Self-Assembling [2.2]Paracyclophanes

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Self-Assembling 2.2Paracyclophanes
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english
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Meese,Michael J,Jr
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University of Florida
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Gainesville, Fla.
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Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
Castellano, Ronald K
Committee Members:
Dolbier, William R
Reynolds, John R

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Subjects / Keywords:
assembly -- paracyclophane -- self -- stack
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, M.S.
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theses   ( marcgt )
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Abstract:
The unique molecular shape and structure of 2.2paracyclophane has attracted the attention of chemists for over sixty years, but the platform has only recently emerged as an interesting building block for the construction of -conjugated materials for organic optoelectronic applications. Two short carbon bridges hold its two benzene rings in a confined geometry, and allow for efficient through-space interactions between the rings. Reported here is the synthesis and investigation of the first 2.2paracyclophane derivatives that are rationally designed for self-assembly through hydrogen bonding. The design, guided by molecular mechanics calculations, positions amide functional groups at the 4, 7, 12, and 15 positions of the 2.2paracyclophane core. This substitution pattern allows for both intra- and intermolecular amide hydrogen bonding, and ideally, the formation of one-dimensional assemblies. The synthesis of four tetra-amides and two mono-amides (as model systems) begins from appropriately halogenated 2.2paracyclophane precursors and follows with lithium-halogen exchange, quenching with CO2, and amide bond formation. Spectroscopic studies in solution (by IR, 1H NMR, and CD) have characterized the hydrogen bonding properties of the molecules in response to temperature, concentration, and solvent. The results of bulk studies, including polarized optical microscopy (POM) and thermogravimetric analysis (TGA), show that hydrogen bonding confers long-range structural order and remarkable thermal stability to the otherwise thermally-sensitive 2.2paracyclophane core.
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In the series University of Florida Digital Collections.
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Includes vita.
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Statement of Responsibility:
by Michael J Meese.
Thesis:
Thesis (M.S.)--University of Florida, 2011.
Local:
Adviser: Castellano, Ronald K.
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RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2013-08-31

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1 SELF ASSEMBLING [2.2]PARACYCLOPHANES By MICHAEL JOSEPH MEESE JR. A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2011

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2 2011 Michael Joseph Meese Jr.

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3 To my p arents

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4 ACKNOWLEDGMENTS First and for emost I would like to thank my p arents, Michael and Catherine Meese, for their love and support throughout my education. I would not have gotten to where I am today without them. I would like to thank my wife, Mary Kate Meese, for her constant love and care during the course of my gra duate career. I would also like to thank my s ister Rebecca Meese, for her friendship and endless support as well as my friends, old and new, for influencing me throughout my life. You have always been there for me to count on. I would also like to thank my advisor, Dr. Ronald K. Castellano for his help and guidance during my time here at th e University of Florida. His direction has been unparalleled throughout my graduate career. I would like to thank the members of the Castellano group; t heir assistance was vital to the research I have completed and I could not have done it without them. I would like to thank my committee m embers, Professors John Reynolds and William Dolbier, for their willingness to help in my pursuit of this degree. Finally, I would like to thank the University of Florida Department of Chemistry and NSF for the fundin g of this research.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 LIST OF ABBREVIATIONS ................................ ................................ ........................... 10 ABSTRACT ................................ ................................ ................................ ................... 11 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ .... 13 Supramolecular Chemistry ................................ ................................ ...................... 13 Hydrogen Bonding ................................ ................................ ............................ 14 ................................ ................................ ................................ 15 Aromatic 1 D Columnar Stacks ................................ ................................ ............... 17 Supramolecular Polymers ................................ ................................ ................ 17 Examples of 1 D Columnar Assembly ................................ .............................. 19 ................................ ................................ ........................ 19 s ................................ ................................ ...................... 20 ................................ ................................ ........................... 21 Applications and Advantages of Supramolecular Polymers ............................. 22 [2.2]Paracyclophane ................................ ................................ ............................... 23 Through Bond and Through Space Interactions ................................ .............. 24 [2.2]Paracyclophane Containing Polymers ................................ ....................... 25 Stacked Paracyclophane Polymers ................................ ................................ .. 27 Applications of [2.2]Paracyclophane ................................ ................................ 28 Design of a Self Assembling [2.2]Paracyclophane System ................................ .... 29 2 RESULTS AND DISCUSSION ................................ ................................ ............... 31 Design ................................ ................................ ................................ ..................... 31 Molecular Modeling ................................ ................................ .......................... 32 Synthetic Scheme ................................ ................................ ............................ 33 Synthesis of mono and tetra amides ................................ ........................ 34 Unsuccessful synthetic attempts ................................ ................................ 35 Characterization of Assembly ................................ ................................ ................. 37 Infrared Spectroscopy ................................ ................................ ...................... 37 1 H Nuclear Magnetic Resonance Spectroscopy ................................ ............... 39 Concentration study ................................ ................................ ................... 42 Temperature study ................................ ................................ ..................... 4 6 Circular Dichroism ................................ ................................ ............................ 47

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6 Polarized Optical Microscopy Images ................................ .............................. 49 Thermogravimetric Analysis ................................ ................................ ............. 50 3 CONCLUSION ................................ ................................ ................................ ........ 53 Concluding Comments ................................ ................................ ............................ 53 Future Directions ................................ ................................ ................................ .... 54 Characterization of Compound 7d ................................ ................................ .... 54 Other Model Systems ................................ ................................ ....................... 55 Synthesis of Other Derivatives of 7 ................................ ................................ .. 55 Synthesis of Other Hydrogen Bonding Groups ................................ ................. 56 Using [3.3]Paracyclophane as an Aromatic Core ................................ ............. 56 4 EXPERIMENTAL ................................ ................................ ................................ .... 57 General ................................ ................................ ................................ ................... 57 Materials ................................ ................................ ................................ ........... 57 Molecular Modeling ................................ ................................ .......................... 57 Infrared Spect roscopy ................................ ................................ ...................... 57 Nuclear Magnetic Resonance Spectroscopy ................................ .................... 57 Circular Dichroism ................................ ................................ ............................ 58 Thermogravimetric Analysis ................................ ................................ ............. 58 Polari zed Optical Microscopy ................................ ................................ ........... 58 Mass Spectrometry ................................ ................................ .......................... 58 Synthetic Schemes and Characterization ................................ ............................... 58 [2.2]Paracyclophane (1) ................................ ................................ ................... 58 () 4 Br omo[2.2]paracyclophane (2) ................................ ................................ 59 () 4 Carboxy[2.2]paracyclophane (3) ................................ .............................. 59 () 4 Mono( n butyl)amide[2.2]paracyclophane (4a) ................................ ......... 59 () 4 Mono(phenyl)amide[2.2]paracyclophane (4b) ................................ ......... 60 () 4,7,12,15 Tetra bromo[2.2]paracyclophane (5) ................................ .......... 61 () 4,7,12,15 Tetra carboxy[2.2]paracyclophane (6) ................................ ........ 61 () 4,7,12,15 Tetra( n butyl)amide[2.2]paracyclophane (7a) ............................. 62 () 4,7,12,15 Tetra(phenyl)amide[2.2]paracyclophane (7b) ............................. 63 4,7,12,15 Tetra[((S) methyl)benzyl]amide[2.2]paracyclophane (7c) ............. 64 () 4,7,12,15 Tetra[(1,3,5 trisdodecyloxy)phenyl]amide[2.2]paracyclophane (7d) ................................ ................................ ................................ ................ 65 APPENDIX: N UCLEAR M AGNETIC R ESONANCE SPECTRA ................................ .... 67 LIST OF REFERENCES ................................ ................................ ............................... 71 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 75

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7 LIST OF TABLES Table page 2 1 1 H NMR (300 MHz) chemical shift of NH peak for model systems in CDCl 3 at 50 mM and 5 mM ................................ ................................ ................................ 41 2 2 1 H NMR (300 MHz) chemical shift of NH peak for tetra amide systems in CDCl 3 at 0.25 mM ................................ ................................ ............................... 42 2 3 Peak shift maxima and minima and K dim for NH and CH aromatic peaks ........... 46 2 4 1 H NMR (300 MHz) NH chemical shift of 7a at different temperatures ............... 47

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8 LIST OF FIGURES Figure page 1 1 Cartoon drawings of A) a catenane, B) a rotaxane ................................ ............. 13 1 2 cyclodextrin (seven glucose rings) ................................ ................................ ................................ ..... 14 1 3 Example of intermolecular hydrogen bonds between amide groups .................. 15 1 4 benzene rings. A) stacked benzenes, B) T shaped benzene rings, C) slip stacked benzene rings ................................ .................... 15 1 5 Example of perfluorinated derivatives. A) 1,3,5 tris(phenethynyl)benzene, B) 1,3,5 tris(perfluorophen ethynyl)benzene, C) co crystal (CSD code: WEVYIF) 9 ................................ ................................ ................................ ........... 16 1 6 Cartoon drawings of the three types of supramolecular polymerization mechanisms. A) isodesmic, B) ring chain, C) cooperative (arrows indicate polymer growth) ................................ ................................ ................................ .. 18 1 7 C 3 symmetric discotic system, B) figure showing the hydroge n bonding within an individual columnar stack ......... 20 1 8 Examples of systems developed by Nuckolls. A) alkyne system, B) alkoxy system ................................ ................................ ................................ ................ 21 1 9 Example of a system developed by Geerts ................................ ........................ 22 1 10 Models derived from molecular mechanics using AMBER forcefield of [2.2]paracyclophane A) top view, B) side view ................................ ................... 23 1 11 [2.2]Paracyclophane. A) distances between carbons on [2.2]paracyclophane, B) numbering scheme of [2.2]paracyclophane carbons 40 ................................ ... 24 1 12 Common naming patterns of substituted [2.2]paracyclophanes 40 ...................... 24 1 13 Emission of cyclophane containing oligomers. A) Example of emission from cyclophane state, B) example of emission from chromophore state (figure adapted fr om reference 44) ................................ ................................ ................ 26 1 14 [2.2]paracyclophane is aligned into columns ................................ ...................... 27 1 15 System developed by the Collard group to align [2.2]paracyclophanes into stacks ................................ ................................ ................................ ................. 28 1 16 Structures of mono and tetra amide substituted [2.2]paracyclophanes ............. 30

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9 1 17 Models of methyl derivatives A) 4 B) 7 (parallel intramolecular hydrogen bonds), C) anti parallel intramolecular hydrogen bonds) ................................ .... 30 2 1 Enantiomers of cyclophanes 4 and 7 ................................ ................................ 31 2 2 Molecular models (with hydrogen bonds shown) of amides synthesized in this thesis A) 4a B) 4b C) 7a D) 7b ................................ ................................ 33 2 3 Molecular models for dimers of methyl derivatives A) 4 B) 7 (hydrogen bonds shown in anti parallel conformation). ................................ ....................... 33 2 4 Synthetic scheme for synthesis of 4a and 4b ................................ ..................... 34 2 5 Synthetic scheme for the preparation of 7a d ................................ .................... 36 2 6 Attempt to synthesize a tetra nitrile as a precursor to amide derivatives ............ 36 2 7 Attempted synthesis of 4,12 di amides ................................ ............................... 37 2 8 IR in chloroform solution. A) 4a (0.5mM), B) 4b (0.5 mM), C) 7a (0.25 mM), D) 7b (0.25 mM) ................................ ................................ ................................ 39 2 9 1 H NMR (300 MHz) concentration study of 7a in CDCl 3 . ................................ ... 43 2 10 One face of 7a from above, showing the labeling of unique hydrogens ............ 44 2 11 Plots of the peak chemical shifts for 7a at variable concentrations ..................... 44 2 12 Determination of dimerization constants A) dimerization equation, B) NH curve fit C) CH aromatic curve fit ................................ ................................ ........ 45 2 13 1 H NMR (300 MHz ) NH peak chemical shift for 7a at different temperatures. .... 47 2 14 Circular dichroism of 0.25 mM solutions of 7c ................................ .................... 50 2 15 Polarized optical microscopy images of 7b A) 20X magnification, B) 40X magnification, C) same image as A but with the polarizers crossed, D) same image as B but with the polarizers crossed. ................................ ....................... 51 2 16 T hermogravimetric analysis of amide systems A) 4a B) 4b C) 7a D) 7b ........ 52 3 1 Structure of [3.3]paracyclophane ................................ ................................ ........ 56

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10 LIST OF ABBREVIATION S AMBER Assisted model building with energy r efinement CD Circular d ichroism DCM Dichloromethane DMF Dimethylformamide IR Infrared NMR Nuclear magnetic resonance POM Polarized optical m icroscopy TGA Thermo gravimetric a nalysis XRD X ray d iffraction

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11 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science SELF ASSEMBLING [2.2]PARACYCLOPHANES By Michael Joseph Meese, Jr. August 2011 Chair: Ronald K. Castellano Major: Chemistry The unique molecular shape and structure of [2.2]paracyclophane has attracted the attention of chemists for over sixty years, but the platform has only recently emerged as an interesting building block for the construction of conjugated materials for org anic optoelectronic applications. Two short carbon bridges hold its two benzene rings in a confined geometry, and allow for efficient through space interactions between the rings. Reported here is the synthesis and investigation of the first [2.2]paracyc lophane derivatives that are rationally designed for self assembly through hydrogen bonding. The design, guided by molecular mechanics calculations, positions amide functional groups at the 4, 7, 12, and 15 positions of the [2.2]paracyclophane core. This substitution pattern allows for both intra and intermolecular amide hydrogen bonding, and ideally, the formation of one dimensional assemblies. The synthesis of four tetra amides and two mono amides (as model systems) begins from appropriately halogenat ed [2.2]paracyclophane precursors and follows with lithium halogen exchange, quenching with CO 2 and amide bond formation. Spectroscopic studies in solution (by IR, 1 H NMR, and CD) have characterized the hydrogen bonding properties of the molecules in res ponse to temperature, concentration, and solvent. The results of

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12 bulk studies, including polarized optical microscopy (POM) and thermogravimetric analysis (TGA), show that hydrogen bonding confers long range structural order and remarkable thermal stabili ty to the otherwise thermally sensitive [2.2]paracyclophane core.

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13 CHAPTER 1 INTRODUCTION Supramolecular Chemistry Supramolecular chemistry has exte nsively been studied in natural systems. 1 Scientists have long studied the double helical structure of DNA that forms as a result of self assembly. T he helical structure of the tobacco mosaic virus is another interesting example of self assembly in biologi cal systems. 2 Learning from these classic examples synthetic organic chemists have been able to take a dvantage of hydrogen bonding, interactions, and other non covalent interactions to induce self assembly in organic molecules Take, for example, the host guest chemistry of cyclodextrins, a class of cyclic oligosaccharides (Figure 1 2 ) 3 The rigid, hydrophobic cavity of the molecules makes them excellent hosts for a number of small molecules and is central to applications ranging from drug delivery to deodorizers. Other systems that utilize self assembly include cat enanes and rotaxanes (Figure 1 1 ). 4 Catenanes take advantage of hydrogen bonding, ionic interactions, stacking, and other non covalent interactions to interlock two macrocycles, while rotaxanes use these same interactions to lock a The intermolecular interactions help to interlock the molecules. Once the systems are locked into place they no longer rely on intermolecular interact ions to hold them in place. Figure 1 1. Cartoon drawings of A) a catenane, B) a rotaxane

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14 Figure 1 2 Cyclodextrins. A ) cyclo dextrin (six glucose ring s ), B ) cyclodextrin (seven glucose ring s ) Hydrogen Bond ing Studies on the hydrogen bond began in organic chemistry today. A hydrogen bond is typically described as the interaction X HA, where X H bears a strong dipole ( X H ) and A is an electronegative atom ( A ) 5 The strength of a hydrogen bond is typically weak and ranges from about 0.2 kcal/mol to 40 kcal/mol. A bond angle of 180 is favored in these interactions and the bond length of HA lies between 1.2 and 2.2 . If the length of HA is short then the hydrogen bond will be strong compared to an HA with a long bond length. Hydrogen bonds are most commonly studied using 1 H NMR and IR. Due to the decreased electron density around a hydrogen bonded hydrogen atom, the signal arising from this proton in the 1 H NMR shifts downfield. 6 Likewise, the lengthening of the X H bond causes a red shift for the vibrational stretching peak in the IR. One common motif used in self assembly mediated by hydrogen bonds is X HO=C, where X is O or N. Carboxylic acids and amide functional groups (Figure 1 3), along with their

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15 derivatives, are commonly used to promote self assembly. In this thesis, amide functional groups will be used to help promote self assembly. Figure 1 3 Example o f intermolecular hydrogen bonds between amide groups A second non covalent interaction that supramolecular chemists utilize to help promote self 4) are weak intermolecular int eractions that occur between orbitals to occur, the negative electrostatic potential of the orbital on one molecule must overlap with the positive electrostatic potential of the orbital on the other molecule 7 In a si mple benzene system, two benzene rings are unable to stack directly on top of each other due to the misalignment of orbitals (Figure 1 4A) In this alignment, the orbitals are arranged in a way in which the orbitals repulse each other. However, when aligned in a T shaped (Figure 1 4B) or slip stacked fashion (Figure 1 4C), the orbitals are arranged in a way in which these interactions can occur. Figure 1 4. benzene rings. A) stacked benzenes, B) T shaped benzene rings, C ) slip stacked benzene rings

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16 e in protein folding and enzyme substrate recognition. 8 Supramolecular chemists have shown that an aromatic system containing electron accepters can partner with an aromatic ring containing electron donors to form face to of one ring will interac perfluorinated aromatic rings has been shown to give almost perfectly aligned stacks when partnered with a non fluorinated derivative (Figure 1 5). 9 The assembly of aromatic rings into 1 D colum nar stacks has been a particular area of interest for supramolecular chemists 10 and will be the main focus of this thesis. Figure 1 5 Example of perfluorinated derivatives. A ) 1,3,5 tris(phenethynyl )benzene, B ) 1,3,5 tris(perfluorophen ethynyl)benzene C ) c o crystal ( CSD code : WEVYIF ) 9

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17 Aromatic 1 D Columnar Stacks As stated previously, the assembly of aromatic systems into 1 D columnar stacks is widely studied among supramolecular chemists. What makes these systems so interesting are the through space interactions that occur between the overlapping orbitals of the aromatic rings. These interactions give rise to charge transfer possibilities through the 1 D columns. There are many common non covalent strategies to induce order ed stacking of aromatic systems, 11 including hydrogen bonding, metal ligand interactions, electrostatic interactions, and hydrophobic interactions. For this thesis, hydrogen bonds will be utilized to promote the 1 D assembly of an aromatic system. Supramolecular Polymers The 1 D self assembly of aromatic systems is an example of a s upramolecular polymerization Supramolecular polymers are defined by Meijer as 1 2 arrays of monomeric units that are brought together by re v ersible and highly directional secondary interactions, resulting in polymeric properties in dilute and concentrated solution as well as in the bulk. The directionality and strength of the supramolecular bonding are important features of systems that can be regarded as polymers and that beha v e according to well established theories of polymer physics. There are three types of supramolecular polymerization mechanisms; isodesmic, ring chain, and cooperative 1 3 An isodesmic polymerization (Figure 1 6A) is characterized by the formation of identical non covalent in teractions throughout the polymer chain. The monomers in this mechanism have one binding constant C 3 symmetric amides in Figure 1 7 B for an

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18 example of a supramolecular polymer with identical non covalent interactions). A ring chain polymerization (Figure 1 6B) is characterized by monome rs containing comple mentary end groups that form reversible non covalent interactions and are connected via a flexible hydrocarbon chain. A cooperative polymerization (Figu re 1 6C) is characterized by a linear isodesmic polymerization. The difference between an isodesmic polymerization and a cooperative polymerization is that the re is only one binding constant in an isodesmic system, whereas the binding constant changes in a cooperative system. This change in the binding constant comes from additional interactions that occur in the polymer as the chain continues to grow that help to stabilize the polymer allowing the polymer to grow in an ordered step wise manner Electronic structural, and hydrophobic effects can lead to a supramolecular polymer forming via the cooperative mechanism over an isodesmic mechanism. This thesis will explore new synthesized small molecules that may form supramolecular polymers. Studies will dete this new class of molecules Figure 1 6 Cartoon drawings of the three types of supramolecular polymerization mechanisms. A ) isodesmic, B ) ring chain, C ) cooperative (arrows indicate polymer growth)

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19 Examples of 1 D Columnar Assembly There have been many studies on the supramolecular polymerization of conjugated systems. 14 Particularly interesting to th e work performed in this thesis are the 1 D assembled aromatic sy stems developed by Meijer, Nuckolls, and Geerts Meijer has designed a series of C 3 symmetric aromatic disks (Figure 1 7). 15 2 6 These systems are typically benzene rings substituted in the 1, 3, and 5 positions with amide or urea function al groups (amides shown in Figure 1 7A). The amides and ureas allow for hydrogen bonding between benzene rings (Figure 1 7B). The rings are generally aligned in a slip stacked the stacks. The amount of slipping in the stacks is dependent on the side arms extending from the amides. Often times, side chains with additional non covalent interactions are used to induce higher ordering. 1 5 The polymerization mechanism for odesmic or cooperative depending on the arms extending from the amides. The benzene triamides have been extensively studied with various R groups (Figure 1 7). The 1 D columnar stacks that form from the self assembly can have several interesting propert ies and applications, and the properties of the systems can be altered based on the R groups. Some derivatives form thin fibrous crystals in the solid state, 16 while amides with long alkyl chains have been shown to form liquid crystals. 1 7,18 Other derivatives form organogels in solution. 18 When a chiral R group is used, chiral supramolecular assemblies can form. 19 Helices formed from chiral side chains have shown to form more ordered stacks and are formed via a cooperative mechanism. 20,21

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20 M eijer has shown that the assembly of the benzenes in solution can be studied by several methods. IR can be used to study the stretching of the N H bond and C=O bond of the amide. 22 CD can be used to study the helical stacks that form from chiral R groups. 23 25 Both of these methods will be used in this thesis to study the assembly of [2.2]paracyclophane systems that will be discussed in more detail in the next chapter. Figure 1 7 A) e C 3 sym metric discotic system, B) f igure showing the hydrogen bonding within an individual columnar stack system s Similar aromatic C 3 symmetric amides that assemble into 1 D columnar arrays have been studied by Nuckolls (Figure 1 8). 27 32 These that the benzene rings are hexa substituted. In addition to amides in the 1, 3, and 5 positions, there are alkynyl (Figure 1 8A) or alkoxy (Figure 1 8B) groups in the 2, 4, and 6 posit ions. The additional groups stericall y hinder the amides and force them out of the plane of the benzene ring core. Thus the amides are forced into a position that better promotes intermolecular hydrogen bonding. Like the systems studied by Meijer, these systems have been shown to form well ordered 1 D arrays. The alkynyl and

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21 alkoxy groups can also be used as substitution points for probes to help study the assembly of the disks. By attaching chromophores to the benzene rings, the fluorescence of these systems can be studied. When aggregat ed into 1 D stacks the fluorescence spectra often show a red shift, indicating delocalization of the excited state over at least several molecules in a supramolecular structure. Some of the derivatives have been shown to have liquid crystal line properties Figure 1 8 Example s of systems developed by Nuckolls. A ) alkyne system B ) alkoxy system Geerts has also developed a system that self assembles to form 1 D columnar stacks through a combination of stacki ng and amide based hydrogen bonding (Figure 1 9) 33 ,3 4 the hexaazatriphenylene moiety makes up the aromatic core instead of a benzene ring. The hexaazatriphenylene core is substituted with six amide groups. This design has been shown to give a similar 1 systems. Studies suggest that these systems could have applications in organic electronics due to their charge tr ansport capabilities.

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22 Figure1 9 Example of a system developed by Geerts Applications and Advantages of Supramolecular Polymers 1 D Self assembled systems like the ones described above can have many applications. As stated previously, many of the systems can serve as liquid crystals or organogelators. The charge transport throughout the supramolecular polymer chain. This interesting property allows for possible applications in organoelectronics, such as organic semiconductors or organic light emitting diodes. 35,36 1 D systems studied by Wasielewski have been sho wn to have light harvesting applications. 37 There are numerous other supramolecular polymeric systems that have been studied in addition to 1 D columnar stacks. Other systems have been shown to function as organic field effect transistors. 3 8 In these sys tems, highly ordered aromatic small molecules act as the semiconductor. The advantage to using organic small molecules in comparison to inorganic molecules is that organic molecules can be finely tuned, cost effective, flexible, and lightweight. Non coval ent interactions have the advantage over covalent bonds in that they can be manipulated based on solvent concentration, polarity, and temperature to induce the desired assembly.

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23 [2.2]Paracyclophane [2.2]Paracy c lophane is an interesting aromatic molecule that has been studied for over sixty years 3 9 The [2.2 ] paracyclophane molecule features two benzene rings connected in the para position by two ethylene bridges ; the short spacers prevent the two benzene rings from rotating (Figures 1 10 and 1 11) The pro ximity of the two benzene rings also causes the rings to distort out of plane into a boat like conformation. The carbon carbon bond length between the two CH 2 groups in the bridge is 1.63 (Figure 1 11 A) The distance between the two bridgehead carbons on the two benzene rings is 2.78 . The distance between the two non bridgehead carbons on the two benzene rings is 3.09 . 40 When heated above 180 C, one of the ethylene bridges can cleave allowing the benzene rings to rotate freely. Figure 1 11 B shows the common numbering pattern s for substituted [2.2]paracyclophanes and Figure 1 12 gives the common naming for the molecules based on substitution of the aromatic rings Figure 1 10. Models derived from molecular mechanics using AMBER forcefield of [2.2 ]paracyclophane A) top view, B) side view

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24 Figure 1 11 [2.2]Paracyclophane. A) distances between carbons on [2.2]paracyclophane, B) numbering scheme of [2.2]paracyclophane carbons 40 Figure 1 12 Common naming patterns of substituted [2.2]paracyclophanes 40 Through Bond and Through Space Interactions Because of the close proximity of the two benzene rings, [2.2]paracyclophanes have been shown to have interesting through bond and through space inter actions. A computational study of [2.2]paracyclophane was performed by Caramori and Galembeck. 41 Using Natural Bond Order (NBO) analysis, through bond interactions the orbitals on the same benzene ring and have a value of about 20 kcal/mol. In other words, as the authors state, delocalization of electrons stabilizes the molecule and aromaticity is maintained in the ring systems. bridge carbon to one of the rings. This interaction was calculated to have a value of about 3 kcal/mol and is also stabilizing Using Molecular Orbital (MO) analysis, Caramori and Galembeck were able to conclude that the shape of the frontier molecular

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25 orbitals suggests the presence of through space interactions between the benzene rings. The transport ability of [2.2]paracyclophane in thin films has been studied by Hu et al. 4 2 In this study, [2.2]paracyclophane was vapor deposit ed into thin films under vacuum. The films produced were found to have a bulk electron mobility minimum of 0.03 cm 2 V 1 s 1 This value is comparable to other small aromatic compounds. [2.2]Paracyclophane Containing Polymers Many research groups have begu n using [2.2] paracyclophanes in conjugated polymers, due to the through space interactions observed in this compound 4 3 ,4 4 The entire [2.2]paracyclophane compound is not fully conjugated due to the two CH 2 CH 2 bridges. However, w hen the conjugated systems are covalently bonded through the opposite rings of the cyclophanes these polymers still exhibit properties of conjugated polymers. This is because the through space interactions of the two benzene rings conjugation. Much of the work on cyclophane containing polymers has been performed by Morisaki and Chujo. 45 46 These conjugated cyclophane containing polymers often exhibit a red shift in the absorption spectra and are photoluminescent with good quantum efficiencies. An interesting aspect of cyclophane containing polymers is that the polymer can emit from either the chromophore state or from the cyclophane state depending on the energy needed to exc ite the chromophore (Figure 1 13 ). If the energy needed t o excite the chromophore is higher than the energy level of the cyclophane excited state, then the chromophore will relax to the cyclophane state and emit from this state. If the energy needed to excite the chromophore is less than the energy level of the cyclophane e xcited state, then the chromophore will emit from its current state For

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26 polymers that emit from the cyclophane state, there is a greater Stokes shift than for polymers that emit from the chromophore state. Figure 1 13 Emission of cyclophane containing oligomers. A ) Example of em ission from cyclophane state, B ) example of emission from chromophore state (figure adapted from r eference 44)

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27 Stacked Paracyclophane P olymers Most of the polymers synthesized by Morisaki and Chujo have the [2.2]paracyclophanes positioned within the main conjugated chain in a linear fashion. The team has reported one oligomer system in which the cyclophanes are aligned into stacks. This system utilizes a xanthene hinge to hold the [2.2]paracyclophanes close enough to disable any rotation (Figure 1 14) 46 The oligomers synthesized range from three to eight stacked paracyclophane rings and were capped with various aromatic end groups. These oligomers are particularly interesting due to their capability of charge transfer via t hrough space interactions of the stacked benzene rings. The cyclophanes in this system have shown to have an efficient fluorescence resonance energy transfer (FRET) to anthracene end groups. End caps of ferrocene and nitrobenzene have shown to quench the fluorescence emitted from the stacked paracyclophanes. Figure 1 14 Example of Morisaki oligomeric system in which [2.2]paracyclophane is aligned into columns A recent polymeric system in which [2.2]paracyclop hanes were stacked in a columnar fashion has been synthesized by the Collard group. 4 7 This system is

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28 comprised of two separate columns of [2.2]paracyclophane that go back and forth due to their pseudo geminal substitution (Figure 1 15) This system exhibits a large Stokes shift in the emission spectrum. However, the cyclophanes are only aligned when they are connected in the pseudo geminal position. Other model systems were made in which the [2.2]paracyclophanes were substituted in the pseudo ortho, pseudo meta, and pseudo para position and were therefore not aligned. These systems did not exhibit similar Stokes shifts. UV/vis of the model compounds more closely resembled the UV/vis of the monomer. The stacked polymer is red shifted compared to th e monomer and model systems, indicating that this shift comes from the stacking of the [2.2] paracyclophane core. Figure 1 15 System developed by the Collard group to align [2.2]paracyclophanes into stacks Applications of [2.2]Paracyclophane [2.2]Paracyclophane containing compounds have been shown to have many applications. Ade and Harada have developed [2.2]paracyclophane containing systems that have applications as photoresponsive organogelators and photochromic materia ls. 48 50 Valenti and co workers are studying [2.2]paracyclophane containing molecules for use in organic solar cells. 51 Rozenberg and Hopf have developed

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29 thermotropic liquid crystals based on a [2.2]paracyclophane core. 52,53 It is clear that the unique g eometric and electronic structure of the molecules make them exciting to study. Design of a Self Assembling [2.2]Paracyclophane System Although [2.2]paracyclophane containing small molecules and polymers have been studied in great detail in recent history the area of [2.2]paracyclophane self assembled systems has not been studied to a great extent The self assembly of [2.2]paracyclophane into 1 D columnar stacks is particularly interesting due to its unique system. Inspired by the sy stems pioneered by Meijer, Nuckolls, and Geerts, a system was envisioned in which amides are positioned in a geometry that induces both intra and inter molecular hydrogen bonding (Figures 1 16 and 1 17 ) By positioning amide groups on the 4, 7 12, and 1 5 carbons of the [2.2] paracyclophane body the amides that are pseudo ortho to each other are close enough to intramolecularly hydrogen bond. This forces the amide groups to go out o f plane with the cyclophane, and into a position that will promote interm olecular hydro gen bonding with amide groups from other [2.2]paracyclophane cores. This chain should continue to grow via supramolecular polymerization similarly to the systems discussed above The intramolecularly hydrogen bonded amides on each side of the [2.2]paracyclophane core can be either parallel or anti parallel to each other. However, both geometries align the amide groups in a way that induce in termolecular hydrogen bonding. Aligning [2.2]paracyclophane into discotic columnar stacks should sho w similar charge transfer properties that are observed in stacked [2.2]paracyclophane conjugated polymers. In addition to 4, 7, 12, 15 tetra su bstituted amides ( 7 ) mono amides ( 4 ) were envisioned as model systems. The models were synthesized to help stu dy the hydrogen bonding

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30 features of these systems. Molecular models of 4 and 7 can be seen in Figure 1 17 for the methyl derivatives. These models will be discussed in more detail in Chapter 2. Figure 1 1 6 Structures of mono and tetra amide substituted [2.2]paracyclophanes Figure1 17 Model s of methyl derivatives A) 4 B) 7 (parallel intramolecular hydrogen bonds), C) anti parallel intramolecular hydrogen bonds)

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31 CHAPTER 2 RESULTS AND DISCUSSI ON Design In this study, two different amide functionalized [2.2]paracyclophane systems were synthesized and studied: 4 mono amide[2.2]paracyclophane (4 ) and 4,7,12,15 tetra amide[2.2]paracyclophane (7) The amide substituted paracyclophanes were synthesize d as racemic mixtures of the p S and p R enantiomers ( planar chirality of the molecules; see Figure 2 1 below ). 54 ,56 The mono amides were synthesized as model s ystems to compare to the tetra amides. The models are a system in which int ramolecular hydrogen bonding is not possible and intermolecular hydrogen bonding only allows for dimers to form. Due to only one site for intermolecular amide hydrogen bonding, the dimers are expected to be weak in solution (e.g., chloroform). The tetra amides are a system in which the functional groups are arranged on the cyclophane core close enough to intramolecularly hydrogen bond. This hydrogen bond forces the amides out of plane and into a conformation that should promote intermolecular hydrogen bon ds to form, allowing 1 D columnar assembly. Figure 2 1. Enantiomers of cyclophanes 4 and 7

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32 Molecular Modeling Energy minimized structures were obtained from molecular mechanics as implemented in Macromodel v. 9.1 (Schrodinger, LLC) using the AMBER forcefield 55 for compounds 4 a (Figure 2 2 A), 4b (Figure 2 2 B), 7a (Figure 2 2 C) and 7 b (Figure 2 2D). Calculations on compounds 4 a and 4b show that the amide group is forced out of plane with the aromatic ring due to steric hindrance from the bridge CH 2 Energy minimization of 7 a and 7b shows that the lowest energy conformation is the one in which the pseudo ortho amides are intramolecularly hydrogen bonded. This is due to the close, constrained geometry of the amide functional groups and also the same steric hindrance seen in 4 a and 4b The intramolecular hydrogen bond distance (defined as the distance between the O and H atoms) is 1.78 according to these calculations. Since the energy minimum for this compound lies in the intramolecularly hydrogen bonded conformation, these bonds should exist independent of concentration (assuming the solvent is not polar enough to interfere with the intramolecular interactions). Meanwhile, the intermolecular hydrogen bonds will be dependent on the concentration due to the number of amide groups in close proximity within the solution. An e nergy minimized structure was also obtained for the dimer of the methyl derivatives for 4 (Figure 2 3A) and 7 (Figure 2 3 B) to sh ow the intermolecular hydrogen s (Figure 2 3). As the number of amide groups increases from one to four the dimers form more ordered 1 D assemblies Only system 7 allows for additional sites of intermolecular hydrogen bonding and thus supramolecular polymerization to occur. The intermolecular hydrogen bonds that characterize both dimer systems were calculated to be 1.79 , almost identical to the intramolecular hydrogen bonds.

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33 Figure 2 2. Molecular models (with hydrogen bonds shown) of amides synthesized in this thesis A) 4a B) 4b C) 7a D) 7b Figure 2 3. Molecular models for dimers of methyl derivatives A) 4 B) 7 (hydrogen bonds shown in anti parallel conformation) Synthetic Scheme Several attempts were made to synthesize amide functionalized [2.2]paracyclo phanes. To functionalize the cyclophane core, [2.2]paracyclophane ( 1 ) was first brominated to create a rea ctive site (Figure 2 4 ). Compound () 4 bromo [2.2]paracyclophane ( 2 ) was synthesized according to Row lands and Seacome 5 6 using one equivalent of Br 2 and a catalytic amount of iron. Compound () 4,7,12,15

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34 tetrabromo [2.2]paracyclophane ( 5 ) was synthesized according to Reich and Cram, 57 using neat Br 2 and a catalytic amount of I 2 (Figure 2 5) Synthesis of mono and tetra a mides A literature search for 4 mono amide[2.2]paracyclophanes results in a handful of hits. Synthesis of these previously reported amides utilize a lithium halide exchange of compound 2 and the subsequent addition of CO 2 to form carboxylic acid 3 54 Compound 3 was treated with thionyl chloride to produce the acid chlo ride. The acid chloride was immediately reacted with a primary amine in the presence of Et 3 N to give the amide. 5 8 Two derivatives of 4 were synthesized for this thesis following this scheme. n Butyl ( 4a ) was used as an example of a simple alkyl group and phenyl ( 4b ) was used as an example of a simple aryl system ( yields for these compounds can be seen in Figure 2 4 below ) Compounds 4a and 4b were used as model systems to compare to the newly synthesized tetra amides. Figure 2 4 Synthetic scheme for synthesis of 4a and 4b Synthesis of compounds 6 and 7 ha s not previously been reported. However, utilizing the same synthetic scheme to produce 4 compound 5 was used to successfully produce compounds 6 and subsequently 7 in low yields (Figure 2 5 ). Four different derivatives of 7 were synthesized following the scheme shown. n Butyl ( 7a ) wa s used as an example of a simple alkyl substituent and phenyl ( 7b ) was used as a simple aryl

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35 substituent. Both of these compounds are fairly insoluble in most organic solvents and purification was achieved by first washing the crude solid with a small amo unt of cold methylene chloride followed by recrystallization from methanol. (S) M ethylbenzyl ( 7c ) was used as an R group in order to create a chiral derivative. This compound was also purified as described above Because of the chirality of the amine u sed for this derivative, the amide is expected to form as diastere omers. However, upon recrystallization from methanol, 1 H NMR, 13 C NMR, TLC, and CD analysis all show evidence of only one diastereomer. It is possible that one diastereomer was removed duri ng the methylene chloride wash. To determine which diastereomer was formed, the same reaction could be conducted on enantiomerically pure 6 59 and analysis on each product could be completed. 3,4,5 Tris dodecyloxyphenyl ( 7d ) was used as an R group to synthesize a derivative with higher solubility. The higher solubility of the molecule meant that the compound required a different method of purification. For purification, the compound was dissolved in a minimum amount of methylene chloride and methanol was added until the compound crashed out of solution. This was done three times until the compound was pure. Characterization of the assembly of this compound is still underway and will not be discussed in much detail in this thesis. Unsuccessful synthe tic attempts Other efforts to synthesize 7 were attempted but did not produce the desired results. Treatment of 5 with CuCN to produce the tetra nitrile compound does not produce any of the predicted product (Figure 2 6). 60 The crude material obtained fro m this reaction is a complex mixture that appears to arise from degradation of the starting material. The tetra nitrile compound could have been treated with trifluoroacetic acid to give the primary tetra amide. 61

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36 Figure 2 5 Synthetic scheme for the preparation of 7a d Figure 2 6 Attempt to synthesize a tetra nitrile as a precursor to amide derivatives Another model system was envisioned in which only one side of the [2.2]paracyclophan e was substituted in the pseudo ortho position with amides. This model system is an example in which intramolecular hydrogen bonding can occur on only one side of the cyclophane core. Synthesis of a 4,12 di amide model system was attempted many times foll owing the same scheme used to synthesize 4 and 7 starting from 4,12 dibromo[2.2]paracy c lophane (Figure 2 7) The products obtained from these reactions often formed as oils. These oils proved difficult to purify and although

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37 spectroscopic data suggested the desired products were formed, these products could not be isolated as pure compounds. Figure 2 7 Attempted synthesis of 4,12 di amide s Characterization of Assembly I nfrared Spectroscopy IR has proven to be a useful tool in determining the hydrogen bonding that occurs in solution. 22 Meijer has observed some interesting properties for his C 3 symmetric amides in solutions of cyclohexane (1 mM 0.1 mM). In the IR of these systems, there are two peaks in the NH stretchin g region. One peak is typically found around 3400 cm 1 while the other is around 3250 cm 1 The peak around 3400 cm 1 is around 3250 cm 1 is attributed to hydrogen bonded hydrogen bonded NH region comes from the 1 D assembly of the systems. However, not all amides are hydrogen bonding in solution, so there is still a peak observed in the free NH region. IR was performed on 4a,b and 7a,b to observe the NH stretching peaks. Due to the insolubility of 7a and 7b in saturated hydrocarbons, chloroform was used as the solvent. Although saturated hydrocarbons are less polar and would therefore be expected to increase the hydrogen bonding interacti ons, chloroform is still relatively non polar, making it a good solvent to allow for both intra and intermolecular hydrogen

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38 bonding. For this study, IR spectra were taken at low concentrations to allow for 7b to be included in the study ( 7b has a saturation point in chloroform of about 0.25 mM). Compounds 4a and 4b were recorded in a solution of 0.5 mM and compounds 7a and 7b were recorded in a solution of 0.25 mM. When we observe the model compounds 4 a and 4b there is only one peak in th e free NH stretching region. For compound 4a (Figure 2 8 A) this peak appears at 3441 cm 1 and for compound 4b (Figure 2 8 B) this peak appears at 3422 cm 1 This result is what would be expected for this compound. Since there is only one amide on the cycl ophane core, this eliminates any possible intramolecular hydrogen bonding and intermolecular hydrogen bonding would only allow for dimerization. These single intermolecular interactions are most likely too weak to form stable dimers in solution (at the co ncentrations employed) and therefore only non hydrogen bonded NH stretching is observed in the IR. However, when we examine the IR of the compounds 7a and 7b in chloroform, two peaks are observed. One peak is in the hydrogen bonded NH stretching region and the other is in the free NH stretching region. For compound 7 a (Fig ure 2 8 C) the peaks are 3280 cm 1 and 3439 cm 1 and for compound 7b (Figure 2 8 D) the peaks are 3267 cm 1 and 3414 cm 1 Again this is what would be expected for this particular syste m. Molecular modeling shows that the intramolecular hydrogen bonding should help to stabilize the molecule and should therefore occur in chloroform. What the IR does not help to clarify (at least at a single concentration or temperature) is whether the hy drogen bonded NH stretching comes from intra or intermolecular interaction. Certainly intramolecular hydrogen bonds can account for this peak due to the close geometry of the pseudo ortho amides. There may be a small amount of intermolecular hydrogen

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39 bon ds that also make up this peak. However, other methods that will be discussed below have shown to be better methods for studying the intermolecular hydrogen bonds. Figure 2 8 IR in chloroform solution. A) 4a (0.5mM), B) 4b (0.5 mM), C) 7a (0.25 mM ), D) 7b (0.25 mM) 1 H Nuclear Magnetic Resonance Spectroscopy In 1 H NMR, hydrogen bonds have been shown to cause a shift in the peak of the hydrogen involved in the interaction. 6 A hydrogen bonded hydrogen is more deshielded than a non hydrogen bonded hy drogen and therefore is shifted downfield. 1 H NMR has

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40 shown to be a particularly useful tool to study the assembly of 7 The timescale of 1 H NMR is slower than the timescale if IR. For systems 4 and 7 the timescale is slow enough that the free and hydro peaks, as in the IR. This is particularly useful for studying the intermolecular hydrogen bonds. As previously discussed, intramolecular hydrogen bonding will be independent of concentration in chlor oform and other solvents with low polarity. On the other hand, intermolecular hydrogen bonding should be directly dependent on concentration, since the process is governed by thermodynamic equilbria. Therefore, the average of free s should be dependent on concentration. As the arises from this hydrogen will shift downfield. The opposite is true for diluted solutions. Theoretically, in a dilute solution of 4 in which no intermolecular hydrogen bonding is occurring, the NH signal in the NMR should arise from only free, or non hydrogen bonded NHs. In a dilute solution of 7 in which no intermolecular hydrogen bonding is occurring, this signal shou the two. The peak should theoretically reach a point in which it can shift no further downfield. At this point the solution is completely saturated with intra and intermolecular hydrogen bonds. Using variable temperature and concentration 1 H NMR we are able to study how this average shifts is dependent on these two variables. To study compounds 4a and 4b two solutions (5 mM and 50 mM) of each compound were prepared in CDCl 3 (chemical shifts of the NH peak for each solution can be seen in Table 2 1). As seen in the table below, the chemical shift of the NH

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41 peak will be affected by the R group extending from the amide. For alkyl groups, the NH peak will appear around 5.5 ppm in CDCl 3 This is observed in the literature for previously synthesized derivatives of 4 in chloroform. However, concentrations were not reported for these spectra. When the R group is an electron deficient group, such as phenyl, the NH peak is deshielded and shifts downfield to 7.25 ppm. Increasing the concentrations of compounds 4a and 4b from 5 mM to 50 mM only shifts the peak 0.01 ppm. This indicates that there may be a small a mount of intermolecular hydrogen bonds occurring in higher concentrations. However, compared to the data we will see for compound 7a below, the aggregation of 4a and 4b are negligible. Table 2 1 1 H NMR (300 MHz) chemical shift of NH peak for model syste ms in CDCl 3 at 50 mM and 5 mM Compound Chemical shift at 50 mM (ppm) Chemical Shift at 5 mM (ppm) 4a 5.53 5.52 4b 7.25 7.24 The NH chemical shift found in 7a and 7b (Table 2 2) differ greatly from 4a and 4b Due to the relative insolubility of these compounds, 1 H NMR was obtained at a lower concentration for 7a and 7b However, the chemical shift of the NH peak is shifted downfield significantly compared to 4a and 4b We also notice a similar downfield sh ift in the phenyl derivative due to deshielding of the NH from the phenyl ring. The shift in the NH peaks between systems 4 and systems 7 is due to the intra and intermolecular hydrogen bonds in the system 7 It is expected that intramolecular hydrogen b onds account for the majority of the shift. However, there may be some to study the intermolecular hydrogen bonds, 1 H NMR of compound 7a was obtained at

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42 various concentra tions and temperatures (compound 7b proved to be too insoluble in chloroform to obtain such data). Table 2 2. 1 H NMR (300 MHz) chemical shift of NH peak for tetra amide systems in CDCl 3 at 0.25 mM Paracyclophane derivative Chemical shift (ppm) 7a 7.4 2 7b 10.08 Concentration study The intermolecular hydrogen bonds in compound 7a were studied by obtaining 1 H NMR at varying concentrations in CDCl 3 For this study, 1 H NMR spectra of 7a were obtained at concentrations ranging from 0.1 mM to 20 mM (Figure 2 9). This data shows a shift for the NH peak as the concentration is increased. At the lowest concentration this peak appears at 7.40 ppm and shifts all the way to 7.93 ppm at the highest concentration; a range of 0.53 ppm. The NH shift minimu m for 7a looks to be at ~ 7.40 ppm since the shift does not change when the concentration is reduced from 0.2 to 0.1 mM. When these chemical shifts are plotted versus concentration (Figure 2 11A), the output is a sigmoidal like curve. This type of curve is often observed in non cooperative assembly 13 As the amount of hydrogen bonding in the system approaches a minimum or a maximum, the shift of the NH peak slows, causing the sigmoidal like shape. In addition to the NH peak concentration dependence obser ved in 7a the chemical shifts corresponding to the paracyclophane core protons are also concentration dependent. The core protons exhibit a shift opposite to the one observed for the NH protons. Worth noting, the core protons of cyclophane 4 show no change

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43 over a similar concentration range. The aromatic CH peak on the benzene ring (Figure 2 11B) of 7a moves upfield from 6.97 ppm to 6.68 ppm ( = 0.29 ppm) upon increasing the concentration from 0.1 mM to 20 mM. For the protons at the bridge, H a (Figure 2 11C) shifts upfield from 3.67 ppm to 3.52 ppm and H b (Figure 2 11D) moves from 6.70 ppm to 6.47 ppm over the same concentration range ( = 0.12 ppm and 0.13 ppm, respectively; see Figure 2 10 for labeling of bridge hydrogens). When the chemi cal shifts are plotted versus concentration, the cu rves show a similar shape to the one obtained from the NH peak, indicating that all of the changes are likely related to the same self assembly event. The upfield shift trends are not completely understood at the moment, but they are believed to be caused by one of two things: either a geometric or electronic distortion of the cyclophane core as a result of assembly, or from additional shielding from nearby cyclophane systems in the aggregation. Figur e 2 9. 1 H NMR (300 MHz) concentration study of 7a in CDCl 3 The concentrations are 20 mM (blue), 15 mM (green), 10 mM (gray), 5 mM (purple), 2 mM (yellow), 1 mM (light blue), 0.5 mM (black), 0.2 mM (orange), and 0.1 mM (light green). The peak on the left is the NH peak, the peak on the right is the aromatic CH peak and the peak in the middle is the solvent peak.

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44 Figure 2 10. One face of 7a from above, showing the labeling of unique hydrogens Figure 2 11. Plots of the peak chemical shifts for 7a at variable concentrations A) NH chemical shift, B) CH (aromatic) chemical shift C) CH a (bridge) chemical shift, D) CH b (bridge) chemical shift. The lines shown are simply to guide the eye and are not the result of a nonlinear curve fitting procedure

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45 The NH and CH aromatic peaks have been fit to a dimerization curve (Figure 2 12) 62,63 From this equation we are able to determine the dimerization binding constant as well as the shift maxima and minima for each peak (Table 2 3) Both sets of data fit this curve nicely, indicating dimers of these molecules are forming in solution The values of K dim for the NH peak and CH aromatic peak are 42.0 9.1 M 1 and 27.7 5.2 M 1 respectively. Although these values are not identical to one another, they are close in value, signifying that the shifts come from the same dimerization event. What is interesting to note about the dimerization equation is that it is the same equation a s for an isodesmic 1 D assembly, only that the K value is doubled for the isodesmic 1 D equation Since our data fits both equations, we can conclude that 7a is aggregating to form at least dimers in solution and may be forming longer 1 D assemblies. Fi gure 2 12. Determination of dimerization constants A) d imerization equation, B) NH curve fit C) CH aromatic curve fit

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46 Table 2 3. Peak shift maxima and minima and K dim for NH and CH aromatic peaks Peaks Maximum (ppm) Minimum (ppm) K dim (M 1 ) NH 8.56 0.10 7.38 0.011 42.0 9.1 CH aromatic 6.98 0.0043 6.22 0.067 27.4 5.2 Temperature study To further study the aggregation of 7a in a solution of chloroform, a temperature dependent study was completed at a concentration near the NH peak chemical shift minimum (0.25 mM). At 25 C, the NH peak appears at 7.42 ppm, which is slightly downfield from the minimum of 7.40 ppm. This indi cates that there is a small amount of intermolecular hydrogen bonding occurring in solution. When the temperature is varied from 5 C to 45 C, shifts in the same four peaks are observed. The NH peak (Tabl e 2 4 ) has a range of 7.35 ppm 7.51 p pm ; a difference of 0.16 ppm, w hile the cyclophane core peaks do not shift appreciably (not shown). T he difference in the range is only about 0.03 ppm for each of the three peaks. However, when the N H peaks are plotted (Figure 2 13 ), the shift displays a l inear decrease. One explanation for the unexpected shape of the plot is that the strength/geometry of the intramolecular hydrogen bonds is dependent on temperature. It is still recognized that there is a small amount of intermolecular hydrogen bonding oc curring at this concentration, but if the intramolecular hydrogen bonding strength is dependent on temperature, this change may have enough of an effect that the shift arising from intermolecular hydrogen bonds are hidden. If this is the case then tempera ture dependent 1 H NMR studies on these systems may not be as useful in studying intermolecular hydrogen bonds as concentration dependent studies.

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47 Table 2 4 1 H NMR (300 MHz) NH chemical shift of 7a at different temperatures Temp ( C) 5 10 15 20 25 35 45 Chemical Shift (ppm) 7.51 7.49 7.47 7.44 7.42 7.38 7.35 Figure 2 13 1 H NMR (300 MHz) NH peak chemical shift for 7a at d ifferent temperatures. The line shown is simply to guide the eye and is not the result of a linear fit. C ircular D ichroism Meijer has also shown that circular dichroism can be particularly useful to study the helical assembly that forms from his C 3 symmetric triamides with chiral R groups. 23 25 What Meijer found is that when assembled in solution the CD displays a large Cotto n effect arising from the handedness of the helix When the solution is diluted or in a and no assembly is occurring there is only a slight Cotton effect. This C otton effect is negative to the one observ ed in the aggregated solution and arises from the chirality of the small molecule By increasing the temperature of solutions in non polar solvents (typically methylcyclohexane in on effect

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48 increases the Cotton effect diminishes until the system reaches a temperature where the compounds are dissolved to the molecular level. At lower temperatures this d ecline is slow and steady, but as the solution is warmed and the helices break apart the decline increases exponentially until there is no Cotton effect observed. Meijer concludes that this observation is consistent with supramolecular polymers formed by a cooperative mechanism. Compound 7c was synthesized with these studies in mind. CD of 7c was taken in three different s olvents: chloroform (Figure 2 14A), methanol (Figure 2 14 B), and 1,1,2, 2 tetrachloroethane (Figure 2 14 C); at 25 C in 0.25 mM solution s. Chloroform was used as a non polar solvent and methanol was used as a polar solvent. Although the concentration of these solutions are low, concentration studies of 7a show that aggregation should occur in chloroform at this concentration if compounds 7a and 7c behave similarly. It is important to note that the geometry of this assembly is not fully understood. The reason low concentration solutions were used was to not overload the CD detector. polar solutions both display similar Cotton effects. Chloroform has a maximum at 293 nm and a minimum at 244 nm. Methanol has a maximum at 291 nm and a minimum at 244 nm. The shapes of the spectra are also very similar. This suggests that the Cotton effects ar ise from the chirality of the molecule not from a chiral helix. Unfortunately, chloroform does not have a high enough boiling point to study the effects of temperature on the system. To study the temperature effects, 1,1,2,2 tetrachloroethane was used as a solvent. The Cotton effects observed at 25 C of this solution are again similar to the shapes of the

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49 chloroform and methanol spectra. The maximum at 293 nm was recorded from 0 to 105 C. Instead of seeing a quick drop off at high temperatures like Mei compound 7c show s a linear decrease (Figure 2 14 D). Again, this suggests that the Cotton effects arise from the chirality of the molecule and not a chiral helix. This does not verify that assembly is not occurring at all in this solut ion, but no CD effect arises from aggregation. Temperature dependent 1 H NMR studies 7a indicate that temperature may affect the intramolecular hydrogen bonding constant of these systems. This may be wh y a linear decrease in the Cotton effect is observed, similarly to the linear decrease in the NH shift in the temperature dependent 1 H NMR of 7a Another reason for the linear decrease may be due to the interactions between the orbitals of the cyclophane core. The bent shape of benzene rings may cause a repulsion when aligned in a 1 D assembly, causing a chiral helix to be unstable and thus, a different geometry to form from assembly However, t hese interactions are not fully understood. This does not mean assembly is not occurring in solution, just tha t the assembly does not for m a chiral helix P olarized O ptical M icroscopy Images Unfortunately, single crystal XRD data has not been obtained for these compounds. Compounds 7 a c form nice fibrous crystals when dissolved in hot chloroform and the chloroform is allowed to slowly evaporate. However, these crystals are too thin to obtain single crystal XRD data. Polarized optical microscopy (POM) images were obtained of 7b to show the thin fibrous crystals that are formed (Figure 2 15). When the polarizers are crossed these crystals show strong birefringence consistent with highly ordered crystals. These crystals look similar to some of the crystals observed by Meijer in his C 3 sy mmetric columnar stacks. 16

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50 Figure 2 14 C ircular dichroism of 0.25 mM solutions of 7 c A) chloroform solution at 25 C scanning from 370 nm to 230 nm, B) methanol solution at 25 C scanning from 370 nm to 230 nm, C) 1,1,2,2 tetrachloro ethane solution at 25 C scanning from 370 nm to 230 nm, D) 1,1,2,2 tetrachloroethane solution scanning at 293 nm over a range of 0 105 C (scanning at every 1 C) T hermogravimetric A nalysis Thermogravimetric analysis ( TGA ) was performed on 4a b and 7a b to compare the stability of systems 4 to 7 It was hypothesized that the intramolecular hydrogen bonds in 7 would help to stabilize the molecules as compared to the model systems 4 which have no intramolecular hydrogen bonding capabilities. The reason f or this hypothesis is that the additional interactions should help to stabilize the highly strained carbon carbon bridge of the [2.2]paracyclophane core.

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51 Figure 2 15. P olarized optical microscopy images of 7b A) 20X magnification, B) 40X magnificatio n, C) same image as A but with the polarizers crossed, D) same image as B but with the polarizers crossed. As stated previously, the carbon carbon bridges of [2.2]paracyclophane are known to cleave at a temperature of 180 C. This is similar to the temper ature at which 4a (Figure 2 16A) begins to decompose. Compound 4a retains 95% of its mass up to a temperature of 189 C. This proves to be the least thermally stable of the four compounds tested. Compound 4b (Figure 2 16B) decomposes at a slightly higher temperature than 4a (218 C). This may originate from the increased conjugation of the molecule from the phenyl ring. However, when we compare the model systems to compounds 7a (Figure 2 16C) and 7b (Figure 2 16D), we see that 7a and 7b are in fact thermally more stable than their model systems. Compound 7a is stable up to 307 C

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52 and compound 7b is stable up to 370 C. Comparing 7a to 7b it is again observed that the butyl derivative is less stable than the phenyl derivative. Figure 2 16 T hermogravimetric analysis of amide systems A) 4a B) 4b C) 7a D) 7b

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53 CHAPTER 3 CONCLUSION Concluding Comments In conclusion, newly developed tetra amide substituted [2.2]paracyclophanes ( 7 ) have been successfully synthesized. Characterization of the assembly of these compounds in solution and in the bulk is still a work in progress. Much has been concluded about the aggregation of systems 7 in both solution and the bulk. For solutions of 7 IR was used to first determine if hydrogen bonding is occurring. By IR it is verified that hydrogen bonding is occurring in solution. It is likely that a large amount of the hydrogen bonding is intramolecular, especially at lower concentrations. Howe ver, 1 H NMR can be used to study the effects of varying the concentration and temperature of these solutions. NH peaks in the 1 H NMR were studied to determine that intermolecular hydrogen bonding is also occurring in solutions of 7 Theoretically, this peak shift should reach a minimum and a maximum, where no intermolecular hydrogen bonds occur and where the solution is saturated with intermolecular hydrogen bonds, respectively. For compound 7a the minimum appears to occur at a con centration of about 0.2 mM in chloroform, but a maximum has not yet been observed To further study the assembly of 7 in solution, the CD of compound 7c was recorded in polar and non polar solvents. The similar shape of the CD in all solvents and the lin ear decrease in the Cotton effect as temperature is increased is inconsistent with what is expected for signals arising from a chiral helix. This indicates that the signal observed for 7c arises from the molecule not from assembly of the molecule. Bulk pr operties of 7 were studied by POM and TGA. POM images of compound 7b show thin fibrous threads. The birefringence observed when the polarizers are

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54 crossed confirms that these threads are highly ordered crystals, similar to what would be expected for 1 D arrays. TGA also confirms that systems 7 are thermally more stable than model systems 4 This is understood to be because the intramolecular hydrogen bonds help to stabilize the strained CH 2 CH 2 bridge in the [2.2]paracyclophane core. Both of these studie s indicate that assembly is occurring in the bulk. Unfortunately, more studies are required to fully understand the assembly that is occurring in both the solution and the bulk. Future Directions There are still a number of techniques that could be useful in further understanding the assembly of system 7 The ultimate goal for studying the bulk properties is to obtain single crystal XRD data. Since this has proven difficult, an alternative to this would be powder XRD. Due to the low yields of 7 and the relatively high quantities needed for powder XRD, this study was put aside until initial characterization of the assembly was completed. Characterization of C ompound 7d Although compound 7d was synthesized and reported in this thesis, characterization of the assembly of this compound has not yet been completed. 1 H NMR has proven to not be a very effective technique for characterization of assembly for this compound. This is because the NH peak is extremely broad in solutions of chloroform; making is diff icult to get an accurate measurement. Similar side arms However, further understanding of the assembly of system 7 is needed before we can assume these molecules beha ve in a similar style.

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55 Other Model S ystems As previously mentioned, attempts to synthesize another model system (4,12 di amide[2.2]paracyclophanes) were performed in this study. This system is interesting because it should help to study the hydrogen bondi ng in solution. Compared to compounds 7 these compounds only have one site for intramolecular hydrogen bonding and one site on the top and bottom of the cyclophane for intermolecular hydrogen bonding (one donor and one acceptor). This should help to und erstand the hydrogen bonding in compounds 7 For the di amide systems in the 1 H NMR, we would expect the shift of the NH peak to be shifted downfield compared to 4 because of the intramolecular hydrogen bonds. Due to hydrogen bonds on only one side of t he di amide systems, we would not expect concentration and temperature to affect these systems as greatly as 7 Further attempts to successfully synthesize and isolate the di amide model systems are still underway. Synthesis of Other D erivatives of 7 Only a small number of derivatives have been studied for system 7 The derivatives synthesized for this thesis contain small side arms as simple examples of arms with ad ditional hydrogen bonding groups form a more ordered 1 D assembly. It would be interesting to synthesize similar derivatives of 7 to see if this helps induce assembly into 1 D stacks. These new derivatives could also be studied by IR, 1 H NMR, and CD similarly to compounds 7a c

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56 Synthesis of Other Hydrogen Bonding G roups In addition to systems 7 discussed in this thesis, other tetra substituted [2.2]paracyclophanes bearing different hydrogen bonding groups would be interesting to synthes ize. A particularly useful compound to synthesize would be 4,7,12,15 tetra amine [2.2]paracyclophane. If this compound is capable of production 6 4 ,6 5 it could be used as a precursor to several interesting hydrogen bonding systems. For example, by reactin g this compound with four equivalents of an acid chloride, amides could be formed with the nitrogen directly attached to the cyclophane core. This amide system is switched compared to systems 7 4,7,12,15 Tetra amine [2.2]paracyclophane could also be use d to form tetra urea compounds via a reaction with an isocyanate. Both of these new hydrogen bonding groups would be expected to have similar aggregation properties to the ones observed for systems 7 Using [3.3]P aracyclophane as an Aromatic C ore It woul d also be interesting to exchange the [2.2]paracyclophane core with [3.3]paracyclophane. [3.3]Paracyclophane is very similar to [2.2]paracyclophane, but the addition of a CH 2 in each of the bridges allows for less strain between the two benzene rings. 42 Unlike [2.2]paracyclophane, the benzene rings are planar in this system. If there are unfavorable interactions between aligned [2.2]paracyclophane rings because of the strain, using this molecule as a backbone may prove to be a better candidate for format ion of 1 D assemblies. Figure 3 1. Structure of [3.3]paracyclophane

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57 CHAPTER 4 EXPERIMENTAL General Materials Reagents and solvents were purchased from commercial sources and used without further purification. Ether and DCM were degassed in 20 L drums and passed through two sequential purification columns (activated alumina) under a positive argon atmosphere. Thin layer chromatography (TLC) was performed on SiO 2 60 F 254 aluminum plates and observed under UV light. Flash column chromatography was performed using Purasil SiO 2 Chloroform used for IR and CD was spectrophotometric grade, 99+%, purchased from Acros Organics. Molecular Modeling Molecular models w ere obtained from molecular mechanics calculations using Macromodel v. 9.1 (Schrodinger, LLC) using the AMBER forcefield. 55 I nfrared Spectroscopy Solution phase IR spectra were recorded on a Perkin Elmer Spectrum One FT IR Spectrometer using a 1.097 mm Na Cl salt cell at 25 C. Spectra for compounds 4a,b were recorded at a concentration of 0.5 mM in chloroform and spectra for compounds 7a,b were recorded at a concentration of 0.25 mM in chloroform. Nuclear Magnetic Resonance Spectroscopy The temperature d ependent 1 H NMR study of 7a was performed on a 300 MHz Mercury 300 spectrometer All other 1 H NMR and 13 C NMR spectra were recorded on a 500 MHz (125 MHz) Varian INOVA spectrometer. Chemical shifts ( ) are given in parts per million (ppm ) relative to TMS and referenced to residual protonated solvent (CDCl 3 :

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58 H 7.27 ppm, C 77.23 ppm; DMSO d 6 : H 2.50 ppm, C 39.50 ppm). Abbreviations used are singlet (s), doublet (d), triplet (t), quartet (q), quintet (qn), sextet (sx), doublet of double ts (dd), multiplet (m). Circular Dichroism An AVIV 400 Circular Dichroism (CD) spectrometer (equipped with a Thermo Scientific NESLAB Merlin M25 recirculating chiller) was used to record CD spectra of compound 7c at a concentration of 0.25 mM in chloroform methanol, and 1,1,2,2 tetrachloroethane using a 1 mm quartz cell. All three solvents were scanned from 230 nm to 370 nm at 25 C. The 1,1,2,2 tetrachloroethane solution was scanned at every 1 C from 0 C to 105 C at a wavelength of 293 nm. Thermograv imetric Analysis TGA was performed on compounds 4a,b and 7a,b using a TA Instruments Q5000 TGA at a heating rate of 10 C/min using 1 2 mg in a 100 L platinum pan. Polarized Optical Microscopy POM images of crystals of 7b grown from the slow evaporation o f chloroform were imaged on a Leica DMLP polarizing microscope at 25 C. Mass Spec t rometry ESI and APCI mass spectra were recorded on a Bruker APEX II FT ICR s pectrometer and GC EI mass spectra were recorded on a Thermo Scientific Trace GC DSQ Synthetic Schemes and Characterization [2.2]Paracyclophane (1) [2.2]Paracyclophane was purchased from Frinton Laboratories, Inc. in Hainesport, New Jersey. No further purification was performed on this compound.

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59 () 4 Bromo[2.2]paracyclophane (2) () 4 Bromo[2.2]pa racyclophane was synthesized according to the literature, 5 6 using 1 (5.04 g, 24.2 mmol) Br 2 (1.30 mL, 25.2 mmol), and a catalytic amount of Fe. Compound 2 was isolated as a white solid (4.06 g, 59 %). 1 H NMR data of the isolated compound matched the data reported in the literature. () 4 Carboxy[2.2]paracyclophane (3) () 4 Carboxy[2.2]paracyclophane was synthesized according to the literature, 5 4 using 2 (3.51 g, 12.2 mmol), a 2.5 M solution of n butyllithium in n hexane (5.50 mL, 13.7 mmol), and excess d ry ice. Compound 3 was isolated as a white solid (1.23 g, 39%). 1 H NMR data of the synthesized compound matched the data reported in the literature. () 4 M ono( n butyl)amide [2.2]paracyclophane (4a) To a round bottom flask, 3 (0.506 g, 2.01 mmol ) and thionyl chloride (1.00 mL, excess) were added and brought to reflux. The mixture was heated to reflux for 3 h and then excess thionyl chloride was distilled from the reaction flask. Portions of toluene (3 10 mL) were added to the reaction flask a nd evaporated under reduced pressure in succession to remove the remaining thionyl chloride. To the reaction flask, methylene chloride (15 mL) was added and the temperature was reduced to 0 C. To this solution, a mixture of n butylamine (0.220 mL, 2.19 mmol) and triethylamine (0.310 mL, 2.23 mmol) in methylene chloride (10 mL) was added and the reaction mixture was slowly warmed to rt. This reaction mixture was allowed to stir overnight. After completion of the reaction, the solution was diluted with a dditional methylene chloride (25 mL) and the organic layer was washed (3 25 mL) with 1 M hydrochloric acid/brine mixture (1:1). The organic layer was washed with additional brine (50 mL) and dried over anhydrous

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60 magnesium sulfate. The solution was then evaporated under reduced pressure to give the crude reaction mixture. Compound 4a was separated from the mixture by silica gel column chromatography using a 90:10 mixture of hexanes and ethyl acetate as the eluent. The final product, 4a was isolated as a white solid (0.135 g, 25%). 1 H NMR (500 MHz, CDCl 3 (50 mM)) = 0.98 (t, 3H, J = 12.5 Hz), 1.42 (m, 2H), 1.59 (m, 2H), 3.08 (m, 7H), 3.42 (m, 2H), 3.67 (m, 1H), 5.53 (s (broad), 1H), 6.42 (d, 1H, J = 15 Hz), 6.48 (d, 1H, J = 15 Hz), 6.55 (t, 2H, J = 5 Hz ), 6.58 (dd, 1H, J = 15 Hz, 5 Hz), 6.66 (d, 1H, J = 5 Hz), 6.81 (d, 1H, J = 15 Hz). 13 C NMR (125 MHz, CDCl 3 (50 mM)) = 13.8, 20.2, 31.8, 34.8, 35.1, 35.3, 35.4, 39.5, 131.5, 131.9, 132.4, 132.5 132.6, 134.8, 135.2, 135.9, 139.0, 139.1, 139.8, 140.1, 169. 2 ppm. HRMS (ESI, [M+Na] + ) calcd for C 21 H 25 NO: 330.1828; found: 330.1844. () 4 M ono(phenyl)amide [2.2]paracyclophane (4b) To a round bottom flask, 3 (0.492 g, 1.95 mmol) and thionyl chloride (1.00 mL excess) were added and brought to reflux. The mixture was heated to reflux for 3 h and then excess thionyl chloride was distilled from the reaction flask. Portions of toluene (3 10 mL) were added to the reaction flask and evaporated under reduced pre ssure in succession to remove the remaining thionyl chloride. To the reaction flask, methylene chloride (15 mL) was added and the temperature was reduced to 0 C. To this solution, a mixture of aniline (0.200 mL, 2.21 mmol) and triethylamine (0.310 mL, 2 .17 mmol) in methylene chloride (10 mL) was added and the reaction mixture was slowly warmed to rt. This reaction mixture was allowed to stir overnight. After completion of the reaction, the solution was diluted with additional methylene chloride (25 mL) and the organic

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61 layer was washed (3 25 mL) with 1 M hydrochloric acid/brine mixture (1:1). The organic layer was washed with additional brine (50 mL) and dried over anhydrous magnesium sulfate. The solution was then evaporated under reduced pressure t o give the crude reaction mixture. Compound 4 b was separated from the mixture by silica gel column chromatography using a 90:10 mixture of hexanes and ethyl acetate as the eluent. The final product, 4 b was isolated as a white solid (0.222 g, 34%). (500 MH z, CDCl 3 (50 mM)) = 3.17 (m, 7H), 3.72 (t, 1H, J = 12.5 Hz), 6.46 (d, 1H, J = 12.5 Hz), 6.57 (m, 3H), 6.66 (d, 1H, J = 12.5 Hz), 6.81 (s, 1H), 6.87 (d, 1H, J = 12.5 Hz), 7.16 (t, 1H, J = 12.5 Hz), 7.25 (s(broad), 1H), 7.39 (t, 2H, J = 12.5 Hz), 7.62 (d, 2H, J = 12.5 Hz). 13 C NMR (125 MHz, CDCl 3 (50 mM) ) = 34.8, 35.1, 35.3, 35.5, 119.7, 124.3, 129.1, 131.6, 131.8, 132.4, 132.5, 132.6, 135.4, 136.1, 138.2, 139.2, 139.5, 139.8, 140.5, 167.2 ppm. HRMS ( GC EI, [M ] + ) calcd for C 23 H 21 NO: 327.1623; found: 327.1619. () 4,7,12,15 Tetra bromo [2.2]paracyclophane (5) () 4,7,12,15 Tetrabromo[2.2]paracyclophane was synthesized according to the literature 5 7 using 1 (10.0 g, 48 mmol), Br 2 (15 mL, excess), and a catalytic amount of I 2 Compound 5 was formed as a wh ite solid (8.31 g, 33 %). 1 H NMR data of the synthesized compound matched the data reported in the literature. () 4,7,12,15 Tetra carboxy [2.2]paracyclophane (6) To a flame dried, three neck round bottom flask, 5 (8.02 g, 15 mmol ) was added under an argon atmosphere. To this reaction chamber, ether (400 mL) was added via cannula. This solution was stirred at rt and n butyllithium (2.5 M in n hexane, 26.4 mL, 66 mmol) was slowly added. After stirring for 5 h at rt, excess dry ic e was added to the reaction and stirring was continued. Upon completion, water (200 mL) was added to the

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62 reaction flask and the aqueous layer was separated and set aside. The organic layer was extracted with additional water (200 mL) and the two aqueous layers were combined and acidified with 1 M HCl (pH ~ 2). This aqueous layer was extracted with ethyl acetate (2 200 mL) and the combined organic layers were washed with brine (400 mL) and dried over anhydrous magnesium sulfate. The solvent was evapora ted under reduced pressure to give compound 6 as a light brown solid (3.23 g, 56%). 1 H NMR (500 MHz, DMSO d 6 ) = 2.97 (sx, 4H, J = 5 Hz), 3.92 (sx, 4H, J = 5 Hz), 7.14 (s, 4H), 12.81 (s(broad), 4H) 13 C NMR (125 MHz, DMSO d 6 ) = 35.0, 134.9, 136.2, 142.7 167.8 ppm HRMS (ESI, [M H] ) calcd for C 2 0 H 16 O 8 : 383.0772; found: 383.0773. () 4,7,12,15 T etra( n butyl)amide [2.2]paracyclophane (7a) To a round bottom flask, 6 (0.991 g, 2.56 mmol) and thionyl chloride (5.00 mL excess) were added and brought to reflux. The mixture was heated to reflux for 3 h and then excess thionyl chloride was distilled from the reaction flask. Portions of toluene (3 10 mL) were added to the reaction flask and evaporated under reduced pre ssure in succession to remove the remaining thionyl chloride. To the reaction flask, methylene chloride (50 mL) was added and the temperature was reduced to 0 C. To this solution, a mixture of n butylamine (1.10 mL, 11.0 mmol) and triethylamine (1.60 mL 11.2 mmol) in methylene chloride (25 mL) was added and the reaction mixture was slowly warmed to rt. This reaction mixture was allowed to stir overnight. After completion of the reaction, the solution was diluted with additional methylene chloride (75 mL) and the organic layer was washed (3 75 mL) with 1 M hydrochloric acid/brine mixture (1:1). The organic layer was washed with additional brine (150 mL) and dried over anhydrous

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63 magnesium sulfate. The solution was then evaporated under reduced pressu re to give the crude reaction mixture. Compound 7a was separated from the mixture by recrystallization from a minimum amount of methylene chloride. The resulting off white powder could further be purified by recrystallization in a minimum amount of methan ol. The final product, 7a was isolated as a white solid (0.282 g, 18%). (500 MHz, CDCl 3 (5 mM)) = 1.02 (t, 12H, J = 6 Hz), 1.48 (sx, 8H, J = 6 Hz), 1.70 (qn, 8H, J = 6 Hz), 2.59 (sx, 4H, J = 6 Hz), 3.47 (q, 8H, J = 6 Hz), 3.60 (sx, 4H, J = 6 Hz), 6.83 (s, 4H), 7.69 (s, 4H). 13 C NMR (125 MHz, CDCl 3 (5 mM)) = 14.1, 20.6, 31.7, 34.1, 40.7, 132.5, 138.0, 138.4, 169.0 ppm. HRMS (ESI, [M+Na] + ) calcd for C 36 H 52 N 4 O 4 : 627.3881; found: 627.3889. () 4,7,12,15 Tetra( phenyl)amide [2.2]paracyclophane (7b) To a round bottom flask, 6 (0.513 g, 1.32 mmol) and thionyl chloride (2.50 mL, excess) were added and brought to reflux. The mixture was heated to reflux for 3 h and then excess thionyl chloride was distilled from the reaction flask. Portions of to luene (3 10 mL) were added to the reaction flask and evaporated under reduced pressure in succession to remove the remaining thionyl chloride. To the reaction flask, methylene chloride (50 mL) was added and the temperature was reduced to 0 C. To this solution, a mixture of aniline (0.50 mL, 5.62 mmol) and triethylamine (0.80 mL, 5.59 mmol) in methylene chloride (25 mL) was added and the reaction mixture was slowly warmed to rt. This reaction mixture was allowed to stir overnight. After completion of the reaction, the solution was diluted with additional methylene chloride (75 mL) and the organic layer was washed (3 75 mL) with 1 M hydrochloric acid/brine mixture (1:1). The organic layer was washed with additional brine (150 mL) and dried over anhyd rous

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64 magnesium sulfate. The solution was then evaporated under reduced pressure to give the crude reaction mixture. Compound 7 b was separated from the mixture by recrystallization from a minimum amount of methylene chloride. The resulting off white powde r could further be purified by recrystallization in a minimum amount of methanol. The final product, 7b was isolated as a white solid (0.231 g, 26%). 1 H NMR (500 MHz, DMSO d 6 ) = 3.29 (m, 4H) 7.18 (t, 4H, J = 6 Hz), 7.24 (s, 4H), 7.44 (t, 8H, J = 6 Hz), 7.90 (d, 8H, J = 6 Hz) 10.91 (s(broad), 4H) 13 C NMR (125 MHz, DMSO d 6 ) = 34.8, 120.9, 124.9, 129.6, 132.9, 139.0, 139.7, 140.0, 167.3 ppm HRMS (ESI, [M+Na] + ) calcd for C 44 H 36 N 4 O 4 : 707.2629; found: 707.2637. 4,7,12,15 Tetra[((S ) methyl)benzy l]amide [2.2]paracyclophane (7c) To a round bottom flask, 6 (0.487 g, 1.26 mmol) and thionyl chloride (2.50 mL, excess) were added and brought to reflux. The mixture was heated to reflux for 3 h and then excess thionyl chloride was distilled from the react ion flask. Portions of toluene (3 10 mL) were added to the reaction flask and evaporated under reduced pressure in succession to remove the remaining thionyl chloride. To the reaction flask, methylene chloride (25 mL) was added and the temperature was reduced to 0 C. To this solution, a mixture of (S) ( methyl)benzylamine (0.70 mL, 5.78 mmol) and triethylamine (0.80 mL, 5.59 mmol) in methylene chloride (10 mL ) was added and the reaction mixture was slowly warmed to rt. This reaction mixture was allowed to stir overnight. After completion of the reaction, the solution was diluted with additional methylene chloride (35 mL) and the organic layer was washed (3 35 mL) with 1 M hydrochloric acid/brine mixture (1:1). The organic layer was washed with additional brine (70 mL) and dried

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65 over anhydrous magnesium sulfate. The solution was then evaporated under reduced pressure to give the crude reaction mixture. Co mpound 7 c was separated from the mixture by recrystallization from a minimum amount of methylene chloride. The resulting off white powder could further be purified by recrystallization in a minimum amount of methanol. A single diastereomer of the final p roduct, 7c was isolated as a white solid (0.186 g, 9%). 1 H NMR (500 MHz, CDCl 3 ) = 1.66 (d, 12H, J = 6 Hz), 2.13 (m, 4H), 3.27 (m, 4H), 5.31 (qn, 4H, J = 6 Hz), 6.69 (s, 4H), 7.29 (t, 4H, J = 6 Hz), 7.41 (t, 8H, J = 6 Hz), 7.50 (d, 8H, J = 6 Hz), 8.09 (d 4H, J = 6 Hz 13 C NMR (125 MHz, CDCl 3 ) = 22.2, 33.9, 49.8, 126.8, 127.6, 128.8, 132.5, 138.3, 138.4, 143.9, 167.8 ppm HRMS (ESI, [M+Na] + ) calcd for C 52 H 52 N 4 O 4 : 819.3881; found: 819.3913. () 4,7,12,15 Tetra[(1,3,5 trisdodecyloxy)phenyl] amide [2.2]paracyclophane (7d) To a round bottom flask, 6 (0.257 g, 0.665 mmol) and thionyl chloride (1.50 mL, excess) were added and brought to reflux. The mixture was heated to reflux for 3 h and then excess thionyl chloride was distilled from the reaction fl ask. Portions of toluene (3 10 mL) were added to the reaction flask and evaporated under reduced pressure in succession to remove the remaining thionyl chloride. To the reaction flask, methylene chloride (13 mL) was added and the temperature was reduce d to 0 C. To this solution, a mixture of (1,3,5 trisdodecyloxy) phenylamin e (1.87 g, 2.90 mmol) and triethylamine (0.400 mL, 2.81 mmol) in methylene chloride (5 mL) was added and the reaction mixture was slowly warmed to rt. This reaction mixture was al lowed to stir overnight. After completion of the reaction, the solution was diluted with additional methylene chloride (20 mL) and the organic layer was washed (3 20 mL) with 1 M hydrochloric

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66 acid/brine mixture (1:1). The organic layer was washed with additional brine (40 mL) and dried over anhydrous magnesium sulfate. The solution was then evaporated under reduced pressure to give the crude reaction mixture. Compound 7d was purified by dissolving the crude reaction mixture in a minimum amount of methy lene chloride. To this solution methanol was added until compound 7d began to crash out of solution. The mixture was filtered and repeated two additional times to give 7d as a brown solid (0.097 g, 5%). 1 H NMR (500 MHz, CDCl 3 (5 mM)) = 0.89 (t, 36H, J = 6 Hz), 1.28 (m, 192H), 1.47 (m, 24H), 1.78 (m, 24H), 2.77 (s (broad), 4H), 3.76 (s (broad, 4H), 3.99 (m, 24H), 7.11 (s (broad), 4H), 7.21 (s (broad), 8H), 9.32 (s (broad), 4H) 13 C NMR (125 MHz, CDCl 3 ) = 14.4, 23.0, 26.5 29.6, 29.7, 29.8, 29.9, 30.0, 3 0.1, 30.7, 32.2, 69.7, 73.8, 99.5, 153.6 ppm HRMS ( APCI [M+ H ] + ) calcd for C 188 H 324 N 4 O 16 : 2897.4802; found: 2897.4778

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67 APPENDIX N UCLEAR M AGNETIC R ESONANCE SPECTRA

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71 LIST OF REFERENCES 1. Philp, D.; Stoddart, J. F., Angew. Chem. Int. Ed., 1996 35 1154 2. Klug, A.; Angew. Chem. Int. Ed. 1983, 22 565. 3. Saenger W.; Angew. Chem. Int. Ed. 1980, 19 344. 4. Schill G ; Catananes, Rotaxanes, and Knots Academic Press. New York. 1971 5. Steiner, T., Angew. Chem. Int. Ed. 200 2, 41 48 6. Prins, L. J.; Reinhoudt, D. N.; Timmerman, P., Angew. Chem. Int. Ed. 2001 40 2382 7. Anslyn, E.V.; Dougherty, D.A., Modern Physical Organic Chemistry University Science Books. California. 2006, 184. 8. Meyer, E. A.; Castellano, R. K.; Diederich, F., Angew Chem Int Ed, 2003 42 1210. 9. F. Ponzini, R. Zagha, K. Hardcastle, J. S. Siegel; Angew. Chem. Int. Ed. 2000 39 2323 10. Yamauchi Y. et al., J Am. Chem. Soc 2010 132 9555. 11. Klosterman, J K.; Yamauchi, Y.; Fujita, M., Chem. Soc. Rev. 200 9, 38 1714 12. Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Chem. Re v 200 1 101 4071. 13. De Greef, T. F. A.; Smulders, M. M. J.; Wolffs, M.; Schenning, A. P. H. J.; Sijbesma, R. P.; Meijer, E. W., Chem. Rev., 2009 109 5687 14. Hoeben, F. J. M.; Jonkheijm, P.; Meijer, E. W.; Schenning, A. P. H. J., Chem. Rev. 2005 105 149. 15. van Herrikhuyzen, J.; Jonkheijm, P.; Schenning, A. P. H. J.; Meijer, E. W., Org. Biomol. Chem. 200 6, 4 1539 16. van den Hout, K.; Martn Rapn, R.; Vekemans, J .; Meijer, E., Chem. Eur. J. 2007, 13 8111 17. Stals, P.; Smulders, M.; Martn Rapn, R.; Palmans, A.; Meijer, E., Chem. Eur. J. 2009 15 2071 18. Stals, P. J. M.; Haveman, J. F.; Palmans, A. R. A.; Schenning, A. P. H. J., J. Chem. Ed 2009 86 230

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75 BIOGRAPHICAL SKETCH Michael Joseph Meese, Jr. was born in Cincinnati, Ohio to parents Michael, Sr. and Catherine Meese. He has one sibling, a younger sister, Rebecca Meese. He graduated with honors from the Univers ity of Cincinnati with a B achelor of S cience in c hemistry in 2008, working in the labs of Dr. Anna Gudmundsdottir. He moved to Gainesville, Florida in the summer of 2008 to continue his education at the University of Florida under the advisement of Dr. Ronald K. Castellano, where he currently resides with his wife Mary Kate Meese.