DESIGN, SYNTHESIS, AND CHARACTERIZATION OF DYNAMIC METALLO-SUPRAMOLECULAR POLYMERS STABILIZED BY NON-COVALENT INTERACTIONS

Transcription

1 1 DESIGN, SYNTHESIS, AND CHARACTERIZATION OF DYNAMIC METALLO-SUPRAMOLECULAR POLYMERS STABILIZED BY NON-COVALENT INTERACTIONS A Thesis Presented to Honors Tutorial College Ohio University In Partial Fulfillment of the Requirements for Graduation from the Honors Tutorial College with the Degree of Bachelor of Science in Chemistry By Anna O. Nkrumah May 2013

2 2 This thesis has been approved by The Honors Tutorial College and the Department of Chemistry and Biochemistry Dr. Eric Masson Assistant Professor, Chemistry Thesis Advisor Dr. Lauren E. H. McMills Assistant Professor, Chemistry Director of Studies, Honors Tutorial College Dr. Jeremy Webster Dean, Honors Tutorial College

3 3 Acknowledgements When I began my college career four years ago, I never imagined I would be where I am now, so interested in research and fervent to continue laboratory work after my undergraduate years. I owe much of this growth in my aspirations to my thesis advisor, Dr. Eric Masson. My first research experience was in Dr. Masson s lab, and as confused and lost as I was, he never lost his enthusiasm or patience. What struck me about Dr. Masson and what will remain with me in whatever research groups I join in the future is how excited and passionate he is about science and research. I remember many conversations with him where he was proposing an idea or explaining a concept, and the enthusiasm that always radiated from him never failed to amaze me and boost up my own fervor. Thank you, Dr. Masson, for the valuable experiences and skills you have given me by accepting me into your lab. Thank you for being a fantastic mentor, for guiding me through this field that was at first so new to me, and for giving me the confidence to continue. I am also very thankful to the other members of the Masson lab. We are quite a dynamic group, and there is never a moment of boredom in our lab. I think that in the years I have spent at Ohio University, I have not laughed harder with any other group of people. I appreciate the energy they gave me when I felt dejected and frustrated with lab and classes, and for pushing me to keep going. Out of this group, I must show special appreciation to Dr. Roymon Joseph, my other mentor in lab who dedicated many hours of his time to run experiments with me and to answer the questions that flowed endlessly from me.

4 4 Next, I would also like to thank Honors Tutorial College and those affiliated with the college. I am very grateful to Dr. Lauren McMills, the Director of Studies of the Chemistry program, who always had helpful answers to my inquiries and bore patiently with me as I tried to figure out how to arrange my classes so I could major in both Chemistry and French and still graduate on time. I am thankful to Dean Jeremy Webster for the research funding he provided me. I am also thankful to Jan Hodson, to Kathy White, and to Margie Huber for serving as mother figures to me and to all the other H.T.C. students. For my dear mother, Catherine Nkrumah. Thank you, Maa, for not only giving me life, but also for motivating me to keep climbing. Whenever I feel as if I can climb no longer, I look for your hand, and it is immediately there to pull me forward.

5 5 Table of Contents List of Figures List of Schemes List of Tables Introduction Supramolecular Chemistry Cucurbit[n]urils CB[n]-Polymer Chemistry Terpyridine-Metal Organic Frameworks Project Goals Design and Synthesis of Covalently-Linked Functionalized Terpyridine Metal Complexes Design and Synthesis of CB[n]-Assisted, Non-Covalently Bonded Terpyridine Metal Complex Polymers Formation of Covalently Bonded Polymers Synthesis of Monomer Synthesis of a Covalently Bonded Polymer Discussion Cucurbit[n]uril-Assisted Formation of Non-Covalently Bonded Polymers Synthesis of Monomers Preliminary Studies with CB[7] NMR Studies of CB[7] with Complexes 14 and 15 Thermodynamic Characterization of Guests 14 and 15

6 6 Synthesis of a Supramolecular Polymer in the Presence of CB[8] Conclusion Experimental Section References List of Figures Figure Title Page 1 X-ray crystal structures of CB[5] through CB[8] 13 2 The perfect polyrotaxane 16 3 CB[8]-assisted formation of a 3D polymeric hydrgel H NMR spectrum of p-formylphenyl bis-terpyridine iron complex 24 1 H NMR titration of p-formylphenyl bis-terpyridine Fe(II) complex 26 6 Integrated 1 H NMR spectrum of C in Figure Integrated 1 H NMR spectrum of D in Figure H NMR spectrum of E in Figure H NMR titration of p-formylphenyl bis-terpyridine Fe(II) complex 31 1 H NMR spectrum of A in Figure H NMR spectrum of C in Figure H NMR of p-formylphenyl bis-terpyridine iron complex 33 1 H NMR spectrum of A in Figure H NMR spectrum of B in Figure Titration of p-methylphenyl bis-terpyridine complex with CB[7] 39

7 7 16 Titration of p-naphthyl bis-terpyridine Fe(II) complex with CB[7] CH---O bond between Proton 3 and carbonyl rim of CB[7] ITC titration of p-methylphenyl bis-terpyrdine Fe(II) with CB[7] ITC titration of p-naphthyl bis-terpyrdine Fe(II) with CB[7] Titration of p-methylphenyl bis-terpyrdine Fe(II) with CB[8] Titration of p-naphthyl bis-terpyrdine Fe(II) complex with CB[8] DOSY spectra of complex 14 s interaction with CB[8] DOSY spectra of complex 15 s interaction with CB[8] ITC titration of guest 14 with CB[8 List of Schemes Scheme Title Page 1 Preparation of CB[n]s CB[6]-assisted formation of covalently linked polymer 17 3 CB[6]-assisted formation of non-covalently-linked polymer 17 4 Ruthenium(II)-coordinated polymer 21 5 Preparation of p-formylphenyl bis-terpyrdine Fe(II) complex Preparation of covalently-linked polymer The two components of the covalently-linked polymer study 36 8 Synthesis of p-methylphenyl bis-terpyridine Fe(II) complex Synthesis of p-naphthyl bis-terpyridine Fe(II) complex 15 37

8 8 10 Schematic description of guest 14 s binding mode with CB[7] Schematic description of guest 15 s binding mode with CB[7] π-π stacking of the p-methylphenyl group of 14 inside CB[8] π-π stacking of the p-naphthyl group of 15 inside CB[8] 46 List of Tables Table Title Page 1 Physiochemical properties of CB[n]s 13 2 Summary of CB[7] s interaction with complexes 14 and Diffusion coefficients (D) of the monomers and polymers 51

9 9 1. Introduction 1.1. Supramolecular Chemistry By 1987, supramolecular chemistry had become an established enough field that three scientists Donald J. Cram, Jean-Marie Lehn, and Charles J. Pederson were awarded the Nobel Prize for their efforts in applying the concepts of supramolecular chemistry to synthetic systems 1-4 While they focused on different aspects of supramolecular chemistry Cram on spherands, Lehn on cryptands, and Pederson on crown ethers the complexes the three developed were based on hostguest interactions where a host selectively recognizes and binds to a guest. 6-9 Supramolecular chemistry is by definition the chemistry beyond the molecule, bearing on the organized entities of higher complexity that result from the association of two or more chemical species held together by intermolecular forces. 3,5 The interaction of two or more species to form a supramolecular architecture is driven by self-recognition and self-assembly where, under a given set of conditions, the species involved are able to recognize each other and spontaneously bind. Because the interactions are mainly non-covalent in nature (e.g. hydrogen-bonding, van der Waals attractive force, ion-dipole interactions, π-π interactions, and metal-to-ligand coordinative interactions), they are weaker and usually reversible compared to covalent bonds. 9 Before the pioneering works of Cram, Lehn, and Pederson on artificial supramolecular complexes, scientists had already been studying molecules in nature that displayed this form of interactions. Indeed, nature presents classic prototypes for

10 10 the design and synthesis of supramolecular systems since inter- and intra-molecular non-covalent interactions are crucial for many biological processes. 10 Some pertinent examples are substrate binding to receptor proteins, important in enzymatic catalysis of biological reactions that would otherwise take deleteriously longer time to proceed forward; protein assembling and folding; intermolecular replication, transcription, and translation of the genetic code; and signal transduction to drive cellular processes and allow inter- and intra-cellular communication. 11 A most archetypal example of supramolecular systems in nature is the DNA molecule, where a helical structure is able to self-assemble due to the self-recognition of complementary base-pairs that interact through multiple hydrogen-bonds. 1,11,35 The development of crown ethers, spherands, and cryptands marked the creation of a sub-field of supramolecular chemistry, namely host-guest interactions. As defined by Cram, a host-guest interaction involves a complementary stereoelectronic arrangement between host and guest, with the binding sites of the host molecule or ion converging in the host-guest complex while the binding sites of the guest diverge into the complex. 1 Hosts can therefore be regarded as the synthetic equivalents of biological substrates while guests can be seen as synthetic forms of substrates. In order for complexation to occur between host and guests, the attraction between the binding sites of the host and the guest must be strong enough to overcome any non-bonded repulsions that might be present. In a sense then, stable complexation is a process in which binding sites in both host and guest are brought together and arranged in a suitable pattern that will allow a good fit between the two species. As

11 11 mentioned before, the existence of multiple contact sites between the host and the guest is also an important factor that results in stable complexation. 12,13 If the host and guest are in contact over a large area, then the host is able to establish numerous noncovalent interactions with the guest, thus fitting the two together in a more stable arrangement. Preorganization, a process that occurs before the joining of the binding sites of the receptor and substrate and one that is crucial to host-guest chemistry, is an important factor in determining the binding power between a host and its guest. According to the principle of preorganization, in addition to good arrangement and organization of host and guest prior to complexation, low solvation of the free guest and host is also required to produce stable complexes. 1,14,15 This general requirement is important because during complexation, the solvent molecules that are surrounding the binding sites of both host and guest must be displaced before the complexation process can be completed. This desolvation process is favored entropically but disfavored enthalpically, thus any net free-energy costs must be accounted for by the decrease in free energy as the host and guest complex. The better organized the binding sites of the host and guest are and the more these sites complement each other (in terms of physical size and structure as well as intermolecular attractions), the less the free energy of interaction will be, and the more favored the binding will be overall. 9 Over the years, a great variety of receptor host molecules has been synthesized for the recognition of a plethora of different substrates, ranging from hosts that are spherical to those that are tetrahedral, linear/branched, charged/neutral,

12 12 organic/inorganic/biological, etc. One of these hosts spherical in nature and one of the important molecules used in this project is cucurbit[n]uril Cucurbit[n]urils Cucurbit[n]urils (abbreviated henceforth as CB[n]) are a family of macrocyclic methylene-bridged glycoluril oligomers made by the condensation of glycoluril 1 and formaldehyde under high acidic conditions These supramolecular hosts are known as cucurbiturils because of their resemblance to pumpkins, which belong to the plant family Cucurbitaceae. The first mixture of CB[n]s was synthesized in 1905 by Behrend and coworkers, 16 although it was not until 1981 that a member of this mixture containing 6 glycoluril units was isolated and characterized by the Mock group. 20,21 This member was called Cucurbit[6]uril or CB[6] with the 6 representing the number of glycoluril units on the top and bottom rims of the macrocycle. Since CB[6] was isolated, more members of the CB[n] family have also been crystalized, including CB[5], CB[7], CB[8], and CB[10]. 17,18 A general scheme for the preparation of CB[n]s is shown in Scheme 1 while x-ray crystal structures of CB[5]-CB[8] have been shown in Figure Scheme 1: Preparation of CB[n]s from glycoluril (1) and formaldehyde under acidic conditions.

13 13 Figure 1: X-ray crystal structures of CB[5] through CB[8] (carbon atoms in gray, nitrogen atoms in blue, and oxygen atoms in red. 20,22 The ability of CB[n]s to form supramolecular interactions with guest molecules is mainly due to their two hydrophilic carbonylated rims and their hydrophobic cavity. Compound Portal Diameter (Å) Cavity Diameter (Å) Total Depth (Å) Solubility in H 2 O (mm) Highest Recorded Binding Affinity(K a ) (M -1 ) CB[5] CB[6] x CB[7] x CB[8] < x CB[10] < Table 1: Physiochemical properties of CB[n]s 17,18,22,24-27 With a cavity diameter ranging from 4.4 Å to 12.4 Å and a portal diameter ranging from 2.4 Å to 10.6 Å, CB[n]s have the remarkable ability of forming complexes with a wide range of molecules, with the most favorable interactions

14 14 occurring with positively charged amphiphilic compounds (see Table 1 for a more expanded list of physio-chemical properties of CB[n]s). The hydrophobic parts of these guests are able to interact with the hydrophobic cavity of the CB[n] host while the positively charged areas interact with the hydrophilic, carbonylated rim of the host. The strongest binding affinity measured thus far for the CB[n] family was for CB[7] s interaction with a charged adamantane derivative (compound 2a), with a binding affinity of 5.0 x M -1, 18,28 followed closely by CB[7] s interaction with a charged ferrocene derivative (compound 3a), with a binding affinity of 3.0 x M ,29 These values represent the strongest non-covalent interactions ever measured between a synthetic receptor and substrate, comparing competitively with the M -1 binding affinity that exists between the natural biological substrates avidin and biotin. 18,30,31 These values attest to the strong ability of these macrocycles to act as host molecules, especially in the case of CB[7]. 18,28,32 The usual binding constant between CB[7] and its guests is between 10 7 and M -1, interactions that are uncommonly strong when compared with other synthetic host molecules. 18,34 While neutral molecules like alcohols and carboxylic acids bind weakly to CB[7] (with binding constants in the range of M -1 ), 18 there are some few exceptional cases where higher binding affinities have been recorded, as in the case of the hydroxymethylferrocene (compound 3b), which binds to CB[7] with an affinity of 3.0 x 10 9 M ,33 Along with CB[7], CB[8] also shows amazingly strong binding constants towards large amphiphilic guests like adamantane derivatives 2b and 2c, with an affinity measuring up to 4.3 x M ,34

15 15 The remarkable recognition properties of CB[n]s as well as the diversity in their guest-binding behavior have resulted in an increasing development of a variety of interdisciplinary applications. CB[n]s have been shown to acts as catalysts, possessing the ability to change the thermodynamic and kinetic parameters of certain reactions. They are also promising carriers for drug delivery, due not only to their low toxicity inside biological systems, but also to their ability to cross cell membranes and to target a specific site. Of particular application to this research project is CB[n] s ability to assist in polymer formation, covalently or non-covalently connecting monomers or polymers together to form longer assemblies. 17,18, CB[n]-Polymer Chemistry The study of CB[n] s ability to promote the formation of polymers is a rapidly growing field due to the many applications involved in this sector. CB[n]-based polymers have the potential of being used as stimulus-controlled drug delivery systems, as dendrimers, as nanosheets and films, and even as hydrogels. 18,56 A range

16 16 of CB[n]s such as CB[6], CB[7], and CB[8] have been shown in past studies to be capable of covalently or non-covalently joining monomers together to form polymers. An example of CB[6]-catalyzed polymer formation was reported in 1999 by Steinke et. al.., in which the macrocycle connected azide and alkyne functional groups together in a cycloaddition reaction to form a structurally perfect polyrotaxane. 18,55 Polyrotaxanes refer to long, linear chains threaded through cyclic molecular structures like CB[n]s. A rotaxane is made more perfect when joined monomers in the chain are repeated a significant amount of time, and there is little chance of the macrocycle slipping of the chain due to a stopper that has been incorporated into the axel. This perfect rotaxane is depicted in Figure Figure 2: The perfect polyrotaxane, as designed by Steinke et. al. 55 To create this perfect polyrotaxane, a 1, 3-dipolar cycloaddition reaction was catalyzed between diammonium diazido 5 and diammonium dialkyne 4 inside CB[6] s cavity to produce polyrotaxane 6 (Scheme 2).

17 17 Scheme 2: CB[6]-assisted formation of a polymer through covalent interactions. 18,55 In another CB[6]-catalyzed polyrotaxane study this one formed noncovalently Kim et. al. first threaded the macrocycle onto oligomer 7, then coordinated this new functional monomer to Ag(III), which then continued the chain by coordinating to another functional unit (Scheme 3). Intriguingly, coordination polymer 8 was found to be a racemic helical mixture. 57 Scheme 3: CB[6]-assisted formation of polymer through non-covalent interactions. 57

18 18 In an exciting development in CB[n]-polymer chemistry, the Scherman group reported the CB[8]-assisted synthesis of a polymeric hydrogel whose cross-link density could be controlled by external stimuli. As one of the members of the CB[n] family to possess a larger cavity, CB[8] is able to encapsulate more than one host and thus affect the interaction between these hosts. 18,56 In this study, electron deficient viologen (marked in Figure 3 as the acceptor ) and electron-rich naphthol (marked as donor ) were connected as side chains on their own respective polymeric scaffolds. The addition of 0.5 eq CB[8] to a mixture of these two polymers afforded a bright red viscous gel (Fig. 3d), indicative of an electron-charge transfer between the viologen and the naphthol substituents inside CB[8] s cavity. This complex inside CB[8] created cross-links between the two polymers (Fig 3e, 3f), resulting in an increase in the viscosity of the solution. This complexation was found to be fully reversible and sensitive to external factors Heating of the gel decreased its cross-linked density, making it less viscous and giving it a sol-like consistency. Upon cooling, the gel assumed its initial viscosity, attesting to the sensitivity yet stability of the complex. Along with temperature, the concentration of CB[8] could also be used to modulate the degree of cross-linking, with higher amounts of CB[8] resulting in higher degrees of cross-linking and vice-versa.

19 19 Figure 3: CB[8]-assisted formation of a 3D polymeric hydrogel. a) Solution of the viologen-attached polymer. b) Solution of the naphthol-attached polymer. c) Solution of a 1:1 mixture of the two polymers. d) Formation of a red hydrogel upon addition of 0.5 eq CB[8]. e) Scanning electron micrograph of the hydrogel. 18,56 Figure reprinted with permission from Ref Terpyridine Metal Organic Frameworks Along with host-guest interactions, another important type of interaction in the field of supramolecular chemistry is metal-ligand coordination, most famously those involving 2,2'-bipyridine (compound 9) and 2,2':6',2"-terpyridine (compound 10a). 35 2,2':6',2"-terpyridine (referred to henceforth simply as terpyridine) was first prepared in 1930 by Morgan and Burstal by the heating of FeCl 3 with pyridine at 50atm for 36 h In the presence of Fe(II), the solution immediately turned purple, a sign that terpyridine could complex with the iron. 35 Numerous functionalized derivatives of terpyridine have been synthesized since its isolation, and the complexation of these derivatives to transition metal ions have resulted in various applications. The structure of terpyridine and the way in which the three nitrogen atoms are arranged in the compound allow it to act as a tridentate ligand capable of forming stable complexes with metals (general structure 10b). While the type of functional groups on the

20 20 terpyridine affects the overall electronic properties of the complex, studies have shown terpyridine metal complexes to have remarkable redox and photophysical properties. 35,38,39 As photochemical agents, terpyridine metal complexes have applications as luminescent devices and as sensitizers for solar cells in light-toelectricity conversion. 35,40-45 Some terpyridine metal complexes are also capable of forming more complex supramolecular arrangements, with the ability to self-assemble into layers on surfaces like graphite, gold, and TiO 2. 35,46-48 Some other important applications of terpyridine metal complexes arise from their ability to self-assemble into polymers under the right set of conditions. Due to their rigid geometric structure, functionalized terpyridine metal complexes can form quite stable complexes in their polymerized forms. Polymerization of these complexes has been achieved both through covalent and non-covalent interactions. An example is polymer 11, linked non-covalently through the coordination of monomer 11a with Ru(II), as synthesized by Schmelz and Rehahn (Scheme 4). 58,59 While the design and synthesis of polymeric functionalized terpyridine complexes can be difficult, this area of study is worth-while due to the novel products and functions they can serve. One application of these polymers studied by a growing number of labs is their ability to

21 21 form grid-like assemblies. Depending on the reaction conditions, how the chelating terpyridine ligand is functionalized, and the metal ion to which the ligands are bound, various grid structures can be formed. These types of grid structures, depending on the electronic and photophysical properties of the metal ion, could be used in the future as optical nano-devices, as sensitizers in solar cells, and as molecular storage devices. 35,49,50,51,52 Scheme 4: Ruthenium(II)-coordinated polymer designed and synthesized by Rehahn. 58

22 Project Goals Design and Synthesis of Covalently-Linked Functionalized Terpyridine Metal Complexes This part of the project focused on developing a functionalized terpyridine metal complex polymer in which the monomers are linked together through covalent interactions. The thermodynamic and kinetic characteristics of the reaction mechanism would be studied, and the type of polymers produced would be characterized. CB[n] would be added to the reaction system to ascertain the effect of this macrocycle on the general mechanism of the reaction Design and Synthesis of CB[n]-Assisted Non-Covalently Bonded Terpyridine Metal Complex Polymer The second part of the project also focused on creating terpyridine metal complexbased polymers, but this time the monomers would be linked through non-covalent interactions, thus creating a higher and more reversible form of supramolecular architecture. CB[n] would be added to the system to aid in this polymer formation, and the thermodynamic and kinetic properties of the reaction and product(s) would be studied.

23 23 2. Formation of Covalently-Bonded Polymers 2.1. Synthesis Scheme 5: Preparation of p-formylphenyl-substituted bis-terpyrdine iron complex 12. To prepare the p-formylphenyl functionalized bis-terpyridine iron complex 12 (Scheme 5), 2-acetylpyridine was coupled to p-tolualdehyde to afford terpyridine 12a. This compound underwent free radical bromination to produce benzylbromide derivative 12b, which was subsequently reacted with DMSO and NaHCO 3 to afford p- formylphenyl derivative 12c. Complexation of this compound with iron(ii) chloride afforded the desired product 12 (see Figure 4 for the 1 H NMR spectrum of this compound).

24 24 Figure 4: 1 H NMR spectrum of p-formylphenyl functionalized bis-terpyridine iron complex Polymer Formation After obtaining unit 12, the next step was to perform a Schiff base reaction in which complex 12 was treated with diammonium salt 13a to produce polymerized imine 13b which would subsequently be reduced to amine 13 using the reducing agent sodium cyanoborohydride (NaBH 3 CN) (Scheme 6).

25 Scheme 6: Preparation of covalently-linked polymer

26 26 The reaction was followed by 1 H NMR (taken in D 2 O) to ascertain whether or not the polymerized product was forming (Figure 5). Trimethylsilane (TMS) (its signal is boxed in black in Fig. 5) was added as an internal standard to track changes in the amount of the iron complex as the aldehyde functional group was converted to an imine and then to the amine. The proton next to the aldehyde that was tracked to observe these changes is boxed in red in Fig. 5 and indicated on the compound. Figure 5: 1 H NMR titration of aldehyde 12 (2.0 mm) with diammonium 13a and sodium cyanoborohydride in D 2 O. Changes in aldehyde 12 s concentration were tracked using the proton signal marked in red corresponding to the red hydrogen marked on the compound. Spectrum A corresponds to monomer 12 before the addition of diammonium 13a. B represents the free diammonium salt 13a. Spectrum C shows a solution containing both complex 12 and salt 13a. D depicts the mixture when cyanoborohydride has been added to reduce any imines that are formed to amines. E was taken after the reaction had been heated for two days at 60 o C.

27 27 In a reaction such as this in which an aldehyde is being reduced to an amine, a change in shift is expected for the signal corresponding to the hydrogens next to the changing functional groups (marked in red in Fig. 5). However, it seems that after the addition of the ammonium and the reducing agent, the reaction was still not progressing. An interesting phenomenon that was observed was that addition of NaBH 3 CN immediately caused a precipitate to form in the mixture. Figure 6: Integrated 1 H NMR spectrum of C in Fig. 5. The alpha aldehyde proton (marked in red on the compound) is integrated as 1.13.

28 28 Figure 7: Integrated 1 H NMR spectrum of D in Fig. 5 (the reaction mixture after the addition of NaBH 3 CN. The alpha aldehyde proton (marked in red on the compound) integrates as 0.46 against the internal TMS standard. An integration of spectrum D indicated that the aldehyde peak had indeed decreased in comparison to before the addition of the reducing agent (Figures 6 and 7). Before the addition of the reducing agent, the alpha aldehyde proton integrated as 1.13 against the internal TMS standard (Fig. 6) but after addition of the cyanoborohydride, its integration decreased to 0.46 (Fig. 7). Even though the concentration of the aldehyde complex was reducing, no new signals were forming elsewhere to indicate formation of the amine (Fig. 5).

29 29 To determine if heat would increase the rate of the reaction and dissolve the precipitated solid back into the mixture, the reaction was heated to 60 o C for 48 h. Figure 8: 1 H NMR spectrum of E in Fig. 5, showing the state of the species in the reaction mixture after a 48 h heating period. Heating the reaction mixture did not re-dissolve the precipitate back into solution, and while the concentration of the aldehyde remained around the same as before heating the alpha hydrogen s integration as 0.43 (Fig. 8) did not differ greatly from the pre-heated complex s integration at 0.46 no new signals appeared that indicated that the Schiff base reaction and subsequent reduction of the base to an amine were occurring. Even though the data compiled up to this point suggested the instability of the aldehyde iron complex in the presence of sodium cyanoborohydride, the standard against which the aldehyde was integrated could not be completely trusted. TMS as a

30 30 standard usually gives a very sharp peak at 0 ppm, and its concentration is supposed to remain the same regardless of what is happening to the other reagents in the solution. In this manner, the amount of the other reagents can be tracked over time in the way they compare to the amount of TMS in solution. The TMS peak in the reaction mixture depicted in Fig. 5 is not sharp, however, but broad, indicating that it might have become bound to a compound in the solution instead of remaining a free species. To make sure then that TMS was correctly indicating that the amount of aldehyde complex in solution was decreasing, we re-ran the experiment, this time using an external TMS standard. In this case, instead of adding TMS directly to the reaction mixture, it was sealed in a capillary before being added. As before, the aldehyde complex was first mixed with the diammonium salt to initiate formation of the Schiff base. NaBH 3 CN was added to the mixture to reduce any formed imines to amines (Scheme 6). The same trend was observed in which a precipitate formed in the reaction tube upon addition of the NaBH 3 CN. Again, the alpha carbonyl proton signal did not shift in the presence of the diammonium salt and NaBH 3 CN (Figure 9), indicating the desired reaction might not be occurring. Integrating spectrum A (Figure 10), which corresponds to the reaction mixture before the addition of the NaBH 3 CN reducing agent, and spectrum C (Figure 11) showed that the alpha carbonyl proton decreased in integration from 1.63 to 0.84.

31 31 Figure 9: 1 H NMR titration of aldehyde 12 (2.0 mm) with 13a and NaBH 3 CN in D 2 O at 25 o C. Changes in aldehyde 12 s concentration were tracked via the alpha carbonyl proton signal marked in red. Spectrum A corresponds to free monomer 12. B represents free diammonium 13a. C shows a solution containing both 12, 13a, and NaBH 3 CN. Figure 10: 1 H NMR spectrum of A in Fig. 9 integrated against the external standard. The alpha carbonyl proton peak is integrated as 1.63.

32 32 Figure 11: 1 H NMR spectrum of C (the reaction mixture with cyanoborohydride) in Fig. 9 integrated against the external standard. The alpha carbonyl proton peak is integrated as Two possible explanations at this point was that the aldehyde was simply crashing out of solution without reacting with the diammonium to form the polymer, or that the polymer indeed was forming, but it was insoluble in the water medium and was thus crashing out of solution. To obtain a clearer view as to what was happening in the reaction, we decided to test the stability of complex 12 alone with sodium cyanoborohydride. If the concentration of the aldehyde decreased and a precipitate formed, this would imply that the iron complex is unstable in the presence of the reducing agent, and it was precipitating instead of forming the polymer. The 1 H NMR

33 33 study of the reaction of the aldehyde iron complex with cyanoborohydride has been shown in Figure 12. Figure 12: 1 H NMR of aldehyde 12 s (2.0 mm) interaction with NaBH 3 CN taken in D 2 O at 25 o C. Changes in 12 s concentration were tracked via the alpha carbonyl proton signal marked in red. Spectrum A corresponds to monomer 12 before the addition of cyanoborohydride while B represents the solution after the addition of the reducing agent. Adding cyanoborohydride to aldehyde 12 caused the alpha carbonyl proton signal to decrease in integration from 0.91 (Figure 13) to 0.13 (Figure 14). Like before, a visible precipitate was observed upon the addition of cyanoborohydride to Fe(II) complex 12.

34 34 Figure 13: 1 H NMR spectrum of A (free aldehyde 12 before addition of NaBH 3 CN) in Fig. 12 integrated against the external standard. The alpha carbonyl proton signal integrates as Figure 14: 1 H NMR spectrum of B (the reaction mixture with NaBH 3 CN) in Fig. 12 integrated against the external standard. The alpha carbonyl proton signal integrates as 0.13.

35 Discussion A study published by Diner et. al. in 1993 and another published by the same group in 1994 support this finding that cyanide has the ability to bind to iron(ii) complexes. 53,54 In the studies, the Diner group found that CN is able to bind competitively to the non-heme Fe(II) site of Photosystem II in plants. At ph greater than 6.5, at least two cyanides were able to displace NO from the iron binding site and bind to the iron instead. At higher ph concentrations, the bound cyanide intrinsically affected the iron by changing its spin state from 2 to 0, thus effectively changing it from a high-spin state metal complex to a low spin-state complex. We did not perform further studies to characterize the specific effects cyanide had on Fe(II) complex 12 and how it caused the complex to precipitate from solution instead of reacting with diammonium salt 13a, but the data compiled at this point suggested that the desired reactions needed to occur to form the polymer were not occurring. While we could have used a different reducing agent, the stability of NaBH 3 CN in water was ideal. The reactions needed to occur in water media since CB[n]s have maximal soluble in water compared to other solvents. If the polymer had indeed formed, then we could have made the transition to adding CB to the reaction under the same solvent conditions as before. Scheme 7 depicts the possible routes of this study: first, the polymer would be synthesized without CB[n] (route A). In the case that a product was obtained, another study would then be performed in which CB[n] would be added to determine if it had any kinetic or thermodynamic effects on the reaction mechanism (route B).

36 Scheme 7: The two components of this study. First, polymer 13 would be synthesized without CB[n] (route A). If this reaction had been successful, then another reaction would have been performed in which CB[n] was added to the reaction mixture (route B). 36

37 37 3. Cucurbit[n]uril-Assisted Formation of Non-Covalently Bonded Polymers 3.1. Synthesis of the Monomers Two main functionalized bis-terpyridine metal complexes 14 (Scheme 8) and 15 (Scheme 9) were prepared and used in this study. Scheme 8: Synthesis of p-methylphenyl functionalized bis-terpyridine Fe(II) complex 14. Scheme 9: Synthesis of p-naphthyl functionalized bis-terpyridine Fe(II) complex 15.

38 Preliminary Studies with CB[7] After the synthesis of complexes 14 and 15, their mode of interaction with CB[7] the member of the CB[n] family that displays the strongest binding affinity toward guests 18 was studied so as to obtain a general idea of their binding kinetics and thermodynamics with CB[n] NMR Studies of CB[7] with Compounds 14 and 15 A 1 H NMR study was performed in which increasing concentrations of CB[7] was added to bis-terpyridine 14 (Scheme 10, Figure 15) and 15 (Scheme 11, Figure 16). No significant changes appear in the spectra after approximately 2.00 equivalencies of CB[7] have been added to both guests 14 and 15, indicating that this is a 2:1 binding in which two molecules of CB[7] are binding to each compound. Scheme 10: Schematic description of the binding mode of guest 14 in 2:1 binding at saturation with CB[7].

39 39 Figure 15: Titration of complex 14 (2.0 mm) with CB[7] in D 2 O at 25 o C. The chemical shifts of the hydrogen units of guest 14 are tracked with dashed arrows. Scheme 11: Schematic description of the binding mode of guest 15 in 2:1 binding at saturation with CB[7].

40 40 Figure 16: Titration of complex 15 (2.0 mm) with CB[7] in D 2 O at 25 o C. The chemical shifts of the hydrogen units of guest 15 are tracked with dashed arrows. Based on the chemical shifts of hydrogens in guests 14 and 15 upon interaction with CB[7], it is possible to approximate the location of CB[7] in the complex. In the case of assembly 14, the significant upfield shifts of protons 7, 3", and 2" (approximately 0.5 ppm) indicate that they are inside the cavity of CB[7], and that the p-methylphenyl group of the complex is perched inside the cavity of the macrocycle while the terpyridine moeity remains outside. A similar scenario occurs for compound 15, in which only the protons on the naphthyl group experience an upfield shift, meaning this part of the compound is inside CB[7] while the terpyridine part is outside.

41 41 What is of particular interest is the way the proton at position 3 in the terpyridine part of either complex interacts with CB[7]. In the case of guest 14, proton 3 experiences a strong downfield shift from 8.5 ppm to 9.5 ppm. In complex 15, proton 3 does not experience as significant a downfield shift, but its movement from 8.5 to 9ppm is still notable. These considerable changes in shifts indicate that proton 3 is interacting strongly with the carbonyl oxygens at the rim of CB[7], in effect though a CH---O hydrogen-bonding type of interaction. While the binding sites of CB[7] on 14 and 15 are not positively charged, the charge on the Fe(II) center in each compound is able to diffuse through the compounds. This diffusion of charge could be more pronounced at position 3 of the terpyridine unit, thus prompting the interaction of that hydrogen with the macrocycle s oxygens. This postulation has been depicted in Figure 17.. Figure 17: Proton 3 in either complex forming a CH---O non-covalent bond with the carbonyl rim of CB[7].

42 Thermodynamic Characterization of Guests 14 and 15 Upon CB[7] Binding Once NMR studies were carried out, isothermal titration calorimetry (ITC) experiments were performed to find the thermodynamic parameters of the binding event. The enthalpic, entropic, and free energy contributions produced for the interaction of CB[7] with guests 14 (Figure 18) and 15 (Figure 19) have been plotted and summarized (Table 2). Figure 18: ITC titration of guest 14 with CB[7]; 2:1 binding model (i.e. the interaction of one p-methylphenyl unit with CB[7] does not affect the affinity of the other p-methylphenyl moiety towards the macrocycle.

43 43 Figure 19: ITC titration of guest 15 with CB[7]; 2:1 binding model (i.e. the interaction of one p-naphthyl unit with CB[7] does not affect the affinity of the other p-naphthyl moiety towards the macrocycle. Compound N K (M -1 ) ΔH (kcal/mol) TΔS (kcal/mol) ΔG (kcal/mol) x x Table 2: Summary of CB[7] s interaction with complexes 14 and 15 obtained from ITC plot. N represents inverse number of binding sites, ΔH represents binding enthalpy, TΔS is the entropic component of the binding. and ΔG is the free energy of the binding.

44 44 As mentioned in the introductory part of this paper, the strongest binding affinity observed to date for CB[7] is for its interaction with the positively charged adamantane derivative 2a, with an affinity of 5.0 x M -1. The strongest interaction CB[7] has had with a neutral species is with the ferrocene derivative 3b, this time measuring up to 3.0 x 10 9 M -1. While the two Fe(II) complexes binding affinities are some factors away from these record-breaking values, the two still display a significant affinity for CB[7] than might otherwise be expected. It is to be noted that even though guests 14 and 15 have a positively charged iron center, the sites at which CB[7] is bound are neutral. For a guest to have a strong fit inside CB[n]s and to display favorable interactions with this host molecule, it is usually the case that the guest be amphiphilic, with the hydrophobic part interacting with the cavity of the CB molecule while the charged or polar hydrophilic part interacts with the carbonyl rim. In this case, however, the component (proton 3 on the terpyridine unit of the complexes) of the complexes that is stabilizing the carbonyl rim of CB[7] is not overtly charged or polar, but might be instead be deriving the positive charge it needs to hydrogen-bond with the oxygens from the Fe(II) center. Other aspects of interest are the very low enthalpy and entropic component of binding. While the binding of CB[7] to the two Fe(II) complexes is very favored enthalpically, it is also very disfavored entropically as seen in the low entropic components of kcal/mol for complex 15 and kcal/mol for complex 9 (Table 2).

45 Synthesis of a Supramolecular Polymer in the Presence of CB[8] The strong interaction that guests 14 and 15 displayed towards CB[7] was mirrored in their interaction with CB[8], though this interaction afforded a different set of products. As we expected, adding increasing concentrations of CB[8] to guest 14 (Scheme 12, Figure 20) and to complex 15 (Scheme 13, Figure 21) resulted in the formation of non-covalently bonded polymers via π-π stacking of the terpyridine substituents inside of the macrocycle. Scheme 12: π-π stacking of the p-methylphenyl group of 14 inside the CB[8] cavity.

46 46 Scheme 13: π-π stacking of the p-naphthyl group of 15 inside the CB[8] cavity to form non-covalently bound polymers. Saturation was reached after the addition of 1 equivalent of CB[8] to each complex (Figures 20 and 21), indicated by the broadening of the signals at stoichiometric and excess amount of CB[8] in each spectra. The broadening of the signals after saturation is also an indication of polymer formation, where the substituents on the terpyridine metal complexes are π-π stacking inside of CB[8] (Schemes 12 and 13).

47 47 Figure 20: Titration of complex 14 (2.0 mm) with increasing amounts of CB[8] in D 2 O at 25 o C. Figure 21: Titration of complex 15 (2.0 mm) with increasing amounts of CB[8] in D 2 O at 25 o C.

48 48 Because the signals broadened after saturation, it was difficult to follow proton chemical shifts by 1D and 2D 1 H NMR, but it is very likely that due to the size constraints of complexes 14 and 15, CB[8] cannot move very far past the p- methylphenyl and p-naphthyl groups of each compound, and is thus binding at the same sites as CB[7]. Figure 22: Stacked DOSY spectra of complex 14 interacting with CB[8]. A corresponds to free CB[8]. B contains free complex 14. C depicts 0.5 eq CB[8] added to guest 14. D corresponds to a 1:1 mixture of complex 14: CB[8].

49 49 Figure 23: Stacked DOSY spectra of complex 15 interacting with CB[8]. A corresponds to free CB[8]. B contains free complex 15. C depicts 0.5 eq CB[8] added to guest 15. D corresponds to a 1:1 mixture of complex 15: CB[8]. In order to further confirm that the complexes were π-π stacking inside CB[8] and polymerizing, DOSY experiments were run to determine the amount of species in a saturated solution of CB[8] and the comparative sizes of these species. The stacked DOSY spectra for complex 14 are shown in Figure 22 while the spectra for complex 15 are shown in Figure 23. As free compounds, CB[8], guest 14, and guest 15 each

50 50 have a log diffusion (log D) coefficient of approximately 9.5. With the addition of 0.5 eq CB[8] to guest 14 (Figure 22C), two species with two distinct diffusion coefficents are present. One (boxed in red) appears at log D of 9.8, while the other (boxed in blue) appears around log D of 9.5. The species boxed in blue is monomer 14 since it has the same chemical shifts and logd as the free complex in spectrum B. The higher logd value of the species marked in red corresponds to a compound that has a higher molecular weight, thus implying the existence of the polymer at this equivalency of CB[8]. Because the solution is not completely saturated with CB[8], only about half of complex 14 in solution is able to polymerize while the other half remains free. With a stoichiometric of CB[8] (Figure 22D), species have a log D value of about 10.3 to Compared to the lower log D coefficients of 9.5 for the monomers, this higher diffusion coefficient again points to the possible formation of a polymer. At least two species are present in D, pointing to the existence of polymers of different sizes. The same analysis can be performed for complex 15, where the addition of 0.5 equivalents of CB[8] (Figure 23C) results in at least two species where one exists at log D 9.5 and another at a higher log D of approximately 9.8. At saturation (Figure 23D), some excess free CB[8] is found in the solution (boxed in green), along with species above a log D of 10. As in the case of complex 14, it is likely that 15 forms polymers of different sizes upon interaction with CB[8] since the red-boxed species in Spectrum D exists across a range of diffusion coefficients. The diffusion coefficents for the polymerized version of each complex and how they compare to the monomers have been summarized in Table 3.

51 51 Compound logd D CB[8] x x x CB[8] Polymer to x to 3.2 x CB[8] Polymer to x to 3.2 x Table 3: Diffusion coefficients (D) of monomers 14, 15, and CB[8] and their polymerized complexes. To determine the binding affinity of the polymer with CB[8], ITC studies were performed for the interaction of complex 14 with the macrocycle. The plot produced by the experiment is shown in Figure 24 while the data has been summarized in Table 4. Data for studies done with complex 15 is not shown here since we could not obtain an adequate plot.

52 52 Figure 24: ITC titration of guest 14 with CB[8]; 1:1 binding model (i.e. the interaction of one p-methylphenyl unit with CB[8] does not affect the affinity of the other p-methylphenyl moiety towards the macrocycle. Compound N K (M -1 ) ΔH (kcal/mol) TΔS (kcal/mol) ΔG (kcal/mol) x Table 3: Summary of binding kinetics of 14 with CB[8] as given by ITC experimentation, where N represents number of binding sites, K is the binding affinity, ΔH is binding enthalpy, and TΔS is the entropic component of the interaction, and ΔG is the free energy of binding.

53 53 As mentioned in the introductory part of this paper, the strongest binding affinity observed to date for CB[8] was for its interaction with the positively charged adamantane derivatives 2b and 2c measuring up to 4.3 x M -1. While being some factors away from this value, complex 14 still displays a significant affinity for CB[8] with its 10 6 M -1 binding affinity. 4. Conclusions Due to their photochemical, electronic, and magnetic properties, polymerized terpyridine metal complexes have a wide array of functions. In this study, we successfully synthesized and characterized three functionalized terpyridine derivatives. p-formylphenyl 12, with its dialdehyde functional groups, was ideal for coupling with diammonium salt 13a in a reductive amination reaction to form covalently-bound polymers. Due to the instability of complex 12 in the presence of the reducing agent, however, the polymer product could not be obtained. Terpyridine metal complexes 14 and 15, synthesized with the goal of creating non-covalently bound polymers with the aid of CB[n], showed strong binding affinities towards both CB[7] and CB[8]. We were successful in forming noncovalently bound polymers of these two complexes with the assistance of CB[8], achieved through π-π stacking of the p-methylphenyl (complex 14) and p-naphthyl (complex 15) units inside the cavity of the macrocycle. Future experiments will focus on modifying the metal complex system with different substituents, perhaps with those that are more conjugated and thus have more

54 54 pronounced electronic character. Our lab is also in the process of designing and synthesizing chiral terpyridine substituents that may have the ability to form helical structures, applicable as molecular storage units. We will also complex the terpyridine derivatives to transition metals containing different charges to study the effect of charge on the binding constants of the monomers interactions with CB[n]. Different types of microscopic techniques will be used to characterize the results of these interactions, examples being Tunneling Electron Microscopy (TEM), Atomic Force Microscopy (AFM), and Scanning Electron Microscopy (SEM).

55 55 Experimental Section 4 -(4-Bromomethylphenyl)-[2,2 :6,2 ]terpyridine 12b. 60 To a solution of terpyridine 12a (2.5 g, 7.7 mmol) in dry CCl 4 (25 ml) was added N- bromosuccinimide (1.7 g, 9.3 mmol), and, -azoisobutyronitrile (0.10 g, 0.61 mmol) and the reaction mixture was refluxed for 6 h under inert atmosphere. The warm reaction mixture was filtered and the solvent was evaporated. Recrystallization from ethanol gave light yellow solid (1.2 g, 39%). 1 H NMR (300 MHz, CDCl 3 ): 8.74 (s, Ar-H, 4H), 8.68 (d, J = 7.9 Hz, Ar-H, 2H), (m, Ar-H, 4H), 7.54 (d, J = 8.1 Hz, Ar-H, 2H), 7.37 (t, J = 5.0 Hz, Ar-H, 2H), 4.57 (s, Ar-CH 3, 3H) ppm. 4 -(4-Formylphenyl)-[2,2 :6,2 ]terpyridine 12c. 60 To a solution of terpyridine 12b (0.55 g, 1.4 mmol) in DMSO (10 ml) was added an excess amount of sodium bicarbonate (2.5 g). The reaction mixture was kept at 120 C for 48 h under inert atmosphere. The reaction mixture was cooled to 25 C, poured into ice-cold water and the precipitate was filtered to afford the title compound as a light yellow solid (0.35 g, 76%). 1 H NMR (300 MHz, CDCl 3 ): (s, Ar-CHO, 1H), (m, Ar-H, 4H), 8.68 (d, J = 7.8 Hz, Ar-H, 2H), 8.04 (q, J = 8.1 Hz, Ar-H, 4H), 7.90 (t, J = 7.0 Hz, Ar-H, 2H), 7.38 (t, J = 6.3 Hz, Ar-H, 2H) ppm. 4 -(Methylphenyl)-2,2 :6,2 -terpyridine 12a. 61 To a solution of 2- methylbenzaldehyde (2.4 g, 20 mmol) in ethanol (0.10 L) was added 2-acetylpyridine (4.8 g, 40 mmol), sodium hydroxide (1.6 g, 40 mmol) and aqueous ammonia (0.60 L,