................... 47 Scheme 3-1 Attempted demethylation reactions with 11 and 13 ................................................. 63 Scheme 3-2 Synthesis of aniline-derived monomers .................................................................... 65 Scheme 3-3 Synthesis of amine-functionalized trimer ................................................................. 66 Scheme 3-4 Attempted intermolecular coupling of amine-functionalized trimer ........................ 67 Scheme 3-5 Attempted ((boc)2O) protection of amine monomer ................................................. 68 Scheme 3-6 Acetylation of amine-functionalized monomers ....................................................... 69 Scheme 3-7 Attempted coupling of acetylated amine monomers ................................................ 70 Scheme 3-8 Synthesis of mono-iodinated tert-butylaniline, 20.................................................... 71 xi Scheme 3-9 Synthesis of amine functionalized trimer, 21 ........................................................... 72 Scheme 3-10 Attempted synthesis of amine-functionalized pentamer ......................................... 73 Scheme 4-1 Proposed post-synthetic modification of amine functional groups ........................... 84 xii List of Symbols and Abbreviations Å angstrom (1-10 meter) AEM arylene-ethynylene macrocycle boc di-tert-butyldicarbonate °C degrees Celsius d doublet δ chemical shift dd doublet of doublets ESI electrospray ionization g gram h hour J coupling constant K Kelvin kJ kilojoule min minute mL milliliter mol mole mmol millimole MS mass spectrometry m/z mass to charge ratio nm nanometer NMR nuclear magnetic resonance ppm parts per million xiii RT room temperature s singlet TMS trimethylsilyl TOF time-of-flight xiv Acknowledgements I have the deepest gratitude for my supervisor, Prof. Mark MacLachlan, and for the brilliant and patient post-doctoral fellows who I have had the privilege of working closely with: Dr. Nick White, Dr. Greg Gibson, and Dr. Miguel Ángel Soto Muñoz. I want to thank past and present members of the MacLachlan and Wolf groups for their comradery and support both in and out of the lab. My labmates Andrea Terpstra, Veronica Carta, Guillaume Beaulieu-Houle, Hessam Mehr, Zhengyu Chen, Brian Sahli, and Mohammad Chaudhry have been especially important to me throughout my time at UBC. I would also like to acknowledge my undergraduate supervisor, Prof. Danny Leznoff, as well as Ryan Roberts, John Thompson, and Jeff Ovens from the Leznoff group at SFU for introducing me to research and supporting me into my graduate studies. I am indebted to my friends and family, especially Lucy Ford and Oliver Longman, and my endlessly supportive parents, Lien Tiet and Be Van Le. I would like to thank NSERC for their generous funding. I respectfully acknowledge that this work was conducted on the unceded, ancestral, and traditional territory of the Musqueam people.1 Chapter 1: Introduction 1.1 Historical Context In 1961, Charles Pedersen was working for DuPont to investigate the effects of phenolic ligands on the catalytic properties of vanadyl(IV) complexes. He made an interesting observation while synthesizing one of his target ligands (Scheme 1-1); among the amorphous reaction mixture, a white, crystalline product was formed in less than 1% yield.1,2 Scheme 1-1 Pedersen's ligand synthesis with dibenzo-[18]-crown-6 as a side product This by-product was initially insoluble in methanol but became solubilized upon the addition of a sodium salt. With further characterization, this compound was determined to be what is now known as dibenzo-[18]-crown-6, the first of many crown ethers. It became clear to Pedersen that the solubility of this new molecule was affected by its ability to complex with alkali metal cations. Pedersen’s metal cation inside a crown ether was the first example of a synthetic host-guest complex (Figure 1.1). 2 Figure 1.1 Complexation of sodium ion with dibenzo-[18]-crown-6 The serendipitous discovery of a discrete chemical structure held together by non-covalent interactions marked the advent of a new area of research. This field was termed “supramolecular chemistry” by Jean-Marie Lehn to describe chemistry beyond the molecule.3 In 1987, the Nobel Prize in Chemistry was shared between the pioneers of supramolecular chemistry: Charles Pedersen, Jean-Marie Lehn, and Donald Cram for their development and use of molecules with highly selective, structure-specific interactions.1,3,4 Further recognition was given to the area of supramolecular chemistry in 2016, when the Nobel Prize in Chemistry was awarded to Jean-Pierre Sauvage, Fraser Stoddart, and Bernard Feringa for their research in molecular machinery and interlocked structures.5–7 Na+3 1.2 Supramolecular Chemistry Described as chemistry beyond the molecule, supramolecular chemistry involves molecular assemblies held together by intermolecular or non-covalent interactions.8,9 These molecular assemblies formed between discrete molecular or ionic building blocks are referred to as supramolecular complexes. Encompassing aspects of both organic and inorganic chemistry, supramolecular chemistry is a multidisciplinary field that can also be studied through a physical or biological lens. While other disciplines such as organic chemistry involve the construction of individual molecules from atoms, a task that occurs on the scale of about 1-100 Å, supramolecular complexes can form on much larger scales of 1-100 nm.10,11 The intermolecular forces identified in supramolecular complexes include electrostatic interactions, such as ion-dipole, hydrogen bonding, π-π stacking, and van der Waals forces, as well as hydrophobic or solvophobic effects.11,12 Compared to covalent bonds, which have bond energies from about 150 kJ·mol-1 to over 1000 kJ·mol-1, non-covalent interactions span a weaker range from 2 kJ·mol- 1 for dispersion forces to 250 kJ·mol- 1 for ion-ion coulombic interactions (Figure 1.2).12 Figure 1.2 Relative strengths of intermolecular interactions Interaction strength in kJ·mol-10 2 5 10 20 100 400 1000dispersiondipole-dipoleion-dipoleH-bondingCovalent bondsion-ion4 In the context of supramolecular assemblies, it is important to consider not only the strength of an interaction but also its directionality. Ion-ion interactions are the strongest of the electrostatic interactions and are nondirectional (Figure 1.3a), meaning the interaction can occur in any orientation.9 Similarly, van der Waals interactions rely on nondirectional electrostatic interactions between transient dipoles that occur with fluctuations in electron distribution (Figure 1.3b).9 Van der Waals interactions have a greater effect on larger molecules because they are more polarizable. On the other hand, ion-dipole (Figure 1.3c) and dipole-dipole interactions (Figure 1.3d) are directional and require proper alignment between entities for the interactions to occur.9 The hydrogen bond, a special type of dipole-dipole interaction, occurs between a hydrogen atom that is attached to an electronegative atom (such as oxygen or nitrogen) and an electron-rich neighboring functional group, such as a hydroxyl oxygen (Figure 1.3d). Aromatic molecules may also interact directionally via π-π interactions that are oriented face-to-face or edge-to-face (Figure 1.3e).9 5 Figure 1.3 Intermolecular forces: (a) ion-ion interactions (b) van der Waals interaction caused by a transient dipole (c) ion-dipole interactions with directional alignment of dipole, (d) hydrogen bonding due to permanent dipoles, and (e) different orientations of π-π stacking interactions The hydrophobic effect is not strictly a type of intermolecular interaction, but it brings non-polar entities together in aqueous solutions. The effect arises because water molecules interact preferentially with themselves or other polar groups, so non-polar entities aggregate to minimize free energy.9,13 Supramolecular complexes containing amphiphilic molecules are arranged by the hydrophobic effect in aqueous environments. This can result in formations such as micelles and bilayers and is observed in some complexes containing barrel-shaped hosts such as cyclodextrins and cucurbiturils. Supramolecular building blocks are functionalized with groups that can establish attractive intermolecular interactions to produce a supramolecular complex with a desired conformation, stoichiometry, and hierarchical array.11 By incorporating a variety of functional groups, interactions with different strengths and directionality can act in tandem. The stability of the displaced edge-to-face stackedδ+δ+δ-δ-Cl -Na+------ ------------------------------IIIIIIa b cdeCl-Cl- Cl-Cl-Cl- Cl-Cl-Cl- Cl-Na+Na+Na+Na+6 supramolecular complex is determined by the type of interaction present, as well as the number of possible interactions. Although in some cases individual interactions may be weak, the combination of many weak forces can result in a very strong cooperative effect. As previously mentioned, dispersion forces are individually the weakest type of intermolecular interaction; however, the overall effect of many van der Waals forces can be quite strong. This is known as the cooperative effect, which might even impact the physical properties of a bulk material. This is observed in the high melting points of polymers, which are typically in the range of 100-300 °C.14 The cooperative effect is observed not only in artificial molecular systems but also in nature. The nanostructure of geckos’ feet results in such a large surface area that the huge number of van der Waals interactions between the feet and a surface are strong enough to prevent a gecko from falling as it runs up a wall.15 Self-Assembly Supramolecular chemistry includes the study of self-assembly, which encompasses supramolecular systems where the components do not have a significant size difference.9 The process of self-assembly occurs when a disordered system of subunits forms an organized structure or pattern with a drive towards a thermodynamic minimum.9 A supramolecular complex is held together by local interactions between the subunits and the individual components that make up a supramolecular system are referred to as building blocks. These supramolecular building blocks are not strictly just molecules, as ions, nano-, meso-, and macroscopic structures are also known to self-assemble into higher order structures.16,17 Self-assembly can be further classified into intermolecular self-assembly, which results in the formation of a supramolecular complex, and intramolecular self-assembly, which is exhibited by the folding of foldamers and polypeptides. 7 An inherent advantage to non-covalent systems is the reversibility of the interactions. During the self-assembly of building blocks into supramolecular structures, the use of non-covalent, intermolecular interactions allows undesired bond formation to be corrected until a thermodynamic minimum is reached. Due to the reversibility of self-assembly, generally the structures formed by this method are free of defects. Furthermore, reversible interactions allow for dynamic supramolecular systems to exist where perturbations in the system can cause structural change. The external stimuli may be the introduction or removal of solvent, change in temperature, or even mechanical stress. Synthetic self-assembled systems rely on the chemist’s ability to design molecules containing complementary functionalities. Knowledge of existing chemistry of how functional or structural motifs interact is used to make judicious choices in the design of supramolecular building blocks. It is well known that certain molecules, metals, or functional groups have preferences for binding in certain ways.18 For example, the preferred coordination geometries of some transition metals (Figure 1.4) and binding preferences of ligands are often considered to dictate the manner in which the process of self-assembly proceeds. In this way, square planar Pd2+ ions were coordinated with linear bipyridine molecules to form a square-shaped metallomacrocycle, as depicted in Figure 1.5.19 Figure 1.4 Representative binding geometries of common transition metals 8 Figure 1.5 Self-assembly of a square structure using square planar metal ions and a rigid ligand Within self-assembling systems, there are usually multiple types of interaction present. In the process of self-assembly, the strongest interactions tend to form first, followed by weaker interactions. For example, the double-stranded helix of DNA contains hydrogen bonds that hold two complementary parallel strands together, and this double-strand is further wound into a helical geometry by π-π stacking (Figure 1.6).20 This hierarchical process allows complex shapes to be achieved through self-assembly. Protein strands have high degrees of freedom and can fold randomly into many different conformers, but through the process of hierarchical self-assembly (Figure 1.7), proteins are able to fold into their most stable conformation within minutes, as opposed to an estimated 1027 years if the process should occur randomly.21 4×4×4×4×9 Figure 1.6 Hydrogen bonding of DNA base pairs and the DNA double helix Figure 1.7 Protein folding from (a) primary structure to (b) secondary and (c) tertiary structure Self-assembly is a valuable tool in supramolecular chemistry for the synthesis of templated structures. Template-directed synthesis is a molecular synthesis method which uses intermolecular interactions to pre-organize structures into a desired geometry before joining them together with covalent bonds.9 A template molecule interacts with reactants and facilitates the reaction by holding their reactive sites together.9 This strategy allows for the creation of molecules or bac10 structures that are difficult to obtain by regular synthesis because the necessary conformation for the reaction is unlikely to occur. Pre-organization with a template also serves to minimize side reactions and lower the activation energy of the reaction.9 Situations where template-directed synthesis is used include the preparation of large macrocycles, complex molecular knots, or when a specific stereochemistry is needed.22 Host-Guest Chemistry Another area of supramolecular chemistry includes the study of host-guest complexes, which are systems where a host molecule with an internal space or cavity binds to a guest molecule via non-covalent interactions (Figure 1.8).23 In such a complex, the host component is typically larger than its guest; however, a more accurate distinction is that the host component has binding sites which converge in the complex, while the guest component has binding sites that diverge.9 Host and guest molecules with the appropriate binding capabilities to form a complex are said to be complementary. Figure 1.8 Schematic representation of the formation of a host-guest complex Molecular hosts are not necessarily limited to being neutral or ionic molecules and can be proteins,24 cages,25 or even extended structures like metal-organic frameworks.26 Molecular structures such as macrocycles, cavitands, and cages have been shown to host a variety of small 11 molecules, metal cations, anions, and metal clusters.23,27,28 Host-guest chemistry is a valuable route to developing new compounds that may be useful in catalysis,29 molecular transport,30 or molecular sensing.31 The ability of a host to discern a specific molecule or types of molecules from others is referred to as its selectivity. A highly selective host will bind specifically to an analyte without binding other molecules, while a host with low selectivity will bind a wide range of guests. At the same time, affinity describes the sensitivity of a host for a chosen analyte or molecule. A host that is complementary to a specific guest has high selectivity, but other factors such as solvent effects or secondary interactions also affect the intercomponent affinity. To achieve strong, selective binding, the interaction site(s) of the host must be complementary to the guest in terms of its functional groups, electronic properties, and steric features (Figure 1.9).9 Ensuring molecular complementarity involves designing a host with specific functional groups or structural characteristics that can interact with the functional groups of the guest. For example, hydrogen donors such as primary and secondary amines will tend to bind with hydrogen receptors such as carboxylates.9 Electron donating Lewis bases and electron accepting Lewis acid functionalities can also be used in host-guest design. Another consideration is that polarizability of these functional groups can also influence complementarity since hard Lewis bases tend to prefer hard Lewis acids, and soft Lewis bases tend towards soft Lewis acids.9 12 Figure 1.9 Model of selectivity between hosts and guests Different levels of selectivity may be desired for diverse applications of molecular recognition. For example, biological G-protein-coupled receptors must have high selectivity for specific neurotransmitters or hormone molecules for an organism to function properly.32 In using supramolecular vessels for drug delivery, lower selectivity may be desirable to accommodate a range of pharmaceuticals.24 An advantage to using a combination of many weak, non-covalent interactions is that they can be tuned to increase or decrease selectivity for a variety of different applications. An interesting field of supramolecular chemistry that uses host-guest chemistry involves the formation of interlocked structures such as rotaxanes and catenanes. Interlocked structures are held together mechanically, through only their topology, rather than by chemical interactions. A rotaxane (Figure 1.10a) consists of one or more cyclic molecules, or macrocycles, threaded by a linear molecule, where the capped ends of the linear molecule prevent the macrocycle(s) from unthreading.9 Two or more interlocked macrocycles are referred to as catenanes (Figure 1.10b).9 The synthesis of rotaxanes and catenanes usually involves molecular recognition and the formation of a supramolecular complex.9 Intermolecular interactions can hold the components of these 13 structures together in the correct geometry to form an interlocked structure. A common challenge in the study of interlocked structures is that the overall yield for the final product tends to be low. The statistical probability for threading a linear molecule through a macrocycle has been estimated to be less than 1%. With the use of a supramolecular template, the synthesis of interlocked structures has improved yields from less than 10% to over 90%. 22 Figure 1.10 Schematic representations of (a) a rotaxane and (b) a catenane 1.3 Macrocyclic hosts One class of hosts that are seen in supramolecular chemistry are macrocycles: cyclic molecules that often contain heteroatoms or functional groups that allow for them to participate in non-covalent interactions, opening the possibility for further binding or modification.28 Depending on chemical composition, cavity size, and electronic properties, macrocycles show different affinities to guests. Cyclic molecules play a large role in supramolecular chemistry as receptors in host-guest chemistry,33 building blocks in self-assembled structures,34 templates,35 components in rotaxanes or catenanes,31 and mesogens in liquid crystals.36 The first artificial macrocycle hosts discovered were Pedersen’s crown ethers: cyclic oligomers of ethylene oxide. Crown ethers (Figure 1.11a) can bind certain metal cations through ion-dipole interactions between the guest cation and the lone pairs of the oxygen atoms 14 incorporated in their backbone.1 Compared to their linear counterparts, crown ethers exhibit higher affinities to their guests. This can be attributed to the preorganization of the oxygen atoms around a central cavity, allowing them to bind to guests without having to undergo significant conformational changes.9 The enhanced binding of cyclic hosts compared to their acyclic analogs is referred to as the macrocyclic effect.37 This effect is further enhanced by cryptands (Figure 1.11b), which are crown ethers with bridges spanning across the crown ether ring, first synthesized by Lehn.10 Cryptands form more stable complexes and exhibit increased selectivity for their hosts when compared to crown ethers because the three-dimensional binding cavity in cryptands can better encapsulate metal cations, and the glycolic bridges act as additional binding sites.37 These added binding sites increase the stability of cryptand complexes through the entropically driven chelate effect, where a molecular host with multiple binding sites replaces more solvent molecules that were previously associated with the host. The increase in the number of free molecules in solution gives the system more degrees of freedom, resulting in higher entropy. While crown ethers and cryptands have prearranged binding sites before ion complexation, their backbones are flexible, and some degree of ligand rearrangement must still occur to complex the guest ion. Cram recognized that further restricting the conformational freedom of cyclic hosts would lead to an even smaller entropic penalty from binding the guest, thus increasing binding strength.4 This was achieved by synthesizing rigid receptors with preformed cavities of the correct size, orientation, and functional groups to accept guest species. These rigid macrocycles were termed spherands (Figure 1.11c) and exhibited stronger and more selective binding to metal ions than their flexible predecessors.4 15 The early examples of synthetic macrocycles demonstrate that higher selectivity and stronger binding can be achieved with preorganization and increased rigidity. Hosts that have additional binding sites surrounding the guest also exhibit a chelate effect. Effective host-guest chemistry is exemplified by biological enzymes, which can encapsulate their guest in their active site. Synthetic macrocycles that can similarly encapsulate guests in three-dimensional binding sites include calixarenes, pillararenes and cucurbiturils, as well as cyclodextrins. Calixarenes are a versatile group of macrocycles that are well known in host-guest chemistry. The combination of a cup or bowl-shaped hydrophobic cavity and pendant hydroxyl groups allows calixarenes to interact with a wide range of ionic or molecular guests through π- π stacking interactions and hydrogen bonding (Figure 1.12a).38 The rims can also be modified with other functional groups, further increasing the scope of guests that can be accommodated by calixarenes. Having differently functionalized rims allows some calixarenes to bind a combination of different species at once. A drawback to this dual functionality is that calixarenes have low solubility in almost all solvents.9 While the aromatic backbone suggests that these macrocycles would be rigid, the phenyl groups have some rotational freedom and calixarenes are found as a mixture of conformers in solution (Figure 1.12b). The cone formation often dominates this Figure 1.11 Examples of (a) a crown ether, (b) a cryptand, and (c) a spherand 16 equilibrium due to strong intramolecular hydrogen-bonding between the hydroxy groups.38 However, a calixarene can be locked into certain conformations upon coordinating to metal ions or by the presence of bulky substituents on the phenolic oxygens.38 OHOH HOOH ORORORpartial coneOROROROROR1,3-alternateROOR OROR1,2-alternateconeOH OHOHOHR RRRcup-shaped representationab Figure 1.12 (a) A simplified representation of the calixarene cone shape and (b) different conformers of calixarenes Pillararenes and cucurbiturils are structurally similar to calixarenes and have the ability to form useful host-guest complexes. Pillararenes (Figure 1.13a) are macrocycles composed of hydroquinone units linked in the para position.39 Like calixarenes, they can form π- π interactions and hydrogen bonds but are more soluble in organic solvents. Cucurbiturils (Figure 1.13b) are composed of glycoluril monomers linked by methylene bridges.40 The inward tilt of the oxygen atoms around the rim of these macrocycles give them a rounded shape and an enclosed cavity.40 17 Cucurbiturils bind guests through hydrophobic interactions as well as through ion-dipole interactions. However, like calixarenes, their solubility tends to be limited in organic and aqueous environments.9 Figure 1.13 Example of (a) a pillararene and (b) a cucurbituril Cyclodextrins (Figure 1.14) are a family of cyclic oligosaccharides that have a defined funnel shape.41 They have outward-facing hydroxy groups resulting in hydrophilic, water soluble exteriors, while also having hydrophobic interiors.41 The preorganized funnel shape is held together by an intramolecular hydrogen bonding network.41 A wide range of small molecules can be accommodated by the hydrophobic cavity, and cyclodextrins are particularly useful for binding molecules that have limited solubility in water.41 The inclusion of these guests within the macrocycle cavity is an example of the hydrophobic effect. 18 Figure 1.14 Structures and three-dimensional representations of α- β- and γ-cyclodextrin The macrocycles mentioned so far have been presented in order of increasing degrees of pre-organization, corresponding with stronger binding and better selectivity for their hosts. However, these macrocycles still have some degree of flexibility in their backbones and are not considered shape-persistent. OOHHOOHOOOHHOOHOOOHOHOHOOOHOHOHOOOHOHHOOOOHOHHOOOOHHOHOOOOHHOOHOOOHHO OHOOOHOHOHOOOOHOHHOOOHOHHOOOOHHOHOO5.7Å13.7Å7.8Å15.3Å 16.9Å9.5Å7.8Å19 Shape-Persistent Macrocycles A category of macrocycles that has garnered interest in supramolecular chemistry are shape-persistent macrocycles. In contrast to macrocycles with flexible backbones, shape-persistent macrocycles are cyclic molecules with rigid, non-collapsible structures.28 These molecules have few degrees of conformational freedom since they are constructed with rigid building blocks, such as aromatic rings and alkynyl groups. Diverse shape-persistent macrocyclic structures have been studied for uses in supramolecular chemistry (Figure 1.15).42–46 Due to their internal void, typically planar structure, and large molecular surface, shape-persistent macrocycles are promising candidates for constructing supramolecular structures. Liquid crystals,36 tubular structures such as nanowires and ion channels,47,48 non-collapsible nanoporous solids, and 2D networks35 are some of the highly ordered structures that have been achieved with shape-persistent macrocycles. 20 Figure 1.15 Some examples of shape-persistent macrocycles 21 One feature of shape-persistent macrocycles is that they have defined endo-annular and exo-annular positions (Figure 1.16). When the positions on a macrocycle are fixed, functional groups can be introduced at specific positions around the cyclic backbone to obtain macrocycles with different interior and exterior chemical environments. Functional groups pointing to the inside of shape-persistent macrocycles (R1) allow them to act as supramolecular hosts for the recognition of molecular or ionic guests.49 The presence of functional groups on the outside of a macrocycle (R2) can promote interactions between macrocycles, leading to the formation of extended networks. The exo-annular side groups also tend to determine the solubility of a macrocycle, so modifying these groups is often a good way to make macrocycles that are soluble in appropriate solvents. While the substituents on shape-persistent macrocycles tend to be fixed in place, depending on the molecular structure, a substituent on the macrocyclic backbone may have free rotation (R3), allowing the functional groups that are attached to this substituent to switch between endo-annular or exo-annular positions.49 The orientation of these adaptable functional groups may be influenced by external parameters, like solvent, and may have applications in switchable or responsive chemical systems. 22 Figure 1.16 Macrocycle with endo-annular (R1, blue), exo-annular (R2, red), and adaptable (R3, green) functional group positions Another important property of shape-persistent macrocycles is that the rigid backbones form internal voids with defined shapes. Since they maintain their shape in the absence of guest molecules or solvents, they can be designed to have specific dimensions and functional groups that are preorganized to bind the desired guests. The internal voids maintain their structure in different conditions, like changes in solvent, so shape-persistent macrocycles have been used to create 23 porous structures after self-assembly. In addition, tubular structures can be formed by the stacking of these macrocycles so that the internal voids overlap and form a continuous channel.50 Schiff-Base Macrocycles One family of conjugated, shape-persistent macrocycles are those formed by Schiff-base condensation reactions (Scheme 1-2). Salen and salphen ligands are well known classes of compounds with tetradentate nitrogen and oxygen-containing pockets that can bind transition metals to form stable coordination complexes. Schiff-base condensation reactions have enabled researchers to synthesize a variety of macrocycles with salen or salphen motifs.51 The synthesis of these macrocycles involves reacting a diamine with dicarbonyl units of the appropriate geometry to yield a macrocycle (Scheme 1-3).51,52 The condensation of an amine and an aldehyde to give an imine is known to be reversible, so the macrocyclic product usually has low angle strain, maximized intramolecular interactions, and requires little or no purification. Scheme 1-2 Schiff base condensation to form salen (top) and salphen (bottom) compounds 24 Scheme 1-3 Schiff base condensation to produce [3+3] macrocycle Schiff-base macrocycles are of interest to supramolecular chemists because of their ease of formation and potential as receptors in host-guest chemistry. The salen or salphen motif present throughout the macrocycle backbone can bind metals through the donating imine nitrogen and phenolic oxygens. Salen-based ligands are known to form transition metal complexes with useful catalytic or optical properties and many examples of Schiff-base macrocycles being used in cation binding exist.52 Incorporating these into self-assemblies (for example, tubular assemblies and other aggregates) has been studied and their potential in supramolecular chemistry continues to be explored. The formation of different shapes or sizes of Schiff-base macrocycles is achieved by altering their monomeric precursors. By starting with various dicarbonyl compounds and diamines, the syntheses of many symmetrical and asymmetrical macromolecules have been reported. However, the geometries of these macrocycles are limited by which building blocks have the appropriate structure and functionalities to self-assemble. Even with careful design of the precursors, components of a Schiff-base macrocycle can assemble differently than predicted, giving unexpected shapes. 25 Arylene-Ethynylene Macrocycles While Schiff-base macrocycles offer many possibilities as hosts or building blocks for supramolecular structures, notable drawbacks are the limited shapes that can be synthesized and difficulty in post-functionalization. Another class of shape-persistent macrocycles are arylene-ethynylene macrocycles (AEMs). Characterized by repeating phenyl and ethynylene structural subunits, these are rigid macrocycles with well-defined central cavities.50 The conformational rigidity of AEMs is provided by aromatic moieties that are linked directionally with ethynylene spaces. The ethynylene motif is an attractive building block to form shape-persistent macrocycles because of its potential for extended conjugation and simple linear geometry, and a vast body of organic chemistry research is available for designing molecules with carbon backbones. Thanks to the versatility of their syntheses, diverse shapes of AEMs can be constructed. The first synthesis of a six-fold AEM was reported by Staab in 1974 via the six-fold coupling of copper m-iodophenyl acetylide in a one-step oligomerisation/cyclisation strategy (Scheme 1-4).53 The yield of this type of reaction was low (about 5%) because the kinetically controlled product distribution included linear and cyclic oligomers or polymers of different chain length. Due to the impracticality of synthesizing large quantities of these macrocycles, they were not significantly studied until Moore and coworkers developed a versatile and efficient route to synthesize AEMs in 1992.54 This route used Pd-Cu catalyzed cross-coupling and protecting groups to synthesize phenylene-ethynylene oligomers that could then be ring closed using a Sonogashira reaction (Scheme 1-5).54 The improved yield (60-80%) and precise control that this method granted made AEMs accessible for further research. 26 Scheme 1-4 Staab’s initial synthesis of an AEM Presently, AEMs are typically synthesized by a route similar to Moore’s, using palladium-catalyzed Sonogashira couplings or copper-catalyzed Glaser-type couplings under kinetic conditions. One downside of this method is that the irreversible reactions allow the opportunity for overshooting the length of oligomers. The cyclisation step in AEM synthesis usually involves the coupling of rigid oligomers or the intramolecular coupling of a linear precursor. When the cyclisation of oligomers is used, the synthesis of polymers or other non-desired oligomeric products typically occurs, decreasing the yield. While the use of high dilution conditions can help mitigate this problem, yields achieved by this synthetic route are usually less than 50%. The method of intramolecular cyclisation from a linear precursor can have an improved yield of over 90%.55 Unfortunately, the synthesis of precursors up to this step is still cumbersome, involving multiple reactions. Overall, the yield and purification of arylene-ethynylene macrocycles continues to be a challenge in this area of chemistry. 27 Scheme 1-5 Moore's step-wise AEM synthesis Despite difficulties with synthetic yield and purification, the step-wise synthesis of AEMs is still widely used. One reason why this method is useful is that the step-wise synthesis allows for functional groups to be incorporated at specific positions on the macrocycles. Considering phenyl subunits as vertices and ethynylene spaces as edges, macrocycle geometry can be altered by changing the substitution pattern of phenyl and ethynylene units. Various shapes and sizes are 28 accessible by using combinations of ortho-, meta- and para-phenylenes to make shapes with 60°, 120°, or 180° bond angles, respectively (Figure 1.17). In addition, incorporating ethynylene units of different lengths allows for tuning of the size and shape of AEMs. Figure 1.17 AEMs with ortho- meta- and para-connectivity (respectively) The presence of functional groups in the interior of AEMs allows them to act as hosts for small molecules. Furthermore, in considering hosts for molecular recognition, size and shape of the molecules are two of the most important factors. Being able to precisely control the geometry and position of functional groups in arylene-ethynylene macrocycles is advantageous when designing and synthesizing building blocks for supramolecular chemistry. AEMs have the potential for long-range ordering and have been known to organize into higher-order supramolecular assemblies including 3D nanostructures, discotic liquid crystals, extended tubular channels, host-guest complexes, and porous organic solids.27,28 Synthesis of Macrocycles Methods of synthesizing macrocycles can be broadly categorized into step-wise or one-pot syntheses. Step-wise synthesis of macrocycles usually involves the synthesis of linear oligomers as precursors followed by intramolecular cyclooligomerization to form a cyclic product, or the intermolecular cyclization of two or more oligomers (Figure 1.18).50 29 On the other hand, a one-pot approach involves designing oligomeric precursors to self-assemble in solution into macrocycles, with or without a template (Figure 1.19).50 Figure 1.19 Schematic of single-step self-assembly of building blocks into a macrocycle (top) and template-assisted self-assembly of a macrocycle followed by removal of template (bottom) T=Figure 1.18 Schematic of intramolecular cyclization of an oligomer (top) and intermolecular cyclization between two oligomers (bottom) 30 The step-wise synthesis of macrocycles usually involves a high-dilution step, where small quantities of reactants are mixed together at a controlled rate in a large volume of solvent. The slow addition of starting materials into the reaction vessel ensures that a low reactant concentration is sustained. This favors macrocycle formation over polymerization since an oligomer in a dilute solution has a greater chance of reacting with itself to form a closed ring than reacting with another molecule to form a polymer.50 The problem of forming polymers rather than cyclic molecules arises from the irreversible coupling reactions used in this method. Since undesired bond formations cannot be corrected, the product distribution is kinetically determined. When synthesizing macrocycles through cyclooligomerization, possible products include both cyclic and linear oligomers of various sizes.50 Synthesizing oligomers before intermolecular coupling to form a macrocycle helps avoid overshooting the coupling reactions, but this method can involve many synthetic steps prior to ring closure.50 Despite the challenges with this synthetic strategy, it is still often used in the synthesis of macrocycles because it allows for the modification of functional groups at different positions and provides reliably predictable products. The self-assembly approach to synthesizing macrocycles is characterized by a different set of advantages and disadvantages. The use of reversible reactions under equilibrium conditions allows for undesired bond formation to be corrected, resulting in a thermodynamically favorable product.50 Using careful consideration of preferred metal ions with preferred geometries, and of rigid organic molecules with defined shapes and angle strain, precursors can be designed to self-assemble into a desired structure. Macrocycles and more complex structures have been achieved using this method, some with the use of a template to help ensure the formation of the desired product. However, molecular design has yet to give precise control over the dimensions of self-assembled macrocycles and unpredicted geometries often appear. Furthermore, structures formed 31 via intermolecular interactions may break down with the removal of solvent or a template. Post-synthetic modification can also be difficult with self-assembled structures, so the functionalities in the final macrocycle are usually limited to the ones that were present in its precursors. 1.4 Goals and Scope of this Thesis Arylene ethynylene macrocycles have been shown to host small molecules or other organic compounds, and have been studied for their self-assembly into tubes, liquid crystals, and other higher order structures. However, relatively few examples of using these organic macrocycles in inorganic chemistry exist. Hosting metal ions or metal clusters in a rigid, macrocyclic host is a new avenue to pursuing host-guest complexes with interesting properties. This thesis is concerned with the synthesis, structures, and behaviors of extended arylene-ethynylene structures and macrocycles that may be used to form complexes with transition metal ions or clusters. Inspired by the multi-metallic enzymes found in nature, the syntheses of polymetallic complexes are of interest. These complexes may be used as models of metalloenzymes to provide insight into their structure, properties, and functions. Furthermore, they may exhibit interesting electronic, magnetic, and optical properties due to the conjugated backbone and its interaction with coordinated metal centers. The initial goal for this research project was to synthesize an arylene-ethynylene macrocycle with functional groups pointing towards the interior. The route to synthesizing a new methoxy-functionalized macrocycle as well as its characterization are described in Chapter 2. In Chapter 3, post-functionalization of the macrocycle and other amine-functionalized arylene-ethynylene ligands are explored. Finally, Chapter 4 provides some conclusions and future directions for this work. 32 Chapter 2: Synthesis of a Novel Arylene-Ethynylene Macrocycle 2.1 Introduction Macrocyclic molecules have long attracted the attention of chemists for investigations in supramolecular chemistry, medicine, and molecular electronics. One class of macrocycles that have been extensively studied are arylene-ethynylene macrocycles. Characterized by repeating phenyl and ethynylene structural subunits, these are rigid macrocycles with well-defined central cavities, and are typically planar or have nearly planar conformations.50 AEMs are valuable building blocks to supramolecular assemblies because they have been shown to spontaneously organize into ordered assemblies. The large aromatic surfaces tend to stack face-to-face, maximizing van der Waals and π-π stacking interactions.50 The synthesis of AEMs usually involves a step-wise, modular process where aromatic and ethynyl structural units can be linked at different positions using coupling reactions.50 Due to their synthetic versatility, there is enormous structural diversity within the AEM family. This includes examples with a variety of cavity geometries and sizes, as well as with different chemical functionalities — both on the inside of the cavities and around the outside of the macrocycles (Figure 2.1).43,56–59 The defined central cavities of AEMs suggest that these macrocycles should function as versatile supramolecular hosts. 33 RRRRRROPrPrOPrOOPrOR ROOPrPrOPrOOPrOR RORRRRRRRRRRRRNRRRRNRRRRN NRORONNORORROOOR = nC6H13Pr = nC3H7R = nC18H37R = nC6H13R = CO2nC8H17R = Ph Figure 2.1 Some examples of previously reported AEMs Several examples of molecular recognition with AEMs exist. The size of the guests that can by hosted by AEMs depends on the connectivity of the macrocycles. Ortho-connected macrocycles tend to be smaller and able to host only single atoms. For example, the triangular ortho-AEM first reported by Youngs et al. (Figure 2.2a) was shown to coordinate Ni(0) in its cavity, as well as Cu(I) and Co(0), but not larger atoms such as Ag(I), which could not fit in the macrocycle and would form sandwich complexes instead.60 Para-AEMs can be significantly larger and have been used to host molecules such as alkylated benzenes and even fullerenes in their central cavities (Figure 2.2b).61 However, macrocycles constructed using only para-phenylenes 34 have nonplanar, hoop-like structures in contrast to the planar ortho- and meta-connected AEMs. Meta-connected macrocycles can be made to be larger than their ortho-connected counterparts while maintaining planarity. Many examples of these have been reported, but few have been characterized with guests in the central cavity. One example of host-guest chemistry with meta-connected AEMs is a macrocycle reported by Miljanic that could bind fluorinated benzenes (Figure 2.2c).62 Figure 2.2 Examples of host-guest complexes with AEMs 35 Constructing AEMs with benzene derivatives of different connectivity opens possibilities for synthesizing AEMs with different shapes and sizes. A combination of meta- and para-phenylenes are often coupled together to form larger, planar macrocycles. These macrocycles have been used extensively in supramolecular chemistry, but metal host-guest complexes with AEMs are hardly represented in literature. A goal of this thesis was to synthesize AEMs with functional groups oriented towards their interiors to form metal host-guest complexes. Not only are these complexes underrepresented in literature, but they also may exhibit interesting electronic, magnetic, or optical properties for applications such as catalysis and bioimaging. We hypothesized that rigid, shape-persistent AEM frames may act as templates for metal clusters, allowing for greater control over the formation of these clusters. To investigate metallic AEM complexes, we first set out to synthesize a new arylene-ethynylene macrocycle. This chapter will describe the attempts to synthesize arylene-ethynylene derivatives needed to yield the target macrocycle (Figure 2.3). Figure 2.3 Target arylene-ethynylene macrocycle with interior functional groups, R 36 2.2 Results and Discussion The macrocycle shown in Figure 2.4 was chosen as our target molecule since its synthesis could provide a framework for building a series of macrocycles with the same functionalities but different sizes. The macrocyclic building blocks we used were benzene-derived monomers with three types of functionalities. These functional groups each had specific positions on the benzene ring (Figure 2.4): a main functional group capable of establishing intermolecular interactions with metals (R, shown in blue), halide or alkyne groups to be used in cross-coupling reactions (yellow), and a solubilizing alkyl group (red). For the main functional group to line the interior of the completed macrocycle, the cross-coupling functionalities needed to be in the ortho positions. Solubilizing groups would be most effective around the exterior of the macrocycle, so a tert-butyl group was positioned para to the main functionality. The tert-butyl group was chosen because it would help solubilize the final macrocycle in organic solvents and might also help with the crystallization of the final product. Figure 2.4 Position of different functional groups on the starting monomers and target macrocycle RRRRRRIRIR37 Initial Attempts with Phenol Derivatives We began with phenol derivatives as starting materials to synthesize our macrocyclic building blocks, since the hydroxy groups could be converted to esters after synthesizing a macrocycle. Phenols are known to be ortho- and para-directing, but since para-tert-butylphenol is already substituted at the para position, only the ortho positions are available for electrophilic aromatic substitution. Using a literature procedure, para-tert-butylphenol was iodinated using potassium iodide and sulfuric acid to synthesize 2 (Scheme 2-1). Column chromatography was used to remove any monosubstituted product before coupling with trimethylsilylacetylene, using Pd(PPh3)2Cl2 as a catalyst, CuI as a co-catalyst, and triethylamine as a base to form compound 3. This was followed by deprotection of the TMS-capped acetylene groups using potassium carbonate in methanol to yield 4. Finally, compound 4 was purified with column chromatography to remove any unreacted or partially reacted by-products. These monomers had good separation from their by-products when using an eluent mixture of dichloromethane and hexanes and silica gel as the stationary phase and could be isolated at about 70% yield. The eluent ratio used in the column chromatography of 2 was 1:2 dichloromethane:hexanes, while a 1:1 ratio of these solvents was used as the eluent for the purification of 4. Scheme 2-1 Synthesis of phenol-derived monomers 38 After synthesizing two phenolic building blocks, 2 and 4, our stepwise approach involved coupling two molecules of the iodinated compound (2) to either side of the alkyne-functionalized monomer, 4 (Scheme 2-2). A slight excess of two equivalents of 2 was added to the reaction vessel to prevent overshooting the oligomerization. This reaction was attempted in triethylamine with Pd(PPh3)2Cl2 and CuI as a catalyst and co-catalyst, respectively, and conducted at room temperature for 24 hours, or at 60 °C for 12 hours. In a third room temperature trial, a solvent mixture of triethylamine and tetrahydrofuran was used. The Sonogashira coupling between two functionalized phenols was not successful under these various conditions. 1H NMR of the product mixture (Figure 2.5) showed the presence of the starting compound 2 only, with no evidence of an alkyne peak from 4 or any aromatic proton coupling patterns that would be expected for the trimeric product. This result was consistent between the different trials and the absence of the alkyne-functionalized starting material suggested that 4 may have oligomerized during the reaction. Any oligomer or polymer side product may have been lost during the reaction workup. To prevent any side reactions that might have occurred with the phenol groups, a protecting group was introduced to our monomers. Scheme 2-2 Attempted coupling of phenol-derived monomers 39 The starting compound 2 was reacted with ethyl chloroacetate to protect the phenol group before continuing with the same Sonogashira coupling and deprotection strategy previously used (Scheme 2-3). This protecting group was chosen because it could be post-synthetically cleaved to a carboxylic acid. After recrystallizing in methanol, compound 5 was obtained at 64% yield. Then, with the same procedures used to prepare compounds 3 and 4, compounds 6 and 7 were synthesized, with 7 being obtained in 16% yield. Figure 2.5 1H NMR spectra (300 MHz in CDCl3) of 4 (top), 2 (middle), and reaction product (bottom) 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)9.400.842.009.110.982.008.831.880.961.94CHCl3CH2Cl2CHCl340 Scheme 2-3 Synthesis of ester-capped monomers Once compounds 5 and 7 were obtained, the coupling of 7 with excess 5 was attempted to form a trimer (Scheme 2-4). The different trials for this reaction all used Pd(PPh3)2Cl2 and CuI as the catalyst and co-catalyst, but the temperature and solvents were varied. Neat triethylamine, a mixture of tetrahydrofuran and triethylamine, or a mixture of toluene and diisopropylamine were used as solvents in different trials. These reactions were done at room temperature and repeated at 70 °C. In the reactions using a THF/TEA solvent mixture, triphenylphosphine was also added to the reaction. However, like their phenol analogs, these monomers failed to oligomerize under various Sonogashira coupling conditions and only the iodo-compound 5 was isolated from the reaction mixture (Figure 2.6). One explanation for this is that the protecting group may have sterically prevented the iodo- and ethynyl- functional groups of 5 and 7 from coupling. Since the alkyne-functionalized starting material, 7, is not observed in the product by 1H NMR spectroscopy, it is possible that oligomerization of this starting material was more favorable than the desired cross-coupling reaction and that the oligomerized product was lost in the reaction workup. 41 Scheme 2-4 Attempted coupling of ester-capped monomers Figure 2.6 1H NMR spectra (300 MHz in CDCl3) of 7 (top), 5 (middle), and reaction product (bottom) 10.392.711.822.032.041.947.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)8.562.942.001.961.829.013.032.002.001.89CHCl3CHCl3CHCl3CH2Cl242 Syntheses with Methoxybenzene Derivatives The next set of building blocks we sought to synthesize were methylated versions of our monomers, since the methoxy functional group is relatively unreactive, unlikely to participate in side reactions and is less sterically bulky. The phenol of compound 2 was methylated using methyliodide in basic solution and, following the same synthetic route described for the previous monomers, compounds 8, 9, and 10 were synthesized (Scheme 2-5). These compounds were isolated relatively easily using flash column chromatography on silica gel and a 1:1 eluent mixture of dichloromethane and hexanes. Scheme 2-5 Synthesis of methoxy-capped monomers Sonogashira coupling between these monomers using Pd(PPh3)2Cl2, CuI, and triethylamine at room temperature was successful in forming a trimer, 11 (Scheme 2-6). The synthesis of a trimer rather than just the presence of starting material was confirmed by the absence of an alkyne peak in the 1H NMR spectrum along with the presence of three different aromatic proton environments (Figure 2.7). Mass spectrometry also confirmed the chemical composition of the product, with an observed mass-to-charge ratio of m/z = 811.0 for the parent mass with a sodium ion, compared to the calculated mass of 811.1 g·mol-1. The trimer was further functionalized with terminal alkyne groups through room temperature Sonogashira cross-coupling with trimethylsilylacetylene, using Pd(PPh3)2Cl2 and CuI in triethylamine, followed by the removal of the trimethylsilane by refluxing 43 with K2CO3 in methanol, yielding compound 12. In an alternative approach, we tried reacting 8 with an excess of 10 to obtain compound 12 directly from the monomers. While the presence of some product was detected by 1H NMR spectroscopy using this method, the yield was too small for the product to be isolated after purification. Having higher concentrations of the diethynyl-substituted monomer in the reaction mixture may have led to a greater chance of overshooting the oligomer length. Synthesizing 11 from monomers through Sonogashira cross-coupling resulted in higher yields and easier purification, so the oligomer 11 was isolated and then post-functionalized with alkyne groups to make the trimer 12. The 1H NMR spectrum of 12 (Figure 2.8, top) confirms its structure with three different aromatic proton environments, two methoxy proton environments, and the presence of a peak consistent with the terminal alkyne protons. The mass spectrum of 12 was also consistent with the expected parent mass with an added sodium ion, 607.3 g·mol-1, with an observed mass-to-charge ratio of m/z = 607.1. Scheme 2-6 Synthesis of methoxy-capped trimers 44 Figure 2.7 1H NMR spectra (300 MHz in CDCl3) of 10 (top), 8 (middle) and product 11 (bottom) with enlarged partial spectrum of the aromatic region of 11 Once the oligomers 11 and 12 were obtained in sufficient amounts, the intermolecular coupling of the two oligomers into a hexameric macrocycle was attempted. The same Pd(PPh3)2Cl2/Cu(I) catalyst and co-catalyst were used in these trials. Under several different Sonogashira reaction conditions, which included changing the temperature from room temperature to 40 °C to 70 °C, increasing reaction time from 24 h to 72 h, and adding tetrahydrofuran to the solvent mixture, however, a six-fold symmetric macrocycle could not be obtained (Scheme 2-7). 9.112.003.002.087.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)18.308.886.093.124.081.95DL 40.001.esp8.973.142.01CHCl3CHCl3CHCl37.8 7.7 7.6 7.5 7.4Chemical Shift (ppm)4.081.95CH2Cl2CH2Cl245 Scheme 2-7 Attempted intermolecular coupling of methoxy-capped trimers The 1H NMR spectrum of the reaction mixture had the same peaks present as the iodo-functionalized starting compound, 11 (Figure 2.8). This suggested that only compound 11 was recovered after the reaction and compound 12 formed some by-products that were lost in the reaction workup. It is possible that 12 could have polymerized to form an insoluble solid that was filtered out during the workup. 46 Another approach we tried was a Glaser-type coupling between two alkyne-functionalized trimers. This was conducted using a copper(II) catalyst in a 3:1 solvent mixture of acetonitrile:dichloromethane (Scheme 2-8). To avoid polymerization, this reaction was conducted under dilute conditions and the time for the reaction was extended to 72 hours. Purification of the crude product was conducted using flash column chromatography with silica gel as the stationary phase and a 5:2 mixture of chloroform:hexanes as the eluent. Using these reaction conditions, the macrocycle, 13, was obtained in 7% yield. The physical appearance of compound 13 was that of a colourless solid. No fluorescence was noticed when the solid was put under a UV lamp. The 18.119.051.926.043.012.021.942.1118.699.206.153.094.132.057.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)CHCl3CHCl3CHCl3CH2Cl2CH2Cl2CH2Cl2Figure 2.8 1H NMR spectra (300 MHz in CDCl3) of 12 (top), 11 (middle), and their reaction product (bottom) 47 isolated yields of the trimer and macrocycle products were low due to the formation of side products and difficulty in separation using column chromatography. Scheme 2-8 Synthesis of macrocycle 13 via intermolecular coupling of methoxy-capped trimers The synthesis of a macrocycle was confirmed with 1H and 13C NMR spectroscopy as well as mass spectrometry. The 1H NMR spectrum of 13 (Figure 2.9) resembles its oligomeric precursor 12, with two singlets corresponding to the two methoxy-proton environments and three aromatic proton environments. The alkyne peak at 3.3 ppm in the NMR spectrum of 12 is not present in the NMR spectrum of 13. The disappearance of the alkynyl proton in the NMR spectra is consistent with cross-coupling between half-macrocycles at their alkyne-terminals to form a macrocycle. The observed mass-to-charge ratio on the mass spectrum of 13 is m/z = 1165.5, which is consistent with the calculated mass of the macrocycle plus a proton, 1165.6 g·mol-1. 48 Figure 2.9 1H NMR spectra (300 MHz in CDCl3) of compound 12 and macrocycle 13 with enlarged partial spectra of the aromatic regions 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)18.189.026.002.992.072.102.082.021.942.11DL 51 f36.001.esp18.119.051.926.043.012.021.942.11CH2Cl2CH2Cl2CHCl3CHCl3Chemical Shift (ppm)7.7 7.6 7.5 7.4Chemical Shift (ppm)2.072.102.0849 2.3 Conclusion The synthesis of an arylene-ethynylene macrocycle was attempted using phenol derivatives and ester protected phenol derivatives as building blocks. These building blocks failed to oligomerize, but the failed reactions helped to rationalize a successful strategy. The phenol monomers were methylated in hopes that the smaller, less reactive methoxy functional group would tolerate oligomerization. A novel shape-persistent macrocycle with inter-annular methoxy functionalities was synthesized using a step-wise approach to synthesize oligomers, followed by intermolecular oligocyclization. Sonogashira coupling between two oligomers to form a macrocycle with six-fold symmetry was challenging so a less symmetric macrocycle was obtained using alkyne coupling. The synthetic route developed to make this macrocycle can be followed to synthesize similar structures. 50 2.4 Experimental General experimental details Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. All other chemicals were purchased from Sigma Aldrich or Alfa Aesar and used as received. Column chromatography was conducted using a stationary phase of silica gel with pore size 60 Å, 230-400 mesh particle size, and 40-63 μm particle size. 1H NMR (300 MHz) and 13C NMR (100.7 MHz) spectra were recorded on Bruker Avance 300 or Bruker Avance 400dir spectrometers and were referenced internally to residual protonated solvent. Synthetic procedures Synthesis of 2: 4-(tert-butyl)-2,6,-diiodophenol was synthesized following a literature preparation63 whereby 4-tert-butylphenol (3.004 g, 0.02 mol) and KI (6.641g, 0.04 mol) were added to a solution of concentrated H2SO4 (1.6 mL, 0.03 mol) in methanol (100 mL). To the reaction mixture, H2O2 (30%, 9.1 mL, 0.08 mol) was added. The mixture was stirred at 40 °C for 2 hours, then dichloromethane (300 mL) was added to the reaction mixture before transferring to a separatory funnel. The organic layer was washed with a NaHSO3(aq) solution (0.1 M, 200 mL), a Na2S2O3(aq) solution (10%, 200 mL), and water (200 mL) before drying with MgSO4(s). The organic layer was 51 then filtered and the solvent was removed under reduced pressure. The product was then purified using column chromatography (SiO2) with 1:2 dichloromethane:hexanes to give a red oil. Yield: 5.3669 g, 0.01335 mol, 67 %. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.64 (s, 2H), 5.58 (s, 1H), 1.26 (s, 9H), which is consistent with literature values.63 Synthesis of 3: 4-(tert-butyl)-2,6,-diiodophenol (0.4028 g, 1 mmol) was added to a round bottom flask with (Ph3P)2PdCl2 (0.0796 g, 0.1 mmol) and CuI (0.0387 g, 0.2 mmol). Triethylamine (10 mL) was added to the flask and the mixture was stirred at room temperature for 12 hours. The resulting brown slurry was filtered through Celite and washed with diethyl ether. The filtrate was transferred to a separatory funnel and washed with saturated ammonium chloride solution (2 x 40 mL) and water (3 x 80 mL). The organic layer was dried over MgSO4 and filtered, and the filtrate was taken to dryness with a rotary evaporator to give a brown solid. All product was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.36 (s, 2H), 6.12 (s, 1H), 1.27 (s, 9H), 0.28 (s, 18H). 52 Synthesis of 4: 4-(tert-butyl)-2,6-bis((trimethylsilyl)ethynyl)phenol (1 mmol, assumed) was dissolved in methanol (5 mL) and K2CO3 (0.659 g, 4.5 mmol) was added. The mixture was refluxed for 45 minutes. HCl(aq) (1 M, 3 mL) was added to the cooled reaction mixture and the mixture was transferred to a separatory funnel. Diethyl ether (2 x 40 mL) was used to extract the aqueous layer. The organic layers were combined and washed with water (2 x 40 mL) and brine (1 x 40 mL). The organic layer was dried with MgSO4, filtered, and taken to dryness with a rotary evaporator. The crude product was purified using flash column chromatography (SiO2) with a mixture of 1:1 dichloromethane:hexanes to give a red-orange oil. Yield: 0.150 g, 0.757 mmol, 75%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.45 (s, 2H), 6.05 (s, 1H), 3.42 (s, 2H), 1.30 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 156.25, 143.20, 130.94, 108.28, 82.91, 78.58, 34.07, 31.18. MS(ESI): m/z calc. for [C14H13O]-:197.1; found [M]-: 197.1. 53 Synthesis of 5: 4-(tert-butyl)-2,6,-diiodophenol (0.4020 g, 1 mmol), NaI (0.1508 g, 1 mmol), and K2CO3 (0.2784 g, 2 mmol) were added to a round bottom flask. Acetone (5 mL) and ethyl chloroacetate (0.1296 g, 1 mmol) were added to the flask and the mixture was refluxed under N2 flow for 12 h. The reaction mixture was filtered, washing with dichloromethane. The combined filtrate was transferred to a separatory funnel and washed with water (2 × 10 mL) and brine (10 mL). The organic layer was dried with MgSO4, filtered, and taken to dryness with a rotary evaporator to obtain a yellow oil. Yield: 0.3119 g, 0.6390 mmol, 64%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.75 (s, 2H), 4.58 (s, 2H), 4.39-4.32 (q, 3J= 7.08 Hz, 2H), 1.4-1.35 (t, 3J = 7.08 Hz, 3H), 1.29 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 167.68, 154.30, 151.76, 137.17, 89.96, 68.91, 61.34, 34.27, 31.14, 14.24. MS(ESI): m/z calc. for [(C14H18I2O3)Na]+: 510.9; found [MNa]+: 510.9. 54 Synthesis of 6: (PPh3)2PdCl2 (0.0423 g, 0.06 mmol) and CuI (0.0259 g, 0.13 mmol) were added to a Schlenk tube under N2. Compound 5 (0.3119 g, 0.64 mmol) was dissolved in triethylamine (3 mL) and added to the Schlenk tube via a syringe. The reaction was stirred at room temperature for 12 h and then the reaction mixture was filtered through Celite, and washed with diethyl ether. The brown filtrate was taken to dryness under reduced pressure to yield a brown oil. This product was used in its crude form in the next reaction. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.39 (s, 2H), 4.80 (s, 2H), 4.33-4.26 (q, 3J= 7.08 Hz, 2H), 1.35-1.30 (t, 3J = 7.08 Hz, 3H), 1.28 (s, 9H), 0.25 (s, 18H). Synthesis of 7: 55 Compound 6 (from the previous reaction) was dissolved in ethanol (5 mL) and K2CO3 (0.454 g, 3.2 mmol) was added to the solution. The mixture was refluxed under N2 for 30 minutes before cooling. To the cooled reaction mixture, HCl(aq) (1 M, 6 mL) was added. The product was extracted using diethylether (3 × 30 mL), washed with water (2 × 25 mL) and brine (2 × 25 mL), then dried with MgSO4. The organic layer was then dried under reduced pressure and purified using flash column chromatography on silica gel with a 3:1 dichloromethane:hexanes solvent mixture. The isolated product was a yellow oil. Yield: 0.0277 g, 0.09741 mmol, 16 %. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.47 (s, 2H), 4.89 (s, 2H), 4.32-4.24 (q, 3J= 7.18 Hz, 2H), 3.29 (s, 2H), 1.34-1.29 (t, 3J = 7.18 Hz, 3H), 1.29 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 168.65, 158.52, 146.60, 131.99, 115.09, 81.93, 79.41, 69.72, 61.05, 34.16, 30.99, 14.09. MS(ESI): m/z calc. for [(C18H20O3)Na]+: 306.8; found [MNa]+: 307.2. Synthesis of 8: 1,3-Diiodo-2-methoxy-5-(tert-butyl)benzene was synthesized following a literature procedure.64 4-(tert-butyl)-2,6,-diiodophenol (0.4071 g, 1 mmol) and K2CO3 (0.4180 g, 3 mmol) were added to a round bottom flask with acetone (5 mL). Methyl iodide (0.125 mL, 2 mmol) was added to the flask and the mixture was refluxed for 12 hours. The reaction was cooled and dissolved in dichloromethane. The mixture was then transferred to a separatory funnel and washed with water. The aqueous layer was extracted with dichloromethane (3 × 10 mL) and the organic 56 layers were combined, dried with MgSO4, and taken to dryness under reduced pressure to give a yellow oil. Yield: 0.3744 g, 0.8999 mmol, 89%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.74 (s, 2H), 3.84 (s, 3H), 1.28 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 156.33, 151.00, 136.94, 90.25, 60.55, 34.13, 31.16. MS(ESI): m/z calc. for [(C11H14I2O) – CH3]-: 400.9; found [M – CH3]-: 400.8. The proton NMR spectrum found is consistent with previously reported values.65 Synthesis of 9: 5-(tert-butyl)-1,3-diiodo-2-methoxybenzene (4.6994 g, 11 mmol), (Ph3P)2PdCl2 (0.7076 g, 1 mmol), and CuI (0.3848 g, 2 mmol) were added to a round bottom flask. The mixture was dissolved in triethylamine (83 mL) and ethynyltrimethylsilane (5.6 mL, 40 mmol) was added. After stirring at room temperature for 24 hours, the mixture was filtered over Celite and washed with dichloromethane. The combined filtrate was taken to dryness under reduced pressure to obtain a brown solid. The crude product was used for the subsequent reaction. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.37 (s, 2H), 3.98 (s, 3H), 1.26 (s, 9H), 0.25 (s, 18H). 57 Synthesis of 10: ((5-(tert-butyl)-2-methoxy-1,3-phenylene)bis(ethyne-2,1-diyl))bis(trimethylsilane) (assumed 11 mmol) was dissolved in methanol (100 mL) in a round bottom flask. To the flask, K2CO3 (7.6289 g, 55 mmol) was added and the mixture was refluxed for 1 hour. After cooling, HCl(aq) (1 M, 100 mL) was stirred into the mixture and the mixture was transferred into a separatory funnel. The product was extracted using diethyl ether (3 × 100 mL) and the organic layer was washed with H2O (2 × 100 mL) and brine (1 × 100 mL). The ether was then dried using MgSO4, filtered, and taken to dryness under reduced pressure. The crude product was purified using flash chromatorgraphy in 1:1 dichloromethane:hexanes to obtain a reddish brown oil. Yield: 1.8516 g, 8.722 mmol, 80%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.46 (s, 2H), 4.03 (s, 3H), 3.27 (s, 2H), 1.28 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 160.78, 146.31, 131.95, 115.55, 81.19, 79.77, 61.31, 34.19, 31.07. MS(ESI): m/z calc. for [(C15H16O)Na]+: 235.1; found [MNa]+: 235.2. Synthesis of 11: 58 5-(tert-butyl)-1,3-diiodo-2-methoxybenzene (0.9496 g, 0.6 mmol) and 5-(tert-butyl)-1,3-diethynyl-2-methoxybenzene (0.0284 g, 0.1 mmol) were dissolved in triethylamine (1 mL) in a vial. (Ph3P)2PdCl2 (0.0076 g, 0.01 mmol) and CuI (0.0044 g, 0.02 mmol) were added to the vial. The vial was sealed and the reaction was stirred at room temperature for 24 hours, then filtered through Celite, washing with dichloromethane. The filtrate was taken to dryness under reduced pressure and HCl(aq) (1 M, 5 mL) was added. The product was extracted using dichloromethane (3 × 50 mL) and the organic layers were combined and washed with H2O (2 × 50 mL) and brine (50 mL). The organic layer was dried with MgSO4 and taken to dryness with a rotary evaporator. The crude product was purified using flash column chromatography with 1:1 dichloromethane:hexanes and then with 1:3 dichloromethane:hexanes to obtain a thick, reddish brown oil. Yield: 0.0182 g, 0.0231 mmol, 17%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.77-7.76 (d, 4J = 2.31Hz, 2H), 7.53 (s, 2H), 7.52-7.52 (d, 4J = 2.31 Hz, 2H), 4.17 (s, 3H), 4.05 (s, 6H), 1.36 (s, 9H), 1.32 (s, 18H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 159.68, 158.07, 148.56, 146.54, 136.90, 131.00, 130.96, 116.66, 116.63, 91.70, 89.43, 61.56, 61.07, 34.39, 34.30, 31.22. MS(ESI): m/z calc. for [(C37H42I2O3)Na]+: 811.1; found [MNa]+: 811.0. Synthesis of 12: 59 The trimer 11 (0.3999 g, 0.5071 mmol), (Ph3P)2PdCl2 (0.0349 g, 0.0497 mmol), and CuI (0.0191 g, 0.100 mmol) were added to a round bottom flask. The mixture was dissolved in triethylamine (8 mL) and ethynyltrimethylsilane (0.25 mL, 1.8 mmol) was added. After stirring at room temperature for 24 hours, the mixture was filtered through Celite while washing with dichloromethane. The filtrate was then taken to dryness under reduced pressure. The resulting solid was dissolved in methanol (50 mL) and refluxed with K2CO3 (0.3479 g, 2.517 mmol) for 1 hour. HCl(aq) (1 M, 30 mL) was added to the reaction mixture once it was cooled to room temperature. The mixture was then extracted with dichloromethane (3 × 50 mL), washed with water (2 × 50 mL) and brine (50 mL). The organic layer was combined, dried with MgSO4, and taken to dryness. After flash column chromatography with 1:1 dichloromethane:hexanes, then 2:1 dichloromethane:hexanes, a red oil was collected. Yield: 0.1929 g, 0.3299 mmol, 65%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.55-7.54 (d, 4J = 2.31 Hz, 2H), 7.53 (s, 2H), 7.48-7.47 (d, 4J = 2.56 Hz, 2H), 4.18 (s, 3H), 4.13 (s, 6 H), 3.29 (s, 2H), 1.36 (s, 9H), 1.33 (s, 18H). MS(ESI): m/z calc. for [(C41H44O3)Na]+: 607.3; found [MNa]+: 607.1. 60 Synthesis of 13: The alkyne-terminated trimer 12 (0.4489 g, 0.7676 mmol) was dissolved in acetonitrile (75 mL) and dichloromethane (25 mL) in a round bottom flask. Cu(CH3COO)2 (0.3884 g, 1.945 mmol) was added and the mixture was refluxed for 72 hours. After cooling and taking the reaction to dryness under reduced pressure, the green solid was taken up in H2O and extracted with dichloromethane (3 × 100 mL). The organic layers were combined and taken to dryness. After flash column chromatography with 5:2 chloroform:hexanes, a white solid was isolated. Yield: 0.0325 g, 0.0279 mmol, 7%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.57-7.56 (d, 4J = 2.56 Hz, 4H), 7.54 (s, 4H), 7.49-7.49 (d, 4J = 2.31 Hz, 4H), 4.28 (s, 6H), 4.23 (s, 12H), 1.37 (s, 18H), 1.35 (s, 46H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 161.71, 160.75, 146.51, 131.26, 131.05, 130.29, 117.14, 117.07, 115.58, 90.17, 89.47, 78.48, 77.72, 61.86, 61.62, 34.40, 31.16, 29.70. MS(ESI): m/z calc. for [(C82H84O6)H]+: 1165.7; found [MH+]: 1165.5. 61 Chapter 3: Functionalizing Arylene-Ethynylene Hosts 3.1 Introduction Nature is a master of host-guest chemistry, as demonstrated by the many enzymes which facilitate the intricate chemical reactions required for life. Essential processes such as photosynthesis and metabolism are carried out by enzymes with remarkable control and under mild conditions.66 A prime example of this is the fixation of atmospheric dinitrogen into usable nitrogen-containing molecules such as ammonia. Nitrogenase enzymes that are found in microorganisms fix nitrogen at ambient temperature and pressure, a stark contrast to the energy-expensive, industrial Haber-Bosch process which requires high temperature and pressure in addition to an iron-based catalyst. Nitrogenase and other metalloenzymes employ metal clusters in their active sites to catalyze reactions.67 These enzymes provide inspiration for the synthesis of metal-containing host-guest complexes, which can be studied to provide insight into the function of natural enzymes and potentially be used in practical applications for their electronic or catalytic properties. The metal clusters in metalloenzymes are usually coordinated non-covalently by donor atoms from the protein’s amino acid chain that are oriented towards the enzyme active site. In a similar fashion, the macrocycle synthesized in the previous chapter was designed to have functional groups pointing towards the interior. With the synthetic approach toward our macrocycle established, we sought to functionalize the macrocycle with metal-coordinating groups. 62 3.2 Results and Discussion Demethylation attempts In Chapter 2, the synthesis of a methoxy-functionalized macrocycle (13) was described. Methoxy groups provide little opportunity for metal coordination, so we sought to demethylate these groups to obtain a hydroxy-lined macrocycle that could be appropriately functionalized. Both 13 and the trimer 11 were used in reactions in attempts to demethylate them. First, 13 and 11 were treated under reflux in glacial acetic acid with a catalytic amount of concentrated HBr. Even after 48 hours under reflux, only starting material was recovered from the reaction, as observed by 1H NMR spectroscopy. Next, 11 was treated under reflux in pyridine hydrochloride, which also did not demethylate the compound. Microwaving 11 in pyridine was also attempted, however no reaction appeared to occur and only starting material was observed by 1H NMR spectroscopy. The final attempts to demethylate compounds 11 and 13 involved reacting them with boron tribromide in dichloromethane. The presence of many different proton environments on the 1H NMR spectrum of the product mixture made it difficult to discern what the products of these reactions were. The reaction mixture separated into several different spots after using thin layer chromatography. These results suggest that reacting 11 and 13 with BBr3 caused the decomposition of the starting material. These demethylation attempts are summarized in Scheme 3-1. 63 Scheme 3-1 Attempted demethylation reactions with 11 and 13 64 Towards amine-functionalized macrocycles In our attempts to demethylate the macrocycle 13, either no reaction occurred, or the reactions resulted in the decomposition of the initial product. It seemed that the methoxy groups were too stable to react before the backbone of the macrocycle was compromised. Rather than continuing attempts to demethylate the methoxy-functionalized compounds, a different set of building blocks was used to reattempt the synthesis of a macrocycle from its monomers. The amine functional group was chosen since amines are known to participate in metal coordination and have been used as handles for post-synthetic functionalization to form ligands with different functional groups. Like hydroxides, aromatic amines are also ortho/para-directing, which is necessary to synthesize monomers to form a meta-connected macrocycle. Amine-functionalized monomers were synthesized using 4-tert-butylaniline as the starting reagent. First, 4-tert-butylaniline was iodinated using iodine monochloride in acidic solution. This yielded the diiodinated compound 14 which was easily isolated at 82% yield using column chromatography with a 1:1 mixture of dichloromethane:hexanes as the eluent on a silica gel stationary phase. Next, Sonogashira coupling of 14 with trimethylsilylacetylene was conducted at room temperature using Pd(PPh3)2Cl2 and CuI in triethylamine base. This reaction was followed by the removal of the TMS groups using potassium carbonate in methanol to give 16. Purification of the product was conducted using column chromatography with an eluent of 1:2 dichloromethane:hexanes on silica gel, resulting in a 67% isolated yield. The synthesis of the iodine-functionalized and alkyne-functionalized monomers 14 and 16 is outlined in Scheme 3-2. 65 Scheme 3-2 Synthesis of aniline-derived monomers Monomers 14 and 16 were used to form a trimer via a Sonogashira coupling reaction with Pd(PPh3)2Cl2 and CuI in triethylamine. For this reaction, a small excess of two equivalents of 16 was reacted with one equivalent of 14 to form a trimer with alkyne functional groups on either end (Scheme 3-3). Column chromatography of this product was conducted on silica gel using a 1:1 dichloromethane:hexanes eluent mixture. Poor separation occurred between 17 and its by-products, so the amount of product recovered was relatively low at 8% yield. However, the coupling reaction was successful as confirmed by 1H NMR data (Figure 3.1). The aromatic region of the NMR spectrum shows three different proton environments with splitting patterns consistent with the expected product. Additionally, two separate amine proton environments are observed for the outer and inner amine functionalities. Mass spectrometry of the product showed a peak at m/z = 562.7, which agrees with the mass of the product plus a sodium ion, 562.3 g·mol-1. 66 Scheme 3-3 Synthesis of amine-functionalized trimer 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)9.421.932.062.019.282.007.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)27.471.903.932.163.842.23Figure 3.1 1H NMR spectra (300 MHz in CDCl3) of 16 (top), 14 (middle), and 17 (bottom) 67 The amine-functionalized trimer 17 was synthesized to have terminal alkyne groups so that two trimers could be coupled together via a Glaser-type alkyne-to-alkyne coupling. The coupling of two equivalents of 17 was attempted to synthesize an amine-functionalized macrocycle (Scheme 3-4). The same conditions used to form the methoxy-functionalized macrocycle (13) were employed: copper(II) acetate was used to catalyze the reaction in a dilute solution of 3:1 acetonitrile:dichloromethane. The macrocyclization did not appear to be successful according to the corresponding NMR experiment, although a trace amount of macrocycle was detected by mass spectrometry (m/z observed = 1074.2, compared to the expected mass of 1074.6 g·mol-1 for M-). It is possible that the amine functional groups were participating in other reactions in the reaction conditions used, so adding a protecting group to the amine groups was investigated next. Scheme 3-4 Attempted intermolecular coupling of amine-functionalized trimer 68 Amine protection Attempts to protect the amine functional groups were explored. First, di-tert-butyl dicarbonate ((boc)2O) protection was attempted on 2,6-diiodo-tert-butylaniline under various conditions (Scheme 3-5). These attempts to protect the amine-functionalized monomer, 14, involved reacting 14 in neat di-tert-butyldicarbonate or with ((boc)2O) in one of the following solvents at room temperature: 1,2-dioxane, water, methanol, or acetonitrile. The reaction in methanol was repeated at reflux. All the attempts at boc protection resulted in only starting material, which might be due to the steric bulk of the iodo groups ortho to the amine preventing the boc group from approaching the amine. Scheme 3-5 Attempted ((boc)2O) protection of amine monomer Next, acetylating 2,6-diiodo-tert-butylaniline was conducted as an alternative protecting strategy with a less sterically hindered protecting group. Both compounds 14 and 16 were acetylated through refluxing in glacial acetic anhydride with a catalytic amount of concentrated sulfuric acid (Scheme 3-6). This resulted in the formation of a diacetanilide in both cases which was identified by 1H NMR spectroscopy (Figure 3.2) and mass spectrometry. This conclusion was supported by literature reports on the formation of diacetanilides that contain electron-withdrawing substituents in the ortho position.68 These diacetylated monomers were used in the Sonogashira cross-coupling conditions used for other monomers in attempts to form a trimer, but the formation 69 of a trimer was unsuccessful (Scheme 3-7). This may be attributed to the steric bulk of the diacetylated amine group preventing the monomers from getting close enough in solution. Acetylating the trimer, 17, using acetic acid and catalytic sulfuric acid was also attempted but was unsuccessful. Furthermore, deacetylating 18 using a 30% solution of KOH in 1:1 water:methanol did not remove the protecting group. Overall, the protecting group strategies attempted were not suitable for improving cross-coupling between the amine monomers. Ideally, a protecting group would be easily reacted onto the amine functionality and readily cleaved to deprotect the amine. A protecting group with less steric bulk would also be preferred since too much steric bulk may hinder the cross-coupling of monomers into a trimer. Scheme 3-6 Acetylation of amine-functionalized monomers 70 N+NIIPd(PPh3)2Cl2CuItriethylamineRTNR2INR2 R2NI19 18OO O OR =O Scheme 3-7 Attempted coupling of acetylated amine monomers 9.566.131.982.007.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)9.056.052.00CH2Cl2CHCl3CHCl3H2OFigure 3.2 1H NMR spectra (300 MHz in CDCl3) of diacetylated monomers 19 (top) and 18 (bottom) 71 Amine-functionalized crescent Although the synthesis of a macrocycle with amine functionalities was not achieved, the trimers could still be used in host-guest chemistry. To synthesize an amine-functionalized trimer without the terminal alkyne functional groups, the synthesis of compound 16 was adjusted to increase the yield of one of its by-products, the mono-iodinated aniline, 20 (Scheme 3-8). For this synthesis, 4-tert-butylaniline was reacted with iodine monochloride in a HCl(aq) solution, but only one equivalent of ICl was used. The product could be isolated at 94% yield using column chromatography on silica gel with a 1:1 mixture of dichloromethane:hexanes as eluent. Scheme 3-8 Synthesis of mono-iodinated tert-butylaniline, 20 Reacting 16 with slightly over two equivalents of 20, shown in Scheme 3-9 resulted in the synthesis of trimer 21. This compound was purified using column chromatography on a silica gel stationary phase with a mixture of chloroform, hexanes, and triethylamine (1:3:1 ratio, respectively) as eluent and isolated at 65% yield. The 1H NMR spectrum of 21 (Figure 3.3) shows two different amine proton environments and three separate aromatic proton environments with the expected splitting pattern for the product. Although the initial goal was to synthesize a macrocycle, the rationale behind synthesizing this product was to use it as a model compound for host-guest chemistry using an amine-functionalized arylene-ethynylene host. 72 Scheme 3-9 Synthesis of amine functionalized trimer, 21 10.011.962.032.069.591.981.031.030.997.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)17.979.003.561.722.312.134.00CHCl3(C2H5)2O(C2H5)2OCHCl3CHCl3CH2Cl2Figure 3.3 1H NMR spectra (300 MHz in CDCl3) of 16 (top), 20 (middle) and trimer product 21 (bottom) 73 Another molecule that was targeted is the pentamer shown in Scheme 3-10. The Sonogashira coupling of two equivalents of 2-iodo-4-tert-butylaniline to 17 to give the pentamer was pursued, but the 1H NMR spectrum of the reaction product suggested the presence of several different species with a small amount of the desired pentamer. After purifying the crude product with column chromatography there was not enough material left to be analyzed. Scheme 3-10 Attempted synthesis of amine-functionalized pentamer We intended to synthesize the molecules shown in Figure 3.4 so that a series of amine-functionalized arylene-ethynylene molecules could be compared in terms of their host-guest chemistry. Due to difficulties with synthesis and the formation of by-products using irreversible Sonogashira reaction conditions, the pentamer and macrocyclic products were not isolated and only the trimer, 21, is reported. 74 Figure 3.4 Amine-functionalized arylene-ethynylene molecules of varying shapes and sizes 3.3 Conclusion Several approaches were taken towards synthesizing arylene-ethynylene host molecules. First, demethylation of the methoxy-functionalized molecules synthesized in Chapter 2 was attempted. Unfortunately, under different reaction conditions this was not achieved. Next, the synthesis of a macrocycle was attempted using amine-functionalized monomers. Although product yields were low and purification was difficult, an amine-functionalized trimer with terminal alkynes was synthesized using a stepwise approach with Sonogashira cross-coupling. However, the final Glaser-type coupling to form a macrocycle was not successful. A suitable protecting group for the amine functionalities was not found, so overall an amine-functionalized macrocycle was not obtained. Instead, an amine-functionalized trimer with no terminal functional groups that could be used in host-guest chemistry was synthesized. 75 3.4 Experimental General experimental details Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. Triethylamine was distilled and stored over KOH(s) prior to use. All other chemicals were purchased from Sigma Aldrich or Alfa Aesar and used as received. Column chromatography was conducted using a stationary phase of silica gel with pore size 60 Å, 230-400 mesh particle size, and 40-63 μm particle size. 1H NMR (300 MHz) spectra were recorded on Bruker Avance 300dir spectrometers and were referenced internally to residual protonated solvent. Synthetic procedures Synthesis of 14: 4-tert-butyl-2,6-diiodoaniline was synthesized according to a previously reported procedure.63 4-tert-butylaniline (2.0874 g, 13.987 mmol) was dissolved in a solution of HCl (conc., 1.5 mL) in water (15 mL) in a round bottom flask. ICl (5.5 g, 34 mmol) was dissolved in a solution of HCl (conc., 4.4 mL) in water (18 mL) and added dropwise to the round bottom flask. After stirring at room temperature for 3 hours, chloroform (100 mL) was added to the reaction mixture. The chloroform was washed with KOH (1 M, 100 mL), Na2S2O3 (10 %, 100 mL), and H2O. After drying with MgSO4, the solution was taken to dryness under reduced pressure. The resulting dark purple oil was purified using flash column chromatography on silica gel with 1:1 dichloromethane:hexanes as the eluent. Yield: 4.6033 g, 11.479 mmol, 82%. 1H NMR (300 MHz, 76 CDCl3) δ (ppm) = 7.63 (s, 2H), 4.47 (s, 2H), 1.25 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 144.47, 143.61, 136.39, 81.75, 33.63, 31.28. MS(ESI): m/z calc. for [(C10H13I2N)H]+: 401.9; found [MH]+: 401.9. The NMR spectra are consistent with previously reported values.63 Synthesis of 15: 4-(tert-butyl)-2,6-diiodoaniline (4.0135 g, 10.079 mmol), (Ph3P)2PdCl2 (0.2901 g, 0.4133 mmol), and CuI (0.1617 g, 0.8490 mmol) were added to a round bottom flask. The mixture was dissolved with triethylamine (100 mL) and ethynyltrimethylsilane (5.0 mL, 36.17 mmol) was added. After stirring at room temperature for 24 hours, the mixture was filtered through Celite while washing with dichloromethane. The filtrate was then taken to dryness under reduced pressure and resulted in a dark brown solid. The yield was assumed to be quantitative and the crude product was used immediately in the next reaction. 1H NMR (300 MHz, CDCl3) δ (ppm) = 8.43 (s, 2H), 4.70 (s, 2H), 1.23 (s, 9H), 0.26 (s, 18H). Synthesis of 16: 77 The brown solid, 15, was dissolved in methanol (100 mL) and refluxed with K2CO3 (7.002 g, 50.66 mmol) for 1 hour. The reaction was then cooled to room temperature and H2O (100 mL) was added. The mixture was then extracted with diethylether (3 × 50 mL), washed with water (2 × 50 mL) and brine (2 × 50 mL). The organic layer was combined, dried with MgSO4, and taken to dryness. After flash column chromatography on silica gel with 1:2 dichloromethane:hexanes as the eluent, a dark red oil was collected. Yield: 1.4241 g, 7.2187 mmol, 67%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.37 (s, 2H), 4.73 (s, 2H), 3.40 (s, 2H), 1.26 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 147.95, 139.67, 130.38, 105.78, 82. 36, 80.49, 33.66, 31.11. MS(ESI): m/z calc. for [(C14H15N)H]+: 198.1; found [MH]+: 198.4. Synthesis of 17: 4-(tert-butyl)-2,6,-diiodoaniline (0.5124 g, 1.278 mmol) and an excess of 4-(tert-butyl)-2,6-diethynylaniline (1.4241 g, 7.2187 mmol) was dissolved in triethylamine (20 mL) with (Ph3P)2PdCl2 (0.0826 g, 0.118 mmol) and CuI (0.0460 g, 0.242 mmol). After stirring at room temperature for 24 hours, the reaction mixture was filtered through Celite while washing with dichloromethane. The filtrate was taken to dryness, then taken up in H2O (80 mL), and extracted with diethylether (3 × 50 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried with MgSO4, and taken to dryness. After flash column chromatography on 78 silica gel with 1:1 dichloromethane:hexanes, a red-orange solid was obtained. Yield: 0.0581 g, 0.108 mmol, 8%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.41 (d, 4J = 1.80 Hz, 2H), 7.39 (s, 2H), 7.39 (d, 4J = 1.54 Hz, 2H), 4.81 (s, 2H), 4.81 (s, 4H), 3.42 (s, 2H), 1.28 (s, 9H), 1.27 (s, 18H). MS(ESI): m/z calc. for [(C38H41N3)Na]+: 562.3; found [MNa]+: 562.7. Synthesis of 18: 4-(tert-butyl)-2,6-diiodoaniline (0.2559 g, 0.6381 mmol) was dissolved in acetic anhydride (2 mL), forming a red solution. Three drops of concentrated H2SO4(aq) was added to the solution using a pipette and the mixture was heated to 100°C for 2 minutes, after which the reaction mixture turned orange. The mixture was diluted with H2O (5 mL) and extracted with dichloromethane (3 × 20 mL). The organic layer was then washed with H2O (20 mL), dried with MgSO4, and then taken to dryness under reduced pressure. The product was obtained as an orange solid. Yield: 0.2893 g, 0.5964 mmol, 94%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.89 (s, 2H), 2.31 (s, 6H), 1.32 (s, 9H). MS(ESI): m/z calc. for [(C14H17I2NO2)Na]+: 507.9; found [MNa]+: 508.3. 79 Synthesis of 19: 4-(tert-butyl)-2,6-diethynylaniline (0.3115 g, 1.579 mmol) was dissolved in acetic anhydride (2 mL) to form an orange solution. Three drops of concentrated H2SO4(aq) was added to the solution using a pipette. The resulting mixture was heated to 85°C for 2 minutes, forming a yellow precipitate. After the reaction was cooled, water (10 mL) was added to the mixture. The product was extracted using diethylether (3 × 15 mL). The organic layer was dried with MgSO4(s) and taken to dryness under reduced pressure. The product was then purified using column chromatography with SiO2 as the stationary phase and dichloromethane as the eluent, after which a yellow solid was obtained. Yield: 0.0334 g, 0.119 mmol, 7%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.16 (s, 2H), 3.23 (s, 2H), 2.31 (s, 6H), 1.34 (s, 9H). MS(ESI): m/z calc. for [(C18H19NO2)Na]+: 304.1; found [MNa]+: 304.5. Synthesis of 20: 4-tert-butylaniline (1.974 g, 13.23 mmol) was dissolved in a solution of HCl(aq) (1.5 mL, concentrated) in water (15 mL) and in a separate flask, ICl (3.10 g, 19.1 mmol) was dissolve in a 80 solution of HCl(aq) (2.2 mL, concentrated) in water (9 mL). The ICl(aq) solution was then added dropwise to the 4-tert-butylaniline solution. The mixture was stirred overnight at room temperature. Chloroform (50 mL) was then added to the flask and the reaction mixture was neutralized with KOH(aq) (80 mL, 1 M). The chloroform layer was washed with Na2S2O3(aq) (30 mL, 10% concentration), H2O (30 mL), and brine (30 mL). The organic solution was then dried with MgSO4(s) and the solvent was evaporated under reduced pressure. The product was purified using column chromatography with silica as the stationary phase and a 1:1 mixture of dichloromethane and hexanes as the eluent. The product was isolated as a reddish-purple oil. Yield: 3.4188 g, 12.446 mmol, 94%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.64-7.63 (d, 4J = 2.06 Hz, 1H), 7.20-7.17 (dd, 4J = 2.06 Hz, 3J = 8.22 Hz, 1H), 6.73-6.70 (d, 3J = 8.45 Hz, 1H), 3.98 (s, 2H), 1.27 (s, 9H). 13C NMR (100.7 MHz, CDCl3) δ (ppm) = 144.13, 143.03, 135.47, 126.37, 114.42, 84.48, 33.69, 31.33. MS(ESI): m/z calc. for [(C10H14IN)H]+: 276.0; found [MH]+: 276.1. Synthesis of 21: 4-(tert-butyl)-2,6-diethynylaniline (0.1993 g, 1.037 mmol) and two equivalents of 4-tert-butyl-2-iodoaniline (0.6966 g, 2.532 mmol) were dissolved in triethylamine (25 mL) with (Ph3P)2PdCl2 (0.0646 g, 0.0920 mmol) and CuI (0.0379 g, 0.199 mmol). After stirring at room temperature for 72 hours, the reaction mixture was filtered through Celite while washing with dichloromethane. The filtrate was taken to dryness, then took up in H2O (50 mL), and extracted 81 with diethylether (3 × 50 mL). The organic layers were combined and washed with H2O (50 mL), and brine (50 mL) before drying with MgSO4 and being taken to dryness under reduced pressure. After flash column chromatography on silica gel with 1:3:1 chloroform:hexanes:triethylamine, a dark red, viscous oil was obtained. Yield: 0.3318 g, 0.6748 mmol, 65%. 1H NMR (300 MHz, CDCl3) δ (ppm) = 7.40-7.39 (d, 4J = 2.74 Hz, 2H), 7.23-7.19 (dd, 4J = 2.28 Hz, 3J = 8.45 Hz, 2H), 6.73-6.70 (d, 3J = 8.35 Hz, 2H), 4.83 (s, 2H), 4.19 (s, 4H), 1.31 (s, 9H), 1.30 (s, 18H). MS(ESI): m/z calc. for [(C34H41N3)H]+: 492.3; found [MH+]: 492.7. . 82 Chapter 4: Conclusion 4.1 Overview The goal of this thesis was to develop rigid, shape-persistent macrocycles with arylene-ethynylene backbones. The idea behind these macrocycles was to use them to form host-guest complexes with metal ions or clusters. While our proposed synthetic route to build trimers in a step-wise fashion was mostly successful, the final macrocyclization step between two trimers posed a challenge. Ultimately, a set of methoxy-functionalized and amine-functionalized arylene-ethynylene molecules was synthesized. Their development helps to pave the way for the synthesis of other AEMs with interior-facing functionalities, which may be used to develop novel host-guest complexes. 4.2 Significance of findings The study of polymetallic complexes as models of the many metalloenzymes found in nature can provide insight into the structure, properties, and function of these enzymes. Inspired by the important role of naturally occurring polymetallic complexes for functions such as electron transport and catalysis, new polymetallic complexes can be targeted to possess unique properties for diverse applications in catalysis, magnetism, and bioimaging. The MacLachlan group has considerable experience in the rational design and synthesis of macrocyclic structures as well as using a variety of large ligands to form multimetallic complexes. For these reasons, we were motivated to investigate the synthesis of modular, shape-persistent macrocyclic structures that could participate in metal complexation and perhaps act as models for metalloenzymes in nature. One challenge in the synthesis of metallic clusters or nanoparticles is uniformity in size and shape of these particles. We hypothesized that if a rigid, shape-persistent macrocycle was used 83 to template the formation of metal clusters or particles, the size of the resulting cluster would be controlled by the size and shape of the macrocycle. Our proposed synthesis of AEMs involved the step-wise coupling of oligomers to build up to a macrocycle. While the building of monomers using our proposed method proceeded as expected, macrocyclization of the oligomers did not proceed as expected. Although the scope of this thesis does not reach any complexation studies, we were able to establish a route to synthesizing arylene-ethynylene hosts that can be modified to incorporate different functional groups or structural characteristics. 4.3 Future directions To further this research project, arylene-ethynylene hosts with extended structures or different functional groups may be pursued. Following the step-wise strategy used to synthesize the compounds described in this thesis, a family of model molecules can be obtained to study the complexation of metal clusters in binding pockets of varying size. Extended ligands can be synthesized by coupling additional building blocks into the arylene-ethynylene backbone (Figure 4.1). Different metal-coordinating groups can also be incorporated into arylene-ethynylene molecules during the synthesis. For example, 2,2’-bipyridine is a linear molecule known to form complexes to many transition metals, so coupling this moiety into an AEM backbone may provide another route to synthesizing AEM host molecules. 84 Figure 4.1 Arylene-ethynylene groups that can be incorporated into ligand backbone by coupling reactions Additionally, the amine functional groups present on the molecules described in Chapter 3 provide handles for post-synthetic functionalization and can be converted into carboxylic acids or other functional groups through coupling with an acyl chloride (Scheme 4-1). New functionalities introduced through post-synthetic modification would broaden the scope of metal clusters that may be complexed by the ligands. Scheme 4-1 Proposed post-synthetic modification of amine functional groups Another research area that was not explored in this thesis is the aggregation behaviour of the new molecules. The methoxy-functionalized macrocycle and other arylene-ethynylene structures synthesized for this project may have the tendency to stack and form columns or other 85 aggregates. The solution behaviour of arylene-ethynylene macrocycles may prove to be interesting and can be investigated using variable temperature or variable concentration NMR spectroscopy and mass spectrometry. Observing aggregation effects between arylene-ethynylene molecules with different sizes, shapes, or substituents may give insight into how these factors affect aggregation numbers. Finally, in future studies the molecules described in this thesis should be reacted with transition metal salts to attempt to form complexes. Having a diversity of arylene-ethynylene host molecules would allow for the investigation of the effect of host structure on the templated metal cluster. Whether or not the size and shape of a metal cluster can be controlled by a rigid host molecule would be a significant finding in the field of host-guest chemistry. 86 Bibliography (1) Pedersen, C. J. The Discovery of Crown Ethers (Nobel Address). Angew. Chem. Int. Ed. 1988, 100, 1053–1059. (2) Pedersen, C. J. Cyclic Polyethers and Their Complexes with Metal Salts. J. Am. Chem. Soc. 1967, 89, 7017–7036. (3) Lehn, J. ‐M. Supramolecular Chemistry—Scope and Perspectives Molecules, Supermolecules, and Molecular Devices (Nobel Lecture). Angew. Chem. Int. Ed. 1988, 27, 89–112. (4) Cram, D. J. The Design of Molecular Hosts, Guests, and Their Complexes (Nobel Lecture). Angew. Chem. Int. Ed. 1988, 27, 1009–1112. (5) Sauvage, J. P. From Chemical Topology to Molecular Machines (Nobel Lecture). Angew. Chem. Int. Ed. 2017, 56, 11080–11093. (6) Stoddart, J. F. Mechanically Interlocked Molecules (MIMs)—Molecular Shuttles, Switches, and Machines (Nobel Lecture). Angew. Chem. Int. Ed. 2017, 56, 11094–11125. (7) Feringa, B. L. The Art of Building Small: From Molecular Switches to Motors (Nobel Lecture). Angew. Chem. Int. Ed. 2017, 56, 11060–11078. (8) Lehn, J. M. Towards Complex Matter: Supramolecular Chemistry and Self-Organization. Eur. Rev. 2009, 17, 263–280. (9) Steed, J.; Turner, D.; Wallace, K. Core Concepts in Supramolecular Chemistry and Nanochemistry; 2008. (10) Lehn, J. M. Cryptates: Inclusion Complexes of Macropolycyclic Receptor Molecules. Pure Appl. Chem. 1978, 50, 871–892. (11) Beer, P. D.; Gale, P. A.; Smith, D. K. Supramolecular Chemistry; Oxford University 87 Press, 1999. (12) Buckingham, A. D.; Fowler, P. W.; Hutson, J. M. Theoretical Studies of van Der Waals Molecules and Intermolecular Forces. Chem. Rev. 1988, 88, 963–988. (13) Biedermann, F.; Nau, W. M.; Schneider, H. J. The Hydrophobic Effect Revisited - Studies with Supramolecular Complexes Imply High-Energy Water as a Noncovalent Driving Force. Angew. Chem. Int. Ed. 2014, 53, 11158–11171. (14) Hu, W. B. The Melting Point of Chain Polymers. J. Chem. Phys. 2000, 113, 3901–3908. (15) Autumn, K.; Liang, Y. A.; Hsieh, S. T.; Zesch, W.; Chan, W. P.; Kenny, T. W.; Fearing, R.; Full, R. J. Adhesive Force of a Single Gecko Foot-Hair. Nature 2000, 405, 681–685. (16) He, J.; Liu, Y.; Babu, T.; Wei, Z.; Nie, Z. Self-Assembly of Inorganic Nanoparticle Vesicles and Tubules Driven by Tethered Linear Block Copolymers. J. Am. Chem. Soc. 2012, 134, 11342–11345. (17) Reches, M.; Snyder, P. W.; Whitesides, G. M. Folding of Electrostatically Charged Beads-on-a-String as an Experimental Realization of a Theoretical Model in Polymer Science. Proc. Natl. Acad. Sci. 2009, 106, 17644–17649. (18) Wilkinson, G.; Gallard, R. D.; McCleverty, J. A. Comprehensive Coordination Chemistry: The Synthesis, Reactions, Properties, & Applications of Coordination Compounds; 1987. (19) Stang, P. J.; Whiteford, J. A. Mixed, Neutral-Charged, Platinum-Platinum and Platinum-Palladium Macrocyclic Tetranuclear Complexes. Organometallics 1994, 13, 3776–3777. (20) Timsit, Y.; Moras, D.; Moras, D. DNA Self-Fitting: The Double Helix Directs the Geometry of Its Supramolecular Assembly. EMBO J. 1994, 13, 2737–2746. (21) Fabian, H.; Naumann, D. Protein Folding and Misfolding. Nature 2003, 426, 6968. (22) Hubin, T. J.; Busch, D. H. Template Routes to Interlocked Molecular Structures and 88 Orderly Molecular Entanglements. Coord. Chem. Rev. 2000, 200–202, 5–52. (23) Schneider, H.-J.; Yatsimirsky, A. K. Selectivity in Supramolecular Host–guest Complexes. Chem. Soc. Rev. 2008, 37, 263–277. (24) Douglas, T.; Young, M. Host-Guest Encapsulation of Materials by Assembled Virus Protein Cages. Nature 1998, 393, 152–155. (25) Cullen, W.; Thomas, K. A.; Hunter, C. A.; Ward, M. D. PH-Controlled Selection between One of Three Guests from a Mixture Using a Coordination Cage Host. Chem. Sci. 2015, 6, 4025–4028. (26) Anand, R.; Borghi, F.; Manoli, F.; Manet, I.; Agostoni, V.; Reschiglian, P.; Gref, R.; Monti, S. Host-Guest Interactions in Fe(III)-Trimesate MOF Nanoparticles Loaded with Doxorubicin. J. Phys. Chem. B 2014, 118, 8532–8539. (27) Smith, M. K.; Miljanić, O. Š. Arylene Ethynylene Macrocycles: From Molecular Hosts to Components of High-Performance Supramolecular Architectures. Org. Biomol. Chem. 2015, 13, 7841–7845. (28) Höger, S. Shape-Persistent Macrocycles: From Molecules to Materials. Chem. Eur. J. 2004, 10, 1320–1329. (29) Yoshizawa, M.; Tamura, M.; Fujita, M. Diels-Alder in Aqueous Molecular Hosts: Unusual Regioselectivity and Efficient Catalysis. Science 2006, 312, 251--254. (30) Newcomb, M.; Toner, J. L.; Helgeson, R. C.; Cram, D. J. Host-Guest Complexation. 20. Chiral Recognition in Transport as a Molecular Basis for a Catalytic Resolving Machine. J. Am. Chem. Soc. 1979, 101, 4941–4947. (31) Langton, M. J.; Beer, P. D. Rotaxane and Catenane Host Structures for Sensing Charged Guest Species. Acc. Chem. Res. 2014, 47, 1935–1949. 89 (32) Iacovelli, L.; Franchetti, R.; Grisolia, D.; De Blasi, A. Selective Regulation of G Protein-Coupled Receptor-Mediated Signaling by G Protein-Coupled Receptor Kinase 2 in FRTL-5 Cells: Analysis of Thyrotropin, Α1B-Adrenergic, and A1 Adenosine Receptor-Mediated Responses. Mol. Pharmacol. 1999, 56, 316–324. (33) Hu, W.-B.; Hu, W.-J.; Liu, Y. A.; Li, J.-S.; Jiang, B.; Wen, K. Multicavity Macrocyclic Hosts. Chem. Commun. 2016, 52, 12130–12142. (34) Frischmann, P. D.; Guieu, S.; Tabeshi, R.; MacLachlan, M. J. Columnar Organization of Head-to-Tail Self-Assembled Pt4 Rings. J. Am. Chem. Soc. 2010, 132, 7668–7675. (35) Chen, T.; Pan, G.; Wettach, H.; Fritzsche, M.; Ho, S.; Wan, L.; Yang, H.; Northrop, B. H.; Stang, P. J. 2D Assembly of Metallacycles on HOPG by Shape-Persistent Macrocycle Templates. J. Am. Chem. Soc. 2010, 132, 1328–1333. (36) Seo, S. H.; Jones, T. V; Seyler, H.; Peters, J. O.; Kim, T. H.; Chang, J. Y.; Tew, G. N. Liquid Crystalline Order from Ortho-Phenylene Ethynylene Macrocycles. J. Am. Chem. Soc. 2006, 9264–9265. (37) Buschmann, H. J. The Macrocyclic and Cryptate Effects. 5. Complexation of Alkali Ions by Monocyclic and Bicyclic Ligands in Methanol. Inorg. Chim. Acta 1986, 125, 31–35. (38) Gutsche, C. D.; Levine, J. A. Calixarenes. 6. Synthesis of a Functionalizable Calix[4]Arene in a Conformationally Rigid Cone Conformation. J. Am. Chem. Soc. 1982, 104, 2652–2653. (39) Xue, M. I. N.; Yang, Y.; Chi, X.; Zhang, Z.; Huang, F. Pillararenes, a New Class of Macrocycles for Supramolecular Chemistry. Acc. Chem. Res. 2012, 45, 1294–1308. (40) Freeman, W. A.; Mock, W. L.; Shih, N. Y. Cucurbituril. J. Am. Chem. Soc. 1981, 103, 7367–7368. 90 (41) Crini, G. Review: A History of Cyclodextrins. Chem. Rev. 2014, 114, 10940–10975. (42) Shetty, A. S.; Zhang, J.; Moore, J. S.; August, R. V. Aromatic π -Stacking in Solution as Revealed through the Aggregation of Phenylacetylene Macrocycles. J. Am. Chem. Soc. 1996, 118, 1019–1027. (43) Hensel, V.; Lützow, K.; Jacob, J.; Gessler, K.; Saenger, W.; Schlüter, A. D. Repetitive Construction of Macrocyclic Oligophenylenes. Angew. Chem. Int. Ed. 1997, 36, 2654–2656. (44) Velten, M. R. Synthesis, Solution Properties and Conversion of Poly(2,9-o-Phenanthroline-Alt-(2’,5’-Dihexyl)-4,4"-p-Terphenylene)s into Soluble, Well-Defined Copper(I) and Silver(I) Complex Polymers. Macromol. Chem. Phys. 1998, 199, 127–140. (45) Wu, Z.; Hu, T.; He, L.; Gong, B. One-Pot Formation of Aromatic Tetraurea Macrocycles. Org. Lett. 2012, 14, 2504–2507. (46) Tobe, Y.; Utsumi, N.; Nagano, A.; Sonoda, M.; Naemura, K. Synthesis of Butadiyne-Bridged [4n] Metacyclophanes Having Exo-Annular t-Butyl Groups. Tetrahedron 2001, 57, 8075–8083. (47) Frischmann, P. D.; Sahli, B. J.; Guieu, S.; Patrick, B. O.; MacLachlan, M. J. Sterically-Limited Self-Assembly of Pt4 Macrocycles into Discrete Non-Covalent Nanotubes: Porous Supramolecular Tetramers and Hexamers. Chem. Eur. J. 2012, 18, 13712–13721. (48) Chen, S.; Yan, Q.; Li, T.; Zhao, D. Arylene Ethynylene Macrocycles with Intramolecular π - π Stacking. Org. Lett. 2010, 12, 4784.4787. (49) Zhao, D.; Moore, J. S. Shape-Persistent Arylene Ethynylene Macrocycles : Syntheses and Supramolecular Chemistry. Chem. Commun. 2003, 807–818. (50) Zhang, W.; Moore, J. S. Shape-Persistent Macrocycles: Structures and Synthetic 91 Approaches from Arylene and Ethynylene Building Blocks. Angew. Chem. Int. Ed. 2006, 45, 4416–4439. (51) Gawroński, J.; Kołbon, H.; Kwit, M.; Katrusiak, A. Designing Large Triangular Chiral Macrocycles: Efficient [3 + 3] Diamine-Dialdehyde Condensations Based on Conformational Bias. J. Org. Chem. 2000, 65, 5768–5773. (52) MacLachlan, M. J. Conjugated Shape-Persistent Macrocycles via Schiff-Base Condensation: New Motifs for Supramolecular Chemistry. Pure Appl. Chem. 2006, 78, 873–888. (53) Staab, H. A.; Neunhoeffer, K. Metacyclophane-1,9,17,25,33,41-Hexayne from m-Iodophenylacetylene by Sixfold Stephens-Castro Coupling. Synthesis 1974, 424. (54) Moore, J. S.; Zhang, J. Efficient Synthesis of Nanoscale Macrocyclic Hydrocarbons. Angew. Chem. Int. Ed. 1992, 31, 922–924. (55) Gross, D. E.; Zang, L.; Moore, J. S. Arylene-Ethynylene Macrocycles: Privileged Shape-Persistent Building Blocks for Organic Materials. Pure Appl. Chem. 2012, 84, 869–878. (56) Opris, D. M.; Franke, P.; Schlüter, A. D. Shape-Persistent Macrocycles with Bipyridine Units: Progress in Accessibility and Widening of Applicability. Eur. J. Org. Chem. 2005, 822–837. (57) Höger, S.; Xiao, H. C.; Ramminger, A. D.; Enkelmann, V.; Rapp, A.; Mondeshki, M.; Schnell, I. Discotic Liquid Crystals with an Inverted Structure. Angew. Chem. Int. Ed. 2005, 44, 2801–2805. (58) Tobe, Y.; Utsumi, N.; Kawabata, K.; Nagano, A.; Adachi, K.; Araki, S.; Sonoda, M.; Hirose, K.; Naemura, K. M-Diethynylbenzene Macrocycles: Syntheses and Self-Association Behavior in Solution. J. Am. Chem. Soc. 2002, 124, 5350–5364. 92 (59) Campbell, K.; Kuehl, C. J.; Ferguson, M. J.; Stang, P. J.; Tykwinski, R. R. Coordination-Driven Self-Assembly: Solids with Bidirectional Porosity. J. Am. Chem. Soc. 2002, 124, 7266–7267. (60) Ferrara, J. D.; Tessler-youngs, C.; Youngs, W. J. Synthesis and Characterization of a Copper(I) Triflate Complex of 1,2:5,6:9,10-Tribenzo-Cyclododeca-1,5,9-Triene-3,7,11-Triyne. Organometallics 1987, 6, 676–678. (61) Yu, C.; Jin, Y.; Zhang, W. Shape-Persistent Arylene Ethynylene Organic Hosts for Fullerenes. Chem. Rec. 2015, 15, 97–106. (62) Popov, I.; Chen, T.; Belyakov, S.; Daugulis, O.; Wheeler, S. E.; Miljanić, O. Š. Macrocycle Embrace : Encapsulation of Fluoroarenes by m - Phenylene Ethynylene Host. Chem. Eur. J. 2015, 21, 2750–2754. (63) Iskra, J.; Stavber, S.; Zupan, M. Nonmetal-Catalyzed Iodination of Arenes with Iodide and Hydrogen Peroxide. Synthesis 2004, 2004, 1869–1873. (64) Bonanno, N. M.; Lough, A. J.; Prosser, K. E.; Walsby, C. J.; Poddutoori, P. K.; Lemaire, M. T. A Stable Open-Shell Redox Active Ditopic Ligand. Dalt. Trans. 2016, 45, 5460–5463. (65) Helgeson, R. C.; Selle, B. J.; Goldberg, I.; Knobler, C. B.; Cram, D. J. 18-Membered-Ring Spherands Containing Five Anisyl Groups. J. Am. Chem. Soc. 1993, 115, 11506–11511. (66) Kuah, E.; Toh, S.; Yee, J.; Ma, Q.; Gao, Z. Enzyme Mimics: Advances and Applications. Chem. Eur. J. 2016, 22, 8404–8430. (67) Hoffman, B. M.; Lukoyanov, D.; Yang, Z.; Dean, D. R.; Seefeldt, L. C. Mechanism of Nitrogen Fixation by Nitrogenase : The Next Stage Mechanism of Nitrogen Fixation by Nitrogenase : The Next Stage. Chem. Rev. 2014, 114, 4041–4062. 93 (68) Ayyangar, N. R.; Srinivasan, K. V. Effect of Substituents in the Formation of Diacetanilides. Can. J. Chem. 1984, 62, 1292–1296.
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Chemistry
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Towards arylene-ethynylene based supramolecular hosts
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