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Design, Synthesis and Supramolecular Properties of Highly Functionalized Donor-Sigma-Acceptor Molecules

Permanent Link: http://ufdc.ufl.edu/UFE0022130/00001

Material Information

Title: Design, Synthesis and Supramolecular Properties of Highly Functionalized Donor-Sigma-Acceptor Molecules
Physical Description: 1 online resource (176 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: donor, dynamic, gel, self, supramolecular
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 1-Aza-adamantanetriones (AATs) constitute an important class of donor-sigma-acceptor molecules that show unique electronic and macromolecular properties upon self-assembly. Described are the design, rational syntheses, and characterization of new AAT derivatives to draw structure-property relationships with the materials toward potential applications. AATs bearing expanded aromatic side chains, naphthyl substituents, form organogels at the lowest concentration (critical gelation concentration = 0.2% by weight) to date (in benzene and toluene) that are also thermally robust (Tg = 70 Degree Celsius). SEM and XRD studies explore the underlying fibrous networks, and organization, in the solid state. In solution, fluorescence emission spectra show intermolecular excimer formation (wavelength = 433 nm) upon assembly and implicate pi-pi stacking interactions as being important for association. Likewise, concentration- and temperature-dependent NMR and IR studies show that intramolecular H-bonding of peripheral amide functional groups likely preorganizes the molecules for self-assembly. Finally, dynamic light scattering (DLS) studies show for the first time how the assembly of functionalized AATs responds reversibly to concentration and temperature in organic solution, where large aggregates are formed at exceedingly low concentrations ( < 0.1 mM). New synthetic methodology is described to prepare differentially-functionalized and even chiral AATs that involves the selective formation and then ring opening of mono-, di-, and trilactones derived from phloroglucinol derivatives. Temperature is the key to controlling the ring-opening reactions and product distributions. In this fashion the first chiral AAT is reported, where the tricyclic core bears three different substituents: an isopropyl ester, an alkyl amide, and an aryl amide. Such molecules appear as new types of chiral tertiary amines that could have potential applications in asymmetric catalysis or chiral recognition. The lactone-based methodology also allows introduction of ether functional groups to the AAT scaffold for the first time. To demonstrate this advance, AATs outfitted with TBS-protected ethylene glycol units have been prepared. Deprotection should afford the first hydrophilic and potentially hydrogelating AATs.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Castellano, Ronald K.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022130:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022130/00001

Material Information

Title: Design, Synthesis and Supramolecular Properties of Highly Functionalized Donor-Sigma-Acceptor Molecules
Physical Description: 1 online resource (176 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: donor, dynamic, gel, self, supramolecular
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: 1-Aza-adamantanetriones (AATs) constitute an important class of donor-sigma-acceptor molecules that show unique electronic and macromolecular properties upon self-assembly. Described are the design, rational syntheses, and characterization of new AAT derivatives to draw structure-property relationships with the materials toward potential applications. AATs bearing expanded aromatic side chains, naphthyl substituents, form organogels at the lowest concentration (critical gelation concentration = 0.2% by weight) to date (in benzene and toluene) that are also thermally robust (Tg = 70 Degree Celsius). SEM and XRD studies explore the underlying fibrous networks, and organization, in the solid state. In solution, fluorescence emission spectra show intermolecular excimer formation (wavelength = 433 nm) upon assembly and implicate pi-pi stacking interactions as being important for association. Likewise, concentration- and temperature-dependent NMR and IR studies show that intramolecular H-bonding of peripheral amide functional groups likely preorganizes the molecules for self-assembly. Finally, dynamic light scattering (DLS) studies show for the first time how the assembly of functionalized AATs responds reversibly to concentration and temperature in organic solution, where large aggregates are formed at exceedingly low concentrations ( < 0.1 mM). New synthetic methodology is described to prepare differentially-functionalized and even chiral AATs that involves the selective formation and then ring opening of mono-, di-, and trilactones derived from phloroglucinol derivatives. Temperature is the key to controlling the ring-opening reactions and product distributions. In this fashion the first chiral AAT is reported, where the tricyclic core bears three different substituents: an isopropyl ester, an alkyl amide, and an aryl amide. Such molecules appear as new types of chiral tertiary amines that could have potential applications in asymmetric catalysis or chiral recognition. The lactone-based methodology also allows introduction of ether functional groups to the AAT scaffold for the first time. To demonstrate this advance, AATs outfitted with TBS-protected ethylene glycol units have been prepared. Deprotection should afford the first hydrophilic and potentially hydrogelating AATs.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: Castellano, Ronald K.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022130:00001


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1 DESIGN, SYNTHESIS AND SUPRAMOLEC ULAR PROPERTIES OF HIGHLY FUNCTIONALIZED DONOR-ACCEPTOR MOLECULES By LING YUAN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2008

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2 2008 Ling Yuan

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3 To my parents To my husband and our daughter

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4 ACKNOWLEDGMENTS I would like to thank m y advisor, Dr. R onald K. Castellano, for affording me the opportunity to study in his labora tory. The time spent under his dir ection has been invaluable. I am thankful for his patience, guidance, and en couragement. I am honored to be one of his students and have learned a lot in science, and in character from him. I am and will continue to benefit from all of these thr oughout my whole life. I would like to thank my lab mates in the Castellano group. Special thanks go to Dr. Andy Lampkins, Dr. Vladimir Gubala, Jennifer Mattler, and Adnan Javed who shared the excitin g AAT chemistry with me. I thank Yan Li for his help in the lab and discussi ons on lactone chemistry. I thank Dr. Roslyn Butler, Dr. Alisha Martin, Pam Cohn, Matt Baker, and Rach el Giessert for their friendship. I would also like to thank my collaborators Dr. Kunlun Hong and Dr. Masashi Osa in the Center for Nanophase Materials Sciences (CNM S) at Oak Ridge Nati onal Laboratory (ORNL), Dr. Nathanael Stevens in the Particle Engineering Research Center (PERC) at the University of Florida, Dr. Erik Berda, Dr. I on Ghiviriga, and Dr. Katsu Ogawa in the chemistry department, Dr. Junghun Jang in the Major Analytical Instrument ation center (MAIC) at the University of Florida, for their scientific discus sions and assistance in my studies. I would like to thank my committee members: Prof. Lisa McElwee-White, Prof. Alan Katritzky, Prof. George Christou, and Prof. Joanna Long for being on my committee and for their scientific advice and efforts. Finally, the foremost and special thanks go to my family. I would like to thank my parents, Yiling Zhong and Zhineng Yuan for their uncond itional love and support. I thank my husband, Junliang Zhang for his understand ing. The most special thanks go to my little daughter, Helen S. Zhang. She brings so much happiness and many surp rises to my life. Her smile is the best gift after all of my hard work.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4LIST OF TABLES................................................................................................................. ..........7LIST OF FIGURES.........................................................................................................................8LIST OF ABBREVIATIONS........................................................................................................ 12ABSTRACT...................................................................................................................................13CHAPTER 1 INTRODUCTION..................................................................................................................15Supramolecular Chemistry..................................................................................................... 15Introduction to Supramolecular Chemistry..................................................................... 15Self-Assembly.................................................................................................................17Through-Bond Interactions and -Coupled Donor-Acceptor Molecules............................... 22Through-Bond Interactions.............................................................................................23Donor-Acceptor Molecules and Their Traditional Applications.................................24-Aminoketones..............................................................................................................251-Aza-Adamantanetrione (1-AAT) Platform.................................................................. 29Self-Assembly of AATs......................................................................................................... 31AATs Bearing Simple Aromatic Side Chains................................................................. 31Amides In the Periphery.................................................................................................. 33Emergent Electronic Structure........................................................................................ 34Scope of Dissertation..............................................................................................................352 DESIGN, SYNTHESIS, AND PROPERTIES OF 1-AZA-ADAMANTANETRIONE S WITH EXPANDED AROMATIC ARMS............................................................................. 37Introduction................................................................................................................... ..........37Design and Synthesis........................................................................................................... ...38Design of AATs with Expanded Aromatic Arms............................................................ 38Synthesis..........................................................................................................................40Gel Formation and Characterization....................................................................................... 45Solid State Properties......................................................................................................... .....47Morphology of Critical Point Dried Gels........................................................................ 47X-Ray Diffraction (XRD)................................................................................................ 49Thermal Properties.......................................................................................................... 51Solution Phase Assembly....................................................................................................... 54UV Absorption Spectra...................................................................................................54Fluorescence and Excimer Emission............................................................................... 56H-Bonding in Amide-Functionalized AATs................................................................... 60

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6 Dynamic Light Scattering................................................................................................65Summary and Conclusions.....................................................................................................69Experimental Section........................................................................................................... ...70Materials..........................................................................................................................70Characterization Techniques...........................................................................................70Synthesis..........................................................................................................................723 DIFFERENTIALLY FUNCTIONALIZED AND CHIRAL AATS FROM LACTONE PRECURSORS ..................................................................................................................... ..86Introduction................................................................................................................... ..........86A Lactone-Based Strategy......................................................................................................88Approach to Differentially-Substitu ted AATs from Butenolide Precursors..........................92Chiral AATs Derived fro m Lactone Methodology................................................................ 94Interesting Thermal and Optical Properties of Differentially-Substituted AATs................... 97Summary...............................................................................................................................100Experimental Section........................................................................................................... .101Characterization Technique...........................................................................................101Synthesis........................................................................................................................1014 EFFORTS TOWARD HYDROPHILIC AND HYDROGE LATING AATS...................... 124Introduction of Hydrogels and Their Broad Applications.................................................... 124Synthesis of Hydrophilic AATs............................................................................................125Experimental Section........................................................................................................... .1285 CONCLUSIONS AND OUTL OOK.................................................................................... 137Summary and Conclusions...................................................................................................137Outlook.................................................................................................................................138Arms Functionalized with H-bonding Recognition Groups..........................................139Hydrophilic and Hydrogelating AATs.......................................................................... 139Differentially-Functionalized AATs.............................................................................139APPENDIX NMR SPECTRA.................................................................................................141 LIST OF REFERENCES.............................................................................................................166BIOGRAPHICAL SKETCH.......................................................................................................176

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7 LIST OF TABLES Table page 1-1 Comparison of average bond lengths (reported in ) f rom the X-ray crystal structures of 1-9 1-10, and related tricyclic molecules from Figure 1-15.76.....................312-1 Solubility and gelation properties of compound 2-1a, 2-1b and 2-12..............................472-2 Amide NH IR frequency (cm-1) for 2-1a and representative molecules from the literatures............................................................................................................................633-1 Nucleophilic ring opening of monoand di butenolides with amines and subsequent cyclization with HMTA.....................................................................................................933-2 Phase transition temperatures and enthalpies for 3-5a and 3-7a .......................................99

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8 LIST OF FIGURES Figure page 1-1 Schematic representation of the column ar liquid -crystalline phase formed by the assembly of disk-shaped molecules ( d = intercolumnar distance).37.................................181-2 Chemical structure of Stupps peptide am phiphiles, highlighting five key structural features...............................................................................................................................191-3 Schematic diagram of the packing in (a ) H-type aggregates of per6dodecbenzamide perylenebisimide derivative in solu tion and (b) J-type aggregates of per6dodecbenzester perylenebisi mide derivative in solution.42.........................................201-4 The chemical structure of a merocyanine dye and a model for its self-assembly into 1-D stacks that are stabilized by -stacking and dipolar interactions............................... 211-5 Vanadium-oxo linear chain compounds that organize into polar stacks through coreto-core dipolar in teractions and -stacking interactions.45................................................221-6 A schematic representation of the requir ed orientation for optimal TBI between two nitrogen lone pair s separated by three -bonds.58.............................................................231-7 Verhoevens molecules that illustrate of the conformational requirements for CT absorption.66, 67...................................................................................................................241-8 Examples of rigid donor-acceptor molecules.69.............................................................251-9 Donor-acceptor arrangement in cyclic -aminoketones; N -methylpiperidone ( 1-3 ), tropinone (1-4 ), and 1-aza-adamantanone (1-5 ).76.............................................................261-10 Synthesis of cis -3,5-dibenzyl piperidin-4-ones..................................................................261-11 Plot of the HOMO for the axial epimer ( 1-8a-ax) which shows delocalization of the nitrogen lone pair onto the phenyl, the adjacent C C of the piperidione backbone, and the carbonyl.................................................................................................................281-12 Plot of the HOMO for the equatorial epimer ( 1-8a-eq ) which shows delocalization of the nitrogen lone pair onto the phenyl, the adjacent C C of the piperidione backbone.... 281-13 Synthesis of the 1-aza-adma ntanetrione (AAT) platform.................................................. 291-14 X-ray crystal structure of compound 1-9 and 1-10 .76........................................................301-15 The chemical structure of compound 1-11 (Ar = p-chlorophenyl), 1-12 (Ar = pnitrophenyl, and 1-13.76.....................................................................................................311-16 Generic structure of AATs b earing aromatic side chains.................................................. 32

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9 1-17 (a) Organogel of the trib enzyl AAT derivative 1-14 (Ar = Ph) in DMSO. (b) SEM image of the xerogel formed from critical point drying of an 0.5 wt % DMSO gel. (c) TEM image of the xerogel formed from critical point drying of an 0.5 wt % DMSO gel.56...................................................................................................................................321-18 (a) Energy-minimized lowest energy all-arms-up conformation. (b) The NOE contacts identified from a NOESY experiment for 1-14 (Ar = Ph). (c) Total charge density isosurface for the gas-phase optimized dimmer, ( 1-14)2.......................................331-19 Amide functions on the periphery of the tricyclic core stabilize a C3-symmetric monomer conformation by intramol ecular hydrogen bonding and dipole dipole interactions.55, 91.................................................................................................................341-20 (a) SEM image of rope-like fibers of 1-15 (R = H) formed upon solvent evaporation. (b) X-ray diffraction pattern of neat 1-15 (R = H). (c) Solid-state NMR data using an 15N-labeled derivative of 1-15 (where R = H).55, 91...........................................................341-21 Calculated (DFT(LDA)/cc-pVDZ) dimer and stacking arrangement for 1-14 (Ar = Ph): (a) the HOMO charge density isosur face for the dimer showing delocalization over both AAT cores; (b) 1-D periodic stacking of 1-14 (Ar = Ph) monomers into wire-like assemblies.89, 90, 92...............................................................................................352-1 One-dimensional packing (J-aggregation) of salicylideneaniline derivative along the b axis in the crystal state.................................................................................................... 392-2 Synthesis approach of alkyl substituted naphthylamines................................................... 412-3 Synthesis of a naphthylamine substituted with an electr on-withdrawing group...............422-4 Synthesis of naphthyl amide-functionalized AATs........................................................... 432-5 Synthesis of desymmetrized AAT using a lactone-based strategy....................................442-6 Synthesis of model compound 2-13...................................................................................452-7 Organogel from trinapht hyl-1-aza-adamantanetrione 2-1a (0.2 wt % in toluene after heating and cooling)........................................................................................................... 462-8 SEM images of a xerogel formed from critical point drying the 0.2 wt % toluene gel of compound 2-1a. .............................................................................................................492-9 X-ray diffraction patte rn of the neat powder 2-1a .............................................................502-10 X-ray diffraction patte rn of the neat powder 2-1b .............................................................512-11 DSC traces for compound 2-1a..........................................................................................512-12 DSC traces for compound 2-1b .........................................................................................52

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10 2-13 TGA measurements of solid 2-1a. .....................................................................................532-14 TGA measurements of solid 2-1b ......................................................................................532-15 Absorption spectra for compound 2-1a in chloroform (light path length: 3 mm).............552-16 Absorption intensity at 285 nm vs. concentration for compound 2-1a..............................552-17 Absorption spectra for compound 2-12 in chloroform (light path length: 10 mm)........... 562-18 Absorption spectra for compound 2-13 in chloroform (light path length: 10 mm)........... 562-19 Emission spectrum of 2-1a at exc = 285 nm in chloroform.............................................. 572-20 Emission spectrum of 2-13 at exc = 285 nm in chloroform.............................................. 582-21 Emission spectrum of 2-1a at exc = 285 nm in chloroform with concentration 2 x 105 M......................................................................................................................................592-22 Emission spectrum of 2-12 at exc = 285 nm in chloroform.............................................. 602-23 The IR spectrum of 2-1a at 1.6 mM in chloroform...........................................................622-24 The IR spectrum of 2-13 at 0.13 M in chloroform............................................................ 622-25 1H NMR spectra of 2-1a in C2D2Cl4 (5.4 mM) at differe nt temperatures......................... 642-26 1H NMR spectra of 2-13 in C2D2Cl4 (5.4 mM) at differe nt temperatures......................... 642-27 1H NMR spectra of 2-1a in C2D2Cl4 at different temperatures......................................... 652-28 1H NMR spectra of 2-13 in C2D2Cl4 at different temperatures......................................... 652-29 Size distrubution of 1-15 ( R = C12H25) at various concentration in chloroform (25 C, (scattering angle) = 104 )...............................................................................................662-30 Size distrubution of 1-15 chloroform solutions (c = 0.0059 %) at various temperatures ( (scattering angle) = 104 )........................................................................ 672-31 Time-intensity correlation functions ( g(2)( ) 1) for 2-1a at various concentrations in toluene (25 C, (scattering angle) = 88 )........................................................................ 672-32 Time-intensity correlation functions ( g(2)( ) 1) for 2-1a in toluene at various temperatures (c = 0.019 wt%)............................................................................................ 682-33 Time-intensity correlation functions ( g(2)( ) 1) for chloroform solutions of 2-1a and 1-15 at c = 0.019 wt%........................................................................................................ 69

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11 3-1 Current methodology used to construct the C3 symmetric AATs. BBr3 labile functionality is not tolerated in the current scheme........................................................... 873-2 From symmetric to asy mmetric triamide AATs................................................................883-3 Synthetic methodology used to selectivel y annulate mono-, di-, and tributenolides from a common intermediate, an ester phloroglucinol derivative.91.................................893-4 Synthetic methodology used to selectivel y annulate mono-, di-, and tripentenolides from a common intermediate, an ester phloroglucinol derivative.91.................................903-5 The synthetic approach of amide-functionalized lactones................................................. 913-6 Preparation of mixed amide and es ter AATs derived from the monoand dibutenolides......................................................................................................................923-7 Synthesis of differential amide func tionalized AATs from amide mono-lactone............. 933-8 Synthesis of differential amide func tionalized AATs from amide dilactone.................... 943-9 Different ring opening patterns of the dilactone 2-10 at different re action conditions..... 953-11 The 1H NMR of compound 1-15 (in DMSOd6), 3-9b (in pyridined5), and 3-16b (in CDCl3). See Figure 3-10 for the proton assignments........................................................ 973-12 DSC curves obtained for 3-5a for the first (red lines) and the sec ond (blue lines) heating cooling cycles. A Cold-crystallization exotherm is identified in the second heating cycle (heating and cooling rate 10 C/min).......................................................983-13 DSC curves obtained for 3-7a for the first (red lines) and second (blue lines) heating cooling cycles. Two cold-crystalliza tion exotherms and one endothermic transition are identified in the first heating cycle............................................................... 993-14 Cross-polarized optical microscopy images of compound 3-5a: (a) The original solid sample shows needle-like crystals at room temperature. (b) to (h) Crystal growth in about 42 seconds in the s econd heating cycle (rate 10 C/min). The temperature of (b) was 135 C and the temperature of (h) was 142 C. (I) Fully grown cold crystalline 3-5a .................................................................................................................1004-1 A bisurea based supramolecular polymer that forms hydrogels.201.................................1254-2 Initial reaction between the unprotec ted aminoalcohol and tripentenolides.................... 1264-3 The synthesis of protected ethylene glycol building block.............................................. 1264-4 The synthesis of hydrophilic AATs derived from mono-, di-, and tributenolides........... 1274-5 The synthesis of hydrophilic AATs derived from mono-, di-, and tripentenolides......... 128

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12 LIST OF ABBREVIATIONS AAT 1-aza-adm antanetrione TBI Through-bond interaction DMF Dimethylformamide DCM Dichloromethane DLS Dynamic light scattering DSC Differential scanning calorimetry TGA Thermal gravimetric analysis CPD Critical point drying SEM Scanning electron microscopy POM Polarized optical microscopy XRD X-ray diffraction DCC 1,3-Dicyclohexylcarbodiimide EWG Electron withdrawing group HMTA Hexamethylenetetramine TFA Trifluoroacetic acid PAH Polycyclic aromatic hydrocarbon

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13 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy DESIGN, SYNTHESIS, AND SUPRAMOL ECULAR PROPERTIES OF HIGHLY FUNCTIONALIZED DONOR-ACCEPTOR MOLECULES By Ling Yuan May 2008 Chair: Ronald K. Castellano Major: Chemistry 1-Aza-adamantanetriones (AATs) cons titute an important class of donor-acceptor molecules that show unique el ectronic and macromolecular properties upon self-assembly. Described are the design, rational syntheses, a nd characterization of new AAT derivatives to draw structure-property relati onships with the materials towa rd potential applications. AATs bearing expanded aromatic side chains, naphthyl substituents, form organogels at the lowest concentration (critical gelation c oncentration = 0.2% by weight) to date (in benzene and toluene) that are also thermally robust ( Tg = 70 C). SEM and XRD studies explore the underlying fibrous networks, and organization, in the solid state. In solution, fluorescence emission spectra show intermolecular excimer formation (max = 433 nm) upon assembly and implicate stacking interactions as being importan t for association. Likewise, concentrationand temperaturedependent NMR and IR studies show that intramolecular H-bonding of peripheral amide functional groups likely preorgan izes the molecules for self-assembly. Finally, dynamic light scattering (DLS) studies show for the first time how the assembly of functionalized AATs responds reversibly to concentration and temperat ure in organic solution, where large aggregates are formed at exceedingly low concentrations (< 0.1 mM).

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14 New synthetic methodology is described to pr epare differentially-func tionalized and even chiral AATs that involves the selective forma tion and then ring opening of mono-, di-, and trilactones derived from phlorogluc inol derivatives. Temperature is the key to controlling the ring-opening reactions and product di stributions. In this fashion th e first chiral AAT is reported, where the tricyclic core bears thr ee different substituents: an isopr opyl ester, an alkyl amide, and an aryl amide. Such molecules appear as new ty pes of chiral tertiary amines that could have potential applications in asymmetric catalysis or chiral recognition. The lactone-based methodology also allows introduction of ether functional groups to the AAT scaffold for the first time. To demonstrate this advance, AATs outf itted with TBS-protected ethylene glycol units have been prepared. Deprotection should a fford the first hydrophilic and potentially hydrogelating AATs.

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15 CHAPTER 1 INTRODUCTION Supramolecular Chemistry Supram olecular chemistry is defined as the area of chemistry that focuses on the noncovalent interacti ons of molecules.1, 2 With the rapid development of this field over recent years, the focus has changed from constructing fu nctional molecules via the formation of direct covalent linkages to creating function al systems by molecu lar self-assembly.3-7 Introduction to Supramolecular Chemistry Lehn describes supram olecular chemistry as the design chemistry of the intermolecular bond,1 and the field finds its insp irational roots in some of the now well-known functional assemblies of nature. The DNA double helix, which forms from two complementary singlestranded polynucleotides, is a familiar example. The strands recognize each other by selective hydrogen bonds between the base pair s and base stacking interactions.8 Other natural supramolecular assemblies include enzymesubstr ate complexes, antibodyantigen complexes, and membrane receptors. The cell membrane itself is another example; it is a highly functionalized and oriented system that plays an essential role in basic biological functions like ion and molecular transport, and signal transduction.8 The design of systems that can mimic biologica l functions remains a challenge to chemists and biochemists.9, 10 The artificial membrane ion channe ls based on self-assembled cylindrical sheet peptides made by the Ghadiri group11 represent one of many successful examples. Here cyclic peptide structures comprised of alte rnating D and L amino acids adopt a flat ring conformation and stack to form a hydrogen-bond ed hollow tubular structure. The assembly displays good channel-mediated ion-transport activity. Indeed, supramolecular chemistry is closely related to bioorganic and bioinorganic chemistry.12

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16 The principles of supramolecular chemistry have more recently been systematically employed in nanotechnology and materials science,13, 14 and borrowing Natures strategies appears as a useful approach to controlling the optical and phot ophysical properties of functional molecules and ultimately, their performance in devices.14-16 Numerous supramolecular systems have found practical applications. Liquid crystals are an exemplary clas s of materials whose unique properties rely on noncovalent interactions Their applications ex tend from liquid crystal displays (LCDs) which appear in everyday life,17 to various medical areas18 and chemical analysis.19 Supramolecular chemistry likewise un derlies many technologies involving surfactants,20 organic semiconductors, conductors,21 and molecular rectifiers.22 Organogels, like liquid crystals, form as a consequence of noncovalent interactions and therefore fall within the realm of supramolecular chemistry. Gels appear when organic solvents are immobilized by a three-dimensional network composed of aggregated gelators;23 their unusual rheological properties and thermoreversibility make them useful materials in diverse fields that include fo od science, medicine (e.g., drug delive ry), cosmetics, and pharmacology.24 The chemical structures of the gelators dete rmine the self-assembly of the molecules. In general, gelation is thought to arise from en tangled fibers, which become cross-linked by noncovalent interactions and are able to trap solvent molecu les. As a consequence, the organogels are often thermally reversible and the gel properties can ea sily be controlled by changing the temperature, the structures of the interacting functional gr oups, or by mechanical agitation of the suspension.25 A challenge that unites synt hetic supramolecular systems is understanding how the fundamental structures of the molecular building blocks (e.g., gelators) relates to the properties and potential applications of th e self-assembled aggregates.

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17 Self-Assembly Central to su pramolecular chemistry is the concept of self-assembly, defined as the process by which a supramolecular species forms spontaneously from its components.7 Liquid crystal formation,26 the growth of crystals,27 metal coordination complexes,28 formation of the DNA double helix, and generation of synthetic lipid bilayers29 all involve the spontaneous assembly of small components to form larger structures. Various inte rmolecular interactions mediate the self-assembly of molecules; these, in addition to shape complementarity, are the keys to controlling structure and macromolecu lar properties. Noncovale nt interactions are reversible, and the resultant se lf-assembled structures are ther efore under thermodynamic control and in thermodynamic equilibrium with their molecular components. The idea of error correction7 extends from these principles and is important for both biol ogical and synthetic molecules that may experience numerous possibl e intermolecular interactions on the way to desired (and often complex) assembly structure. Molecular self-assembly thus stands as one of the most efficient and economical ways to synthesize complex materials. Many traditional intermolecular interactions come to the fore in the self-assembly of molecules. These include hydrogen bonding, stacking, electrostatic interactions, van der Waals, and hydrophobic interactions. The first two are the most commonly exploited in the design of self-assembled systems.30-33 Stacking6 is perhaps best known through its role in stabilizing DNA duplex formation through vertical base-pair interactions. However, such interactions play a prominent role in many synthetic self-ass embled systems. Thermotropic liquid crystals (Figure 1-1), for example, are formed from the -stacking of molecules with a central aromatic core and alkyl chains attached on the periphery. Triphenylbenzene,34 hexabenzocoronenes (HBCs),35, 36 and their derivatives are typica l examples of discotic liquid

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18 crystal mesogens. The size and shape of the core as well as the length of th e side chains help to control the functional properties of these materials,37 which include one-dimensional charge transport.37, 38 The conducting properties of discotics are useful for various photovoltaic devices, in particular, solar cells and or ganic field-effect transistors.39, 40 The -stacking interactions of naphthalene, the simplest polycyclic aromatic hydrocarbon (PAH), are exploited in Chapter 2 of this dissertation. Figure 1-1. Schematic representation of the co lumnar liquid-crystalline phase formed by the assembly of disk-shaped molecules ( d = intercolumnar distance).37 H-bonding interactions are also commonly used in the design of self-assembled systems.3033 These weak, but directional interactions play significant roles in cont rolling the structure and conformation of most biologi cal supramolecules, like proteins. The Stupp group employs a variety of interactions, including H-bonding, in th e self-assembly of pe ptide-amphiphiles (PAs, Figure 1-2).41 The molecules assemble in water into cylindrical micelles and fibers; the alkyl chains pack in the center of the micelles (hydrophobic interacti ons) while the more polar peptide segments associate by H-bonding clos er to the aqueous exterior.

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19 H N O N H H N N H H N N H H N O O O O O O SH SH SH SH N H H N N H H N O O P OH HO O O NH H2N NH O O OH O OH O 1 2 3 4 5 Figure 1-2. Chemical structure of Stupps peptide amphiphiles, hi ghlighting five key structural features. The long alkyl chai n of region 1 conveys hydrophobic character. Region 2 is the peptide main chain which is composed of four consecutive cy steine residues that may form disulfide bonds to crosslink the self-assembled structure when oxidized. Region 3 is a flexible linker region that serves as a hydrophilic head group. Region 4 and 5 feature special molecular recognition functionality.41 A hydrogen-bonding-induced conformational cha nge from Jto Haggregates in fluorescent liquid-crystalline perylenebisimides shows how stacking and H-bonding interactions can muturall y support self-organization.42 Recently prepared and highly fluorescent liquid-crystalline perylenebisimide molecules feature amide or ester linkages and are end-capped by phenyl, monododecyloxy phenyl, or tridodecyl oxy phenyl units (Figure 1-3). The amidefunctionalized series self-organizes to form Htype aggregates regardless of the end-cap in organic solvents like tetrahydrofuran (THF), toluene, and dichloromethane (Figure 1-3a). On the other hand, only the monododecyloxy phenyl end-cappe d molecule in the ester series shows a tendency to self-organize with a typical Jt ype aggregation in tolu ene (Figure 1-3b). The development of this new series of perylenebi simide based liquid-crystalline materials was accomplished using both hydrogen bonding and interactions as well as balancing the rigidity (aromatic core)-flexibility (alkyl chains) ratio of the molecular shape.42

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20 N N O O O O O O O O OC12H25 C12H25O b) Figure 1-3. Schematic diagram of the packing in (a) H-type aggregates of per6dodecbenzamide perylenebisimide derivative in solu tion and (b) J-type aggregates of per6dodecbenzester perylenebisi mide derivative in solution.42 The above examples show how tradit ional noncovalent interactions like -stacking and Hbonding can be used to control the structures and properties of self-assembled materials. As supramolecular structures become more complex, numerous interactions are often responsible for self-assembly. Wrthner a nd coworkers have shown, using -conjugated donoracceptor

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21 chromophores (e.g. merocyanine dyes, Figure 1-4), how dipolar (electrosta tic) interactions can be combined with other nonc ovalent interactions (like -stacking) to promote small-molecule self-assembly into gels,43 liquid crystals,44 and supramolecular polymers.43 Similar dipolar interactions are important to the self-assembly of the donor-acceptor molecules discussed in this dissertation. Figure 1-4. The chemical structure of a merocyan ine dye and a model for its self-assembly into 1-D stacks that are stabilized by -stacking and dipolar intera ctions. The graphic also shows how the molecules might be oriented in an electric fiel d (D = electron donor: A = electron acceptor).43 Shape complementarity is important for self-a ssembly processes; molecules that can fit together well can also optimize the noncovale nt interactions between them. Swager and coworkers have used shape, dipole, van der Waals, and -stacking interactions together to create unidirectional (head-to-tail) liquid-crysta lline linear chain poly mers (Figure 1-5).45 Other researchers, like Kato,46-49 Collet,50-52 and Tschierske53, 54 have similarly used interesting molecular shape in their assembly designs.

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22 Figure 1-5. Vanadium-oxo linear chain compounds that organize into polar stacks through coreto-core dipolar in teractions and -stacking interactions.45 Self-assembly provides access to molecular aggr egates and organized matter on size scales well beyond what can be achie ved through bond-by-bond construction.9 The strategy, however, is limited by our ability to predict how assemb lies will form, what noncova lent interactions can be used in the process, and what properties will emerge from th e equilibrium structures. This dissertation explores these ge neral concepts in the contex t of new building blocks for supramolecular chemistry, -coupled donor-acceptor molecules. Through-Bond Interactions and -Coupled Donor-Acceptor Molecu les Noncovalent interactions play a crucial role in controlling th e structures and properties of supramolecular assemblies; identifying new inter actions, and studying the molecular structures that feature them, is an important research area. Recently the Cast ellano group initiated a research program that employs donor-acceptor (D-A) molecules as building blocks in supramolecular architectures. One goal is to study strong -coupled donor-acceptor interactions

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23 as complements to traditional noncovalent forces in the directed self-organization of functional molecules.55, 56 Through-Bond Interactions The term through-bond interaction (TBI) was introduced in 1968 by Hoffmann and coworkers to designate the intramolecular intera ction between functional groups via intervening -bonds.57, 58 This definition was later expanded to include the experimental results of Heilbronner59 and the higher-level theory of Dewar and Wasson, researchers who also showed the dependence of such interac tions on the geometry of the -bridge.60 Indeed, these types of hyperconjugative interactions are ve ry sensitive to the orientati on of the interacting donor and acceptor orbitals with respect to the -relay that connects them Theoretical studies57, 58, 61, 62 have shown that TBI between two n itrogen lone pairs separated by three -bonds will be optimized for the conformation depicted in Fi gure 1-6, where the interacting groups adopt an antiperiplanar relationship and are pa rallel to the cen tral carbon-carbon -bond. Hudec and Cooksons examples63, 64 of constrained biand tricyclic donor-acceptor (D-A) molecules illustrate this phenomenon nicely. Figure 1-6. A schematic representation of the re quired orientation for optimal TBI between two nitrogen lone pair s separated by three -bonds.58

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24 Donor-Acceptor Mo lecules and Their Traditional Applications Studies63-68 have shown that an intramolecular charge transfer (CT) absorption and emission can arise from through-bond interactions between a properly orie nted strong electron donor (D) and strong electron accepto r (A)even if the functional groups are separated by three or more -bonds. Verhoeven and coworkers have used this spectroscopic signa ture to elucidate the stereoelectronic requirements for the donor acceptor interactions in various cyclic systems. Each molecule in Figure 1-7 contains a nitroge n lone pair as an elec tron donor and a 1-cyano-1carbethoxyethylene as an acceptor separated by three -bonds.66, 67 The nitrogen lone pair in the aza-adamantane 1-1 is locked into an equatorial orientation with respect to the six-membered ring, and therefore lies antip arallel to the central C C bond. A strong CT absorption is observed. Piperidine 1-2 displays no CT absorption although it co ntains the same donor and acceptor as in 1-1 The lone pair occupies the axial position as the methyl group preferentially a dopts the more stable equatorial conformation and is not suitably aligned for TBI. N Me NC COOEt 1-2noCT-absorptionN COOEt NC 1-1 CT=316nm =4900M-1cm-1(n -hexane,20oC) Figure 1-7. Verhoevens molecule s that illustrate of the conf ormational requirements for CT absorption.66, 67 Numerous donor-acceptor chromophores have been pr epared over the years and studied at the molecular level to model photoinduced charge transfer over fixed distances. The

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25 compounds shown in Figure 1-8 are just two examples.69 The interesting electron transfer properties of such molecules has gradually filtered into applications70, 71 that include molecular rectification,70 nonlinear optics (as NLO chromophores),71 and electroluminescent (EL) devices,72 etc. Only recently have -bridged donor-accepter molecule s been incorporated into polymers, like high molecula r weight linear polyesters.73-75 The use of D-A building blocks for various supramolecular materials, including mol ecular assemblies, are pr omising but hitherto virtually unexplored. Figure 1-8. Examples of rigid donor-acceptor molecules.69 -Aminoketones The -aminoketone fragment is among the simplest that has been studied with respect to donoracceptor through-bond interactions76 and appears as a good starting point for the development of new supramolecular building blocks. The donoracceptor interactions are optimized when the nitrogen lone pair (donor), C C bond, and carbonyl system (acceptor) are in a zig-zag arrangement (Figure 1-9). Thre e cyclic examples are shown that differ with respect to the permanence of their donoracceptor in teractions. The lone pair of the nitrogen atom in N -methylpiperidone 1-3 and tropinone 1-4 is transiently maintained in the optimum configuration for communication with the carbo nyl; this configurati on is fixed in 1-azaadamantanone 1-5

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26 N O N O N O H3C H3C X 1-3 1-41-5 Figure 1-9. Donor-acceptor arrangement in cyclic -aminoketones; N -methylpiperidone ( 1-3 ), tropinone (1-4 ), and 1-aza-adamantanone (1-5 ).76 Verhoeven and coworkers, using molecules like 1-2 have demonstrated the effect of through-bond interactions on nitrogen configuration in such molecules.68, 77 The Castellano group has focused on functionalized versions of 1-3 and 1-5 (i.e., those bearing groups that facilitate molecular assembly) with respect to their molecular and supramolecular properties. Various 3,5-disubstituted piperidone derivatives were the topic of th is authors masters research; the findings are summarized here as they include more recent results.78 Two representative compounds are shown, 1-8a and 1-8b (Figure 1-10), that were synthesized to explore the effects of through-bond interactions on th e conformation, nitrogen confi guration, and the self-assembly properties of functionalized -aminoketones in the solid state. N O R PhCHO Yb(OTf3) N O R Ph Ph N O R Ph Ph H2(60psi) Pd/C(10%) EtOH 1-61-7 1-8 a R=Ph a R=Ph(45%) b R=CH3a R=Ph(41%) b R=CH3(58%) >80% d.e. Figure 1-10. Synthesis of cis -3,5-dibenzyl pipe ridin-4-ones.

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27 X-ray crystallographic analysis of 1-8a and 1-8b reveals that both molecules adopt standard chair conformations with the benzyl groups in the equatorial position. The nitrogen substituent of 1-8b a methyl group, occupies the equatorial position with respect to the piperidone ring, a configuration that does not optimize throug h-bond interactions with the carbonyl acceptor. For compound 1-8a, however, both the equatorial ( 1-8a-eq ) and axial ( 1-8aax) nitrogen epimers are accommodated in the crystal lattice in a 2.5:1 ra tio (at 173 K) based on refined values of occupancy factors. Detailed structural an alysis shows that the packing environments of each epimer are nearly identic al. Given that the t ypical packing effect argument does not sufficiently rationa lize the significant population of 1-8a-ax, what does? The fundamental properties and equilibrium stru ctures of the axial a nd equatorial epimers of 1-8 and nearly a dozen model compounds were ex amined using extensive first principles calculations in collaboration with Dr. Bobby Sumpter at Oak Ridge National Laboratory. To summarize the results, 1-8a-ax is found (at various levels of th eory that treat correlation effects well: MP2, CCSD(T), B3LYP, CASSCF, etc.), despite claims for N -alkyl and N -arylpiperidines and ones in the literature, to be quite close in energy to 1-8a-eq Structure-property studies reveal that the relative stability of the axial epimer increases upon conversion of N -CH3 to N -Ph (a better electron donor), substitution of the 3 and 5 positions of the piperidine ring, and introduction of the carbonyl acceptor. Natural bond orbital (NBO) analysis, based on the optimized wavefunctions (at th e MP2/6-311G** level) for the 1-8a epimers, quantify the stability that comes from hype rconjugative interactions for 1-8a-ax. Molecular orbital plots show the contributions graphically (F igure 1-11 and 1-12). For both isomers, the HOMO plot reveals significant delocalization of the N lone pair into the adjacent C=C orbitals of the phenyl ring.

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28 However, only in 1-8a-ax is there significant delocalization of the N lone pair into the CC antibonding orbitals (o f the piperidone ring) and orbital of the carbonyl group. The work concludes with the idea that thr ough-bond interact ions and assembly structure are inextricably linked in the solid-state structures of simple functionalized -aminoketones like 1-8 The studies also show an inherent stability for the axial epimers of these molecules, previously assumed inaccessible; that the conf iguration that optimizes donor-acceptor throughbond interactions can be preserved in the solid state bodes well for the use of the systems in solid-state applications. Figure 1-11. Plot of the HOMO for the axial epimer (1-8a-ax) which shows delocalization of the nitrogen lone pair onto the phenyl, the adjacent C C of the piperidione backbone, and the carbonyl. Figure 1-12. Plot of the HOMO for the equatorial epimer ( 1-8a-eq ) which shows delocalization of the nitrogen lone pair onto the phenyl, the adjacent C C of the piperidione backbone.

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29 1-Aza-Adamantanetrione (1-AAT) Platform Can -coupled donor ac ceptor interactions be used to influence the self-assembly properties of small molecules in solution from which useful macromolecular properties can emerge? The unique 1-aza-adaman tanetrione platform (Figure 1-13) has been used in the Castellano group as a vehicle to explore this question. Figure 1-13. Synthesis of the 1-aza-adamantanetrione (AAT) platform. The AAT platform boasts many features that make it a useful tool to draw structureproperty relationships. First, it is efficiently constructed by a single-step cyclization of phloroglucinol derivatives with hexamethylenetetramine (HMTA); a Mannich-type reaction (Figure 1-14).33, 79-83 Second, three sites exist on the core that can be easily synthetically modified. Next, the enforced shape of the core is suitable for predictable assembly, amenable to high-level computation, and optimizes commun ication between the bridgehead nitrogen lone pair and carbonyl systems (via three intervening -bonds). The AAT also has a sizable ground state dipole moment; together with its shape, di rectional assembly is conceivable. These small molecules have afforded an excellent opportuni ty to comprehensively study the fundamental changes in structure, reactivity, and macrom olecular properties that can accompany the donor acceptor arrangement in rigid -coupled donor-acceptor molecules. Recently, definitive evidence for strong thr ough-bond interactions in the AATs has been reported.76 X-ray crystal structures of triester 1-9 and its corresponding mono-reduction product,

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30 alcohol 1-10 (Figure 1-14), have provided some of the best evidence for through-bond interactions at the molecular level. Comparativ e bond length data from the crystal structures of compounds 1-9 1-10, and various analogues (f or example, compounds 1-11, 1-12, and 1-13, Figure 1-15) availabl e in the literature84-86 is included in Table 1. Analysis of the data shows that somewhat shortened C N bonds ( a) and considerably elongated C C bonds ( b ) result when through-bond interactions are optimized. The bond length alternati on is a classically predicted consequence of hyperconjugation.76, 87, 88 More evidence, such as changes in bond angles, spectroscopic propertie s (e.g., the presence of the so-called -coupled transition in the UV-Vis spectra of 1-9 and 1-10), and reactivity are all consistent w ith theoretical expectations for welldefined -coupled donor-accepto r interactions. N O O O O O O O O O 1-9 b c d a Figure 1-14. X-ray crystal structures of compounds 1-9 and 1-10 .76

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31 Figure 1-15. The chemical structure of compound 1-11 (Ar = p-chlorophenyl), 1-12 (Ar = pnitrophenyl, and 1-13.76 Table 1-1. Comparison of averag e bond lengths (reported in ) from the X-ray crys tal structures of 1-9 1-10, and related tricyclic molecules from Figure 1-15.76 Bond 1-11 1-12 1-10 1-9 1-13 a 1.49 1.48 1.44 1.45 b 1.53 1.55 1.59 1.59 1.55 c 1.53 1.51 1.52 1.51 1.51 d 1.21 1.21 1.22 1.22 Given such readily measured consequences of strong through-bond interactions in the AATs, this platform has been used to draw structure-property relationships at the macromolecular and supramolecular level. Self-Assembly of AATs The Castellano group has been exploring donor accepto r through-bond interactions at the macromolecular/supramolecular level where they can complement traditional forces (e.g., hydrogen bonding, -stacking, etc.) in controlling mol ecular architecture and emergent properties.55, 56, 89, 90 For initial studies the AAT framework has been employed, the through-bond interactions of which (i.e., between N and C= O) were found to be unusually assessable and addressable in the ground state.76 AATs Bearing Simple Ar omatic S ide Chains The first generation of functionalized AATs fou nd to readily self-assemble in solution are shown in Figure 1-16; the molecules are decora ted with simple aromatic side chains and represent a new class of organogelators.56 Optically clear gels fo rm upon heating and cooling

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32 compounds like 1-14 (Ar = Ph) in DMSO. The critical ge lation concentration (CGC) is 0.5% by weight and the gel exhibits a sol-gel temperature ( Tgel) of 45 C.56 SEM and TEM techniques were used to explore the morphologies of the xero gels, formed from either critical point drying or conventional freeze drying techniques. Extended fibr illar structures appear that are consistent with the on-average 1-D self-assembly of the molecules. Figure 1-16. Generic structure of AATs bearing aromatic side chains. Figure 1-17. (a) Organogel of the tribenzyl AAT derivative 1-14 (Ar = Ph) in DMSO. (b) SEM image of the xerogel formed from critical point drying of an 0.5 wt % DMSO gel. (c) TEM image of the xerogel formed from critical point drying of an 0.5 wt % DMSO gel.56 Subsequent DFT-LDA/cc-pVDZ calculations id entified the lowest en ergy conformation as the all arms up structure shown in Figure 1-18a, a conformation also present in solution based on NMR experiments (NOEs are observed between hydrogens Hc on the aromatic ring and Ha on the core; Figure 1-18b). Further molecular dyna mics simulations by Sumpter and coworkers90 revealed the tendency of these donor-acceptor molecule to self-assemble (in the gas phase) in a

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33 head-to-tail fashion to create polar columns. Th e predicted (homochiral) stacked dimer (Figure 1-18c) is stabilized by dipole-dipole interactions and stacking to the tune of ~ 13 kcal mol-1 (the intercore spacing in the optimized dimer is ~ 5.1 ). Figure 1-18. (a) Energy-minimized lowest en ergy all-arms-up conformation. (b) The NOE contacts identified from a NOESY experiment for 1-14 (Ar = Ph). (c) Total charge density isosurface for the gas-phase optimized dimer, ( 1-14)2, obtained from DFT(LDA)/cc-pVDZ calculations.55, 56, 89-92 Amides in the Periphery Triam ide derivatives of the 1-aza -adamantanetriones (Figure 1-19)55 were next studied to show how polar functional groups on the outside might interact in specific ways with the donor-acceptor core and affect macr omolecular behavior. Triamides 1-15 show enhanced aggregation properties and signifi cantly more order in solution, the gel phase, and the bulk (compared with 1-14). This comes, in part, from confor mational stabilizati on (preorganization) of the arms by intramolecular H-bonding and favor able intramolecular dipolar interactions. Robust gels form from chloroform solutions of 1-15 (R = C12H25) quickly at low monomer concentration (~ 0.5 wt %); the sol gel transition temperature ( Tgel) is 57 oC.55 A representative SEM image (Figure 1-20a) shows ro pe-like fibers upon evaporation of 1-15 (R = H) from a toluene/pyridine (3:1) solution. X-ray diffraction (XRD) studies (Figure 120b) then reveal longrange periodic order for th e neat (solid) samples of 1-15. Final evidence for the C3-symmetric

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34 conformation proposed for 1-15 comes through solid-state NMR studies performed with 15Nenriched 1-15 (Figure 1-20c). 1-15 Figure 1-19. Amide functions on the periphe ry of the tricyclic core stabilize a C3-symmetric monomer conformation by intramol ecular hydrogen bonding and dipole dipole interactions.55, 91 Figure 1-20. (a) SEM image of rope-like fibers of 1-15 (R = H) formed upon solvent evaporation. (b) X-ray diffraction pattern of neat 1-15 (R = H). (c) Solid-state NMR data using an 15N-labeled derivative of 1-15 (where R = H).55, 91 Emergent Electronic Structure Com putational analysis has shown that an unpr ecedented electronic structure could result from assembly of AAT 1-14 (Ar = Ph), first into a homochiral dimer, and then into linear 1-D stacks (Figure 1-21).89-91 Notable reduction of the HOM O-LUMO gap is predicted upon dimerization and oligomerization; ultimately a band structure develops akin to what is described for -conjugated molecular systems. Formation of molecular wires through the self-assembly of

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35 novel non-aromatic architectures is an importa nt development toward organic electronic devices.92 Figure 1-21. Calculated (DFT(LDA)/cc-pVDZ) dimer and stacking arrangement for 1-14 (Ar = Ph): (a) the HOMO charge density isosur face for the dimer showing delocalization over both AAT cores; (b) 1-D periodic stacking of 1-14 (Ar = Ph) monomers into wire-like assemblies.89, 90, 92 High-level computation has shown that the peripheral amides can also tune the electronic structure of these 1-AAT syst ems. The HOMO-LUMO gap for 1-15 is calculated to be substantially lower than that of its aryl isostere 1-14. This reduction is largely due to lowering of the LUMO energy (by 0.7 eV, as compared to the tribenzyl system), which originates from the three hydrogen bonds between the amide NHs and the core ketones.89-93 The amide functional group provides a tunable element of electronic control over the resu lting self-assembled structures.91 Scope of Dissertation Extensive experim ental and computational stud ies have been performed to understand how through-bond donor-acceptor interactions might complement traditional noncovalent forces, such as H-bonding and stacking, in molecular self-assembly. One unique class of -coupled donor-acceptor molecules, the AATs, has been developed for the studies. Several challenges remain. First, theoretical studies suggest th at exciting electronic properties should accompany

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36 assembly of the AATs into 1-D arrangements. This level of order in solution and the solid state has yet to be achieved. Second, many of the more exciting AAT targets ar e those that are less symmetrical and even chiral; currently these are not readily accessible. Lastly, much work remains to understand the dynamic self-assembly behavior of the AATs in solution, and how macromolecular behavior emerges from this process. This dissertation is focused on the design, rati onal synthesis, and self-assembly properties of new 1-aza-adamantanetrione derivatives. Chapter 2 describes the synthesis and self-assembly studies of AATs bearing expanded aromatic arms. The work shows the role of the AAT periphery in controlling the macr omolecular properties of the assemblies that result, where the most robust gelating species from the AAT cla ss are now described. Numerous characterization methods are used to study the assemblies, and some, including fluorescence spectroscopy and dynamic light scattering, are used for the first time. The data shows how AAT self-assembly responds to temperature, solvent, concentrati on, and structure. Chapter 3 is focused on new synthetic methodology that has been developed to prepare desymme trized and asymmetric AATs. Accessing AATs bearing multiple periphera l functional groups could afford new macromolecular properties that are uniquely t unable. Chapter 4 highlights efforts made to prepare the first hydrophilic a nd potentially hydrogelating AATs, using, in part, the strategies presented in Chapter 3. Conclusions and futu re directions for the unconventional donoracceptor molecules are discussed in Chapter 5.

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37 CHAPTER 2 DESIGN, SYNTHESIS, AND PROPERTIES OF 1-AZA-ADAMANTANETRIONE S WITH EXPANDED AROMATIC ARMS Introduction Low m olecular weight organogelators (LMW Gs) constitute an important class of functional materials that have recently emerged.24, 94-96 Interest in gels derived from LMWGs continues to grow because of their many potential applications in dive rse areas including drug delivery,97, 98 organic light emitting devices,99 cosmetics,100 and sensing.101 Organogels result when small organic molecules form nanoscale, cross-linked fibrous aggregates by noncovalent self-assembly. H-bonding, stacking, metal coordination, th e hydrophobic effect, and van der Waals interactions are typical forces responsib le for gel formation.14, 24, 32 Gels are readily identified as jelly-like materi als that feature large volumes of immobilized organic solvent (generally the number of solven t molecules exceeds the number of organogelator molecules by several orders of magnitude), ar e thermoreversible, and have inte resting rheologica l properties. It has recently been shown that unconventional donor-acceptor molecules, 1-azaadamantanetriones (AATs), constitu te a new class of organogelators.55, 56 Extensive experimental55, 56 and electronic st ructure calculations89, 90 have been used to explore the mechanism of AAT self-assembly and the properties of the resultant supramolecular structures. Several important conclusions have emerged from the work. At the molecular level, recent comprehensive studies by X-ray crystallography, UV/Vis, and NMR76 confirm that strong through-bond donor-acceptor interactions58, 62, 63, 102 characterize the AAT core. These interactions create understandabl e changes in bond structure a nd molecular dipole, but also respond to substitution on the core. Both experime ntal and theoretical studies have then shown that self-assembly involves dipolar interactions (modulated by the intramolecular donoracceptor interactions) and traditional intermolecular forces.55, 56, 89, 90 Among the latter, for molecules like

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38 1-14 (Ar = Ph) and 1-15 (R = C12H25), -stacking is particularly important. In dimers of 1-14 (Ar = Ph) studied by computation in the gas phase, MP2 calculations predict that nearly half of the binding energy arises from slipped face-to-f ace stacking interactions between the phenyl substituents.89 Further work has considered the interesti ng electronic structure that arises when the same molecules organize into periodic 1-D structures that feature close core-to-core interactions.90 Both dipolar and -stacking interactions are importa nt for self-assembly of the AAT molecules in solution. In a goal to create well-ordered assemblies of the AATs to better probe their supramolecular electronic properties and pot entially create ordered phases like liquid crystals, one approach is to e nhance the interactions between th e peripheral substituents. This chapter describes the design, synthesis, and prope rties of a class of AAT molecules which have expanded aromatic arms to potentially strengthen stacking interactions between the molecules. The structure-propert y relationships that emerge w ill help in better understanding the mechanism of AAT self-assembly, to create new materials, and to afford new macromolecular properties. Design and Synthesis Design of AATs with Expanded Aromatic Arms In a recent theoretical study90 of AAT self-assembly, a mechanism was proposed for organization of compound 1-14 (Ar = Ph) into 1-D stacks (Figure 1-20b). The emergent electronic structure of this assembly was then shown to be dependent on the interaction of the cores. Given this model, enhancing the aromatic interactions between the molecules by using expanded aromatic surfaces could significantly in crease the interactions of the AAT units and potentially confer these systems long-range order and interesting supramolecular and electronic

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39 behavior. Certainly aromatic in teractions are important in ma terials design strategies and influence broad areas like crystal engineering,103, 104 host-guest chemistry,105 and molecular recognition.106, 107 The notion of using shape along with aromatic interactions to promote 1-D self-assembly has been explored in a variety of other systems.45, 108-110 In a recent example, V-shaped salicylidene-aniline derivatives we re shown to pack into polar 1-D columns (Figure 2-1) through strong interactions.111, 112 These compounds could gelate various organic solvents, such as 1butanol, 1-octanol, butyl acetate, carbon tetrachlo ride, benzene, and toluene. Studies further explored the hierarchical self-assembly of the mo lecules. First, left-handed helical nanofibers formed through unimolecular layer p acking; these further twisted in to thicker fibers capable of forming 3-D interpenetrated networks (and gel phases) that exhibi ted strong fluorescence enhancement.111 N N O H H O Figure 2-1. One-dimensional packing (J-aggrega tion) of salicylideneaniline derivative along the b axis in the crystal state.

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40 Naphthalene, which is the simplest polycyclic aromatic compound,113-120 has been chosen for incorporation into the AATs due to its availability and well understood electronic and optical properties. Furthermore, theoretical studies121-123 predict that the st abilization energy of optimized parallel-displaced (PD) dimers of naphth alene is over three times that of benzene in the gas phase (2.60 kcal/mol for benzene versus 7.72 kcal/mol for naphthalene at the LMP2/631G* level). Additionally, naphthyl substituents offer useful absorption and emission properties that can be used to probe solution-phase assemb ly. The idea of using si mple fluorescent aryl groups as reporter units in supramolecular sy stems has certainly been exploited before,124, 125 and fluorescent signaling is one of the most sensitive techniques to monitor molecular association events. To this end, a small family of naphthyl-substituted AATs has been made and their gelation, solid-state and solution-phase assembl y, and thermal properties have been studied. Synthesis Naphthylamines are the most im portant buildi ng blocks for the synt hesis of naphthalene functionalized AAT molecules, based on genera l approaches that have been established previously to prepare amide-substituted AATs in the Castellano group. Napthylamine itself is commercially-available, however alkyl-substitut ed napthylamines are less common. We chose to install butyl and dodecyl substituents on the na phthyl ring to improve the solubility of the molecules55, 76 and enhance the van der Waals interactions of the side chains. The synthesis of alkyl substituted naphthylamines is outlined in Figure 2-2. Important to note, naphthalene derivatives have wide industr y and commercial applications but their toxic effects126 are welldocumented. Careful handling of these materials is required. Commercially-available 6-bromo2-naphthanol is first protecte d as its methyl ether using iodomethane and potassium carbonate to provide compound 2-2 in quantitative yield.127 Alkyl groups are then introduced using Negishi cross-coupling128-130 between the bromide and

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41 appropriate organozinc reagent in the presence of Pd(PPh3)4. The organozinc reagent is formed through reaction of an alkyl Grignard reagen t or alkyllithium reagent with anhydrous zinc bromide. Suzuki-Miyaura cross c oupling can alternatively be used for this type of reaction as reported by Najera.131 Deprotection of the methyl ether using BBr3 affords 6-alkyl-naphthanol 24; subsequent reaction with trifl uoromethane-sulfonic anhydride c onverts the naphthanol to the corresponding triflate 2-5 .132 Hydrobromic acid can alternatively be used for the demethylation.133 Subsequent coupling134, 135 of the naphthalene triflates 2-5 with LiN(SiMe3)2 in the presence of Pd(dba)2 and P(t-Bu)3, followed by deprotection of the silylamide using aqueous HCl, provides 2-6 Toluene is the best solvent for the coupling reaction and room temperature is sufficient to consume all of the triflate starti ng materials. THF could also be used for this reaction but required heating (60 C); starting material rema ined after stirring at room temperature overnight. As an alternative, naphthol 2-4 can be converted to naphthylamine 2-6 via the Bucherer reaction,136 but this transformation requires harsh conditions. Figure 2-2. Synthesis of alkyl substituted naphthylamines. Naphthylamine 2-6c that bears an electron-withdrawing group (EWG), was prepared as shown in Figure 2-3. This derivative could be th e basis for a) exploring how electrostatics would

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42 affect aromatic interactions in AAT assemblies (even mixed component assemblies), b) increasing the acidity of the am ide proton that might also in crease the intramolecular H-bonding between the amide NH and core C O (Figure 1-17), or c) provi ding a synthetic handle that could later be functionalized. Commercially-ava ilable 6-amino-2-naphthoic acid was simply converted to its n-butyl ester 2-6c by treatment with the appropriate alcohol137 and a catalytic amount of sulfuric acid. Figure 2-3. Synthesis of a naphthylamine subs tituted with an elec tron-withdrawing group. With the alkyl-substituted naphthylamine building blocks in hand, similar methods55, 56, 91, 138 to those described previously for phenyl am ide AATs were used to prepare the naphthyl derivatives (Figure 2-4). Coupli ng of triacid chloride compound 2-7b with the more electron rich amines 2-6a and 2-6b provided 2-8a and 2-8b in moderate yield. Deactivated 6-amino-2naphthoate 2-6c unfortunately showed no a ppreciable reactivity with 2-7b The derivatives 2-8 could then be deprotected with BBr3 as described above to provide the immediate AAT precursors, phloroglucinols 2-9a and 2-9b Subsequent cyclization of the naphthyl amide-functionalized phloroglucinol derivatives with hexamethylenetetramine (HMTA) to afford the AAT targets was particularly tricky. Either no product or complex mixtures were obtained in the in itial runs, and attempts to change the amount of HMTA from one to three equivalents, solvent (from isopropanol to DMF to acetonitrile), and temperature (using a conventional oil bath or microwave irradiation) led to little improvement. The reason is probably the poor solubility of the amide phloroglucinol

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43 derivatives. Fortunately, it was found that dilute solution (< 1 mM) and longer reaction times (heating to reflux for three days) could pr ovide the target AATs in typical yields. Figure 2-4. Synthesis of napht hyl amide-functionalized AATs. Model compound 2-12 (Figure 2-5), which contains only one naphthyl arm in the AAT, and model compound 2-13 (Figure 2-6) were also prepared for control experiments (vide infra). Synthesis of 2-12 relies on the lactone-based desymmetrization chemistry91 pioneered by Dr. Andy Lampkins in the Castellano group. Andy f ound that ester functionalized phloroglucinol derivatives can form the mono-, di-, and trila ctones selectively under appropriate conditions.91 We found that this approach can be expanded to amides (detailed information is provided in Chapter 3). Along these lines, dilactone 2-10 is available from napht hyl amide-functionalized phloroglucinol derivative 2-9b by heating in a mixture of TFA and toluene. The C2-symmetric

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44 dilactone 2-10 is formed preferentially under these conditions. Nucleophilic attack with two equivalents of aniline in DMF at 120 C opens both of the lactone rings to afford the new phloroglucinol 2-11. The amount of the nucleophilic reagen t and the reaction temperature are critical for this reaction. Compound 2-11 can then be converted to the corresponding desymmetrized AAT 2-12 by reaction with HMTA. Figure 2-5. Synthesis of desymmetrized AAT using a lactone-based strategy. Compound 2-13 (Figure 2-6) was also prepared as a control and contains the important functional groups of 2-1 and 2-12 but lacks the donoracceptor core. The synthesis involves a simple coupling of 4-oxopentanoic acid with -naphthylamine in the presence of DCC as a dehydrating agent. This naphthylamide will be useful for probing intramolecular sevenmembered ring H-bond formation139 between the amide NH a nd ketone carbonyl oxygen, a structural feature potentially important to the conformation and self -assembly of the AAT

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45 derivatives. It also will shed light on the mu tual roles of the naphthyl substituents and donoracceptor core in the macromolecular behavior of 2-1 and 2-12 Figure 2-6. Synthesis of model compound 2-13. Gel Formation and Characterization Organogels are broadly studi ed m aterials in terms of their structure-property relationships140-143 due to their potential te chnological uses and unique macromolecular profiles. Most gelation processes involve H-bonding and stacking interactions between gelator molecules. The consideration of through-bond donor acceptor interactions as important components of these materials is new. The solubility and gelation properties (Table 2-1) of compounds 2-1a and 2-1b were evaluated in various polar and a polar solvents. The model compound 2-12 was also studied for comparison. The triamides 21a and 2-1b are sparingly soluble in most organic solvents except for pyridine, DMF, and DMSO. Interestingly, compound 2-1a forms optically clear gels (Figure 2-7) in aromatic solvents such as toluene and benzene. The gels are formed in the conventional way. First, a homogeneous solution of 2-1a is obtained by heating the compound in the appropriate aromatic solvent (to the boiling po int). The solution is then cooled to room temperature, and gel formation is evidenced by the complete immobilization of the solvent (the gel supports its weight upon invers ion of a vial as shown in Figur e 2-7). The gels are transparent and obtained immediately upon cooling. An 1H NMR spectrum of the toluene gel shows broad resonances and weak signals char acteristic of network formation, but confirms that the molecule

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46 has not decomposed. Also characteristic of gel systems, the organogels of 2-1a are thermally reversible. The mechanism of gel formation is presumably similar to other systems. The molecules of 2-1a first self-assemble into elongated a ggregates; when these structures are sufficiently long they become entangled and entr ap solvent molecules in an infinite network.144 Gels are typically described using two parameters, the critical gelation concentration (CGC) and the sol-gel transition temperature ( Tg). The former is determined by measuring the lowest amount of gelator required to co mpletely immobilize the solvent. For 2-1a, the CGC is 0.2% by weight (~ 1.4 mM). The Tg is measured using the dropping ball method145 (see the Experimental Section) and is the temperature at which the gel begins to flow. This value is 72 C for 2-1a. The CGC is the lowest value and the Tg the highest value that we have observed to date for AAT gelators.55, 56 Figure 2-7. Organogel from trin aphthyl-1-aza-adamantanetrione 2-1a (0.2 wt % in toluene after heating and cooling). Compound 2-1a forms gels in chloroform as well as toluene and benzene, but only at low temperature ( C). Compounds 2-1b and 2-12 do not form gels in any of the solvents tested, presumably due to their poor solubility. Neither compound is soluble in toluene or benzene even upon heating and sonication.140, 146 This behavior parallels what was observed for phenylamides 1-15 (R = C12H25).

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47 Table 2-1. Solubility and gelation properties of compound 2-1a, 2-1b and 2-12. ORGANIC SOLVENT 2-1A 2-1B 2-12 hexanes I I I toluene G I I benzene G I I chloroform G at 45 C I I pyridine S S S THF I I I 2-propanol I I I acetonitrile P P P DMF S S S DMSO S S S Key: I = insoluble, P = precipitate, G = gel, S = soluble. Solid State Properties The solid -state organization of the naphthyl-substituted AATs has been studied by scanning electron microscopy (SEM) and powder x-ray diffraction (XRD), and the thermal properties of the materials have been probed by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA). Morphology of Critical Point Dried Gels Scanning electron m icroscopy (SEM) is widely used to explore the morphologies of nanoscale materials. To gain better insight into the molecular organization of the toluene gel of 2-1a, SEM was used to observe dried gel samples. The solvent was removed from the gels (e.g., Figure 2-7) via critical point drying (CPD). The CPD technique involves removal of the solvent from the wet gel under superc ritical conditions, where the bulk solvent is first exchanged for liquid CO2. Simple evaporation of the liquid from a sa mple can result in the build-up of tensile stresses which cause the underl ying supramolecular network to collapse as the vapor-liquid interface recedes.147 CPD is conducted using liquid CO2 which undergoes a phase change (from liquid to gas) at the critical poi nt (critical temperatur e 304.2 K, critical pressure 72.8 bar), where the densities of the liquid and va por are the same. The process re duces the interfacial (surface)

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48 tension148, 149 and therefore minimizes shrinkage of the gel and better preserves its structure. Drying gels by CPD is known to reveal structur al features not found in air-dried blends.150 Freeze drying is an alternative technique for drying gel samples, and we have used this approach as well in the past. In this method, the gel is qui ckly frozen in liquid nitrogen and then dried by sublimation to prevent the forma tion of a liquid-vapor meniscus. It is known, however, that the gel network may be destroyed by the nucleation and growth of solvent crystals in this process.151 In the CPD gel sample of 2-1a, a lamellar sheet ar chitecture is observe d with layers of uniform thickness of about 5 m (Figure 2-8). The surface of the sheets reveals ~3 m entangled fibers. Smaller fibers are observed among the entangl ed fibers that comprise the self-assembled network. The three-dimensional networks are fo rmed through molecular self-assembly of the gelator compound 2-1a and the gel network is able to en capsulate a large volume of organic solvent upon heating and cooling. Freeze-dried gels were also i nvestigated for comparison (not shown). These samples did show sheet-like packing but no finer features on the surfaces could be detected. Both fibrous and lamellar architectures have been observed before in the AAT systems,55, 56 but this is the first ca se where both morphologies ar e visible in one sample.

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49 Figure 2-8. SEM images of a xerogel formed fr om critical point drying the 0.2 wt % toluene gel of compound 2-1a. X-Ray Diffraction (XRD) In order to better understand the m echanism of self-assembly of the naphthyl-substituted AATs like 2-1a and 2-1b numerous attempts were made to obtain single crystals suitable for Xray crystallographic anal ysis. All attempts to date have failed using primarily the solvent diffusion technique (the AAT was dissolved in pyridine and expos ed to hexane, ethyl acetate, ethyl ether, THF, or methanol). Particularly important for future attempts, it was recognized that the AATs gradually decompose in pyridine upon prolonged storage. It is possible that other solubilizing solvents could afford better results in the future.

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50 Powder X-ray diffraction is frequently used in lieu of single crystal analysis for ascertaining the molecular packing of self-assemblies152-154 and to shed light on assembly mechanism.155 The data is reported for 21a (Figure 2-9) and 21b (Figure 2-10) as plots of 2 versus intensity. The most intense peak is observed at a d -spacing of 4.1 for 21a and 4.2 for 21b This is likely attributable to packing of the naphthalene groups at a slightly longer140 than optimal stacking distance due to steric constraints.6, 156 The relatively small peak at d-spacing of 3.3 for 2-1a and 2-1b is very close to the typical stacking157 and may correspond to a different pattern of packing. The remaining peaks are less intense and at approximately the same positions for both compounds, despite the difference in their size. It appears therefore that the alkyl side chains of 2-1a, the packing of which is identified by the broad peak at ~ 4 in Figure 2-9, do not significantly change the organization of the cores and naphthyl groups between the two systems. For example, the largest d-spacing for 21a, 25.4 is only ~ 1 longer than that of 21b (24.4 ). Molecular dynamics calculations are currently underway to help identify assembly modes of the molecules that might rationalize these distances. Figure 2-9. X-ray diffraction pattern of th e neat powder 2-1a

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51 Figure 2-10. X-ray diffraction pattern of the neat powder 2-1b Thermal Properties Therm al transitions of compounds 2-1a and 2-1b were measured (Figure 2-11 and 2-12) using differential scanning calorimetry (DSC, TA instruments) and thermal stabilities were investigated (Figure 2-13 and 2-14) by thermal gravimetric analysis (TGA). Figure 2-11. DSC traces for compound 2-1a.

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52 Figure 2-12. DSC traces for compound 2-1b The DSC thermograms of 2-1a and 2-1b were recorded at a rate of 10 C/min. Compound 2-1a melts at 218 C and then decomposes at 228 C in th e first heating cycle; consequently, no further transitions are observed upon cooling or upon a 2nd heating and cooling. Compound 2-1a does show a broad transition prio r to melting in the first heating cycle, possibly related to reorganization of the molecules upon heating (and the alkyl side chains). No ordered phases were observed by polarized optical micros copy (POM) upon a first heating of 2-1a; the solid melts at ~ 218 C with no subsequent change. The dried gel sample of 2-1a (from toluene) behaves similarly. For AAT 2-1b only a broad transition is observed from 50 C; no melting transition is found. It appears that the molecule decomposes before this temperature (vide infra). The TGA data for both 2-1a and 2-1b show that the AAT molecules are thermally stable up to ~ 225 C. Decomposition then ensues with significant molecular weight loss up until ~ 500 C. Simple calculations suggest the fragments that may be lost. The molecular weight of 2-1a (Figure 2-13) is 1233.7 g/mol. The remaining weight at 650 C equals 18% of 1233.7, or 222 g/mol. Likewise, the molecular weight of 2-1b (Figure 2-14) is 728.8 and the remaining weight

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53 at high temperature equals 30% of 728.8 (= 219 g/ mol). The average weight of the remaining fragment is therefore ~ 221 g/mol, the same mass as the trimethyl AAT core (C12H15NO3 = 221 g/mol). This fragment would emerge from consecutive loss of the amide arms; such a stepwise decomposition is reflected in the TGA trace of 2-1b Figure 2-13. TGA measurements of solid 2-1a. Figure 2-14. TGA measurements of solid 2-1b

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54 Solution Phase Assembly UV Absorption Spectra UV/Vis m easurements were performed for AAT compound 2-1a and model compounds 212 and 2-13 in chloroform. Five absorp tion spectra at various concen trations in chloroform are shown for compound 2-1a (Figure 2-15). There are two significant absorption bands that can be assigned to the naphthylamide chromophore. By analogy to naphthalene, the higher-energy absorption at 250 nm can be assigned to a non-emitting 1( La) transition.158 The lower energy absorption band at 285 nm is the emitting band and characterized as the 1( Lb) transition;159, 160 noteworthy also is the appare nt vibronic structure within th is band. This absorption is due principally to a longitudinally po larized transition with respect to the naphthalene chromophore and is therefore most sensitive to substitution in the 2, 3, 6, and 7 positions. Indeed, this band is red-shifted relative to unsubsti tuted naphthalene by about 10 nm.161 Data from Figure 2-15 was then plotted to confirm that th e optical density (at 285 nm) vari es linearly with concentration (Figure 2-16). This is the case, a nd the molar extinction coefficient () at 285 nm, calculated from the plot, is 44080 M-1cm-1. The absorption spectra for model compounds 2-12 and 2-13 are shown in Figures 2-17 and 2-18, respectively. The molar extinction coefficient at 285 nm, calculated from plots of absorbance versus concentration, is 7570 M-1cm-1 for 2-12 and 8053 M-1cm-1for 2-13. The absorbance of both compounds varies linearly with concentration. Somewhat surprising is that the molar extinction coefficient for 2-1a, with its three naphthalene rings, is larger than three times the value for 2-12 (~ 5.8 times larger) and 2-13 (~ 5.5 times larger). The origin of this enhancement is not currently known.

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55 Figure 2-15. Absorption spectra for compound 2-1a in chloroform (light path length: 3 mm). Figure 2-16. Absorption intensity at 285 nm vs. concentration for compound 2-1a.

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56 Figure 2-17. Absorption spectra for compound 2-12 in chloroform (light path length: 10 mm). Figure 2-18. Absorption spectra for compound 2-13 in chloroform (light path length: 10 mm). Fluorescence and Excimer Emission Naphthalene groups are sensitive spectroscopi c probes of self-assem bly processes since they can fluoresce from either the singlet exci ted state (S1) or through excimer formation. The

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57 latter is only possible when one ground state and one excited state molecule share a special geometric relationship and therefore the phe nomenon reports on chromophore aggregation.162 The fluorescence emission of compound 2-1a, in chloroform at 25 C, as a function of concentration is presented in Figure 2-19. Two emission bands can be observed upon excitation ( exc = 285 nm): one with a maximum emission at 355 nm (monomer) and an additional redshifted emission band, centered at 433 nm, assigned to the excimer.163-166 The emission spectra of model compound 2-13 versus concentration were measured as a control. Only observed is monomer emission at 355 nm (Figure 2-20). Figure 2-19. Emission spectrum of 2-1a at exc = 285 nm in chloroform.

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58 Figure 2-20. Emission spectrum of 2-13 at exc = 285 nm in chloroform. Excimer emission167, 168 for 2-1a suggests the stacking of its naphthyl groups.169 The emission can be interpreted as a consequence of the short-range approach of two naphthyl chromophores either in the same AAT molecule or within an assembly.168, 170 Typical concentrationand temperaturedependent fluorescence experiments171 have not been particularly conclusive with respect to distinguishing the scenarios. The max of emission spectra for 2-1a (in chloroform) is concentration inde pendent (Figure 2-19) over a four-fold concentration range; the Ie/ Im (ratio of excimer emission intensity to monomer emission intensity) changes by ~ 1.4 in favor of the m onomer emission over the same range. The poor solubility of 2-1a in chloroform complicates these experiments.172 Additionally, very little temperature dependence171 of Ie/ Im was observed from 25 C to 55 C for a 2 x 10-5 M solution of 2-1a (Figure 2-21). Certainly part of this behavior can be ratio nalized by intramolecular excimer formation, although it is possible th at aggregation of the molecules also results in conformational changes that inhibit the close -stacking required for this emission.

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59 Figure 2-21. Emission spectrum of 2-1a at exc = 285 nm in chloroform with concentration 2 x 10-5 M. Model compound 2-12 provides additional informati on since it contains only one naphthalene ring and eliminates the possibility of intram olecular excimer emission. The concentration-dependent fluorescence emission spectra of this compound, in chloroform at 25 C, are presented in Figure 2-22. Some exci mer emission is noted which suggests that contribution from intermolecular aromatic interac tions of the naphthalene groups is possible in these systems. Very little concentration dependence of Ie/ Im was observed for a chloroform solution of 2-12 over a nine-fold concentration range. Interestingly, excimer emission of the above compounds has not been observed in other organic solvents including toluene, acetonitrile, and DMSO. It is not completely clear why the solvent should ha ve such a profound effect. The broad emission band from 300 nm to 450 nm of to luene may overlap with the excimer emission from AAT molecules. The poor solubility of 2-1a and 2-12 in acetonitrile may compromise the excimer formation. Lastly, DMSO may disrupt the intramolecular H-bonding which might be important to the stacking in this solvent.

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60 Figure 2-22. Emission spectrum of 2-12 at exc = 285 nm in chloroform. H-Bonding in Amide-Functionalized AATs H-bonding interactions involving the am ide side ch ains play an important role in the selfassembly of the AAT molecules. Observed in earlier systems, the amide protons can form intramolecular H-bonds with the carbonyl gr oups on the AAT core and stabilize the conformation of the molecules (preorganizatio n). The amides also presumably provide conformational stability through th e favorable and prefered ali gnment of their dipoles with respect to the dipolar AAT core.55, 91 Data from the N H stretching region in IR spectra can provide insight into the degree of hydrogen bond formation in nonpolar solvents be cause the time scale of IR spectroscopic measurements is sufficiently short to distinguish clearly between the N H stretchings of hydrogen-bonded and non-hydrogen-bonded states.173 Model compound 2-13 shows a single NH absorption at 3309 cm-1 that presumably arises from intramolecular H-bonding in the solid stat e. This value is similar to the reported NH

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61 stretch (3325 cm-1) for intramolecular H-bonding in -ketoamides in the solid state.174 However this value is ~ 50 cm-1 red shifted compared to ot her intramolecularly H-bonded -ketoamides ( NHO = 3360 cm-1)55 in solution but still in the accepted hydrogen bonding range (3300 cm-1). The solid-state IR spectrum of 2-1a shows an absorption at 3385 cm-1, the free NH stretch, while a second absorp tion is detected at 3287 cm-1 that possibly arises from intermolecular H-bonding. Both absorptions are ~ 40 50 cm-1 red shifted versus the free NH stretch and the intermolecu lar H-bonding stretch in N -phenylacetamide55 2-14 in solution. Similar phenomena were reported by Bane rjee in studies of synthetic peptides.174 No band is visible at a wavenumber 3430 cm-1 for the reported peptides in the solid state while a band is observed at 3436 cm-1, suggesting the occurrence of free NH groups in solution.174 Most of the free NH stretches in the solid state for thei r peptides were observed around 3370 cm-1. The bulk IR data overall suggests that AAT 2-1a enjoys some intermolecular H-bonding in the solid state (Table 2-2). In chloroform solution, the model compound 2-13 shows expected -ketoamide behavior (Figure 2-24) based on our previous work55 and that of others:139, 175 A sharp absorption is found at 3430 cm-1 and a broad absorption at 3360 cm-1 which represent the solvent-associated (free) NH stretch and intramolecularly H-bonded NH stretch, respectively. Similar frequencies are reported for intramolecularly H-bonded -ketoamides ( NHO = 3335 cm-1 and NH free = 3440 cm-1 (at 1 mM in CCl4)).173, 176 For 21a, a sharp NH absorption is found (Figure 223) at 3430 cm-1 while a broad absorption is detectable at 3383 cm-1 (with a shoulder at 3360 cm1). We tentatively assign the higher energy ab sorption to the free NH stretch. Presumably then the 3383 cm-1 stretch comes from intramolecular H-bonding.176, 177 The bands appear in the reported range of the IR spectral absorpti on bands of the non-hydrogen-bonded amide N-H

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62 (3450-3400 cm-1) and hydrogen bonded amide N H (3300-3400 cm-1)173, 176, 177 regions in solution. For comparison, phenylamide substituted aza-adamantane 2-15 was reported178 as presenting a strong band at 3290 cm-1 indicating the presence of in termolecular H-bonding in the solid state while showing a free NH stretch at 3446 cm-1 in CDCl3. Figure 2-23. The IR spectrum of 2-1a at 1.6 mM in chloroform. Figure 2-24. The IR spectrum of 2-13 at 0.13 M in chloroform.

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63 NH O 2-14 H N O Cl Cl 2-15 N O O O O N H Ph 1-15 H N O O 2-13 N H O Ph HN O Ph Table 2-2. Amide NH IR frequency (cm-1) for 2-1a and representative molecules from the literature. Solid State (KBr) Solution (CHCl3) Free NH Intermolecular H-bonding Intramolecular H-bonding Free NH Intermolecular H-bonding Intramolecular H-bonding 1-1555 3360 2-1455 3440 3325 2-1a 3385 3287 3430 3383 (3360) 2-13 3309 3430 3360 2-15178 3290 3446 The IR studies in solution are supported by VT-NMR measurements176, 177 of 2-1a and model compound 2-13. VT-NMR measurements of 2-1a at 5.4 mM in the higher boiling C2D2Cl4 confirm a very small temperature dependence (Figure 2-25) for the amide proton (7.86.65 ppm from 298 K; / T = .3 ppb/K), consistent with intramolecular H-bonding.176, 177 For comparison, the NH shift (the assignment of the NH proton was made by adding a drop of D2O to the NMR tube) of model compound 2-13 at the same concentration (5.4 mM) in C2D2Cl4 (Figure 2-26) shows a similarly small temp erature dependence (7.62.42 ppm from 273K, / T = .6 ppb/K).

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64 Figure 2-25. 1H NMR spectra of 2-1a in C2D2Cl4 (5.4 mM) at different temperatures. Figure 2-26. 1H NMR spectra of 2-13 in C2D2Cl4 (5.4 mM) at different temperatures. The 1H NMR spectra of compounds 2-1a and 2-13 in C2D2Cl4 (Figures 2-27 and 2-28, respectively) at different concentrations were al so measured to further probe H-bonding effects. Relatively small chemical shift changes are observed with concentration for 2-1a and 2-13, ~ 0.1 ppm for 2-1a (5.4 mM to 1.5 mM) and ~ 0.05 ppm for 2-13 (14.5 mM to 3.2 mM). Interestingly, the NH chemical shift of 2-1a is ~ 0.2 ppm further downfield than that of 2-13, likely speaking to a difference in environment, H-bond acceptor (C =O electronic structure), and conformational equilibrium. Overall the solution-phase IR a nd NMR data show evidence of intramolecular Hbonding in the napthylamide AATs.

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65 Figure 2-27. 1H NMR spectra of 2-1a in C2D2Cl4 at different concentrations. Figure 2-28. 1H NMR spectra of 2-13 in C2D2Cl4 at different concentrations. Dynamic Light Scattering Dyna mic light scattering (DLS) is a powerful technique wh ich can be used to determine the size distribution of particles in solution. The dynamic information of the particles is derived from an autocorrelation of the intensity trace r ecorded during the experime nt. The scattered light signal decay is then related to the motion of th e particles, the diffusion coefficient. CONTIN analysis is the ideal method for analyzing th e autocorrelation functi on of heterodisperse systems.179, 180

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66 With the help of collaborators at the Cent er for Nanophase Materials Sciences at Oak Ridge National Lab, DLS has been used to examin e the self-assembly of various AATs that bear amides on their periphery (e.g., compound 1-15, R = C12H25). Figure 2-29 shows the concentration-dependent size distribution of 1-15 in chloroform. Largely non-spherical aggregates are found, where the main distributi on of the hydrodynamic radii is about 100 nm. The population of larger-sized aggregates, in the micrometer range, increases with concentration. Important to note, however, is that the actual percentage of the la rgest aggregates is quite small given a 106 dependence of intensity on size. Figure 2-29. Size distribution of 1-15 ( R = C12H25) at various concentration in chloroform (25 C, (scattering angle) = 104 ). The temperature-dependent size distribution of 1-15 in chloroform (c = 0.0059 wt%) is shown in Figure 2-30. There is overall observed a shift to smaller-sized assemblies upon increasing the temperature, consis tent with the effect of temp erature on the self-assembly of molecules.

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67 Figure 2-30. Size distribution of 1-15 chloroform solutions (c = 0.0059 %) at various temperatures ( (scattering angle) = 104 ). Figure 2-31. Time-intens ity correlation functions (g(2)( ) 1) for 2-1a at various concentrations in toluene (25 C, (scattering angle) = 88 ). DLS experiments were performed with 2-1a in toluene and pyridine solution.181 The autocorrelation functions obtained by collecting th e scattered radiations as the function of decay time at five different concentrations (in toluen e) are reported in Figure 2-31. The plots clearly show how the maximum value of the y-axis in the correlation function de creases with decreasing solution concentration. A single decay is obser ved and the relaxation becomes slower with increasing concentration.182, 183 The time-intensity correlation function at various temperatures

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68 (Figure 2-32) also shows intere sting behavior. The shifting to shorter relaxation times with increasing temperature from 25 C follows what is expected for reversible assembly.184 However, the dynamic functions appear almost flat when the temperature is further decreased to 10 C and C. It appears that at these temperatures the assemblies are essentially immobilized185 as stationary cluste rs of gel networks;186, 187 the consequence is a partially heterogeneous and strongly scattering mixture. Figure 2-32. Time-intens ity correlation functions (g(2)( ) 1) for 2-1a in toluene at various temperatures (c = 0.019 wt%). Additional DLS studies show how the assembly process responds to solvent; essentially no aggregation is observed in pyridine consistent with the monomers good solubility in this medium. Another reason for the extremely low scat tering signal in pyridine is the solvents low dn/d c value. Final comparison of naphthylamide 2-1a with phenylamide 1-15 (R = C12H25) at the same concentration in chloroform nicely shows the so lution-phase consequence of introducing larger aromatic arms to the AAT core (Figure 2-33); compound 2-1a forms significantly larger assemblies.

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69 Figure 2-33. Time-intens ity correlation functions (g(2)( ) 1) for chloroform solutions of 2-1a and 1-15 at c = 0.019 wt%. Summary and Conclusions A system of amide functionalized AATs w ith expanded aromatic arms has been synthesized and its properties have been fully characterized. These molecules show significantly enhanced self-assembly properties in both the bulk state and soluti on relative to derivatives with smaller aromatic appendages. In the solid st ate, SEM and powder XRD show well-organized structures. In solution, UV/Vis absorption, fluorescence emission, IR, and NMR spectroscopies have confirmed the role of the aromatic side chains in self-assembly and shown that the conformation of the molecules is important. Excimer emissi on bands were observed th at provide evidence for stacking; a component of this emission was shown to be intermolecular by comparison of the target AAT molecules with model compounds. C oncentration, solvent, temperature, and Hbonding effects on self-assembly were measured by NMR and IR. The data show the importance of intramolecular H-bonding to the amide functiona lized AATs that presumably preorganizes the molecules and facilitates self-assembly.55, 91 Dynamic light scatte ring studies provided

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70 independent evidence for self-assembly and showed the dependence of assembly size on solvent, concentration, temperature, and AAT structure. In particular, the AATs b earing larger aromatic side chains appear to form larger assemblies in solution. The expanded aromatic arms provide enhanced stacking in the AAT assemblies and these interactions complement core-to-core dipolar intera ctions and hydrogen bonding. The supramolecular networks from these unconventional donor-acceptor molecules are complex and additional studies are underway to cont inue drawing important structure-property relationships with the systems. Experimental Section Materials Reagents an d solvents were purchased from Acros, Aldrich, or Fl uka and used without further purification. THF, ether, CH2Cl2, and DMF were degassed in 20 L drums and passed through two sequential purification columns (activ ated alumina; molecular sieves for DMF) under a positive argon atmosphere using the GlassC ontour solvent system (GlassContour, Inc.). Thin layer chromatography (TLC) was performed on DURASIL TLC aluminum sheets with visualization by UV light or staining. Characterization Techniques Melting points (m .p.) were determined on a MEL-TEMP melting apparatus and are uncorrected. 1H (300) and 13C NMR (75 MHz) spectra were recorded on a Varian Mercury 300 (300 MHz) and VXR 300 (300 MHz) sp ectrometers. Chemical shifts ( ) are given in parts per million (ppm) relative to TMS and referenced to residual protonated solvent (CHCl3: H 7.27 ppm, C 77.00 ppm; DMSO: H 2.50 ppm, C 39.00 ppm; pyridine: H 7.22 ppm, C 123.90 ppm; C2H2Cl4: H 5.92 ppm). MS spectra (HRMS and LRMS) were recorded on a Finnigan MAT95Q Hybrid Sector spectrometer. Fluorescence emissi on spectra were recorded using a fluoromax

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71 spectrophotometer. UV-Vis absorption spectra were measured on a Varian Cary 100 UV-Vis instrument. IR spectra were recorded usi ng a Perkin Elmer 1600 Series spectrometer. Scanning electron microscopy (SEM). For all scanning electron microscopy (SEM) experiments, a JEOL JSM 6400 scanning electron microscope was used. Samples were adhered to SEM stubs using conductive c opper tape, then sputtered with Au/Pd to improve the resolution of the images. The sputtering current was 45 mA, the Ar pressure was 75 mTorr, and the sputtering time was 60 s. This yielded an Au/Pd film that was ~ 16 nm thick. The SEM measurements were operated at 15 kV. X-ray diffraction (XRD) XRD data were collected on a Philips APD 3720 X-ray diffractometer with Cu K radiation ( = 1.5406 ). The pure solid was deposited onto a lowscattering quartz plate for the measurement. Th e step size of the scan was 0.02 degrees and the time per step was 1 second. Critical point drying (CPD). Super critical fluid drying wa s performed in a 3000 psi rated vessel (Parr Instruments) to make the xerogels. Samples were placed into regenerated cellulose dialysis bags with a pore diameter of 12000 to 14000 MWCO (Fisher Scientific, USA). Samples were placed inside the drying chamber and liquid CO2 was introduced. Toluene was exchanged with liquid CO2 over 5 solvent exchange steps. Afte r complete solvent removal, the vessel containing the liquid CO2 was heated via a water jacket and water bath to 50 C and 1500 psi. At equilibrium the supercritical CO2 was released from the vessel at a rate no greater than 4 L/min. Dynamic light scattering (DLS). Dynamic light sca ttering measurements were performed with an ALV/CGS-5022F goniometer system equipped with a He-Ne laser ( = 632 nm). The sample solutions were filtered through a 0.45 m filter at room temperature. The samples for Figure 2-31 were filtered through 1.0 m filters at 40 C.

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72 Differential scanning calorimetry (DSC) a nd thermal-gravimetric analysis (TGA). The DSC experiments were performed on a TA Instruments Q1000 equipped with a liquid nitrogen cooling accessory calib rated using sapphire and high-purity indium metal. All samples were prepared in hermetically sealed pans ( 2 mg/sample) and were referenced to an empty pan. The scan rate was 10 C/min. Thermogravimetric analysis (TGA) was performed on a TA Instruments Q5000 IR using the dynamic high-resolution analysis mode and a two point Curie temperature calibration (alumel a lloy and high purity nickel). Gel formation and Tgel determination. Gels were formed by combining AAT 2-1a (5 mg) and toluene or benzene in a s ealed vial. The vial was then heated with a heat gun until a homogenous solution was formed. The vial was then allowed to gradually cool to room temperature on the bench top during which time the gel rapidly formed. To determine the Tgel, a steel ball with a diameter of 2 mm was placed on top of the gel and the vial was placed in an oil bath. The temperature was slowly increased (ca. 0.5 C/min), and monitored using a thermometer submerged in a vial containing neat solvent also in the oil bath, while observing the position of the steel ball. The temperature at wh ich the ball touched the bottom of the vial was taken as the Tgel. Synthesis 2-Bromo-6-methoxynaphthalene (2-2) .127 To a stirring solution of 6-bromonaphthalen-2ol (8.9 g, 40 mmol) in DMF (40 mL) in a 100 mL round-bottomed flask was added potassium carbonate (8.3 g, 60 mmol) and methyl iodide (3 .8 mL, 60 mmol) in one portion. The reaction mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4. The

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73 solvent was removed on a rotary evaporator to afford a white solid (9.4 g, 99%). 1H NMR (300 MHz, CDCl3) 3.96 (s, 3H), 7.15 (m, 2H), 7.58 (m, 3H), 7.93 (m, 1H). 13C NMR (75 MHz, CDCl3) 55.73, 106.15, 117.43, 120.17, 128.78, 128.89, 130.01, 130.05, 130.41, 133.45, 158.28. The NMR data match the literature.127 2-Dodecyl-6-methoxynaphthalene (2-3a) .133 To a stirred mixture of magnesium (0.60 g, 25 mmol) and dry THF (20 mL) in a 100 mL th ree-necked round-bottomed flask was slowly added 1-bromododecane (3.8 mL, 15 mmol) with h eating. The reaction mixture was heated to reflux for 3 h under argon to prepare the Grignard reagent. In a separate reaction vessel, zinc bromide (5.0 g, 23 mmol) was added. The vessel was flame-dried, cooled, and then the zinc bromide was dissolved in dry THF (20 mL). The dodecyl-Grignard reagent was transferred to the zinc bromide solution and stirred for 10 min. To the stirred mixture was added 2-bromo-6methoxynaphthalene (2.8 g, 10 mmol) and Pd(PPh3)4 (23 mg, 0.20 mmol). The reaction mixture was stirred at 60 C overnight. Water was ad ded and the mixture was extracted with ethyl acetate and the combined organic layers were dried with Na2SO4. The solvent was removed on a rotary evaporator and the crude product was purified by column chromatography using hexane to afford a white solid (2.4 g, 72%). 1H NMR (300 MHz, CDCl3) 0.88 (t, 3H, J = 6.9 Hz), 1.27 (m, 18H), 1.69 (m, 2H), 2.74 (t, 2H, J = 7.5 Hz), 3.92 (s, 3H), 7.13 (m, 2H), 7.27 (m, 2H), 7.54 (s, 1H), 7.68 (m, 2H). 13C NMR (75 MHz, CDCl3) 14.11, 22.69, 29.36, 29.56, 29.62, 29.65, 29.68, 31.48, 31.93, 35.91, 55.24, 105.64, 118.54, 126.13, 126.57, 127.92, 128.56, 132.87, 138.13, 157.05.

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74 C4H9 H3CO 2n -Butyl-6-methoxynaphthalene (2-3b) .131 Compound 2-3b was synthesized from 2bromo-6-methoxylnaphthalen e (4.2 g, 18 mmol) and 1.6 M n-butyllithium in hexanes (16.6 mL, 26.6 mmol) according to the same procedure reported for 2-3a to afford 2-3b (2.1 g, 55%) as a white solid. 1H NMR (300 MHz, CDCl3) 0.92 (t, 3H, J = 7.5 Hz), 1.33 (m, 2H, J = 7.5 Hz), 1.64 (m, 2H, J = 7.5 Hz), 2.70 (t, 2H, J = 7.5 Hz), 3.85 (s, 3H), 7.09 (m, 2H), 7.25 (d, 1H, J = 8.4 Hz), 7.50 (s, 1H), 7.61 (m, 2H). 13C NMR (75 MHz, CDCl3) 13.97, 22.37, 33.61, 35.60, 55.21, 105.62, 118.53, 123.55, 126.13, 126.57, 127.63, 127.90, 128.85, 138.05, 157.04. The NMR data match the literature.131 C12H25 HO 2-Dodecyl-6-naphthanol (2-4a). BBr3 (4.5 mL, 48 mmol) was added dropwise to a solution of 3-3a (7.9 g, 24 mmol) in 80 mL of CH2Cl2 at C. After 4 h the mixture was allowed to warm to room temperature, and stirring was continued overnight. The mixture was quenched with saturated NaHCO3 at 0 C and then extracted with CH2Cl2. The organic layer was dried with anhydrous Na2SO4 and the solvent was removed u nder vacuum to provide a white solid (7.4 g, 99%). 1H NMR (300 MHz, CDCl3) 0.88 (t, 3H, J = 6.3 Hz), 1.25 (m, 18H), 1.67 (m, 2H), 2.72 (t, 2H, J = 7.2 Hz), 4.82 (s, 1H), 7.01 (m, 2H), 7.27 (m, 1H), 7.61 (m, 3H). 13C NMR (75 MHz, CDCl3) 14.12, 22.69, 29.35, 29.54, 29.60, 29.67, 31.45, 31.92, 35.91, 109.31, 117.56, 126.67, 128.16, 129.27, 137.50, 138.17, 152.67.

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75 2-Butyl-6-naphthanol (2-4b).133 Compound 2-4b was synthesized from 2n-butyl-6methoxynaphthalene (1.6 g, 7.6 mmol) and BBr3 (1.5 mL, 15 mmol) according to the same procedure reported for 2-4a to afford 2-4b (1.5 g, 97%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 0.95 (t, 3H, J = 7.2 Hz), 1.41 (m, 2H), 1.68 (m, 2H), 2.74 (t, 2H, J = 7.5 Hz), 4.81 (s, 1H), 7.09 (m, 2H), 7.28 (m, 1H), 7.63 (m, 3H). 13C NMR (75 MHz, CDCl3) 14.21, 22.61, 33.82, 35.80, 109.55, 117.81, 126.43, 128.40, 129.51. 6-Dodecylnaphthalene-2-triflu oromethanesulfonate (2-5a). To a stirred solution of 2dodecyl-6-naphthanol (7.2 g, 23 mmol), pyridine (4.5 mL, 55 mmol), and CH2Cl2 (60 mL) was added trifluoromethanesulfonic anhydride (4.6 mL, 28 mmol) slowly at 0 C. The reaction mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with methylene chloride and the co mbined organic layers were dried with Na2SO4. The solvent was removed on a rotary evaporator and the crude product was purified by column chromatography using hexanes/et hyl actate (20:1) to afford a white solid (10.2 g, 98%). 1H NMR (300 MHz, CDCl3) 0.89 (t, 3H, J = 8.1 Hz), 1.31 (m, 18H), 1.71 (m, 2H), 2.79 (t, 2H, J = 8.1 Hz), 7.35 (m, 2H), 7.80 (m, 4H). 13C NMR (75 MHz, CDCl3) 14.10, 22.68, 29.28, 29.35, 29.50, 29.57, 29.65, 31.23, 31.92, 36.04, 118.94, 119.44, 126.29, 127.84, 129.23, 129.99, 131.71, 132.61, 142.17, 146.58. HRMS (ESI, (M+Na)+) calcd for C23H31F3O3S: 467.1838; found: 467.1853.

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76 6-Butylnaphthalen-2-yl trif luoromethanesulfonate (2-5b) Compound 2-5b was synthesized from 2-dodecyl-6-naphthanol ( 1.5 g, 7.5 mmol) and trifluoromethanesulfonic anhydride (2.5 mL, 15 mmol) according to the same procedure reported for 2-5a to afford 2-5b (1.8 g, 72%) as a colorless oil. 1H NMR (300 MHz, CDCl3) 0.96 (t, 3H, J = 8.1 Hz), 1.42 (m, 2H), 1.70 (m, 2H), 2.81 (t, 2H, J = 7.8 Hz), 7.35 (m, 1H), 7.45 (m, 1H), 7.79 (m, 4H). 13C NMR (75 MHz, CDCl3) 13.92, 22.33, 33.36, 35.73, 118.94, 119.46, 126.31, 127.85, 129.24, 129.98, 131.71, 142.13. HRMS (ESI, (M+Na)+) calcd for C15H15F3O3S: 355.0586; found: 355.0642. 6-Dodecyl-2-naphthylamine (2-6a). To a flame-dried reaction tube containing Pd(dba)2 (72 mg, 0.13 mmol) was added P(t-Bu)3 (0.13 mmol from a 0.24 M stock solution in toluene) followed by THF (10 mL). The solution was s tirred at room temperature for 10 min. 6Dodecylnaphthalene-2-trifluoromethane-s ulfonate (1.1 g, 2.5 mmol) and LiN(SiMe3)2 (5 mmol) were then added. The reaction mixture was sti rred at 60 C overnight. The silylamide was deprotected by adding aqueous 1N HCl. The mixtur e was transferred to a separatory funnel and washed with aqueous 1N NaOH. Th e organic layer was dried over Na2SO4, filtered, and concentrated at reduced pressure. The residu e was purified by chromography (hexane/EtOAc 10:1) to afford a brown solid (0.36 g, 46%). 1H NMR (300 MHz, DMSOd6) 0.84 (t, 3H, J = 6.6 Hz), 1.22 (m, 18H), 1.59 (m, 2H), 2.60 (t, 2H, J = 7.2 Hz), 5.23 (s, 2H), 6.77 (s, 1H), 6.88 (m, 1H), 7.12 (m, 1H), 7.47 (m, 3H). 13C NMR (75 MHz, DMSOd6) 13.45, 21.59, 28.19, 28.38, 28.49, 30.51, 30.78, 34.54, 37.67, 38.17, 105.42, 117.87, 124.53, 125.36, 125.98,126.75,

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77 127.44, 132.88, 134.11, 145.43. HRMS (ESI, (M+H)+) calcd for C22H33N: 312.2686; found: 312.2689. 6-Butylnaphthalen-2-amine (2-6b).136 Compound 2-6b was synthesized from 6butylnaphthalen-2-yl trif luoromethanesulfonate 2-5b (1.5 g, 4.4 mmol) and LiN(SiMe3)2 (8.8 mmol), P(t-Bu)3 (0.22 mmol from a 0.24 M stock solution in toluene) and Pd(dba)2 (0.13 g, 0.22 mmol) according to the same procedure reported for 2-6a to afford 2-6b (0.36 g, 42%) as a yellow oil. 1H NMR (300 MHz, DMSO) 0.90 (t, 3H, J = 7.2 Hz), 1.30 (m, 2H), 1.58 (m, 2H), 2.62 (t, 2H, J = 7.5 Hz), 5.22 (s, 2H), 6.77 (m, 1H), 6.88 (m, 1H), 7.14 (m, 1H), 7.45 (m, 3H). 13C NMR (75 MHz, DMSO) 13.30, 21.24, 32.68, 34.19, 105.41, 117.85, 124.51, 125.33, 125.96, 126.72, 127.41, 132.84, 134.05, 145.35. HRMS (ESI, (M+H)+) calcd for C14H17N: 200.1434; found: 200.1437. n -Butyl 6-amino-2-naphthoate (2-6c). To a stirred solution of 6-amino-2-naphthoic acid (0.4 g, 2 mmol) in n-butyl alcohol (20 mL) was added concentrated sulfuric acid (2.0 mL) slowly at room temperature. The reaction mixture was st irred at reflux for 44 h. The mixture was cooled to room temperature. The solvent was removed on a rotary evaporator and the crude solid was suspended in water. Sodium hydroxide was added (2 M) to adjust the pH to 10. The mixture was filtered to afford a white solid (0.31 g, 64 %). 1H NMR (300 MHz, DMSOd6) 0.95 (t, 3H, J =

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78 7.2 Hz), 1.45 (m, 2H), 1.73 (m, 2H),4.29 (t, 2H, J = 6.6 Hz), 5.87 (br s, 2H), 7.08 (m, 2H), 7.78 (m, 3H), 8.38 (s, 1H). 13C NMR (75 MHz, DMSOd6) 13.62, 18.77, 30.36, 64.12, 109.69, 119.99, 125.32, 126.03, 126.64, 130.46, 130.79, 136.81, 166.04. 2-{3,5-Bis-[(6-dodecylnaphthylcarbam oyl)-methyl]-2,4,6-tri methoxynaphthyl}N -(6dodecylnaphthyl)-acetamide (2-8a). A solution of triacid 2-7a (51 mg, 1.5 mmol) and thionyl chloride was heated to reflux for 2 h and the so lvent was then removed in vacuo. The remaining crude brown oil ( 2-7b ) was then dissolved in dry THF (20 mL ) and slowly added to a solution of 6-dodecyl-2-naphthylamine (1.54 g, 4.95 mmol), TEA (2.1 mL, 15 mm ol), and dry THF (20 mL) in a dry round-bottomed flask. The resulting solution was allowed to stir under a blanket of argon overnight. The reaction mixture was then diluted with methylene chloride (50 mL), washed with 10% aq HCl (25 mL), water (20 mL ), and brine (20 mL). The solution was further dried over MgSO4, evaporated in vacuo. The residue was purified by chromography (CH2Cl2/MeOH = 20/1) to afford 2-8a (0.85 g, 46%) as a off-white solid: 1H NMR (300 MHz, pyridined5) 0.89 (t, 3H, J = 6Hz), 1.27 (m, 18H), 1.69 (m, 2H), 2.75 (t, 2H, J = 6.6 Hz), 4.03 (s, 3H), 4.11 (s, 2H), 7.38 (d, 1H, J = 7.8 Hz), 7.89 (m, 4H), 8.84 (s, 1H), 11.06 (s, 1H). 13C NMR (75 MHz, pyridined5) 14.99, 23.65, 30.32, 30.54, 30.61, 30.66, 32.42, 32.83, 34.46, 36.90, 62.72, 117.36, 121.20, 121.62, 127.26, 128.61, 129.08, 129.17, 131.82, 133.82, 138.19,

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79 140.17, 159.41, 171.33. HRMS (ESI, (M+Na+H)+) calcd for C81H111N3O6: 1246.7623; found: 1246.7619. N -Naphthyl-2-(2,4,6-trimethoxy-3,5-bisnaphthylcarbamoylmethyl-naphthyl)acetamide (2-8b). This compound was synthesized from triacid chloride 2-7b (504 mg, 1.47 mmol), 2-naphthylamine (695 mg, 4.86 mmol), a nd TEA (2.1 mL, 15 mmol) according to the same procedure reported for 2-8a to afford 2-8b (0.49 g, 46%) as an white solid: m.p. 198 200 C. 1H NMR (300 MHz, DMSOd6) 3.76 (s, 5H), 7.63 (m, 6H), 8.29 (s, 1H), 10.40 (s, 1H). 13C NMR (75 MHz, DMSOd6) 33.12, 62.04, 115.70, 119.97, 120.64, 125.16, 127.07, 127.91, 128.12, 129.02, 130.36, 134.14, 137.68, 158.25, 170.56. HRMS (ESI, (M+Na)+) calcd for C45H39N3O6: 740.2731; found: 740.2731. 2-{3,5-Bis-[(6-dodecylnaphthylcarbam oyl)-methyl]-2,4,6-tri hydroxy-naphthyl}N -(6dodecylnaphthyl)-acetamide (2-9a). To a solution of 2-8a (0.37 g, 0.30 mmol) in dry

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80 methylene chloride (15 mL) s tirring at C was added BBr3 (0.17 mL, 1.8 mmol). The reaction was allowed to stir, under argon, at that temperature for 2 h before gradual warming to room temperature and stirring overnight. The so lution was then cooled to 0 C, quenched via careful addition of saturated aq NaHCO3, and filtered to remove all solid material. The filtrate was then extracted with methylene chloride (50 mL 3). The organics were then combined, dried over MgSO4, and evaporated in vacuo to afford 2-9a (0.26 g, 72%) as a brown solid. 1H NMR (300 MHz, pyridined5) 0.88 (t, 3H, J = 6.6 Hz), 1.32 (m, 18H), 1.68 (m, 2H), 2.73 (t, 2H, J = 7.2 Hz), 4.38 (s, 2H), 7.39 (d, 1H, J = 8.7 Hz), 7.89 (m, 5H), 8.63 (s, 1H), 11.74 (s, 1H). 13C NMR (75 MHz, pyridined5) 14.61, 23.26, 29.93, 30.14, 30.22, 30.27, 32.00, 32.44, 36.52, 105.30, 118.31, 121.61, 123.12, 126.89, 128.33, 128.72, 128.77, 131.77, 133.15, 136.82, 140.25, 155.92, 174.34. HRMS (ESI, (M+Na)+) calcd for C78H105N3O6: 1202.7901; found: 1202.7805. OH OH HO H N O HN O H N O N -Naphthyl-2-(2,4,6-trihydroxy-3,5-bis-na phthylcarbamoylmethyl-naphthyl)acetamide (2-9b). This compound was synthesized from 2-8b (0.92 g, 1.3 mmol) and BBr3 (7.7 mmol) according to the same procedure used for 2-9a to afford 2-9b (0.68 g 77%) as a brown solid. 1H NMR (300 MHz, DMSOd6) 3.81 (s, 2H), 7.66 (m, 5H), 8.29 (s, 1H), 9.31 (s, 1H), 10.37 (s, 1H). 13C NMR (75 MHz, DMSOd6) 116.13, 120.83, 125.23, 127.04, 127.98, 128.11, 128.99, 130.43, 134.10, 137.40, 172.76. HRMS (ESI, (M+Na)+) calcd for C42H33N3O6: 698.2231; found: 698.2230.

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81 2-{5,7-Bis-[(6-dodecyl-naphthylcarbamoyl)-methyl]-4,6,10-trioxo-1-aza-tricyclo [3.3.1.13,7]dec-3-yl}-N -(6-dodecyl-naphthyl)-acetamide (2-1a). A solution of 2-9a (120 mg, 0.10 mmol), HMTA (42 mg, 0.30 mmol) and isopropanol (5 mL) was heated to reflux for 72 h under a blanket of argon. After cooling the reactio n to rt, the mixture was filtered to afford a brown solid then the solid was washed with 5% HCl and water. The solid was purified via recrystallization from ethyl acetate/dioxane to afford 13a (78 mg, 49%) as a brown solid: m.p. 213 215 C. 1H NMR (300 MHz, pyridined5) 0.88 (t, 3H, J = 7.2 Hz), 1.27 (m, 18H), 1.69 (m, 2H), 2.74 (t, 2H, J = 7.2 Hz), 3.40 (s, 2H), 4. 36 (s, 2H), 7.37 (d, 1H, J = 8.7 Hz), 7.83 (m, 5H), 11.15 (s, 1H). 13C NMR (75 MHz, pyridined5) 14.98, 23.63, 26.75, 28.34, 30.30, 30.33, 30.53, 30.60, 30.65, 32.40, 32.81, 36.90, 72.11, 75.87, 117.39, 121.57, 127.24, 128.55, 129.02, 131.75, 133.74, 137.98, 140.11, 169.59, 200.21. HRMS (ESI, (M+Na)+) calcd for C81H108N4O6: 1255.8167; found: 1255.8136. Anal. calcd for C81H108N4O6H2O: C, 76.62; H, 8.89; N, 4.41. Found: C, 76.74; H, 9.03; N, 4.67.

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82 N -2-Naphthyl-2-(4,6,10-trioxo-5,7-bis-napht hylcarbamoylmethyl-1-aza-tricyclo [3.3.1.13,7]dec-3-yl)-acetamide (2-1b). A solution of 2-9b (0.30 g, 0.44 mmol), HMTA (188 mg, 1.33 mmol) and isopropanol (25 mL) was heated to reflux for 72 h under a blanket of argon. After cooling the reactio n mixture to rt, the solvent was removed in vacuo and the residue was treated with ethyl acetate (10 mL). The solid was collected by suction filtr ation and purified via recrystallization from ethyl acetate/dioxane to afford 2-1b (0.19 g, 59%) as a white solid: m.p. 277 279 C. 1H NMR (300 MHz, DMSOd6) 2.88 (s, 2H), 4.00 (s, 2H), 7.44 (m, 3H), 7.79 (m, 3H), 8.29 (s, 1H), 10.24 (s, 1H). 13C NMR (75 MHz, DMSOd6) 31.75, 69.77, 108.64, 114.23, 119.30, 123.85, 125.80, 126.68, 126.86, 127.71, 129.03, 132.94, 136.34, 167.31, 176.37, 197.80. HRMS (ESI, (M+Na)+) calcd for C45H36N4O6: 751.2517; found: 751.2517. Anal. calcd for C45H36N4O6.5H2O: C, 71.51; H, 5.20; N, 7.41. Found: C, 71.76; H, 5.20; N, 7.59. O O O O OH H N O 2-(4-Hydroxy-2,6-dioxo-2,3,5,6-tetrahydrobenzofuro[6,5-b]furan-8-yl)-N(naphthalen-2-yl)acetamide (2-10). A solution of 2-9b (0.2 g, 0.3 mmol), TFA (0.6 mL, 8 mmol) and toluene (20 mL) was heated at 80 oC for 2 h under a blanket of argon. After

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83 cooling the reaction mixture to rt, the solvent was removed by filtration and the solid was washed with water to afford 2-10 (0.10 mg, 86%) as a peach-colored solid. 1H NMR (300 MHz, DMSOd6) 3.72 (s, 2H), 3.83 (s, 4H), 7.43 (m, 2H), 7.59 (m, 1H), 7.82 (m, 3H), 8.28 (s, 1H), 10.25 (s, 1H), 10.38 (s, 1H). 13C NMR (75 MHz, DMSOd6) 30.77, 94.43, 104.50, 114.63, 119.34, 123.99, 125.82, 126.68, 126.86, 127.78, 129.17, 132.84, 136.13, 147.26, 152.26, 166.97, 173.56. HRMS (ESI, (M+Na)+) calcd for C22H15NO6: 412.0792; found: 412.0788. 2,2'-(2,4,6-Trihydroxy-5-(2-(napht halen-2-ylamino)-2-oxoet hyl)-1,3-phenylene)bis(Nphenylacetamide) (2-11). A stirring solution of 2-10 (0.1 g, 0.3 mmol) in DMF (10 mL) was treated with aniline (0.1 mL, 1 mmol) and heated to 120 C overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% HCl and water. The combined organic layers were dried with Na2SO4. The solvent was removed on a rotary evaporator and the crude pr oduct was purified by column chromatography (hexane/EtOAc 1:1) to afford a yellow solid (0.10 g, 68%). 1H NMR (300 MHz, DMSOd6) 3.73 (s, 4H), 3.78 (s, 2H), 7.05 (t, 2H, J = 7.5 Hz), 7.30 (t, 4H, J = 7.5 Hz), 7.43 (m, 2H), 7.62 (m, 5H), 7.85 (m, 3H), 8.28 (s, 1H), 9.31 (s, 2H ), 9.32 (s, 1H), 10.19 (s, 2H), 10.37 (s, 1H). 13C NMR (75 MHz, DMSOd6) 13.58, 20.26, 31.86, 59.25, 102. 94, 105.26, 115.01, 117.88, 118.85, 119.55, 120.32, 122.91, 124.5, 125.33, 125.8, 125.9, 126.82, 126.95, 127.84, 127.96, 128.23,

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84 129.29, 132.87, 134.49, 136.02, 138.41, 146.14, 153.15, 171.09, 171.26. HRMS (ESI, (M+Na)+) calcd for C34H29N3O6: 598.1949; found: 598.1944. Mono-naphthylamine-di-phenylamine 1-aza-adamantantrione (2-12). This compound was synthesized from 2-11 (90 mg, 0.16 mmol) and HMTA ( 66 mg, 0.48 mmol) according to the same procedure used for 2-1a to afford 2-12 (41 mg, 43%) as an off-white solid. 1H NMR (300 MHz, DMSOd6) 2.79 (s, 4H), 2.85 (s, 2H), 3.95 (s, 6H), 6.99 (t, 2H, J = 7.5 Hz), 7.26 (t, 4H, J = 7.8 Hz), 7.45 (m, 8H), 7.81 (m, 3H), 8.27 (s, 1H), 10.01 (s, 2H), 10.23 (s, 1H). 13C NMR (75 MHz, DMSO) 33.21, 69.71, 69.88, 114.19, 118.35, 119.28, 122.33, 123.85, 125.81, 126.69, 126.88, 127.72, 128.08, 129.03, 132.95, 136.36, 138.80, 167.03, 167.28, 197.79. HRMS (ESI, (M+Na)+) calcd for C37H32N4O6: 651.2214; found: 651.2208. N -(Naphthalen-2-yl)-4-oxopentanamide (2-13). To a mixture of levulinic acid (0.31 mL, 3.0 mmol) and -naphthylamine (0.47 g, 3.3 mmol) in di chloromethane (10 mL) was added DCC (0.68 g, 3.3 mmol) at 0 C. The mixture was stirred at 0 C for 1 h and then at rt for 2 h. The solids were removed by filtration. The organi c layer was then washed with 1 M HCl, 0.05 M NaOH, and water. The solvent was removed on a rotary evaporator and the crude product was

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85 purified by column chromatography (hexane/EtOAc 1:1) to afford a white solid (0.44 g, 61%). 1H NMR (300 MHz, CDCl3) 2.22 (s, 3H), 2.67 (t, 2H, J = 6.6 Hz), 2.90 (t, 2H, J = 6.0 Hz), 7.43 (m, 3H), 7.74 (3H, d, J = 7.2 Hz), 8.15 (s, 1H), 8.18 (s, 1H). 13C NMR (75 MHz, CDCl3) 30.19, 31.48, 38.86, 116.67, 120.01, 125.16, 126.68, 127.75, 127.86, 128.94, 130.82, 134.06, 135.54, 170.62, 208.33. HRMS (ESI, (M+Na)+) calcd for C15H15NO2: 264.0995; found: 264.1003.

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86 CHAPTER 3 DIFFERENTIALLY-FUNCTIONALIZED AND CHIRAL AATS FROM LACTONE PRECURSORS Introduction The 1-aza-adam antanetriones (AATs) are a new class of unconventional donoracceptor molecules which display interesting se lf-assembly and macromolecular properties upon proper functionalization of the adamantanoid core Experiments have shown that the electronic structure of the molecules (defined by multiple through-bond donoracceptor interactions) responds to appended substituents in unique ways and dramatic changes have been observed between phenyl-substituted AAT 1-14 and phenylamide-substituted AAT 1-15 in terms of solution-phase behavior and solid -state organization. Likewise, the most robust AAT organogels to date have been prepared by converting the phenylamide group (of 1-15) to a naphthylamide substituent (as in 2-1 ). Peripheral functional groups are th erefore the key to fine tuning the shape, dipole, solubility, and self-recogn ition capabilities of the AAT platforms. This chapter first reviews the typica l synthetic approaches to prepare C3-symmetric but functionalized AATs and then introduces new, more versatile strate gies based on lactone intermediates (derived from phloroglucinol) that afford access to differentially-functionalized and even chiral compounds. The synthetic scheme to access C3-symmetric amide-based AATs is shown in Figure 3-1 and highlights two significant lim itations. First, the protocol requires that a strong Brnsted or Le wis acid (HBr, HI, BBr3, etc.) be used in the me thyl-phenyl ether cleavage step for phloroglucinol synthon pr eparation. Milder conditions do not work efficiently for this multi-site deprotection. The procedure limits the functional groups that can be incorporated into the AAT periphery. While most amides, bulky es ters, and alkyl/aryl gro ups survive, delicate (and chiral) biomonomers like amin o acids, nucleosides, or glycos ides, cant be introduced by this route. The latter functionalities are important for using the AATs as scaffolds to probe

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87 interactions at biomolecula r interfaces, for example, or as potential drug targets.188 Alternative synthetic methods would ideally allow preparation of derivatives beari ng a wide variety of functional groups in the AAT periphery. Figure 3-1. Current methodology used to construct the C3-symmetric AATs. BBr3 labile functionality is not tolerated in the current scheme. The second limitation implied by Figure 3-1 is that only C3-symmetric AAT derivatives are easily accessible. C3-symmetric scaffolds are certainly widely used as supramolecular building blocks,189 asymmetric catalysts, a nd in chiral recognition.189-191 The last two applications generally require ch iral compounds that are often prepared by introducing chiral centers to the otherwise symme tric objects. Developing synthetic methodology through which functionality can be differentiall y installed, selectively, into the arm units of the AAT core would greatly expand the potentia l applications of the molecules. That said, differentiating tripodal scaffolds is difficult and historically achieved statistically by unselectiv e reactions; it therefore often involves tedious separation techniques to obtain mono-, di-, or trifunctionalized materials.192 Interesting opportunities exis t for the amide-based AATs if the peripheral groups can be independently addressed (Figure 3-2) The symmetry would be reduced from C3 to Cs upon introduction of two different arms, and further to C1 upon installation of three different appendages. In this last case, the bridgehead nitrogen appears as one of four chiral centers. Such molecules could then potentially share the proper ties of chiral tertiary amines (e.g., sparteine) that have enjoyed widespread ap plication in chiral recognition and asymmetric catalysis.194-196

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88 Similarly, the compounds could serve as building bl ocks for a variety of chiral self-assembled materials, present unusual chiroptical properties, and offer challenges and opportunities with respect to chiral separation. Figure 3-2. From symmetric to asymmetric triamide AATs. A Lactone-Based Strategy A strategy f or preparing differentially substitu ted and even chiral AAT amides comes from the lactone chemistry91 pioneered by Dr. Andy Lampkins in the Castellano group. Figures 3-3 and 3-4 revisit the discovery of these useful intermediates, initially the by-products of BBr3 demethylation reactions.91 With optimization, ester functionali zed phloroglucinol derivatives can form the mono-, di-, and trilactones (Figure 3-3 and 3-4) selectively under appropriate conditions. Temperature is the key to c ontrolling the lactone formation.91 Figure 3-3 shows the preparation of butenolides 3-1a through 3-1c While the basic chemistry of coumaran-2-ones like 3-1a has been described before,193 3-1b and 3-1c are novel scaffolds and ongoing work in the Castellano lab is exploring their properties and reactivity. For example, it is interesting that C2-symmetric 3-1b is formed quantitatively at the expense of its Cs-symmetric regioisomer (not shown). Shown schematically is how trilactone 3-1c can be converted, in two steps (ring opening with an amine and then HMTA cyclization), to C3symmetric AATs like the ones that have been desc ribed thus far. The same two-step sequence can be applied to the monoand dilactones to prepare differentially-functionalized AATs (vide

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89 infra). The difference in each case versus Figure 3-1 is that the peripheral functional groups are introduced at a late synthetic stage and not subsequently subjected to the harsh BBr3 conditions. The complementary preparation of pentenolides 3-2ac is shown in Figure 3-4; cyclization of these less strained six-membered ring lactones re quires lower temperatures and is generally met with higher yields. Notably, Cs-symmetric 3-2b is isolated as the majo r dilactone product here. Finally, as with the butenolides, the intermediates can be converted in two steps to various AAT derivatives.194 OH OH HO O O O O O O PhH,TFA,reflux,15min 72% HOAc,reflux quant. PhCH3,conc.HCl,reflux, 12h,28% O O O O O O OH HO OH O O O O O O O O O O O O 3-1a 3-1b 3-1c 1.RNH2CH3CN 2.HMTA i -PrOH N O HN R N H O R O N H R O O O Figure 3-3. Synthetic methodology us ed to selectively annelate mono-, di-, and tributenolides from a common intermediate, an ester phloroglucinol derivative.91

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90 Figure 3-4. Synthetic methodology us ed to selectively annulate m ono-, di-, and tripentenolides from a common intermediate, an ester phloroglucinol derivative.91 Toward triamide AAT target s like those presented in Fi gure 3-2, the lactone-based methodology has now been extended to phlorogluci nol triamides. Amide functional groups play an important role in the self-assembly of AATs through structural preorganization that involves intramolecular H-bonding.55, 91 Figure 3-5 shows the reasonably se lective formation of the monoand dilactones from amide-f unctionalized phloroglucinol 3-17 under various conditions. The initial synthetic approach was to use the conditions of Figure 3-3 and apply them to 3-17. Treatment of the phloroglucinol derivatives with TFA at elevated temperature formed, instead of the monolactone as reported fo r the esters, the thermodynamic C2-symmetric dilactone 3-3b as the major product. The same conditions were used to prepare dilactone 2-10 (Figure 2-5) from naphthyl amide-functionalized phloroglucinol 2-9b Shorter heating times, as shown by Yan Li

PAGE 91

91 in the Castellano group, can give the Cs-symmetric dilactone regioisomer, 3-3c The two regioisomers are readily distinguished by their 1H NMR spectra; 3-3c shows three singlets (in a 1:1:1 ratio) for the three se ts of chemically unique -CH2 protons while only two singlets (in a 2:1 ratio) are observed for 3-3b Decreasing the temperature to room temperature yields monolactone 3-3a in moderate yield. Comparing the conditi ons used in Figures 3-3 and 3-5, it is apparent that the amides generally cyclize at lower temperatures to provide the corresponding lactones. This rate di screpancy is presumably related to the difference in carbonyl electrophilicity between the bulky isopropyl esters and activated phenyl amides. Figure 3-5. The synthetic approach of amide-functionalized lactones.

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92 Approach to Differentially-Substitute d AATs from Buten olide Precursors The five-membered ring lactones should s how good reactivity toward nucleophiles under mild conditions195 due to relief of ring st rain upon ring opening. To explore this reactivity and also prepare new desymmetrized AATs, ester intermediates 3-1a and 3-1b were treated with various aryl and alkyl amine nuc leophiles (Figure 3-6 and Table 31). Under reflux conditions in DMF or acetonitrile, one or two equivalents of the amine are sufficient to afford the corresponding phloroglucinol derivatives 3-4 and 3-6 respectively, in moderate to good yields. Subsequent cyclization with HMTA affords the corresponding differe ntially-substituted AATs 35 and 3-7 Various aryl amines were selected to ultimately explore potential stacking interactions in the context of self-assembly. Pyrene, for example,113-120 was selected (with two different connectivities to th e AAT core) due to its well understood electronic and optical properties that could be useful to study AAT self-assembly in solution. Figure 3-6. Preparation of mixed amide a nd ester AATs derived from the monoand dibutenolides.

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93 Table 3-1. Nucleophilic ring opening of monoa nd dibutenolides with amines and subsequent cyclization with HMTA. Ar group entry product yield product yield 1 3-4a 84% 3-5a 42% 2 3-6a 68% 3-7a 47% 3 3-4b 73% 3-5b 49% 4 3-6b 44% 3-7b 38% 5 3-4c 70% 3-5c 45% 6 3-6c 73% 3-7c 51% 7 3-4d 52% 3-5d 41% 8 3-6d 51% 3-7d 62% The amide-functionalized butenolides show a similar reactivity toward amine nucleophilic attack. Monolactone 3-3a reacts with both aryl and alkyl amines to form differentiallyfunctionalized phloroglucinol and AAT triamides (Figure 3-7). O O OH HO HN O H N O 3-3a R NH2DMF OH OH HO H N O HN O H N O R HMTA i -PrOH N O N H R O HN Ph N H O Ph O O O 3-8 3-9 3-8a :R=naphthyl70% 3-8b :R= n -C6H1380% 3-9a :R=naphthyl41% 3-9b :R= n -C6H1348% Figure 3-7. Synthesis of differential amide functionalized AATs from amide mono-lactone. The -naphthylamine requires heating at 120 C in DMF overnight to consume all of the monolactone starting material while n-hexylamine reacts with 3-3a at room temperature. The

PAGE 94

94 differences are understandable given the primary alkyl amine and primary aryl amine. Dilactone 2-10 reacts with anilines in DMF at 120 C to afford the phlorogluci nol products where both of lactone rings have been opened (Figure 3-8). Figure 3-8. Synthesis of di fferentially-functionalized AAT s from an amide dilactone. Chiral AATs Derived from Lactone Methodology An approach to synthesizing the first chiral AATs has em erged in the process of preparing the differentially-substituted AATs described above. One of the two lactone rings of the C2symmetric dilactones (e.g. 2-10, 3-1b etc.) can be selectivel y opened upon addition of one equivalent of amine at 60 C; the remaining lactone ring reacts at higher temperature (120 C) in DMF (Figure 3-9). Figure 3-6 shows the temperature-dependent reactivity for 2-10 where reasonable selectivity is observed for the sing le and double ring opening w ith aniline (to give 3-

PAGE 95

95 12 and 3-10a respectively). Further cyclization of 3-10a with HMTA produces the AAT that is a hybrid of 1-15 and 2-1b The intermediate monolactone 3-12 of course then provides the opportunity to introduce a second amine (in this case p-dodecylamine) and produce the Cssymmetric and prochiral phl oroglucinol derivative 3-13. Figure 3-9. Different ring ope ning patterns of the dilactone 2-10 under different reaction conditions. The ester-functiona lized dilactone 3-1b reacts similarly to 2-10 giving 3-14 (Figure 3-10). This reaction has yet to be optimized since the st arting material and product have nearly the same Rf values by thin layer chromatography, making routine monitoring of the reaction difficult. Even so, the isolated 3-14 can be reacted with n -hexylamine to generate differentiated 3-15a. Subsequent cyclization with HMTA affords asymmetric AAT 3-16 as a racemic mixture. Initial attempts to visualize the mixt ure of stereoisomers were made. An 1H NMR spectrum of 3-16a recorded in the presence of a chiral shift reagent (1 R )-(-)-10-camphorsulfonic

PAGE 96

96 acid196 did show doubling of the major peaks, bu t the spectrum was complex. Attempts to separate the enantiomers by ch iral HPLC (columns used: (S ,S) Whelk-01 10/100 kromasil FEC from Regis and chiral cel OB-H from Daicel ch emical) failed due to poor peak resolution. Given these results, 3-15b was prepared from reaction of 3-14 with L-()--methylbenzylamine with the intention of ultimately forming two separable diastereomers of 3-16b upon cyclization with HMTA (Figure 3-10, see inset). Unfortunately, the cyclization product 3-16b has been difficult to purify and clean NMR spectra have yet to be obtained. O O OH O O O O aniline/DMF 80oC,49% O O OH HN O Ph HO O O RNH2/DMF OH OH HO H N O HN O Ph O O R 3-1b 3-14 3-15 3-15a :R= n -C6H1388% 3-15b :R=L-(-)-methylbenzyl92% HMTA i -PrOH N O N H R O HN Ph O O O O O ()3-16a: R= n -C6H1342% 3-16b :R=L-(-)-methylbenzyl a b R1* R3 R2 N R1* R2 R3 N *R1=L-(-)-methylbenzylamide R2=phenylamide R3= i -propylester 3-16b: Vs.Figure 3-10. Chiral AAT derived from lactone methodology. 1H NMR spectroscopy (Figure 3-11 ) nicely shows the result of reducing the symmetry in the AAT derivatives from C3 (compound 1-15), to Cs (compound 3-9b ), to C1 (compound 3-16a). The expected multiplicity for each set of protons a and b (Figure 3-11) across this series is one peak (singlet), five peaks (two doublets and a singlet), and 12 peaks (6 doublets). The AATs show this increase in complex ity although the protons are not resolved at 300 MHz and have very similar chemical shifts.

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97 Figure 3-11. The 1H NMR of compound 1-15 (in DMSOd6), 3-9b (in pyridined5), and 3-16b (in CDCl3). See Figure 3-10 for the proton assignments. Interesting Thermal and Optical Propert ies of Differentially-Substitu ted AATs With a small library of differentially-substi tuted AATs in hand, initial structure-property studies with respect to therma l and optical properties were pursued. The former come through differential calorimetry measurements (DSC) an d the latter through ther mal optical polarized microscopy (TOPM); both techniques probe bulk phase changes and possible liquid-crystalline behavior. In the DSC runs, two heating and c ooling cycles were used with a rate of 10 C/min. Most of the AAT molecules show normal endot hermic transitions at their melting points and exothermic transitions upon coo ling and crystallization. Compounds 3-5a and 3-7a show more complex thermal phase transition behavior (Figures 3-12 and 3-13, and Table 3-2).

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98 Figure 3-12. DSC curves obtained for 3-5a for the first (red lines) and the second (blue lines) heating cooling cycles. A cold-crystallization exotherm is identif ied in the second heating cycle (heating and cooling rate 10 C/min). The DSC thermogram of 3-5a (Figure 3-12) shows melti ng of the solid at 183 C in the first heating cycle and then shows a broad exothermic transition upon cooling. A negative (exothermic) peak (cold crystallization197-199) is observed at 125 C upon second heating. Apparently, the melting of the solid erases its organizational hist ory and the compound reorganizes only upon a second he ating. The DSC curves of 3-7a (Figure 3-13) show two cold crystallization exotherms and one small endotherm ic transition prior to the melting transition in the first heating cycle. The phase transition temp eratures and enthalpies for the transitions for 35a and 3-7a are summarized in Table 3-2.

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99 Figure 3-13. DSC curves obtained for 3-7a for the first (red lines ) and second (blue lines) heating cooling cycles. Two cold-crystalliza tion exotherms and one endothermic transition are identified in the first he ating cycle (heating and cooling rate 10 C/min). Table 3-2. Phase transition temp eratures and enthalpies for 3-5a and 3-7a 3-5a 3-7a Transtion K I K K1 K1 I K K1 K1 K2 K2 K3 K3 I T ( C) 183.3 125.0 181.7 160.3 199.8 232.8 249.1 H (kJ/mol) 46.19 22.82 42.15 7.05 5.64 11.55 54.52 K, K1, K2, K3: crystalline phase; I: isotropic phase. Thermal optical polarization microscopy (TOP M) was used to probe the phase changes optically for the two compounds upon heating and cooling. Compound 3-5a shows needle-like crystals in the original solid state (Figure 3-14a ). The first heating cycl e accesses the isotropic state (not shown) upon melting. Upon a second heating, a birefringent crystal phase is formed at 124 C that matches well the DSC transition. Crystal lization into extended fibers or needles occurs from a central nucleation site (Figure 3-14b to 3-14i) upon second heating. A similar TOPM with 3-7a did not show any remarkable features; no obvious morphology changes were observed at temperatures corresponding to the DSC transitions.

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100 Figure 3-14. Cross-polarized optic al microscopy images of compound 3-5a: (a) The original solid sample shows needle-like crystals at r oom temperature. (b) to (h) Crystal growth in about 42 seconds in the second heating cycle (rate 10 C/min). The temperature of (b) was 135 C and the temperature of (h) was 142 C. (I) Fully grown cold crystalline 3-5a Summary A library of differentially-substituted AATs has been prepared using a lactone-based strategy that allows for moderately selective fu nctionalization of the phl oroglucinol core. The approach allows, for the first time, a) the rational synthesis of ch iral AATs and b) the introduction of sensitive functional groups to the periphery. Ongoing work seeks to use the synthetic methods to develop self-assembling AATs that can form chiral materials.

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101 Experimental Section Characterization Technique Thermal optica l polarized microscopy (TOPM) For all thermal optical polarized microscopy (TOPM) experiments, a Leica DMLP polarization microscope with a Linkam heating and cooling stage (temperature range of 196 to 350 C) and a 35 mm automated camera system was used. The heating and cooling rates were 10 C/min. Synthesis O OH O HO HN O H N O 2,2'-(4,6-Dihydroxy-2-oxo-2,3-dihy drobenzofuran-5,7-diyl)bis( N -phenylacetamide) (3-3a) A mixture of N -phenyl-2-(2,4,6-trihydroxy-3,5-di -phenylcarbamoylmethylphenyl)acetamide55 (1.05 g, 2.00 mmol) and TFA (1.85 mL, 24.0 mmol) was stirred at room temperature for 3 h in toluene (40 mL). The solvent was then removed in vacuo and the remaining crude product was dissolved in ethyl acetate. The resulting solution was washed with 10 % NaOH solution, water, and brine. The orga nic layer was further dried over Na2SO4 and the solvent was removed on a rotary evaporator. The crude pr oduct was purified by column chromatography (hexanes/EtOAc = 3/2) to affo rd a white solid (0.41 g, 47%). 1H NMR (300 MHz, DMSOd6) 3.68 (s, 2H), 3.69 (s, 2H), 3.75 (s, 2H), 7.05 (m, 2H), 7.29 (m, 4H), 7.59 (d, 4H, J = 8.1 Hz), 9.56 (s, 1H), 9.71 (s, 1H), 10. 07 (s, 1H), 10.26 (s, 1H). 13C NMR (75 MHz, DMSOd6) 31.14, 31.29, 31.43, 97.93, 100.04, 106.20, 118.51, 118.75, 122.51, 122.88, 128.17, 128.23, 138.45, 138.80,

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102 149.97, 151.69, 154.53, 169.20, 169.82, 174.16. HRMS (ESI, (M+H)+) calcd for C24H20N2O6: 433.1394; found: 433.1410. O OH O H N O O O 2-(4-Hydroxy-2,6-dioxo-2,3,5,6-tetrahydrobenzofuro[6,5-b]furan-8-yl)-N phenylacetamide (3-3b) A solution of N -phenyl-2-(2,4,6-trihydroxy-3,5-di-phenylcarbamoylmethylphenyl)-acetamide55 (0.41 g, 0.78 mmol), TFA (0.80 mL, 9.4 mmol) and toluene (20 mL) was heated at 90 oC for 3 h under a blanket of argon. Afte r cooling the reaction mixture to room temperature, the solvent was removed by filt ration and the solid was washed with water to afford 3-3b (0.17 g, 67%) as a off-white solid: m.p. 266 268 C. 1H NMR (300 MHz, DMSOd6) 3.65 (s, 2H), 3.82 (s, 4H), 7.04 (t, 1H, J = 7.2 Hz), 7.30 (t, 2H, J = 8.4 Hz), 7.58 (d, 2H, J = 7.8 Hz), 10.16 (s, 1H), 10.24 (s, 1H). 13C NMR (75 MHz, DMSOd6) 31.91, 32.03, 95.71, 105.74, 119.74, 123.88, 129.41, 139.83, 148.48, 153.47, 167.94, 174.84. HRMS (ESI, (M+H)+) calcd for C18H13NO6: 340.0821; found: 340.0802.

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103 OH OH HO H N O O O O O Isopropyl 2,2'-(2,4,6-trihydroxy-5-(2-oxo-2-(phenylamino)ethyl)-1,3-phenylene) diacetate (3-4a). A stirring solution of 3-1a (0.37 g, 1.0 mmol) in CH3CN (10 mL) was treated with aniline (0.10 mL, 1.0 mmol) and heated to reflux for 12 h. The solution was then concentrated to a crude oil and purified via column chromatogr aphy (hexanes/EtOAc = 2/1) to afford 3-4a (0.38 g, 84%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 1.28 (d, 12H), 3.77 (s, 4H), 3.81 (s, 2H), 5.01 (m, 2H, J = 6.3 Hz), 7.15 (m, 1H), 7.32 (m, 2H), 7.50 (m, 2H), 8.66 (s, 1H), 9.10 (s, 2H). Isopropyl 2,2'-(5-(2-(4-dodecylpheny lamino)-2-oxoethyl)-2,4,6-trihydroxy-1,3phenylene)diacetate (3-4b). The compound was synthesized from 3-1a (0.17 g, 0.46 mmol) and 4-dodecylaniline (0.12 g, 0.46 mmol) according to the same procedure used for 3-4a to afford 34b (0.21 mg, 73%) as a yellow oil. 1H NMR (300 MHz, CDCl3) 0.88 (t, 3H, J = 6.6 Hz), 1.26 (m, 30H), 1.55 (m, 2H), 2.54 (t, 2H, J = 7.5 Hz), 3.73 (s, 2H), 3.75 (s, 4H), 5.02 (m, 2H, J = 6.0 Hz), 7.08 (d, 2H, J = 8.7 Hz), 7.35 (d, 2H, J = 8.7 Hz), 8.58 (s, 1H), 9.13 (s, 2H). 13C NMR (75 MHz, CDCl3) 14.07, 21.61, 22.65, 29.17, 29.31, 29.62, 29.45, 29.55, 29.59, 30.53, 31.42,

PAGE 104

104 31.88, 33.62, 35.32, 69.93, 102.79, 103.61, 120.44, 128.78, 134.63, 139.81, 153.85, 153.88, 172.54, 175.67. HRMS (ESI, (M+Na)+) calcd for C36H53NO8: 650.3663; found: 650.3649. OH OH HO H N O O O O O Isopropyl 2,2'-(2,4,6-trihydroxy-5-(2-oxo-2-(pyren-1-ylmethylamino)ethyl)-1,3phenylene)diacetate (3-4c). A stirring solution of 3-1a (0.55 g, 1.5 mmol) in CH3CN (10 mL) was added with DMAP (238 mg, 1.95 mmol ), and 1-pyrenmethylamine hydrochloride (0.40 g, 1.5 mmol) and heated to 60 C for 12 h. The solution was concentrated to a crude oil and the remaining crude product was dissolved in CH2Cl2. The resulting solution was washed with 1N HCl, water, and brine. The organic layer was further dried over Na2SO4 and the solvent was removed on a rotary evaporator. The crude pr oduct was purified by column chromatography (CH2Cl2/MeOH = 100/1) to afford 3-4c (0.66 g, 70%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 1.27 (d, 12H, J = 6.6 Hz), 3.67 (s, 2H), 3.75 (s, 4H), 4.98 (m, 2H), 5.07 (d, 2H, J = 5.4 Hz), 6.48 (t, 1H, J = 5.4 Hz), 8.08 (m, 9H), 8.61 (s, 1H), 9.27 (s, 2H). 13C NMR (75 MHz, CDCl3) 21.62, 30.54, 32.51, 42.37, 69.91, 102.75, 103.74, 109.61, 122.44, 124.74, 125.39, 125.44, 126.10, 127.03, 127.27, 127.62, 128.29, 128.94, 129.91, 130.66, 131.18, 131.33, 153.86, 154.01, 174.05, 175.66. HRMS (ESI, (M+Na)+) calcd for C35H35NO8: 620.2260; found: 620.2243.

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105 Isopropyl 2,2'-(2,4,6-trihydroxy-5-(2-oxo-2-(pyren-4-ylami no)ethyl)-1,3-phenylene)diacetate (3-4d). A stirring solution of 3-1a (0.42 g, 1.2 mmol) in DMF (10 mL) was added with 1-pyrenamine (0.25 g, 1.2 mmol) and heated to 120 C for 2 days. The solution was concentrated to a crude oil and the remaining crude product was dissolved in CH2Cl2. The resulting solution was washed with 1N HCl, water, and brine. The organic layer was further dried over Na2SO4 and the solvent was removed on a rotary evaporator. The crude product was purified by column chromatography (CH2Cl2/MeOH = 100/3) to afford 3-4d (0.35 g, 52%) as a yellow solid: 1H NMR (300 MHz, DMSOd6) 1.20 (d, 12H, J = 6.6 Hz), 3.62 (s, 2H), 4.00 (s, 4H), 4.91 (m, 2H, J = 5.4 Hz), 8.13 (m, 9H), 9.09 (s, 1H), 9.55 (s, 1H), 10.47 (s, 2H). 13C NMR (75 MHz, DMSOd6) 21.23, 31.79, 66.40, 76.31, 84.20, 102.93, 121.67, 122.77, 123.31, 123.80, 124.43, 124.76, 125.89, 126.73, 127.86, 129.91, 130.29, 130.92, 153.15, 153.27, 170.84, 171.94. HRMS (ESI, (M+Na)+) calcd for C34H33NO8: 606.2098; found: 606.2090. N N H O O O O O O O O Mono-phenylamine-di-isopropyl ester 1-aza-adamantanetriones (3-5a). A solution of 3-4a (0.38 g, 0.83 mmol), HMTA (234 mg, 1.66 mmol) and isopropanol (10 mL) was heated to

PAGE 106

106 reflux overnight under a blanke t of argon. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo a nd the residue was dissolved in ethyl acetate. The organic layer was washed with 1N HCl and br ine. The solution was then concentrated to a crude oil and purified via column chromat ography (hexanes/EtOAc = 1/1) to afford 3-5a (0.21 g, 42%) as a white solid: m.p. 180 182 C. 1H NMR (300 MHz, DMSOd6) 1.17 (d, 12H, J = 6.6 Hz), 2.62 (s, 4H), 2.75 (s, 2H), 3.70 (s, 4H), 3.88 (s, 4H), 4.81 (m, 2H), 7.01 (m, 1H), 7.26 (m, 2H), 7.56 (m, 2H), 10.00 (s, 1H). 13C NMR (75 MHz, DMSOd6) 21.34, 31.79, 33.64, 63.68, 63.84, 67.25, 69.86, 70.02, 70.80, 118.76, 122,81, 128.59, 139.36, 167.32, 168.47, 197.74, 197.92. HRMS (ESI, (M+Na)+) calcd for C27H32N2O8: 535.2051; found: 535.2047. Anal. calcd for C27H32N2O8: C, 63.27; H, 6.29; N, 5.47. Found: C, 63.24; H, 6.30; N, 5.37. N N H O O O O O O O O C12H25 Mono-(4-dodecyl-phenylamine)-di-isopropyl ester 1-aza-adamantanetriones (3-5b). This compound was synthesized from 3-4b (0.34 g, 0.54 mmol) and HMTA (229 mg, 1.62 mmol) according to the same procedure used for 3-5a to afford 3-5b (0.18 g, 49%) as an offwhite solid: m.p. 133 135 C. 1H NMR (300 MHz, CDCl3) 0.88 (t, 3H, J = 7.2 Hz), 1.23 (m, 30H), 1.56 (m, 2H), 2.53 (t, 2H, J = 7.2 Hz), 2.73 (s, 4H), 2.89 (s 2H), 3.76 (m, 6H), 4.98 ( m, 2H), 7.10 (d, 2H, J = 7.8 Hz), 7.38 (d, 2H, J = 7.8 Hz), 7.93 (s, 1H). 13C NMR (75 MHz, CDCl3) 14.34, 21.87, 22.91, 29.47, 29.58, 29.74, 29.86, 29.90, 31.78, 32.14, 32.43, 34.92, 35.60, 68.70,

PAGE 107

107 70.51, 70.63, 70.74, 71.12, 120.20, 129.00, 135.55, 139.37, 167.59, 169.30, 197.24, 198.20. HRMS (ESI, (M+Na)+) calcd for C39H56N2O8: 703.3929; found: 703.3937. Mono-1-pyrenmethylamine-di-isopropyl ester 1-aza-adamantanetriones (3-5c). A solution of 3-4c (0.56 g, 0.89 mmol), HMTA (374 mg, 2.66 mmol), and isopropanol (10 mL) was heated to reflux for 36 h under a blanket of argon. After cooling the reaction mixture to room temperature, the solvent was removed in vacuo and the residue wa s dissolved in ethyl acetate. The organic layer was washed with 1N HCl and brine. The solution was then concentrated to a crude oil a nd purified via column chromatography (CH2Cl2/MeOH = 100/2) to afford 3-5c (0.29 g, 45%) as an off-white solid: m.p. 197 199 C. 1H NMR (300 MHz, DMSOd6) 1.55 (d, 12H, J = 6.6 Hz), 2.64 (s, 6H), 3.72 (s, 4H), 3.92 (s, 2H), 4.81 (m, 2H), 4.99 (d, 2H, J = 5.4 Hz). 13C NMR (75 MHz, DMSOd6) 20.84, 31.31, 66.71, 69.33, 69.53, 70.13, 122.83, 124.13, 124.56, 124.64, 125.69, 126.03, 126.42, 126.86, 126.93, 129.50, 129.79, 130.27, 132.47, 168.03, 168.06, 197.19, 197.35. HRMS (ESI, (M+Na)+) calcd for C38H38N2O8: 673.2520; found: 673.2537.

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108 Isopropyl 2-(2,4,6-trihydroxy-3,5-bis(2-oxo-2 -(phenylamino)ethyl)phenyl)acetate (36a). A stirring solution of 3-1b (380 g, 1.24 mmol) in DMF (10 mL ) was treated with aniline (220 mg, 2.36 mmol) and heated to 120 C for 12 h. The solution was then concentrated to a crude oil and purified via column chromatogr aphy (hexanes/EtOAc = 1/1) to afford 3-6a (0.41 g, 68%) as an off-white solid: m.p. 151 153 C. 1H NMR (300 MHz, DMSOd6) 1.19 (d, 6H, J = 6.3 Hz), 3.53 (s, 2H), 3.69 (s, 4H), 4.88 (m, 1H, J = 6.3 Hz), 7.05 (t, 2H, J = 8.1 Hz), 7.60 (d, 4H, J = 8.1 Hz), 8.92 (s, 2H), 9.22 (s, 1H), 10.18 (s, 2H). 13C NMR (75 MHz, DMSOd6) 22.54, 30.60, 33.26, 67.66, 120.17, 124.28, 139.60, 140.05, 140.31, 154.15, 172.07, 172.45. HRMS (ESI, (M+H)+) calcd for C30H31N3O7: 493.1969; found: 493.1953. OH OH HO H N O HN O O O C12H25 C12H25 Isopropyl 2-(3,5-bis(2-(4-dodecylphenyla mino)-2-oxoethyl)-2,4,6-trihydroxyphenyl)acetate (3-6b). This compound was synthesized from 3-1b (0.50 g, 1.7 mmol) and 4-dodecylaniline (0.30 g, 3.3 mmol) according to the same procedure used for 3-6a to afford 3-6b (0.33 g, 44%) as a yellow solid. 1H NMR (300 MHz, DMSOd6) 0.85 (t, 6H, J = 6.0 Hz), 1.20 (m, 48

PAGE 109

109 H), 1.52 (m, 4H), 3.52 (s, 2H), 3.67 (s, 4H), 4.87 (m, 1H, J = 6.3 Hz), 7.10 (d, 4H, J = 7.8 Hz), 7.47 (d, 4H, J = 7.8 Hz), 9.01 (s, 2H), 9.37 (s, 1H), 10.13 (s, 2H). 13C NMR (75 MHz, DMSOd6) 13.95, 21.71, 22.10, 28.57, 28.70, 28.85, 29.00, 30.97, 31.28, 32.41, 34.53, 66.81, 103.19, 119.46, 128.39, 136.32, 137.52, 153.15, 171.27, 171.56. HRMS (ESI, (M+H)+) calcd for C54H79N3O7: 829.5725; found: 829.5737. OH OH HO H N O HN O O O Isopropyl 2-(2,4,6-trihydroxy3-(2-oxo-2-(pyren-1-ylmethylamino)ethyl)-5-(2-oxo-2(pyren-2-ylmethylamino)ethyl)phenyl)acetate (3-6c). A stirring solution of 3-1b (0.31 g, 1.0 mmol) in CH3CN (10 mL) was treated with 1-pyrenmethylamine hydrochloride (0.54 g, 2.0 mmol) and DMAP (0.32 g, 2.6 mmol) then heated to reflux for 12 h. The solution was then concentrated to a crude oil and purified via co lumn chromatography (CH2Cl2/MeOH = 100/1) to afford 3-6c (0.56 mg, 73%) as a yellow solid. 1H NMR (300 MHz, DMSOd6) 1.17 (d, 6H, J = 6.3 Hz), 3.50 (s, 2H), 3.60 (s, 4H), 4.87 (m, 1H), 5.02 (d, 4H, J = 5.4 Hz), 8.15 (m, 18H), 9.02 (s, 1H), 9.53 (s, 2H), 10.14 (s, 1H). HRMS (ESI, (M+H)+) calcd for C49H40N2O7: 791.2728; found: 791.2704.

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110 Isopropyl 2-(3-(2-dihydropyren-4-ylamino )-2-oxoethyl)-2,4,6-tr ihydroxy-5-(2-oxo-2(pyren-4-ylamino)ethyl)phenyl)acetate (3-6d). This compound was synthesized from 3-1b (0.31 g, 1.0 mmol) and 1-pyrenamine (0.43 g, 2.0 mmol) according to the same procedure used for 3-6a to afford 3-6d (0.38 g, 51%) as an off-white solid. 1H NMR (300 MHz, DMSOd6) 1.17 (d, 6H, J = 6.3 Hz), 3.62 (s, 2H), 4.00(s, 4H), 4.91 (m, 1H), 8.15 (m, 18H), 9.09 (s, 2H), 9.55 (s, 1H), 10.46 (s, 2H). 13C NMR (75 MHz, DMSOd6) 13.51, 20.18, 21.16, 29.36, 31.75, 59.17, 66.33, 102.93, 103.30, 121.56, 122.66, 123.27, 123.75, 124.35, 124.69, 125.80, 126.10, 126.65, 127.83, 129.85, 130.24, 130.85, 153.08, 153.24, 170.77, 171.90. HRMS (ESI, (M+Na)+) calcd for C47H38N2O7: 763.2415; found: 763.2390. Di-phenylamine-mono-isopropyl est er 1-aza-adamantanetrione (3-7a). A solution of 36a (0.41 g, 0.80 mmol), HMTA (0.22 g, 1.6 mmol) and isopropanol (5 mL) was heated to reflux overnight under a blanket of ar gon. After cooling the reaction mixt ure to room temperature, the solvent was removed in vacuo and the residue was dissolved in et hyl acetate. The organic layer

PAGE 111

111 was washed with 1N HCl and brine. The soluti on was then concentrated to a crude oil and purified via column chromatography (CH2Cl2/MeOH = 20/1) to afford 3-7a (0.21 g, 47%) as a white solid: m.p. 240 241 C. 1H NMR (300 MHz, DMSOd6) 1.13 (d, 6H, J = 6.0 Hz), 2.63 (s, 2H), 2.77 (s, 4H), 3.73 (s, 2H), 3.90 (s, 4H), 4.80 (m, 1H, J = 6.6 Hz), 7.00 (t, 2H, J = 7.2 Hz), 7.26 (t, 4H, J = 7.8 Hz), 7.53 (d, 4H, J = 7.5 Hz), 10.01 (s, 2H). 13C NMR (75 MHz, DMSOd6) 11.75, 22.05, 34.40, 67.98, 70.64, 70.79, 71.26, 119.47, 123.53, 129.31, 140.05, 168.12, 169.29, 198.72, 198.96. HRMS (ESI, (M+H)+) calcd for C30H31N3O7: 546.2235; found: 546.2271. Di-(4-dodecyl-phenylamine)-mono-isopropyl ester 1-aza-adamantanetrione (3-7b). This compound was synthesized from 3-6b (510 mg, 0.615 mmol) and HMTA (172 mg, 1.23 mmol) according to the same procedure used for 3-7a to afford 3-7b (0.21 g, 38%) as an offwhite solid: m.p. 194 195 C. 1H NMR (300 MHz, DMSOd6) 0.85 (t, 6H, J = 6.3 Hz), 1.13 (d, 6H, J = 6.3 Hz), 1.22 (m, 36H), 1.51 (m, 4H), 2.46 (t, 4H, J = 6.6 Hz), 2.62 (s, 2H), 2.74 (s, 4H), 3.72 (s, 2H), 3.89 (s, 4H), 4.81 (m, 1H), 7.05 (d, 4H, J = 7.8 Hz), 7.42 (d, 4H, J = 8.4 Hz), 9.90 (s, 2H). 13C NMR (75 MHz, DMSOd6) 13.95, 21.36, 22.10, 28.56, 28.71, 28.87, 29.02, 31.04, 31.29, 31.88, 34.52, 67.26, 70.04, 70.11, 70.54, 118.83, 128.23, 136.68, 137.11, 167.14,

PAGE 112

112 168.55, 197.70, 197.92. HRMS (ESI, (M+H)+) calcd for C54H79N3O7: 882.5991; found: 882.5976. Di-1-pyrenmethylamine-mono-isopropyl ester 1-aza-adamantanetrione (3-7c). A solution of 3-6c (0.12 g, 0.16 mmol), HMTA (66 mg, 0.47 mmol) and isopropanol (10 mL) was heated to reflux 2 days under a blanket of argon. After cooling the react ion mixture to room temperature, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N HCl and br ine. The solution was then concentrated to a crude oil and purified via column chromatography (CH2Cl2/MeOH = 20/1) to afford 3-7c (65 mg, 46%) as an off-white solid: m.p. 218 220 C. 1H NMR (300 MHz, DMSOd6) 1.15 (d, 6H, J = 6.0 Hz), 2.66 (s, 2H), 2.68 (s, 4H), 3.75 (s, 2H), 3.93 (s, 4H), 4.82 (m, 1H), 5.00 (d, 4H, J = 6.0 Hz), 8.21 (m, 18 H), 8.66 (t, 2H, J = 5.4 Hz). 13C NMR (75 MHz, DMSOd6) 22.10, 33.29, 70.62, 70.80, 71.16, 124.00, 124.62, 124.68, 125.37, 125.78, 125.85, 126.89, 127.16, 127.62, 128.07, 128.16, 128.70, 130.69, 131.01, 131.48, 133.70, 169.39, 169.49, 198.68, 198.93. HRMS (MMI(APCI) TOF, (M+Na)+) calcd for C52H43N3O7: 844.2993; found: 844.3042.

PAGE 113

113 N N H O O HN O O O O O Di-1-pyrenamine-mono-isopropyl est er 1-aza-adamantanetrione (3-7d). This compound was synthesized from 3-6d (0.33 g, 0.45 mmol) and HM TA (190 mg, 1.35 mmol) according to the same procedure used for 3-7c to afford 3-7d (0.22 g, 62%) as an off-white solid: m.p. 246 248 C. 1H NMR (300 MHz, DMSOd6) 1.18 (d, 6H, J = 6.0 Hz), 2.72 (s, 2H), 3.09 (m, 4H), 3.82 (s, 2H), 4.09 (m, 4H), 4.85 (m, 1H), 8.19 (m, 18H), 10.44 (s, 2H). 13C NMR (75 MHz, DMSOd6) 14.78, 21.46, 22.13, 32.69, 34.16, 60.45, 68.00, 70.81, 71.29, 123.32, 123.97, 124.58, 125.06, 125.43, 125.53, 125.78, 126.98, 127.14, 127.57, 127.93, 128.77, 131.16, 131.52, 132.73, 169.42, 169.49, 198.77, 199.22. HRMS (MMI(APCI) TOF, (M+Na)+) calcd for C50H38N3O7: 816.2680; found: 816.2728. 2,2'-(2,4,6-Trihydroxy-5-(2-(naphthalen-2-ylamino)-2-oxoethyl)-1,3-phenylene)bis(N phenylacetamide) (3-8a) A stirring solution of 3-3a (86 mg, 0.20 mmol) in DMF (5 mL) was treated with -naphthylamine (34 mg, 0.24 mmol) and heated to 120 C for 12 hours. The

PAGE 114

114 solvent was removed in vacuo and the residue was dissolved in et hyl acetate. The organic layer was washed with 10% HCl and water. The co mbined organic layers were dried with Na2SO4. The solvent was removed on a rotary evaporator and the crude product was purified by column chromatography (hexane/EtOAc 1:1) to afford a yellow solid (80 mg, 70%). 1H NMR (300 MHz, DMSOd6) 3.73 (s, 4H), 3.78 (s, 2H), 7.05 (t, 2H, J = 7.5 Hz), 7.30 (t, 4H, J = 7.5 Hz), 7.43 (m, 2H), 7.62 (m, 5H), 7.85 (m, 3H), 8.28 (s, 1H), 9.31 (s, 2H), 9.32 (s, 1H), 10.19 (s, 2H), 10.37 (s, 1H). 13C NMR (75 MHz, DMSOd6) 13.58, 20.26, 31.86, 59.25, 102.94, 105.26, 115.01, 117.88, 118.85, 119.55, 120.32, 122.91, 124.5, 125.33, 125.8, 125.9, 126.82, 126.95, 127.84, 127.96, 128.23, 129.29, 132.87, 134.49, 136.02, 138.41, 146.14, 153.15, 171.09, 171.26. HRMS (ESI, (M+Na)+) calcd for C34H29N3O6: 598.1949; found: 598.1944. OH H N O OH HN O HO H N O C6H13 2,2'-(5-(2-(Hexylamino)-2-oxoethyl)2,4,6-trihydroxy-1,3-phenylene)bis(Nphenylacetamide) (3-8b) A stirring solution of 3-3a (90 mg, 0.21 mmol) in DMF (5 mL) was treated with n-hexylamine (0.030 mL, 0.25 mmol) and stirre d at room temperature for 3 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (10 mL). The organic layer was washed with 10% HCl and wate r. The combined organic layers were dried with Na2SO4. The solvent was removed on a rotary evaporator and the crude product was purified by column chromatography (hexane/EtOAc 3:2) to afford 3-8b as an off-white solid (89 mg, 80%). 1H NMR (300 MHz, DMSOd6) 0.84 (t, 3H, J = 7.2 Hz), 1.30 (m, 8H), 3.05 (m,

PAGE 115

115 2H), 3.50 (s, 2H), 3.69 (s, 4H), 7.05 (t, 2H, J = 7.2 Hz), 7.29 (t, 4H, J = 7.5 Hz), 7.59 (d, 4H, J = 8.4 Hz), 8.46 (br, 1H), 9.36 (s, 1H), 9.94 (s, 2H), 10.17 (s, 2H). 13C NMR (75 MHz, DMSOd6) 13.39, 21.51, 25.53, 28.11, 30.39, 31.72, 102.26, 102.90, 118.82, 122.85, 128.19, 138.46, 153.11, 153.30, 171.05, 173.17. HRMS (ESI, (M+H)+) calcd for C30H35N3O6: 534.2599; found: 534.2597. Mono--naphthylamine-di-phenylamine 1aza-adamantanetrione (3-9a). A solution of 3-8a (90 mg, 0.16 mmol), HMTA (66 mg, 0.48 mmol) and isopropanol (5 mL) was heated to reflux 2 days under a blanket of argon. After cool ing the reaction mixture to room temperature, the mixture was filtered to afford an off-white solid. The solid was washed with 5% HCl and water to afford 3-9a (41 mg, 43%) as an off-white solid. 1H NMR (300 MHz, DMSOd6) 2.79 (s, 4H), 2.85 (s, 2H), 3.95 (s, 6H), 6.99 (t, 2H, J = 7.5 Hz), 7.26 (t, 4H, J = 7.8 Hz), 7.45 (m, 8H), 7.81 (m, 3H), 8.27 (s, 1H), 10.01 (s, 2H), 10.23 (s, 1H). 13C NMR (75 MHz, DMSO) 33.21, 69.71, 69.88, 114.19, 118.35, 119.28, 122.33, 123.85, 125.81, 126.69, 126.88, 127.72, 128.08, 129.03, 132.95, 136.36, 138.80, 167.03, 167.28, 197.79. HRMS (ESI, (M+Na)+) calcd for C37H32N4O6: 651.2214; found: 651.2208.

PAGE 116

116 Mono-hexylamine-di-phenylamine 1-aza-adamantanetrione (3-9b) This compound was synthesized from 3-8b (53 mg, 0.10 mmol) and HMTA (28 mg, 0.20 mmol) according to the same procedure used for 3-5a to afford 3-9b (32 mg, 48%) as a white solid. 1H NMR (300 MHz, pyridined5) 0.79 (t, 3H, J = 6.6 Hz), 1.13 (m, 6H), 1.53 (m, 2H, J = 7.2 Hz), 3.14 (s, 2H), 3.28 (s, 4H), 3.39 (m, 2H, J = 6.0 Hz), 4.27 (s, 4H), 4.34 (s, 2H), 7.08 (t, 2H, J = 7.5 Hz), 7.32 (t, 4H, J = 7.8 Hz), 7.95 (d, 2H, J = 7.8 Hz), 8.45 (t, 1H, J = 7.2 Hz), 10.96 (s, 2H). 13C NMR (75 MHz, pyridined5) 14.50, 23.15, 27.31, 30.30, 32.05, 34.27, 35.26, 40.19, 71.36, 71.53, 71.62, 120.49, 129.47, 140.85, 169.19, 169.99, 199.66, 199.69. HRMS (ESI, (M+Na)+) calcd for C33H38N4O6: 609.2684; found: 609.2718. 2,2'-(2,4,6-Trihydroxy-5-(2-(naphthalen-2-ylamino)-2-oxoethyl)-1,3-phenylene)bis(N (4-dodecylphenyl)acetamide) (3-10b). This compound was synthesized from 2-10 (90 mg, 0.23 mmol) and p-dodecylaniline (0.29 g, 0.93 mmol) according to the same procedure used for 2-11 to afford 3-10b (76 mg, 36%) as a yellow solid. 1H NMR (300 MHz, DMSOd6) 0.84 (t, 6H, J

PAGE 117

117 = 7.2 Hz), 1.20 (m, 36H), 1.51 (m, 4H), 2.50 (m, 4H), 3.71 (s, 4H), 3.77 (s, 2H), 7.09 (d, 4H, J = 8.7 Hz), 7.48 (m, 6H), 7.62 (m, 1H), 7.83 (m, 3H), 8.29 (s, 1H), 9.40 (s, 2H), 9.48 (s, 1H), 10.14 (2H), 10.38 (s, 1H). 13C NMR (75 MHz, DMSOd6) 14.66, 22.79, 29.28, 29.41, 29.55, 29.69, 31.69, 31.98, 33.01, 35.23, 104.10, 104.20, 116.18, 120.17, 120.74, 127.09, 128.02, 128.13, 129.03, 129.12, 130.47, 134.07, 137.16, 137.24, 138.17, 154.37, 172.24, 172.45. HRMS (ESI, (M+Na)+) calcd for C58H77N3O6: 912.5885; found: 912.5852. Mono--naphthylamine-di-p -dodecylphenylamine 1-aza-adamantantrione (3-11b). This compound was synthesized from 3-10b (0.08 g, 0.08 mmol) and HMTA (34 mg, 0.24 mmol) according to the same procedure used for 3-8a to afford 3-11b (38 mg, 49%) as a white solid. 1H NMR (300 MHz, pyridined5) 0.88 (t, 6H, J = 7.2 Hz), 1.27 (m, 34H), 1.61 (m, 4H), 2.57 (t, 4H, J = 7.2 Hz), 3.32 (s, 4H), 3.36 (s, 2H), 4.32 (s, 6H), 7.43 (m, 3H), 7.82 (m, 4H), 7.93 (m, 4H), 8.68 (m, 4H), 10.87 (s, 2H), 11.11 (s, 1H). 13C NMR (75 MHz, pyridined5) 14.65, 23.30, 29.87, 29.97, 30.18, 30.26, 30.32, 32.35, 32.47, 35.22, 35.92, 71.43, 71.69, 116.90, 120.59, 121.12, 123.16, 127.08, 128.23, 128.36, 129.13, 129.40, 131.08, 138.42, 138.55, 168.95, 169.26, 198.44, 199.74. HRMS (ESI, (M+Na)+) calcd for C61H80N4O6: 987.5976; found: 987.6036.

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118 2-(4-Hydroxy-2,6-dioxo-2,3,5,6-tetrahydrobenzofuro[6,5-b]furan-8-yl)-N (naphthalen-2-yl)acetamide (2-10). A solution of 2-9b (0.2 g, 0.3 mmol), TFA (0.6 mL, 8 mmol) and toluene (10 mL) was heated at 80 C for 2 h under a blanket of argon. After cooling the reaction mixture to room temperatur e, the solvent was removed by filtration and the resulting solid was washed with water to afford 2-10 (0.10 mg, 86%) as a peach-colored solid. 1H NMR (300 MHz, DMSOd6) 3.72 (s, 2H), 3.83 (s, 4H), 7.43 (m, 2H), 7.59 (m, 1H), 7.82 (m, 3H), 8.28 (s, 1H), 10.25 (s, 1H), 10.38 (s, 1H). 13C NMR (75 MHz, DMSOd6) 30.77, 94.43, 104.50, 114.63, 119.34, 123.99, 125.82, 126.68, 126.86, 127.78, 129.17, 132.84, 136.13, 147.26, 152.26, 166.97, 173.56. HRMS (ESI, (M+Na)+) calcd for C22H15NO6: 412.0792; found: 412.0788. 2-(4,6-Dihydroxy-2-oxo-5-(2-oxo-2-(phenylamino)ethyl)-2,3-dihydr obenzofuran-7-yl)N -(naphthalen-2-yl)acetamide (3-12). A stirring solution of 2-10 (0.15 g, 0.46 mmol) in DMF (10 mL) was treated with aniline ( 0.17 mL, 1.9 mmol) and heated at 70 80 C for 12 h. The

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119 solution was then concentrated to a crude oil and purified via column chromatography (hexanes/EtOAc = 1/1) to afford 3-12 (0.10 g, 65%) as a white solid: 1H NMR (300 MHz, DMSOd6) 3.71 (s, 2H), 3.74 (s, 2H), 3.76 (s, 2H), 7.02 (t, 1H, J = 7.5 Hz), 7.29 (t, 2H, J = 7.8 Hz), 7.43 (m, 2H), 7.62 (m, 3H), 7.83 (m, 3H), 8.28 (s, 1H), 9.56 (s, 1H ), 9.70 (s, 1H), 10.06 (s, 1H), 10.44 (s, 1H). 13C NMR (75 MHz, DMSOd6) 13.54, 20.21, 31.15, 31.26, 59.20, 97.93, 100.06, 102.94, 106.20, 114.93, 118.53, 118.86, 119.46, 122.50, 124.10, 125.86, 126.77, 126.89, 127.82, 128.13, 129.27, 132.84, 136.00, 138.75, 149.96, 151.72, 153.13, 154.52, 169.39, 169.77, 169.82, 174.11. HRMS (ESI, (M+Na)+) calcd for C28H22N2O6: 505.1370; found: 505.1369. N -(4-Dodecylphenyl)-2-(2,4,6-trihydroxy-3-(2-(naphthalen-2-ylamino)-2-oxoethyl)-5(2-oxo-2-(phenylamino)ethyl )phenyl)acetamide (3-13). A stirring solution of 3-12 (60 mg, 0.13 mmol) in DMF (10 mL) was treated with 4dodecylaniline (0.13 g, 0.50 mmol) and heated at 120 C for 12 h. The solution was then concentrated to a crude oil a nd purified via column chromatography (hexanes/EtOAc =3/1) to afford 3-13 (40 mg, 43%) as a brown solid: 1H NMR (300 MHz, DMSOd6) 0.84 (t, 3H, J = 6.6 Hz), 1.22 (m, 18 H), 1.52 (m, 2H), 3.72 (s, 2H), 3.73 (s, 2H), 3.78 (s, 2H), 7.09 (m, 4H), 7.42 (m, 6H), 7.62 (m, 3H), 7.84 (m, 3H), 8.29 (s, 1H), 9.33 (s, 1H), 9.41 (s, 2H), 10.14 (s, 1H), 10.18 (s, 1H), 10.37 (s, 1H). 13C NMR (75 MHz, DMSOd6) 13.43, 21.57, 28.07, 28.18, 28.33, 28.48, 30.46, 30.77, 31.86, 34.03, 38.17, 102.90, 102.98, 115.03, 118.58, 118.87, 118.99, 119.56, 122.89, 124.12, 125.86, 126.80, 126.91, 127.90, 128.01,

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120 128.13, 129.29, 132.86, 135.94, 136.01, 137.00, 138.40, 153.16, 171.06, 171.26. HRMS (ESI, (M+Na)+) calcd for C46H53N3O6: 766.3827; found: 766.3867. O O OH HN O HO O O Isopropyl 2-(4,6-dihydroxy-2-oxo-5-(2-oxo-2-(phenylamino)ethyl)-2,3-dihydrobenzofuran-7-yl)acetate (3-14) A stirring solution of 3-1b (0.41 g, 1.3 mmol) in DMF (10 mL) was treated with aniline ( 0.13 mL, 1.3 mmol) and heated at 80 C overnight. The solution was then concentrated to a crude oil a nd purified via column chromat ography (hexanes/EtOAc =2/1) to afford 3-14 (0.26 g, 49%) as a white solid: 1H NMR (300 MHz, DMSOd6) 1.19 (d, 6H, J = 6.3 Hz), 3.51 (s, 2H), 3.69 (s, 2H), 3.74 (s, 2H), 4.89 (m, 1H, J = 6.3 Hz), 7.03 (t, 1H, J = 7.2 Hz), 7.29 (t, 2H, J = 7.2 Hz), 7.59 (d, 2H, J = 7.8 Hz), 9.30 (s, 1H), 9.56 (s, 1H), 10.11 (s, 1H). 13C NMR (75 MHz, DMSOd6) 21.08, 28.96, 31.17, 66.93, 97.56, 100.02, 106.04, 118.57, 122.61, 128.16, 138.66, 149.87, 151.74, 154.10, 169.65, 170.02, 174.00. HRMS (ESI, (M+Na)+) calcd for C21H21NO7: 422.1210; found: 422.1212.

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121 Isopropyl 2-(3-(2-(hexylamino)-2-o xoethyl)-2,4,6-trihyd roxy-5-(2-oxo-2(phenylamino)ethyl)phenyl)acetate (3-15a) A solution of 3-14 (0.10 g, 0.25 mmol) in DMF (5 mL) was treated with hexylamine (0.04 mL, 0.3 mmol) and stirred at room temperature for 1.5 h. The solution was then concentrated to a cr ude oil and purified via column chromatography (hexanes/EtOAc =2/1) to afford 3-15 (0.11 g, 88%) as a white solid: m.p. 64 65 C. 1H NMR (300 MHz, CDCl3) 0.85 (t, 3H, J = 7.2 Hz), 1.26 (m, 12H), 1.45 (m, 2H, J = 6.9 Hz), 3.17 (q, 2H, J = 7.2 Hz), 3.60 (s, 1H), 3.76 (s, 2H), 3.77 (s, 2H), 5.02 (m, 1H, J = 6.3 Hz), 6.25 (t, 1H, J = 5.4 Hz), 7.12 (m, 1H), 7.26 (m, 2H), 7.46 (m, 2H), 8.13 (s, 1H), 9.21 (s, 1H), 9.49 (s, 1H), 9.73 (s, 1H). 13C NMR (75 MHz, DMSOd6) 13.45, 21.19, 22.01, 25.99, 28.68, 30.10, 30.88, 32.09, 33.29, 39.66, 69.57, 102.06, 102.73, 103.17, 120.04, 124.52, 128.47, 136.72, 153.32, 153.39, 153.65, 172.42, 174.04, 175.59. HRMS (ESI, (M+H)+) calcd for C27H36N2O7: 501.2595; found: 501.2634. OH OH HO H N O HN O O O ( S )-Isopropyl 2-(2,4,6-trihydroxy-3-(2-oxo-2-(1-phenylethylamino) ethyl)-5-(2-oxo-2(phenylamino)ethyl)phenyl)acetate (3-15b). This compound was synthesized from 3-14 (0.2 g,

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122 0.5 mmol) and L-(-)--methylbenzylamine (0.08 mL, 0.6 mmol) according to the same procedure used for 3-15a to afford 3-15b (0.24 g, 92%) as a yellow solid: [ ]24 D = 20.3 (c 0.52, CHCl3). 1H NMR (300 MHz, CDCl3) 1.29 (m, 6H), 1.49 (d, 3H, J = 6.6 Hz), 3.65 (m, 2H), 3.77 (d, 4H, J = 4.2 Hz), 5.04 (m, 1H), 6.35 (d, 1H, J = 7.2 Hz), 7.16 (m, 1H), 7.28 (m, 6H), 7.50 (d, 1H, J = 8.4 Hz), 7.92(s, 1H), 9.20 (s, 1H ), 9.41 (s, 1H), 9.90 (s, 1H). 13C NMR (75 MHz, CDCl3) 21.63, 21.77, 30.53, 32.56, 33.70, 49.53, 70.07, 102.51, 103.21, 103.49, 120.42, 124.96, 125.98, 127.51, 128.74, 128.92, 137.13, 142.30, 153.75, 153.83, 154.02, 172.84, 173.72, 176.10. HRMS (MMI(APCI) TOF, (M+H)+) calcd for C29H32N2O7: 521.2282; found: 521.2306. Mono-phenylamine-mono-hexylamine-mono-iso propyl ester 1-aza-adamantanetrione (3-16). A solution of 3-15a (50 mg, 0.10 mmol), HMTA (28 m g, 0.20 mmol) and isopropanol (5 mL) was heated to reflux overnight under a blanke t of argon. After coolin g the reaction mixture to room temperature, the solvent was removed on a rotary evaporator and the residue was purified by column chromatography (ethyl acetate/triethylamine = 100/1) to afford 3-16 (16 mg, 42%) as a yellow solid. 1H NMR (300 MHz, CDCl3) 0.86 (t, 3H, J = 6.9 Hz), 1.26 (m, 18H), 2.69 (s, 2H), 2.74 (s, 2H), 2.89 (s, 2H), 3.20 (q, 2H, J = 6.6 Hz), 3.72 (s, 2H), 3.82 (q, 3H, J = 13.5 Hz), 4.97 (p, 1H, J = 6.3 Hz), 5.95 (t, 1H, J = 6.6 Hz), 7.09 (t, 1H, J = 7.5 Hz), 7.30 (t, 2H, J = 7.2 Hz), 7.49 (d, 2H, J = 7.8 Hz), 7.98 (s, 1H). 13C NMR (75 MHz, CDCl3) 14.00, 21.66, 22.54, 26.55, 29.39, 31.42, 32.25, 33.62, 34.86, 39.73, 68.54, 70.30, 70.44, 70.49, 70.55, 70.81,

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123 119.89, 124.36, 128.92, 137.71, 167.30, 168.83, 169.17, 197.48, 197.82, 198.37. HRMS (ESI, (M+Na)+) calcd for C30H39N3O7: 576.2680; found:576.2639.

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124 CHAPTER 4 EFFORTS TOWARD HYDROPHIL IC AND HYDROGE LATING AATS Introduction of Hydrogels and Their Broad Applications Hydrogels are a class of biom aterials that ha ve broad applications in drug delivery, threedimensional cell cultures, screening biomolecu les, wound healing, and tissue engineering.200-202 Typically hydrogelation is a prope rty of polymeric species of the right molecular composition, however the discovery and design of small or ganic molecules capable of gelling aqueous solvents is a rapidly expanding area of research.95 Such gels are referred to as supramolecular hydrogels, and the small molecules are referre d to as supramolecu lar hydrogelators or molecular hydrogelators.200 Low-molecular weight hydrogela tors offer several advantages over polymeric versions, but most notably they biodegrade more easily si nce they are generally derived from small, biocompatible components that are held together by noncovalent forces.95 Assembly of small organic molecules in aque ous solvents into fibr ous structures poses interesting challenges in the fi eld of self-assembly. To achieve gelation, there must be a balance between the tendency of the molecules to molecularly dissolve or to aggregate.95 Hydrophobic forces become important for assembly in aqueous environments while hydrogen bonding (vide supra), a common driving force for a ggregation, plays a secondary role.95 Generally in hydrogelator design, functional groups are select ed that are both hydrophilic and provide good solubility in water.201 Among these, polyethylene glycol units are commonly used in supramolecular hydrogelator construction.201, 202 Figure 4-1 shows one example of a monomer that forms hydrogels primarily by hydrophobic inte ractions, and secondarily through hydrogen bonding.201 The center of the molecule features a bisurea motif that is well known to form strong hydrogen bonds in low polarity environments, in this case foster ed, upon hydrophobic assembly,

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125 by the nearby alkyl chain segments. The polyeth ylene glycol tails in the outer region are hydrophilic and directly inter act with the solvent. N N N N O O (CH2)m H H H H (CH2)m O O n O O n solubilityhydrophobic hydrogenbonding Figure 4-1. A bisurea based supramol ecular polymer that forms hydrogels.201 The design of new hydrogelators is a rapid expanding area of research especially due to their possible practical applications.95 The AATs are known to self-assemble in and gel organic solvents such as chloroform, DMSO, toluene, and benzene through hydrogen bonding, aromatic interactions, and dipolar interact ions. The introduction of hydrophili c groups (side chains), such as polyethylene glycol units, to the AAT mol ecules should increase their hydrophilic character and possibly allow the formation of the first hydrogels from donor-acceptor molecules. Synthesis of Hydrophilic AATs Discussed in Chapter 3, the lactone methodology allows incorporation of sensitive/labile functional groups into the AAT peri phery at a late synthetic stage. Prior to the developm ent of this methodology, polyethylene glycol units (the most commonl y employed hydrophilic functional groups for hydrogelator design) were incompatible with the otherwise harsh BBr3 demethylation chemistry (Figure 3-1). The lacton e strategy overcomes this limitation and allows for the introduction polyethers into the AAT periphery where they can influence the selfassembly and hydrophilic properties of the molecules. To test this methodology in the context of simple oligoethers, (aminomethoxy)methanol was selected as the peripheral functional group. The more reactive amino functionality should selectively ring open the lactone intermediates discussed in Chapter 3. In itial reactions between

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126 the unprotected aminoalcohol and tripentenolides (s hown in Figure 4-2) led to water soluble but intractable products. Figure 4-2. Initial reaction between the unprotected aminoalcohol and tripentenolides. To help with purification and reduce side reactions, the (aminomethoxy)-methanol was alternatively first protected as its TBS ether (Figure 4-3).203 Compound 4-1 was then used as the nucleophile in reactions with mono-, di-, and trilactones derived from the butenolides and pentenolides. Subsequent cycli zation with HMTA affords interm ediates en route to the first hydrophilic AATs (Figure 4-3). Figure 4-3. The synthesis of protect ed ethylene glycol building block. Reaction of primary amine 4-1 with the butenolides occurs at room temperature in DMF to afford the corresponding substituted phloroglucinol derivatives in moderate yields (Figure 4-4). Subsequent AAT formation occurs using the same conditions as describe d previously, but the purification of the polar syst ems is challenging. Compounds 4-3a and 4-3b were successfully isolated after column chromatogr aphy using pure ethyl acetate; C3-symmetric 4-3c observed by mass spectrometric analysis, could not be purified and isolated in this fashion. One reason is that the species is hard to visualize on silica gel even with UV light or staining (KMnO4, p-

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127 anisaldehyde, cerium molybdate, and phosphomolybdic acid were tried). KMnO4 remains the most successful stain used to date that allo ws visualization at high product concentrations. Figure 4-4. The synthesis of hydrophilic AATs de rived from mono-, di-, and tributenolides. The pentenolides react with 2-(2-(tert -butyldimethylsilyl)ethoxy)ethanamine 4-1 similarly to the butenolides, again at room temperature in DMF, to afford phloroglucinol derivatives 4-4ac Figure 4-5 summarizes the resu lts. Subsequent cyclization of 4-4a-c with HMTA provides the desired AATs in typical yields for this reaction.55, 56, 91 Like 4-3c the purification of 4-5c is difficult. In this case, running the reaction in larger scale allowed TLC detection of the product upon concentration of the fractions during column chromatography.

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128 OH HO 4-1 DMF,r.t. OH OH HO O O N O O O HMTA i -PrOH 3-2a H N 4-4a 4-5a 4-1 DMF,r.t. OH OH HO N H O N O O O O HMTA i -PrOH H N 4-4b 4-5b N H HN 3-2b 4-1 OH OH HO N H N H N O O O HMTA i -PrOH H N 4-4c 4-5c N H HN DMF,r.t. 3-2c R= O OTBS 52% 46% 52% 65% 51% O O O O O O N H O R O O O R O O O O O O O O HO O O O R O R O O R O R O O O O O O O R R O O O R O R O R H N O R 35% Figure 4-5. The synthesis of hydrophilic AATs de rived from mono-, di-, and tripentenolides. We have successfully introduced hydrophilic groups to the periphery of the AAT core, the first step toward creating hydrogelating AATs. The ne xt step will be to de protect the silyl groups of the compounds 4-3a,b and 4-5a-c and test their baseline aqueous assembly properties. The flexibility of the lactone-based synthetic met hodology should allow fine-tuning of the solubility and hydrophilic/hydrophobic character of the molecules for future applications. Experimental Section 2-(2-(Tert-butyldimethylsily loxy)ethoxy)ethanamine (4-1) .203 A stirring solution of 2(2-aminoethoxy)ethanol (2.1 g, 20 mmol) in CH2Cl2 (10 mL) was treated with TBSCl (3.6 g, 24

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129 mmol) and imidazole (2.7 g, 40 mmol) then stir at room temperature overnight. The solution was then diluted with CH2Cl2 and the organic layer was washed with water then dried with anhydrous Na2SO4. The solvent was removed on a rotary evaporator to afford 4-1 (3.8 g, 75%) as a colorless oil: 1H NMR (300 MHz, CDCl3) 0.06 (s, 6H), 0.82 (s, 9H), 2.47 (s, 2H), 2.78 (t, 2H, J = 6.0 Hz), 3.45 (m, 4H), 3.69 (t, 2H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3) 5.74, 17.89, 25.43, 41.31, 62.23, 71.96, 72.64. HRMS (ESI, (M+H)+) calcd for C10H25NO2Si: 220.1727; found: 220.1755. Isopropyl 2,2'-(2,4,6-trihyd roxy-5-(2,2,3,3-tetramethyl-11oxo-4,7-dioxa-10-aza-3-sila dodecan-12-yl)-1,3-phenylene)diacetate (4-2a) A stirring solution of 3-1a (0.20 g, 0.55 mmol) in DMF (10 mL) was treated with 4-1 (0.12 g, 0.55 mmol) and stirre d at room temperature for 2 hours. The solvent was removed on a rotary evapor ator after which the re sidue was dissolved in ethyl acetate. The resulting organic layer was wa shed with 10% HCl and brine then dried with anhydrous Na2SO4. The solution was concentrated to a crude oil and purified via column chromatography (hexanes/EtOAc = 2/1) to afford 4-2a (0.19 g, 59%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.08 (s, 6H), 0.90 (s, 9H ), 1.28 (m, 12H), 3.42 (q, 2H, J = 5.1 Hz), 3.54 (m, 4H), 3.66 (s, 2H), 3.77 (m, 6H), 5.02 (m, 2H), 6.62 (t, 1H, J = 5.1 Hz), 8.54 (s, 1H), 9.36 (s, 2H). 13C NMR (75 MHz, CDCl3) 4.90, 14.53, 18.74, 22.00, 26.28, 30.89, 32.75, 40.17, 60.75,

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130 63.09, 69.67, 70.14, 72.90, 103.02, 104.15, 154.13, 154.41, 174.83, 175.93. HRMS (ESI, (M+H)+) calcd for C28H47NO10Si: 586.3042; found: 586.3126. Isopropyl 2-(2,4,6-trihydroxy-3,5-bis(2,2,3,3tetramethyl-11-oxo-4,7-dioxa-10-aza-3siladodecan-12-yl)phenyl)acetate (4-2b). The compound was synthesized from 3-1b (0.20 g, 0.65 mmol) and 4-1 (0.29 g, 1.3 mmol) according to the same procedure used for 4-2a to afford 4-2b (0.26 g, 53%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.09 (s, 12H), 0.90 (s, 18H), 1.29 (d, 6H, J = 6.3 Hz), 3.43 (m, 4H), 3.56 (m, 8H), 3.61 (s, 4H), 3.77 (m, 6H), 5.01 (m, 1H), 6.63 (t, 2H, J = 5.1 Hz), 9.44 (s, 2H), 10.18 (s, 1H). 13C NMR (75 MHz, CDCl3) 5.28, 18.35, 21.61, 25.90, 30.49, 32.37, 39.78, 62.70, 69.26, 69.79, 72.50, 102.18, 103.35, 153.89, 154.12, 174.56, 175.88. HRMS (ESI, (M+H)+) calcd for C35H64N2O11Si2: 745.4121; found: 745.4210. OH OH HO H N O O OTBS H N O O TBSO HN O O OTBS 2,2',2''-(2,4,6-Trihydroxybenzene -1,3,5-triyl)tris(N-(2-(2-(te rt-butyldimethylsilyloxy)ethoxy)ethyl)acetamide) (4-2c) The compound was synthesized from 3-1c (0.10 g, 0.41 mmol) and 4-1 (0.29 g, 1.3 mmol) according to the same procedure used for 4-2a to afford 4-2c (0.29 g,

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131 78%) as a yellow oil.1H NMR (300 MHz, CDCl3) 0.08 (s, 6H), 0.90 (s, 9H), 3.42 (q, 2H, J = 5.1 Hz), 3.54 (p, 4H, J = 4.8 Hz), 3.61 (s, 2H), 3.77 (t, 2H, J = 5.1 Hz), 6.70 (t, 1H, J = 5.1 Hz), 10.22 (s, 1H). 13C NMR (75 MHz, CDCl3) 5.29, 18.33, 25.88, 32.33, 39.77, 62.67, 69.25, 72.48, 102.94, 153.97, 174.69. HRMS (ESI, (M+H)+) calcd for C42H81N3O12Si3: 904.5206; found: 904.5200. Mono-2-(2-(tert-butyldimeth ylsilyloxy)ethoxy)ethanamine -di-isopropyl ester 1-azaadamantanetrione (4-3a). A solution of 4-2a (0.18 g, 0.31 mmol), HMTA (0.13 g, 0.93 mmol), and isopropanol (5 mL) was heated to reflux fo r 2 days under a blanket of argon. After cooling the reaction mixture to room temp erature, the solvent was remove d in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N HCl and brine. The solution was then concentrated to a crude oil and purified via column chromatography (pure ethyl acetate) to afford 4-2b (78 mg, 35%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.08 (s, 6H), 0.88 (m, 12H), 2.33 (m, 2H), 2.76 (m, 4H), 3.24 (m, 4H), 3.60 (m, 4H), 3.76 (m, 6H), 4.98 (m, 2H), 6.10 (br, 1H). 13C NMR (75 MHz, CDCl3) -5.23, 14.10, 18.39, 21.76, 22.68, 25.92, 29.34, 29.68, 31.91, 33.60, 33.95, 35.37, 39.43, 44.58, 44.73, 57.97, 58.34, 59.43, 62.67, 66.77, 67.95, 68.31, 69.66, 72.48, 170.40, 171.02, 201.79, 202.70.

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132 Mono-isopropyl ester di-2-(2-(tert-butyldimethylsilyloxy)ethoxy)ethanamine 1-azaadamantanetrione (4-3b). A solution of 4-2b (0.13 g, 0.17 mmol), HMTA (72 mg, 0.52 mmol), and isopropanol (5 mL) was heated to reflux ove rnight under a blanket of argon. After cooling the reaction mixture to room temp erature, the solvent was remove d in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N HCl and brine. The solution was then concentrated to a crude oil and purified via column chromatography (pure ethyl acetate) to afford 4-2b (60 mg, 40%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.08 (s, 12H), 0.90 (s, 18H), 1.24 (d, 6H, J = 6.0 Hz), 2.69 (s, 4H), 2.72 (s, 2H), 3.44 (m, 6H), 3.55 (m, 8H), 3.77 (m, 6H), 3.86 (s, 2H), 4.98 (m, 1H), 6.29 (t, 2H, J = 5.4 Hz). 13C NMR (75 MHz, CDCl3) 5.23, 18.38, 21.66, 25.92, 29.67, 32.17, 33.43, 39.38, 45.83, 62.67, 68.34, 69.67, 70.37, 70.63, 72.45, 169.07, 169.21, 197.53, 197.95. HRMS (ESI, (M+Na)+) calcd for C38H67N3O11Si2: 820.4206; found: 820.4227. Isopropyl 3,3'-(2,4,6-trihydroxy-5-(2,2,3,3-tetramethyl-11-oxo-4,7-dioxa-10-aza-3silatridecan-13-yl)-1,3-phenylene)dipropanoate (4-4a) The compound was synthesized from

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133 3-2a (0.14 g, 0.33 mmol) and 4-1 (77 mg, 0.35 mmol) according to the same procedure used for 4-2a to afford 4-4a (0.11 g, 52%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.07 (s, 6H), 0.90 (s, 9H), 1.21 (d, 12H, J = 6.3 Hz), 2.70 (m, 6H), 2.88 (m, 6H), 3.47 (m, 6H), 3.74 (t, 2H, J = 5.1 Hz), 4.98 (p, 5H, J = 6.3 Hz), 6.02 (t, 1H, J = 5.1 Hz), 8.21 (s, 1H), 8.72 (s, 2H). 13C NMR (75 MHz, CDCl3) 5.69, 17.98, 21.26, 25.47, 34.09, 35.04, 39.18, 62.21, 68.47, 68.96, 72.00, 107.98, 108.47, 152.30, 152.57, 174.91, 176.91. OH OH HO N H O O OTBS O O N H O O TBSO Isopropyl 3-(2,4,6-trihydroxy-3,5-bis(2,2,3,3tetramethyl-11-oxo-4,7-dioxa-10-aza-3silatridecan-13-yl)phenyl)propanoate (4-4b) The compound was synthesized from 3-2b (0.10 g, 0.29 mmol) and 4-1 (0.13 g, 0.58 mmol) according to the same procedure used for 4-2a to afford 4-4b (0.15 g, 65%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.06 (s, 12H), 0.89 (s, 18H), 1.20 (d, 6H, J = 6.3 Hz), 2.64 (m, 6H), 2.87 (m, 6H), 3.41 (m, 4H), 3.49 (m, 8H), 3.73 (t, 4H, J = 5.1 Hz), 4.97 (p, 1H, J = 6.3 Hz), 6.00 (t, 2H, J = 5.4 Hz), 8.69 (s, 2H), 9.19 (s, 1H). 13C NMR (75 MHz, CDCl3) 5.30, 18.24, 18.30, 18.35, 21.65, 25.85, 34.49, 35.44, 39.54, 62.58, 68.78, 69.33, 72.37, 108.19, 108.66, 152.90, 153.16, 175.36, 177.37. HRMS (ESI, (M+H)+) calcd for C38H70N2O11Si2: 787.4596; found: 787.4600.

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134 3,3',3''-(2,4,6-Trihydroxybenzene -1,3,5-triyl)tris(N-(2-(2-(te rt-butyldimethylsilyloxy)ethoxy)ethyl)propanamide) (4-4c). The compound was synthesized from 3-2c (0.20 g, 0.69 mmol) and 4-1 (0.50 g, 2.3 mmol) according to the same procedure used for 4-2a to afford 4-4b (0.33 g, 51%) as a colorless oil: 1H NMR (300 MHz, CDCl3) 0.06 (s, 6H), 0.89 (s, 9H), 2,62 (m, 2H), 2.87 (m, 2H), 3.39 (m, 2H), 3.48 (m, 4H), 3.71 (t, 2H, J = 5.1 Hz), 6.06 (t, 1H, J = 5.4 Hz), 9.15 (s, 1H). 13C NMR (75 MHz, CDCl3) 5.28, 18.28, 18.33, 25.88, 35.47, 39.54, 62.60, 69.37, 72.39, 108.52, 153.08, 175.47. HRMS (ESI, (M+Na)+) calcd for C45H87N3O12Si3: 968.5490; found: 968.5614. Mono-2-(2-(tert-butyldimeth ylsilyloxy)ethoxy)ethanamine-di-isopropylester 1-azaadamantantrione (4-5a) A solution of 4-4a (60 mg, 0.10 mmol), HMTA (42 mg, 0.30 mmol), and isopropanol (5 mL) was heated to reflux fo r 3 days under a blanket of argon. After cooling the reaction mixture to room temp erature, the solvent was remove d in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N HCl and brine. The solution

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135 was then concentrated to a crude oil and purified via column chromatography (pure ethyl acetate) to afford 4-5a (35 mg, 46%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.08 (s, 6H), 0.89 (s, 9H), 1.23 (d, 12H, J = 6.3 Hz), 2.04 (m, 6H), 2.37 (m, 2H), 2.48(m, 4H), 2.78 (t, 2H, J = 7.8 Hz), 3.06 (t, 2H, J = 7.8 Hz), 3.38 (m, 8H), 3.55 (m, 4H), 3.77 (t, 2H, J = 6.0 Hz), 5.00 (q, 2H, J = 6.3 Hz), 6.01 (t, 1H, J = 5.4 Hz). 13C NMR (75 MHz, CDCl3) 5.24, 17.51, 21.84, 22.30, 22.90, 25,92, 28.17, 28.68, 30.04, 39.21, 62.65, 67.65, 69.82, 71.31, 72.43, 72.75, 72.83, 172.45, 172.86, 200.22, 200.24. HRMS (ESI, (M+Na)+) calcd for C34H56N2O10Si: 703.3596; found: 703.3609. Mono-isopropylester-di-2-(2-(tert-butyldi methylsilyloxy)ethoxy)ethanamine 1-azaadamantantrione (4-5b) The compound was synthesized from 4-4b (90 mg, 0.11 mmol) and HMTA (48 mg, 0.34 mmol) according to the same procedure used for 4-5a to afford 4-5b (55 mg, 52%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.08 (s, 12H), 0.90 (s, 18H), 1.22 (d, 6H, J = 5.7 Hz), 2.08 (m, 6H), 2.45 (m, 6H), 2.79 (t, 2H, J = 7.2 Hz), 3.06 (t, 2H, J = 6.6 Hz), 3.38 (m, 6H), 3.55 (m, 6H), 3.77 (s, 4H), 5.00 (m, 1H), 6.06 (t, 2H, J = 6.6 Hz). 13C NMR (75 MHz, CDCl3) 5.78, 16.43, 17.46, 21.11, 21.57, 22.22, 25.29, 27.08, 27.89, 28.73, 61.68, 66.34, 68.65, 69.17, 70.40, 71.12, 171.77, 172.05, 199.85. HRMS (ESI, (M+Na)+) calcd for C41H73N3O11Si2: 862.4681; found: 862.4803.

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136 N H N O O OTBS H N O O O O O TBSO N H O O OTBS Tri-2-(2-(tert-butyldimethylsilyloxy)eth oxy)ethanamine 1-aza-adamantantrione (45c) The compound was synthesized from 4-4c (0.75 g, 0.79 mmol) and HMTA (0.33 g, 2.4 mmol) according to the same procedure used for 4-5a to afford 4-5c (0.28 g, 35%) as a yellow oil: 1H NMR (300 MHz, CDCl3) 0.05 (s, 6H), 0.87 (s, 9H), 2.02 (t, 2H, J = 6.9 Hz), 2.35 (t, 2H, J = 6.9 Hz), 3.32 (s, 2H), 3.38 (q, 2H, J = 5.4 Hz), 3.50 (q, 4H, J = 5.4 Hz), 3.74 (t, 2H, J = 5.7 Hz), 6.05 (t, 1H, J = 5.7 Hz). 13C NMR (75 MHz, CDCl3) 4.84, 18.75, 23.40, 26.31, 30.65, 39.62, 63.01, 70.21, 71.53, 72.80, 73.12, 173.10, 200.97. HRMS (ESI, (M+Na)+) calcd for C48H90N4O12Si3: 1021.5755; found: 1021.5777.

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137 CHAPTER 5 CONCLUSIONS AND OUTLOOK Summary and Conclusions The design, rational synthesis, and supram ol ecular properties of a series of highly functionalized amide-based AATs with expanded aromatic arms have been described. These molecules show significantly enhanced self-a ssembly properties in both the bulk state and solution relative to derivatives w ith smaller aromatic arms. Compound 2-1a forms stable gels in aromatic solvents such as toluene and benzene with the lowest CGC and highest Tgel values that have been observed to date for AAT gelators. In the solid state, SEM of the dried gels shows well-organized structures and powder XRD shows evidence of stacking. Thermal behavior of the AATs was studied by DSC and TGA for the firs t time; the latter shows that the core of the AAT molecules is stable up to 600 C. In solution, UV/Vis, fluorescence, IR, and NMR spectroscopies were used to study the role of the aromatic side chains in self-assembly and have revealed structur e-property relationships for the molecules. Excimer emission bands were observed that provided evidence for stacking; at least a component of this arises from intermolecular aromatic interactions of the naphthyl arms by comparison of the target AAT molecules with model compounds. The Hbonding effects of the peripheral amide functional groups of the AAT molecules were studied by concentration-dependent and temperature-dependent NMR and IR spectroscopy. The data shows the importance of intramolecular H-bonding to th e amide-functionalized AATs that presumably preorganizes the molecules and facilitates self-assembly.55, 91 The first ever dynamic light scattering studies of the AATs showed that the de rivatives bearing larger aromatic side chains appear to form larger assemblies in solution th an the AAT derivatives with smaller aromatic arms at similar concentrations. Light-scattering provides independent evidence for self-assembly

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138 of the AATs and shows the dependence of assembly size on solvent, concentration, temperature, and molecular structure. Differentially-functionalized and chiral AATs were prepared using a new lactone-based strategy from 5and 6-membered ring ester a nd amide-functionalized lactones. The lactone strategy allows for late-stage synthetic introducti on of sensitive or chemically labile functional groups and also provides a method for cont rolling the symmetry of an otherwise C3-symmetric scaffold. Installation of three different arms on th e AAT core gives a chiral molecule that should share the properties of chiral te rtiary amines and therefore ha ve potential applications in asymmetric catalysis and chiral recognition. The first application of this synthetic methodology was the synthesis of model compound 2-12, which was used to explore interversus intramolecular stacking effects in the naphthyl-s ubstituted AATs. A small library of differentially-functionalized and chiral AATs was subsequently made and their thermal properties were studied by DSC and POM. Unex pected phase behavior (e.g., cold-crystalline phenomena) was found for compound 3-5a that was identified by both DSC and POM. The lactone synthetic methodology allows th e synthesis of AATs bearing hydrophilic groups that are not availa ble otherwise. The targets work towa rd the preparation of water soluble and hydrogelating AATs; hydrogels are an importa nt class of biomaterials with numerous applications. Outlook AAT molecules constitute a unique class of donor-acceptor m olecules. Their selfassembly relies on both traditional noncovalent interactions as well as dipolar interactions of the donor-acceptor cores. The supram olecular networks derived from these unconventional

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139 molecules are complex and further functionaliza tion of the cores could work toward further understanding their structureproperty relationships and to ward specific applications. Arms Functionalized with H-bonding Recognition Groups H-bonding is one of the most im portant and widely exploited noncovale nt interactions in supramolecular chemistry. Columnar aggrega tion via hydrogen bonding and formation of liquid crystals and gels has been described for many C3-symmetric molecules consisting of a single benzene ring. These notably include the 1,3,5-ben zenetriamides that assemble through amide hydrogen bonding,204, 205 benzenehexamine derivatives that assemble via 6-fold intermolecular hydrogen bonding,206 and the tris(stearoylamino)triphenylamines that assembles via three-fold intermolecular hydrogen bonding.207 Introducing functional groups which could form welldefined intermolecular H-bonds between AAT monome rs, such as ureas, amides, and peptides, should facilitate long-range organi zation in the solid phase and li quid crystallinity in solution. The lactone strategy allows for the late-stage introduction of numerous functional groups to the AAT periphery. Improving the solubility of the AAT molecules would also help with single crystal growth in order to fully understand the pack ing patterns of the systems and their assembly mechanisms. Hydrophilic and Hydrogelating AATs The successful introduction of hydrophilic func tional groups to the AAT periphery makes the form ation of hydrogelating molecules worthwh ile targets. The strategy could also be expanded to include installation of peptidic and polyethylene gl ycol units into the arms to investigate a variety of smart material s and biomedically interesting molecules.208 Differentially-Functionalized AATs The lactone strategy provides a m ethod for breaking the symmetry of otherwise C3symmetric phloroglucinol, and therefore AAT, scaffolds. Installation of three different arms on

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140 the AATs offers a chiral molecule that should shar e the properties of chir al tertiary amines and therefore have potential applications in asymmetric catalysis and chiral recognition.189-191 Meanwhile, installation of three different arms which have different f unctionalities may largely enhance the properties and functions of the molecules in part icular applications. For example, two arm units can be functiona lized with groups designed to recognize and bind a substrate, while the third arm unit could be equipped with a group that would improve the solubility or hydrophilic properties of the system.

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141 APPENDIX A NMR SPECTRA

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176 BIOGRAPHICAL SKETCH Ling Yuan was born in Jianyang, Sichuan Province, P. R. China. She received her B.S. in m edicinal chemistry from West China Univers ity of Medical Sciences in July 1996. After working 7 years in West China University of Medical Sciences, Shanghai Institute of Organic Chemistry and then Wuxi Pharmatech company in China, she came to the University of Florida as a graduate student of organic chemistr y in August 2003. She joined Prof. Ronald K. Castellanos group in September 2003 and she recei ved her M.S. in organic chemistry from University of Florida in December 2005. Ling Yuan will receive her Ph.D. in April 2008. Beginning in May 2008, she will join the Dow chemical company in Shanghai, China.