Formation of Functionalized Supramolecular Metallo-Organic Oligomers with Cucurbituril a Thesis Presented to the Faculty Of

Formation of Functionalized Supramolecular Metallo-organic Oligomers with

Cucurbituril

A thesis presented to

the faculty of

the College of Arts and Sciences of Ohio University

In partial fulfillment

of the requirements for the degree

Master of Science

Ian M. Del Valle

December 2015

This thesis titled

Formation of Functionalized Supramolecular Metallo-organic Oligomers with

Cucurbituril

IAN M. DEL VALLE

has been approved for

the Department of Chemistry and Biochemistry

and the College of Arts and Sciences by

Eric Masson

Associate Professor of Chemistry and Biochemistry

Robert Frank

Dean, College of Arts and Sciences 3

Abstract

DEL VALLE, IAN M., M.S., December 2015, Chemistry

Formation of Functionalized Supramolecular Metallo-organic Oligomers with

Cucurbituril

Director of Thesis: Eric Masson

The goal of this project is to functionalize supramolecular oligomer chains with amino acids and nucleic acids in order to observe interactions with proteins and DNA.

Chiral substituents are also desirable to induce helicality in the oligomer much like DNA.

We explored different pathways to afford these oligomers.

The first project involves forming metallo-organic oligomers using non-covalent bonds and then functionalizing them. We synthesize ligands and use alkyne-azide cycloadditions to functionalize them. These ligands can then be coordinated to various transition metals. The aromatic regions of these oligomers can then self-assemble into tube-like chains with the participation of cucurbit[8]uril.

Second, we explore an alternate pathway to form functionalized chains. This second set of chains coupled amines with carboxylic acid groups attached to the ligands.

This project hopes to avoid solubility problems experienced with the first project. We also explore other alterations to the ligand being used.

Dedication

Dedicated to my family

Acknowledgements

First, I would like to thank my advisor Professor Eric Masson for his support, patience, and mentoring throughout my time at Ohio University. Then I would like to thank my committee members: Professor Katherine Cimatu and Professor Jennifer V.

Hines for their advice and encouragement during my study. I want to offer my sincere gratitude to past and current members of Prof. Masson’s research group Dr. Xiaoyong

Lu, Lawrence Kyeremeh-mensah, Dr. Roymon Joseph, Anna Nkrumah, Stefan Saretz,

Curran Rhodes, Danielle Price, Mersad Raeisi, and Kondalarao Kotturi for their assistance and thoughtful input throughout my stay in the group. I would also like to thank the faculty of the Department of Chemistry and Biochemistry for all the ways they have guided my study throughout the past five years.

Table of Contents

Abstract ...... 3 Dedication ...... 4 Acknowledgements ...... 5 List of Figures ...... 7 Chapter 1: Introduction ...... 9 1.1 Supramolecular Metal-ligand Complexes: a Brief Overview ...... 9 1.2 Assembly of Complexes ...... 11 1.2.1 1D Metal-Organic Frameworks ...... 13 1.2.2 2D Metal-Organic Frameworks ...... 15 1.2.3 3D Metal-Organic Frameworks ...... 17 1.3 Selected Properties of Metal-Organic Frameworks ...... 19 1.4 Previous Work ...... 27 Chapter 2: Metal Triazole-Pyridine-Triazole/CB[8] Oligomers...... 30 2.1 Objectives ...... 30 2.2 Design and Synthesis of Starting Material ...... 30 2.3 Conclusions ...... 35 Chapter 3: Terpyridine CB[8] Oligomers ...... 36 3.1 Objectives ...... 36 3.2 Synthesis of Precursors ...... 36 3.3 Interactions with CB[n]’s...... 45 3.4 Conclusions ...... 52 Chapter 4: Extensions ...... 53 4.1 Project Goals ...... 53 4.2 Complex Library ...... 53 4.3 CB[n] Recognition ...... 53 4.4 Targeting of Biologically Relevant Entities ...... 54 Chapter 5: Experimental Section ...... 55 5.1 Generalities ...... 55 5.2 Materials and Methods ...... 55 Bibliography ...... 63

List of Figures

Figure 1.1 (a) Subunit 2 forms the cyclic polymer with polyethylene glycol. (b) Scheme for cyclic polymer with polystyrene chain O (red), Ru (orange), C (blue), H (light blue), and aromatic rings (green). Reprinted with permission from reference 9. Copyright 2013 American Chemical Society...... 11 Figure 1.2 Phenanthroline 3a, tetrapyridophenazine 3b, terpyridine 3c, pyridine-2,6- dicarboxylic acid 3d, porphyrins 3e, and pincer ligands 3f...... 12 Figure 1.3 Construction of coordination polymer using Aluminum(III) Porphyrins (Simplified as straight lines in scheme), Reproduced from ref. 15...... 14 Figure 1.4 (a) Metallo-rectangle 4 ligand used in the assembly of ladder complex. (b) Hydrogen bonding between subunits. Reproduced from ref. 16...... 15 Figure 1.5 (a) Compound 5 is the organic linker. (b) The 2D lattice formed from the linker coordinating with cobalt. Reprinted with permission of reference 17. Copyright 2005 American Chemical Society...... 16 Figure 1.6 (a) The organic linker 7 used in the framework. (b) Functionalized alkynes 8a- 8e undergo click reactions with the azide groups. (c) Organic linkers are arranged into a 3D network coordinated with zinc (shown in red). The product is a network with functional groups attached via click reactions. Reprinted with permission of 20. Copyright 2008 American Chemical Society...... 18 6+ Figure 1.7 Scheme of [Zn4O] clusters and ditopic linear dicarboxylate linkers assembled into a 3D structure. Reproduced from ref. 21...... 19 Figure 1.8 Shows the scheme for disassembly and reassembly by heating and cooling. Reproduced with permission of reference 23. Copyright 2013 American Chemical Society...... 20 Figure 1.9 Scheme for structure using organic linker 9 and transition metals. Reproduced with permission of reference 24. Copyright 2012 American Chemical Society...... 21 Figure 1.10 (a) The organic ligand subunit 10 used in the assembly of complexes. (b) The schematic representation of the formation of a metallo-supramolecular gel-like material. Reproduced from reference 25...... 22 Figure 1.11 Electrochromic coordination polymer 11 reproduced from ref. 26...... 23

Figure 1.12 (a) Cartoon of the 3D assembly. Blue squares are Cu2 Padwheels; pink rectangles are carbonane bis(isophthalic acid) ligands (b) Lilac spheres represent the largest sphere shaped voids that can be found within the evacuated motif. (c) Space filling model. C = gray; H = white; O = red; B = pink; Cu = blue. Reprinted with permission of reference 28. Copyright 2013 American Chemical Society...... 24 8

Figure 1.13 Schematic depiction of electron hopping through Ru-bpy complex excited states. Reprinted with permission of reference 29. Copyright 2010 American Chemical Society...... 25 Figure 1.14 Reaction scheme of transesterification catalysis in metal-organic framework to form 12 and 13. Reproduced from ref. 34...... 26 Figure 1.15 Lithium doped metal organic framework and a graph depicting the adsorption of H2 at 300 K as wt% vs. pressure (bar). Reprinted with permission of reference 35. Copyright 2007 American Chemical Society...... 27 Figure 1.16 Crystal structure of CB[6] top view and side view. Reprinted with permission of reference 37. Copyright 1981 American Chemical Society...... 28 Figure 1.17 Terpyridine oligomer...... 29 Figure 2.1 Scheme for triazole-terpyridine-triazole oligomer...... 30 Figure 2.2 Scheme for functionalization of oligomer via click chemistry...... 35 1 Figure 3.1 H NMR spectrum of terpyridine 35 in CDCl3...... 41 1 Figure 3.2 H NMR spectrum of terpyridine 36 in CDCl3...... 42 1 Figure 3.3 H NMR spectrum of [Fe•352] Cl2 in D2O...... 43 1 Figure 3.4 H NMR spectrum of [Fe•362] Cl2 in D2O...... 44 Figure 3.5 1H NMR titration of terpyridine 35 with CB[7] in D2O. The peaks are labeled to correspond to Figure 3.3.1. (a) guest with no CB[7], (b) 0.5 equivalent of CB[7], (c) 1.0 equivalent of CB[7], (d) 1.5 equivalents of CB[7], and (e) 2.0 equivalents of CB[7].46 1 Figure 3.6 H NMR spectra of the titration of [Fe•352] Cl2 with CB[8]. (a) guest with no CB[8], (b) 0.5 equivalent of CB[8], (c) 1.0 equivalent of CB[8], (d) 1.5 equivalents of CB[8], and (e) 2.0 equivalents of CB[7]...... 48 1 Figure 3.7 H NMR Titration of [Fe•362] Cl2 in D2O with CB[8]. (a) Free guest only, (b) 0.5 equivalent CB[8], (c) 1.0 equivalent CB[8], (d) 1.5 equivalent CB[8], and (e) 2.0 equivalent CB[8]...... 50

Figure 3.8 Fluorine NMR spectra form titration of [Fe•362] Cl2 in D2O with CB[8]. (a) Free guest only, (b) 0.5 equivalent CB[8], (c) 1.0 equivalent CB[8], (d) 1.5 equivalent CB[8], and (e) 2.0 equivalent CB[8]...... 51

Chapter 1: Introduction

1.1 Supramolecular Metal-ligand Complexes: a Brief Overview

Metal-organic networks or coordination polymers are composed of transition metals coordinating with organic ligands.1 These polymers are supramolecular structures that form long chains via non-covalent bonds.2 Metal-organic frameworks are one of the fastest areas of growth in chemistry due to the ability to functionalize and alter the arrangement of these structures.3 There are countless combinations of organic ligands, transitions metals, and geometries to be explored. There are many different types of metal-organic frameworks. They consist of one-, two-, and three-dimensional complexes that contain metal ions coordinating with organic linkers.4 These topologies introduce new possibilities for supramolecular binding. The increasing relevance of supramolecular

(i.e. non-covalent) chemistry has driven scientists to develop new supramolecular polymers.5 The increase in demand will require further research in the field to understand complex formation and their uses.

Researches have been finding ways to develop self-assembled complexes for decades. The use of self-assembly to synthesize materials can provide ways to achieve structures that are difficult to obtain through traditional organic synthesis. Maverick and co-workers designed the first known self-assembled cyclic compound in 1986 (see compound 1).6

Pedersen and co-workers first studied interactions between molecules through non-covalent interactions in the 1960’s.7 As mentioned above, non-covalent interactions are the driving force of these assemblies. Hydrogen bonding, π−π stacking, metal−ligand interactions, electrostatic forces, strong dipole−dipole association, hydrophobic forces, and steric repulsion can all be used to direct the process of self-assembly.8 These interactions are reversible and allow for structure alterations.

One example is the cyclic brush polymers, which create new frameworks to build upon (see figure 1.1).9 The alkene groups on the cyclopenta[c]pyrrole end can be polymerized on both ends. These units connect to form the backbone of the cyclic polymer. The terpyridine complex is attached to these complexes and branch out from the backbone. This complex carries another polymer on the other end which forms the brush. 11

American Chemical Society.

1.2 Assembly of Complexes

Metal-organic assemblies are typically formed in a one-pot procedure while the ligands are synthesized individually. Inorganic chemists have focused on the metals in the center of the assemblies while organic chemists focus on synthesizing new ligands to bind to these metals. Self-assembly can occur in both solution and in the solid state.10 A better understanding of how these complexes assemble is needed to predict and direct the synthesis of new complexes. 12

When designing an organic-metallic structure characteristics like rigidity and functions must be taken into consideration. Flexible ligands can rotate around bonds giving them versatility that rigid ligands do not have.11 However, too much flexibility can lead to a lack of organization. The selection of ligands and metals can be used to predict what product will form so only certain topologies and characteristics can be targeted.

Some of the common ligands that are used in these complexes include phenanthroline, tetrapyridophenazine, terpyridine, pyridine-2,6-dicarboxylic acid, porphyrins, and pincer ligands (see ligands 3a-3f).12 Each ligand has unique properties to consider when predicting how the assemblies will form.

Figure 1.2 Phenanthroline 3a, tetrapyridophenazine 3b, terpyridine 3c, pyridine-2,6- dicarboxylic acid 3d, porphyrins 3e, and pincer ligands 3f.

Complementary ligands can be selected to design metal-organic solid crystal structures.13 Metal coordination to ligands and may allow for the ligands to be substituted. Further modification after the complex formation is also possible. Through 13 thermal reactions, redox chemistry, and photochemical reactions, post synthetic modifications have been used to modify ligands in assemblies.14

1.2.1 1D Metal-Organic Frameworks

Polymers are formed from repeating units. In order to assemble a polymer, a strategy must be devised for the continuation of the chain. This coordination polymer based on aluminum(III) porphyrins uses isonicotinic acid to connect the porophyrins.15

The nitrogen and oxygen atoms on the chain both bind aluminum to form a continuous chain (see Figure 1.3).

Figure 1.3 Construction of coordination polymer using Aluminum(III) Porphyrins

(Simplified as straight lines in scheme), Reproduced from ref. 15.

Molecular ladders can also be formed to prepare large macromolecular chain structures. An example of a supramolecular polymer containing a metallomacrocycle using hydrogen bonding to assemble in solution is shown (see Figure 1.4).16 Platinum– acetylene linkages connect the ligands to form metallo-rectangles. The complementary 15 organic ligands form hydrogen bonds and stack on top of each other. The alignment of the hydrogen bonding can vary but the ladders are always linear.

Figure 1.4 (a) Metallo-rectangle 4 ligand used in the assembly of ladder complex. (b)

Hydrogen bonding between subunits. Reproduced from ref. 16.

1.2.2 2D Metal-Organic Frameworks

An example of two-dimensional metal organic framework is a flat sheet that can be formed from organic linkers and a coordinating metal. One of these 2D frameworks can be formed from paracyclophane and cobalt (see Figure 1.5).17 In this case, a 16 nonregular net which has two different types of binding is formed. The symmetry of nets are typically regular or semiregular. This example is the first net described with two separate polygonal cavities. The cobalt coordinates with the nitrogen to connect the linkers in this arrangement.

Figure 1.5 (a) Compound 5 is the organic linker. (b) The 2D lattice formed from the linker coordinating with cobalt. Reprinted with permission of reference 17. Copyright

2005 American Chemical Society.

The formation of cages and macrocyclic architectures are often targets of these complexes to take advantage of the predictable design.18 An example of this is a chiral molecular square using rhenium as the corners (see compound 6).19 Two organic ligands form right angles with each rhenium atom.

1.2.3 3D Metal-Organic Frameworks

3D metal-organic frameworks are often restricted by multiple functionalization.

For example, functionalization of tertaphenyl with both carboxylic acid and azide groups allows a 3D assembly upon “click-reaction” with alkynes (see Figure 1.6).20 Several functionalized alkynes are coupled with the azides in the framework to modify the structure.

Figure 1.6 (a) The organic linker 7 used in the framework. (b) Functionalized alkynes 8a-

8e undergo click reactions with the azide groups. (c) Organic linkers are arranged into a

3D network coordinated with zinc (shown in red). The product is a network with functional groups attached via click reactions. Reprinted with permission of 20.

6+ Another example of 3D framework is a network composed of [Zn4O] clusters and ditopic linear dicarboxylate linkers(see Figure 1.7).21 The backbone of the structure can be modified while preserving the overall design of the system. The size of the pores 19 and functionalities can be modified with the selection of the linker type. Longer linkers are used to create the larger pores.

6+ Figure 1.7 Scheme of [Zn4O] clusters and ditopic linear dicarboxylate linkers assembled into a 3D structure. Reproduced from ref. 21.

1.3 Selected Properties of Metal-Organic Frameworks

Many metal-organic systems can respond to stimuli. Assemblies have been shown to exhibit thermo-, chemo-, mechanoresponses, as well as light-emitting behavior.22 The effects of stimuli can often be reversible because of the nature of non-covalent bonds.

Thermoreversible supramolecular polymer gels have been shown to disassemble when heated then reassemble when cooled.23 This coordination complex is formed with poly(4- 20 vinylpyridine)-b-poly(ethyl acrylate)-b-poly(4-vinylpyridine) triblock copolymer and zinc chloride in a hydrophobic ionic liquid (see figure 1.8).

Figure 1.8 Shows the scheme for disassembly and reassembly by heating and cooling.

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A mechanoresponsive material reassembles after experiencing physical stress from pressure. This example using copper and cadmium as metals and pyridine-3,5- bis(benzimidazole-2-yl) as an organic ligand can form a gel that can withstand significant mechanical stress (see figure 1.9).24 The bonds between the metals and the nitrogen atoms of the linkers are self-assembled so once they are broken by mechanical stress they can reassemble when the stress is gone. π-π stacking between the aromatic rings of the linkers also occurs. Cu(II) and Cadmium(II) were the metals used in the complex. Sulfate 21 and halides were the counter ions used in the formation of the gel shown as X in the figure.

Some supramolecular polymers have shown orthogonal responses to different stimuli. These materials will respond differently depending on the type of stimulus applied. A metallo-supramolecular polymer gel like material using a combination of 22 lanthanoid and transition metal ions demonstrates a multi stimuli responsive material (see figure 1.10).25 This material shows a response to thermal, mechanical, and photo stimuli.

Changing the transition metal used can alter the nature of these responses. Thermal stimuli response was demonstrated by turning the solution from yellow to red by heating and returned to yellow by cooling. Mechanoresponsive behavior was demonstrated by shaking the solution. The mixture in acetonitrile became swollen when shaken but would eventually return to normal after resting. Photoluminescence is shown by exposing the samples to UV which causes the solution to emit light.

Figure 1.10 (a) The organic ligand subunit 10 used in the assembly of complexes. (b) The schematic representation of the formation of a metallo-supramolecular gel-like material.

Reproduced from reference 25.

Electrochromic films can be assembled from coordination polymers. These films will display different colors depending on their oxidation state. An example is a polymer functionalized with terpyridine and complexed with zinc that can display three different colors depending on its oxidation state (see Figure 1.11).26 The change in ionization state will change the wavelength emitted. In the example shown the complex displays yellow in neutral state, brownish gray after first oxidation, and blue after second oxidation.

Figure 1.11 Electrochromic coordination polymer 11 reproduced from ref. 26.

Metal-organic framework often forms porous networks. These pore sizes are tailored to allow for guests of a certain volume.27 The guests can be bound inside the pores in the framework. A Cu−carborane based metal−organic framework used for methane, carbon dioxide, and hydrogen adsorption can store these molecules within its frame (see Figure 1.12).28 24

Photochemistry is a major area of metal-organic framework application. The first light harvesting systems that recreated natural systems was reported by Lin, Meyer and 25 coworkers.29 Chromophore–quencher complexes are used as models for photosynthesis.30

There has been a lot of interest in chromophore-tethered ligands in which the metallic and aromatic components are held within a specific arrangement in order to optimize the absorption of light.31 These compounds can be used to prepare light absorbing material.

MOFs (metal-organic frameworks) are often used to build photosynthesis and photocatalysis cells, which is a major area of solar energy research.32 A system was built with 2,20-bipyridine-4,40-dicarboxylic acid bridging ligands and transition metals to mimic light absorption in natural systems (see Figure 1.13).29 The organic ligands are coordinated with Os(II) or Ru(II) and stimulated with UV light. The energy transfer rate was measured using various ratios of metals.

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Supramolecular metal-organic frameworks are often used as catalysts for organic reactions.33 For example, a hexagonal large-pore structure composed of zinc coordinating with pyridyl groups catalyzes transesterification. In this case, the macrocylic MOF catalyzes the reaction by facilitating deprotonation of the reactant alcohol (see Figure

1.14).34

Figure 1.14 Reaction scheme of transesterification catalysis in metal-organic framework to form 12 and 13. Reproduced from ref. 34.

Gas storage is another common application for 3D metal-organic frameworks.

One example is this lithium doped metal-organic framework used to absorb hydrogen

(see Figure 1.15).35 A chart shows the rate of hydrogen adsorption at 300 K. Structures can be modified with different linkers and metals in order to optimize adsorption of gases.

Figure 1.15 Lithium doped metal organic framework and a graph depicting the adsorption of H2 at 300 K as wt% vs. pressure (bar). Reprinted with permission of reference 35. Copyright 2007 American Chemical Society.

1.4 Previous Work

Our current research is building on a project reported by one of our former colleagues, Dr. Roymon Joseph.36 Cucurbit[n]uril (CB[n], n=7,8) was incorporated in the design and synthesis of organometallic oligomers. Cucurbituril is a pumpkin shaped molecule made of glycouril subunits (see figure 1.16).37 The size of the cavity can vary based on the number of these subunits.38 CB[n]’s have been shown to be a useful tool for non-covalently binding organic molecules in aqueous solutions.

Terpyridine ligands with aromatic substituents in the 4’ position, which is the para position of the central pyridine, are bound to transition metals Fe(II) or Ir(III). CB[n] is strongly bound to the 4’ substituents through coulombic and CH···O hydrogen bonding.

The positive charge of the transition metals interact with the carbonyls on CB[n] despite the large distance between them. Cucurbituril is able to encapsulate aromatic rings in its 29 hydrophobic cavity.39 The encapsulation of hydrophobic subunits within the cavity paired with hydrogen bonding between the carbonylated rim of CB[n] created strong binding.

Aromatic substituents in the 4’ position of the terpyridine stack inside the cavity of CB[8] can fit two of these rings at a time. Two 4-tolyl, 2-naphthyl, and 2,3,5,6- tetrafluorophenyl substituents can stack inside CB[8], and are used to assemble these organic ligands coordinated with metals into oligomers (see figure 1.17). The oligomers are tube-like chains that self-assemble in water.

Figure 1.17 Terpyridine oligomer.

Chapter 2: Metal Triazole-Pyridine-Triazole/CB[8] Oligomers

2.1 Objectives

Like in our previous work, we use a transition metal to coordinate with nitrogen on organic ligands. The unique aspect of this project is using click chemistry with azides to form triazole-pyridine-triazole ligands (see scheme below).40 The azides can carry various sub-units to functionalize the chains (see our substituent R in scheme below). Our plan is to use nucleic acids and peptides to observe any binding of DNA or protein using the synthesized chains. By attaching chiral substituents, changing the structure of the chains might induce helicality in the whole structure.

Figure 2.1 Scheme for triazole-terpyridine-triazole oligomer.

2.2 Design and Synthesis of Starting Material

Pathway A: The starting material in the synthetic route was 2,6-dibromopyridine.

It was then oxidized using trifluoroacetic acid and 35% hydrogen peroxide to form compound 14. A nitro group was added to the para position, and the pyridinium was reduced with nitric acid in 20% oleum to yield 15.41 31

47% 45%

Then the nitro group was replaced with a bromo group in the para position to prepare 2,4,6-tribromopyridine using acetyl bromide and phosphorous bromide.42

20%

Once 2,4,6-tribromopyridine was obtained it was allowed to react in a sonogashira coupling with trimethylsilylacetylene and a palladium catalyst. The trimethyl acetylene unit replaces the bromo groups in both of the ortho positions to afford compound 17.43

<10%

The pyridine compound with trimethyl acetylene in the ortho positions and a bromo group in the para position was dissolved in methanol and desilylated with 25% potassium carbonate to afford product 18.44 32

<10%

We were unable to afford product 18 due to side reactions. We were unable to produce 17 without side products and they interfered with the synthesis of 18.

Pathway B: Product 19 was formed upon metalation with butyl lithium/tetramethylpiperidine, magnesium chloride, and subsequent reaction with tetramethyl borate. This group was then allowed to react with HCl to form the corresponding boronic acid.45

17%

A Suzuki coupling was then performed between the boronic acid on the dibromopyridine and 2-bromonaphthalene derivative. 21 was formed with 58% yield.46

14% 33

Trimethylsilylacetylene was then coupled to the ortho positions with a sonogashire reaction to afford compound 22 with 51% yield.44

<10%

After problems obtaining a clean product because of side products during the synthesis of 21 an alternate route was attempted.

First tetramethylethylenediamine was allowed to react with zinc chloride in tetrahydrofuran to form reagent 23.47

19%

Pathway C: The Reagents 23 and [(tetramethylpiperidine)Lithium] are used to metalate 2,6-dibromopyridine at the para-position. Iodine is then added to yield product

24 in 20% yield.48 34

20%

A Suzuki coupling reaction is then carried out with 2-naphthyl boronic acid to form 21 as iodo groups react faster than the ortho-bromide substituents with 58% yield. 46

58%

The sonogashira reaction with trimethylsilylacetylene was attempted. Once again the product was subsequently allowed to react with 25% K2CO3 in methanol to deprotect the acetylene groups and subsequently form product 25 with 45% yield.44

45%

2.3 Conclusions

The azide coupling reaction and formation of the metal-ligand complex were carried out by another group member, but the complex was not water-soluble in the absence and presence of CB[n] (see scheme below).49 This is extremely problematic, and the project had to be put on hold.

Figure 2.2 Scheme for functionalization of oligomer via click chemistry.

Chapter 3: Terpyridine CB[8] Oligomers

3.1 Objectives

This project is similar to chapter 2 but with a different ligand: we replace the triazole-pyridine-triazole ligand with a functionalized terpyridine. The motivation is to bind the functionalized terpyridine oligomer with DNA, protein, and nanoparticles.

Different transition metals like iron, ruthenium, and iridium are also used to create a library of complexes. We will also vary the substituent in the 4’ position of the terpyridine to include naphthyl, tolyl, and other aromatic rings that can form dimers inside the cavity of CB[8]. The ligands will also be varied by coupling amines to carboxylic acids at the 4 and 4” positions of the terpyridine ligand (see scheme below).

The amide side chains formed can be used to interact with other systems.

3.2 Synthesis of Precursors

Ethyl isonicotinate is allowed to react with paraldehyde, iron sulfate heptahydrate, trifluoroacetic acid, and tert-butyl peroxide in acetonitrile to synthesize pyridine 37 derivative 26.50 Ethyl-2-acetylisonicotinate was coupled to 2-naphthyldehyde in methanol to afford intermediate 27 with acetic acid and piperidine.51 Pyridinium iodide salt 28 was synthesized with iodine in pyridine mixed with ethyl 2-acetylisonicotinate (26).52

35% 64%

71%

These two intermediates were placed in a methanolic solution with ammonium acetate to form terpyridine 29.52

23%

The first attempt was to convert the ester groups into amide with isopropylamine using potassium tert-butoxide in tetrahydrofuran (THF). This reaction failed to yield the 38 desired product. There was also an attempt to allow the ester groups to react with tert- butyl amine using acetic acid as a catalyst. This was also unsuccessful.

The ester groups were saponified with lithium hydroxide in THF and water to afford compound 30. The acetate groups were then converted to carboxylic acids with

HCl in methanol to prepare compound 31.53 We then attempted to convert the carboxylic acid groups to isoamylamide groups. 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexaﬂuorophosphate (HBTU) was used as the coupling reagent but the attempt was unsuccessful.

95%

99%

The amine coupling reactions were then tested with isonicotinic acid. We were able to form the amide with isonicotinic acid alone in high yield (see product 32).54 Yet, the same conditions did not yield the bis-amides using terpyridine 31. The preparation of the bis amide is now being investigated by a coworker.

99%

Using a structure with fluorine could be helpful for the future of this project.

Therefore, 19F NMR spectroscopy can be used to monitor the binding of CB[n]’s to these ligands. Therefore, we devised a synthetic route using 3,5-difluorobenzene in place of naphthalene. Less signals in the aromatic region of the 1H NMR spectra makes the spectrum easier to decipher. 3,5-difluorobenzaldehyde is combined with ethyl 2- acetylisonicotinate in methanol to form compound 33.36

65%

Intermediates 28 and 33 were then combined to synthesize the terpyridine with the 3,5-difluorophenyl unit at position 4’ (see product 34).51

14%

We attempted to couple compound 34 to various amines through different pathways but had no success. In order to test the binding of CB[8] to the fluorinated terpyridine without carboxylic acids at the positions of 4 and 4” we devised a pathway to form the plain terpyridine in one step. Using 2-acetylpyridine and 3,5- difluorobenzaldehyde in ethanol with 30% ammonia (see terpyridine 35).36

28%

1 Figure 3.1 H NMR spectrum of terpyridine 35 in CDCl3.

The procedure was then repeated with 2,6-difluorobenzaldehyde to generate terpyridine 36.

37%

1 Figure 3.2 H NMR spectrum of terpyridine 36 in CDCl3.

Ligand 35 was then complexed with FeCl2 in dichloromethane. Iron binds the terpyridine nitrogens to form complex 37. 43

18%

a c, d b f g e

1 Figure 3.3 H NMR spectrum of [Fe•352] Cl2 in D2O.

The iron complex is also formed with ligand 36 to form complex 38. 44

20%

b c g e

1 Figure 3.4 H NMR spectrum of [Fe•362] Cl2 in D2O.

3.3 Interactions with CB[n]’s

Terpyridine 34, which bears a 3,5-difluorophenyl group at the 4’ position, was titrated with CB[7] and was found to bind tightly to the cavity of the macrocycle.

Cucurbituril binding can be easily monitored with 1H NMR spectroscopy due to dramatic upfield shifts of hydrogens located within the cavity of the macrocycle.55 The electronegative carbonyl groups cause a downfield shift in hydrogen nuclei that are located close to the portals of CB[n]s as shown in figure 3.5.56 46

Figure 3.5 1H NMR titration of terpyridine 35 with CB[7] in D2O. The peaks are labeled to correspond to Figure 3.3.1. (a) guest with no CB[7], (b) 0.5 equivalent of CB[7], (c)

1.0 equivalent of CB[7], (d) 1.5 equivalents of CB[7], and (e) 2.0 equivalents of CB[7].

[Fe•352] Cl2 was then titrated using CB[8] and the binding was found to be weaker. The tube-like chains formed, which can be seen through the broadening of peaks on the NMR spectra, but not until 2 equivalents of CB[8] were added. Furthermore, NMR spectra clearly show that a complex mixture of metal-ligand/CB[8] assemblies are formed. 47

1 Figure 3.6 H NMR spectra of the titration of [Fe•352] Cl2 with CB[8]. (a) guest with no

CB[8], (b) 0.5 equivalent of CB[8], (c) 1.0 equivalent of CB[8], (d) 1.5 equivalents of

CB[8], and (e) 2.0 equivalents of CB[7].

The same titration with CB[8] was attempted using complex [Fe•362] Cl2, that bears a 2,6-difluorophenyl substituent at position 4’ but also showed week binding.

Without strong binding, we decided to not continue with either of these ligands. Weak and non-specific binding was observed again. 49

1 Figure 3.7 H NMR Titration of [Fe•362] Cl2 in D2O with CB[8]. (a) Free guest only, (b)

0.5 equivalent CB[8], (c) 1.0 equivalent CB[8], (d) 1.5 equivalent CB[8], and (e) 2.0 equivalent CB[8].

Titration was also monitored by 19F NMR spectroscopy. The downfield shift observed upon binding indicates that the fluorine is located inside the cavity of CB[8]. 51

Figure 3.8 Fluorine NMR spectra form titration of [Fe•362] Cl2 in D2O with CB[8]. (a)

Free guest only, (b) 0.5 equivalent CB[8], (c) 1.0 equivalent CB[8], (d) 1.5 equivalent

CB[8], and (e) 2.0 equivalent CB[8].

The free guest appears at -115 ppm. CB[8] binds to one substituent at a time which can be seen in the titration. When CB[8] is bound to the opposite substituent the fluorine undergoes a small downfield shift. The bound substituent signal appears at -

112.2 ppm. When both substituents in a complex are bound the signal moves slightly further downfield. In the stacked spectra shown above, we can observe there are both 52 saturated complexes and complexes bound at only one substituent even at 2 equivalent

CB[8]. This is proof that the CB[8] has weak binding with the fluorinated substituents.

3.4 Conclusions

CB[8] binding was neither strong nor selective enough to continue to use these ligands. An alternate pathway was used by a colleague that successfully produced terpyridine ligands that were functionalized with amide groups. Various 4’ substituents are screened in our group to achieve strong binding to CB[8].

Chapter 4: Extensions

4.1 Project Goals

Since CB[8] binding with the fluorinated terpyridine was weak and non-specific more 4’ substituents must be tested. Now that we have found a pathway to functionalize the terpyridine with amides we can begin designing target specific attachments. Other transition metals will be used to form complexes with the ligands.

4.2 Complex Library

The transition metals used to form complexes with terpyridine will be Fe(II),

Ru(II), and Ir(III). The amide side chains will consist of positive, negative, neutral side chains that mimic amino-acid residues.57 We have also obtained 5-(aminomethyl)uracil from uracil which can also be used as a side chain58 and we can explore other side chains.

4.3 CB[n] Recognition

Binding affinities of the complexes towards CB[7] could be determined by isothermal titration calorimetry and by competitive titration using 1H NMR spectroscopy.

We can use this data to assess the impact of different transition metals on binding. The side chains could potentially form hydrogen bonds with the carbonyls at the CB[n] portals. To test whether there is hydrogen bonding we can monitor the rate of hydrogen/deuterium exchange of the amide of positions 4 and 4” of the terpyridine ligand. A slower exchange rate will indicate that hydrogen bonding is occurring.59 This hydrogen bonding could increase the affinity of the ligand towards CB[n]s. 54

4.4 Targeting of Biologically Relevant Entities

Dynamic combinatorial chemistry is used to develop new compounds that target biological entities.60 The reactants form a dynamic equilibrium that can be influenced by the addition of a target compound. This method can develop new target binding complexes that also assists in the understanding of the host binding site and the guest.

The nanorods that we will attempt to form should self-organize when a target is introduced. Peptides and DNA duplexes will be used as targets.

Chapter 5: Experimental Section

5.1 Generalities

Starting materials were purchased from Sigma-Aldrich (St. Louis, MO),36 Acros

(Hampton, New Hampshire),45 and TCI America (Portland, OR).46Cucurbit[7]- and

[8]uril (CB[7] and CB[8]) were prepared using known procedures. Characterization by nuclear magnetic resonance spectroscopy (NMR) was carried out using a Bruker 300 spectrometer (Billerica, MA) and a Bruker 500 spectrometer (Billerica, MA).

5.2 Materials and Methods

2,6-Dibromo-4-(naphthalen-2-yl)pyridine (21).46 4-Iodo-2,6-dibromopyridine (0.12 g,

0.32 mmol), 2-naphthalene boronic acid (55 mg, 0.32 mmol), LiOH (31 mg, 1.3 mmol), and Pd(PPh3)4 (18 mg, 16 µmol) were added to an oxygen-free mixture of acetonitrile and water (10:1, 40 mL), was and were heated to 70 ºC overnight under nitrogen atmosphere. The solvent was evaporated and water (25 mL) was used to dissolve the remaining solid. The aqueous layer was extracted with chloroform (3 × 20 mL), and then the organic layer was dried with sodium sulfate. The crude material was purified by column chromatography with hexane as the eluent and an ethyl acetate gradient. Solvent

1 was evaporated to afford the title compound (68 mg, 58%); H NMR (CDCl3, 300 MHz):

δ = 8.08 (s, 1H), 7.94 (dd, J = 20.7, 10.1 Hz, 4H), 7.79 (s, 2H), 7.67 (dd, J = 8.5, 1.4 Hz,

1H), 7.58 ppm (dd, J = 6.4, 3.1 Hz, 3H).

4-(Naphthalen-2-yl)-2,6-bis((trimethylsilyl)ethynyl)pyridine (22).44 2,6-Dibromo-4-

(naphthalene-2-yl)pyridine (36 mg, 99 µmol), Pd(PPh3)4 (2.4 mg, 2.0 µmol), CuI (0.43 mg, 2.0 µmol), and trimethylamine (0.23 mL, 1.6 mmol) were added to toluene (3.0 mL). 56

Trimethylsilylacetylene (0.66 mL, 4.7 mmol) was then added dropwise. The pale yellow solution was heated to 60 ºC and left overnight at 60 ºC. Another aliquot of Pd(PPh3)4

(2.4 mg, 2.0 µmol) was added, and the reaction was continued for another night. The crude material was purified by column chromatography with hexane as the eluent. The

1 eluent was evaporated to afford the title compound (20 mg, 51%); H NMR (CDCl3, 300

MHz): δ = 8.14 (s, 2H), 8.02 – 7.82 (m, 3H), 7.76 (dd, J = 8.6, 0.8 Hz, 1H), 7.71 (s, 1H),

7.55 (dd, J = 6.1, 3.3 Hz, 2H), -0.01 ppm (s, 12H).

1 1 2 2 47 Dichloro(N ,N ,N ,N -tetramethylethane-1,2-diamine)zinc (T-4)- (23) ZnCl2 (2.1 g,

15 mmol) was heated for 1 h at 80 ºC under vacuum for 1 h. THF (40 mL) was then added, and the mixture was stirred under N2. tetramethylethylenediamine (4.6 mL, 31 mmol) was slowly added at room temperature and stirred for 2 h. The product was allowed to precipitate. The precipitate was filtered and washed with hexane to afford the

1 title compound as a powdery white solid (1.5 g, 19%); H NMR (CDCl3, 300 MHz): δ =

2.73 (s, 4H), 2.62 ppm (s, 12H).

2,6-Dibromo-4-iodopyridine (24).48 THF (10 mL), 2,2,6,6-tetramethylpiperidine (1.0 mL, 6.0 mmol), ZnCl2•TMEDA (0.51 g, 2.0 mmol) were combined, and BuLi (2.4 mL,

6.0 mmol) was added and stirred for 15 min at O ºC. 2,6-Dibromopyridine (95 mg, 4.0 mmol) was added and stirred for 2 h at 25 ºC. I2 was then added (1.5 g, 6.0 mmol), and the mixture was stirred overnight at 25 ºC. The solution was treated with Na2S2O3 (20 mL, 4.4 M), and extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. 57

Purification by chromatography on silica gel with hexane as the eluent afforded the title

1 compound (0.28 g, 20%); H NMR (CDCl3, 300 MHz): δ = 7.84 ppm (s, 2H).

2,6-Diethynyl-4-(naphtalen-2-yl)pyridine (25).44 4-(Naphthalen-2-yl)-2,6- bis((trimethylsilyl)ethynyl)pyridine (24 mg, 65 µmol) was dissolved in methanol (2.0 mL). Potassium carbonate (2.3 mg, 16 µmol) was added and it was stirred for 1 h at 25

ºC. Ethyl acetate (20 mL) was added to the mixture and extracted with ammonium chloride (3 × 20 mL) then washed with brine (3.0 mL). The solvent was evaporated to

1 afford the title compound (6.5 mg, 45%); H NMR (CDCl3, 300 MHz): δ = 8.13 (s, 2H),

8.04 – 7.84 (m, 4H), 7.76 (d, J = 7.0 Hz, 2H), 7.55 (dd, J = 6.2, 3.2 Hz, 3H), 3.75 ppm (t,

J = 6.3 Hz, 2H).

Ethyl 2-acetylisonicotinate (26).50 Paraldehyde (2.0 mL, 15 mmol) and ethyl isonicotinate (0.50 mL, 3.3 mmol) were stirred in a solution of acetonitrile (6.6 mL).

FeSO4•7H2O (8.3 mg, 30 µmol), trifluoroacetic acid (0.26 mL, 1.5 mmol), and 70% tert- butyl hydroperoxide (0.90 mL, 8.3 mmol) were added to the solution, and the mixture was refluxed for 4 h. Solvent was removed and the residue was dissolved in a saturated sodium carbonate solution (10 mL). The aqueous layer was extracted three times with dichloromethane (3 × 10 mL). Combined organic fractions were dried with Na2SO4, filtered, and the solvent removed. The crude material was purified with 10% ethyl acetate in hexane. Solvent was evaporated to afford the title compound (0.22 g, 35%); 1H NMR

(CDCl3, 500 MHz): δ = 8.83 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 8.03 (dd, J = 4.9, 1.6 Hz,

1H), 4.44 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.42 ppm (t, J = 7.1 Hz, 3H). 58

Ethyl (E)-2-(3-(naphtalen-2-yl)acryloyl)isonicotinate (27).51 In a methanolic (3.0 mL) solution ethyl 2-acetylisonicotinate (0.10 g, 0.52 mmol) was mixed with naphthalene-2- aldehyde (81 mg, 0.52 mmol). Piperidine (5.6 µL, 0.58 mmol) was added and the mixture was left to stir overnight at 25 ºC. Acetic acid (3.3 µL, 0.58 mmol) was added and the mixture was refluxed for 5 h. A precipitate formed when the solution was allowed to cool. The precipitate was isolated through filtration then was washed with methanol to

1 afford the title compound (0.11 g, 64% yield); H NMR (CDCl3, 500 MHz): δ = 8.92 (d,

J = 4.8 Hz, 1H), 8.73 (s, 1H), 8.40 (d, J = 16.0 Hz, 1H), 8.21 – 8.09 (m, 2H), 8.09 – 7.99

(m, 1H), 7.97 – 7.79 (m, 6H), 4.01 ppm (s, 3H).

52 1-(2-(4-(Ethoxycarbonyl)pyridine-2-yl)-2-oxoethyl)pyridine-1-ium iodide (28). I2

(0.13 g, 0.52 mmol) was added to pyridine (0.74 mL) at 60 ºC and was stirred under N2.

Ethyl 2-acetylisonicotinate (0.10 g, 0.52 mmol) was added and the mixture was heated to

100 ºC for 1 h. Crystals formed upon cooling and were filtered and washed with chloroform and diethyl ether to afford the title compound (0.14 g, 71% yield); 1H NMR

(CDCl3, 500 MHz): δ = 9.31 (d, J = 5.8 Hz, 1H), 8.98 – 8.80 (m, 2H), 8.56 (s, 1H), 8.27 –

8.13 (m, 1H), 8.04 (d, J = 13.2 Hz, 2H), 7.08 (s, 1H), 4.55 – 4.32 (m, 2H), 2.75 (s, 2H),

1.43 ppm (t, J = 6.9 Hz, 3H).

Dimethyl 4’-(naphthalene-2-yl)-[2,2’:6’,2”-terpyridine]-4,4”-dicarboxylate (29).52 1-

(2-(4-(Ethoxycarbonyl)pyridine-2-yl)-2-oxoethyl)pyridine-1-ium iodide (60 mg, 0.16 mmol) and ethyl (E)-2-(3-(naphtalen-2-yl)acryloyl)isonicotinate (50 mg, 0.16 mmol) were dissolved in methanol (1.5 mL). Ammonium acetate (0.38 g, 5.0 mmol) was added to the mixture. The mixture was then refluxed overnight. A precipitate was formed upon 59 cooling. The precipitate was isolated by filtration and washed with methanol. The solid was then dissolved in chloroform, concentrated, filtered, and washed with methanol again to afford the title compound as a light yellow solid. (17 mg, 23% yield); 1H NMR

(CDCl3, 500 MHz): δ = 8.93 (d, J = 4.9 Hz, 2H), 8.73 (s, 2H), 8.40 (d, J = 16.0 Hz, 2H),

8.20 – 8.09 (m, 4H), 8.06 (d, J = 4.9 Hz, 2H), 7.88 (ddd, J = 11.6, 9.5, 5.6 Hz, 8H), 7.53

(dd, J = 9.3, 1.8 Hz, 4H), 4.01 (s, 6H).

Lithium 4’-(naphthalen-2-yl)-[2,2’:6’,2”-terpyridine]-4,4”-dicarboxylate (30).54

Dimethyl 4’-(naphthalen-2-yl)-[2,2’:6’,2”-terpyridine]-4,4”-dicarboxylate (0.41 g, 0.87 mmol) was added to a solution of THF/H2O 1:1 (35 mL) and stirred. Lithium hydroxide

(85 mg, 3.6 mmol) was then added and the solution was stirred overnight at 25 ºC. The

1 solvent was evaporated to afford the title compound (0.40 g, 95% yield); H NMR (D2O,

500 MHz): δ = 8.36 (s, 2H), 8.18 (s, 2H), 7.98 (d, J = 17.6 Hz, 3H), 7.84 – 7.66 (m, 4H),

7.50 (d, J = 7.9 Hz, 2H), 7.33 ppm (s, 2H).

4’-(Naphthalen-2-yl)-[2,2’:6’,2”-terpyridine]4,4”-dicarboxylic acid (31).53 Lithium

4’-(naphthalen-2-yl)-[2,2’:6’,2”-terpyridine]-4,4”-dicarboxylate (0.40 g, 0.82 mmol) was dissolved in methanol (2.0 mL) with 0.50 M HCl. The solvent was evaporated to afford the title compound (0.37 g, 99% yield); 1H NMR (DMSO, 500 MHz): δ = 9.02 (s, 2H),

8.98 (d, J = 4.9 Hz, 2H), 8.92 (s, 2H), 8.57 (s, 1H), 8.20 – 8.15 (m, 1H), 8.14 (d, J = 8.6

Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.02 (dd, J = 5.8, 3.4 Hz, 1H), 7.97 (d, J = 4.1 Hz, 2H),

7.61 ppm (dd, J = 6.2, 3.1 Hz, 2H).

N-isopropylisonicotinamide (32).54 N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1- yl)uronium hexafluorophosphate (0.21 g, 0.55 mmol) was added to a stirred mixture of 60 trimethylamine (0.23 mL, 1.7 mmol) and anhydrous dichloromethane (2.0 mL).

Isopropylamine (41 µL, 0.50 mmol) in dichloromethane (5.0 mL) was added to the mixture and was then stirred overnight at 25 ºC. The crude material was purified by column chromatography with 10% methanol in dichloromethane as an eluent. The solvent was evaporated to afford the title compound (89 mg, 99% yield); 1H NMR

(CDCl3, 500 MHz): δ = 8.68 (d, J = 6.0 Hz, 2H), 7.62 (d, J = 6.1 Hz, 2H), 4.36 – 4.18 (m,

1H), 1.25 (d, J = 6.6 Hz, 6H).

Methyl (E)-2-(3-(3,5-difluorophenyl)acryloyl)isonicotinate (33).36 To a solution of ethyl 2-acetylisonicotinate (0.10 g, 0.52 mmol) in methanol (3.0 mL) was added 3,5- difluorobenzaldehyde (74 mg, 0.52 mmol) and piperidine (56 µL, 0.58 mmol). The reaction mixture was kept at 25 ºC overnight. Acetic acid (33 µL, 0.58 mmol) was added, and the solution was refluxed for 5 h. A precipitate was formed when cooled. The precipitate was isolated through filtration then washed with methanol to afford the title

1 compound (0.10 g, 65% yield); H NMR (CDCl3, 500 MHz): δ = 8.89 (d, J = 4.2 Hz,

1H), 8.83 (d, J = 4.1 Hz, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.26 (d, J = 16.0 Hz, 1H), 8.04

(dd, J = 21.7, 4.3 Hz, 2H), 7.82 (d, J = 16.0 Hz, 1H), 4.00 ppm (s, 3H).

Dimethyl 4’-(3,5-difluorophenyl)-[2,2’:6’,2”-terpyridine]-4,4”-dicarboxylate (34).51

1-(2-(4-(Ethoxycarbonyl)pyridine-2-yl)-2-oxoethyl)pyridine-1-ium iodide (0.23 g, 0.71 mmol) and methyl (E)-2-(3-(3,5-difluorophenyl)acryloyl)isonicotinate (0.21 g, 0.71 mmol) were dissolved in methanol (7.0 mL). Ammonium acetate (1.7g, 22 mmol) was added to the solution. The solution was then refluxed overnight. A precipitate was formed upon cooling. The precipitate was isolated by filtration and washed with methanol to 61

1 afford the title compound as a light yellow solid (47 mg, 14% yield); H NMR (CDCl3,

500 MHz): δ = 8.95 – 8.79 (m, 4H), 8.71 (s, 2H), 8.63 (d, J = 2.6 Hz, 2H), 8.56 (s, 1H),

8.03 (s, 2H), (d, J = 7.9 Hz, 6H).

4’-(3,5-Difluorophenyl)-2,2’:6’,2”-terpyridine (35).36 A mixture of 2-acetylpyridine

(1.4 mL, 13 mmol), 3,5-difluorobenzaldehyde (0.85 g, 6.0 mmol) and sodium hydroxide

(0.50 g, 13 mmol) was dissolved in a solution of aqueous ammonia (33 mL, 28% in water) and ethanol (60 mL) to form a pale yellow liquid. The reaction mixture was stirred at 25 ºC for 45 h, and the resulting precipitate was filtered and washed with, ethanol, water, and dimethylforamide. The product was recrystallized from toluene to afford the

1 title compound as a white solid (46 mg, 5.2%); H NMR (CDCl3, 500 MHz): δ = 8.72 (s,

2H), 8.66 (d, J = 8.9 Hz, 4H), 8.00 (s, 2H), 7.88 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 6.6 Hz,

2H), 7.36 (s, 2H), 6.89 (t, J = 8.4 Hz, 1H).

4’-(2,6-Difluorophenyl)-2,2’:6’,2”-terpyridine (36).36 A mixture of 2-acetylpyridine

(0.35 mL, 3.1 mmol), 2,6-difluorobenzaldehyde (0.16 mL, 1.5 mmol) and sodium hydroxide (0.13 g, 3.1 mmol) was dissolved in a solution of aqueous ammonia (8.1 mL,

28% in water) and ethanol (15 mL) to form a pale yellow liquid. The reaction mixture was stirred at 25 ºC for 45 h, and the resultingprecipitate was filtered and washed with, ethanol, water, and dimethylforamide. The product was recrystallized from toluene to

1 obtain the title compound as a white solid (48 mg, 37%); H NMR (CDCl3, 500 MHz): δ

= 8.78 – 8.61 (m, 4H), 8.58 (s, 1H), 7.88 (t, J = 7.5 Hz, 1H), 7.63 (s, 2H), 7.35 (d, J = 4.7

Hz, 2H), 7.24 – 7.10 (m, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H). 62

36 [Fe•352] Cl2 A solution of methanol (8.0 mL) and iron(II) chloride (30 mg, 0.15 mmol) was added to a solution of terpyridine 1 (0.11 g, 0.31 mmol) in dichloromethane (4.0 mL). The reaction mixture was stirred at 25 ºC overnight under nitrogen. The product was precipitated by addition of diethyl ether (0.10 L), and the solid was filtered to afford

1 the title compound as was a violet solid (46 mg, 18%); H NMR (D2O, 500 MHz): δ =

9.23 (s, 4H), 8.60 (d, J = 8.0 Hz, 2H), 7.92 (t, J = 7.9 Hz, 8H), 7.33 (t, J = 10.1 Hz, 2H),

7.23 (d, J = 5.5 Hz, 4H), 7.09 ppm (dd, J = 13.2, 7.0 Hz, 4H).

36 [Fe•362] Cl2 A solution of methanol (4.0 mL) and iron(II) chloride (15 mg, 75 µmol) was added to a solution of terpyridine 1 (48 mg, 0.14 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at 25 ºC overnight under nitrogen. The product was precipitated by addition of diethyl ether (0.10 L), and the solid was filtered to afford

1 the title compound as a violet solid (20% yield); H NMR (D2O, 500 MHz): δ =9.14 (s,

4H), 8.54 (d, J = 6.9 Hz, 4H), 7.90 (t, J = 6.2 Hz, 4H), 7.84 - 7.87 (m, 2H), 7.43 (t, J =

8.1 Hz, 4H), 7.29 (s, 4H), 7.10 ppm (s, 4H).

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