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(3+3) Schiff-base metallomacrocycles and their aggregation in solution 2005

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[3+3] SCHIFF-BASE METALLOMACROCYCLES AND THEIR AGGREGATION IN SOLUTION by Tsz Lui Cecily Ma B.Sc , The University of British Columbia, 2002 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF THE REQUIREMENTS FOR THE DEGREE OF M A S T E R OF SCIENCE in THE F A C U L T Y OF G R A D U A T E STUDIES CHEMISTRY THE UNIVERSITY OF BRITISH C O L U M B I A February 2005 © Tsz Lui Cecily Ma, 2005 Abstract Conjugated macrocycles are attractive precursors to new materials such as porous solids, synthetic ion channels, catalysts and other supramolecular materials. The development of these cyclic molecules for applications has been limited by the synthetic difficulties inherent in assembling a complex molecule. Imine formation by the condensation of an amine and an aldehyde is a convenient method for assembling large molecules. Since this reaction is reversible, macrocycles can be obtained under thermodynamic control. Large shape-persistent conjugated macrocycles (14-16) with tunable pore diameters in the nanometer regime were prepared by employing Schiff-base chemistry without the necessity of an added template. These new self-assembled macrocycles contain three N2O2 pockets, which can bind to multiple metal ions (e.g. Zn 2 + ), forming soluble luminescent complexes (17 and 18a). The fluorescence of the macrocycles (14-16) could also be quenched by the coordination of metal ions (e.g. N i , Cu 2 + ) in the three N2O2 pockets. The aggregation behaviour of the zinc metallated macrocycles (17 and 18a) in solution was investigated by ] H N M R , absorption and fluorescence spectroscopies. It was discovered that solvent can play a crucial role in the association of the metallomacrocycles. The macrocyclic assemblies can sense coordinating bases, which cause deaggregation of the supramolecular assemblies. The aggregation was not disrupted by polar solvents, suggesting the association of the metallomacrocycles involved an additional interaction, Zn—O coordination, rather than solely hydrogen bonding or n- stacking of aromatic units. 11 Table of Contents Page Abstract ij Table of Contents i i i List of Symbols and Abbreviations v List of Figures viii List of Schemes xii Acknowledgements xiii Chapter 1: Introduction 1 1.1 Supramolecular Chemistry 1 1.2 Hollow Nanotubes 4 1.3 Macrocycles 6 1.3.1 7i-7i Stacking of Macrocycles 9 1.3.2 Hydrogen bonding 10 1.3.3 Coordinative bonding 12 1.4 Schiff-base Macrocycles 14 1.5 Aim of Thesis 18 1.6 References 22 Chapter 2: [3+3] Schiff-base Macrocycles 27 2.1 Background 27 2.2 Experimental 29 2.3 Results and Discussion 41 2.3.1 Synthesis and characterization of bis(salicylaldehydes) 42 2.3.2 Synthesis and charaterization of macrocycles 48 2.4 References 57 Chapter 3: Metal-Containing [3+3] Schiff-base Macrocycles 60 3.1 Background 60 3.2 Experimental 63 3.3 Results and Discussion 68 3.3.1 Synthesis of metallomacrocycles 68 3.3.2 Titration experiments 81 3.4 References 89 Chapter 4: Aggregation of [3+3] Schiff-base Metallomacrocycles 90 4.1 Background 90 4.2 Experimental 92 4.3 Results and Discussion 95 4.4 References 108 Chapter 5: Future work and Conclusions 111 5.1 Conclusions 111 5.2 Future Work 112 iv List of Symbols and Abbreviations A angstroms (A = 1 x 10"10 m) a.m.u. atomic mass units °C degrees Celsius ca. circa (about) l 3 C N M R carbon-13 nuclear magnetic resonance cm centimeters C H C I 3 chloroform C D C I 3 deuteriated chloroform D C M dichloromethane DMSO dimethylsulfoxide d deuterium (NMR) d doublet (NMR) 8 chemical shift s molar extinction coefficient e.g. for example equiv. equivalents d frequency g grams h hours ' H N M R proton nuclear magnetic resonance HR-EI-MS high resolution electron impact mass spectrometry Hz Hertz IR infrared X wavelength J coupling constant (NMR) L litres M mol/L MALDI-TOF-MS matrix-assisted laser desorption/ionization time- of-flight mass spectrometry mL millilitres mmol millimoles mol moles mp melting point m multiplet (NMR) uL microlitres Me methyl group MeCN acetonitrile MeOH methanol MHz megahertz min minutes m/z mass-to-charge ratio nm nanometers N M R nuclear magnetic resonance Ni(OAc) 2 -4H 2 0 nickel(II) acetate tetrahydrate Ni(acac)2 nickel(II) acetylacetonate ppm parts per million (NMR) % percent q quartet (NMR) R alkyl group s singlet (NMR) salen 2,2' -N ,N ' -bis(salicylidene)ethylenediamine salphen 2,2'-N,N'-bis(salicylidene)phenylenediamine t triplet (NMR) temp. temperature TOF time-of-flight THF tetrahydrofuran TMS tetramethylsilane UV-vis ultraviolet-visble Zn(OAc)2-2H20 zinc(II) acetate dihydrate List of figures Page Figure 1.1. 18-crown-6 bound to a potassium ion 2 Figure 1.2. Mushroomlike supramolecular structure 3 Figure 1.3. Oligophenylacetylene folding equilibrium between the open 5 and helical folded structure. Figure 1.4. Examples of macrocycles with a) a flexible core and b) a rigid core 8 Figure 1.5. Shape persistent macrocycles have an interior diameter d that is 8 equal to the contour length / of their molecular backbone divided by it. Figure 1.6. Macrocycle that self-associates due to n-n interactions. 10 Figure 1.7. Structure of expanded porphyrin with Schiff-base moieties. 15 Figure 1.8. Examples of triangular [3+3] Schiff-base macrocycles. 15 Figure 1.9. Schiff-base complex 16 Figure 1.10. a) Robson-type 10 and b) McKee-type 11 macrocycles 17 Figure 1.11. [3+3] Schiff-base macrocycle 18 Figure 1.12. [3+3] Schiff-base macrocycle with peripheral alkoxy side chains. 19 Figure 1.13. Chemical structures of the target [3+3] Schiff-base macrocycles. 20 Figure 1.14. Chemical structures of [3+3] metallomacrocycles 17-19. 21 Figure 2.1. Bis(salicylaldehyde) precursors of [3+3] Schiff-base macrocycles 14, 42 15 and 16. Figure 2.2. ' H N M R spectra of bis(salicylaldehyde) 24 (300 MHz; CDC1 3). 47 Figure 2.3. ' H N M R spectra of a) bis(salicylaldehyde) 25 (300 MHz; CDC1 3). 47 Figure 2.4. ' H N M R spectra of a) bis(salicylaldehyde) 26 (300 MHz; CDC1 3). 48 Figure 2.5. [ H N M R spectrum of [3+3] Schiff-base macrocycle 14a 50 (300 MHz; CDC1 3). Figure 2.6. MALDI-TOF mass spectrum of [3+3] Schiff-base macrocycle 14a. 51 Figure 2.7. ' H N M R spectrum of [3+3] Schiff-base macrocycle 14b 51 (300 MHz; CDC13). Figure 2.8. *H N M R spectrum of [3+3] Schiff-base macrocycle 15 53 (300 MHz; <i#-THF). Figure 2.9. ' H N M R spectra of [3+3] Schiff-base macrocycle 16 53 (300 MHz; d8-TKF). Figure 2.10. ' H N M R of supernatant solution from preparation of 14a 55 (300 MHz; CDCI3) Figure 3.1. Structures of Schiff-base dicopper (II) complex. 61 Figure 3.2. [3+3] Schiff-base metallomacrocycle 40. 62 Figure 3.3. Target metal-containing [3+3] Schiff-base macrocycles. 62 Figure 3.4. ' H N M R spectrum of metallomacrocycle 17 (300 MHz; d8-TBF). 71 Figure 3.5. MALDI-TOF mass spectrum of metallomacrocycle 17. 72 Figure 3.6. ' H N M R spectrum of metallomacrocycle 18a (300 MHz; <is-THF). 73 Figure 3.7. MALDI-TOF mass spectra of 18a. 74 Figure 3.8. MALDI-TOF mass spectra of 18b. 75 Figure 3.9. MALDI-TOF mass spectra of 18c. 76 Figure 3.10. ' H N M R spectrum of metallomacrocycle 19 (300 MHz; d8-TBF). 78 Figure 3.11. ' H N M R spectrum of metallomacrocycle 20 (300 MHz; ^ - T H F ) . 78 Figure 3.12. MALDI-TOF spectra of metallomacrocycle 19. 79 Figure 3.13. MALDI-TOF spectra of metallomacrocycle 20. 80 Figure 3.14. UV-visble and emission spectra of macroccyles 17, 19 and 20. 81 Figure 3.15. Photograph of fluorescence from macrocycle 14a (i) with no 81 metal, (ii) with zinc acetate, and (iii) with nickel acetate. Solvent: THF, 5x 10"5 M ; A,eXc = 365 nm. Figure 3.16. (a) UV-visible and fluorescence spectra of macrocycle 14a 82 upon titration with Ni(OAc) 2 (THF). ix Figure 3.17. Stern-Volmer plots for the fluorescence quenching of 83 macrocycle 14a (kmax = 564 nm), 15 (A,max = 562 nm) and 16 (A,m a x = 560 nm). Figure 3.18. Graph of fluorescence intensity (normalized) vs. equiv. Ni(OAc)2 83 added to macrocycle 14a, 15 or 16 in THF. Figure 3.19. Structure of salphen 41. 85 Figure 3.20. UV-visible and fluorescence spectra of salphen 41 upon 85 titration with Ni(OAc) 2 (THF). Figure 3.21. Stern-Volmer plots for the fluorescence quenching of 86 salphen 41 (X,max= 538 nm). Figure 3.22. Graph of fluorescence intensity (normalized) vs. equiv. 86 Ni(OAc) 2 added to salphen 41 in THF. Figure 3.23. (a) UV-visible and fluorescence spectra of macrocycle 15 87 upon titration with Ni(OAc) 2 (THF). (b) UV-visible and fluorescence spectra of macrocycle 16 upon titration with Ni(OAc) 2 (THF). Figure 3.24. UV-visible and fluorescence spectra of macrocycle 14a 88 upon titration with Zn(OAc) 2 (THF). Figure 4.1. Macrocycle that self-associates due to n-n interactions. 91 Figure 4.2. Conjugated macrocycles 13,14,17,18. 92 Figure 4.3. a) MALDI-TOF mass spectrum of macrocycle 17. The inset 96 shows the isotope distributions for the molecular ions of b) 18a c) 18b d) 18c. Figure 4.4. ' H N M R spectra (300 MHz) of macrocycle 17 in varying ratios 97 of D C M - d 2 : THF-dg ([17] = ca. 6 x 10"4 M for all of the spectra). Figure 4.5. Structure of compound 37. 98 Figure 4.6. (a) UV-vis spectra of 18b in varying ratios of D C M and THF, 99 between 1:0 and 0:1 in 10% increments. [18b] = 9.0 x 10"7 M (b) UV-vis spectra of 18c the same solvent combinations. [18c] = 9.8 x 10"7 M Figure 4.7. UV-vis and fluorescence spectra of (a) 17 and (b) 18a in varying 100 ratio of THF and D C M , between 1:0 and 0:1 in 10% increments. [17] = 1 x 10"6 M ; [18a] = 1.1 x 10"6 M . Figure 4.8. UV-visible and fluorescence spectra of macrocycle 17 in different 102 solvents. x Figure 4.9. Graph of absorbance at 380 nm as a function of concentration (M) of 102 17. Figure 4.10. UV-vis and fluorescence spectra of the titration of 18a with 18c. 103 Figure 4.11. UV-vis and fluorescence spectra of metallomacrocycle 17 104 titrated with a) pyridine (3.6 x 10"3- 0.020 M ; step size: 1.81 x 10"3 M) and b) lutidine (1.26 x 10"3- 0.014 M ; step size: 1.26 x 10"3 M). [17] = 1.8 x 10" 6 M. The arrows show the direction of increasing concentration of base. Figure 4.12. Illustration of aggregation and coordination-assisted 105 deaggregation of multimetallic macrocycles. Left: Macrocycles in THF. Middle: macrocycles aggregated in CH2CI2. Right: Macrocyclic assemblies deaggregate after reaction with a coordinating solvent. Figure 4.13. a) UV-vis and emission spectra of the titration of 17 106 with quinuclidine in D C M . [17] = 1.4 x 10"6 M b) Plot of Io/I as a function of equivalents quinuclidine at 575 nm. Figure 4.14. Stacked *H N M R spectra of macrocycle 17 with 107 3 equivalents and 6 equivalents of quinuclidine. In all spectra, [17] ~ 3.24 x 10"3 M in CD 2 C1 2 ; 300 MHz. XI List of schemes Page Scheme 1.1. Self-assembly of [Cu12(199)4]12+ 2 Scheme 1.2. Schematic representation of the assembly of a columar liquid 5 crystal phase from gallate-based amphiphile. Scheme 1.3. Self-assembly of metallomacrocycles into a hollow tubular structure. 6 Scheme 1.4. Self-assembly of bis-urea macrocycle 5 into a nanotube. 11 Scheme 1.5. Schematic diagram of nanotube assembly from cyclic D, L-peptides. 12 Scheme 1.6 Metallomacrocycle and ladder arrangement. 13 Scheme 1.7. Double-stranded conjugated porphyrin polymer ladder. 14 Scheme 2.1. Schiff-base condensation reaction between an aldehyde and a primary 28 amine. Scheme 2.2. Synthesis of [3+3] Schiff-base macrocycle. 29 Scheme 2.3. Synthetic route to bis(salicylaldehyde) 24 44 Scheme 2.4. Alternative route to 4-halosalicylaldehydes 45 Scheme 2.5. Synthesis of bis(salicylaldehyde) 26 46 Scheme 2.6. Synthesis of bis(salicylaldehyde) 25 46 Scheme 2.7. Synthesis of [3+3] Schiff-base macrocycles 14a 50 Scheme 2.8. Synthesis of [3+3] macrocycles 15 and 16 52 Scheme 3.1. Metalation of [3+3] Schiff-base macrocylce 14a. 70 Scheme 3.2. Synthesis of metallomacrocycles 19-20. 77 Acknowledgement I would like to express my deepest gratitude to my supervisor Professor Mark MacLachlan, who gave me valuable suggestions and support during my research. Working with him has been both exciting and intellectually stimulating. His enthusiasm and commitment towards chemistry will continue to inspire me. He has not only taught me a great deal about chemistry, but has also looked out for my best interests. I am also grateful to the rest of the MacLachlan group for their encouragement and support; I wish you all the best of luck. To Amanda, Britta and Joseph, I hope your macrocycle stories will be a success. You guys are a great subgroup. To Amir and Andy, I enjoyed working with you on the macrocycles; you have inspired me in many ways. To Alfred, thank you so much for your help and suggestions on the experiments I did, and I look forward to reading your paper about the Schiff-base polymer. To Jon, thank you for drawing the figure for my paper; your computer skill is much appreciated. To Ago and Jian, thank you for your friendship and support. I would like to acknowledge our captain, Dr. Marc Sauer, who challenged me with questions, which help me to think independently. I would also like to thank the people in the Department of Chemistry who have helped me with my research, especially Dr. Nick Burlinson (NMR). Lastly, I could not possibly thank my family enough for their love and encouragement during my graduate studies. xiii Chapter 1 Introduction 1.1 Supramolecular Chemistry Supramolecular chemistry has been a topic of much interest in recent years. Cram,1 Lehn 2 and Pederson3 are pioneers in this field and their contributions to the area of molecular recognition were recognized with the 1987 Nobel Prize for chemistry. Figure 1.1 shows an example of a host-guest system in which 18-crown-6 selectively binds to a potassium ion. Lehn and coworkers also reported a macrocycle in 1997 (Scheme l . l ) . 4 The macrocycle was formed by the treatment of tetrahedral Cu(I) ions with a rigid, linear ligand, resulting in a cyclic structure. This example demonstrates an important concept of supramolecular chemistry, in which molecular building blocks are assembled into discrete structures, leading to new properties such as molecular recognition for host-guest chemistry, and supramolecular devices. Another major principle in supramolecular chemistry is the self-assembly of molecular building blocks into higher-ordered arrays. A well-known example is the aggregation of triblock copolymers into macroscopic films prepared by Stupp et. al. (Figure 1.2).5a The cross-linking of such supramolecular clusters yielded macromolecular objects that exhibit liquid crystallinity.5b The concept of supramolecular assembly was inspired by nature, and is apparent in biological structures such as transmembrane ion channels,6 the double helical structure of DNA, and the structures of proteins.7 Owing to the remarkable functions of these self- assembled structures in biological systems, considerable effort has been devoted to the 1 development of new materials employing this concept. Examples include catalysts, organic nanotubes,9 supramolecular polymers 10and chemical sensors.11 1 Figure 1.1 18-crown-6 bound to a potassium ion. Scheme 1.1 Self-assembly of [Cui2(199)4] 2 Figure 1.2 Mushroom-like supramolecular structure.5 One of the important requirements of supramolecular assembly is that the building blocks are assembled reversibly by intermolecular forces, rather than by conventional covalent bonds. Intermolecular interactions include a range of attractive forces, such as hydrogen-bonding, n-n stacking and coordinative bonding. As a single interaction, the non-covalent force is much weaker than a covalent bond; however, the combination of many of such interactions may lead to supramolecular species that are both thermodynamically and kinetically stable. Complex forms of organized materials are difficult to prepare bond-by-bond. Therefore, non-covalent synthesis allows one to generate supramolecular entities having features and architectures that are challenging to prepare by covalent synthesis. 3 1.2 Hollow nanotubes Hollow tubular structures have numerous applications in biological systems. Beautiful examples of tubular assembly from nature are transmembrane ion channels,6 which are essential for chemical transport and other biological functions. Many scientists have been inspired by nature to construct synthetic tubular materials for both biological and nanotechnological purposes. Examples include ion sensors, liquid crystal displays and carbon nanotubes. Carbon nanotubes can be synthesized by chemical vapour deposition, which requires high temperature up to 850-1000°C. 1 2 The syntheses of such tubular structures not only require harsh conditions, but are also limited to small quantities. There is an intense effort to use noncovalent processes since they possess advantages over covalent synthesis such as high efficency, error correction during the self-assembly process, chemical modification of the nanotube assembly, and control of assembly through subunit design. 1 3 ' 1 4 There are many possible ways to construct hollow tubular structures. For example, tubular arrays can be formed by coiling of linear precursors into hollow helical structures. Moore and coworkers have described the folding of phenylene ethynylene oligomers into helical conformations (Figure 1.3).15 Wedge-shaped molecules can assemble into discs that subsequently stack to form cylinders. This motif is illustrated by the assembly of wedge-shaped trialkylated gallate in a discotic fashion, leading to the formation of hollow columnar liquid crystalline phase (Scheme 1.2).16 Finally, hollow tubular arrays can be formed by the stacking of macrocycles into continuous tubes. The packing of these cycles into tubular structures is of interest since the pore size and properties can be controlled by varying the size of the ring core and the peripheral substituents. Incorporation of metal 4 ions into the macrocycles may lead to hollow nanotubes with metal-organic frameworks. Hong and coworkers have shown the self-assembly of metallomacrocycles into nanosized rings by coordination chemistry (Scheme 1.3).17 R R R R R R H V S A V W S I M E A R R R R R R R=C02(CH2CH20)CH3 Figure 1.3 Oligophenylacetylene folding equilibrium between the open and helical folded structure.9'1 5 Scheme 1.2 Schematic representation of the assembly of a columar liquid crystal phase from gallate-based amphiphile. 9 ' 1 6 5 Scheme 1.3. Self-assembly of metallomacrocycles Into a hollow tubular structure,17 1.3 Macrocycles The term macrocycle can be defined as a cyclic macromolecule containing nine or more atoms in the ring. 1 8 Macrocycles are of interest because they display a diverse range of chemistry which can be applied in the fields of biology and material science.19 For example, porphyrins exist in biological systems as heme, which is essential for cellular respiration. Moreover, with chelating functionalities, macrocycles can behave as polydentate ligands, which are involved in a variety of catalytic systems and molecular 9 0 architectures such as rotaxanes. Macrocycles can be rigid or flexible depending on the structure of their backbone. Flexible macrocycles contain unsaturated alkyl chains that allow facile rotation of bonds (Figure 1.4a). Shape-persistent, rigid macrocycles, on the other hand, possess 9 9 unsaturated hydrocarbon backbones that restrict bond rotation (Figure 1.4b). The study of shape-persistent, rigid macrocycles, which combines the concepts of organic synthesis and supramolecular chemistry, has established itself as a rapidly growing research area. The term shape-persistent macrocycle means that the building blocks of the ring are rigid and its final structure contains a well-defined internal void. A more precise definition of 6 shape-persistence is based on the flexibility of the final structure, in which shape- persistent macrocycles have an interior (diameter) d that is equal to the contour length / of their molecular backbone divided by % (Figure 1.5). Unlike flexible structures such as crown ethers or cycloalkanes, shape-persistent macrocycles are non-collapsible; therefore, they are ideal for the formation of hollow tubular superstructures. The synthesis and design of shape-persistent macrocycles with different shapes and sizes involve the development of new synthetic methods. The backbone of these macrocycles can be modified with peripheral side chains with various functionalities, which not only improve solubility but also give rise to their unique properties. Of more recent interest are the interactions of shape-persistent macrocycles to form supramolecular assemblies. 7 Figure 1.5 Shape persistent macrocycles have an interior diameter d that is equal to the contour length 1 of their molecular backbone divided by 7 i . 2 3 The rigidity and inner void of shape-persistent macrocycles make them interesting candidates as building blocks for supramolecular structures. The axial stacking of the disc-like molecules may give rise to porous supramolecular architectures such as hollow 8 nanotubes, ion channels, discotic liquid crystals and catalysts. Another advantage of the use of rigid macrocycles to form supramolecular assemblies is that the various sizes of different rigid spacers could lead to tunable pore sizes and properties. It has also been shown that intermolecular interactions in supramolecular structures can alter the properties of the individual molecules, including their optical and electronic properties.24 The attractive forces between macrocycles can vary greatly, ranging from strong coordinative bonding, hydrogen-bonding to weak 71-71 stacking. 1.3.1 n-n stacking of macrocycles Aromatic % stacking plays a significant role in supramolecular chemistry. The interactions between aromatic units can be used to induce stacking of macrocycles to form higher order structures. For instance, owing to their extended 7t systems, porphyrins and phthalocyanines exhibit aggregation tendency, forming dimeric and oligomeric species in solutions. Moore and Hoger have also shown that in polar solvents, rigid, conjugated phenyleneethynylene macrocycles (PAMs) self-associate through face-to-face 7i-7i interactions to form tubular structures.26 It has been well documented, however, that such aggregation is weak and strongly relies on the electronic character of substituents on 27 the PAMs. Macrocycles with electron-withdrawing ester groups were observed to dimerize to a significant degree in chloroform as opposed to these with electron-donating alkoxy groups, in which no intermolecular aggregation was observed. It is also known that 71-stacking interactions of these macrocycles are strongly influenced by solvent.243 Phenyleneethynylene macrocycles with an ester group have been demonstrated to self- 27 associate to a different degree in various solvents (Figure 1.6). 9 R R R = COO n C 4 H 9 4 Figure 1.6 Macrocycle that self-associates due to n-n interactions. 1.3.2 Hydrogen bonding Chemists have employed the concept inspired by nature to construct supramolecular structures by means of hydrogen-bonding. The double helix of D N A is an excellent example of a self-associated species assembled through hydrogen-bonding. A bis-urea macrocycle was synthesized and shown to be stacked together by intermolecular hydrogen bonding between the urea carbonyl group and urea amide group, leading to a nanotubular structure. (Scheme 1.4).28 Other examples of hydrogen-bonded structures are found in the nanotubes based on cyclic D, L-peptide rings prepared by Ghadiri (Scheme 1.5).29 The cyclic peptides assemble into hollow tubes, which are stabilized by hydrogen bonding along its rim. One of the advantages of cyclic D, L-peptide nanotubes is the possibility of controlling the internal diameter and properties of the nanotube by varying the size of the peptide ring and the choice of amino acid side chains. Similar to n 10 stacking, solvents also have a pronounced effect on hydrogen bonding; solvents containing hydrogen donor or acceptor groups may decrease aggregation. H H / \ Scheme 1.4 Self-assembly of bis-urea macrocycle 5 into a nanotube. Scheme 1.5 Schematic diagram of nanotube assembly from cyclic D, L-peptides. 9 ' 2 9 1.3.3 Coordinative bonding Large macrocycles may be formed by the self-assembly of metal-coordination complexes in solution 3 0 ' 3 1 In these reactions, metals serve to define the structure of the final macrocyclic product, and are in its backbone. The incorporation of metals into rigid, covalently bonded scaffolds may offer opportunities for developing supramolecular materials and sensors triggered by ligand coordination to the metal. Unfortunately, there are few reports of shape-persistent organic macrocycles that bind multiple metals. A new trend in this area is to incorporate heteroatoms which can coordinate to metals. Macrocycles with chelating donor atoms such as nitrogen and oxygen can serve as ligands, allowing their unique geometry to modify the properties of their guests. Furthermore, the inclusion of chelating moieties allows interactions with metal ions to be used in the formation of supramolecular structures. For instance, a [2+2] Schiff-base macrocycle with two Zn(II) ions coordinated in N2O2 tetradentate binding sites can be 12 used as a "platform" in the formation of a molecular "ladder". The addition of a bridging ligand such as 4,4'-bipyridine to a solution of metallomacrocycles resulted in the 33 octahedral coordination of the Zn centres to form the ladder structures (Scheme 1.6). Anderson and co-workers explored the use the 4,4'-bipyridine to link the porphyrin polymer into a double-stranded ladder (Scheme 1.7).34 With the addition of more 4,4'- bipyridine, the polymers may assemble into a two-dimensional supramolecular system. The use of coordination chemistry offers a wide selection of ligands and metals, thus providing the potential of tuning the properties of the supramolecular structure by combinations of components. Scheme 1.6 Metallomacrocycle and ladder arrangement. 13 R2N R3W O o Ar Scheme 1.7 Double-stranded conjugated porphyrin polymer ladder. 1.4 Schiff-base macrocycles Although many examples of organic macrocycles have been reported, they remain challenging to synthesize, often involving a large number of steps, the use of protecting groups or templates, high dilution and proceeding in low yields. 3 5 ' 3 6 Schiff-base condensation, which involves the condensation between formyl and amine groups to yield imines, offers a convenient route to small macrocycles. The reaction is straightforward and reversible; it also offers the advantage of minimization of other side products such as oligomers.36 Schiff-base chemistry, as a result, has been central to the synthesis of various macrocycles such as expanded porphyrins 6 prepared by Sessler and co-workers in 1998 (Figure 1.7) and the triangular [3+3] Schiff-base macrocycles 7 and 8 (Figure 1.8).38 In addition, macrocycles with Schiff-base and hydroxyl moieties have attracted attention due to their ability to from multi-metallic complexes. Schiff-base complexes, such as salphens (Figure 1.9), are attractive compounds to incorporate into macrocycles due to their interesting catalytic and optical properties. They can be prepared 14 in very high yield by the condensation of a diamine and salicylaldehyde. With Zn in the tetradentate N2O2 site, these complexes are highly luminescent and have been used in blue LEDs . 3 9 6 Figure 1.7 Structure of expanded porphyrin with Schiff-base moieties. 7 8 Figure 1.8 Examples of triangular [3+3] Schiff-base macrocycles. 15 M = Metal 9 Figure 1.9 Schiff-base complex. Robson-type macrocycles are [2+2] Schiff-base macrocycles formed from the condensation of two dialdehydes and two diamines and have been widely studied for over 30 years (Figure 1.10a).40 These macrocycles are capable of coordinating two metal ions within the N2O2 cavities, and because of the close proximity of the metals within the macrocycles, metal-metal interactions have been observed and investigated.41 McKee and co-workers synthesized expanded versions of the Robson-type macrocycles that can coordinate up to 4 transition metals (Figure 1.10b).42 Since metals occupy the pores within the Robson and McKee macrocycles, extended porous structures from these macrocycles are not possible. Moreover, the syntheses of these metal-free [2+2] macrocycles are plagued with difficulties, resulting in a mixture of monomeric, dimeric, oligomeric, and partially reduced species 4 3 The problem can be solved by employing a metal template, in which a metal salt is used to promote cyclization. In contrast, Akine and coworkers reported the synthesis of a [3+3] triangular Schiff-base macrocycle without the presence a template, allowing the addition of metal ions in a further reaction (Figure 1.11).44 There are three N2O2 binding sites, analogous to three salphen groups, 16 available for coordinating transition metals. In addition, unlike the Robson-type and McKee-type macrocycles, the core of the macrocycle 12 possesses an empty cavity, which makes it a potential candidate of porous supramolecular structures. Macrocycle 12, however, is insoluble in most solvents due to the lack of peripheral chain substituents. a) b) R" 10 11 Figure 1.10 a) Robson-type 10 and b) McKee-type 11 macrocycles. 17 12 Figure 1.11 [3+3] Schiff-base macrocycle. 1.5 Aims of the thesis The MacLachlan group has previously investigated [3+3] macrocycle 13 which has alkoxy chain substituents attached to its periphery in order to promote solubility (Figure 1.10).45 The macrocycle possesses three N2O2 pockets that are capable of binding metals, as well as a pocket in the center surrounded by six oxygen atoms resembling the geometry of 18-crown-6. It was discovered that the macrocycles aggregate into stacks upon addition of alkali metal salts, with the small cations coordinated to the central phenolic oxygen atoms of macrocycle 13 rather than to the tetradentate N2O2 ligands. The assembly of multimetallic macrocycles that contain a pore in the middle is a potential route to new porous materials. Due to the small interior pore and constrained geometry, however, macrocycle 13 is nonplanar even when transition metals are coordinated to the salphen pockets. As a step to developing large, flat macrocycles that can be assembled into nanotubes, we needed access to larger macrocycles with the metals spaced farther 18 apart. By incorporating rigid moieties such as acetylene and phenyl into the [3+3] Schiff- base macrocycles, inner pores with different diameters can be obtained. Chapter 2 will highlight the synthesis and characterization of the new, expanded [3+3] Schiff-base macrocycles 14-16 (Figure 1.13), as well as the preparations of their bis(salicylaldehyde) precursors. Chapter 3 will describe the incorporation of metals into of the macrocycles; the optical properties of these metallomacrocycles will be discussed (Figure 1.14). In Chapter 4, the aggregation behaviour of the metallomacrocycles in solution will be described. In addition, the coordination-assisted deaggregation of metallomacrocycles 17-20 and preliminary evidence for cooperative binding to the metal centres will be discussed. Chapter 5 will describe ideas for future work and conclusions of the project. These macrocycles represent a new class of giant soluble metal-containing macrocycles. R O O R R - nCeHi3 13 Figure 1.12 [3+3] Schiff-base macrocycle with peripheral alkoxy side chains. 19 RO OR 16 (R=nC8H1 7) gure 1.13 Chemical structures of the target [3+3] Schiff-base macrocycles. RO OR 17 (R = n C 8 H 1 7 ) , 18 (R = 2-ethylhexyl) l9(R = n C 1 0 H 2 1 ) 20 (R = n C 8 H 1 7 ) M = Zn 2 + , Ni 2 +, Cu 2 + Figure 1.14 Chemical structures of [3+3] metallomacrocycles 17-19. 21 1.6 References 1. Cram, D. J.; Cram, J. M . Science 1974,183, 803-809. 2. (a) Dietrich, B.; Lehn, J-M.; Sauvage, J.-P. Tetrahedron Lett. 1969, 10, 2889-2892. (b) Dietrich, B.; Lehn, J .-M.; Sauvage, J.-P.; Blanzat, J. Tetrahedron 1973, 29, 1629-1645. 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Engl. 2003, 42, 5307-5310. 26 Chapter 2 [3+3] Schiff-base macrocycles 2.1 Background Shape-persistent, rigid macrocycles are fascinating targets for creating new materials, including discotic liquid crystals, chemical sensors, catalysts and fluorescent substances.1"5 Metallomacrocycles such as porphyrins are also essential for a variety of biological functions, including photosynthesis and cellular respiration. Moreover, the incorporation of metals into rigid, conjugated and covalently bonded macrocycles may offer opportunities for developing supramolecular materials by employing coordination chemistry. The preparation of shape-persistent organic macrocycles that bind multiple metal centers, however, has not been explored thoroughly. The development of a simple method to synthesize macrocyclic ligands that can be metallated with various transition metal ions is required. Schiff-base condensations between amines and aldehydes have played a prominent role in macrocyclic chemistry. They are one of the simplest and most popular methods for the preparation of macrocycles.6 In the Schiff-base reaction, an aldimine moiety (-N=CH-) is formed from the reaction of an aldehyde and a primary amine (Scheme 2.1). The process involves nucleophilic attack at the carbonyl group by the primary amine, followed by elimination of water to generate an imine. 27 Scheme 2.1. Schiff-base condensation reaction between an aldehyde and a primary amine. Schiff-base chemistry has been employed in the construction of various [2+2] macrocycles such as Robson-type macrocycles7,8 and McKee-type macrocycles.9"11 These reactions often involve metal ion templates, and their outcome depends on the nature of the template. In the absence of metal ions, the reactions are slow and often lead to a mixture of products. On the other hand, larger triangular [3+3] macrocycles formed by condensation of a dialdehyde with a diamine have been reported only a few years ago. Among the known [3+3] cyclocondensed macrocycles, some of them could be obtained without the presence of metal ion templates. The MacLachlan group reported the synthesis of a soluble [3+3] triangular Schiff-base macrocycle without using a template.14 The triangular macrocycle was obtained by the reaction of 3,6-diformylcatechol and an o- phenylenediamine (Scheme 2.2). The geometry of the precursors was designed to form flat macrocycles by a [3+3] cyclocondensation with 22 at the vertices of the triangular macrocycle 23. Employing this concept, we have designed bis(salicylaldehydes) with the appropriate geometry to give giant [3+3] Schiff-base triangular macrocycles with tunable pore size. In addition, the resultant compounds possess three N2O2 pockets, which can bind to transition metals. This chapter describes the synthesis and characterization of the new expanded Schiff-base macrocycles. 28 RO OR + 6 H 2 0 N N RO RO OR OR 21 22 (R=nC6H1 3) 23 (R=nC6H1 3) Scheme 2.2. Synthesis of [3+3] Schiff-base macrocycle. 2.2 Experimental Materials. o-Anisidine, ./V-bromosuccinimide, sodium hydrosulfite, «-butyl lithium, anhydrous dimethylformamide, boron tribromide, copper(I) iodide, trimethylsilyl acetylene, and triphenylphosphine were obtained from Aldrich. Trans- dichlorobis(triphenylphosphine) palladium(II) was obtained from Strem Chemicals, Inc. Tetrahydrofuran (THF) was distilled from sodium / benzophenone under nitrogen. Triethylamine was distilled from NaOH under nitrogen. Chloroform and acetonitrile were purged with nitrogen gas before use. Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. 4,5-Diamino-l,2-dialkoxybenzene (37a,b, 38) and 1,4-diiodo- 2,5-dimethoxybenzene (36) were prepared by literature methods.15"17 Equipment. A l l reactions were carried out under nitrogen atmosphere unless otherwise noted. 300 M H z ! H N M R spectra and 75.5 MHz 1 3 C N M R spectra were recorded on a 29 Bruker AV-300 spectrometer. ' H and 1 3 C N M R spectra were calibrated to the residual protonated solvent at 5 7.24 and 5 77.00 ppm in C D C I 3 , respectively. UV-vis spectra were obtained (ca. xlO" 6 M) on a Varian Cary 5000 UV-vis-near-IR spectrophotometer using a 1 cm quartz cuvette. IR spectra were obtained as KBr discs with a Bomem M B - series spectrometer. Fluorescence spectra were obtained in distilled THF on a Photon Technology International QuantaMaster fluorimeter using a 1 cm quartz cuvette. 18 Quantum yield was referenced to a solution of anthracene in EtOH (O = 0.30). M A L D I mass spectra were obtained in a dithranol matrix at the U B C Microanalytical Services Laboratory on a Micromass LCT time-of-flight (TOF) mass spectrometer. Electron Impact (EI) mass spectra and elemental analyses were also performed at the UBC Microanalytical Services laboratory. Melting points were obtained on a Fisher-John's melting point apparatus. Raman spectra were obtained on a Renishaw Raman microscope 1000 with excitation at 785 nm. Molecular modeling and calculations were performed with Spartan '04. Synthesis of 4-bromo-2-methoxyaniline 28. o-Anisidine (8.01 g, 65.1 mmol) was dissolved in ca. 300 mL of acetonitrile in a 1000 mL Erlenmeyer flask. The solution was stirred in an ice-bath a 0°C for 10 min. N-Bromosuccinimide (11.62 g, 65.3 mmol) was dissolved in ca. 250 mL acetonitrile and added by pipette over 10 min. After 16 h, the solution was concentrated by rotary evaporation and 200 mL of water was added. The aqueous layer was extracted with ca. 3 x 200 mL of D C M . The organic layers were combined, dried over MgS04, filtered and dried by rotary evaporation. The crude product was filtered through a pad of silica gel using D C M and the solvent was removed in vacuo 30 to yield the product as a brown crystalline solid. The crude product was recrystallized in pet ether, obtaining light brown crystals (11.50 g, 87 %). *H N M R (300 MHz, CDC13) 5 6.88 (dd, 3 J H H = 8.95 Hz, 4 J H h = 3.17 Hz, 1H, aromatic CH), 6.86 (s, 1H, aromatic CH), 6.55 (d, 3 J H H = 8.65 Hz, 1H, aromatic CH), 3.81 (s, 3H, OCH3), 2.73 (s, 2H, N/fc) ppm; 1 3 C N M R (75.5 MHz, CDC13) 5 147.88, 135.32, 109.56 (aromatic Q , 123.69, 115.70, 113.77 (aromatic CH), 55.68 (OCH 3). EI-MS: m/z = 201 ( M + , 94%), 186 ( M + - C H 3 , 100%). UV-vis (CH2CI2): Xmax (e) = 298 nm (4.86 x 103) (L mor'cm"1). IR (KBr): v = 3431, 3300, 2923, 2856, 1661, 1609, 1260, 1181, 1169, 902, 891, 796, 752, 704 cm"1. Anal. Calc'd for C 7 H 8 ONBr: C, 41.61; H , 3.99; N , 6.93. Found: C, 41.98; H , 4.00; N , 7.13. Synthesis of 4-bromo-l-iodo-2-methoxybenzene 29. Concentrated HC1 (ca. 250 mL) was added to compound 28 (33.374 g, 184.9 mmol) in a 1000 mL Erlenmeyer flask and was cooled to 0 °C. Sodium nitrite (14.04 g, 203 mmol) dissolved in 150 mL water was slowly added to the mixture over 10 min and the reaction was stirred for 1 h at 0 °C. Potassium iodide (33.76, 203 mmol) was dissolved in ca. 150 mL of water and added dropwise over 15 min at 0 °C, then the resulting suspension was stirred for 16 h at room temperature. The solution was extracted with ca. 3 x 250 mL petroleum ether. The organic phases were combined, washed with an aqueous sodium hydrosulfite solution, and dried over MgSC»4. The solution was filtered, concentrated by rotary evaporation, then purified on silica gel using hexane as the eluent. The solution was removed by rotary evaporation to afford a pale yellow crystalline solid (43.8 g, 76 %). *H N M R (300 MHz, C D C I 3 ) 5 7.57 (d, 3 J H H = 8.26 Hz, 1H, aromatic CH), 6.90 (d, 4 J H H = 2.05 Hz, 1H, 31 aromatic CH), 6.83 (dd, 3 J H H = 8.26 Hz, 4 J H H = 2.05 Hz, 1H, aromatic CH), 3.84 (s, 3H, OCH3) ppm; 1 3 C N M R (75.5 MHz, CDC13) 8 158.80, 122.94, 84.16 (aromatic Q, 140.16, 125.53, 114.55 (aromatic CH), 56.56 (OCH 3). EI-MS: m/z = 312 ( M + , 100%), 297 ( M + - C H 3 , 11%), 170 (M + -1 - C H 3 , 23%). UV-vis (CH 2C1 2): X m a x (e) = 242 (7.07 x 104) nm (L modern"1). IR (KBr): v = 1570, 1554, 1470, 1441, 1384, 1249, 1124, 1034, 1011, 845, 796 cm"1. Mp. 33-35 °C. Anal. Calc'd for C 7 H 6 OBrI: C, 26.87; H , 1.93. Found: C, 26.87; H, 1.90. Synthesis of 4-bromo-2-methoxybenzaldehyde 30. In a 500 mL Schlenk flask, compound 29 (43.79 g, 139.9 mmol) was dissolved in ca. 200 mL dry diethyl ether under N 2 . "BuLi (1.6 M in hexane; 96.18 mL, 153.9 mmol) was added slowly to the solution over 30 min at -78 °C. The reaction was stirred for 1 h, followed by the addition of anhydrous D M F (11.90 mL, 153.9 mmol) over 30 min. The reaction was slowly warmed to room temperature. After stirring for 3 h, concentrated HC1 (30 mL) was added to 100 mL of water. The acidic solution was added to the reaction mixture and extracted with ca. 3 x 250 mL of diethyl ether. The organic phases were combined and dried over MgSC>4. Recrystallization from hexane afforded a yellow solid (23.0g, 72.1 %). %). ' H N M R (300 MHz, CDC13) 8 10.38 (s, 1H, CH=0), 7.67 (d, 3 J H H = 8.18 Hz, 1H, aromatic CH), 7.16 (d, 3 J H H = 8.32 Hz, 1H, aromatic CH), 7.14 (s, 1H, aromatic CH), 3.91 (s, 3H, OCH3) ppm; 1 3 C N M R (75.5 MHz, CDC13) 8 188.67 (CH=O),161.90, 130.51, 114.80 (aromatic O , 129.65, 124.17, 115.36 (aromatic CH), 55.97 (OCH 3). EI-MS: m/z = 214 ( M + , 100%), 199 ( M + - C H 3 , 48%), 184 ( M + - O C H 3 , 20%). UV-vis (CH 2C1 2): W (e) = 318 (5.74 x 103) 32 nm (L mor'cm"1). IR (KBr): v = 2927, 2855, 1663, 1660, 1458, 1181, 1168, 891, 752, 704 cm"1. Anal. Calc'd for C 8 H 7 0 2 B r : C, 44.68; H, 3.28. Found: C, 45.00; H, 3.48. Synthesis of 4-bromosalicylaldehyde 31. Compound 30 (19.009 g, 83.0 mmol) was dissolved in ca. 250 mL dry D C M in a 500 mL Schlenk flask under N 2 and was cooled to 0°C. Boron tribromide (16.60 mL, 176 mmol) was added, and the solution was stirred overnight, slowly warming to room temperature. The mixture was poured into 250 mL ice water and stirred for 10 min. The mixture was extracted with ca. 3 x 250 mL D C M , and the combined organic layers were dried over MgSC>4, filtered and dried by rotary evaporation. The crude product was filtered through silica gel using 2:1 DCM/hexane as eluent. After rotary evaporation and recrystallization from hexane, the product was afforded as white crystals (7.1 g, 40 %). Alternative route: 3-Bromophenol (2.361g, 13.6 mmol), anhydrous magnesium chloride (1.543g, 16.2 mmol) and paraformaldehyde (2.200g, 73.1 mmol) was dissolved in ca. 50 mL of dry MeCN in a 250 mL Schlenk flask under N 2 . Triethylamine (5 mL, 35.9 mmol) was added to the mixture. It was then stirred and heat to reflux overnight at 90°C. The mixture was poured into HC1/H 20 (ca. 20%) solution and was extracted with 3 x 200 mL Et 2 0. The organic layers were combined, dried over MgS04, and filtered before removing the solvent under vacuum. The crude product was filtered through silica gel using 1:1 DCM/hexane as eluent. Recrystallization from hexane afforded white crystals in 13 % yield. ' H N M R (300 MHz, CDC13) 5 11.10 (s, 1H, OH), 9.84 (s, 1H, CH=0), 7.39 (d, 3 J H H = 8.18 Hz, 1H, aromatic CH), 7.18 (s, 1H, aromatic CH), 7.15 (dd, 3 J H H = 33 8.22 Hz, 4 J H H = 1-70 Hz, 1H, aromatic CH); 1 3 C N M R (75.5 MHz, CDC13) 5 195.73 (CH=0), 161.88, 131.92, 119.47 (aromatic Q , 134.47, 123.46, 121.02 (aromatic CH), 55.97 (OCH3). EI-MS: m/z = 202 ( M + , 98%), 184 ( M + - OH, 48%), 173 ( M + - CH=0, 10%). UV-vis (CH2CI2): m̂ax (e) = 325 (6.80 x 103) nm (L modern"1). IR (KBr): v = 3431, 2927, 2856, 1665, 1557, 1474, 1260, 1181, 1168, 903, 796, 752, 704 cm"1. Mp. 51-52 °C. Anal. Calc'd for C 7 H 5 0 2 B r : C, 41.82; H, 2.51. Found: C, 42.20; H, 2.73. Synthesis of 4-iodosalicylaldehyde 35. The procedure is identical to the alternative route of 31 except 3-iodophenol was used in the place of 3-bromophenol. Yield: 31 %. . ' H N M R (300 MHz, CDC13) 5 11.00 (s, 1H, OH), 9.83 (s, 1H, CH=0), 7.42 (s, 1H, aromatic CH), 7.38 (d, 3 J H H = 7.99 Hz, 1H, aromatic CH), 7.21 (d, 3 J H H = 8.06 Hz, 1H, aromatic CH). I 3 C N M R (75.5 MHz, CDC13) 5 220.95 (CH=0), 196.02 134.15, 129.38, 127.23, 105.11, 97.69. EI-MS: m/z = 247.8 ( M + , 100%). UV-vis (CH 2C1 2): Xmax (e) = 327 (5.32 x 103) nm (L m o r W 1 ) . IR (KBr): v = 3431, 2927, 2856, 1665, 1609, 1458, 1260, 1169, 891, 796, 752, 704 cm"1. Anal. Calc'd for C 7 H 5 0 2 I : C, 33.90; H , 2.03. Found: C, 34.11; H, 2.10. Synthesis of 4-trimethylsilylacetylenesaIicylaldehyde 32. Under a nitrogen atmosphere, 4-bromosalicylaldehyde (31) (1.55 g, 7.7 mmol), Pd(PPh 3) 2Cl 2 (0.11 g, 2 mol %) and PPI13 (0.03 g, 1.5 mol %) were dissolved in anhydrous THF (ca. 25 mL), followed by the addition of dry NEt3 (2 mL, 15 mmol) and trimethylsilylacetylene (1.2 mL, 8.5 mmol), giving an orange solution. After stirring for 20 mins, Cul cocatalyst (0.044 g, 3 mol %) was added to the mixture, resulting in a dark brown solution. The reaction was stirred 34 overnight at room temperature, and solvent was removed by rotary evaporation. The dark brown solid was dissolved in tt-pentane and filtered through celite, giving a yellowish solution. Solvent was removed by rotary evaporation. Recrystallization from hexanes gave 1.48 g (88 %) of yellow crystals. ] H N M R (300 MHz, CDC13) 8 10.97 (s, 1H, OH), 9.84 (s, 1H, CH=0), 7.46 (d, 3 J H H = 8.48 Hz, 1H, aromatic CH), 7.06 (d, 3 J H H = 8.01 Hz, 1H, aromatic CH), 7.04 (s, 1H, aromatic CH), 0.24 (s, 9H, Si-CH3); 1 3 C N M R (75.5 MHz, CDC13) 8 195.74 (CH=0), 133.31, 123.28, 120.78, (aromatic CH), 161.23, 131.65, 120.21, (aromatic Q , 103.52, 99.64 {C=Q, -0.29 (Si-CH 3). EI-MS: m/z = 218 ( M + , 25%), 203 ( M + - C H 3 , 100%). UV-vis (CH 2C1 2): X m a x (e) = 295 (3.26 x 104) nm (L mol" 'cm"1). IR (KBr): v = 3216, 2956, 2159, 1654, 1620, 1554, 1493, 1296, 1248, 973, 858, 844 cm' 1. Mp. 79-81 °C. Anal. Calc'd for C i 2 H 1 4 0 2 S i : C, 66.02; H , 6.46. Found: C, 65.92; H, 6.51. Synthesis of 4-ethynylsaIicylaIdehyde 33. 4-Trimethylsilylacetylenesalicylaldehyde (32) (1.98 g, 9.05 mmol) was dissolved in distilled THF (ca. 20 mL). K O H (0.51 g, 9.05 mmol) was dissolved in MeOH (ca. 10 mL) and added to the solution. The reaction mixture was stirred under air overnight at room temperature. Solvent was removed by rotary evaporation, 100 mL H 2 0 was added and the product was extracted with 3 x 200 mL CHC1 3. Acetic acid (ca. 0.5 mL) was added to the aqueous layer and was further extracted with 3 x 200 mL of CHC1 3. The organic phases were combined and dried over MgSCv The solution was filtered, followed by removal of solvent to obtain brown crystals. Recrystallization from hexanes afforded a yellow powder (0.694 g, 53%). ' H N M R (300 MHz, CDC13) 8 10.99 (s, 1H, OH), 9.87 (s, 1H, CH=0), 7.50 (d, 3 J H H = 8.35 Hz, 1H, 35 aromatic CH), 7.11-7.08 (m, 2H, aromatic CH), 3.27 (s, 1H, -C=C-H); 1 3 C N M R (75.5 MHz, CDC13) 195.84 (CH=0), 161.19, 130.59, 120.48 (aromatic Q , 133.41, 123.41, 121.14 (aromatic CH), 82.34, 81.42 {C=Q. EI-MS: m/z = 146 ( M + , 100 %), 145 (M + -H , 78 %). UV-vis (CH2CI2): W (s) = 283 (2.24 x 104) nm (L m o r W ) . IR (KBr): v = 3277, 2962, 1659, 1625, 1556, 1494, 1262, 1197, 1125, 1120, 966, 860, 845, 809, 759 cm"1. Mp. 54-57 °C. Anal. Calc'd for C 9 H 6 0 2 : C, 73.97; H, 4.14. Found: C, 73.57; H, 3.93. Synthesis of bis(salicylaldehyde) 24. Under a nitrogen atmosphere, 4- bromosalicylaldehyde (31) (1.7 g, 8.4 mmol), 4-ethynylsalicylaldehyde 33 (1.2 g, 8.4 mmol), triphenylphosphine (0.03 g, 0.13 mmol) and trans-dichlorobis(triphenylphosphine) palladium(II) (0.12 g, 0.17 mmol) were dissolved in 25 mL of anhydrous THF. Dry triethylamine (4.7 mL, 34 mmol) was added, turning the solution from yellow to orange. After stirring for 20 mins, copper(I) iodide (0.05 g, 0.25 mmol) was added, turning the solution to dark brown. After heating at reflux (70°C) for 47 hours, the solution was cooled to room temperature. The yellow precipitate was isolated on a Buchner funnel and washed with cold dichloromethane. Yield: 0.865g (39%). ! H N M R (300 MHz, CDC13) 5 11.03 (s, 2H, OH), 9.89 (s, 2H, CH=0), 7.54 (d, 3 J H H = 8.37 Hz, 2H, aromatic CH), 7.17 (dd, 3 J H H = 8.10 Hz, 4 J H H = 1-26 Hz, 2H, aromatic CH), 7.14 (s, 2H, aromatic CH). 1 3 C N M R (75.5 MHz, DMSO-d 6 ) 8 190.38 (CH=0), 160.34, 128.70, 122.76 (aromatic Q, 129.13, 122.76, 119.81 (aromatic CH), 91.34 (C=Q. EI-MS: m/z = 266 ( M + , 100 %), 265 ( M + - H , 85 %). UV-vis (CH 2C1 2): X m a x (e) = 325 (3.26 x 104) nm (L mor'cm"1). IR (KBr): v = 3206, 2962, 1659, 1622, 1631, 1554, 1498, 1224, 1184, 1125, 986, 867,816, 808 cm" 36 Mp. 218-222 °C. Anal. Calc'd for Ci 6 H,o0 4 : C, 72.18; H, 3.79. Found: C, 71.77; H, 3.14. Synthesis of bis(saiicylaldehyde) 25. Under a nitrogen atmosphere, compound 33 (1.476g, 12.1 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.017g, 0.024 mmol), copper(I) iodide (0.023g, 0.1 mmol) and benzoquinone (1.177 g, 10.9 mmol) were dissolved in dry toluene (ca. 60 mL). Diisopropylamine (0.018 mmol, 2.5 mL) was added to the mixture, which was then stirred overnight at room temperature. The reaction mixture was diluted with 150 mL water, and the aqueous layer was extracted with 3 x 150 mL methylene chloride. The organic phases were combined and solvent was removed by rotary evaporation. The brown product was purified by filtration through a small plug of Si02 using dichloromethane. Recrystallization from dichloromethane yielded the product as a yellow solid (0.521g, 35 %). ' H N M R (300 MHz, CDC13) 5 11.02 (s, 2H, OH), 9.89 (s, 2H, CH=0), 7.53 (d, 3 J H H = 8.43 Hz, 2H, aromatic CH), 7.15 (dd, 3 J H H = 8.043 Hz, 4 J H H = 1.38 Hz, 2H, aromatic CH), 7.13 (s, 2H, aromatic CH). 1 3 C N M R (75.5 MHz, CDC13) 8 195.78 (CH=0), 161.18, 129.67, 120.87 (aromatic Q , 133.54, 123.74, 121.50 (aromatic CH), 88.30, 77.23 (C=Q. EI-MS: m/z = 290 ( M + , 100 %). UV-vis (CH 2C1 2): Xmax (e) = 338 nm (35000 L modern"1). IR (KBr): v = 3179, 2873, 2348, 1912, 1660, 1615, 1554, 1436, 1270, 1190, 1123,967, 868,795, 761 cm - 1. High res MS Calc'd for C i 8 H i 0 O 4 : 290.05791. Found: 290.0812. Anal. Calc'd for C20H14O4: C, 75.46; H, 4.43. Found: C, 73.17; H, 3.20. Synthesis of bis(salicylaldehyde) 26. Compound 33 (0.500g, 3.42 mmol), 1,4-diiodo- 2,5-dimethoxybenzene 36 (0.65lg, 1.67 mmol), trans-dichlorobis(triphenylphosphine) 37 palladium(II) (0.048g, 2 mol%), and triphenylphosphine (0.013g, 1.5 mol%) were dissolved in dry THF (ca. 25 mL) under nitrogen, followed by the addition of diisopropylamine (ca. 5 mL). The mixture was stirred for 20 mins before the addition of copper(I) iodide (0.019g, 3 mol%). The reaction mixture was heated to reflux overnight under nitrogen. After cooling to room temperature, the solvent was removed by rotary evaporation. The dark brown solid was dissolved in chloroform and was filtered through a short plug of silica gel to remove inorganic catalysts and salt. Recrystallization from methylene chloride yielded a yellow solid (0.345g, 24%). *H N M R (300 MHz, CDC13) 8 11.04 (s, 2H, OH), 9.88 (s, 2H, CH=0), 7.52 (d, 3 J H H = 8.31 Hz, 2H, aromatic CH), 7.19 (dd, 3 J H H = 8.39 Hz, 4 J H H =1.51 Hz, 2H, aromatic CH), 7.16 (s, 2H, aromatic CH), 7.03 (s, 2H, aromatic CH), 3.90 (s, 6H, OCH3). 1 3 C N M R (75.5 MHz, DMSO-d 6 ) 8 190.46 (CH=0), 160.56, 153.89, 129.71, 122.63, 112.68 (aromatic Q, 129.28, 122.58, 119.59, 115.95 (aromatic CH), 94.26, 89.43 (C=C), 56.57 (OCH 3). EI-MS: m/z = 426 ( M + , 100 %), 411 ( M + - C H 3 , 16 %). UV-vis (CH 2C1 2): ^ m a x (e) = 398 (3.51 x 104), 328 (2.58 x 104), 295 (1.86 x 104) nm (L mor'cm"1). IR (KBr): v = 3442, 2925, 2853, 2215, 1669, 1621, 1401, 1236, 1217, 1041, 974, 818, 793 cm"1. High res MS Calc'd for C 2 6H 1 8 0 6 : 426.11034. Found: 426.11048. Macrocycle 14a. Under a nitrogen atmosphere, compound 24 (0.106 g, 0.40 mmol) and l,2-dioctyloxy-4,5-diaminobenezne 37a (0.145 g, 0.40 mmol) were combined in 15 mL of degassed CHC1 3 and 5 mL of degassed MeCN, resulting in a cloudy orange solution. The solution was heated to reflux (90°C) for 24 h, giving a clear, red solution. Upon cooling, a red powder precipitated, which was isolated on a Buchner funnel and washed 38 with MeCN. Yield: 0.16 g (67%). *H N M R (300 MHz, THF-d 8) 5 13.20 (s, 6H, OH), 8.79 (s, 6H, C//=N), 7.48 ( d , 3 J H H = 8.13 Hz, 6H, aromatic CH), 7.15 (s, 6H, aromatic CH), 7.07-7.06 (m, 12H, aromatic CH), 4.09 (t, 3 J H H = 6.33 Hz, 12H, OCH2), 1.80-0.89 (m, 90H, OCU2C7Hi5). MALDI-TOF-MS: m/z = 1785 ([M+H]+). UV-vis (THF): X m a x (s) = 406 (1.20 x 105), 373 (1.13 x 105), 333 (8.79 x 104), 301 (6.73 x 104) nm (L m o r W 1 ) . IR (KBr): v = 3457, 2951, 2924, 2853, 2131, 1607, 1522, 1507, 1493, 1264, 1199, 1116, 986, 871, 808 cm"1. Raman: v = 2208, 1610, 1586, 1546, 1521, 1496, 1437, 1316, 1237, 1187, 1095 cm"1. Mp. > 300 °C. Anal. Calc'd for C 1 1 4 H 1 3 8 N 6 0 1 2 • H 2 0 : C, 75.97; H, 7.83; N , 4.66. Found: C, 75.85; H , 7.93; N , 4.96. Fluorescence: O = 0.14 % Macrocycle 14b. Under a nitrogen atmosphere, bis(salicylaldehyde) 24 (0.123 g, 0.46 mmol) and l,2-di-2-ethylhexyloxy-4,5-diaminobenezne 37b (0.160 g, 0.44 mmol) were combined in 10 mL of degassed C H C I 3 and 10 mL of degassed MeCN, resulting in a cloudy orange solution. The solution was heated to reflux (90°C) for 24 h, giving a clear, red solution. Upon cooling, a red powder precipitated, which was isolated on a Buchner funnel and washed with MeCN. Yield: 0.125 g (45%). *H N M R (300 MHz, CD 2C1 2) 5 13.37 (s, 6H, OH), 8.68 (s, 6H, C//=N), 7.44 (d , 3 J H H = 7.71 Hz, 6H, aromatic CH), 7.23 (s, 6H, aromactic CH), 7.13 (d, 3 J H H = 7.92 Hz , 6H, aromatic CH), 6.89 (s, 6H, aromatic CH), 3.98 (d, 3 J H H = 5.01 Hz, 12H, OCH2), 1.80-0.89 (m, 90H, O C H 2 C 7 / / / 5 ) . M A L D I - TOF-MS: m/z = 1785 ([M+H]+). UV-vis (THF): Xmax (s) = 410 (1.14 x 105) nm (L mol" 'cm"1). IR (KBr): v = 3456, 2960, 2927, 2861, 1604, 1382, 1259, 1197, 985 cm"1. Anal. Calc'd for C i i 4 H 1 3 8 N 6 0 , 2 - 9H 2 0: C, 70.34; H, 8.08; N , 4.32. Found: C, 70.00; H, 7.32; N , 4.22. 39 Macrocycle 15. Compound 25 (0.150 g, 0.47 mmol) and l,2-didecyloxy-4,5- diaminobenzene 38 (0.198 g, 0.47 mmol) were combined in a 100 mL Schlenk flask under nitrogen. Degassed acetonitrile (ca. 4 mL) and degassed chloroform (ca. 12 mL) were added to the flask, giving a cloudy orange solution. The solution was heated to reflux overnight. Upon cooling to room temperature, a red solid precipitated, which was isolated on a Buchner funnel and washed with MeCN. Yield: 0.216 g (62 %). ' H N M R (300 MHz, THF-d 8) 513.19 (s, 6H, OH), 8.79 (s, 6H, C/f=N), 7.48 (d, 3 J H H = 8.28 Hz , 6H, aromatic CH), 7.14 (s, 6H, aromatic CH), 7.09-7.06 (m, 12H, aromatic CH), 4.08 (t, 3 J H H = 6.42 Hz, 12H, OCH2), 1.94-0.86 (m, 114H, OCH 2 C 9 #/ 9 ) . MALDI-TOF-MS: m/z = 2025 ([M+H]+, 100), 2047 ([M+Na]+, 12), 2082 ([M+H 20+K] + , 15). UV-vis (DCM): kmax (e) = 374 (1.32 x 104) nm (L morW). IR (KBr): v = 3457, 2951, 2924, 2853, 2131, 1607, 1522, 1507, 1493, 1264, 1199, 1116,986,871,808 cm"1. Raman: v = 2212, 1615, 1605, 1585, 1574, 1540, 1518, 1501, 1434, 1381, 1343, 1308, 1267, 1239, 1184, 1132, 1019, 905, 817, 592, 577, 512, 484, 413 cm"1. Anal. Calc'd for C i 3 2 H , 6 2 N 6 0 1 2 • H 2 0 : C, 77.61; H, 8.09; N , 4.11. Found: C, 77.31; H, 7.89; N , 4.36. Fluorescence: O = 0.15 % Macrocycle 16. Under a nitrogen atmosphere, compound 26 (0.232 g, 0.54 mmol) and l,2-dioctyloxy-4,5-diaminobenzene 37a (0.198 g, 0.54 mmol) were dissolved in 18 mL of degassed C H C I 3 and 6 mL of degassed MeCN. The solution was heated to reflux (90°C) for 24 h, then cooled to room temperature, yielding red powder. The red solid, macrocycle 16, was isolated on a Buchner funnel, washed with cold MeCN, and dried under vacuum. Yield: 0.17 g (40 %). ' H N M R (300 MHz, THF-dg) 513.16 (s, 6H, OH), 8.78 (s, 6H, C#=N), 7.47 (d, 3 J H H = 8.31 Hz, 6H, aromatic CH), 7.13-7.04 (m, 24H, 40 aromatic CH), 4.09 (t, 3 J H H = 6.26 Hz, 12H, OCH2), 3.90 (s, 18H, -OCH3), 1.7-0.8 (m, 90H, OCU2C1Hi5). MALDI-TOF-MS: m/z = 2265([M+H]+, 100), 2326 (10). UV-vis (THF): lmax (s) = 408 (1.87 x 104), 329 (9.02x 104) nm (L mor'cm"1). IR (KBr): v = 3428, 2923, 2851, 2202, 1608, 1490, 1263, 1217, 1039, 804 cm"1. Raman: v = 2201, 1603, 1587, 1552, 1513, 1432, 1363, 1315, 1272, 1237, 1178, 1079 cm"1. Anal. Calc'd for C,44H 1 6 2N 6Oi8 • 5H 2 0: C, 73.44; H, 7.36; N , 3.57. Found: C, 73.37; H, 7.16; N , 3.94. Fluorescence: O - 0.13 %. 2.3 Results and Discussion Large triangular macrocycles with different sizes could be prepared by reacting 1,2- dialkoxy-4,5-phenylenediamine with various bis(salicylaldehydes). Carbon-carbon triple bonds have been incorporated in many macrocycles such as phenylacetylene macrocycles (PAMs). 2 Moreover, owing to the well-documented methods of connecting an sp carbon to an sp2 or sp carbon center, and small steric hinderance and structural linearity, the acetylene linkage is a useful candidate to be incorporated into the dialdehydes in order to create macrocycles of different sizes.1 9 We embarked on our research by preparing bis(salicylaldehydes) 24, 25 and 26, which are the precursors of macrocycles 14, 15 and 16 respectively (Figure 2.1). 41 26 Figure 2.1. Bis(salicylaldehyde) precursors of [3+3] Schiff-base macrocycles 14, 15 and 16. 2.3.1 Synthesis and characterization of bis(salicylaldehydes) In order to access bis(salicylaldehyde) precursors of the correct geometry, we needed to prepare 4-bromosalicylaldehyde 31. While the derivative with the Br oriented para to the oxygen (5-bromosalicylaldehyde) is commercially available, this derivative is not. Compound 31 has been previously prepared in 2 % yield as a byproduct in the Reimer- 20 Tiemann reaction of 3-bromophenol. We sought an improved synthesis of compound 31. Bromination of commercially available o-anisidine using N-bromosuccinimide (NBS) readily afforded compound 28 high yield. The reaction is regioselective. The product was then converted to to 4-bromo-1 -iodo-2-methoxybenzene 29 using a Sandmeyer reaction (NaNC>2, HC1, KI) in 76 % yield. The resulting compound was then treated with "BuLi and DMF, giving the intended product 30 after workup with aqueous HC1 with high selectivity. Deprotection of the phenol with boron tribromide yielded the desired 4- bromosalicylaldehyde 31 with an overall yield of 19 % (Scheme 2.3). Simpler alternative 42 routes to the desired 4-halo-salicylaldehydes were also investigated. 3-Bromophenol can be formylated by treatment with paraformaldehyde in toluene in the presence of tin(IV) chloride and triethylamine; however, the reaction only led to compound 31 in 5 % yield. On the other hand, treatment of 3-bromophenol or 3-iodophenol with anhydrous magnesium chloride, triethylamine and paraformaldehyde, affording the desired 4- bromosalicylaldehyde 31 or 4-iodosalicylaldehyde 35 in 13 % and 31 % yield, respectively (Scheme 2.4). The higher yield for the reaction of 3-iodophenol may be due to the steric hinderance of the iodide, which could minimize the formation of 2- iodosalicylaldehyde, a likely byproduct of this reaction. Pd-catalyzed Sonogashira- Hagihara cross-coupling of 31 and trimethylsilane acetylene followed by cleavage of the TMS group yielded the intended 4-ethynylsalicylaldehyde 33. Coupling of compound 33 with 31 or 35 gave bis(salicylaldehyde) 24 (Scheme 2.3). 43 OMe OMe OMe NBS MeCN, 0°C ,NH 2 a) HC1, NaN0 2 • b) KI, 0°C 27 28 29 a) "BuLi, Et 2 0, -78°C b) DMF, -78°C to r.t. c) H 2 0 , HC1 OH a) BBr 3 , D C M , 0°C b) H 2 0 a) Pd(PPh 3) 2Cl 2, PPh 3 ' 3 1 b) NEt 3 c) Trimethylsilylacetylene / T H F r t d) Cul TMS a) Pd(PPh 3) 2Cl 2, PPh 3 b) NEt 3 c) Cul \ Scheme 2.3. Synthetic route to bis(salicylaldehyde) 24. OH M g C l 2 , ( C H 2 0 ) „ • MeCN, 90°C 31 X = Br 35 X = I Scheme 2.4. Alternative route to 4-halosalicylaldehydes. Bis(salicylaldehyde) 26 was synthesized via Sonogashira-Hagihara coupling of 4- ethynylsalicylaldehyde 33 with l,4-diiodo-2,5-dimethoxybenzene 36 (Scheme 2.5). Compound 25 was prepared by Glaser oxidative coupling of 4-ethynylsalicylaldehyde (Scheme 2.6). The conditions of the oxidative coupling were similar to Sonogashira coupling, with the addition of benzoquinone as an oxidant.21 Two other procedures of Glaser coupling were found in the literature and were investigated.22"23 One procedure used PdCi2(PPh3)3, Cul, N E t 3 and PPI13 as catalysts; another procedure employed CuCb, CuCl catalyst and pyridine. However, these reactions did not proceed to give the intended product. The formation of bis(salicylaldehydes) 24 (Figure 2.2), 25 (Figure 2.3) and 26 (Figure 2.4) was confirmed by ' H N M R spectroscopy. The *H N M R spectra of all three bis(salicylaldehydes) revealed the presence of a single aldehyde and a strongly hydrogen- 13 bonded OH signal. The C N M R spectrum of compound 24 showed only one environment (5 91.34) for the C=C moiety, consistent with the structure of the bis(salicylaldehyde) 24. The 1 3 C N M R spectra obtained for compounds 25 and 26 showed two resonances between 77-95 ppm assigned to the alkyne moieties. The C=0 45 stretching modes were observed at 1659, 1660 and 1669 cm"1 for compounds 24, 25 and 26, respectively. Scheme 2.5. Synthesis of bis(salicylaldehyde) 26. a) Pd(PPh3)2Cl2, PPh3 b) iPr2NH c) Cul d) 0.9 eq. benzoquinone Toluene, r.t. \ /r\. OH 25 Scheme 2.6. Synthesis of bis(salicylaldehyde) 25. 46 V S dpin 11.0 10.5 10.0 9.5 9.0 B.5 8.0 7.5 7.0 Figure 2.2. ' H N M R spectra of bis(salicylaldehyde) 24 (300 MHz; CDC13). *r «r i n tri t\i Figure 2.3. ' H N M R spectra of a) bis(salicylaldehyde) 25 (300 MHz; CDC1 3). Figure 2.4. ' H N M R spectra of a) bis(salicylaldehyde) 26 (300 MHz; CDC1 3). 2.3.2 Synthesis and charaterization of macrocycles The reaction of compound 24 with diamine 37a was performed under nitrogen, affording a red powder 14a in 68% yield (Scheme 2.7). The ] H N M R spectrum of macrocycle 14a revealed the presence of a single imine (5 8.58) and a strongly hydrogen- bonded OH resonance (8 13.27), consistent with Dj/, symmetry for macrocycle 14a (Figure 2.5). MALDI-TOF mass spectrometry showed the molecular ion at m/z = 1785 a.m.u, supporting the structure of 14a (Figure 2.6). The Raman spectrum of compound 14a showed a single C=C stretching mode at 2208 cm"1. A single imine stretching mode was observed at 1607 cm"1 in the IR spectrum. The absence of any C=0 stretches at 1660-1715 cm"1 or N - H stretches at 3300-3500 cm' 1 confirmed that the diamine and dialdehyde were absent in the product. 48 Solvent choice was found to be critical for the macrocycle preparations. The solvent C H C I 3 : MeCN ratio was adjusted to 3:1 such that only the cyclic trimer would precipitate from the solution once it was formed. The driving force to form the large macrocycle is likely to be entropic, as well as the low solubility of the macrocycle in 3:1 C H C I 3 : MeCN. To improve the solubility of the macrocycle, the linear alkoxy substituents can be replaced by chiral branched alkoxy chains, such as 2-ethylhexyloxy groups. The ethylhexyl analogue, 14b, was prepared by a similar procedure, in which bis(salicylaldehyde) 24 was treated with diamine 37b to yield the desired macrocycle 14b in 45% yield (Scheme 2.7). The CHC1 3 : MeCN ratio was adjusted to 1:1, as the ethylhexyl macrocycle 14b was more soluble than 14a in C H C I 3 . The structure of macrocycle 14b was confirmed by ' H N M R spectroscopy (Figure 2.7). The ' H N M R spectrum of 14b showed only one environment for each of the hydroxyl and imine protons, consistent with the 3-fold symmetry of the macrocycle. Macrocycle 14b was also characterized by MALDI-TOF mass spectrometry. The correct molecular weight (M+l) was observed for macrocycle 14b. 49 37a (R = " C 8 H : 7 ) 37b (R = 2-ethylhexyl) RO OR 14a (R = n C 8 H 1 7 ) 14b (R = 2-ethylhexyl) Scheme 2.7. Synthesis of [3+3] Schiff-base macrocycles 14. o> en S \F "Ml \ M VP1 \M - J r ppm Figure 2.5. ' H N M R spectrum of [3+3] Schiff-base macrocycle 14a (300 MHz; d8-TUF) 50 6 0 0 8 0 0 1 0 0 0 1 2 0 0 1 4 0 0 1 6 O 0 1 8 0 0 m / z Figure 2.6. MALDI-TOF mass spectrum of [3+3] Schiff-base macrocycle 14a. i n to o i n m to n (\J o ED <£i I D cn T o m v r-- i n m o i n P I o i o i o i cn 12.5 10.0 7.5 5.0 5/ppm 2.5 0.0 -2.5 Figure 2.7. ' H N M R spectrum of [3+3] Schiff-base macrocycle 14b (300 MHz; CDC13). 51 To generalize and test the [3+3] Schiff-base condensation route to giant macrocyclic proligands, longer bis(salicylaldehydes) 25 and 26 were reacted with diamines 38 and 37a, which were chosen for reasons of solubility, yielding macrocycles 15 and 16, respectively (Scheme 2.8). Remarkably, these macrocycles were obtained in 62 and 40 % yield, respectively. The structures of macrocycle 15 and 16 were confirmed by ' H N M R spectroscopy (Figure 2.8 and 2.9) and MALD-TOF mass spectrometry. Recrystallization of the macrocycles was attempted in DMF, DMSO, a mixture of CHCi3/MeCN, pyridine, diethyl ether, D C M / M e C N mixture and THF. Unfortunately, good quality crystals were not obtained. A l l three macrocycles 14a, 15 and 16 are weakly luminescent in THF (O = 0.13 - 0.15 %) with emission wavelengths at 561, 556, 562 nm, respectively. The UV-Vis spectra of macrocycles 14-16 showed peaks at 406, 409 and 408 nm in THF. Scheme 2.8. Synthesis of [3+3] macrocycles 15 and 16. 52 ID m i ID o r - i n i n i o o i i n i o f i ID •« D3 ifl o a j i D « N r l i n i ( n « W i D ' J - m ' T - o o f f l i n r ) ^ o ) ( B ( O N i r i n i n ' ) v n <n m en i n a> II i Figure 2.8. ' H N M R spectrum of [3+3] Schiff-base macrocycle 15 (300 MHz; ds-THF). ID —' ID — O - ^ N O l O I O O O W N t r\j o N o i ^ o r > - c n o c j i i D r - - c o o m " CD m o i m cn o r-- »* C\J o ( U i 1 ^ * V S \ l / H \ IU UL - i — i — . — • — i — [ - - , — , — , — , — i — | - 12.5 10.0 7.5 5.0 2.5 0.0 -2.5 Figure 2.9. ' H N M R spectra of [3+3] Schiff-base macrocycle 16 (300 MHz; J S-THF). 53 It is surprising that the one-pot, template-free synthesis of these expanded macrocycles proceeded in moderate to good yield, given the rotational flexibility of the precursor bis(salicylaldehydes) 24-26. Whereas in the preparation of macrocycle 23, the diformyldihydroxybenzene precursor has a fixed geometry, there is nearly free rotation around the benzene-alkyne bond in 24-26. These reactions were not conducted under dilute conditions, with removal of water, or in the presence of a template. *H N M R spectroscopy of the supernatant solution from the preparation of 14a showed only the macrocycle and a fragment formed by the condensation of 24 and 37a in a 1:2 ratio, without the formation of oligomeric or polymeric materials (Figure 2.10).24 We believe that the reversibility of the imine condensation reaction allows the reaction to reach the thermodynamically favoured [3+3] condensation products rather than other macrocycles or polymer. The driving force for formation of these [3+3] macrocycles is considered to be the increase of entropy and the multiple intramolecular hydrogen-bonds within the cyclic trimers. The hydroxyl protons of the macrocycles showed narrow peaks in the 1H N M R spectra and were observed at around 13 ppm, indicating the existence of strong hydrogen bonding, which stabilized the [3+3] macroycle. 54 1 ' 1 I 1 — 1 ' I ' 1 ' I 1 1 ' I ' ' ' I 1 ' 1 1 1 1 • [ 1 PB« 12 10 B 6 4 2 0 Figure 2.10. ' H N M R of supernatant solution from preparation of 14a. (300 MHz; CDCI3) Semiempirical calculations of their flat conformations indicate that macrocycles 14 and 15 have edge lengths (from the center of the salen pockets) of about 13.3 and 15.5 A , respectively. Macrocycle 16, a covalently bound ring with 66 atoms, has an interior diameter of > 15 A , and the salen pockets are arranged in an equilateral triangle separated by about 20.0 A. The incorporation of phenyleneethynylene spacers into the backbone of the macrocycles has enabled the facile preparation of large macrocycles with tunable diameters. In summary, the target [3+3] Schiff-base macrocycles were obtained. They were characterized by ! H N M R spectroscopy, MALDI-TOF mass spectrometry, IR spectroscopy, UV-vis spectroscopy, and fluorescence spectroscopy. The efficient methods for synthesizing [3+3] Schiff-base macrocycles allow us to build new large 55 shape-persistent conjugated macrocycles with tunable pore diameters in the nanometer regime. These macrocycles are of interest as they possess salphen functionality which could potentially bind to transition metals. They also represent a new type of molecular building block for the assembly of porous material. 56 2.4 Reference 1. (a) Moore, J. S.; Zhang, J. Angew. Chem. Int. Ed. Engl. 1992, 31, 922-944. (b) Hoger, S.; Meckenstock, A.-D. ; Pellen, H. J. Org. Chem. 1997, 62, 4556-4557. 2. (a) Zhao, D.; Moore, J. S. Chem. Commun. 2003, 807-818. (b) Hoger, S. Chem. Eur. J. 2004,10, 1320-1329. 3. (a) Bunz, U.H.F.; Rubin, Y. ; Tobe, Y. Chem. Soc. Rev. 1999, 28, 107. (b) Faust, R. Angew. Chem. Int. Ed. Engl. 1998, 37, 2825-2828. 4. Grave, C ; Schluter, A . D. Eur. J. Org. Chem. 2002, 3075-3098. 5. For recent examples of shape-persistent, conjugated macrocycles, see: (a) Yamaguchi, Y. ; Kobayashi, S.; Miyamura, S.; Okamoto, Y. ; Wakamiya, T.; Matsubara, Y . ; Yoshida, Z. Angew. Chem. Int. Ed. Engl. 2004, 43, 366-369. (b) Muller, P.; Uson, I.; Hensel, V. ; Schluter, A . D.; Sheldrick, G. M . Helv. Chim. Acta 2001, 84, 778-785. (c) Mayor, M . ; Didschies, C. Angew. Chem. Int. Ed. Engl. 2003, 42, 3176-3179. (d) Tobe, Y. ; Utsumi, N . ; Nagano, A. ; Naemura, K. Angew. Chem. Int. Ed. Engl. 1998, 37, 1285-1287. (e) Campbell, K.; Tiemstra, N . M . ; Prepas-Strobeck, N . S.; McDonald, R.; Ferguson, M . J.; Tykwinski, R. R. Synlett 2004, 182-186. (f) Fischer, M . ; Lieser, G.; Rapp, A . ; Schnell, I.; Mamdouh, W.; De Feyter, S.; De Schryver, F. C ; Hoger, S. J. Am. Chem. Soc. 2004,126, 214-222. (g) Hoger, S.; Enkelmann, V. ; Bonrad, K.; Tschierske, C. Angew. Chem. Ent. Ed. Engl. 2000, 39, 2267. (h) Eisler, S.; Tykwinski, R. R.; Angew. Chem. Int. Ed. Engl. 1999, 38, 1940-1943. 6. Lindoy, L. F., The Chemistry of Macrocylic Ligand Complexes. 1989, Cambridge: Cambridge University Press. P. 1-269. 57 7. Atkins, A . J.; Black, D.; Blaske, A. J.; Marin-Becerra, A. ; Parson, S.; Rui-Ramirez, L.; Schroder, M . Chem. Commun. 1996, 457-464. 8. Pilkington, N . H. ; Robson, R. Aust. J. Chem. 1970, 23, 2225-2236. 9. Tandon, S. S.; Thompson, L. K.; Bridson, J. N . ; McKee, V. ; Downard, A . J. Inorg. Chem. 1992, 31, 4635-4642. 10. Kruger, P. E.; McKee, V. Chem. Commun. 1997, 1341-1342. 11. McCrea, J.; McKee, V. ; Metcalfe, T.; Tandon, S. S.; Wikaira, J. Inorg. Chim. Acta 2000, 297, 220-230. 12. Tian, Y. ; Tong, J.; Frenzen, G.; Sun, J. J.Org. Chem. 1999, 64, 1442-1446. 13. For recent examples of [3+3] Schiff-bases macrocycles, see: (a) Gawrohski, J.; Kolbon, H. ; Kwit, M . ; Katrusiak, A. J. Org. Chem. 2000, 65, 5768. (b) Kuhnert, N . ; Rossignolo, G.M. ; Lopez-Periago, A . Org. Biomol. Chem. 2003, 1, 1157-1170. (c) Shimakoshi, H. ; Kai, T.; Aritome, I.; Hisaeda, Y. Tetrahedron Lett. 2002, 43, 8261-8264. (d) Kwit, M . ; Gawrohski, J. Tetrahedron Asymmetry 2003, 14, 1303-1308. (e) Gao, J.; Martell, A . E. Org. Biomol. Chem. 2003, 1, 2795-2800. (f) Chadim, M . ; Budesinsky, M . ; Hodacova, J.; Zavada, J.; Junk, P. C. Tetrahedron Asymmetry 2001, 12, 127-133. (g) Akine, S.; Taniguchi, T.; Nabeshima, T. Tetrahedron Lett. 2001, 42, 5307-5310. 14. Gallant, A . J.; MacLachlan, M . J. Angew. Chem. Int. Ed. Engl. 2003, 42, 5307-5310. 15. Kim, D.-H.; Choi, M . J.; Chang, S.-K. Bull. Korean Chem. Soc. 2000, 21, 145-147. 16. Tromelin, A. ; Demerseman, P.; Royer, R.; Gayral, P.; Fourniat, J. Eur. J. Med. Chem. 1986, 21, 397-402. 17. Waybright, S. M . ; Singleton, C. P.; Wachter, K.; Murphy, C. J.; Bunz, U . H. F. J. Am. Chem. Soc. 2001,123, 1828-1833. 58 18. Parker, C. A . Photoluminescence of Solutions, I s ed.; Elsevier Publishing Company: Amsterdam, 1968; p 261. 19. (a) Sonogashira, K.; Tohda, Y. ; Hagihara, N . Tetrahedron Lett. 1975, 4467-4470. (b) Hundertmark, T.; Littke, A . F.; Buchwald, S. L.; Fu, G.C. Org. Lett. 2000, 2, 1729-1731. (c) Siemsen, P.; Livingston, R. C ; Diederich, F. Angew. Chem. Int. Ed. 2000, 39, 2632- 2657. 20. Sazanovich, I. V. ; Balakumar, A. ; Muthukumaran, K.; Hindin, E.; Kirmaier, C ; Diers, J. R.; Lindsey, J. S.; Bocian, D. F.; Holten, D. Inorg. Chem. 2003, 42, 6616-6628. 21. Willliams, V . E.; Swager, T. M . J. Polym. Scl, Part A: Polym. Chem. 2000, 38, 4669- 4676. 22. Fairlamb, J. S.; Bauerlein, P. S.; Marrison, L. R.; Dickinson, J. M . Chem. Commun. 2003,632-633. 23. Hoger, S.; Meckenstock, A. D.; Muller, S. Chem. Eur. J. 1998, 4, 2423-2434. 24. ' H N M R (300 MHz, CDC13) data for condensation product of 24 and 37a in 1:2 ratio. 5 13.24 (s, 2H, OH) 8.53 (s, 2H, CH=N), 7.35(d, 2H, CH), 7.16 (d, 2H, CH), 7.10 (dd, 2H, CH), 6.77 (s, 2H, CH), 6.34 (s, 2H, CH), 3.94 (m, 4H, OCH2), 3.85 (s, 4H, N#2).1.8- 0.8 (m, 60H, C7H15). 59 Chapter 3 Metal-Containing [3+3] Schiff-base Macrocycles 3.1 Background The incorporation of metals into organic macrocycles may lead to promising new materials for a range of applications, including catalysis and sensing. Multimetallic macrocycles have been extensively pursued owing to their potential applications in catalytic and host-guest chemistry.1 Metal-containing macrocycles can be prepared by the self-assembly of metal-coordination complexes in solution. These metallomacrocycles, however, are held together by metal-ligand bonds, and the stability of macrocycles depends on coordinate bonding. The addition of transition metals to conjugated and covalently-bonded macrocycles is anticipated to give new properties to the macrocycles. Moreover, by making use of coordination chemistry, the metallomacrocycles may be linked by intermolecular bridging ligands such as 4, 4'-bipyridine to generate hierarchical structures. Schiff-base complexes are attractive compounds to incorporate into macrocycles since they possess N2O2 binding sites that can chelate to metal ions. The resultant Schiff- base complexes are of current interest for their catalytic and optical properties. It has been well-documented that metallosalens offer high reactivity and selectivity in epoxidation of olefins.2 Molecular systems containing multiple metal centres capable of cooperative interactions are attractive materials for the development of efficient catalysts. Schiff-base dicopper(II) macrocycles have been used in catalysis (Figure 3.1). Schiff- base complexes have also been previously identified as highly luminescent; recent studies revealed that tetradentate Schiff-base Pt(II) complexes exhibit white emission.4 60 Luminescent Schiff-base complexes have also been used in blue LEDs. Conjugated macrocycles incorporating metallosalphen complexes could be luminescent and may be excellent candidates for metal-organic LED materials. 39 Figure 3.1. Structure of Schiff-base dicopper (II) complex. The MacLachlan group has prepared [3+3] Schiff-base metallomacrocycles 40 (Figure 3.2). However, the metallomacrocycles are nonplanar due to their constrained geometry. The expanded metal-containing [3+3] Schiff-base macrocycles highlighted in this chapter can be prepared by the reaction of [3+3] Schiff-base macrocycles 14-16 with transition metals such as Zn(II) and Ni(II) (Figure 3.3). It is anticipated that the macrocycles can coordinate at least three metal ions in their three salphen-type pockets and would have a relatively planar geometry compared to metallomacrocycles 40. The resultant [3+3] metallomacrocycles are expected to exhibit different optical properties compared with the metal-free macrocyclic ligands. Unlike the Robson-type metallocycles, where the metal ions occupy the central voids, these new [3+3] metallocycles possess central cavities, and thus have the potential to be stacked into hollow tubular structures with coordination chemistry. 61 RO OR 40 (R= nC 6H 1 3) Figure 3.2. [3+3] Schiff-base metallomacrocycle 40. RO OR 17(R = n C 8 H 1 7 ) , M = Zn 18 (R = 2-ethylhexyl), M = Zn, Ni, Cu 19(R = n C 1 0 H 2 1 ) , M = Zn 20 (R = "C 8 H 1 7 ) , M = Zn Figure 3.3. Target metal-containing [3+3] Schiff-base macrocycles. 62 3.2 Experimental Materials. Zinc(II) acetate, nickel(II) acetate, copper(II) acetate were obtained from Aldrich. Trans-dichlorobis(triphenylphosphine) palladium(II) was obtained from Strem Chemicals, Inc. Tetrahydrofuran (THF) was distilled from sodium / benzophenone under nitrogen. Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. Macrocycles 14-16 were prepared by the procedure described in Chapter 2. Equipment A l l reactions were carried out under nitrogen atmosphere unless otherwise noted. 300 M H z ' H N M R spectra and 75.5 MHz 1 3 C N M R spectra were recorded on a Bruker AV-300 spectrometer. ' H N M R spectra were calibrated to the residual protonated solvent at 5 7.24 in C D C I 3 or 5 3.58 in THF-ds. UV-vis spectra were obtained in THF (ca. x 10"6 M) on a Varian Cary 5000 UV-vis-near-IR spectrophotometer using a 1 cm quartz cuvette. IR spectra were obtained as KBr discs with a Bomems MB-series spectrometer. Fluorescence spectra were obtained in distilled THF on a Photon Technology International QuantaMaster fluorimeter using a 1 cm quartz cuvette. Quantum yield was referenced to a solution of anthracene in EtOH (<B = 0.30). M A L D I mass spectra were obtained in a dithranol matrix at the UBC Microanalytical Services Laboratory on a Micromass LCT time-of-flight (TOF) mass spectrometer. Electron Impact (EI) mass spectra and elemental analyses were also performed at the U B C Microanalytical Services laboratory. Melting points were obtained on a Fisher-John's melting point apparatus. Raman spectra were obtained on a Renishaw Raman microscope 1000 with excitation at 785 nm. 63 Synthesis of metallomacrocycle 17. Under a nitrogen atmosphere, macrocycle 14a (0.102 g, 0.05 mmol) and Zn(OAc) 2 • 2H 2 0 (0.040 g, 0.18 mmol) were dissolved in 20 mL of dry THF. After heating at reflux (70°C) for 2 h, the red solution was cooled to room temperature. The solvent was evacuated and macrocycle 17 was isolated on a Buchner funnel and washed with hot MeOH. Yield: 0.090g (80 %). *H N M R (300 MHz, THF-dg) 5 8.85 (s, 6H, CH=N), 7.40 (s, 6H, aromatic CH), 7.24 (d, 3 J H H = 8.39 Hz, 6H, aromatic CH), 7.16 (s, 6H, aromatic CH), 6.56 (d, 3 J H H = 8.55 Hz, 6H, aromatic CH), 4.13 (t, 3 J H H = 6.60 Hz, 12H, OCH2), 1.94-0.90 (m, 90H, OCH2C7HJ5). MALDI-TOF- MS: m/z = 1974 ([M+H]+), 1972 ([M+H-Zn]+), 1848 ([M+H-2Zn]+), 1785 ([M+H-3Zn]+) UV-vis (THF): Xmax (s) = 481 (9.08 x 104), 442 (1.33 x 105), 379 (8.64 x 104), 353 (9.73 x 104) nm (L mof'cm"1). IR (KBr): v = 3438, 2950, 2924, 2854, 2131, 1606, 1586, 1507, 1481, 1467, 1384, 1375, 1268, 1170, 1134 cm"1. Mp. > 300 °C. Anal. Calc'd for Cii 4H,32N 60i2 Zn 3- 9H 2 0 : C, 64.08; H, 7.08; N , 3.93. Found: C, 63.95; H , 7.08; N , 4.12. Fluorescence: O = 0.86 %. A, m a x = 558 nm. Synthesis of metallomacrocycle 18a. Under nitrogen atmosphere, macrocycle 14b (0.052g, 0.03 mmol) and Zn(OAc) 2 • 2 H 2 0 (0.020 g, 0.09 mmol) were dissolved in 20 mL of dry THF. After heating at reflux (70°C) for 2 h, the red solution was cooled to room temperature. The solvent was evaculated and macrocycle 18a was isolated on a Buchner funnel and washed with hot MeOH. Yield: 0.031 g (54 %). ' H N M R (300 MHz, THF-dg) 8 8.86 (s, 6H, CH=N), 7.40 (s, 6H, aromatic CH), 7.25 ( d , 3 J H H = 7.84 Hz, 6H, aromatic CH), 7.17 (s, 6H, aromatic CH), 6.56 (d, 3 J H H = 8.54 Hz, 6H, aromatic CH), 4.06 (t, 3 J H H = 4.81 Hz, 12H, OCH2), 1.94-0.90 (m, 90H, OCH 2 C 7 / / / j ) . MALDI-TOF- 64 MS: m/z = 1974 ([M+H]+). UV-vis (THF): X m a x (e) = 482 (8.13 x 105), 442 (1.18 x 106), 378 (7.40 x 105), 352 (8.48 x 105) nm (L mol"'cm"'). IR (KBr): v = 3437, 2956, 2923, 2861, 1605, 1507, 1480, 1383, 1266, 1134 cm"1. Anal. Calc'd for CuHniNeOizZna- 13H 20: C, 61.99; H, 7.21; N , 3.81. Found: C, 61.50; H, 6.68; N , 3.57. Synthesis of macrocycle 18b. Macrocycle 14b (0.059 g, 0.033 mmol) and Ni(acac)2 (0.027, 0.010 mmol) were added to 30 mL dry THF in a 100 mL Schlenk flask. The solution was heated to reflux for 3 h. After solvent was removed under reduced pressure, the remaining solid was washed with hot methanol followed by filtration to yield dark red solid as product (0.059 g, 91 %). The compound was too insoluble to obtain a ' H N M R spectrum in CDC1 3 or THF. MALDI-TOF-MS: m/z - 1955 ([M+H]+). UV-vis (THF): kmax (e) = 439 (1.27 x 105), 416 (1.33 x 105), 351 (8.33 x 104) nm (L mor'cm"1). IR (KBr): v = 3442, 2953, 2925, 2855, 1604, 1579, 1482, 1277, 1181 cm"'. Anal. Calc'd for C114H132N6O12 N i 3 - 6H 2 0 : C, 66.39; H, 7.04; N , 4.07. Found: C, 66.29; H, 6.72; N , 4.51. Synthesis of macrocycle 18c. Under nitrogen atmosphere, macrocycle 14b (0.055g, 0.03 mmol) and Cu(OAc) 2 • H 2 0 (0.019 g, 0.096 mmol) were dissolved in dry THF (ca. 25 mL). The solution was heated to reflux for 80 min. After solvent was removed under reduced pressure, compound 18c was isolated on a Buchner funnel and washed with hot methanol, giving dark red solid as product (0.037 g, 61 %). MALDI-TOF-MS: m/z = 1970 ([M+H]+). UV-vis (THF): Xmax (e) = 452 (1.27 x 104), 3 72 (1.33 x 104) nm (L mol" 'cm"'). IR (KBr): v = 3450, 2956, 2927, 2852, 1602, 1580, 1478, 1364, 1270, 1175, 799 65 cm"1. Anal. Calc'd for C , i 4 H 1 3 2 N 6 0 1 2 C u 3 • 13H 20: C, 62.15; H, 7.23; N , 3.81. Found: C, 61.77; H, 6.56; N , 3.81 Synthesis of macrocycle 19. Macrocycle 15 (0.100 g, 0.049 mmol) and Zn(OAc) 2 • 2 H 2 0 (0.033 g, 0.158 mmol) were added to 30 mL dry THF in a 100 mL Schlenk flask. The solution was heated to reflux for 3 hours. After solvent was removed under reduced pressure, the remaining solid was washed with hot methanol followed by filtration to yield dark red solid as product (0.073 g, 55 %). ' H N M R (300 MHz, THF-dg) 5 8.85 (s, 6H, CH=N), 7.40 (s, 6H, aromatic CH), 7.24 (d , 3 J H H = 8.39 Hz, 6H, aromatic CH), 7.16 (s, 6H, aromatic CH), 6.56 (d, 3 J H H = 8.55 Hz, 6H, aromatic CH), 4.13 (t, 3 J H H = 6.60 Hz, 12H, OCH2), 1.94-0.90 (m, 126H, OCU2C9H19). MALDI-TOF-MS: m/z = 2216 ([M+H]+, 100), 2152 ([M+H-Zn]+, 30), 2089 ([M+H-2Zn]+, 15). UV-vis (THF): A™x (e) = 446 (12900) nm (L mor'cm"1). IR (KBr): v = 3439, 2924, 2853, 2854, 2347, 2207, 1607, 1586, 1502, 1466, 1384, 1207, 1129, 981, 871 cm"1. C i 3 2 H i 5 6 N 6 O i 2 Zn 3- 9H 2 0: C, 66.70; H, 7.38; N , 3.54. Found: C, 66.52; H, 7.12; N , 3.82. Fluorescence: O = 0.92 %. Synthesis of macrocycle 20. Under a nitrogen atmosphere, macrocycle 16 (0.165 g, 0.07 mmol) and Zn(OAc) 2 • 2 H 2 0 (0.051 g, 0.23 mmol) were dissolved in dry THF (ca. 25 mL). The solution was heated to reflux for 80 minutes. After solvent was removed under reduced pressure, compound 20 was isolated on a Buchner funnel and washed with hot methanol, giving dark red solid as product (0.139 g, 78 %). ' H N M R (300 MHz, THF-dg) 5 8.87 (s, 6H, CH=K), 7.38 (s, 6H, aromatic CH), 7.25 ( d , 3 J H H = 8.16 Hz, 6H, aromatic 66 CH), 7.12 (s, 6H, aromatic CH), 7.06 (s, 6H, aromatic CH), 6.59 (d, 3 J H H = 8.39 Hz, 6H, aromatic CH), 4.13 (t, 3 J H H = 5.58 Hz, 12H, OCH2), 3.93 (s, 18H, OCH3), 1.94-0.90 (m, 102H, OCH 2C 7Zf/x). MALDI-TOF-MS: m/z = 2456 ([M+H]+, 100), 2392 ([M+H-Zn]+, 35), 1196 ([M+2H] 2 +, 20). UV-vis (THF): lmax (e) = 438 (1.83 x 105), 337 (8.54 x 105) nm (L mor'cm"1). IR (KBr): v = 3423, 2923, 2852, 2385, 2348, 1606, 1586, 1468, 1384, 1267, 1216, 1171, 796 cm"'. Anal. Calc'd for C i 4 4H 1 5 6N 6 0 1 8 Zn 3- 8H 2 0: C, 66.54; H, 6.67; N , 3.23. Found: C, 66.04; H, 6.03; N , 3.35. Fluorescence: <D = 0.90 %. Synthesis of compound 41. Under inert atmosphere, l,2-di-2-ethylhexyloxy-4,5- diaminobenezne 37b (0.364g, 1.00 mmol) and salicylaldehyde (0.244g, 2.00 mmol) were dissolved in dry THF (ca. 25 mL) in a Schlenk flask. The reaction was heat to reflux and stirred overnight. The solvent was removed partially under reduced pressure and methanol was added to precipitate an orange powder. The product was then isolated on a Buchner funnel (0.504 g ,88%). ' H N M R (300 MHz, CDC13) 5 13.20 (s, 2H, OH), 8.60 (s, 2H, C//=N), 7.38-7.30 (m, 4H, aromatic CH), 7.25 (d , 3 J H H = 8.22 Hz, 2H, aromatic CH), 6.90 (t, 3 J H H = 7.39 Hz, 2H, aromatic CH), 6.79 (s, 2H, aromatic CH), 3.92 (t, 3 J H H = 5.72 Hz, 4H, OCH2), 1.79-0.88 (m, 30H, OCH 2 C 7 #,j) . 1 3 C N M R (75.5 MHz, CDC13) 5 161.91. 161.18, 149.40, 135.17, 132.97, 132.08, 119.37, 118.88, 117.51, 104.51 (aromatic Q , 72.11 (OCH 2), 39.63, 30.60, 29.15, 23.94, 23.07, 14.09, 11.21 (OCH 2 C 7 H 1 5 ) . M A L D I - TOF-MS: m/z = 572.9 ([M+H]+). UV-vis (THF): lmax (s) = 3 45 (2.06 x 104) nm (L mol" 'cm"'). IR (KBr): v = 3431, 2959, 2927, 2856, 1609, 1554, 1260, 1181, 1169, 752, 704 cm"'. Anal. Calc'd for C 36H48N 20 4 Zn 3 : C, 75.49; H, 8.45; N , 4.89. Found: C, 75.61; H, 8.24; N , 4.99. 67 Metal Titration Experiments. Titration experiments were performed by adding aliquots (via microlitre syringe) of a metal salt (Zn(OAc)2'2H20 in THF or Ni(OAc)2 in EtOH; 8xl0" 5 M) to a quartz cuvette containing ca. lxlO" 6 M of macrocycle in ~ 3.5 mL of THF. 3.3 Results and Discussion The MacLachlan group has previously reported the synthesis of macrocycle 13.6 Due to its constrained geometry, however, the macrocycle is nonplanar when coordinated to transition metals. Macrocycle 13 was found to be coordinated to seven Zn(II) ions and possessed a bowl-shaped geometry. In order to develop trimetallated and flat macrocycles that can be assembled into nanotubes, we introduced transition metals into the giant macrocycles 14-16 prepared in Chapter 2. These macrocycles possess both nanoscopic pores and three N2O2 binding sites that can coordinate transition metals. 3.3.1 Synthesis of metallomacrocycles Metallation of the giant macrocycles was investigated to demonstrate that these macrocycles can coordinate multiple transition metals in their salen-type pockets. The preparation of the metallated macrocycles was originally conducted in air and wet solvent, resulting in low yield. The presence of water in the solvent and atmosphere may cause the macrocycle to dissociate during the metallation, since the formation of macrocycle is a reversible reaction. The metallomacrocycles were therefore prepared by reacting the macrocyclic ligands with metal(II) acetates or metal(II) acetylacetonates under inert 68 atmosphere and in dry THF. These metal salts were chosen for two primarily reasons. First, no strong acid would be generated during the metallation. Second, since the deprotonated N2O2 pockets of the macrocycle have a corresponding -2 charge, the coordination of metal(II) ions to the N2O2 binding sites would generate a neutral metallomacrocycle. When macrocycle 14a was treated with 3 equiv. of Zn(OAc)2 '2H 20 in THF, a new product 17 was obtained as a dark red solid in high yield (80 %) (Scheme 3.1). The product was washed with hot methanol in order to remove excess Zn(OAc) 2. The ' H N M R spectrum of 17 in C D C I 3 showed broad resonances for the alkoxy side groups, while the resonances associated with the metallomacrocycle were completely diminished. It was anticipated that the peaks on the ] H N M R spectrum of the zinc-containing macrocycle would be sharp since Zn(II) has a d 1 0 electron configuration and thus the metallomacrocycle is diamagnetic. Since all the d-orbitals are filled, the geometry of the zinc centres should not affect the diamagnetism of the macrocycle. When the *H N M R spectrum of 17 was obtained in c^-THF, however, sharp peaks were observed. It is believed that the zinc-containing macrocycle aggregates in chloroform, but not in THF; this is discussed in Chapter 4. 69 R = n C 8 H 1 7 R = n C s H 1 7 Scheme 3.1. Metallation of [3+3] Schiff-base macrocylce 14a. The *H N M R spectrum of compound 17 in t/s-THF revealed the loss of the OH resonance at 13-14 ppm, which coincides with the coordination of the zinc ions in the N2O2 salphen-type pockets. Furthermore, the presence of a single imine (5 8.85) and a triplet O C H 2 (5 4.13) is consistent with the 3-fold symmetry of the metallomacrocycle (Figure 3.4). MALDI-TOF MS of the red product confirmed the incorporation of three Zn(II) ions into the complex and showed fragments consistent with the singly and doubly metallated macrocycles (Figure 3.5). In addition, the Raman spectrum of 17 showed a single C=C stretching mode at 2196 cm"1. The UV-visible spectrum of the complex showed a bathochromic shift relative to macrocycle 14a, consistent with enhanced conjugation in the ligand. Moreover, metallomacrocycle 17 is weakly luminescent in THF (0=0.86%) with peaks at 558 and 596 nm. The IR spectrum of the metallomacrocycle 17 is very similar to the metal-free parent macrocycle. The metal complex has an absorption band at 1606 cm"1, corresponding to the stretching frequency of the imine bond. Although compound 17 does not have any hydroxyl groups, the IR 70 spectrum revealed a broad band at around 3400 cm" , which is likely due to the coordination of water molecules to the metal centres. Macrocycle 14a was also treated with excess of Ni(OAc)2, resulting in a dark red compound. However, the product is insoluble in most organic solvents (DCM, C H C I 3 , THF, DMSO, benzene), and thus characterization of the compound was not conducted. f\J n CD Cft CFl " 7 V O Ifl i n N 0 1 I D v N W I f (M U) N 1 ci (\j m w m tfi J L l I i £ Ol U) O (VI o r - • - ' - i S Si s 3 Figure 3.4. H N M R spectrum of metallomacrocycle 17 (300 MHz; <i5-THF). 71 1200 1700 2200 2700 m/z Figure 3.5. MALDI-TOF mass spectrum of metallomacrocycle 17. Macrocycle 14b was reacted with excess Zn(0Ac)2, Ni(acac)2 or Cu(OAc) 2 to afford metallated macrocycles 18a-c. The ethylhexyl substituents were chosen to improve solubility. The ' H N M R spectra of 18a obtained in CDC1 3 and d2-DCM were broad; the more bulky substituents, 2-ethylhexyl improved solubility, but did not prevent aggregation. The ' H N M R spectrum of the trimetallated compound 18a in d^-THF showed the absence of the phenolic protons and the presence of a single imine, confirming the structure (Figure 3.6). Since nickel-containing macrocycle 18b was not soluble enough to obtain a ' H N M R spectrum, and compound 18c contains paramagnetic metals, MALDI-TOF MS was a useful technique to identify these compounds. M A L D I - TOF MS of metallomacrocycles 18a-c verified their composition (Figure 3.7-3.9). The 72 spectra display a large peak corresponding to the molecular weight of the target metallomacrocycles. For compounds 18a and 18b, small peaks corresponding to the M 2 H + were also observed. The presence of dimer is preliminary evidence for the aggregation of the metallomacrocycles in the solid state. 73 1800 H o o j o > 0 ' - o j r T * t n i D f ^ ( o a i o 00)C7)0>0)0>0)0)0>CtCT)OiatO) at o CM n -t m <o r* i n i o t o u x o t o i o a t o CMCMCMNNOJCMNCsl t o o p r - oven 1600 1400 H t A 1200 1000 800 600 H 400 200 H —T 1 1 1 - "T 1800 2300 2800 3300 m/z m/z ;ure 3.7. MALDI-TOF mass spectra of 18a. 4000 - \ r-. <- IN n t̂- m to M D at o •- CM T u n i o r» to 01 o u-mioNcoen o «- o>m in in in in in in in in ic 10 <o r» p*r- r- r*. co n n KTO n f> i- to en m o) en 01 o> cj» 01 en oi cn cn cn cn a> en cn cn cn o> N N N N N N N N — — (M (N CN CM M CN CM CM co oi enen 3500 3000 t 2500 2 0 0 0 H 1500 H 1 0 0 0 H 5 0 0 -\ 1600 2 1 0 0 2600 m/z • 3 1 0 0 3600 ;ure 3.8. MALDI-TOF mass spectra of 18b. r- Is* r<r* to P- N IS- to t 2200 2 0 0 0 H 1800 1600 1400 - \ 1200 H 1 0 0 0 800 H 600 H 400 200 1900 2000 -1 1 1 1 2200 Figure 3.9. MALDI-TOF mass spectra of 18c. Macrocycles 15 and 16 were treated with excess Zn(OAc)2 - 2H20 in dry THF to produce the trimetallated macrocycles 19 and 20, respectively (Scheme 3.2). The structures of macrocycles 19 and 20 were confirmed by ' H N M R spectroscopy (Figure 3.10 and 3.11) and M A L D - T O F mass spectrometry (Figure 3.12 and 3.13). The absence of the phenolic protons and the presence of the single imine and the triplet - O C H 2 - 76 proton resonances in the H N M R spectra for compounds 19 and 20 are consistent with D3h symmetry for the metallomacrocycles. Moreover, the correct molecular weights of the zinc-containing macrocycles were observed for both 19 and 20 in the MALDI-TOF spectra. In addition to the molecular ion peak, a peak at m/z = 288 above the [M+H]+ peak was observed for both MALDI-TOF spectra. This appears to be a complex formed with the dithranol matrix, which has a structure of [M-H+dithranol+Zn]+. Dithranol complexes of macrocycles have been observed before.8 MeO Scheme 3.2. Synthesis of metallomacrocycle 19-20. 77 ID OJ CD O 01 ^ m i n - I D CD i n 01 10 n 01 m nj n j o tn 01 o oo ^ T N O N (M ru co m m CD I D ro nj M m m m m o m UD C\J 01 I D co co m CD m m n j O J 1 N N ID r- m t (\j o " •̂ r M CT> r-- i n V Figure 3.10. ' H N M R spectrum of metallomacrocycle 19 (300 MHz; afe-THF). -*J O O LO rn oj o t\i m r - r - o 10 CO I D V " I D m oj oj —• o 01 o " 1 -r-i 01 r-. cn C\J 01 o o i i o i f l c o f f i N i n i n i n c i f i a i o i c O ' - i w . . . . c n i D i n i n t r > - - ' C D O j O r ^ p - ) O j r - . *o- m O J --• r- f i l o n j i c n i D v M i M N m o o i -*r T 1 1 r o m m O J O J • r U L L Figure 3.11. ' H N M R spectrum of metallomacrocycle 20 (300 MHz; J S -THF). 78 1200 1000 800 H 400 H 1200 2200 2700 m/z Figure 3.12. MALDI-TOF spectra of metallomacrocycle 19. 79 90O 600 ^ 100 2200 2700 3200m/z Figure 3.13. MALDI-TOF spectra of metallomacrocycle 20. The zinc-metallated macrocycles 17, 19 and 20 were weakly fluorescent (O = 0.86- 0.92 %). It is noteworthy that their fluorescence spectra are nearly identical (Figure 3.14). This suggests that the luminescence is localized to the metal complexes and that there is little electronic coupling of the metal complexes through the organic backbone. In contrast, the nickel-metallated and the copper-metallated macrocycles, 18b and 18c, respectively, were not fluorescent. Figure 3.15 compares the fluorescence of macrocycle 14a upon reaction with Zn(OAc) 2 and Ni(OAc) 2 . 80 0.20 n Figure 3.15. Photograph of fluorescence from macrocycle 14a (i) with no metal, (ii) with zinc acetate, and (iii) with nickel acetate. Solvent: THF, 5 x 10"5 M ; X,exc - 365 nm. 3.3.2 Titration experiments We were surprised that the Ni(II) macrocycles were not luminescent. It is interesting to know whether the partially metallated macrocycles are luminescent. The degree of quenching in the macrocycles may give some indication of the communication between the 3 salphen compoenents of the macrocycles. 81 The metal-free macrocycles 14-16 are weakly luminescent in THF (<& = 0.13-0.15%). When macrocycle 14a was titrated with excess Ni(OAc)2, the fluorescence intensity decreased (Figure 3.16). A large positive deviation from linearity in the Stern-Volmer analysis indicates that the quenching is static with irreversible binding of the metal in the macrocycle (Figure 3.17).7 Figure 3.18 plots the fluorescence intensity decay versus metal concentration, a graph that should be linear if the fluorophores were well-separated (dilute). The nonlinearity in Figure 3.18 arises from the quenching or partial quenching of the fluorescence from macrocycles with 1 or 2 metals. This indicates that the macrocycle with 1 or 2 Ni(II) is still fluorescent, but only weakly. 0.25 Figure 3.16. UV-visible and fluorescence spectra of macrocycle 14a upon titration with Ni(OAc) 2 (THF). 82 250 200 A 150 A Io/I 1 00 50 • A O A • 14a_trial1 I4.i_trial2 15_trial1 15_trial2 16_trial1 16 trial2 A * 0 A • 0 1 2 3 equiv N i ( Q A c ) , ft Figure 3.17. Stern-Volmer plots for the fluorescence quenching of macrocycle 14a (kn = 564 nm), 15 (k^x = 562 nm) and 16 (Xmax= 560 nm). 1 . 2 I/Io 1 . 0 A OS 0 . 6 H 0 . 4 0 . 2 0 0 • * ttajrial 1 A 14*i_trial2 • 15_trial1 15_trial2 • 16_trial1 16Jrial2 A* . 2 3 equiv Ni(0Ac) ; Figure 3.18. Graph of fluorescence intensity (normalized) vs. equiv. Ni(OAc) 2 • 4 H 2 O added to macrocycle 14a, 15 or 16 in THF. For comparison, the salphen monomer, compound 41 (Figure 3.19), was also titrated with excess Ni(OAc)2 (Figure 3.20). Examination of the Stern-Volmer plot (Figure 3.21) 83 revealed a positive deviation from linearity, similar to that of macrocycle 14a. These results are consistent with static quenching of the complex with Ni(II). However, the plot of normalized fluorescence intensity as a function of Ni(OAc)2 added to compound 41 was linear (Figure 3.22). Notably, two equiv. of Ni(II) were required to quench the salphen. However, upon titration with 2 equiv. of Ni(II), the UV-vis spectrum of salphen 41 was very similar to that of the Ni(salphen), indicating that salphen 41 only actually binds to one Ni(II). It is postulated that Ni(OAc)2 is only able to deprotonate one phenolic proton in the ligand. Therefore, two equiv. of Ni(OAc)2 are required to remove the other phenolic proton before the N2O2 pocket can bind with the Ni(II) ion. The non-linearity in Figure 3.18 indicates that there might be electronic communication between the salphen moieties in the large macrocycles, causing the plot of normalized fluorescence intensity as a function of Ni(OAc)2 to deviate from linearity. If the distance between the salphens in the macrocycle increases, the interactions between the salphens should be decreased, leading to quenching as in 41 in the extreme limit. As a result, larger macrocycles 15 and 16 were titrated with Ni(OAc)2. The fluorescence of macrocycles 15 and 16 was quenched when they were titrated with excess Ni(OAc)2 (Figure 3.23). From the Stern-Volmer plots (Figure 3.17), positive deviations were observed for both titration experiments, suggesting static quenching. Non-linearity was still observed for the titrations of macrocycles 15 and 16 (Figure 3.18), and the plots were very similar to that of macrocycle 14a. The increasing distance between the salphen moieties did not have a significant impact on the quenching experiments. 84 RO OR Figure 3.20. UV-visible and fluorescence spectra of salphen 41 upon titration with Ni(OAc) 2 • 4 H 2 0 (THF). 85 Io/I 0 0 0 . 2 0 . 4 0 . 6 0 . 8 1 0 1.2 1.4 1 .6 1.8 2 0 equiv. Ni(OAc) : Figure 3.21. Stern-Volmer plots for the fluorescence quenching of salphen 41 (A.max= 538 nm). 1.0 equiv. Ni(OAc) 2 Figure 3.22. Graph of fluorescence intensity (normalized) vs. equiv. Ni(OAc) 2 added to salphen 41 in THF. 86 (a) 0.20 Figure 3.23. (a) UV-visible and fluorescence spectra of macrocycle 15 upon titration with Ni(OAc)2 (THF). (b) UV-visible and fluorescence spectra of macrocycle 16 upon titration with Ni(OAc) 2 (THF). On the other hand, upon titration with Zn(II), macrocycle 14a undergoes a significant increase in fluorescence, Figure 3.24. This enhanced fluorescence is attributed to the Zn(II) binding to the saphen-type ligands, where it deprotonates the phenol and rigidities 87 the macrocycle. The changes that occurred in the UV-visible spectra arise from the coordination of Zn(II) ions to the N2O2 binding sites. 0.20 A 0.10 J t 0.15 I 0.00 0.05 I 300 400 500 600 700 800 XI nm Figure 3.24. UV-visible and fluorescence spectra of macrocycle 14a upon titration with Zn(OAc) 2 (THF). In summary, the target [3+3] Schiff-base metallomacrocycles were prepared in high yield. The zinc-containing macrocycles showed strong aggregation behaviour in chloroform and D C M , but not in THF. Titration of the macrocycles with Ni(OAc) 2 revealed that the macrocycles remain fluorescent when partially metallated, but the intensity is reduced. The salphen moieties are quenched by energy transfer to the metallated centres in the macrocycles. There was virtually no dependence on the extent of fluorescence quenching as a function of macrocycle ring size. 88 3.4 References (1) (a) Stang, P. J.; Olenyuk, B. Acc. Chem. Res. 1997, 30, 502- 518 (b) Fujita, M . Chem. Soc. Rev. 1998, 27, 417-425. (c) Holliday, B. J.; Mirkin, C. A . Angew. Chem. Int. Ed. 2001, 40, 2022-2043. (d) Dinolfo, P. H.; Hupp, J. T. Chem. Mater. 2001,13, 3113-3125. (2) (a) Linde, C , Koliai, N . , Norrby, P.-O., Akermark, B. Chem. Eur. J. 2002, 8, 2568- 2573. (b) Daly, A . M . , Renehan, M . F., Gilheany, D. G. Org Lett. 2001, 3, 663-666 (c) Leung, W.-H., Che, C . - M . Inorg. Chem. 1989, 28, 4619-4622. (d) Bryliakov, P. K., Talsi, E. P. Inorg. Chem. 2003, 42, 7258-7265. (3) Gao, J.; Reibenspies, H. H. ; Martell, A . E. Angew. Chem. Int. Ed. 2003, 42, 6008- 6012. (4) Che, C-M. ; Chan, S-C; Xiang, H-F.; Chan, M . C. W.; Liu, Y . ; Wang, Y. Chem. Comm. 2004, 1484-1485. (5) Sano, T.; Nishio, Y . ; Hamada, Y . ; Takahashi, H. ; Usuki, U . ; Shibata, K. J. Mater. Chem. 2000,10, 157-161. (6) Gallant, A. J.; MacLachlan, M . J. Angew. Chem. Int. Ed. Engl. 2003, 42, 5307-5310. (7) Murphy, C. B.; Zhang, Y. ; Toxler, T.; Ferry, V. ; Martin, J. J.; Jones, W. E.; Jr. J. Phys. Chem. B 2004, 108, 1537-1543. (8) Hoger, S.; Spickermann, J.; Morrison, D. L.; Dziezok, P.; Rader, H. J Macromolecules 1997, 30, 3110-3111. 89 Chapter 4 Aggregation of [3+3] Schiff-base Metallomacrocycles 4.1 Background One of the most important objectives in supramolecular chemistry is the self- assembly of molecular building blocks into well-defined architectures. Supramolecular chemistry has been defined as "chemistry beyond the molecule" by Nobel laureate Jean- Marie Lehn.1 The most important feature of supramolecular chemistry is that the building blocks are assembled to higher complexity via the association of small units through non- covalent interactions such as hydrogen-bonding, n-n interactions, Van der Waals interactions or coordinative bonding.1"4 The use of non-covalent intermolecular interactions to construct higher-order structures offers advantages over covalent syntheses, which often involve highly sophisticated reagents and catalysts. Moreover, the reversibility of the intermolecular forces also allows the supramolecular system to correct errors that may occur during the self-assembly process.5 Today, supramolecular chemistry has important applications in catalysts,6 organic nanotubes,7 supramolecular polymers and chemical sensors. The aggregation of rigid, shape-persistent macrocycles has become a topic of growing interest in recent years.10 In some solvents, n-n interactions between rigid, conjugated phenylacetylene macrocycles (PAMs) may beget aggregation, leading to nanotubular assemblies." Porphyrins and phthalocyanines, owing to their extended n systems, also aggregate in solution.12 Such aggregation, however, is usually weak and depends on the substituents of the macrocycles for organization.13 Stronger forces such as 90 hydrogen bonding have been used to aggregate D, L-peptides and urea macrocycles.14 Solvents containing hydrogen-bond donors or acceptors may therefore decrease aggregation.15 R R R = C O O N C 4 H 9 4 Figure 4.1. Macrocycle that self-associates due to TC-TC interactions. Schiff-base macrocycles 13 are not aggregated, but aggregate only upon addition of alkali and ammonium cations that can coordinate to the interior of the macrocycle.16 The assembly of multimetallic macrocycles that contain a pore in the middle is a potential route to new porous nanofibres. Larger, conjugated Schiff-base macrocycle 14 (Figure 4.1) is readily prepared in high yields without the use of a template.17 This macrocycle may react with transition metal salts to form trimetallated macrocycles, where metals are incorporated into the tetradentate (N2O2) binding sites of the macrocycles. This chapter will highlight our findings on the aggregation behaviour of metallomacrocycles 17 and 18 in solution. The metal plays an important role in mediating the assembly of the 91 macrocycles. In addition, we demonstrate coordination-assisted deaggregation of the shape-persistent metallomacrocycles. 13 (R = alkyl) 14a (R = n C 8 H 1 7 ) 17 (M = Zn, R = n C 8 H 1 7 ) 14b (R = 2-ethylhexyl) 18a (M = Zn, R = 2-ethylhexyl) 18b (M = Ni, R = 2-ethylhexyl) 18c (M = Cu, R = 2-ethylhexyl) Figure 4.2. Conjugated macrocycles 13,14,17 and 18. 4.2 Experimental Materials. 2,6-Lutidine, quinuclidine, pyridine, zinc(II) acetate, nickel(II) acetate, copper(II) acetate were obtained from Aldrich. Tetrahydrofuran (THF) was distilled from sodium / benzophenone under nitrogen. Dichloromethane Deuterated solvents were obtained from Cambridge Isotope Laboratories, Inc. Macrocycles (14-16) and metallomacrocycles (17-18) were prepared by the procedures described in Chapter 2 and Chapter 3, respectively. 92 Equipment. A l l reactions were carried out under nitrogen atmosphere unless otherwise noted. 300 MHz ] H N M R spectra spectra were recorded on a Bruker AV-300 spectrometer. ' H N M R spectra were calibrated to the residual protonated solvent at 8 7.24 in CDC1 3, 8 5.30 in d2-DCM, or 8 3.58 in d8-T¥LF. UV-vis spectra were obtained in THF, D C M , MeOH, acetone, benzene, acetonitrile and cyclohexane (ca. xlO" 6 M) on a Varian Cary 5000 UV-vis-near-IR spectrophotometer using a 1 cm quartz cuvette. Fluorescence spectra were obtained in THF, D C M , MeOH, acetone, benzene, acetonitrile and cyclohexane on a Photon Technology International QuantaMaster fluorimeter using a 1 cm quartz cuvette. MALDI-TOF mass spectra were obtained in a dithranol matrix at the UBC Microanalytical Services Laboratory on a Micromass LCT time-of-flight (TOF) mass spectrometer. Absorption and fluorescence spectroscopies of macrocycle 17,18a-c in various ratios of DCM:THF. Macrocycles 17 or 18a-c were dissolved in 2 mL of distilled THF. The solution was then added to 10 mL of a solution of THF and D C M solvents (ca. 1 x 10"6 M), which were between 1:0 and 0:1 in 10% increments. Absorption and fluorescence spectroscopies of macrocycle 17 in various solvents. Macrocycle 17 exhibited poor solubility in solvents such as MeOH, acetone, acetonitrile, cyclohexane and benzene. To ensure consistency, macrocycle 17 (0.0006 g) was first dissolved in 2 mL of distilled THF. 50 uL of the solution was then added to 10 mL of various organic solvents (e.g. THF, D C M , pyridine, DMSO, acetone, acetonitrile, MeOH, 93 benzene and cyclohexane) in which [17] ~ 8 x 10"7 M . The absorption and emission spectra of compound 17 was recorded at room temperature in a series of solvents. Titration experiment of macrocycle 18c and 17. The titration experiment was performed by adding aliquots of macrocycle 18c via microlitre syringe to a quartz cuvette containing ca. 1.4 x 10"6 M of macrocycle 17 in ~ 3.5 mL of D C M . Absorption and fluorescence spectroscopies of quinuclidine titration experiments. The titration experiment was performed by adding aliquots of quinuclidine via microlitre syringe to a quartz cuvette containing 1.4 x 10"6 M of macrocycle 17 in -3.5 mL of D C M . *H NMR spectroscopy of quinuclidine titration experiments. The experiments were performed by adding aliquots of quinuclidine (0.0005-0.0011 g ) to an N M R tube containing 3.24 x 10"3 M of macrocycle 17 in CD2CI2. 2,6-Lutidine and pyridine titration experiments. Titration experiments were performed by adding aliquots (via microliter syringe) of 2,6-lutidine or pyridine (0.5-5.5 uL) to a quartz cuvette containing ca. 1.5 xlO" 6 M of macrocycle 17 in ~ 3.5 mL of D C M . Compound 42. Under an inert atmosphere, salicylaldehyde (0.08 mL, 0.66 mmol), 1,2- dihexyloxy-4,5-diaminobenzene (0.10 g, 0.32 mmol) and Zn(acach (0.13 g, 0.49 mmol) were dissolved in dry THF (ca. 5 mL). The solution was heated to reflux overnight. Solvent was removed under reduced pressure, and compound 42 was isolated on a 94 Buchner funnel. The crude product was recrystallized from a mixture of THF and MeOH, yielding yellow crystals (0.15 g, 80 %). *H N M R (300 MHz, DMSO-d 6 ) 8 8.91 (s, 2H, CH=N), 7.44 (s, 2H, aromatic CH), 7.38 (d, 3 J H H = 7.84 Hz, dd, 4 J H H = 1-67, 2H, aromatic CH), 7.17 (t, 3 J H H = 7.84 Hz, 2H, aromatic CH), 6.66 (d, 3 J H H = 8.16 Hz, 2H, aromatic CH), 6.64 (t, 3 J H H = 8.16 Hz, 2H, aromatic CH), 4.09 (t, 3 J H H = 6.36 Hz, 4H, OCH2), 1.75-0.92 (m, 22H, OCH 2 C 5 / / / / ) . 1 3 C N M R (300 MHz, DMSO-d 6 ) 8 171.70 (CH=0), 160.65, 148.71, 135.79, 133.64, 132.76, 122.87, 119.65, 112.73 (aromatic Q , 68.78 (OCH 2), 30.98, 28.73, 25.28, 22.09, 13.83 ( O C H 2 C 5 H n ) . MALDI-TOF-MS: m/z = 579 ([M+H]+). UV-vis (DCM): lmax (s) = 3 79 (2.11 x 104) nm (L mof'cm"1). IR (KBr): v = 3431, 2927, 2856, 1609, 1458, 1260, 1168, 752 cm"1. Anal. Calc'd for C 3 2H38N 2 04Zn H 2 0 : C, 64.26; H, 6.74; N , 4.68. Found: C, 63.60; H, 6.83; N , 4.91. 4.3 Results and Discussion In the previous chapter, the ' H N M R spectra of 17 and 18a in C D C I 3 showed broad resonances for the alkoxy side chains, while the other peaks associated with the macrocycles were completely diminished. MALDI-TOF MS of metallomacrocycles 18a and 18b showed peaks corresponding to the M 2 H + i n addition to the molecular ion. In the case of macrocycle 17, significant aggregation was observed, with ions of up to Mg + present in the spectrum, Figure 4.3. The intensity of the signal arising from the 2+ * aggregates was very large only in the case of macrocycle 14a metallated with Zn (i.e., 17). 95 Figure 4.3. a) MALDI-TOF mass spectrum of macrocycle 17. The inset shows the isotope distributions for the molecular ions of b) 18a c) 18b d) 18c. The aggregation of metallomacrocycle 17 was further investigated by ' H N M R spectroscopy. Figure 4.4 showed the ' H N M R spectra of 17 at a constant concentration with different d2-DCM and 6^-THF composition. In ds-THF, the macrocycle displays sharp peaks that can all be assigned to the macrocycle, including the imine resonance at § 8.85. As the ratio of ^ - D C M : ds-THF is increased, the resonances became broadened to the point that the aromatic groups are no longer visible. This effect is attributed to a significant decrease in the T 2 relaxation time, caused by the formation of large 96 aggregates. Well-defined oligomeric structures (e.g., dimers) would be expected to give rise to sharp peaks, but our results indicate that larger aggregates are present. In pure d.2- D C M , resonances associated with the macrocycle are completely diminished, while those for the alkoxy side groups are broad. Broadening has been observed in the aggregation of PAMs in highly polar solvents.19 For comparison, metal-free macrocycles 14a and monometallated compound 42 (Figure 4.5) do not aggregate at similar concentrations in THF or in D C M . 10 9 8 7 6 5 4 3 2 1 0 8/ppm — Figure 4.4. *H N M R spectra (300 MHz) of macrocycle 17 in varying ratios of t^ -DCM : THF-dg ([17] = ca. 6 x 10"4 M for all of the spectra). 97 RO OR 42 (M = Zn, R = C 6 H 1 3 ) Figure 4.5. Structure of compound 42. Self-association can have a significant effect on the optical properties of macrocycles in solution. To further investigate the aggregation behavior of the macrocycles, UV-vis and fluorescence studies at constant concentration of macrocycles 17-18 were carried out in different compositions of D C M : THF. Macrocycles 18b (M = 9-1- 9 + Ni ) and 18c (M = Cu ) both show UV-vis spectra with several well-defined absorption features. Moreover, there is virtually no difference between the spectra obtained in THF and D C M (Figure 4.6). The spectra of macrocycles 17 and 18a in THF appear very similar to those for macrocycles 18b and 18c, showing several distinct features. However, as the ratio of D C M : THF increases, the UV-visible spectrum for 17 and 18a undergo a dramatic change, leading to a broad, featureless absorption spectrum in D C M (Figure 4.7). Macrocycle 17 is fluorescent in THF (<I> = 0.86%), with peaks at 558 and 596 nm, Figure 4.6. Upon changing the solvent from THF to D C M , the peaks red-shift and diminish in intensity, leading to a broad excimer-like emission for macrocycle 17 in D C M . This band shows no vibrational fine-structure, consistent with the excimer-like nature of the band. Macrocycle 18a with peripheral 2-ethylhexyloxy substituents behaves similarly to 17 with the unbranched alkyl chain. 98 Figure 4.6. (a) UV-vis spectra of 18b in varying ratios of D C M and THF, between 1:0 and 0:1 in 10% increments. [18b] = 9.0 x 10"7 M (b) UV-vis spectra of 18c the same solvent combinations. [18c] = 9.8 x 10"7 M 99 (a) (b) 0.25 0.20 A 0.15 4 0.10 0.05 A 0.00 Pure THF ( A t i s o r b a n c e Fluorescence Pure THF ^ Increasing T H F D C M 500 600 Xfnm » A Absorb ance Flu orescence Increasing THF:DCM Figure 4.7. UV-vis and fluorescence spectra of (a) 17 and (b) 18a in varying ratio of THF and D C M , between 1:0 and 0:1 in 10% increments. [17] = 1 x 10"6 M ; [18a] = 1.1 x 10"6 M . The optical properties for macrocycle 17 were examined in a range of solvents with varying dielectric constant, Figure 4.8. In coordinating solvents (e.g., THF, DMSO, 100 pyridine), the absorption spectrum shows well-defined features and the macrocycle fluoresces with two peaks near - 560 and 600 nm. In weakly or non-coordinating solvents (e.g., acetone, methanol, D C M , benzene, acetonitrile, cyclohexane), the absorption spectrum is broad and nearly featureless, and the emission spectrum is broad and red-shifted. The broad absorption spectra and the lack of any dependence on the dielectric constant corroborate that the aggregation is a ground-state effect, not due to excited-state complexes. These results suggest that in most non-coordinating solvents, macrocycle 17 is aggregated even at 10"6 M . We were surprised that n-n interactions between the macrocycles would be significant at this concentration in a good solvent like D C M , given that the macrocycle is electron rich. 1 3 Since macrocycle 17 aggregates in MeOH, it is unlikely that hydrogen-bonding is an important factor for assembly. It is also surprising that macrocycle 17 aggregates in benzene where TT-TC interactions with the solvent are expected to compete with 71-71 interactions of the macrocycle, suppressing assembly. Moreover, if 71-71 interactions were solely responsible for the assembly, Schiff-base macrocycles with Cu(II) and Ni(II), which are anticipated to be flat with square-planar geometry at the metal, would seem more likely than Zn(II) macrocycles to aggregate. These results suggest that the aggregation of the macrocycles involves an additional interaction, namely Zn—O coordination between macrocycles. The metal coordination of phenolic oxygen atoms in salen-type zinc complexes has been observed in the solid- 101 Figure 4.8. UV-visible and fluorescence spectra of macrocycle 17 in different solvents. Macrocycle 17 is aggregated even at 10"7 M in D C M . As well, a plot of A vs. concentration is nearly linear, indicating very little concentration dependence on the aggregation (Figure 4.9). We could not extract a reliable equilibrium constant from the system, but we estimate that KasS0C must be greater than 10 7. 2 1 0.25 0.0 5.0e-7 1.0e-6 1.5e-6 2.0e-6 2.5e-6 3.0e-6 3.5e-6 [17] / M ^ Figure 4.9. Graph of absorbance at 380 nm as a function of concentration (M) of 17. 102 Addition of paramagnetic Cu(II) macrocycle 18c to a solution of Zn(II) macrocycle 18a led to a small degree of fluorescent quenching (ca. 6 %), but did not disrupt the aggregated state of macrocycle 18a (Figure 4.10). This indicates that the Zn macrocycle 18a prefers to interact with other macrocycles of the same type rather than forming dimers with 18c, further supporting a Zn—O interaction between the macrocycles. 0.3 - A 0.2 - A 0.1 - 0.0 - 3 0 0 400 500 800 700 8 0 0 xl nm — Figure 4.10. UV-vis and fluorescence spectra of the titration of 18a with 18c. The macrocycle aggregation was readily interrupted by coordinating solvents. To prove that coordination was the important interaction, macrocycle 17 was titrated with pyridine and lutidine (Figure 4.11). UV-vis and fluorescence spectroscopy show that macrocycle 17 deaggregates with the addition of pyridine. With lutidine, however, which is more basic but unable to coordinate to the metal, the macrocycle remained aggregated.22 The absence of an isosbestic point in the titration with pyridine is consistent with multiple metal centers being coordinated. 103 a) 0.25 Absorbs nee Fluorescence b) 0.25 0.20 A 0.15 0.10 0.05 Figure 4.11. UV-vis and fluorescence spectra of metallomacrocycle 17 titrated with a) pyridine (3.6 x 10"3- 0.020 M ; step size: 1.81 x 10"3 M) and b) lutidine (1.26 x 10"3- 0.014 M ; step size: 1.26 x 10"3 M). [17] = 1.8 x 10"6 M . The arrows show the direction of increasing concentration of base. The aggregation behaviour of the zinc metallomacrocycles 17 and 18a is illustrated in Figure 4.12. In THF, the molecules are not aggregated. Upon changing the solvent to D C M or benzene, the macrocycles aggregate into supramolecular assemblies. Although we do not know that the assemblies are tubular, this seems likely since the aggregation is dominant at even 10"7 M . Tubular stacking would maximize intermolecular interaction necessary for aggregation. Upon adding a molecule that can coordinate to the macrocycles, they deaggregate and their luminescence is replenished. These assemblies may serve as the basis of a new model for chemosensing of coordinating bases, where the mechanism involves deaggregation of the supramolecular assembly. 104 Figure 4.12. Illustration of aggregation and coordination-assisted deaggregation of multimetallic macrocycles. Left: Macrocycles in THF. Middle: macrocycles aggregated in CH2CI2. Right: Macrocyclic assemblies deaggregate after reaction with a coordinating solvent. To test this mechanism as the basis of a chemical sensor, we titrated the macrocycle assembly of 17 in D C M with quinuclidine. The fluorescence increased rapidly, with a total fluorescence increase of 100 % at 575 nm after 30 equiv. of quinuclidine were added (Figure 4.13). The deaggregation was confirmed by 'H N M R spectroscopy. Whereas the ' H NMR spectrum of macrocycle 17 in CD2CI2 is broadened by aggregation, the spectrum with the addition of only 3-6 equiv. of quinuclidine displays sharp peaks expected for 17 (Figure 4.14). Thus, the deaggregation of the macrocycle assemblies generates a turn-on signal for sensing of coordinating bases, such as quinuclidine. 105 a) 1.0 * loll equivalents quinuclidine Figure 4.13. a) UV-vis and emission spectra of the titration of 17 with quinuclidine in D C M . [17] = 1.4 x 10"6 M . b) Plot of Io/I as a function of equiv. quinuclidine at 575 nm. 106 I I I I I I I I I I 10 9 8 7 6 5 4 3 2 1 0 8/ppm —»~ Figure 4.14. Stacked ' H N M R spectra of macrocycle 17 with 3 equiv. and 6 equiv. of quinuclidine. In all spectra, [17] ~ 3.24 x 10"3 M in CD 2 C1 2 ; 300 MHz. In summary, we have observed strong aggregation of Schiff-base metallomacrocycles in solution that is facilitated by Zn—O interactions between the macrocycles. The macrocyclic assemblies can sense coordinating bases, which cause deaggregation of the supramolecular assemblies. This suggests a new chemical method for controlling the assembly of nanostructures from shape-persistent macrocycles. Future work will involve the use of bidentate ligands (e.g., 1,4-pyrazine) to form supramolecular nanotubes. 107 4.4. References 1. Lehn, J.-M. Angew. Chem. Int. Ed. 1988, 27, 89-112. 2. Moore, J. S. Curr. Opin. Colloid Interface Sci. 1999, 4, 108-116. 3. Whitesides, G. M . ; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312-1319. 4. (a) Huang, W.; Gou, S.; Hu, D.; Chantrapromma, S.; Fun, H.-K.; Meng, Q.; Inorg. Chem. 2001, 40, 1712-1715. (b) Huang, W.; Gou, S.; Hu, D.; Chantrapromma, S.; Fun, H. - K . ; Ming, Q. Inorg. Chem. 2002, 41, 864-868. 5. (a) Lindsey, J. S. New J. Chem. 1991,15, 153-180. (b) Philp, D.; Stoddart, J. F. Angew. Chem. Int. Ed. 1996, 35, 1154-1196. 6. (a) Litvinchuk, S.; Bollot, G.; Mareda, J.; Som, A. ; Ronan, D.; Shah, M . R.; Perrotte, P.; Sakai, N . ; Matile, S. J. Am. Chem. Soc. 2004,126, 10067-10075. (b) Suss-Fink, G.; Faure, M . ; Ward, T. R. Angew. Chem. Int. Ed. 2002, 41, 99-101. 7. Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M . R. Angew. Chem. Int. Ed. 2001, 40, 988-1011. 8. (a) Ikkala, O.; Brinke, G.; Chem. Comm. 2004, 2131-2137 (b) Xu, H. ; Rudkevich, D. M . Chem. Eur. J. 2004,10, 5432-5442. (c) Zhou, Y. ; Yan, D. Angew. Chem. Int. Ed. 2004, 43, 4896-4899. (d) Cornelissen, J. J. L. M . ; Fischer, M . ; Sommerdijk, N . A . J. M . ; Nolte, R. J. M . Science, 1998, 280, 1427-1430. 9. (a) Tsuda, A . ; Sakamoto, S.; Yamaguchi, K.; Aida, T. J. Am. Chem. Soc. 2003,125, 15722-15723; (b) Sun, S.-S.; Lees, A . J. Coord. Chem. Rev. 2002, 230, 171-191; (c) Resendiz, M . J. E.; Noveron, J. C ; Disteldorf, H. ; Fischer, S.; Stang, P. J. Org. Lett. 2004, 6, 651-653. 108 10. (a) Hoger, S.; Bonrad, K. ; Mourran, A. ; Beginn, U . ; Moller, M . J. Am. Chem.. Soc. 2001, 123, 5651-5659; b) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1992, 114, 9701- 9702; c) Tobe, Y . ; Utsumi, N . ; Kawabata, K.; Nagano, A. ; Adachi, K. ; Araki, S.; Sonoda, M . ; Hirose, K.; Naemura, K. J. Am. Chem. Soc. 2002, 124, 5350-5364; d) Hoger, S. J. Polym. Sci. Part A: Polym. Chem. 1999, 37, 2685-2698. 11. Lahiri, S.; Thompson, J. L.; Moore, J. S. J. Am. Chem. Soc. 2000,122, 11315-11319. 12. (a) Zelina, J. P.; Njue, C. K. ; Rusling, J. F.; Kamau, G. N . ; Masila, M . ; Kibugu, J. J. Porphyrins Phthalocyanines 1999, 3, 188-195; b) Choi, M . T. M . ; L i , P. P. S.,;Ng, D. K. P. Tetrahedron, 2000, 56, 3881-3887; c) Mallamace, F.; Micali, N . ; Romeo, A. ; Scolaro, L. M . Curr. Opin. Colloid Interface Sci. 2000, 5, 49-55. 13. Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996,118, 1019-1027. 14. (a) Shimizu, L. S.; Hughes, A . D.; Smith, M . D.; Davis, M . J.; Zhang, B. P.; Zur Loye, H . - C ; Shimizu, K. D. J. Am. Chem. Soc. 2003, 125, 14972-14973; b) Ghadiri, M . R.; Granja, J. R.; Milligan, R. A. ; McRee, D. E.; Khazanovich, N . Nature, 1993, 366, 324- 327. 15. Adrian, J. C ; Wilcox, C. S. J. Am. Chem. Soc. 1991,113, 678-680. 16. Gallant, A. J.; MacLachlan, M . J. Angew. Chem. Int. Ed. Engl. 2003, 42, 5307-5310. 17. Ma, C ; Lo, A. , Abdolmaleki, A. ; MacLachlan, M . J. Org. Lett. 2004, 6, 3841-3844. 18. Evertsson, H. ; Nilsson, S.; Welch, C. J.; Sundelof, L.-O. Langmuir 1998, 14, 6403- 6408. 19. (a) Zhao, D.; Moore, J. S. J. Org. Chem. 2002, 67, 3548-3554. b) Tobe, Y. ; Utsumi, N . ; Kawabata, K.; Nagono, A. ; Adachi, K.; Araki, S.; Sonoda, M . ; Hirose, K. ; Naemura, K. J. Am. Chem. Soc. 2002,124, 5350-5364. 109 20 a) Reglinski, J.; Morris, S.; Stevenson, D. E. Polyhedron, 2002, 21, 2175-2182. b) Dzugan, S. J.; Goedken, V . L. J. Organomet. Chem. 1988, 356, 249-258. c) Akine, T. S.; Taniguchi, T. Nabeshima, Inorg. Chem. 2004, 43, 6142-6144. [21] Looking at the fluorescence spectra of the macrocycles at low concentration (10~6 M), we estimated that less than 10% was present as free (unaggregated) macrocycle. Generally, the association constant for the dynamic systems with moderate equilibrium constants (e.g., PAMs) can be taken as the association constant for dimerization.13 If we take the assumption that the macrocycles are present as dimmers at 10"6 M , then: I / - ••^assoc 2 Macrocycle w (Macrocycle)2 [(Macrocycle)2] 4 . 5 x l 0 " 7 M 7 w - l = uv j i Y 1 > 1 0 ' M "-assoc - ~ [Macrocycle]2 (10" 7 M) 2 Alternatively, i f the equilibrium constant is expressed as the addition of a macrocycle to an "infinite" stack of macrocycles (the initial concentration of macrocycle is 10"6 M and the concentration of free macrocycle is < 10"7 M): ^assoc w (Macrocycle)n + Macrocycle (Macrocycle) n + 1 [(Macrocycle)n+,] ( 9 x l O ' 7 / n ) M > i o 7 M - ' [Macrocycle][(Macrocycle)n (10~7 M)((9x 10-7 / n) M) Thus, the association constant using either model is > 107 M " 1 . [22] A small increase in fluorescence (but no wavelength shift) may be due to neutralizing a trace of residual acid in the solution. 110 Chapter 5 Future work and Conclusions 5.1 Conclusions Schiff-base condensation between dicarbonyl compounds and diamines are among the most convenient procedures for macrocycle synthesis. We have expanded this chemistry to very large macrocycles without the use of a template. The desired [3+3] shape-persistent conjugated macrocycles (14-16) were successfully prepared in high yield, and characterized by various techniques such as ' H N M R spectroscopy, UV-vis spectroscopy, IR spectroscopy, fluorescence spectroscopy and MALDI-TOF spectrometry. The ' H N M R spectra of the macrocycles all revealed a single imine and hydroxyl resonances, consistent with the symmetry of the macrocycles. These expanded metal-free macrocycles were found to be weakly luminescent. Macrocycles with salphen moieties have attracted attention due to their ability to bind multiple metal ions. The incorporation of metal ions into the three salphen-type pockets of the macrocycles has been investigated. When these macrocycles (14-16) were titrated with N i 2 + , the fluorescence intensity decreased. Examination of the Sterm-Volmer plots indicated that the quenching was static. On the other hand, upon titration with Zn , the fluorescence of the macrocycles increased, an effect that was attributed to the enhanced rigidity of the metallomacrocycles upon binding to Z n 2 + ions. During our investigation of the zinc-containing metallomacrocycles (17 and 18a), we observed aggregation in non-coordinating solvents. The supramolecular assemblies can be disrupted by coordinating bases as determined by studying the UV-vis and fluorescence spectra in various coordinating and non-coordinating solvents. Moreover, 111 the ] H N M R spectra of metallomacrocycle 17 in non-coordinating solvents such as D C M was broad and featureless due to aggregation; however, upon addition of coordinating bases, the spectra displayed sharp peaks, indicating the deaggregation of the metallomacrocycles after reaction with coordinating bases. The aggregation is dominant even at high dilution conditions, suggesting that other the assemblies were held together by strong intermolecular interactions. We speculate that Zn—O interactions between the macrocycles was responsible for the strong interaction we observed. 5.2 Future work Many new projects on macrocycles can be developed using Schiff-base chemistry. One of the advantages of Schiff-base condensation is the modularity; macrocycles with different sizes can be synthesized by utilizing various lengths and geometry of dialdehydes. Future work will also involve the use of bidentate ligands to form supramolecular nanotubes. The candidates that will be used as the bridging ligands are 4,4'-bipyridine, pyrazine and D A B C O since these ligands are not only bidentate, but also able to linearly bridge two metal ions in different macrocycles, forming a tubular structure. On the other hand, since the zinc-containing macrocycles aggregate in non- coordinating solvents, they may form nanotubular structure without the use of bridging ligands. The aggregation behaviour of these metallomacrocycles in solution should be studied extensively. For instance, the electronic factor due to peripheral substituents is known to be essential for aromatic association. The aggregation of macrocycles and metal-containing macrocycles with different side chains should be investigated. Furthermore, since only the incorporation of Zn 2 + , Ni 2 + and C u 2 + into the macrocycles has 112 been studied so far, future experiments should examine the coordination of other transition metals in the macrocycles, and probe how these metals affect their aggregation, optical and electronic properties. 113

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