Stable Lanthanide Cryptates As Building Blocks for Solid Phase Peptide Synthesis - Synthesis, Functionalization and Photophysical Properties

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Stable Lanthanide Cryptates as Building Blocks for Solid Phase Peptide Synthesis - Synthesis, Functionalization and Photophysical Properties

Dissertation

zur Erlangung des Grades eines Doktors der Naturwissenschaften der Fakultät für Chemie und Biochemie der Ruhr-Universität Bochum

vorgelegt von

M.Sc. Nicola Alzakhem

Bochum, Dezember, 2012

Die vorliegende Arbeit wurde von Dezember 2008 bis Dezember 2012 am Lehrstuhl für Anorganische Chemie I der Ruhr-Universität Bochum angefertigt.

Referent: Dr. Michael Seitz Korreferent: Prof. Dr. Martin Feigel

To my parents

Danksagung

Ich danke allen, die mich durch ihre Hilfsbereitschaft und Interesse unterstützt haben, insbesonders:

Dr. Michael Seitz für die Vergabe des interessanten Themas und die Einführung in die „Lanthanide Chemistry“. Ich danke ihm für sein entgegengebrachtes Vertrauen und jede wissenschaftliche Diskussion. Jede Phase dieser Arbeit wurde von ihm professionell und motiviert begleitet.

Herrn Prof. Metzler-Nolte für die Aufnahme in seine Gruppe, seine Freundlichkeit und sein Bereitstellen von Analysemöglichkeiten in seinem Arbeitskreis.

Herrn Prof. Martin Feigel für seine freundliche Übernahme des Korreferates.

Herrn Dr. Klaus Merz und Mariusz Molon für die Messungen der Röntgenstrukturanalysen. Frau Andrea Ewald für das Messen zahlreicher ESI-Massenspektren.

Jessica Wahsner, Tuba Güden-Silber und Christine Doffek für die außerordentlich tolle Zusammenarbeit und für das Korrekturlesen. Ein besonderer Dank geht an Jessica für ihr Dasein und für ihr offenes Ohr bei Problemen und ihren guten Rat. Mit Jessica habe ich problemlos den Arbeitsplatz geteilt und sie war eine wunderbare Nachbarin. Desweitern möchte ich mich bedanken bei dem gesamten jetzigen und vorherigen Team der ACI für die freundliche Arbeitsatmosphäre. Besonderer Dank geht an David Köster, Lukasz Raszeja, Johanna Niesel, Nina Hüsken und Jan Dittrich für die besondere Zeit am Lehrstuhl und außerhalb der Uni. Ein ganz besonderer Dank geht an meine Eltern für alles was sie für mich und meine Zukunft getan haben. Ohne euch wäre diese Arbeit unmöglich. Zum Schluss will ich mich aus ganzem Herzen bei Caroline Bischof bedanken. Mit Caro habe ich zusammen gearbeitet, zusammen gesungen und zusammen gelacht. Jede schlechte und gute Phase habe ich mit ihr geteilt. Sie war nicht nur eine besondere Freundin, sondern ist Teil meiner Familie geworden.

PREFACE...... I

1 INTRODUCTION ...... 1

1.1 Lanthanides...... 1

1.2 Applications of lanthanide complexes...... 2 1.2.1 Luminescent lanthanide complexes ...... 2 1.2.2 Magnetism: Lanthanides in NMR spectroscopy ...... 3 1.2.3 Lanthanides as mass tags ...... 4 1.2.4 Other applications ...... 4

1.3 Typical ligands for lanthanide ions ...... 5 1.3.1 Polyamino carboxylates ...... 5 1.3.2 Crown ethers and cryptands...... 7

1.4 Multinuclear lanthanide complexes ...... 9 1.4.1 Homo-polymetallic lanthanide complexes...... 9 1.4.2 Hetero-polymetallic lanthanide complexes...... 11

2 THE AIM OF THE WORK ...... 15

3 RESULTS AND DISCUSSION...... 18

3.1 Cryptand Design-General Considerations...... 18

3.2 Synthesis of anionic cryptands...... 20 3.2.1 Cryptands based on bis(thiazole) ...... 20 3.2.2 BINOL-based cryptates...... 23 3.2.3 2,2 ′-Biphenol-based cryptates...... 24 3.2.4 Stability...... 27 3.2.5 Structural aspects ...... 29

3.3 Functionalization of cryptates ...... 32 3.3.1 Approach I ...... 33 3.3.2 Approach II ...... 44 3.3.3 Synthesis of lysine cryptate conjugates...... 52

3.4 Photophysical properties of the cryptates...... 56

3.5 Influence of the number of bipyridine on the photophysical properties of bpy-based cryptates: . 60 3.5.1 Synthesis of the sodium and lanthanide cryptates...... 60 3.5.2 Triplet state determinations...... 63 3.5.3 Absorption and emission spectra ...... 64 3.5.4 Determination of the quantum yields and lifetimes ...... 65

3.6 A new kind of chiral cryptate ...... 68 3.6.1 Synthesis of the cryptates...... 69

4 SUMMARY...... 73

5 EXPERIMENTAL SECTION:...... 78

6 LITERATURE...... 127

7 APPENDIX...... 132

List of abbreviations and units

Å angstrom [10-10 m] AA any amino acid BINOL 1,1 ′-Bi-2-naphthol δ chemical shift DCM Dichloromethane DMF Dimethylformamide DMSO Dimethylsulfoxide EDC 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide ESI-MS electro-spray ionisation mass spectrometry Fmoc 9-fluorenylmethyloxycarbonyl GC gas chromatography H hour HOSu N-Hydroxysuccinimid HPLC high-pressure liquid chromatography Hz Hertz [s -1] ICP-MS inductively coupled plasma mass spectrometry J coupling constant λ wavelenght [nm] ACN Acetonitrile MRI magnetic resonance imaging m/z mass to charge ratio ν wavenumber [cm -1] NBS N-bromosuccinimide NIS N-iodosuccinimide Nm Nanometer NMR nuclear magnetic resonance o.n. overnight r.t. room temperature SPPS solid phase peptide synthesis TFAA trifluoroacetic acid THF tetrahydrofurane

TLC thin layer chromatography TMEDA N,N,N ′,N ′-tetramethylethylenediamine UHP Urea hydrogen peroxide UV Ultraviolet Vis Visible Vs. Versus

Preface

In our childhood, we played with LEGO bricks and have enjoyed the possibility to build various figures from the same building blocks. These colorful bricks with different shapes can be assembled in many ways to construct different objects such as houses, trees, etc. Similarly, letters are used to build words or texts and musical notes are used to compose beautiful melodies (Figure 0.1).

Figure 0.1. Examples of building blocks from everyday life (adopted from internet). (http://www.amazon.de/LEGO-5539-Steine-Steinebox-Starter/dp/B001CQRVVM) Last access: 20.12.2012 (http://en.wikipedia.org/wiki/File:Chopin_Prelude_7.svg) Last access: 20.12.2012

While all of this is going on at the macroscopic level, similar operations are occurring inside us. At the microscopic level, the chemical processes in our body use various sets of small molecules (e.g. amino acids, nucleic acids, monosaccharides, etc.) as building blocks to construct macrobiomolecules such as peptides, proteins, DNA, polysaccharides, etc. A fascinating example is that of the amino acids. They all possess two chemical groups, the carboxyl group COOH and the amino group NH 2, which allow them to polymerize and hence to form proteins. They react in head-to-tail fashion, eliminating a water molecule and bind covalently with an amide linkage, which is referred to as a peptide bond . It is the side groups R that give each amino acid its identity and make the various amino acids chemically and physically different from each other. Thus, the properties of the produced polypeptides or proteins are dependent on the unique properties and chemical diversity of the amino acids that make up the protein (Figure 0.2).

Preface

CCCOOOOOOHHH This part is common to all amino acids C HHH222NNN HHH RRR This part is different fffor each amino acid.

Figure 0.2. The structure of amino acids.

Inspired by this, chemists have developed a synthetic approach to mimic natural peptide structures or to synthesize modified peptides. This method was called Solid Phase Peptide Synthesis (SPPS) and relies on the stepwise coupling of amino acids on a solid support. However, the use of this method was extended to include unnatural and modified amino acids. More recently, metal complexes were introduced successfully to peptide scaffold, because of the increasing interest in medical and biological activity of the complexes. [1, 2] The use of metal complexes itself as building blocks in SPPS is the motivation of this work, evoked the idea to develop and synthesize lanthanide complexes as “inorganic amino acids”, since lanthanide ions possess unique physical properties and similar coordination chemistry, as we will see in the next section.

Introduction

1 Introduction

1.1 Lanthanides

Historically, lanthanides have been considered as an appendix in the periodic table and have been given the misleading name “rare earth metals”. Nowadays, it is known that they are not rare, since many of them exist in considerable quantities. [3] For example, the rarest of them, thulium, is more common than silver, mercury and the precious metals. However, the exploration of their chemistry has faced at the beginning the challenge of separating them from each other, for which many technologies were developed in the 1960s. [4] This difficulty is, in particular, a result of their similar chemical properties. Lanthanide ions, compared to the d-block metals, possess neither restricted coordination numbers nor a wide range of oxidation states. Their chemistry is dominated by the +3 oxidation state with few exceptions e.g. Eu 2+ and Ce 4+ .[5] In addition, lanthanides have relatively large ionic radii ranging from 1.061 to 0.848 Å for octahedral La 3+ and Lu 3+ , respectively.[6] (Note that the largest ionic radius of trivalent transition metal Ti 3+ is 0.670). The gradual decline of ionic radii is referred to as “lanthanide contraction”. This occurs because, the 4 f orbitals penetrate the xenon core and are inside the filled 5s and 5 p orbitals. Consequently, they are partially shielded from the nuclear charge. As the lanthanide series is traversed, there is a net increase in the effective nuclear charge and each ion shrinks slightly in comparison to its predecessor. The reason of this penetration is that the valence electrons of neutral lanthanides reside in the 4 f, 5 d, and 6 s orbitals. As electrons are removed, these orbitals experience a different degree of stabilisation, with 4 f being stabilized most and 6 s least. When three electrons are removed, the additional stabilisation of the 4 f orbitals is sufficiently large that no electron is retained in the latter two orbitals.[4] Furthermore, the remaining 4 f orbitals are tightly held by the nucleus and, thus, chemically inaccessible. In other words, the 4 f orbitals do not extend outside far enough to interact with the ligand orbitals. As a result, lanthanide complexes are held mostly together by electrostatic interactions (ionic bonding). [7] Moreover, the splitting of f-orbitals in a ligand field is very small ( ∆ ≈ 1 kJmol -1) and thus its stabilization effect on complexes is of minor importance. Consequently, their electronic spectra and magnetic properties are essentially not affected by the environment.

Introduction

1.2 Applications of lanthanide complexes

1.2.1 Luminescent lanthanide complexes

Due to the weak electronic interaction between the lanthanide ion and the ligands, the vibronic coupling in lanthanide compounds is much weaker than in transition metal compounds. Furthermore, the luminescence in lanthanide (III) complexes arises exclusively from the f-f transitions. However, according to the selection rules, the f-f transition is parity forbidden causing a very low molar absorption coefficient ( ε), which makes the direct excitation of lanthanides inefficient. It is possible to overcome this problem by placing the lanthanide ion in close proximity to an organic chromophore (termed “antenna ”), which is usually an aromatic molecule. [8, 9] In such a system, the organic moiety absorbs light of an appropriate wavelength and transfers the energy to the excited levels of the lanthanide ion (Figure 1.1). The resulting emission has a long lifetime and narrow bands as well as large Stokes shift, which all make these elements unique among the known luminescent species. [9] In addition, the small interaction between the f orbitals of the lanthanide ion and the ligand results in element characteristic emission. For example, europium exhibits red light emission, whereas a terbium complex displays green emission.

Figure 1.1: Schematic representation of the antenna effect in lanthanide luminescence.

A very common used chromophore for the sensitization of lanthanides is 2,2´-bipyridine (bpy), whose lowest triplet energy ( 3ππ *) at 23000 cm -1, is sufficiently high to sensitize lanthanide ions such as Eu(III) and Tb(III). This unit was incorporated into several structure types such as “podands”, where the bipyridine units also serve as chelators. Figure 1.2 shows an example of a chelate incorporating four bipyridine units and that was found to give a luminescent europium complex. [10]

Introduction

N N N N N N N N N N

Figure 1.2: Example of typical bipyridyl (bpy)-based podand ligand.

1.2.2 Magnetism: Lanthanides in NMR spectroscopy

Most complexes of lanthanide ions are paramagnetic due to the unpaired electrons in the 4 f orbitals. Since the interaction with the ligands is very weak, the magnetic properties are similar to those of the free lanthanide ions. Due to this paramagnetism, NMR spectra of lanthanide compounds are expected to show very broad signals. However, because lanthanides have rather very short electronic relaxation times, the signals result in often only moderate line-broadening. Among the lanthanide ions, Eu(III), Yb(III) and Pr(III) proved to be the best shift reagents among other paramagnetic metals for up- and downfield shifting. In contrast to these elements, gadolinium with its seven unpaired electrons 4f7 has a longer electronic relaxation time making it an excellent relaxation agent for 1H spins. Therefore, Gd(III) draws the greatest attention for the design of contrast agents for magnetic resonance imaging (MRI). Since this method uses the 1H NMR of water in tissue, paramagnetic gadolinium complexes reduce the relaxation times and, hence, enhance the signals. Figure 1.3 shows several commercially available contrast agents based on gadolinium chelates.

O O 2- O O O O N O N N N N N Gd O O Gd O O Gd O O N O N N N N OH O O O O O O O OH O HO HO Magnevist Prohance Gadovist Figure 1.3: Commercially available gadolinium contrast agents based on chelate ligands.

Introduction

1.2.3 Lanthanides as mass tags

Because of their low background, high sensitivity and less interference, lanthanides proved to be excellent elemental tags for detection with mass spectrometry. Of particular interest is their utilization in the quantification of proteins (proteomics), where lanthanides can be introduced to the proteins by using selective derivatization. Moreover, the similar chemistry of the lanthanide allowed the labeling of several objects using the same chelate. In addition, the existence of several lanthanides as monoisotopic elements (Tm, Tb, Pr, etc.) reduces the overlap between several tags. For detection of these tags, inductively coupled plasma mass spectrometry (ICP-MS) is a widely used method with many unique properties including fast determination, excellent detection limits for most elements and the ability to analyze multi- elements samples. [11, 12] Figure 1.4 illustrates this principle in a glycoprotein assay.

Figure 1.4: Microtiter-plate assay to probe glycoproteins with polymer-conjugated lectins (adopted from Ref. [13] ).

1.2.4 Other applications

Figure 1.5 summarizes the most important applications of lanthanides, which earned them a prominent place in modern science. [14, 15]

Introduction

Figure 1.5: Examples of some modern applications of lanthanide ions.

1.3 Typical ligands for lanthanide ions

Even though the chemical and physical properties of lanthanide ions appear to be ideal for many applications in solution, there is a difficulty in the isolation of their complexes, particularly, from aqueous solution, due to the high rates of exchange of ligands at the metal. An approved method to overcome the kinetic instability is the utilization of chelate or macrocycle effects. [4]

1.3.1 Polyamino carboxylates

− In general, lanthanide ions are typical hard Lewis acids and show a preference for F , H 2O and other O-donor ligands etc. Aminocarboxylates produce stable lanthanide complexes, where the carboxylate groups contribute to high stability of these complexes. They wrap around the metal and protect the lanthanide ions from interaction with solvent molecules. This stability was exploited in the early chemistry of the lanthanide. For example, ethylenediaminetetraacetic acid (EDTA) (Figure 1.6) was used in the separation technology of lanthanides by ion exchange processes. EDTA is a hexadentate ligand that forms lanthanide 5

Introduction complexes with three water molecules occupying the vacant sites at the metal, with 8 or 9 being the preferred coordination number of Ln(III). Therefore, the EDTA-Gd complex was expected to be suitable for MRI. However, this complex was found to exhibit a low kinetic and thermodynamic stability and, hence, released a considerable amount of toxic gadolinium. An improvement of this initial concept was realized by the utilization of the octadentate chelate diethylene triamine pentaacetic acid (DTPA) (Figure 1.6), which forms highly stable 2- TM lanthanide complexes. For example, [Gd(DTPA)(H 2O)] (Magnevist ) has a stability constant log K = 22.5, [16] and was successfully introduced as the first MRI contrast agent administered to humans. [17] Furthermore, this ligand shows very high stability for all lanthanides.

COO OOC COO OOC COO COO N N OOC N N COO OOC N N N COO OOC N N COO OOC

DTPA5- EDTA4- DOTA4- Figure 1.6: Some chelates based on amino carboxylates.

Additional stability was gained by using the cyclic analogue 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA) (Figure 1.6), which was known to form very stable calcium complexes.[18] Because of the similarity between alkaline earth metals and lanthanide ions, it was anticipated that DOTA could also form stable lanthanide complexes. In agreement with - this assumption, [Gd(DOTA)H 2O] showed the highest stability known to that date with a complex constant 10 orders of magnitude bigger than the corresponding EDTA complexes.[19, 20] This outstanding stability is maintained for all lanthanide DOTA complexes. The stability constants (log K) of several lanthanide DOTA and DTPA complexes are given in Table 1. [21]

Table 1 : Stability constants of lanthanide DOTA and DPTA complexes. [21]

Lanthanide log K (DOTA) log K (DTPA)

Eu(III) 23.39 22.39

Gd(III) 24.62 22.46

Tb(III) 24.22 22.71

Introduction

Because of these very high stabilities, DOTA-based ligands have found widespread use in many classes of lanthanide complexes [14] including luminescent lanthanide complexes. This was realized by attaching a chromophore to the scaffold of the macrocyclce. This is of [22] particular interest for applications such as pH, pO2 and anion sensors. In addition, the phosphinate analogues, which are obtained by replacing the carboxylic acid with alkylphosphonate, were developed and investigated. [23-25]

1.3.2 Crown ethers and cryptands

In the 1960s almost at the same time as the macrocycle DOTA was developed, Charles J. Pedersen and Jean-Marie Lehn (who shared in 1987 the Nobel Prize with Donald J. Cram) were working independently on new classes of macrocycles. Pedersen published the first study on crown ethers, which are cyclic polyethers with repeating (O-CH 2-CH 2-O) units. These formed stable complexes with various metals including alkali and alkaline earth metals. [26, 27] As a result of Pedersen’s finding, considerable efforts have been directed to the synthesis of new crown ethers [28] , which could be used as host molecules for many cations, anions and even organic molecules. [29] Simultaneously, Jean-Marie Lehn at the University of Strasbourg was interested in designing molecules, which are able to selectively bind metal cations. His idea was inspired by the transmembrane transport of sodium and potassium ions in nerve cells. His research led him to the development of a new class of macrobicycles, which were obtained by attaching two ether units with nitrogen bridges connected to a third ether unit (Figure 1.7). In 1969 the results appeared in the publication “Les Cryptates”[30] , where the term Cryptand was introduced for the first time. They described their selectivity of binding alkali and alkaline earth metal cations depending on the number of ethoxy linkages. The complexes were found to exhibit very high thermodynamic stability when the size of the metal ion matched the dimension of the cavity. Worthy of note was the smaller dissociation rate in aqueous solution of the divalent calcium cryptate [Ca ⊂2.2.2] 2+ compared to the monovalent sodium analogue [Na ⊂2.2.2] +. This was surprising since the difference in ionic radii is very small and the thermodynamic stability of their cryptates is very similar. These observations suggested that trivalent lanthanide ions could also form thermodynamically stable and kinetically inert lanthanide cryptates. Hence, a series of lanthanide cryptates with [2.2.2] and [2.2.1] cryptands was synthesized. Eu (III) and Gd (III) showed a remarkable stability in aqueous solution at neutral pH, but were only stable for a few hours at pH >10. [31]

Introduction

O N N O O O O O O O O O O O O O O O O N N

18-crown-6 [2.2.2] [2.2.1] Figure 1.7: Structures of early crown ether and cryptands.

In addition to the extensive studies on their structural, thermodynamic, kinetic and electrochemical properties, many spectroscopic investigations have been carried out in the early 1980s. For example, [Eu ⊂2.2.1] 3+ shows significant emission at room temperature in aqueous solution, while simple aqua complexes are not luminescent under the same conditions. This could be attributed to the fact that europium is well shielded from solvent molecules, which cause non-radiative deactivation. However, the determined quantum yield was very low ( φ = 0.03). [32] By exploiting the antenna effect , great improvement on the cryptands was achieved by replacing the three ether units with 2,2´-bipyridine moieties. The resulting tris(bipyridine) cryptand showed an intense absorption band ( ε = 25000 M -1cm -1). Remarkable was the high kinetic stability which could be attained despite the existence of only “soft” nitrogen donor atoms. This could be attributed to the cage-like structure where the metal ion is encapsulated inside the cavity and, hence, well protected from the interaction with the environment. Lanthanide cryptates with europium and terbium were investigated, both showing an intense characteristic emission (Eu: red, Tb: green) and relatively long lifetime. [33, 34] Nevertheless, low quantum yields were determined, which were attributed to the low efficiency of energy transfer from the ligand to the metal. However, higher kinetic stability could be obtained by replacing one bipyridine unit with its oxidized analogous bipyridine N,N ′-dioxide [35] (Figure 1.8). Furthermore, the europium complex of 2 displays enhanced luminescent properties.

Introduction

N N N N N N N N O O N N N N N N N N

1 2

Figure 1.8: Structures of [bpy.bpy.bpy] (left) and [bpy.bpy.bpyO 2] cryptands.

This success spurred wide interest on lanthanide cryptates and various derivatives of the parent compound 1 were synthesized. [36-39] Lanthanide complexes of the 1 type have been also expanded to include ytterbium and neodymium, which emit in the near-IR region. This emission is more desirable for diagnostic imaging due to its deeper penetration into tissue. [40- 42]

1.4 Multinuclear lanthanide complexes

As described in the previous sections, lanthanide coordination chemistry is a well studied field and a large number of complexes has been investigated, which cover different fields of applications and overcome the most critical points such as kinetic lability, thermodynamic instability, low luminescence, etc. This research forms the foundation for new ideas, namely the assembly of several lanthanide complexes. The research can be divided into two areas, one that aims of the improvement of a specific property such as luminescence or magnetism by increasing the number of the lanthanide ions in the complex. The other area is the combination of several properties to obtain new features by synergistic interaction by more than one lanthanide.

1.4.1 Homo-polymetallic lanthanide complexes

The tendency to construct multinuclear lanthanide complexes arose from the successful utilization of gadolinium complexes as MRI contrast agents. Indeed, macromolecular contrast agents can diminish many drawbacks of single complexes. This is reflected in enhanced relaxivity as a result of the increase in the rotational correlation time. Another advantage is the reduction of the dose necessary for imaging of good quality. Therefore, many approaches have been developed based on bifunctional DTPA and DOTA chelates. The existence of two functional groups allowed the linkage of two single chelates together and the conjugation of the resulting agent to biomolecules. The Gd chelates were introduced to several systems such

Introduction as dendrimers [43-45] and polymers [46-48] , or by polymerization of the chelate itself. [49] In general, these macromolecules show a remarkable improvement of relaxivity at intermediate frequency (20-60 MHz). However, the relaxivity decreased rapidly above 100 MHz. Hence, at higher frequencies, rigid molecules of intermediate size are preferred over large ones. For this aim, many molecules were prepared containing two or three Gd-chelates. [50] Figure 1.9 shows an example of multi-nuclear gadolinium contrast agents, where a gadolinium chelate was introduced to lysine dendrimers.

Figure 1.9: Synthesis of dendritic MRI contrast agents with octasilsesquioxane core (adopted from Ref. [51] ).

In accordance with the improvement of Gd-based contrast agents, luminescent lanthanide complexes were also introduced to macromolecule structures such as polymers [52] , dendrimers [53] and upconversion doped oxide materials. [54] The excitation resulted in higher absorption and emission of polylanthanide systems, which is accompanied with enhanced luminescence performance. Polymetallic europium and terbium complexes have been prepared and studied. [55-57] The long lifetime emission in the visible region and, hence, the elimination of the background fluorescence from the organic biomolecules makes them attractive probes for diagnostic assays. Here, kinetically stable complexes based on DOTA- type ligands were usually used. However, their emission limited their use, due to the fact that visible light penetrates the tissue only to the depth of about 8-10 mm. To address this issue,

Introduction lanthanide complexes of near-IR emissive Yb(III) have been reported to improve the penetration into tissue. [58]

1.4.2 Hetero-polymetallic lanthanide complexes

Owning to their very similar chemical and structural properties but very different physical properties from one to the other, assembly of several lanthanide ions could lead to materials exhibiting tunable properties via the choice of the metal ion. For example, lanthanide ions emit light in the entire spectrum ranging from ultraviolet (Gd, La, Lu), visible (Eu, Tb, Sm, Dy, Tm) to near-IR (Yb, Er, Nd, Pr). The wavelengths of the emission do not vary with changes of experiment conditions such as temperature or pH as well the variation of the environment. Additionally, the very narrow emission bands allow detecting several lanthanide emissions independently during the same measurement, a desirable advantage for multiplex analysis. Besides, designing of complexes containing gadolinium as contrast agent and luminescent lanthanide ion is an excellent way for using multimodal assays. Even though the magnetic and photophysical properties of lanthanides appear to be ideal for use in multiplex analysis, there are many limitations. The similar coordination chemistry of the lanthanides hindered the selective complexation. Apart from this, the key host principle is out of reach because of the very small difference in ionic radii between the lanthanide ions (it is only 0.15 Å between La and Lu). In the last decade, several successful approaches were published describing the synthesis and studies of hetero-polymetallic complexes. The pioneering work in the groups of Bünzli and Piguet focused on ligands which can undergo self-assembly in helical form 3 (Figure 1.10). Under thermodynamic control, it was possible to obtain a dinuclear triple helical complex of europium and terbium. [59] However, this system shows at least two drawbacks; the emission of terbium was diminished, while that of europium was equal to the homo dinuclear complex, which can be attributed to intramolecular energy transfer from terbium to europium. Moreover, the statistical distribution of the heterobinuclear complex is relatively low (30 %). Higher yield of the heterometallic product could be obtained by use of an unsymmetrical ligand. This ligand showed remarkable affinity to bind dissimilar ions.[60]

Introduction

N N N N

N N

O O Et2N NEt2 3 Figure 1.10: Two ligands for the self-assembly of lanthanide complexes. [59, 60]

Another approach, which was adopted by several groups, is the exploitation of the differences in kinetic stability between acyclic and cyclic polyaminocarboxylates. In the very first example, two equivalents of [Tb(DO3A)] were reacted with DTPA anhydride and then with Yb 3+ to afford the trimetallic complex [Tb-Yb-Tb] 4 (Figure 1.11). The inertness of the [Tb(DO3A)] complexes hampered any metal exchange between Yb and Tb, which afforded selective complexation of Yb with DTPA. This single complex exhibits green emission bands from Tb and near-IR emission from Yb. Of note is the selective excitation of Tb at 336 nm resulting in high emission from Yb. This indicates an energy transfer from the two Tb ions and demonstrates inter-lanthanide downconversion. [61]

O O N N O N O Yb O O O O O O O O NH HN N N N N O O Tb Tb N N N N O O O O O O 4 Figure 1.11: Trinuclear lanthanide complex [Tb-Yb-Tb]. [61]

Trambly et al. [62] reported the dinuclear complex [Eu-Tb] incorporating DTPA and DOTA- monoamide chelates 5 (Figure 1.12). First, the terbium bimetallic [Tb-Tb] complex was prepared, since both chelates are not able to distinguish between two different lanthanide ions. Benefiting from the fact that the DTPA complex is less kinetically stable under acidic condition than the DOTA-mono amide complex, one terbium ion can be removed from DTPA by applying HPLC under acidic conditions. Subsequently, europium can be introduced

Introduction selectively to the DTPA ligand. The characteristic emission from Tb was observed, while only very low emission intensity from europium was obtained. Worth of note is the higher emission from europium in less polar solvent indicating the influence of the solvent on the intermetallic interaction. Similarly, the bimodal agent 6 was reported containing europium or terbium as a luminescence probe and gadolinium as MRI contrast agent. [63]

O O O N O N N O Eu O O N COO O NH O NH O O O O H H N COO N Tb HN NH COO 2 N N O O O Gd NH COO N N N O O O O N O H O N Tb N N O N O 6 O O

O 5

Figure 1.12: Synthesized lanthanide dimeres.[62, 63]

The group of Stephen Faulkner at the Oxford University has recently reported another interesting procedure based on an orthogonal protection strategy. The used system consists of two DOTA ligands; one of these is protected with an ethyl ester group and the other is protected with a t-butyl ester. While the methyl ester was removed under basic condition, t- butyl ester can be later hydrolysed under acidic condition, enabling the stepwise introduction of two different lanthanide ions 7 (Figure 1.13).[64] Relying on this success, the system was 3+ 3+ extended to obtain tetra-metallic array with two lanthanides [Ln 2-Ln 2′] (Ln = Yb or Nd ). The luminescence from both Yb 3+ and Nd 3+ was observed whereby one is sensitized by benzyl amine and the other by phenol. [65]

O O O HN NH O

N N O O N N Tb O O Yb N N N N O O O O O O

Figure 1.13: Prepared multinuclear lanthanide complexes in the Faulkner group. [64, 65]

Introduction

The last strategy to bind lanthanide complexes appeared very recently describing the assembly of europium and terbium complexes together with disulfide bridges 8 (Figure 1.14). The characteristic emission of terbium and europium was observed with light energy transfer between the metals. Despite the limitation of this method to bind only two complexes, it opened the way for construction of multimodal systems by the choice of the metal center. [66]

O O S NHO O HN S O N O N O Tb N O O N Eu O N O N O S NH O OHN S O O 8

Figure 1.14: Dinuclear lanthanide complex based on disulfide bridges.[66]

Aim of the work

2 The aim of the work

As outlined in the introduction, the construction of multinuclear lanthanide complexes received wide attention in the last decades for either improvement of specific properties or the combination of several functions in one species. There are two features that make lanthanide complexes attractive building blocks for the construction of multinuclear complexes: - The similar coordination chemistry - Element specific physical properties The similar chemistry allows the use of the same ligand for the complexation of the lanthanide ions without expecting huge differences in stability and geometrical properties. The physical properties offer the recognition of each lanthanide in hetero polymetallic complexes. This is possible, because all lanthanide ions are emissive when they absorb light at appropriate wavelength. Yet, each lanthanide exhibits a different emission spectra independent from the ligand and excitation wavelength. Furthermore, their line-like emission minimizes the overlap between the different signals (Figure 2.1). Inductively coupled plasma mass spectrometry can also be used to detect a polymetallic lanthanide complex (Figure 2.1).

Figure 2.1: Right: emission spectra of four lanthanide ions (Tb: green, Dy: yellow, Eu: red, Sm: orange). [15] Left: ICP-MS spectrum of enriched stable isotopes. [67]

In the recent decade, several approaches to construct multi-lanthanide complexes were reported. However, the procedures suffer from at least two limitations; the restricted number of lanthanide complexes which can be linked together in solution and the difficulty to obtain multinuclear lanthanide complexes with more than two different lanthanide ions. Consequently, a new strategy is required that allows the selective linkage of different lanthanide complexes in solution. Solid phase peptide synthesis is a widely used method for the preparation of poly amino acids through stepwise introduction of the single amino acids

Aim of the work on a solid support. Our idea was to use this method to couple appropriate lanthanide complexes together. Therefore, suitable building blocks have to be developed. Two categories of building blocks can be used: either functionalized lanthanide complexes that can be used directly in SPPS or lanthanide complexes coupled to an amino acid such as lysine. In both cases, the ligands have to fulfil several requirements. - High stability and kinetic inertness towards the acidic conditions of the SPPS and HPLC. - Anionic charge of the ligand is very desirable to minimize any possible repulsion interaction between the relative highly charged complexes (+3). For this aim, cryptates are excellent candidates due to their high kinetic stability and synthetic versatility. In comparison to DOTA based ligands, the antenna chromophores are already incorporated in the cryptate structure and mostly results in ability for sensitization of several lanthanides. For example, cryptands 1 and 2 (Figure 1.8) are able to sensitize a wide number of lanthanides including visible emissive europium and terbium and the near-IR emissive Yb, Nd, Er, etc. Therefore, the design of anionic, stable lanthanide cryptands was the main goal of this thesis. These should be synthesized, characterized and the stability of the lanthanide complexes should be examined. In addition to these basic requirements the design should be later extended to include additional functionalities through which the promising cryptates can be either directly used in SPPS or linked to a related amino acid. According to these requirements the project can be divided into four parts as it is illustrated in figure 2.2.

Aim of the work

Part I: Identification of suitable lanthanide cryptates - - High kinetic stability Reduced charge via anionic units

Part II: Functionalization of the promising cryptates X - - X = halogen, amine, carboxylic acid, etc.

Part III: Construction of building blocks for SPPS AA - - AA = amino acid.

Part IV : SPPS of oligomer based on Ln-cryptates

Figure 2.2: Outline of the main work of this thesis.

The photophysical properties of several lanthanide cryptates are also investigated including triplet state determinations as well as lifetime and quantum yield measurements. As a part of this work, the design and the synthesis of a new kind of chiral cryptates are also presented.

Results and Discussion

3 Results and Discussion

3.1 Cryptand Design-General Considerations

Generally, cryptands are accessible by a stepwise procedure involving the synthesis of a related macrocycle and its subsequent bridging. The two macrocycles used here are 9 and 10 . In the first attempts, macrocycle 9 was used because it is commercially available, which facilitates a shorter synthetic pathway. Later, the bpy.bpy macrocycle 10 , which is known in the literature, was synthesized accordingly. For the design of the third unit, several requirements are considered: 1) the ability to offer a negative charge, 2) exhibiting an antenna effect, and 3) a short and flexible synthetic route. Furthermore, the chirality of the resulting cryptands, the possible synthetic pathways for the funtionalization and their influence on the chirality and photo-physical properties are taken into consideration (Figure 3.1).

NH X + NH X

Br * N N H H O O N N HO S S HO O O N N H H N N N N * * * 9 10 Figure 3.1: Schematic representation of the design of novel anionic cryptates.

Accordingly, several units were designed and expected to fulfil all or some of the desired requirements. Bis(thiazole) was thought to provide the cryptate with a single negative charge by deprotonation of its relative acidic proton at the methylene bridge. This concept is similar to bis(heterocycle) chelates, which were widely investigated by the group of G. Pagani. [68]

Results and Discussion

S S N N * *

The other class of anionic units that are used in this work are based on aryl moieties that bear hydroxyl groups. The deprotonated forms of biphenol and binaphthol, which can chelate metals, provide two negatively charged oxygen atoms. In comparison to the bis(thiazole), these units introduce axial chirality to the cryptate. However, the related cryptates were synthesized as racemic mixtures. Nevertheless, the axial chirality is taken into consideration by the functionalization of the related cryptates. In general, there are two approachs for the introduction of functional groups as it is depicted in Figure 3.2 with biphenol cryptate as an example. In the first approach, the introduction of a functional group to the bpy.bpy macrocycle 10 adds a new stereogenic element as a consequence of the incorporation of three different arms with one arm being unsymmetric. This results in a mixture of diastereomers as well as racemic mixtures. However, this feature disappears in the second approach when the functional group is introduced to the biphenol unit. In this case, the cryptate existence as racemic mixture. -

Three different arms

GF FG N N N N N HO N HO N HO N HO N N Unsymmetrical N Axial chirality N Axial chirality arm

Diastereomere mixture Racemic mixture

Figure 3.2: Two possibilities for addition of a functional group to a cryptate structure and their influence on the chirality of the cryptand.

Results and Discussion

3.2 Synthesis of anionic cryptands

3.2.1 Cryptands based on bis(thiazole)

Br Br Br

i ii iii EtO OEt NH2 NH H2N H2N 2 O O O O S S

11 12 13

N O S N iv O Br Na Br S S O N O N N N S

Cl Cl 14 15

-3 Scheme 3.1: Synthesis of bis(thiazole) cryptate 15. i) 2.2 eq. NH 3 (7 N in MeOH), 2.3 x 10 eq. NaOMe, 7 d at r.t. (48%); ii) 1.2 eq. Lawesson’s reagent, THF, reflux overnight (74%); iii) 3.5 eq. 1,3-dichloroacetone, THF,  reflux 4 d. (82%); iv) 1.0 eq. Kryptofix 22, 10 eq. Na 2CO 3, acetonitrile, reflux, 2 d.

The synthesis of the starting material 11 was performed according to a literature procedure.[69] The malonic acid diethyl ester 11 was reacted with either methanolic or aqueous ammonia in the presence of catalytic amounts of sodium methoxide to give the diamide 12 in moderate yield (48%). It was found that concentrated methanolic ammonia (7 N) gave the best yield (up to 50%). This observation is in accordance with the previous reported synthesis of an analogous compound. Moreover, the addition of sodium methoxide enhanced the reaction, since the in situ formed methyl ester reacts more readily than the ethyl ester.[70] The formation of the bis(thiazole) rings was achieved following the same procedure as used for the synthesis of an analogous structure.[71] In the first step, the amides were converted to thioamides 13 using Lawesson’s reagent. The reaction is water sensitive and, hence, thoroughly drying of the diamide 12 is necessary for good yield. This requires drying under vacuum and relative high temperature (60 °C), since 12 is a good water binding molecule via its oxygen and nitrogen atoms. 1H NMR spectra confirmed the accomplishment of the conversion to thioamides since the signals of the CH group and of the amides are shifted to lower field (Figure 3.3).

Results and Discussion

1 Figure 3.3: H NMR of 12 (top, d 6-DMSO, 200 MHz) and 13 (bottom, d 6-DMSO, 200 MHz).

Subsequently, dithioamide 13 was reacted with an excess of 1,3-dichloroacetone to afford 14 in very good yield (82%). This reaction can be easily monitored via TLC (SiO 2, CH 2Cl 2). The  corresponding sodium cryptate 15 was prepared by the reaction of 14 and kryptofix 22 in refluxing acetonitrile in the presence of Na 2CO 3 and NaI under high dilution conditions. This could be obtained by very slow addition of a solution of 14 in acetonitrile via a thin teflon tube. Moreover, the addition of sodium iodide in catalytic amounts is necessary to accomplish the reaction, since the alkyl chloride is less reactive towards nucleophilic substitution than the bromide or the iodide analogue (Scheme 3.1). Initial attempts to prepare 15 without addition of NaI failed. 1H NMR of 15 shows no well defined signals in the aliphatic region between 3- 4 ppm, and also the proton signals of the bromobenzene and thiazole rings overlap. In general, the spectrum is too intricate to make any assignments, but the integration of the signals is in good agreement with the expected number of protons (Figure 3.4). It is known that the CH 2- groups are non-equivalent at room temperature because of the torsional motion around the N,N ′-bridges. By increasing the temperature, this motion can be accelerated so that the signals often coalesce.[36, 37] Therefore, measurements at higher temperature up to 60 °C were carried out but no changes were observed. However, the electrospray ionisation mass spectrum (ESI-

Results and Discussion

MS) shows the molecular ion peak with bromide isotope pattern at m/z 647 corresponding to [M +]. The higher intense peak at m/z 662 can be assigned to the potassium cryptate [M- Na+K]+ (Figure 3.4).

1 Figure 3.4: H NMR (CDCl 3, 200 MHz) spectrum and ESI-MS spectrum of 15.

To examine the ability of the bromide to undergo coupling reactions, several attempts were made on a small scale to couple the sodium cryptate to either a modified phenylalanine 16 via Sonogashira coupling or to benzoic acid methyl ester 17 via Suzuki coupling (Scheme 3.2). Both approaches were not successful and each trial resulted in recovered starting materials which were confirmed by 1H NMR and ESI-MS.

Results and Discussion

Boc N O N O S Br H O S HN OMe N N Sonogashira coupling N O Boc OMe O Na Br Na O O + X O N N O N S O N S

15 16

COOMe N O S N Suzuki coupling O Na COOCH + O 3 X N O B N S HO OH 17

Scheme 3.2: Attempted functionalization of 15.

However, substitution of the bromide with other functional groups such as carboxylic acid, alkyl borate or alkyl stannane via lithiation would be a potential alternative to the previously attempted procedures.

3.2.2 BINOL-based cryptates

H OH

OH OMe OMe iii OMe i ii OH OMe OMe OMe

H OH

rac O -18 rac-19 rac-20 rac-21

Br Br N O OMe v OH vi O HO Br iv Na OMe OH O HO O Br Br N

rac-22 rac-23 rac-24

Scheme 3.3: Synthesis of [Na ⊂⊂⊂binol.2.2.]Br cryptate 24. i) 4 eq. MeI, 6 eq. K 2CO 3, acetone, o.n. reflux (83%); ii) 4.3 eq. n-BuLi (1.6 M in hexane), 5 eq. TMEDA, diethyl ether, o.n. reflux, DMF, HCl (76%); iii) 6.8 eq. NaBH 4, THF/EtOH, 4 h (83%); iv) 1.1 eq. PBr 3, DCM, o.n. (85%); v) 2.6 eq. BBr 3, DCM, 4 h (91%); vi) 1.0 eq.  Kryptofix 22, 10 eq. Na 2CO 3, acetonitrile, 2 d reflux (86%).

All intermediates from rac-18 to rac-23 are known in the literature and were synthesized according to the published procedure.[72] Starting from the commercially available racemic BINOL rac-18, the two hydroxyl groups were first methylated with methyl iodide under reflux in acetone. Introduction of two aldehyde groups in ortho positions was achieved by

Results and Discussion first ortho lithiation via n-BuLi followed by quenching with dimethylformamide to the dialdehyde rac-20 . Reduction to dialcohol rac-21 with NaBH 4 and then nucleophilic substitution of the hydroxyl groups with bromide using phosphorous tribromide provided the dibromide rac-22 . However, no product was obtained by using pyridine as base and solvent as described in the literature. This may be because of the ability of pyridine to substitute the bromide. Removal of the methoxy groups furnished the diol rac-23 in quantitative yield. All 1H NMR data were in agreement with the reported values. The incorporation of rac-23 into a cryptand structure was accomplished following the same procedure as for the synthesis of 15 yielding the new sodium cryptate rac-24 (Scheme 3.3). The 1H NMR spectrum showed the expected signals for the BINOL moiety and a set of multiplets with low intensity between 2.3 1 and 3.9 ppm corresponding to the CH 2 groups. H NMR spectra were also recorded at elevated temperature (up to 100 °C in d 6-DMSO) resulting in enhancement of the intensity of the multiplets. Moreover, the water signals at 3.3 ppm shifted in upfield direction as the temperature increased and, hence, more signals appeared which lay under the water signal at lower temperature. Four protons were missed in the integration of the signals which are suggested to be overlapped either with the water signal or the solvent signal. However, ESI- MS (+) spectrum showed one peak at m/z 595.15 corresponding to the complex cation [M +].

3.2.3 2,2 ′′′-Biphenol-based cryptates

H OH Br

OH i OMe ii OMe iii OMe iv OMe v OH OMe OMe OMe OMe

H OH Br

O 25 26 28 29 27

Br N O OH vi O Br Na HO OH O HO O Br N

30 31

Scheme 3.4: Synthesis of biphenol sodium cryptate 31. i) 4 eq. MeI, 6 eq. K 2CO 3, acetone, o.n. reflux (94%); ii) 4.3 eq. n-BuLi (1.6 M in hexane), 5 eq. TMEDA, diethyl ether, o.n. reflux, DMF, HCl (34%); iii) 6.8 eq. NaBH 4, THF/EtOH, 4 h. (74%); iv) 1.1 eq. PBr 3, DCM, o.n. (61%); v) 2.6 eq. BBr 3, DCM, 4 h (quantitative); vi)  1.0 eq. Kryptofix 22, 10 eq. Na 2CO 3, acetonitrile, reflux, 2d (46%).

Results and Discussion

Intermediate 29 is known in the literature and can be prepared in two steps from 26 including first methylation at the 3,3´-positions to 32, followed by bromination using N- bromosuccinimide (NBS) (Scheme 3.5 ). [73]

OMe OMe 1.1 n-BuLi NBS OMe OMe OMe OMe 1.2 MeI Br

26 32 29 Scheme 3.5: Reported synthetic route for the preparation of 29

However, because of the success in the preparation of 24 , it was more convenient to synthesize 29 using the same chemistry as for the preparation of 22 (Scheme 3.4).

Subsequently, 29 was treated with BBr 3 to furnish the biphenol derivative 30 in quantitative yield. Formations of all intermediates were confirmed by 1H NMR spectra which were in accordance with those reported in the literature. The incorporation of 30 into a cryptate structure to 31 was accomplished in the first attempts under high dilution conditions, as for the previously described sodium cryptates 15 and 24 . Later, it was found that addition of 30 without high-dilution conditions did not decrease the yield. In both procedures, cryptate 31 1 was obtained in moderate yield (43%). The H NMR spectrum in CD 3OD shows two distinct doublets at 7.0 ppm and 7.1 ppm and a triplet at 6.8 ppm for the protons of aromatic CH. Two broad singlets at 2.7 and 3.5 ppm were observed with integrals of 20 and 8 protons corresponding to the CH 2 groups (Figure 3.5). This illustrates a common feature for this class of cryptates, when the torsional motion around the N,N ′-bridgehead is not slow enough at the NMR time scale. However, this relative fast motion is remarkable, since 31 is expected to be rigid because of the biphenol arm. ESI-MS spectrum showed only one peak at m/z 495.1 corresponding to the sodium complex [Na ⊂biph.2.2] +.

Results and Discussion

1 Figure 3.5: H NMR (CD 3OD, 200 MHz) spectrum of 31.

In order to compare the stability and photophysical properties, the flexible aza-crown ether part in the cryptate 9 was replaced by a more rigid bipyridine macrocycle 10 . Consequently, 33 was synthesized following the same procedure as for the synthesis of the previously described sodium cryptate 31 (Scheme 3.6). The bpy.bpy macrocycle 10 was prepared according to a literature procedure without any modification. [74]

Br N N H N N N Na2CO3 Br OH + N CH CN HO OH 3 NaHO N N N H Br N N N

10 33 30 Scheme 3.6: Synthesis of sodium cryptate 33.

The 1H NMR and ESI-MS spectra confirmed the formation of the complex (Figure 3.6). In comparison to 31 , the 1H NMR shows a set of multiplets between 3.6 and 4.4 ppm corresponding to the CH 2 groups. This is an evidence for slower torsional motion around the N,N ′-bridgehead and, hence, more rigidity of the complex structure than the analogous 31.

Results and Discussion

1 Figure 3.6: H NMR (CDCl 3, 200 MHz) and ESI-MS spectra of 33.

3.2.4 Stability

Cryptate stability is an essential issue for further use, as the complex has to be stable during several synthetic steps as well as purification via HPLC under acidic conditions without being degraded. In this regard, the minimum requirements for lanthanide cryptates should be high kinetic stability in aqueous solution and under rather severely acidic conditions. For stability investigations, the yttrium cryptates were prepared by treatment of the related sodium cryptates with YCl 3 · 6H 2O in refluxing acetonitrile. Yttrium was chosen because of its diamagnetic nature suitable for NMR measurements, if necessary. Unfortunately, it was not clear if the lanthanide ion could be introduced into the cryptate 15 . Therefore, this cryptand could not be further investigated. In contrast, the formation of the yttrium cryptate 34 and 35 was confirmed with ESI-MS spectrometry which revealed the masses corresponding to the single positive charged complexes (Figure 3.7).

Results and Discussion

+ N N O N O N Y O Y O O O N O O N N N

34 35 Figure 3.7: Prepared yttrium cryptates 34 and 35 for stability investigation.

The yttrium cryptate 34 seems to be kinetically unstable. This is reflected by identical chromatograms of the sodium cryptate 31 and the corresponding yttrium cryptate 34 that are recorded under HPLC conditions (CH 3CN/H 2O + 1% TFA). Unfortunately, this observation is true for all investigated cryptates containing the aza crownether macrocycle in this work which limits their use and represents a fundamental problem. However, by replacing the ether macrocycle 9 with the bipyridine macrocycle 10 , 35 showed high kinetic stability with no peak being observed corresponding to the sodium cryptate 33 . This higher stability can be attributed to the rigidity of the biphenol unit and the stiffness of the bipyridine macrocycle 10 . The high stability is comparable to its isostructural cryptate 2 (Figure 3.8) that is known to form very high stable cryptates with europium.[75]

N N N N Na O O N N N N

2 Figure 3.8: The isostructural cryptate 2 to the biphenol cryptates 33.

This evoked the interest in this cryptand and was further investigated. It is established that the kinetic stability of the parent cryptand tris(bipyridine) with the late lanthanides decreased rapidly to be very low for Yb and Lu. Therefore, the stability of the late lanthanides cryptate of 2 was investigated. Figure 3.9 shows the chromatogram of the lutetium cryptate (the smallest lanthanide ion), which reveals only one peak corresponding to the lutetium cryptate. This indicates that this cryptand forms highly kinetically stable complexes with the all lanthanide ions. [42]

Results and Discussion

Figure 3.9: Analytical HPLC chromatogram of lutetium cryptate (1%TFA in H 2O/acetonitrile).

3.2.5 Structural aspects

Single crystals of erbium, ytterbium and lutetium complexes of cryptate 2 suitable for X-ray diffraction were obtained from their methanolic solutions. [42, 76] All structures show the same feature. They reveal C2-symmetric complexes in which the bipyridine N,N ′-dioxide is clearly twisted and, hence, axially chiral. This crystal structure shows a 9-coordinated Lu with a chloride atom completing its coordination sphere (Figure 3.10). The coordinated chloride atom was also observed in the crystal structures of the parent cryptate tris(bipyridine). [77]

Figure 3.10 : Crystal structure of [Lu(cryptand)Cl] 2+ (isotropic refinement). The hydrogen atoms and counterions are omitted for clarity. Color scheme: C − gray, N − blue, O − red, Cl − green. Lu – orange.[42]

Results and Discussion

The lanthanide contraction has been demonstrated by comparison of the distance between the oxygen atoms and the lanthanide ion. This is reflected by the decrease of the Ln-O bond length with the decrease of the atomic radii of the lanthanide ions. The tendency is depicted in figure 3.11.

Figure 3.11: Decrease in the average of Ln-O length from Er 3+ via Yb 3+ to Lu 3+ .

For better comparison, selected distances were listed in table 2 which shows in general the same decrease by moving from erbium via ytterbium to lutetium. However, this decrease varies in its magnitude from atom to others.

Results and Discussion

2+ N N(A) (C) N(B) N Cl Ln O (B) O (A) N N N N (C)

Table2: Average distances [Å] from the lanthanide cations (Er, Yb, Lu) to selected atoms.

Distance from Ln 3+ to Er(III) Yb(III) Lu(III)

Cl 2.709 2.681 2.679

Bpy-N(A) 2.594 2.558 2.542

Bpy-N(B) 2.567 2.544 2.401

bridged-N(C) 2.628 2.623 2.629

N,N ′-Oxide 2.366 2.323 2.320

Results and Discussion

3.3 Functionalization of cryptates

+ + N N N N N N N HO Na O Na HO O N N N N N N N

33 2

Figure 3.12: Promising cryptates for further investigations.

From the previously investigated cryptands, 33 was found to satisfy the basic requirements that the ligand is anionic and exhibits high kinetic stability. In addition, cryptate 2 was also found to be suitable because of the exceptional kinetic stability of its lanthanide cryptates, [42] although it does not possess any anionic charge (Figure 3.12). In addition to these basic requirements, the design can be extended to include additional functionalities through which the cryptate can be used in solid phase synthesis. Two synthetic approaches are depicted in Figure 3.13.

X X NH Approach I Br O(H) • Diastereomeric mixture O(H) + Br NH

X NH Br Approach II O(H) + • Racemic mixture O(H) Br NH

Figure 3.13: Retrosynthesis of the monosubstituted cryptands.

Our strategy involved disconnecting the mono substituted cryptand into two fragments: bipyridine macrocycle and methylene bromide derivative such as for the synthesis of the unsubstituted sodium cryptates.

Results and Discussion

3.3.1 Approach I

The key advantage of this approach is that the substituted macrocycle can be used for the synthesis of both functionalized 33 and 2. However, the resulting functionalized cryptates are expected to be existent as a mixture of diastereomers as a consequence of the axial chirality and the existence of three arms with one arm being unsymmetrical. Following this approach, several functional groups were introduced which cover the most important methods for linking metal complexes to other chemical moieties (Scheme 3.7). The bromide in macrocycle 36 can undergo several coupling reactions including Sonogashira reaction. It is also possible to substitute the bromide with an azide group for click- reactions.[78] Macrocycle 37 contains a carboxylic acid methyl ester which can be reacted directly with amine derivatives [79, 80] or can be saponified and then reacted with amine derivatives. The nitro group in macrocycle 38 can be reduced to the related amine which opens several possibilities such as the conversion to isothiocyanates.[81, 82]

O Br O N N MeO N 2 N NNH NNH NNH

N N N N N N H H H N N N

36 37 38

Scheme 3.7: Structures of the synthesized monosubstituted macrocycles.

The synthesis of the macrocycles follows the same procedure as it is depicted in Scheme 3.8. 6,6 ′-Bis(tosylaminomethyl)-2,2 ′-bipyridine 39 can be synthesized according to the literature procedures.[83, 84]

X X N NHTs Br NNH N N

+ N N N N H N NHTs Br

39 X = Br, -COOMe, NO2 Scheme 3.8: Retrosynthesis of the monosubstituted macrocycles.

Results and Discussion

3.3.1.1 Synthesis of the bromo macrocycle

The synthesis of the bromo macrocycle 36 started with 6,6 ′-dimethyl-2,2 ′-bipyridine 40 which was synthesized following a literature procedure.[85] One bipyridine was then selectively oxidized using 1.0 equivalent of m-CPBA in chloroform. Subsequently, nitration of one pyridine ring to 6,6 ′-dimethyl-4-nitro-2,2 ′-bipyridine N-oxide 42 [86] was achieved by heating 6,6 ′-dimethyl-2,2 ′-bipyridine-N-oxide 41 in a mixture of sulphuric acid and nitric acid. [87] The nitro group was then displaced with a bromide in a nucleophilic substitution with acetyl bromide in glacial acetic acid to give 4-bromo-6,6 ′-dimethyl-2,2 ′-bipyridine-N-oxide 43 .[87] Several attempts to optimize this reaction were not successful and the best yield (39%) was obtained by addition of acetyl bromide at 60 °C to the solution of 42 in glacial acetic acid and then refluxing for 2 h. After the oxidation of the second pyridine ring in 43 with m-CPBA, dioxide 44 was acylated via Boekelheide rearrangement with acetic acid anhydride. Saponification of 45 with NaOH to 46 followed by nucleophilic substitution of the hydroxyl [87] groups with bromide using PBr 3 gave 4-bromo-6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine 47 . Following a procedure for analogous compounds,[34, 88] the synthesis of macrocycle 36 was performed by the reaction of 4-bromo-6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine 47 with 6,6’- bis( o-tosylaminomethyl)-2,2 ′-bipyridine 39 and then deprotection of the tosylate groups with conc. H 2SO 4 (Scheme 3.9).

Results and Discussion

NO2 Br

N N N N i ii iii iv N N O N O N O

40 41 42 43

Br Br Br Br

N N N N v N O N OAc viN OH vii N Br O

44 OAc 45 OH 46 Br 47

Br N H N N viii

N N TsNH H N N

36 N TsNH 39

Scheme 3.9: Synthesis of bromo macrocycle 36. i) 1.0 eq. m-CPBA, CHCl 3 (76%). ii) HNO 3, H 2SO 4, 100 °C, 4 h (58%). iii) acetyl bromide, acetic acid, 100 °C, 2 h (39%). iv) 1.5 eq. m-CPBA, r.t., o.n. (92%). v) acetic anhydride (55%). vi) 2.1 eq. NaOH (aq.) (1M), acetone (57%). vii) 5.0 eq. PBr 3, DMF, r.t., o.v. (59%). viii) (a) 1.0 eq. 39 , DMF, 15 eq. K2CO 3, 50 °C; (b) conc. H 2SO 4, 4 h (64%).

The identity and purity of all compounds was confirmed by 1H NMR and ESI-MS which are in agreement with published data of known compounds. Besides the obvious length of the synthetic route (8 steps), the synthesis was plagued with several low yielding steps. One procedure was attempted that could save four steps and is depicted in scheme 3.10. The idea is based on the successful introduction of four bromides to the dinitro 48 by extending the reaction times to two days.[89, 90] However, by applying these conditions on 50 a mixture of four components was obtained and trying to separate them via column chromatography failed. This is presumably because compound 50 is unsymmetric and one pyridine ring with the nitro group is less reactive than the other ring.

Results and Discussion

NO2 Br

O2N Br N N N O N Br a) O

48 Br 49

NO2 Br

N b) N N O x N Br O

Br 50 47 Scheme 3.10: a) Successful synthesis of 49 from 48. b) unsuccessful synthesis of 47 from 50.

Nevertheless, Mukkala and Kankare [87] reported another route involving a direct bromination of the two methyl groups using NBS. Unfortunately, in our hands this procedure did not work as described and gave a mixture of starting material, mono- and di-brominated compounds.

3.3.1.2 Synthesis of the ester macrocycle

The methyl ester 51 used for the preparation of macrocycle 37 was prepared following a literature procedure. [91] The same protocol as for the synthesis of 44 was applied for the preparation of 6,6 ′-dimethyl-2,2 ′-bipyridine-4-carboxylic acid methyl ester-N,N ′-dioxide 52 .[92] In comparison to the synthesis of dibromide 47 , a different strategy was used for the introduction of the bromomethyl substituent.[93, 94] This strategy based on a modified Boekelheide rearrangement. Trifluoroacetic anhydride was used which leads to a trifluoroacetate-protected hydroxymethyl functionality, an intermediate for the nucleophilic substitution with bromide using anhydrous LiBr in a mixture of dry DMF and dry THF. This reaction allowed the synthesis of bromomethyl bipyridine 53 in one step and good yield (58%). The synthesis of the macrocycle 37 was achieved following the procedure as for the preparation of macrocycle 36 . However, the carboxylic acid macrocycle was obtained instead of the methyl ester which can be attributed to the relatively harsh acidic conditions used for removing the tosylate groups. Attempts to isolate this intermediate failed. Consequently, the solvents were simply removed to dryness and the residue was used crude for the esterification step. The methyl ester macrocycle 37 was obtained and characterized with ESI-MS and 1H NMR spectroscopy (Scheme 3.11).

Results and Discussion

O O OMe MeO O MeO O MeO N H N N

N N N N N i ii iii H N N O N Br N O TsHN 51 52 Br 53 N 37

N TsHN 39

Scheme 3.11: Synthesis of ester macrocycle 37. i) 2.5 eq. m-CPBA, CHCl 3(79%). ii) trifluoroacetic anhydride, DCM, reflux, 1.5 h, 10 eq. LiBr, DMF, r.t., o.n. (58%). iii) (a) 1.0 eq. 39 , DMF, 15 eq. K2CO 3, 50 °C; (b) conc. H2SO 4, 4 h; (c) MeOH, H 2SO 4, reflux, o.n. (52%).

However, purification of the macrocycle via column chromatography was difficult. It was found that the purity of the macrocycle may influence the yield of the next step, namely, the formation of the sodium cryptate. Therefore, several extractions and washing with water and an aqueous solution of sodium chloride improved the purity. The color of the solid is a good indicator for the purity. While a dark orange to brown color is a sign of less purity, a light yellow to beige color indicates a higher purity. The 1H NMR confirmed this observation as it can be seen in figure 3.14. This is also true for the other macrocycles prepared in this thesis.

Results and Discussion

1 Figure 3.14: H NMR (CDCl 3, 200 MHz,) spectra of 37 bevor washing (bottom) and after washing (top).

3.3.1.3 Synthesis of the nitro macrocycle

For the synthesis of nitro macrocycle 38 , the same procedure was used as for the synthesis of 37 . 6,6 ′-Dimethyl-4-nitro-2,2 ′-bipyridine N,N ′-dioxide 35 was synthesized by oxidation of 42 using m-CPBA. As for the preparation of 53 , 6,6 ′-bis(bromomethyl)-4-nitro-2,2 ′-bipyridine 54 was isolated in 55 % yield and further used to obtain the macrocycle 38 as it is depicted in scheme 3.12.

Results and Discussion

O2N NO2 NO NO N 2 2 H N N

N N N N N i ii iii H N O N O N Br N O TsHN 42 50 Br 54 N 38

N TsHN 39

Scheme 3.12: Synthesis of nitro macrocycle 38. i) 1.5 eq. m-CPBA, CHCl 3 (57%). ii) trifluoroacetic anhydride, DCM, reflux, 1.5 h, 10 eq. LiBr, DMF, r.t., o.n. (55%). iii) (a) 1.0 eq. 39 , DMF, 15 eq. K2CO 3, 50 °C; (b) conc. H2SO 4, 4 h (74%).

According to the successful bromination of different monosubstituted bipyridine 50 and 52, the analogous Boekelheide reaction was also applied to prepare the unsubstituted bipyridine 56 from dioxide 55 .[86] This compound is a key intermediate for several important building blocks (Schema 3.13).

N H N N N 1.TFAA N N O N Br N N O 2.LiBr H N 60% 55 Br 56 10

TsHN N

N TsHN 39 Scheme 3.13: New synthetic route of 56; an important intermediate for 10 and 39.

However, it is worthy to mention, that bromination via the procedure that was used for the preparation of 47 gave a white solid, while the new procedure produces the product as intense yellow solid. No changes or shifts in 1H NMR were observed and, hence, it is expected that the isolated yellow solid is the desired product.

Results and Discussion

3.3.1.4 Synthesis of the corresponding monofunctionalized sodium cryptates

Previous studies have shown that a carboxylic acid cryptate can be coupled to amino acids, peptides or proteins. Therefore, construction of substituted cryptates from 37 was first attempted. For the synthesis of methyl ester sodium cryptate 57, compound 58 was prepared from 56 by a slightly modified literature procedure. [35] This procedure required 6 equiv. of m- CPBA and relatively long reaction time (4-5 days). Therefore, other oxidation reagents were tried, which have shown an ability to oxidize N-heterocyclic rings. In this procedure [95] , reaction of 38 with urea hydrogen peroxide (UHP) and trifluoroacetic anhydride in dichloromethane furnished the desired product 39 after one day in moderate yield (50%). The two other isolated compounds are the unreacted 38 and the mono oxide, which can be re- oxidized. Condensation of 57 with methyl ester macrocycle 37 in refluxing acetonitrile in the presence of sodium carbonate afforded the methyl ester cryptate 58 in good yield (58%). The methyl ester cryptate 58 was subjected to saponification with sodium hydroxide in a mixture of MeOH/H 2O to give the carboxylic acid cryptate 59 (Scheme 3.14).

O O O Br MeO N N N Br N N NNH MeO N O N N O N NaOH(aq.) N O Na2CO3 Na O Na O O N O N N N N N N + H CH3CN N N N Br N high-dilution N

57 37 58 59

Scheme 3.14: Synthesis reactions of 58 and 59.

The 1H NMR spectra of 58 and 59 are shown in figure 3.14. In general, cryptates containing bipyridine N,N ′-dioxide are known to be more rigid than those of the non-oxidized parent ligand and, hence, the torsional motions are hindered resulting in non-equivalent CH 2 groups.

Similarly, the CH 2 protons for both 58 and 59 appear as a set of doublets which partly overlap. The formation of cryptate 59 is unambiguously confirmed by the presence of the methyl ester signal appearing at 3.89 ppm. However, the complete disappearance of this signal reveals the formation of 59 (Figure 3.15).

Results and Discussion

1 Figure 3.15: H NMR(CD 3OD, 200 MHz) of methyl ester cryptate 58 (bottom) and carboxylic acid cryptate 59 (top) .

Following the same procedure, the first attempt to obtain the isostructural methyl ester cryptate 60 failed and the analytic data were poorly informative to make any suggestions about the reasons. To avoid all possible problems, the two starting materials were freshly prepared and dried very well under vacuum. In addition, a catalytic amount of sodium iodide was added since an in situ formed alkyl iodide is more reactive than an alkyl bromide towards nucleophilic substitution. Consequently, the desired cryptate 60 was obtained in good yield (42%).

O O O Br MeO N N Br N MeO N NNH MeO N Br N OH N Na HO Na2CO3 NaI, Na2CO3 Na HO N HO X OH + N HO CH3CN N N CH CN N H 3 N N high-dilution Br N high-dilution N

60 30 macro-3 60

Scheme 3.15: Synthesis of methyl ester cryptate 60.

The formation of the expected cryptate was confirmed by 1H NMR spectroscopy with the methoxy signal appearing at 3.94 ppm and by ESI-MS with exclusively one peak at m/z 658.2 corresponding to the sodium cryptate (Figure 3.15). However, it was difficult to assign the

Results and Discussion

CH 2 protons since they appear as broad multiplet signals despite longer measurement time which is quite remarkable since the unsubstituted cryptate 31 showed more defined signals.

1 Figure 3.16: H NMR (CDCl 3, 200 MHz) and ESI-MS of 60.

Hydrolysis of the methyl ester cryptate 60 to carboxylic acid cryptate 61 was accomplished by stirring a solution of aqueous sodium hydroxide and 60 in methanol (Scheme 3.16).

O O N Br N MeO N O N N NaOH(aq.) N HO Na HO Na N HO N HO N N N N

60 61 Scheme 3.16: Saponification of cryptate 60 to carboxylic acid cryptate 61.

1H NMR showed that the methyl ester signal had completely disappeared and the remaining signals were retained. Interestingly, the ESI-MS spectrum in positive mode showed very low peak intensity of the cryptate along with three other species. These could be assigned to [M- H+Na +], [M-2H+2Na +] and [M-3H+3Na +] which reflect the progressive deprotonation of the two hydroxyl groups and the carboxylic acid. No peak corresponding to the starting material was detected.

Results and Discussion

To verify the possibility of the other macrocycle to form the related cryptates, similar procedure was applied to obtain bromo cryptate 62 and nitro cryptate 63 (Scheme 3.17). 1H NMR and ESI-MS confirmed the formation of both cryptates. It is worth to mention that both cryptates are obtained without addition of sodium iodide which was required for the preparation of the methyl ester cryptate 60 .

X Br N X N NNH N Br OH N Na2CO3 Na HO OH + N HO N N CH CN H 3 N Br N high-dilution N

30 X = Br 36 X = Br 62 X = NO 38 2 X = NO2 63 Scheme 3.17: Synthesis of bromo cryptate 62 and nitro cryptate 63 .

The bromide 62 was not further investigated because of the long synthetic route, and overall low yields but still provides an alternative for future works. In contrary, attempts were made to explore the ability of the nitro group to be reduced to the related amine. In the first attempts, hydrogenation with palladium on active carbon was used. The reaction was monitored with ESI-MS and TLC. Interestingly, according to mass spectrometry, three components were identified; the desired product, the hydroxylamine derivative and the unsubstituted cryptate. Further reduction of this mixture failed. By using sodium borohydride with Pd/C as catalyst in methanol, the desired amine cryptate 64 was obtained cleanly without the need for further purification (Scheme 3.18). While the 1H NMR spectrum reveals no change and is almost identical to that of 63 , the reaction progress can be easily monitored by change of color from yellow to colorless. Moreover, the reaction success is indicated by ESI- MS. However, the conditions of this step need to be optimized for future work.

+ + H2N N O2N N N N N Na HO N Na HO NaBH4, Pd/C N HO N HO MeOH N N N N

63 64

Scheme 3.18: Reduction of nitro cryptate 63 to the amine cryptate 64.

Results and Discussion

It is probably also possible to incorporate bipyidine N,N ′-dioxide motif 57 into the cryptate structure by the reaction with macrocycle 36 and 38 . However, the nitro group as functional group would be less useful, since removing of the N,N ′-dioxide could occur upon reduction of the nitro group.

3.3.2 Approach II

Although the approach I was successful and several functional groups could be added to the cryptate structure, approach II offers the possibility to obtain functionalized cryptates in racemic mixtures without the occurrence of diastereomers. Moreover, this strategy would have the advantage for any future work that the functionalized bipyridine and biphenol could be reacted with other macrocycles. This approach consists of two parts.

3.3.2.1 Introduction of a functional group to bipyridine dioxide

Compound 65 was synthesized following the same procedure as for the synthesis of 57 . After stirring overnight of the mixture of 53 , UHP and trifluoroacetic anhydride in dry dichloromethane, the product was purified and isolated in 49% yield (Scheme 3.19). The formation of 65 was confirmed by 1H and 13 C NMR.

O O

MeO Br MeO Br N N UHP, TFAA O O N r.t., overnight N Br Br 49% 53 65 Scheme 3.19: Synthesis of dioxide 65.

The incorporation of the 65 into a cryptate structure was achieved by the reaction with the unsubstituted macrocycle 10 to afford the methyl ester cryptate 66 in 39% yield (Scheme 3.20). All analytical data were similar to that of 58 and confirmed the formation of the cryptate. Treatment of 66 with aqueous sodium hydroxide afforded the carboxylic acid cryptate 67 in very good yield (80%) (Scheme 3.20). This was confirmed by 1H NMR by the disappearance of the ester signal and by the corresponding mass in ESI-MS.

Results and Discussion

O O O Br HO Br N N N N OMe N O N NNH N N N O Na CO O NaOH(aq.) N O + 2 3 Na Na O N O N O N N N N N H CH3CN N N 80% N N Br N high-dilution 39% 65 10 66 67

Scheme 3.20: Approach II for the synthesis of 66 and the related 67.

3.3.2.2 Introduction of a functional group to 2,2 ′′′-biphenol

X Br

OH OH

X = Br, NO2

Figure 3.17: The target structure.

The attempts for the synthesis of monofunctionalized biphenol can be divided into two strategies and will be discussed in the following section.

3.3.2.2.1 Strategy I

In this strategy, the attempts focused on using 2,2′-biphenol as starting material. It is known that monofunctionalized BINOL can be obtained by adding a bulky group to one hydroxyl that deactivates the related ring and enables the selective substitution on the other ring. [96, 97] Accordingly, one equivalent of pivaloyl chloride was reacted with biphenol 25 to furnish mono-pivaloyl derivative 68 in 76% yield. With one of the biphenol rings being deactivated, nitration occurred selectively at the 5-position of the other phenol ring to give 68 in 42% yield. Worthy to mention is that nitration under typical conditions (HNO 3/H 2SO 4) failed and gave a black solid. Therefore, it is important to add diethyl ether as solvent in the reaction. Removal of the pivaloyl group was achieved by basic hydrolysis of 69 to afford 6-nitro-2,2 ′- biphenol 70 in 88% yield (Scheme 3.21).

Results and Discussion

O O

OH i O ii O iii OH OH OH OH OH

O2N O2N 25 68 69 70

Scheme 3.21: Synthesis of the functionalized biphenol 70. i) 1.0 eq. pivaloyl chloride, 3.0 eq. Et 3N, acetonitrile, 4 h (76%); ii) H 2SO 4, HNO 3, diethyl ether, 2 h (42%); iii) 3.5 eq. KOH, THF/H2O, 12 h, o.n. (88%).

According to this procedure, it is also possible to introduce a bromide functional group [96] . Introduction of aldehyde groups to 70 via lithiation was attempted (Scheme 3.22). Unfortunately, the desired product was not obtained and the analytical data were poorly informative to make any suggestions about the isolated compounds.

OH OMe OMe i ii OH OMe X OMe H O N O2N O2N 2 O 70 71 72

Scheme 3.22: Attempted synthesis of 72. i) 4 eq. MeI, 6 eq. K 2CO 3, acetone, o.n. reflux (31%); ii) 4.3 eq. n- BuLi (1.6 M in hexane), 5 eq. TEMDA, diethyl ether, o.n. reflux, DMF, HCl.

Attempts to use the same strategy starting from the 2,2 ′-biphenyl-3,3 ′-dicarbaldehyde 73 yielded a mixture of mono- and dipivalate 74 and 75 , which proved difficult to purify (Scheme 3.23). The existence of these two species was confirmed by 1H NMR and TLC.

O O O O H H H H PivCl, Et N BBr at 0 °C OH 3 OPiv + OPiv OMe 3 OH OPiv OH OMe 4 h at rt MeCN H H H H O O O O 27 73 74 75 Scheme 3.23: Attempted synthesis of monopivalyl from 73.

Despite the unsuccessful synthesis of the target molecule, this strategy features a new way for the synthesis of monosubstituted 2,2 ′-biphenol which has not yet been reported.

Results and Discussion

3.3.2.2.2 Strategy II

This strategy is based on cross coupling reactions between two phenol derivatives, which are the most used route for the synthesis of biphenol derivatives or more general biaryl derivatives.[98] As it is generally known, cross coupling reactions occur between an organometallic compound of the type RM (M = B, Sn, etc.) and organic halides of the type R´X (X = I, Br, etc.). Accordingly, two phenol fragments were designed with additional requirements as illustrated in Figure 3.18: - Both fragments should have a functional group ortho to the methoxy group, which can be later converted to the methylene bromide. - Fragment A is designed to have an additional functional group such as bromide or nitro which should be inert during the next steps.

Fragment A Fragment B

functional group that can be converted to alkyl bromide R2B or R3Sn OMe R1 R2 OMe R R halogen (I, Br) 3 1

R4 functional group that can be converted to alkyl bromide

functional group (NO2, Br, etc) Figure 3.18: The target fragments for the coupling reaction.

The initial attempts were based on salicylaldehyde 76 as starting material because of its low cost (Scheme 3.24). The OH group is very activating towards electrophilic substitution (S EAr) and directs to ortho and para positions, whereas the aldehyde is deactivating and directs to the meta position. Following a literature procedure,[99] nitration is achieved in very short time (~10 min) using fuming nitric acid and acetic acid to furnish 77 in 31% yield and the product was isolated cleanly without any further purification. The bromination of nitro salicylaldehyde 77 yielded the desired product 78 in moderate yield (48%) using N- bromosuccinimide (NBS) in conc. sulphuric acid. The most preferred position for the bromination is C6 due to the combination of the directing effects. The relatively low yield can be attributed to the existence of two withdrawing groups (nitro, aldehyde) which deactivate the ring toward electrophilic substitution. It is worth mentioning that the yield reported in the literature is much higher (84%). [100]

Results and Discussion

OH O OH O OH O OMe O Br Br H H H H i ii iii X

NO2 NO2 NO2 76 77 78 79 Scheme 3.24: Attempted synthesis of a phenol halide derivative 79. i) nitric acid (fuming), acetic acid, 60 °C, 10 min. (31%); ii) 1.2 eq. NBS, H 2SO 4, 60 °C, 2 h (48%); iii) 3.5 eq. KOH, THF/H 2O, 12 h, o.n.

Attempts to methylate the hydroxyl group were not successful and gave only traces of the desired product which was difficult to isolate (Scheme 3.24). Therefore, 5-bromosalicylic acid 80 was used instead as starting material, which is also commercially and cheaply available (Scheme 3.25).

OH O OH O OMe O I I OH OH OMe i ii

Br Br Br 80 81 82 Scheme 3.25: Synthesis of halogen phenol derivative 82. i) 1.0 eq. NIS, DMF, r.t., o.n. (91%); ii) 2.0 eq. Me 2SO 4, 2.5 eq. K 2CO 3, reflux, 4 h (81%).

Consequently, an iodide substituent was introduced at the 6-position via electrophilic substitution using N-iodosuccinimide (NIS). [101] The desired product 81 was isolated in excellent yield (91%) without any further purification. Methylation of the carboxylic acid and hydroxyl group was achieved in one step using dimethyl sulfate to afford the methyl ester 82 in 81% yield. 1H NMR confirmed the formation of the derivative 82 (Scheme 3.25).

OH OMe OMe O Br Br Br Br X i ii H

X= B(OH) 85 83 84 2

X= SnBu3 86

Scheme 3.26: Synthesis of boronic acid 85 and stannane derivatives 86. i) 1.3 eq. MeI, acetone, reflux, o.n. (72%); ii) a) 1.0 eq. n-BuLi (1.6 M in hexane), 1.0 eq. B(OMe) 3 or Bu 3SnCl, -74 °C b) 1.08 equiv. n-BuLi (1.6 M in hexane), DMF, - 74 °C.

Compound 85 was prepared adapting a literature procedure (Scheme 3.26).[102] The dibromide 83 was used as a starting material because of its much lower cost than that used in the adapting literature. The starting material 83 was first methylated via a standard procedure

Results and Discussion using methyl iodide in acetone. These conditions gave the best results over other reagents such as trimethyloxonium tetrafluoroborate or dimethylsulfate. The dibromide 84 was then subjected to a consecutive metal-halogen exchange in a one-pot approach. This involved lithiation with n-BuLi (1.0 equiv.) and then transmetalation with alkylboron reagents. Among several boron reagents, B(OMe) 3 gave the best result. The second lithiation (1.1 equiv.) followed by addition of the dimethylformamide to furnish the aldehyde 85 (Scheme 3.26). It was preferred to introduce the aldehyde because it is expected to be inert towards the coupling reaction and, hence, no further protection steps are needed. The 1H NMR of 85 shows the characteristic signal of the aldehyde proton along with two signals in the aromatic region corresponding to the two aromatic protons. The methoxy and methyl groups appear as two singlets at 3.97 and 2.36 ppm, respectively. No signals of the boronic acid were observed (Figure 3.19). However, the ESI-MS spectrum showed no bromide pattern mass indicating a complete exchange of the two bromides. Since the 1H NMR spectrum showed no additional proton in the aromatic region, it was believed that the isolated compound is the desired product.

1 Figure 3.19: H NMR (CDCl 3, 200 MHz) spectrum of 85.

Similarly, the stannane analogue 86 was prepared using tributyltin chloride (Scheme 3.26). 1H NMR confirmed the formation of the target molecule but there was still some impurity of the stannane reagents even after several runs of column chromatography (Figure 3.20). However, 49

Results and Discussion this problem is common to the preparation of this type of reagents and has been already reported. [103]

1.00 1.01 0.85 3.14 3.11 8.43 11.27 6.58 15.52 11 .0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 ppm 1 Figure 3.20: H NMR (CDCl 3, 200 MHz) spectrum of 86.

Palladium-catalyzed Stille and Suzuki coupling reactions were attempted (Scheme 3.27). For the Suzuki coupling, the iodide 82 was reacted with boronic acid 85 in the presence of

Pd(PPh 3)4 as catalyst and potassium carbonate as a base. The Stille coupling between 82 and

86 was performed using Pd(PPh 3)4 as a catalyst. Unfortunately, both procedures failed to provide the coupled product and considerable amounts of both starting materials remained. This might be due to the fact that the reactants are highly substituted and, hence, too hindered to undergo the coupling reaction. However, when the coupling reaction of 2-hydroxymethyl-

5-tri-n-butylstannylfuran 87 with iodide 82 was tried using Cl 2Pd(PPh 3)2 as a catalyst, the coupled product could be isolated in very good yield (75%) (Scheme 3.27). This demonstrated that the aryl iodide can undergo the coupling reaction when there is a sufficiently reactive arylmetal species.

Results and Discussion

OMe O O OMe H I M OMe H OMe + X OMe

Br OMe M= B(OH) 85 (ii) Br 82 2 O M= SnBu3 86 (iii) OH i Bu3Sn O + 87

OMe

OMe Br O 88 Scheme 3.27: Attempted coupling reactions. i) 5 mmol % (PPh 3)2PdCl 2, PPh 3, toluene. ii) 6 mmol % Pd(PPh 3)4, 2.0 equiv. K2CO 3, toluene, o.n. reflux. iii) 6 mmol % Pd(PPh 3)4, toluene, o.n. reflux.

The last attempted approach is based on the fact that halogenides are different in reactivity toward metal-halogen exchange and toward palladium catalyzed cross coupling reactions.

OH O OH O OMe O Br Br MeI, K CO OH NBS, DMF OH 2 3 OMe

overnight, rt acetone, 24 h reflux Cl Cl 41% Cl 89 90 91

1) n-BuLi, -80 °C, 30 min

2) ClSnBu3, -78 °C, 30 min

Bu OMe O Bu Sn Bu OMe

Cl 92 Scheme 3.28: Synthesis of stannane 92.

Bromination of 89 to 90 occurs selectively ortho to the hydroxyl group v ia a standard procedure with NBS in DMF. [101] After methylation to 91 , the stannane 92 formation was accomplished by a selective lithium-bromide exchange via n-BuLi followed by in situ reaction with tributyltin chloride (Scheme 3.28). 1H NMR and ESI-MS spectra confirmed the

Results and Discussion formation of the desired product. Unfortunately, the Stille coupling reactions between 92 and iodide 82 via a standard procedure was not successful and only the starting materials were isolated (Scheme 3.29). O

OMe O OMe O MeO

I Bu3Sn OMe OMe Pd(PPh3)4 HO Br + X HO Cl

Br Cl MeO 82 92 O Scheme 3.29: Attempted Stille coupling.

In conclusion, two different synthetic strategies starting from either a phenol or a biphenol were pursued, but both turned out not to be successful. Therefore, approach I was found to be more convenient for the functionalization of cryptate 33 . However, from the gained knowledge of the previously discussed approaches, the carboxylic acid cryptates are considered to be the most promising because the most simple and straightforward way is to link an amino acid to the carboxylic acid functionality via peptide bond formation. However, the most used methods for the generation of this bond rely on the initial activation of the carboxylic acid to allow the nucleophilic attack of the primary amine.

3.3.3 Synthesis of lysine cryptate conjugates

Lysine was selected as amino acid for conjugation to the cryptate, due to its two amino groups allowing to use the cryptate conjugate in the solid phase synthesis as a modified amino acid. In the first attempt, an adapted literature procedure by Alpha-Bazin et al . was employed. [104] In this approach, the carboxylic acid of cryptate 59 was activated utilizing EDC/HOSu and then reacted with Fmoc-Lys-OH in DMF. The desired product could be detected in the ESI- MS spectrum along with the starting materials. Isolation of the product employing column chromatography on silica proved unsuccessful. Using HATU as coupling reagent, the desired product could be isolated cleanly after column chromatography in low yield (18%) (Scheme 3.30).

Results and Discussion

O FmocHN O N HATU O N O N N N DMF, overnight N H N + N N Na+ O O Na O O N O NHFmoc N N N N N N HO N NH2 O 59 93

Scheme 3.30: Synthesis of lysine cryptate conjugate 93.

Characterization of 93 with 1H NMR showed a set of undefined signals in both the aromatic and the aliphatic region. This is expected due to the formation of diastereomers. However, the integration of the signals are consistent with the expected number of the protons. ESI-MS spectrum displays one major peak corresponding to the cryptate 93 ( m/z 1023.5). No peak corresponding to the sodium cryptate 59 was observed, which is an additional evidence for the purity of the isolated product (Figure 3.21).

Figure 3.21 : ESI-MS (+) of 93.

Results and Discussion

To test the stability of the cryptate, the europium complex cryptate of the lysine conjugate 93 was synthesized by the reaction of EuCl 3·6H 2O and 93 in refluxing acetonitrile. Europium was chosen because europium complexes of this type of cryptate are known to be highly luminescent. [75] In accordance, the europium cryptate of 93 is also highly luminescent and showed the characteristic red light emission upon UV irradiation with a standard laboratory UV lamp ( λ = 366 nm). This red emission was not diminished even after storage of the cryptate in TFA for more than 10 months which indicates high kinetic stability. In addition, the steady state emission spectrum shows the corresponding emission bands for the transitions 5 7 D0→→→ F0,1,2,3,4 (Figure 3.22).

Figure 3.22: Steady state emission spectrum of europium cryptate of 93 in H 2O ( λexc = 315 nm). * Second order excitation peak.

According to the previous success and to verify the ability of 61 to couple with the Fmoc- lysine-OH, a test reaction was carried out following the same procedure (Scheme 3.31).

O NHFmoc O N HATU O N O N N N DMF, over night H N + N + HO O Na HO Na HO N HO NHFmoc N N N N HO N NH2 O 61 94

Scheme 3.31: Attempted introduction of Fmoc-Lysine to cryptate 61.

Results and Discussion

The product could not be purely isolated but the mass spectrum confirmed the formation of the product (Figure 3.23). Even after the column chromatography, a mixture of 61 and 94 was obtained. 1H NMR was poorly informative to make any suggestion about the ratio 61 : 94 .

Figure 3.23: ESI-MS (+) spectrum of 94.

Despite this initial success, the reaction was not easy to reproduce. Therefore, the proper reagents and conditions for this step need to be optimized. For the ease of synthesis, 59 was used for the investigation and attempted optimization of this reaction. The several conditions and reagents were attempted which can be divided into two groups: 1) Without base: This condition has the advantage that one could isolate the product but the yield was still very low even after extending the reaction time to 2 days. 2) With base: Several conditions with two different bases DIPEA or triethylamine have been tried and no better results were obtained by adding base to the reaction mixture. Furthermore , the separation of the product from the reaction mixture has become more laborious. In the last attempt, it was thought that the free carboxylic acid of the lysine could be inconvenient for the reaction, especially, if the carboxylic acid of the cryptate did not react completely with HATU. In this case, the excess of HATU would react with the carboxylic acid of lysine and lead to the coupling between lysine itself. To test this possibility, Fmoc- Lys-OMe was used and the same procedure with HATU was applied. No improvement was obtained and the product still could not be isolated. Obviously, despite the seemingly

Results and Discussion straightforward reaction, there is a need for a more systematic investigation of the reasons why this reaction is not very efficient so far.

3.4 Photophysical properties of the cryptates

One of the very important processes having influence on the luminescence of visible emissive lanthanide ions is the intramolecular energy transfer from the ligand to the lanthanide ions. [105] It is generally accepted that this energy transfer most often occurs from the lowest triplet state of the ligand to the emitting levels of the Ln(III). Therefore, one requirement of the sensitizer to obtain high luminescence intensities is that it has a sufficiently high triplet state. It is generally suggested that the triplet level of the ligand should be at least 2000 cm -1 higher than the emissive states of Eu 3+ and Tb 3+ in order to avoid thermally activated back energy transfer. [106] To determine the triplet states, gadolinium or yttrium can be used. This is due to electronic energy levels that are too high in energy than any useful aromatic chromophore (Gd) or to the absence of f electrons (Y). However, because of our main interest in highly emissive lanthanides (Tb, Eu), gadolinium, the closer lanthanide to both, was used. Consequently, Gd- cryptates were prepared by the reaction of GdCl 3 · 6H 2O and sodium cryptates in acetonitrile or methanol in the presence of triethylamine as base. All other lanthanides cryptates were prepared in the same way (Figure 3.24). ESI-MS confirmed the formation of the all investigated lanthanide cryptates, which appear as single positively charged complexes. Emission spectra of 95a , 96b , and 97a were recorded at 77 K in a mixture of MeOH/EtOH 1:1 and show exclusively the ligand-centered emission. Measurements at low temperature are performed due to the fact that the efficiency of vibrational deactivation by oscillators decrease and hence, the phosphorescence of the ligand increases. [107]

+ + + N N N O O N O O N Ln O Ln O Ln O O O O O N O O O N N N N

Ln = Gd 95a Ln = Gd 96a Ln = Gd 97a

= Eu 95b = Tb 96c = Eu 97b

= Tb 97c Figure 3.24: The investigated lanthanide cryptates based on BINOL and biphenol.

Results and Discussion

The triplet state of 95a is determined to be 20 040 cm -1 (499 nm), significantly above the 5 -1 [108] -1 emitting D0 level of europium (17 200 cm ) but is about 500 cm below the Tb emissive 5 -1 [109] state D4 (20 500 cm ). Therefore, this cryptand is not expected to sensitize Tb(III) emission. By moving from the BINOL cryptate 95a to biphenol 96a the triplet state energy is increased by around 2000 cm -1 and lies at 22 321 cm -1 (443 nm). This triplet state is therefore higher in energy than the emissive states of europium and terbium. Replacing of the ether macrocycle with a bipyridine macrocyle results in a higher triplet state at 22 560 cm -1 which is slightly shifted to shorter wavelength. According to these results, several lanthanide cryptates were prepared following the procedure used for the preparation of Gd-cryptates. Steady state spectra of 95b in D 2O and

H2O show very low intensely emission corresponding to the metal-centered luminescence and strong ligand fluorescence. Parker et. al. reported similar weak luminescence of an europium complex incorporating naphthyl as antenna. [110] The feature of the emission spectrum of 96c indicates that Tb 3+ is indeed sensitized, although 5 7 the intensity is relatively low (Figure 3.25). The transitions D4 →→→ F6,5,4,3 are observed with 5 7 D4 →→→ F5 being the most intense. Remarkably, the spectrum shows high intense fluorescence corresponding to the ligand emission which can be attributed to either insufficient energy transfer from the triplet state to the excited state of Tb 3+ or due to back energy transfer from the metal to the ligand.

Figure 3.25: Steady state emission spectrum of 96c in D 2O ( λexc = 320 nm).

Results and Discussion

To compare the previous results with the cryptate 33 , steady state emission spectra of 97b and 3+ 3+ 97c were recorded in H2O. Both metals (Eu and Tb ) appeared to be sensitized and showed the characteristic emission peaks. No improvement in luminescence intensity was observed for the 97c comparable to 96c, despite the completely absence of any ligand-centered fluorescence. For 97b , higher intensity was observed than for 95b, which can be attributed due to its higher triplet state (Figure 3.26).

Figure 3.26: Steady state emission spectrum of 97b in H 2O ( λexc = 315 nm). * second order excitation peak.

No further spectroscopic investigations were carried out for the previous lanthanide cryptates, since they showed no special luminescence properties over known lanthanide cryptates. The photophysical properties of cryptate 2 are known in literature. This cryptand exhibits a relatively low triplet state at ca. 20500 cm -1. Accordingly, it is expected that this cryptand can sensitize lanthanide ions such as europium and samarium but its triplet energy level is not sufficiently high for other lanthanide ions such as terbium. Indeed, the corresponding [75] europium cryptate exhibits relatively strong emission (φ = 0.15% in H 2O). To verify how the addition of functional group influences the energy of its triplet state, yttrium complexes of the methyl ester cryptates were synthesized (Figure 3.27). 1H NMR and ESI-MS spectra confirmed the formation of the complexes.

Results and Discussion

3+ O 3+ O 3+ N N N OMe N MeO N N N N N N O N N O Y Y O Y N O O N O N N N N N N N N N N

98 99 100 Figure 3.27: The investigated yttrium cryptates 98 , 99 and 100 .

Emission spectra of the ytterium cryptates were recorded at 77 K in a mixture of MeOH/EtOH 1:1. The spectra display the same features and show non-structured, broad emission (Figure 3.28). Surprisingly, these measurements show that the position of the methyl ester can influence the energy of the triplet state. Whereas no change in the emission maximum of 98 was observed, the existence of the methyl ester group on the bipyridine oxide units shifts the emission maximum towards lower energy which limits its use for sensitization of lanthanide ions with higher excited energy levels such as terbium. This observation suggests that the addition of functional groups to the macrocycle 98 is preferred for the sensitization of lanthanide ions such as terbium, due to its higher triplet energy level.

Figure 3.28: Low temperature (77 K) steady state emission spectra of 98 , 99 , and 100 ( λexc = 304 nm, MeOH/EtOH, 1:1, v/v).

Results and Discussion

3.5 Influence of the number of bipyridine on the photophysical properties of bpy-based cryptates:

Lanthanide cryptates based on bipyridine units were among the first cryptates that have been well investigated. The key structure of this research field is the parent cryptand tris(bipyridine) 103 which was reported in 1987. [33] In the initial reports, Lehn and coworkers synthesized and studied the luminescence ability of terbium(III) and europium(III) cryptates with one 2,2 ′-bipyridine unit 101 and a complementary non-photoactive aza crownether moiety, as well as the corresponding tris(2,2’-bipyridine) species 103 (Figure 3.29). Whereas both lanthanide cryptates exhibit high luminescence intensities, there are significant differences in their luminescence efficiencies. To our knowledge, there are no further studies about this behavior and only 103 was the subject for more investigations, presumably due to its higher kinetic stability in biological media compared to 101 . In order to gain more information about how a varying number of bipyridine moieties influences the photophysical properties of the respective cryptates (Figure 3.29), systematic investigations were carried out. These studies involve the synthesis of l02a and 102b , which completes the set of bipyridine based cryptates and investigations of the photophysical properties of the europium complexes including triplet state, lifetime and quantum yield determinations .

3+ 3+ 3+ N N N O N N O N O N N N Ln Ln Ln N O N N N N N O N O N N

little investigated unknown well investigated

Ln = Gd 101a Ln = Gd 102a Ln = Gd 103a = Eu 101b = Eu 102b = Eu 103b

Figure 3.29: Investigated 2,2 ′-bipyridine-based lanthanoid cryptates.

3.5.1 Synthesis of the sodium and lanthanide cryptates

Cryptates 101 and 103 were synthesised according to the literature procedures without any modification.[33, 34] However, the synthesis of 101 starting form the commercially available aza-crownether 9 and 6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine 56 [111] was reported without synthetic details (Scheme 3.32).

Results and Discussion

N Br N H O N CH CN, Na CO O O 3 2 3 O N + Na Br 29% O O O N N H O N N Br

9 56 101

LnCl3 * 6 H2O

CH3CN

N O O N Ln (Cl) O N 3 O N

Ln = Gd 101a = Eu 101b Scheme 3.32: Synthesis of the lanthanoid cryptates 101 .

In the first attempt for the synthesis of the sodium cryptate 102 , a reaction of the bis(bipyridine) macrocycle 10 [74] with the triethylene glycol derivative 104[112] was attempted under standard high-dilution conditions (Scheme 3.33). Unfortunately, this attempt failed and no traces of the product could be observed.

N N I N H N N N O CH3CN, Na2CO3 O Na I + X N N N N O O N H N I

10 104 102 Scheme 3.33: Attempted synthesis of the sodium cryptate 102 .

However, other attempts using the novel macrocycle 108 proved to be successful. This macrocycle was synthesized starting from 6,6 ′-bis(hydroxymethyl)-2,2 ′-bipyridine 105 .[86] Swern oxidation [113] of 105 resulted in the formation of the dicarbaldehyde 106. The analytical data were in agreement with previous reports using other procedures. [114, 115]

Reductive amination of 106 with 107 using MgCl 2 and NaBH 4 as reducing agent afforded 108 in 93% yield. In the final step, the synthesis of 102 was completed by the reaction of 6,6 ′- bis(bromomethyl)-2,2 ′-bipyridine 56 [111] with 108 to give the sodium cryptate in low yields (17%) (Scheme 3.34).

Results and Discussion

NH2 O

1. MgCl , O 2 O OH H NH2 N H N N 107 N O (COCl)2, DMSO

N NEt3, CH2Cl2 2. NaBH4, MeOH N O N H OH 57% H 93% (2 steps) N

O 108 105 106

Br N

CH3CN, Na2CO3 N 17% Br

N N N N N LnCl3 * 6 H2O N O O Na Ln Cl LnCl Br N 3 3 solv. N N CH3CN N O O N N

102 Ln = Gd 102a = Eu 102b Scheme 3.34: Synthesis of the lanthanoid cryptates 102 .

The lanthanide cryptates were all obtained by overnight reactions of the lanthanide chloride with the respective sodium cryptate in refluxing acetonitrile. All complexes are soluble in aqueous media and are highly air- and moisture stable. The elemental analyses of the new cryptates 102a , 102b showed, surprisingly, that these cryptates have the composition

[Ln(cryptand)Cl 3] · LnCl 5 · solvents. However, the presence of the “free” lanthanide cations does not contribute to the luminescence measurements, since they do not possess antenna moieties for the sensitization of the lanthanide ions. Furthermore, the use of water (or D 2O) provides efficient solvent separation between different complex species (cryptate and free lanthanides) and hence, prevents any possible interaction that could distort the measurements.

Results and Discussion

3.5.2 Triplet state determinations

To determine the energy of the triplet states ( 3ππ *), the phosphorescence spectra of the respective gadolinium cryptates 101a and 102a were measured at 77 K in a mixture of MeOH and EtOH (v/v, 1:1). The triplet states were calculated from the shortest wavelength phosphorescence bands. The multiple peaks were fitted with Gauss functions to give triplet levels of 22 243 cm -1 for 101a and 22 234 cm -1 for 102a (Figure 7.1, 7.2, 7.3 Appendix). Remarkably, the energies of the triplet states just differ in 5 cm -1 and are thus about 600 cm -1 above the triplet level energies of the cryptand 103a (21 600 cm -1).[116] However, the triplet state of 103a was in accordance with the literature value. From the point of view of these 5 triplet energies, all cryptands are expected to sensitize Eu(III), since its emissive level D0 (17 200 cm -1) lies sufficiently below the triplet energies of the cryptands. The fluorescent transitions at 77 K from the first excited singlet state S 1 to the ground state S 0 (around 29 000 cm -1) shows an interesting trend (Figure 3.30). With increasing number of bipyridine units (101a via 102a to 103a ), the intensity of this band steadily decreases in comparison to the ligand phosphorescence. This indicates an enhancement of intersystem crossing (ISC) (S 1→

T1) in the same direction (Figure 3.30).

Figure 3.30: Low temperature (77 K) steady state emission spectra of 101a , 102a , and 103a ( λexc = 304 nm, MeOH/EtOH, 1:1, v/v).

Results and Discussion

3.5.3 Absorption and emission spectra

Figure 3.31: Absorption spectra of 101b, 102b and 103b in Tris buffer at pH 6.8.

The absorption maxima of the europium cryptates 101b and 102b are very close with 309 nm and 310 nm, respectively. While 101b displays a very broad absorption band, the 102a spectrum shows a narrow maximum. By increasing the number of bipyridines, the absorption maximum of 103b shifts to shorter wavelength at 304 nm (Figure 3.31). This value is in agreement with previously reported data. [3]

Results and Discussion

S1 25 7D

4 ISC 25 2 ET

) T 2 -1 20 cm 1 3 0 15 Energy (10

10 581 nm 581 703 nm 703 nm 652 nm 614 nm 595

5 7F 4 3 2 S0 1 0 0 Ligand Eu(III)

Figure 3.32: Left : Steady state emission spectra of the europium cryptates 101b , 102b and 103b (λexc = 313 nm, tris buffer, pH 6.8). Right : The possible emission mechanism for the Eu(III) cryptate. ISC: intersystem crossing. ET: Intramolecular energy transfer, dashed arrow: non-radiative transition.

The steady state emission spectra were recorded at room temperature with an excitation wavelength of 313 nm and show the corresponding metal-centered luminescence of Eu 3+ 5 7 ( D0→ FJ). They highlight a number of interesting points. Firstly, the hypersensitive transition 5 7 5 7 D0→ F2 shows the highest intensity and hence, more intense than D0→ F1 indicating that the electric field experienced by Eu 3+ is of relatively low symmetry. Moreover, each emission 5 7 band of D0→ F0 appears as a single peak indicating the presence of one single species. In addition, the relative intensity of this transition decreases gradually from 103b via 102b to 101b indicating the decrease of symmetry in the same direction (Figure 3.32).

3.5.4 Determination of the quantum yields and lifetimes

The efficiency of energy transfer or emissive processes is usually expressed in terms of their quantum yields. In the case of lanthanide emission, the quantum yield is defined as the ratio of the number of photons emitted through lanthanide luminescence to the number absorbed by the sample. For the determination of the quantum yields, absorption and emission spectra for solutions with different concentrations of the europium cryptates were recorded in water. The peaks of the corresponding emission spectra (λexc = 313 nm) were integrated and plotted against the absorption. Employing quinine in sulphuric acid as reference ( φ = 54.6%) [117] and taking into account the refraction index of water (1.33), it was possible to calculate the

Results and Discussion quantum yields. Due to the large uncertainty of this determination, the measurements and calculation were repeated three times. The calculated quantum yields for the Eu cryptates varied significantly among the cryptates. The quantum yield of 101b was determined to be 5.2% and thus, almost twice as high as for 102b and 103b (2.4% and 2.0%, respectively). These results showed an increasing of the quantum yields as the number of bipyridine unit decreases (Table 3).

Table 3. Luminescence data for the lanthanoid complexes 101b , 102b , and 103b in H 2O and D 2O.

b Complex λabs q τ Eu τ τ τ Eu H2O Φ η H2O D2O rad Φ = L sens [nm] Eu [ms] [ms] [ms] τ rad 101b 311 0.39 1.3 1.9 6.2 d 0.063 0.052 0.83 102b 309 0.34 1.1 2.1 6.3 d 0.054 0.024 0.44 103b 304 0.34 a 1.7 a 2.5 8.1 c,d 0.042 0.020 a 0.48 a b [107] c [118] d 3 See ref. 106; q = number of inner-sphere water molecules, see ref. , See ref. ; Calculated using the equation 1/ τrad = A MD,0 ⋅ n ⋅ [119] (I tot / I MD ), see ref.

Lifetime measurements were done in H 2O and D 2O at room temperature. All complexes showed single exponential decays with values similar to those reported for 101b and 103b . However, the lifetime decreases with increasing number of bpy arms. In general, the excited states of europium are particularly sensitive to quenching by vibrational oscillators. The extent to which they are quenched is different in H2O and D 2O. This difference has been used to derive expressions that allow determinations of the number of water molecules that are directly coordinated to the lanthanide center. Practically, this is achieved through a comparison of the rates of depopulation of the lanthanide excited state in both H 2O and D 2O. The appropriate expression for europium is

qEu = 1.2[k H2O – k D2O - 0.25] (1) where 0.25 refers to quenching by second sphere water molecules.[107] 103b was found to be less shielded compared to 101b and 102b (Table 3: 1.9/2.1 vs 2.5). The higher q value might be the result of the rather stiff bipyridine arms comparable to the flexible ethylene arms providing more space in the first coordination sphere of the europium ion for more bound water molecules. Europium represents a special case among lanthanide ions and, hence further investigations are required in order to make meaningful conclusions. According to the Judd-Ofelt theory, the 5 7 radiative lifetime τrad can be determined exploiting the fact that the transition D0→ F1 is a magnetic dipole in nature, which results in it being unaffected by the surrounding ions. [119]

Results and Discussion

Consequently, its emission can be used as a reference with the intensity of other emission bands compared to it. This approach shows much higher τrad ranging form 6.2 to 8.1 ms for

101b-103b . However, the evaluation of τrad allows the determination of the intrinsic quantum

Eu yield Φ Eu using the equation (2), which reflects the quantum yield of the metal-centered emission upon direct excitation into the 4 f level.

Eu τ obs Φ Eu = (2) τ rad The calculated Eu shows the same trend with increasing values from 101b (6.3%) via 102b ΦEu (5.4%) to 103b (4.2%). For the determination of the overall sensitization efficiency, the

Ln combination of the measured absolute quantum yields Φ L and the intrinsic quantum yields

Ln Φ Ln is used in equation (3):

Eu Φ L η sens = Eu (3) Φ Eu

Accordingly, significant differences in sensitization efficiencies were obtained with 101b (83%) via 102b (44%) to 103b (48%). The result suggests that intersystem crossing (ISC) efficiencies increase with a decreasing number of bipyridine rings. Figure 3.33 summarizes the important trends that can be concluded from the photophysical studies. Whereas the energy of the first excited singlet state S 1 and the number of bound solvent molecules increase by increasing the number of the bipyridine units, the triplet energy levels as well as the overall quantum yields decrease. For the latter parameter, the cryptates 101b is approximately twice as emissive as 102b and 103b , the latter two being very similar.

In addition, the sensitization efficiencies ηsens declines with the increasing number of bipyridine units. However, the radiative lifetimes and the intrinsic quantum yields are similar for all three europium cryptates.

Figure 3.33: Summary of the observed trends in the photophysical properties.

Results and Discussion

3.6 A new kind of chiral cryptate

Only very few works about chiral cryptates can be found in the literature. The most used method to obtain a chiral cryptand is based on the introduction of chiral units such as binaphthyl, which is axially chiral and is commercially available in both aR and aS enantiomers.[120, 121] Another used strategy relies on the existence of stereogenic centers in the cryptand structure. [122, 123] In addition, a cryptand can be chiral by virtue of a helical structure. For example, the di-protonated form [2.2.2 ⊂2H +] of cryptand [2.2.2] adopts the conformation in-in and is chiral as a result of the twisting of the bridging chains. [124] During this work, a new kind of chirality was observed as it is discussed in the last chapters. This chirality emerges from the incorporation of three different arms that exclude the existence of any symmetry in the molecule. However, these cryptates are present as a diastereomeric mixture due to the axial chirality of the biphenol or bpy-N,N ′-dioxide units. To present this new unusual of chirality, novel cryptates were synthesized (Figure 3.34). For the design of such a cryptate, two requirements have to be fulfilled: 1) incorporation of three different arms and 2) the existence of one arm that must be unsymmetric. Figure 3.34 shows two designed cryptates that fulfill the above mentioned requirements. It is worthy to mention that the resulting stereogenic element is configuration stable in comparison to other chiralites such as helical chirality in the previous reported example of [2.2.2 ⊂2H +].

+ + N N N O O N O N Na Na N O O O N O N

109 110

Figure 3.34 : Designed sodium cryptands 109 and 110 with unusual chirality.

Results and Discussion

3.6.1 Synthesis of the cryptates

X Cl2Pd(PPh3)2, PPh3 Br O + Bu3Sn O X O N Si toluene N O Si X = OTBS 112 111 OH 113 X = OTBS 114 OH 115

THF/AcOH/H2O PBr3, CH2Cl2 O N O N OH Br Br 116 HO 117

Scheme 3.35: Synthesis of intermediate 117.

The synthesis of the intermediate 117 relied on the Pd-catalyzed cross coupling reaction between the corresponding furane and pyridine derivatives (Scheme 3.35). 2-Bromo-6- hydroxymethylpyridine was synthesized according to a literature procedure. [125] Introduction of the protective group TBS to the hydroxyl group was achieved using TBS-Cl (tributylsilane chloride) to afford 111 in 91% yield. The analytical data of 111 confirmed its formation and were in agreement with the reported data using other procedures.[126, 127] The furane stannane derivative 112 was prepared according to a literature procedure.[128] Stannane 112 was reacted with 111 in the presence of 5 mmol% Cl 2Pd(PPh 3)2 and 10 mmol% PPh 3 in toluene. The desired coupling product 114 was obtained in low yields (29%). Yellow needles could be obtained as the reaction mixture was cooled down. X-ray analysis revealed a dinculear palladium complex where bridging units are two pyridyl derivatives 111 (Figure 3.35, Table 4 Appendix). Each palladium assumes a square-planar configuration with the bromide and the

Cpy being trans to each other as it is expected from the oxidative addition reaction. The coordination sphere is completed with a triphenyl phosphine for each Pd atom. However, similar dinuclear Pd-complexes were reported which isolated from similar coupling reactions catalyst by palladium complexes.[129]

Results and Discussion

Figure 3.35: Crystal structure of [(PPh 3)PdBr(py-TBS)]2. The hydrogen atoms are omitted for clarity. Color scheme: C − gray, N − blue, O − red, Pd −green, P − orange, Br – purple, Si – violet.

Attempts to optimize the reaction by either utilization of other palladium catalyst or by modification of the solvent, reaction time and temperature failed. However, by using furane stannane derivative 113[130] with an unprotected hydroxyl group, the corresponding coupling product 115 was isolated in higher yield (49%). In addition, synthesis and purification of 113 is more accessible, whereas for the preparation of 112 an additional protection step is required and the purification includes distillation at very high temperature and vacuum. Therefore, the unprotected furane 113 was preferred for the coupling reaction. Treatment of protected alcohol 114 and 115 with a mixture of AcOH/H 2O/THF led to the desired dialcohol 116.

Nucleophilic substitution of the alcohol to the dibromide 117 was accomplished using PBr 3 in dichloromethane. For this step, we adopted the synthetic procedure of biphenol dibromide 30 . Other attempts to activate the hydroxyl groups either by the reaction with mesyl chloride or by bromination with CBr 4 were not successful.

Results and Discussion

N O Br Na CO O N 2 3 O Na O HN 117 + CH3CN, reflux O O NH O N

118 109

N N H N Br N O Na2CO3 O N Na 117 + N N O CH3CN, reflux O H O N N

108 110

Scheme 3.36: Incorporation of 117 into cryptate structures.

The dibromide 117 was incorporated into two different macrocycles 118 and 108 (Scheme 3.36). Whereas 118 is commercially available, 108 was synthesized according to the procedure described in scheme 3.34. The formation of the corresponding sodium cryptates 109 and 110 was confirmed by 1H, 13 C NMR and ESI-MS spectroscopy. 1H NMR spectra of both cryptates showed almost the same signal distribution. Whereas the aromatic protons could be easily identified, the protons of the CH 2 groups appeared as a set of multiplets. However, 13 C NMR spectra of both cryptates showed a signal for each single carbon, which can be attributed to the fact that they are completely non-equivalent (Figure 3.36).

Results and Discussion

157.35 151.94 150.67 147.81 137.79 121.15 116.71 109.84 109.75 69.56 69.48 67.46 67.42 67.04 66.82 58.74 54.12 53.88 52.25 52.11 50.98 50.12

O O + N Na

O O N

155 145 135 125 115 105 95 90 85 80 75 70 65 60 55 50 45 40 ppm 13 Figure 3.36: C NMR (CDCl 3, 50 MHz) of 109.

Summary

4 Summary

The main aim of this work was the synthesis of lanthanide cryptates that can be used as building blocks in solid phase peptide synthesis. The latter is a promising method for the construction of multinuclear lanthanide complexes, which combine the unique physical properties of several lanthanide ions. This requires lanthanide complexes, which are, on the one hand, stable under relatively acidic conditions and, on the other hand, provide the necessary functionalization. Another goal was the synthesis of anionic ligands, which can reduce the overall charge of the lanthanide complexes and consequently minimize the repulsion interaction between them. For both synthetic strategies, it was taken into account that the cryptates should contain a chromophore to sensitize lanthanide emission. The starting point for the first part was the synthesis of several sodium cryptates and their characterization.

N O S N N O O Na Br O HO O Na N O HO O N S O N

15 BINOL = 24 Biphenol = 31 Figure 4.1: Investigated anionic cryptates.

The depicted cryptates in figure 4.1 are based on the commercially available aza crownether 9. Three different units, which were thought to provide anionic charges and also a chromophore, were introduced to bridge this macrocycle. Formation of lanthanide cryptates of 15 could not be confirmed by ESI-MS. Therefore, this cryptand was considered to be not suitable for this work and hence, were not studied further. In contrast, cryptates 24 and 31 indeed formed complexes with lanthanide ions with a reduced charge (1+) which was confirmed by ESI-MS. They both exhibit an axial chirality which emerges from the BINOL and biphenol units. However, both cryptates were synthesized in racemic mixtures. The triplet energy levels of both cryptands were determined using the corresponding gadolinium cryptates. While the biphenol cryptate exhibits a triplet energy level sufficiently high for sensitization of Tb(III) and Eu(III), the triplet energy of the BINOL

Summary cryptand is too low to sensitize emission from terbium. Unfortunately, all lanthanides cryptates containing the macrocycle 9 showed low kinetic stabilities under acidic conditions. This observation was true for all lanthanide cryptates containing macrocycle 9.

N N N N N N N Na O Na HO O N HO N N N N N N

2 33 Figure 4.2: Promising cryptates with high kinetic stabilities.

To improve the stability, the more flexible macrocycle 9 was replaced with the rigid bpy.bpy macrocycle 10 . Therefore, sodium cryptate 33 was synthesized and, as intended, its lanthanide cryptates showed high kinetic stability under acidic conditions. These results were comparable to those for the isostructural cryptate 2 that was also found to form high kinetically stable complexes with all lanthanides. Moreover, cryptand 33 exhibits a higher triplet energy and consequently, sensitizes emission of both Tb(III) and Eu(III). With these two stable cryptates in hand (Figure 4.2), which both possess promising photophysical properties, further functionalization was performed. Two approaches were attempted by introduction of a functional group either to the bipyridine macrocycle 10 or to the respective bridging moieties (Figure 4.3).

X X N Approach I Br H N N O(H) O(H) + N N Br H N

X = Br, NO2, COOMe

X N Br H Approach II N N O(H) + O(H) N N H Br N Figure 4.3: Retro synthesis of the mono substituted Cryptands.

Summary

For approach I, a bromide, a nitro and a carboxylic acid methyl ester group were introduced to the macrocyle 10 . The corresponding sodium cryptates were synthesized by addition of either a biphenol or bipyridine N,N ′-oxide (Figure 4.4). The cryptates were obtained in diastereomeric mixtures due to the axial chirality of the bridging moieties. In addition the existence of three different arms with one being unsymmetrical, which cause an unusual chirality of the whole molecule. Although the introduction of different functional groups to the cryptates following approach I was found to be synthetically accessible, approach II offered the possibility to circumvent the formation of diastereomeres.

X N X N N N N N N Na O Na HO O N HO N N N N N N

X = -COOMe 60 X = -COOMe 58 = Br 62 = NO2 63 Figure 4.4: Funcionalized cryptate based on biphenol(right) and biypridine dioxide (left).

For approach II, synthetic efforts started with the application of two different strategies to obtain a functionalized biphenol moiety. However, functionalization of phenol derivatives or directly of the 2,2 ′-biphenol remained unsuccessful. In contrast, introduction of the carboxylic acid methyl ester to bipyridine N,N ′-dioxide could be obtained in satisfactory yield and purity. It was then successfully reacted with the bipyridine macrocyle 10 to afford the corresponding functionalized cryptate 66 (Figure 4.5). The latter was obtained as racemic mixture due to the axial chirality of the bipyridine N,N ′-dioxide. The triplet energy level of this compound was shifted slightly towards low energies which is expected to decrease the ability of this cryptand to sensitize Tb(III).

N N OMe N N Na O O N N N N

66 Figure 4.5: Methyl ester functionalized cryptate 66 .

Summary

All carboxylic acid methyl ester functionalized cryptates were successfully saponified to the corresponding carboxylic acids, which were coupled to Fmoc-lysine-OH in solution (Figure 4.6). The coupling product 93 was isolated and characterized with NMR and ESI-MS. Remarkably, the europium complex of 93 proved to be stable even under harsh acidic conditions. In contrast, cryptate 94 could be observed in ESI-MS but isolation of the pure compound was not possible despite several attempts to optimize this reaction.

O NHFmoc O NHFmoc N O N O N N N N H H N N N HO O Na O O Na O N HO N N N N N N

94 93 Figure 4.6: The prepared building blocks for solid phase synthesis.

In summary, building blocks for solid phase peptide synthesis were prepared from stable cryptates based on biphenol and bipyridine-N,N ′-dioxide. Therefore, different synthetic strategies for the incorporation of functional groups to cryptates were developed, and the relation between structure and photopysical properties were revealed. While coupling of these cryptates to an amino acid was shown to be possible, the optimization of these reactions still remain a challenging task for the continuation of this project.

Within this work, the influence of the number of 2,2 ′-bipyridine moieties on the luminescence properties of europium was also investigated. Therefore, a series of cryptates with increasing number of 2,2’-bipyridine units was studied (Figure 4.7). While the cryptates 101 and 103 are already literature-known, cryptates 102 was synthesized and characterized to complete the series.

3+ 3+ 3+ N N N O N N O N O N N N Ln Ln Ln N O N N N N N O N O N N

little investigated unknown well investigated

Ln = Gd 101a Ln = Gd 102a Ln = Gd 103a

= Eu 101b = Eu 102b = Eu 103b

Figure 4.7: Investigated 2,2 ′-bipyridine-based lanthanoid cryptates.

Summary

Triplet energy measurements using the gadolinium cryptate and lifetime as well as quantum yield determinations using the europium cryptate were performed in aqueous solution. It was found that with increasing number of bipyridine units, the intersystem crossing (ISC) efficiencies and the number of bound water molecules also increase. In contrast, a decrease was found in the same direction for overall quantum yields, triplet energies, and sensitization efficiencies.

In the last part of this work, the synthesis and characterization of novel cryptates with unusual chirality was reported (Figure 4.8). These cryptates were based on an unsymmetrical unit which is a requirement for the molecule to be chiral and was synthesized applying a coupling reaction between pyridine and furane derivatives. This unit was added into two unsymmetrical macrocycles 108 and 118 . The resulting crpytates with three different arms were both synthesized as racemic mixtures.

+ + Three different arms N N N O O N + O N Na Na One unsymmetrical arm N O O O N O N

109 110 chiral cryptates Figure 4.8: Synthesized sodium cryptands 109 and 110 with unusual chirality.

Experimental section

5 Experimental section:

Materials All chemicals, which were obtained from commercial supplier, were used without further purification. The reactions, which include air or water sensitive substances, were carried out under nitrogen atmosphere using standard Schlenck technique. Tetrahydrofurane, toluene, diethyl ether and hexane were dried using a solvent purification system (MBraun SPS). Dichloromethane was dried over calcium hydride. Methanol and ethanol were dried over

Mg/I 2.

Methods NMR-spectroscopy: 1H and 13 C NMR spectra were recorded in deuterated solvents on Bruker DPX 200 ( 1H: 200 MHz, 13 C: 50.1 MHz), DPX 250 ( 1H: 250 MHz, 13 C: 62.9 MHz) DPX 400 (1H: 400 MHz, 13 C: 101 MHz). Chemical shift positions δ in both 1H- and 13 C-NMR are reported in ppm. Coupling constants J are given in Hz. Individual peaks are marked as: singlet (s), doublet (d), triplet (t), q (quartet), m (multiplet) and br (broad).

Elemental analysis: Elemental analyses were performed using vario EL from Elementar Hanau in C,H,N,S mode.

Mass spectrometry: ESI-MS spectra were measured on Bruker Daltonics Esquire6000 and FAB-MS spectra on a VG autospec.

UV-Vis spectroscopy: UV/Vis spectra were recorded on a Jasco-670 spectrophotometer using 1.0 cm quartz cuvettes.

Photophysical measurements: For the measurement of the steady state emission spectra in 1.0 cm quartz cuvettes, a PTI Quantamaster QM4 spectrofluorimeter, equipped with 75 W continuous xenon short arc lamp, was used. The spectra were collected at 90° angle with a PTI P1.7R detector module (Hamamatsu PMT R5509-72 with a Hamamatsu C9525 power supply operated at -1500 V and a Hamamatsu liquid N2 cooling unit C9940 set to -80° C). Low temperature spectra were recorded on frozen glasses of solutions of the gadolinium or yttrium complexes (MeOH/EtOH 1:1, v/v) in standard NMR tubes using a dewar cuvette

Experimental section

filled with liquid N 2 (T = 77 K). Spectral selection was achieved by single grating monochromators (excitation: 1200 grooves/mm, blazed at 300 nm; visible emission: 1200 grooves/mm, blazed at 400 nm). Luminescence lifetimes were determined with the same instrumental setup. The light source for these measurements was a xenon flash lamp (Hamamatsu L4633: 10 Hz repetition rate, pulse width ca. 1.5 µs FWHM). Lifetime data analysis (deconvolution, statistical parameters, etc.) was performed using the software package FeliX32 from PTI. Lifetimes were either determined by fitting the middle and tail portions of the decays or by deconvolution of the decay profiles with the instrument response function which was determined using a dilute aqueous dispersion of colloidal silica (Ludox

AM-30). The estimated uncertainties in τobs are ±10%. All measured values are averages of three independent experiments.

Experimental section

2-(4-Bromophenyl)malonic acid diethyl ester [69] Br

EtO OEt

O O 11

Under N 2, ethyl 4-bromophenylacetate (1.00g, 4.13 mmol, 1.0 equiv.) was dissolved in THF (10 ml), cooled to – 74 °C and subsequently treated with LiMDS. [131] After stirring for 1 h at – 74 °C, ethyl cyanoformate (614 mg, 6.19 mmol, 1.5 equiv.) was added. The reaction mixture was stirred for 30 min at – 78 °C and overnight at room temperature. The reaction mixture was quenched with aq. NH 4Cl and stirred for 30 min. After extraction with hexane, washed with brine and dried over MgSO 4, the solvent was removed and the product was obtained as yellow oil without further purification (1.18 g, 91%). The analytical data of the product were in agreement with the literature. [69]

1 Data for 11: H NMR (CDCl 3, 250 MHz): δ (ppm) 7.51 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.59 (s, 1H), 4.30 – 4.19 (m, 4H), 1.28 (t, J = 7.1 Hz, 6H).

2-(4-Bromophenyl)malonic amide

H2N NH2 O O 12

Under N 2, ammonia (5 ml, 7M in methanol, 35 mmol, 2.2 equiv.) and sodium methoxide (0.002 g, 0.037 mmol, 0.0023 equiv.) were added to 2-(4-bromophenyl)malonic acid diethyl ester 11 (5.00 g, 15.8 mmol, 1.0 equiv.). The mixture was allowed to stand in closed flask at room temperature for 7-8 d. The white precipitate was filtered, washed and dried under vacuum to afford the clean product as white solid (1.88 g, 47%). This compound was reported in the literature without spectroscopic characterization data. [132]

Experimental section

1 Data for 12: H NMR (200 MHz, d6-DMSO): δ (ppm) 7.61 (s(br), 2H, NH 2), 7.54 (d, J = 8.5 13 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.27 (s(br), 2H, NH 2), 4.36 (s, 1H). C NMR (50.1 MHz, + d6-DMSO): δ (ppm) 169.9, 135.7, 130.9, 130.5, 120.4, 57.3. FAB : m/z (%) = 257.0 (50, + + [M] ), 278.9 (23, [M+Na] ). Anal. Calcd. for C 9H9N2O2Br: N, 10.90; C, 42.05; H, 3.53. Found: N, 10.59; C, 42.03; H, 3.59.

2-(4-Bromophenyl)malonic thioamide

H2N NH2 S S 13

Malonic diamide 12 (1.80 g, 7.03 mmol, 1.0 equiv.) and Lawesson’s reagent (3.40 g, 8.41 mmol, 1.2 equiv.) were dissolved in dry THF (100 ml). The mixture was refluxed under N 2 overnight. After removal of the solvent, the yellow solid was treated with dichloromethane and the resulting white precipitate was collected and dried under vacuum to give clean product 13 as a white solid without any further purification (1.5 g, 74%).

1 Data for 13: H NMR (250 MHz, d6-DMSO): δ (ppm) 10.12 (s(br), 2H, NH 2), 9.73 (s(br), 13 2H, NH 2), 7.53 (d, 2H), 7.40 (d, 2H), 5.46 (s, 1H). C NMR (63 MHz, d 6-DMSO) : δ (ppm)

132.6, 132.4, 113.6, 113.3, 99.9, 55.5. Anal. Calcd. for C 9H9BrN 2S2: N, 9.69; C, 37.38; H, 3.14; S, 22.17. Found: N, 9.11; C, 37.87; H, 3.09; S, 20.26.

Experimental section

Bis(thiazole) (14): Br

S S

N N

Cl 14 Cl

A mixture of dithiamide 13 (500 mg, 1.73 mmol, 1.0 equiv.) and 1,3-dichloroacetone (765 mg, 6.07 mmol, 3.5 equiv.) in dry THF (50 ml) was refluxed for 4 d. The solvent was removed and the residue was extracted with dichloromethane. The combined organic layers were dried over MgSO 4. After solvent removal the crude product was subjected to column chromatography (SiO 2, hexane/ethyl acetate 4:1, detection: UV) to afford the product as light yellow solid (610 mg, 82%).

1 Data for 14: H NMR (200 MHz, CDCl 3): δ (ppm) 7.40 (d, J = 8.4 Hz, 2H), 7.32 – 7.16 (m, 13 4H), 6.01 (s, 1H), 4.60 (s, 4H). C NMR (50.1 MHz, CDCl 3): δ (ppm) 169.7, 152.7, 138.5, 132.3, 130.4, 122.5, 118.7, 52.7, 40.9. ESI-MS (+Ve): m/z (%) = 456.7 (100, [M+Na]+).

Bis(thiazol) cryptate [Na ⊂⊂⊂ bthaz.2.2]Cl (15)

N O S N Cl O Na Br O N O N S

A mixture of Kryptofix  22 ( 9) (176.15 mg, 0.67 mmol, 1.0 equiv.), anhydrous sodium carbonate (711.68 mg, 6.7 mmol, 10 equiv.) and NaI (4.5 mg, 0.03 mmol, 0.04 equiv.) in dry acetonitrilee (250 ml) was heated to reflux. At this temperature, bis-thiazole 14 (290 mg, 0.67 mmol, 1.0 equiv.) in aceteonitrile (250 ml) was added dropwise over 1 d and heating was continued for another 1 d. After filtration and removal of the solvent, the brown crude product

Experimental section

was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 9: 1, detection: I 2, UV) to give the product as dark yellow-brown oil (52 mg, 11%).

1 Data for 15: H NMR (200 MHz, CDCl 3): δ (ppm) 7.84 – 6.89 (m, 6H), 6.04 (s (br), 1H), 4.32 – 2.94 (m, 26H), 2.66 (s (br), 2H). ESI-MS (+Ve): m/z (%) = 663.00 (100, [M-Na+K] +), 678.90 (60).

2,2 ′-Dimethoxy-1,1 ′-binaphthyl [72]

OMe OMe

rac- 19

A mixture of racemic BINOL 18 (5.00 g, 17.4 mmol, 1.equiv.), methyl iodide (9.92 g, 69.9 mmol, 4.0 equiv.), potassium carbonate (14.4 g, 104.8 mmol, 6.0 equiv.), and acetone (250 mL) was refluxed for 24 h. After cooling to room temperature, the mixture was concentrated in vacuum and the residue was extracted with CHCl 3. The organic layer was washed with brine and dried over MgSO 4. After removal of the solvent, the residue was subjected to column chromatography (SiO 2, hexanes/ethyl acetate 2:1, detection: UV) affording the product 19 as a yellow powder (4.55 g, 83%). The analytical data of the product were in agreement with the literature.

1 Data for rac-19: H NMR (200 MHz, CDCl 3): δ (ppm) 7.87 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 6.93 - 7.27 (m, 6H), 3.65 (s, 6H).

2,2 ′-Dimethoxy-1,1-binaphthyl-3,3 ′-dicarbaldehyde [72] O

OMe OMe

O rac-20

Experimental section

A solution of 2,2’-dimethoxy-1,1’-binaphthyl 19 (2.0 g, 6.8 mmol) and TMEDA (5.30 mL,

35.3 mmol, 5 equiv.) in Et 2O (150 mL) was cooled to 0 °C. A 1.6 M solution of n-BuLi in hexane (18.4 mL, 29.5 mmol, 4.3 equiv.) was added dropwise over a period of 30 min. The mixture was stirred at 0 °C for 1 h and was then slowly warmed to reflux. After being refluxed for 16-17 h, the resulting pale brown suspension was cooled to 0 °C and DMF (4.1 mL, 54.4 mmol, 8 equiv.) was added dropwise. The mixture was stirred at 0 °C for 90 min, and then 4 N HCl (20 mL, 81.6 mmol) was added slowly under vigorous stirring. The resulting two phases were stirred for 30 min. The organic layer was separated, washed with

0.5 N HCl , a saturated aqueous NaHCO 3 and brine, dried (Mg 2SO 4), and concentrated under reduced pressure to give a yellow solid. The crude product was filtered over a short column

(SiO 2, Et 2O) to give 20 as yellow solid (1.9 g, 75%).

1 Data for rac-20: H NMR (250 MHz, CDCl 3) δ (ppm) 10.57 (s, 2H), 8.08 (d, J = 7.9 Hz, 2H), 7.54 – 7.38 (m, 6H), 7.19 (d, J = 8.4 Hz, 2H), 3.51 (s, 6H).

3,3 ′-Bis(hydroxymethyl)-2,2 ′-dimethoxy-1,1 ′-binaphthyl [72]

OMe OMe

rac-21 To a solution of 20 (1.8 g, 4.8 mmol, 1.0 equiv.) in a mixture of absolute ethanol (130 mL) and THF (20 mL) was added NaBH 4 (1.25 g, 33.0 mmol, 6.8 equiv.) at room temperature. After being stirred for 4 h, the reaction mixture was concentrated under reduced pressure. The residue was taken up in CH 2Cl 2 (200 mL) and 3 N HCl (200 mL) and was vigorously stirred until all solid material was dissolved. The organic layer was separated, and the aqueous layer was extracted with CH 2Cl 2 (2x150 mL). The combined organic layers were dried (MgSO 4) and concentrated under reduced pressure to give 21 (95%) as white foam (1.65 g, 92%).

1 Data for rac-21: H NMR (250 MHz, CDCl 3): δ (ppm) 7.99 (s, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.49 – 7.49 (m, 6H), 4.95 (d, 13.5 Hz, 4H), 3.29 (s, 6H).

Experimental section

3,3 ′-Bis(bromomethyl)-2,2 ′-dimethoxy-1,1 ′-binaphthyl [72]

OMe OMe

rac-22

To a solution of 21 (150 mg, 0.40 mmol, 1.0 equiv.) in CH 2Cl 2 (10 ml) was added PBr 3 (118 mg, 0.44 mmol, 1.1 equiv.) dropwise at 0 °C. The mixture was stirred at room temperature overnight. Water was added cautiously. The organic layer was separated, washed with sat

NaHCO 3, brine and dried over MgSO 4. After removal of the solvent the product was obtained as white foam (100 mg, 50%).

1 Data for rac-22: H NMR (200 MHz, CDCl 3): δ ( ppm ) 8.00 (s, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.09-7.44 (m, 6H), 4.76 ( AB system , J = 9.8 Hz, 4H), 3.29 (s, 6H).

3,3 ′-Bis(bromomethyl)-2,2 ′-dihydroxy-1,1 ′-binaphthyl [72]

OH OH

rac-23

To a cooled (0 °C) solution of 22 (100 mg, 0.20 mmol, 1.0 equiv.) in CH 2Cl 2 (20 mL) was added dropwise BBr 3 (1.0 M in CH 2Cl 2, 0.52 mL, 0.52 mmol, 2.6 equiv.). After the mixture was stirred at room temperature for 4 h a saturated NaHCO 3 solution (10 mL) was added. The mixture was poured into water (100 mL) and was extracted with CH 2Cl 2 (3 x 50 ml). The combined organic layers were washed with 2 N HCl, dried (MgSO 4), and concentrated under reduced pressure to give 23 as pale yellow foam (yield: 70 mg, 70%).

Experimental section

1 Data for rac-23: H NMR (200 MHz, CDCl 3): δ ( ppm ) 8.10 (s, 2H), 7.90-7.93 (m, 2H), 7.45- 7.29 (m, 4H), 7.11-7.14 (m, 2H) 5.41 (s, 2H), 4.97 – 4.64 (m, 4H).

Sodium cryptate [Na ⊂⊂⊂Binol.2.2]Br ( rac-24)

N O Br O HO Na O HO O N

rac-24

A mixture of kryptofix 22 ( 9) (39 mg, 0.14 mmol) 9 and Na 2CO 3 (157.8, 1.4 mmol) in acetonitrile (200 ml) was heated to reflux. At this temperature, dibromide 23 (70 mg, 0.14 mmol) in acetonitrile (150 ml) was added dropwise over 12 h. The light yellow solution was refluxed for further 1 d. and the solvent was then removed. The crude product was chromatographed (SiO 2, CH 2Cl 2/MeOH 9: 1, detection: UV, I 2) to give rac-24 as a yellow solid (85 mg, 86%).

1 Data for rac-24: H NMR (250 MHz, d6-DMSO, 100 °C) δ (ppm) 7.94 – 7.78 (m, 2H), 7.80 – 7.63 (m, 2H), 7.44 – 7.05 (m, 6H), 4.30 (d, J = 12.3, 2H), 3.81 – 3.35 (m, 18H), 2.85 – 2.58 (m, 6H), 2.48 – 2.34 (m, 2H). ESI-MS (+ eV): m/z (%) = 595.15 (100, [M +]).

2,2 ′-Dimethoxybiphenyl

OMe OMe

A mixture of 2,2 ′-biphenol 25 (5.00 g, 26.8 mmol, 1.0 equiv.), methyl iodide (15.2 g, 107.4 mmol, 4.0 equiv.), potassium carbonate (22.2 g, 161.1 mmol, 6.0 equiv.), and acetone (300

Experimental section mL) was refluxed for 24 h. After cooling to room temperature, the mixture was concentrated in vacuum and the residue was extracted with CHCl 3. The organic layer was washed with brine and dried over MgSO 4. After removal of the solvent, the product was isolated as a white solid without any further purification (5.4 g, 94%). The analytical data of the product were in agreement with the literature.

1 Data for 26: H NMR (200 MHz, CDCl 3): δ(ppm ) 3.77 (s, 6H), 7.02 – 7.12 (m, 4H), 7.22- 7.35 (m, 4H).

2,2 ′-Dimethoxy-3,3 ′-diformylbiphenyl O

OMe OMe

O 27

Under N 2, a solution of 2,2 ′-dimethoxy-biphenyl 26 (1.4 g, 6.5 mmol, 1.0 equiv.) and

TMEDA (4.9 mL, 32.6 mmol, 5.0 equiv.) in dry Et 2O (100 mL) was cooled to 0 °C. A 1.6 M solution of n-BuLi in hexane (17.6 mL, 26 mmol, 4.0 equiv.) was added dropwise over a period of 30 min. The mixture was stirred at 0 °C for 1 h and was then slowly warmed to reflux. After being refluxed for 16-17 h the resulting dark yellow suspension was cooled to 0 °C and DMF (4.0 mL, 52 mmol, 8.0 equiv.) was added dropwise. The mixture was stirred at 0 °C for 90 min, and then 4 N HCl (ca. 20 mL, 81.6 mmol) was added slowly under vigorous stirring. The resulting biphasic system was stirred for 30 min. The organic layer was separated, washed with 0.5 N HCl, a saturated NaHCO 3 solution and brine, dried (MgSO 4), and concentrated under reduced pressure to give a light yellow solid. The crude product was subjected to column chromatography (SiO 2, CH 2Cl 2, detection: UV) to give 27 as a light yellow solid (600 mg, 34%). The analytical data matched those reported previously using other synthetic procedure. [133]

1 Data for 27: H NMR (250 MHz, CDCl3): δ (ppm) 10.47 (s, 2H), 7.93 (dd, J = 7.7, 1.7 Hz, 2H), 7.66 (dd, J = 7.5, 1.7 Hz, 2H), 7.33 (t, J = 7.7 Hz, 2H), 3.61 (s, 6H). 13 C NMR (50.1

MHz, CDCl 3): δ (ppm) 189.7, 160.9, 137.5, 131.5, 129.6, 128.7, 124.4, 63.1. ESI-MS (+ Ve):

Experimental section m/z (%) = 292.97 (100, [M – H + Na] +), 324.97 (83). ESI-MS (- Ve): m/z (%) = 256.99 (100, [M - Me] -).

3,3 ′-Bis(hydroxymethyl)-2,2 ′-dimethoxybiphenyl

OMe OMe

28 .

To a solution of 27 (600 mg, 2.22 mmol, 1.0 equiv.) in a mixture of absolute ethanol (15 mL) and THF (2 mL) was added NaBH 4 (185 mg, 4.88 mmol, 2.0 equiv.) at room temperature.

After being stirred for 4 h the mixture was diluted with CH 2Cl 2 (50 mL) and 4 N HCl was added under vigorous stirring until the gas evolution ceased. The organic layer was separated, and the aqueous layer was extracted with CH 2Cl 2 (2 x 50 mL). The combined organic layers were dried (MgSO 4) and concentrated under reduced pressure to give 28 as white solid (450 mg, 74%). The analytical data matched those reported previously using other synthetic procedure. [133]

1 Data for 28: H NMR (250 MHz, CDCl 3): δ = 7.45 (d, J = 7.3 Hz, 2H), 7.38 (d, J = 6.5 Hz, 13 2H), 7.19 (t, J = 7.6 Hz, 2H), 4.68 (s, 4H), 3.52 (s, 6H). C NMR (50.1 MHz, CDCl 3): δ 154.8, 133.1, 130.4, 130.2, 127.5, 122.9, 60.5, 59.8. ESI-MS (+ Ve): m/z (%) = 296.99 (100, [M–H+Na] +), 312.9 (33, [M–H+K]+).

3,3 ′-Bis(bromomethyl)-2,2 ′-dimethoxybiphenyl

OMe OMe

Experimental section

To a solution of 28 (450 mg, 1.64 mmol, 1.0 equiv.) in CH 2Cl 2 (20 ml) was added PBr 3 (483 mg, 1.8 mmol, 1.1 equiv.) dropwise at 0 °C. The mixture was stirred at room temperature overnight. Water was added cautiously. The organic layer was separated, washed with sat.

NaHCO 3, brine and dried over MgSO 4. After removal of the solvent the product 29 was obtained as white solid (400 mg, 61%). The analytical data matched those reported previously using other synthetic procedures. [73, 133]

1 Data for 29: H NMR (250 MHz, CDCl 3): δ (ppm) 7.40 (d, J = 7.3 Hz, 2H), 7.33 (d, J = 6.5 13 Hz, 2H), 7.14 (t, J = 7.6 Hz, 2H), 4.63 (s, 4H), 3.47 (s, 6H). C NMR (50.1 MHz, CDCl 3): δ (ppm) 156.3, 132.5, 131.9, 131.9, 131.1, 124.3, 61.1, 28.6.

2,2 ′-Dihydroxy-3,3 ′-bis(bromomethyl)biphenyl

OH OH

Br 30

To a cooled (0 °C) solution of 29 (400 mg, 1.00 mmol, 1.0 equiv.) in CH 2Cl 2 (30 mL) was added dropwise BBr 3 (1.0 M in CH 2Cl 2, 2.60 mL, 2.60 mmol, 2.6 equiv.). After the light brown mixture was stirred at room temperature for 4 h a saturated NaHCO 3 solution (10 mL) was added. The mixture was poured into water (40 mL) and was extracted with CH 2Cl 2 (3 times). The combined organic layers were washed with 2 N HCl, dried (MgSO 4), and concentrated under reduced pressure to give 30 as pale beige solid (320 mg, 86%).

1 Data for 30: H NMR (250 MHz, CDCl 3): δ (ppm) 7.39 (dd, J = 7.6, 1.7 Hz, 2H), 7.20 (d, J = 13 1.7 Hz, 1H), 7.02 (t, J = 7.6 Hz, 3H), 5.52 (s, 2H, -OH), 4.62 (s, 4H, -CH2). C NMR (50.1

MHz, CDCl 3): δ (ppm) 151.7, 131.9, 131.7, 125.8, 123.5, 121.8, 29.0.

Experimental section

Sodium cryptate [Na ⊂⊂⊂biph.2.2]Br (31)

N O Br O HO Na O HO O N

31  A solution of kryptofix 22 ( 9) (56.7 mg, 0.21 mmol, 1.0 equiv.) and Na 2CO 3 (229 mg, 2.16 mmol, 10 equiv.) in acetonitrile (150 ml) was heated to reflux. At this temperature, dibromide 30 (80.0 mg, 0.21 mmol, 1.0 equiv.) in acetonitrile (100 ml) was added dropwise over 2 h. The light yellow solution was refluxed for 2 d. The solution was filtered and the solvent was removed under reduced pressure. The brown crude product was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 9: 1, detection: I 2, UV) to give 31 as a beige solid (yield: 56 mg, 46%).

1 Data for 31: H NMR (200 MHz, CD 3OD) δ (ppm) 7.25 (d, J = 7.3 Hz, 2H), 7.13 (d, J = 6.6 Hz, 2H), 6.95 (t, J = 7.5 Hz, 2H), 3.90 – 3.30 (m, 20H), 2.88 – 2.45 (m, 8H). 13 C NMR (62.9

MHz, CD 3OD): δ (ppm) 131.5, 130.3, 128.6, 121.4, 79.6, 72.2, 69.4 (br), 58.9, 54.2. ESI-MS (+Ve): m/z (%) = 495.11 (100, [M]+).

6,6 ′-Dimethyl-2,2 ′bipyridine-N,N ′-dioxide [86]

N N O O 55

6,6 ′-Dimethyl-2,2 ′-bipyridine 40 (5.25 g, 28.5 mmol, 1.0 equiv.) was dissolved in CHCl 3 (400 ml). To this solution m-chloroperbenzoic acid (moistened 77wt.%, 16.0 g, 71.2 mmol, 2.5 equiv.) in CHCl 3 (400 ml) was added dropwise at 0 °C in ca. 2 h. The solution was allowed to reach room temperature and was stirred overnight. The mixture was extracted with saturated aqueous solution of Na 2CO 3 and sodium thiosulfate (40 ml) and the organic phase was dried over MgSO 4. After removal of the solvent under reduced pressure, the brown oil was chromatographed (SiO 2, CH 2Cl 2 / MeOH 100:1 → 9:1, detection: UV) to give the product as white solid (yield: 4.4 g, 73 %).

Experimental section

1 Data for 55: H NMR (200 MHz, CD 3OD): δ(ppm) 7.76 – 7.37 (m, 6H), 2.57 (s, 6H).

6,6 ′-Bis(bromomethyl)-2,2 ′-bipyridine

N N Br

Br 56

Under N 2, 6,6 ′-dimethyl-2,2 ′-bipyridine-N,N′-dioxide 55 (1.0 g, 4.6 mmol, 1.0 equiv.) was dissolved in dry CH 2Cl 2 (19 ml), and at room temperature trifluoroacetic anhydride (19 ml) was added. The solution was heated to reflux for 1.5 h. The solvents were evaporated to dryness. The residue was dissolved in a 1:1 mixture of dry DMF and dry THF (30 ml) and added to anhydrous LiBr (4.01 g, 46.1 mmol, 10 equiv., dried at 180 °C for > 3 h) (First the residue was dissolved in THF and the solution was added to LiBr via cannule, then the same with DMF). The resultant mixture was stirred at room temperature overnight. The solvent were evaporated to dryness (70 °C) and the residue was chromatographed (SiO 2, CH 2Cl 2 / MeOH 100:1) to give the product as yellow solid (830 mg, 63%). The analytical data matched those reported previously using other synthetic procedures. [34, 93]

1 Data for 56: H NMR (200 MHz, CDCl 3) δ 8.37 (d, J = 7.9, 2H), 7.81 (t, J = 7.8 Hz, 2H),

7.45 (d, J = 7.7 Hz, 2H), 4.61 (s, 4H). ESI-MS (+ Ve): m/z (%) = 364.84(Br 2-pattern) (47, [M + Na] +).

[bpy.bpy] Macrocycle 10 [74]

N H N N

N N H N

6,6 ′-Bis(bromomethyl)-2,2 ′-bipyridine 56 (950 mg, 2.77 mmol, 1.0 equiv.) was dissolved in dry EtOH (90 ml) and p-toluenesulfonamide monosodium salt [134] (1.10 g, 5.56 mmol, 2.0

Experimental section equiv.) was added and the mixture was refluxed for 2 d. After cooling in an ice bath, the precipitate was collected on a filter, washed with water and ethanol and dried under reduced pressure. The product was obtained as light-yellow solid that was used for the next step without further purification (yield: 580 mg, 30%). ESI-MS (+ Ve): m/z (%) = 725.1 (49, [M+Na]+).

The protected macrocycle (580 mg, 391 µmol) was dissolved in conc. H 2SO 4 (5 ml) and the solution was heated to 110 °C for 3 h. After cooling to room temperature, it was poured onto crushed ice (ca. 10 g). An ice cold aqueous solution of NaOH (4g in 30 ml water) was added dropwise with ice-cooling and vigorous stirring until pH > 13. The resulting cloudy solution was extracted with CHCl 3 (3 x 100 ml), the combined organic phases were dried (MgSO 4), and concentrated. The crude product was dried under vacuum to yield the macrocycle as beige solide (235 mg, 74%, yield over two steps: 21 %).

1 Data for 10: H NMR (200 MHz, CDCl 3): δ (ppm) 7.68 (d, J = 7.7 Hz, 4H), 7.40 (t, J = 7.6 Hz, 4H), 6.92 (d, J = 7.4 Hz, 4H), 4.05 (s, 8H), 3.00 (s, 1H) . ESI-MS (+ Ve): m/z (%) = 417.17 (100, [M + Na]+).

Sodium cryptate [Na ⊂⊂⊂biph.bpy.bpy]Br (33)

N N N Na HO N HO N N

rac-33

A mixture of macrocycle 10 (64 mg, 0.16 mmol, 1.0 equiv.) and Na 2CO 3 (171.9 mg, 1.62 mmol, 10 equiv.) in acetonitrile (200 ml) was heated to reflux. At this temperature dibromide 30 (60 mg, 0.16 mmol, 1.0 equiv.) in acetonitrile (150 ml) was added dropwise over 1 d and the light yellow solution was refluxed for further 2 d. The solvent was then removed and the crude product was purified with column chromatography (SiO 2, CH 2Cl 2 / MeOH 9: 1, detection: I 2, UV) to give 33 as a yellow solid (10 mg, 8.7 %).

1 Data for rac-33: H NMR (250 MHz, CDCl 3): δ (ppm) 7.84 – 7.82 (m, 9H), 7.27 – 7.21 (m, 13 6H), 7.01 (t, J = 7.5 Hz, 2H), 4.70 – 3.42 (m, 12H). C NMR (62.9 MHz, CDCl 3): δ (ppm)

Experimental section

158.3, 152.4, 136.8, 130.4, 130.2, 125.5, 123.3, 121.7, 120.9, 97.6, 60.3, 58.6(because of the overlapping, some signals could not be assigned) (ESI MS (+ Ve): m/z (%) = 627 (100, [M]+1).

6,6'-Bis(bromomethyl)-2,2'-bipyridine N,N' -dioxide

N N O Br O

Br 57

Procedure 1

A stirred soln. of 6,6'-bis(bromomethyl)-2,2'-bipyridinc (130 mg, 0.38 mmol) in CHCl 3, (20 ml) was cooled in an ice-bath. A solution of m-chloroperbenzoic acid (moistened 77wt%,

85 mg, 0.38 mmol, 1.0 equiv. ) in CHCI 3 (20 ml) was added. The mixture was allowed to warm to room temperature and at 10-12 h intervals, equal portions of m-chloroperbenzoic acid (5 x 85 mg) in CHCI 3 (5 x 20 ml) were added within 3 days (TLC monitoring).

Evaporation at 25 °C yielded a yellow solid , which was washed thoroughly with Et 2O and dried in vacuo to yield the product as white solid.

Procedure 2

6,6'-Bis(bromomethyl)-2,2'-bipyridinc (250 mg, 0.73 mmol) was dissolved in dry CH 2Cl 2 (5 ml) and cooled in an ice-bath. To this solution urea hydrogen peroxide (206 mg, 2.19 mmol, 3 equiv.) was added followed by dropwise addition of trifluoroacetic anhydride (0.25 ml, 1.82 mmol, 2.5 eq). The solution was stirred at rt over night. CH 2Cl 2 (10 ml) and sodium thiosulfate ( 5 ml) were added and the mixture was stirred for additional 40 min. After extraction with dichloromethane (3 x 50 ml), the solvent was removed the white crude product was chromatographed (SiO2, CH 2Cl 2/MeOH 50:1) to affored the product as white solid (133 mg, 49 %).

1 Data for 57: H NMR (200 MHz, CDCl 3) δ 7.68 – 7.53 (m, 4H), 7.33 (t, J = 7.9 Hz, 2H), 4.72 (s, 4H).

Experimental section

Sodium cryptate [Na ⊂⊂⊂bpy.bpy.bpyO2]Br ( rac-2) [35]

N N N N Na O O Br N N N N

rac-2

A mixture of bipyridine macrocycle 10 (235 mg, 0.59 mmol, 1.0 equiv.) and Na 2CO 3 (631 mg, 5.9 mmol, 10 equiv.) in acetonitrile (300 ml) was heated to reflux. At this temperature 6,6'-bis(bromomethyl)-2,2'-bipyridine N,N' -dioxide (223 mg, 5.9 mmol, 1.0 equiv.) was added and the mixture was refluxed for further 2 d. After removal of the solvent, the crude product was chromatographed (SiO 2, CH 2Cl 2/MeOH 9:1) to give rac-2 as a white solid (120 mg, 29 %).

1 Data for 2: H NMR (200 MHz, CD 2Cl 2) δ 7.91 – 7.72 (m, 8H), 7.64 (dd, J = 7.6, 2.2 Hz, 2H), 7.54 (dd, J = 7.8, 2.2 Hz, 2H), 7.34 - 7.43 (m, 6H), 4.35 (d, J = 11.7 Hz, 2H), 3.92 (dd, J = 12.9, 5.6 Hz, 4H), 3.53 (d, J = 12.8 Hz, 2H), 3.42 (d, J = 13.0 Hz, 2H), 3.32 (d, J = 11.8 Hz, 2H). ESI-MS (+ Ve): m/z (%) = 629.17 (100, [M] +).

6,6 ′-Dimethyl-2,2 ′-bipyridine N-oxide [87]

N N O

6,6’-Dimethyl-2,2’-bipyridine 40 (7.00 g, 37.9 mmol) was dissolved in CHCl 3 (350 ml). To this solution m-chloroperbenzoic acid (moistened 77wt%, 8.51 g, 37.9 mmol, 1.0 equiv.) in

CHCl 3 (350 ml) was added dropwise at 0 °C in ca. 4 h. The solution was allowed to reach the room temperature over 1 h and stirred overnight. The mixture was extracted with saturated aq.

Na 2CO 3 solution (40 ml) and the organic phase was dried over MgSO 4. After removal of the solvent under reduced pressure, the brown oil was chromatographed (CH 2Cl 2/MeOH 100:1 → 9:1) to give the product as light yellow solid (yield: 5.0 g, 76 %).

Experimental section

1 Data for 41: H NMR (200 MHz, CDCl 3): δ(ppm) 8.52 (d, J = 7.9 Hz, 1H), 7.94 (m, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.30 – 7.08 (m, 3H), 2.58 (s, 3H), 2.55 (s, 3H).

6,6 ′-Dimethyl-4-nitro-2,2 ′-bipyridine N-oxide [87]

NO2

N N O

6,6’-Dimethyl-2,2’-bipyridine N-oxide 41 (3.00 g, 14.98 mmol) was dissolved in conc. H2SO 4

(16 ml) and conc. HNO 3 (12 ml) was added dropwise. The solution was heated at 100 °C for 4 h. The reaction mixture was poured onto crushed ice (ca. 80 g) and the pH was adjusted to 6 by dropwise addition of 10 % aq. NaOH (ca. 250 ml). The precipitate was collected, washed with cold water and dried under reduced pressure to afford the product as yellow solid (yield: 2.1 g, 58%).

1 Data for 42: H NMR (200 MHz, CDCl 3): δ(ppm) 8.93 (d, J = 3.3 Hz, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 3.3 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 2.63 (s, 13 3H), 2.60 (s, 3H). C NMR (50 MHz, CDCl 3): δ(ppm) 158.9, 151.8, 148.5, 147.8, 141.5, 136.8, 124.8, 122.3, 120.2, 118.8, 24.7, 18.8.

4-Bromo-6,6 ′-dimethyl-2,2 ′-bipyridine-N-oxide [87] Br

N N O 43

Under N 2, 6,6’-dimethyl-4-nitro-2,2’-bipyridine N-oxide 42 (770 mg, 3.14 mmol) was suspended in glacial acetic acid (11.5 ml). The solution was heated to 60 °C and at this temperature acetyl bromide (6.0 ml) was added and the colour turned to clear dark yellow solution. This was heated for 2 h at 100 °C. The mixture was poured onto crushed ice and

Experimental section neutralized to pH 5 with aq. NaOH (10%). The white precipitate was collected and the filtrate was extracted with CHCl 3, the organic phases dried (MgSO 4) and concentrated. The residue was purified by column chromatography (SiO 2, CH 2Cl 2 / MeOH 24:1, detection: UV) to yield the product as a light yellow solid (300 mg, 39 %).

1 Data for 43: H NMR (200 MHz, CDCl 3): δ (ppm) 8.61 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 2.9 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 2.9 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 2.60 (s, 3H), 2.53 (s, 3H).

4-Bromo-6,6 ′-dimethyl-2,2 ′-bipyridine-N,N ′-oxide [87] Br

N N O O 44

4-Bromo-6,6 ′-dimethyl-2,2 ′-bipyridine-N,N ′-oxide 43 (1.50 g, 5.37 mmol, 1.0 equiv.) was dissolved in CHCl 3 (50 ml) and the solution was cooled to 0 °C. A solution of m- chloroperbenzoic acid (moistened 77wt%, 1.80 g, 8.06 mmol, 1.5 equiv.) in CHCl 3 (50 ml) was added dropwise in 1 h. The solution was allowed to warm to room temperature and was stirred overnight. The solution was washed with saturated aq. Na 2CO 3 (6 ml), and the aqueous phase was extracted once with CHCl 3. The combined organic phases were dried (MgSO 4) and concentrated. The residue was chromatographed (SiO 2, gradient: CH 2Cl 2 / MeOH 24:1 → 9:1, detection: UV) to give the product as light yellow solid (1.45 g, 92 %)

1 Data for 44: H NMR (200 MHz, CDCl 3): δ (ppm) 7.49 (s (br), 2H), 7.34 – 7.26 (m, 2H), 7.23 – 7.18 (m, 1H), 2.56 (s, 3H), 2.53 (s, 3H).

4-Bromo-6,6 ′-bis(acetoxymethyl)-2,2 ′-bipyridine

N N OAc

45 OAc

Experimental section

4-Bromo-6,6 ′-dimethyl-2,2 ′-bipyridine-N,N ′-oxide 44 (0.40 g, 1.36 mmol) was suspended in

Ac 2O (10 ml) and the mixture was heated at 120 °C overnight. After evaporation of the solvent under reduced pressure, the brown residue was subjected to column chromatography

(SiO 2, gradient: CH 2Cl 2 / MeOH 100:1 → 50:1, detection: UV). The product was obtained as a light yellow, sticky solid (0.28 g, 55%).

1 Data for 45: H NMR (200 MHz, CDCl 3): δ (ppm) 8.54 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 5.28 (s, 2H), 5.25 (s, 2H), 2.19 (s, 3H), 2.18 (s, 3H).

4-Bromo-6,6 ′-bis(hydroxymethyl)-2,2 ′-bipyridine

N N OH

46 OH

4-Bromo-6,6 ′-bis(acetoxymethyl)-2,2 ′-bipyridine 45 (0.28 g, 738 µmol, 1.0 equiv.) was dissolved in acetone (6 ml) and 1M NaOH (1.55 ml, 1.5 mmol, 2.1 eq) was added. The solution was stirred at room temperature for 30 min. Additional 1 M NaOH (ca. 0.2 ml each) were added every 15 min until TLC indicated complete conversion. Water (9 ml) was added.

The mixture was extracted with CH 2Cl 2, the organic phases were dried (MgSO 4) and concentrated. The residue was subjected to column chromatography (SiO 2, gradient: CH 2Cl 2 / MeOH 50:1 → 24:1, detection: UV). The product was obtained as a light yellow solid (120 mg, 57%).

1 Data for 46: H NMR (200 MHz, CDCl 3): δ (ppm) 8.48 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J = 7.7 Hz, 1H), 4.84 (s, 2H), 4.80 (s, 2H).

Experimental section

4-Bromo-6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine [87] Br

N N Br

Br 47

Under N 2, 4-bromo-6,6 ′-bis(hydroxymethyl)-2,2 ′-bipyridine 46 (0.24 g, 813 µmol, 1.0 equiv.) was dissolved in dry DMF (8 ml). At 0 °C, PBr 3 (1.1 g, 0.38 l, 4.06 mmol, 5.0 equiv.) was added dropwise. The brown suspension was stirred at room temperature overnight. The volatiles were removed under reduced pressure and H2O (80 ml) was added cautiously. The pH was adjusted to 6 with sat. NaHCO 3 and the aqueous phase was extracted with CHCl 3.

The combined organic layers were dried (MgSO 4), the solution was concentrated, and the light yellow solid residue was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 100:1, detection: UV) yielding the product as a colorless solid (0.20 g, 59%).

1 Data for 47: H NMR (200 MHz, CDCl 3): δ (ppm) 8.57 (d, J = 1.5 Hz, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 4.62 (s,

13 2H), 4.55 (s, 2H). C NMR (50.1 MHz, CDCl 3): δ(ppm) 157.5, 156.7, 156.6, 154.2, 138.2, 134.4, 126.8, 124.3, 124.0, 120.9, 34.0, 33.1.

6,6’-Bis(tosylaminomethyl)-2,2’-bipyridine [84]

N N NHTs

NHTs 39

[83] Under N 2, 6,6 ′-bis(aminomethyl)-2,2 ′-bipyridine trihydrobromide hydrate (660 mg, 1.38 mmol) was dissolved in an ice-cold solution of NaOH (472 mg, 11.8 mmol, 8.5 eq) in water

(4.5 ml). Ts-Cl (552 mg, 2.89 mmol, 2.1 eq) in Et 2O was added in portions and stirring was continued at 0 °C for 1 h and at room temperature overnight. The white suspension was treated with CHCl 3 (15 ml) and H 2O (9 ml) and the mixture was stirred for ca. 1 h. The solid

Experimental section

was collected on a filter, washed with H 2O and dried under reduced pressure to yield a colourless solid (410 mg, 56%).

1 Data for 39: H NMR (200 MHz, CDCl 3): δ (ppm) 8.10 (d, J = 7.8 Hz, 2H), 7.71 (t, J = 7.5 Hz, 6H), 7.13 (d, J = 8.1 Hz, 6H), 5.95 (s, 2H), 4.31 (s, 2H), 4.28 (s, 2H), 2.28 (s, 6H). ESI- MS (+ Ve): m/z (%) = 545.01 (100, [M+Na] +), 391.05 (47, [M+Na-Ts] +).

Bromo macrocycle (36)

Br N H N N

N N H N

4-Bromo-6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine 47 (200 mg, 0.47 mmol, 1.0 equiv.) was dissolved in dry DMF (10 ml) and anhydrous K 2CO 3 (985 mg, 7.05 mmol, 15 equiv.) was added, followed by 6,6 ′-bis(tosylaminomethyl)-2,2 ′-bipyridine 39 (248 mg, 0.47 mmol, 1.0 equiv.). The mixture was heated at 50 °C overnight. Water (20 ml) was added to the suspension at room temperature. The precipitate was collected on a filter, washed with water and ethanol and dried under reduced pressure. The product was obtained as light-yellow solid (305 mg, 82%) that was used for the next step without further purification.

The protected macrocycle (306 mg, 391 µmol) was dissolved in conc. H 2SO 4 (4 ml) and the solution was heated to 110 °C for 4 h. After cooling to room temperature, it was poured onto crushed ice (ca. 10 g). An ice cold aqueous solution of NaOH (50%) was added dropwise with ice-cooling and vigorous stirring until pH > 13. The resulted cloudy solution was extracted with CHCl 3, the combined organic phases were dried (MgSO 4), and concentrated. The crude product was dried under reduced pressure to yield (120 mg, 64%).

1 Data for 36: H NMR (200 MHz, CDCl 3): δ(ppm) 7.83 (d, J = 1.6 Hz, 1H), 7.77 – 7.66 (m, 3H), 7.65 – 7.38 (m, 4H), 7.16 – 6.94 (m, 3H), 4.38 – 3.98 (m, 8H).

Experimental section

4- Carbomethoxy-6,6 ′-dimethyl-2,2 ′bipyridine N,N ′-oxide [92]

MeO O

N N O O 52

[91] Bipyridine methyl ester 51 (870 mg, 3.59 mmol, 1.0 equiv.) was dissolved in CH 2Cl 2 (70 ml) and the solution was cooled in an ice-bath. m-Chloroperbenzoic acid (moistened 77wt%,

1.55 g pure, 8.97 mmol, 2.5 equiv.) in CH 2Cl 2 (70 ml) was added dropwise over 1 h. the mixture was than stirred for 2 d at room temperature. The solution was washed with saturated aq. Na 2CO 3 (5 ml) and the organic phase was dried (MgSO 4). After removal of the solvent under reduced pressure (T < 40 °C), the residue was chromatographed (SiO 2, gradient: CH 2Cl 2 / MeOH 24:1 → 9:1, detection: UV) to yield a colourless solid (780 mg, 79%).

1 Data for 52: H NMR (200 MHz, CDCl 3): δ (ppm) 7.95 (s, 2H), 7.35 (m, 2H), 7.28 – 7.18 (m, 1H), 3.90 (s, 3H), 2.56 (s, 6H).

4- Carbomethoxy-6,6 ′-bis(bromomethyl)-2,2 ′bipyridine (53)

MeO O

N N Br 53 Br

Under N 2, bipyridine N,N’-oxide methyl ester 52 (500 mg, 1.82 mmol) was dissolved in dry

CH 2Cl 2 (8.5 ml), and at room temperature trifluoroacetic anhydride (8.5 ml) was added. The solution was heated to reflux for 1.5 h. The solvents were evaporated to dryness. The residue was dissolved in a 1:1 mixture of dry DMF and dry THF (14 ml), then anhydrous LiBr (1.58 g, 18.2 mmol, 10 eq, dried at 180 °C for > 3 h). The resultant mixture was stirred at room temperature over night. The solvent were evaporated to dryness (70 °C). The residue was

100

Experimental section

extracted with CH 2Cl 2 and washed with water. The yellow solid was subjected to column chromatography (SiO 2, CH 2Cl 2 / MeOH 100:1, detection: UV) to give the product as yellow solid (420 mg, 58%). The analytical data matched those reported previously using other synthetic procedure. [92]

1 Data for 53: H NMR (200 MHz, CDCl 3): δ(ppm) 8.83 (d, J = 1.4 Hz, 1H), 8.33 (dd, J = 7.9, 0.8 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.45 (dd, J = 7.7, 0.9 Hz, 1H), 13 4.60 (s, 4H), 3.95 (s, 3H). C NMR (50.1 MHz, CDCl 3): δ (ppm) 165.4, 157.5, 156.8, 156.7, 154.6, 139.8, 138.2, 124.2, 122.9, 120.8, 120.1, 53.0, 34.0, 33.5.

[MeOOC-bpy.bpy] Macrocycle 37 O

MeO N H N N

N N H N

Dibromide 53 (155 mg, 0.38 mmol, 1.0 equiv.) was dissolved in dry DMF (10 ml) and anhydrous K 2CO 3 (807 mg, 5.84 mmol, 15 equiv.) was added, followed by 6,6’- bis(tosylaminomethyl)-2,2’-bipyridine (203 mg, 0.38 mmol, 1.0 equiv.). The mixture was heated at 50 °C overnight. Water (20 ml) was added to the suspension at room temperature. The precipitate was collected on a filter, washed with water and ethanol and dried under reduced pressure. The product was obtained as beige solid (280 mg, 95%) that was used for the next step without further purification.

The protected macrocycle (280 mg, 367 µmol) was dissolved in conc. H 2SO 4 (3 ml) and the solution was heated to 100 °C for 3 h. After cooling to room temperature, it was poured onto crushed ice (ca. 10 g). The pH was brought to 3 by adding 5N NaOH where upon a very fine precipitate formed. The solvent was evaporated to dryness under reduced pressure. To the remaining solid, MeOH (50 ml) and conc. H 2SO 4 (1 ml) were added and the mixture was refluxed overnight. The mixture was then filtered and brought to pH 7 by adding saturated aq.

NaHCO 3. The mixture was extracted with CHCl 3 (2 x 70 ml), dried (MgSO 4) and evaporated under reduced pressure to afford the product as a light yellow solid (120 mg, 52 % overall yield).

101

Experimental section

1 Data for 37: H NMR (200 MHz, CDCl 3): δ(ppm) 8.22 (s, 2H), 7.88 – 7.62 (m, 3H), 7.60 – 7.37 (m, 4H), 7.03 (t, J = 8.9 Hz, 2H), 4.18 – 4.07 (m, 8H), 3.97 (s, 3H). ESI-MS (+ Ve): m/z + + (%) = 475.18 (100, [M+Na] ), 453.17 (23, [M+H] ).

6,6 ′-Dimethyl-4-nitro-2,2 ′-bipyridine N,N ′-oxide

NO2

N N O O

6,6 ′-Dimethyl-4-nitro-2,2 ′-bipyridine N-oxide 42 (1.00 g, 4.07 mmol, 1.0 equiv.) was dissolved in CHCl 3 (30 ml) and the solution was cooled to 0 °C. A solution of m- chloroperbenzoic acid (moistened 77wt%, 1.80 g, 1.40 g pure, 8.06 mmol, 1.5 equiv.) in

CHCl 3 (50 ml) was added dropwise in 1 h. The solution was allowed to warm to room temperature and was stirred overnight. The solution was washed with saturated aq. Na 2CO 3 (6 ml), and the aqueous phase was extracted once with CHCl 3 (60 ml). The combined organic phases were dreid (MgSO 4) and concentrated. The residue was chromatographed (SiO 2, gradient: CH 2Cl 2 / MeOH 24:1 → 9:1, detection: UV) to afford the product as light yellow solid (600 mg, 57%).

1 Data for 50: H NMR (200 MHz, CDCl 3): δ (ppm) 8.23 – 8.18 (m, 2H), 7.57 – 7.25 (m, 3H),

13 2.60 (s, 3H), 2.58 (s, 3H). C NMR (50 MHz, CDCl 3): δ (ppm) 150.2, 133.1, 130.0, 129.6, 127.7, 125.5, 124.7, 120.4, 120.0, 18.3, 17.8.

6,6 ′-Bis(bromomethyl)-4-nitro-2,2 ′-bipyridine

NO2

N N Br

54 Br

102

Experimental section

Under N 2, 6,6 ′-dimethyl-4-nitro-2,2 ′-bipyridine-N,N ′-dioxide 50 (300 g, 1.14 mmol, 1.equiv) was dissolved in dry CH 2Cl 2 (8 ml), and at room temperature trifluoroacetic anhydride (4.6 ml) was added. The solution was turned to purple and then dark orange. This was heated to reflux for 1.5 h. The solvents were evaporated to dryness. The residue was dissolved in a 1:1 mixture of dry DMF and dry THF (7 ml), then anhydrous LiBr (997 g, 11.4 mmol, 10 equiv., dried at 180 °C for > 3 h). The resultant mixture was stirred at room temperature overnight.

The solvent were evaporated to dryness (70 °C). The residue was chromatographed (SiO 2,

CH 2Cl 2 / MeOH 100:1) to give the product as yellow solid (181 mg, 40%). The analytical data matched those reported previously using other synthetic procedure. [87]

1 Data for 54: H NMR (200 MHz, CDCl 3): δ(ppm) 9.02 (d, J = 2.0 Hz, 1H), 8.41 – 8.29 (m, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.50 (dd, J = 7.7, 0.9 Hz, 1H), 4.64 (s, 2H), 4.59 (s, 2H).

Nitro macrocycle 38

O N 2 N H N N

N N H N

6,6 ′-Bis(bromomethyl)-4-nitro-2,2′-bipyridine 54 (170 mg, 0.43 mmol) was dissolved in dry

DMF (10 ml) and anhydrous K 2CO 3 (910 mg, 6.58 mmol, 15 eq) was added, followed by 6,6 ′-bis(tosylaminomethyl)-2,2 ′-bipyridine (229 mg, 0.43 mmol ). The mixture was heated at 50 °C over night. Water (20 ml) was added to the suspension at room temperature. The precipitate was collected on a filter, washed with water and ethanol and dried under reduced pressure. The product was obtained as light-yellow solid (300 mg, 91%) that was used for the next step without further purification.

The protected macrocycle (300 mg, 401 µmol) was dissolved in conc. H 2SO 4 (4 ml) and the solution was heated to 110 °C for 4 h. After cooling to room temperature, it was poured onto crushed ice (ca. 10 g). An ice cold aqueous solution of NaOH (50%) was added dropwise with ice-cooling and vigorous stirring until pH > 13. The resulted cloudy solution was extracted

103

Experimental section

with CHCl 3, the combined organic phases were dried (MgSO 4), and concentrated. The crude product was dried under reduced pressure to yield (130 mg, 74%).

1 Data for 38: H NMR (200 MHz, CDCl 3): δ(ppm) 8.38 (d, J = 1.9 Hz, 1H), 7.85 – 7.63 (m, 3H), 7.60 – 7.29 (m, 4H), 7.11 – 6.82 (m, 3H), 4.36 – 4.02 (m, 8H). ESI-MS (+ Ve): m/z (%) = 440.0 (100, [M ] +), 461.9 (61, [M+Na] +).

Sodium cryptate [Na ⊂⊂⊂bpy.bpy.bpy-COOMe]Br (Diast-58)

O N MeO N N N Na O O Br N N N N

Diast-58

Macrocycle methyl ester (92 mg, 0.2 mmol, 1.0 equiv.) and Na 2CO 3 (215 mg, 2.03 mmol, 10 eq) and 6,6 ′-Bis(bromomethyl)-2,2 ′-bipyridine N,N′-Dioxide 57 (76 mg, 0.2 mmol. 1.0 equiv.) were dissolved in acetonitrilee (250 ml) and the light yellow solution was refluxed for 24 h. The hot mixture was filtered and the solvent was removed. The crude product was chromatographed (SiO2, CH 2Cl 2/ MeOH 9: 1, detection: UV, I 2) to give a light yellow solid (89 mg, 58%).

1 Data for 58 ( mixture of diastereomers): H NMR (200 MHz, CD 3OD) δ 8.40 (d, J = 8.5 Hz, 1H), 8.11 – 7.74 (m, 11H), 7.71 – 7.40 (m, 5H), 4.41 – 4.22 (m, 2H), 3.99 (d, J = 2.1 Hz, 3H), 4.83 – 4.19 (m, 4H), 3.76 – 3.37 (m, 6H). ESI-MS (+ Ve): m/z (%) = 687.14 (100, [M]+).

Sodium cryptate [Na ⊂⊂⊂bpy.bpy.bpy-COO -] (Diast-59)

O N HO N N N Na O O N N N N

104

Experimental section

[MeCOO-bpy.bpy.bpyO 2⊂ Na]Br 58 (35 mg, 0.045 mmol) was dissolved in MeOH (9 ml).

To this solution NaOH (9.12 mg, 0.22 mmol, 5 equiv.) in H 2O (4ml) was added dropwise. The Solution was heated at 40 °C for 3 h and the reaction was monitored with TLC (eluent:

MeOH/H 2O 2:1). After complete the reaction, the solvents were removed and the crude product was chromatographed with short column (SiO 2, MeOH/H 2O 2:1, deterction: UV, I 2) to give the product as white solid (29 mg, 96 %).

1 Data for 59 ( mixture of diasteromers): H NMR (200 MHz, CD 3OD) δ(ppm) 8.32 (d, J = 3.8 Hz, 1H), 8.00 – 7.70 (m, 10H), 7.63 – 7.41 (m, 6H), 4.30 (d, J = 11.8 Hz, 2H), 3.93 – 3.79 (m, 4H), 3.64 – 3.37 (m, 6H). ESI-MS (+ Ve): m/z (%) = 673.23 (100, [M]+), 695.05 (12, [M+Na] +).

Sodium cryptate [Na ⊂⊂⊂biph.bpy.bpy-COOMe]Br (Diast -60)

O N MeO N N Na HO N HO Br N N

Diast-60

Under N 2, 37 (77.8 mg, 0.17 mmol), Na 2CO 3 (182 mg, 1.72 mmol, 10 equiv.), NaI (4.5 mg, 0.03 mmol, 0.2 equiv.) were dissolved in acetonitrile (150 ml) was refluxed for 30 min. Biphenol dibromide 30 (64 mg, 0.17 mmol, 1 equiv.) in acetonitrile (100 ml) was added dropwise over 3 h. The light yellow solution was refluxed for further 2 d and the solvent was then removed. The crude product was chromatographed (SiO 2, CH 2Cl 2/ MeOH 9: 1, detection: UV, I 2) to give the product as a yellow solid (55 mg, 42 %).

1 Data for 60 ( mixture of diastereomers): H NMR (200 MHz, CD 3OD ): δ (ppm) 8.22 (s (br), 1H), 8.01 – 7.69 (m, 7H), 7.58 – 7.33 (m, 3H), 7.35 – 7.22 (m, 4H), 7.09 – 6.92 (m, 2H), 3.98 (s, 3H), 4.42 – 3.35 (m, 12H) ESI-MS (+ Ve): m/z 685.22 (100, [M]+).

105

Experimental section

Sodium cryptate [Na ⊂⊂⊂biph.bpy.bpy-COO -] (Diast-61)

O N HO N N Na HO N HO Br N N

Diast-61

[MeCOO-bpy.bpy.bph ⊂ Na]Br (55 mg, 0.071 mmol, 1.0 equiv.) was dissolved in MeOH (12 ml). To this solution NaOH (14.3 mg, 0.36 mmol, 5 equiv.) in H2O (6 ml) was added dropwise. The solution was heated at 40 °C for 2-3 h and the reaction was monitored with

TLC (eluent: MeOH/H 2O 2:1 or 4:1). The solvents were removed and the crude product was chromatographed (SiO 2, eluent: MeOH/H 2O 2:1) to give the product as a light yellow solid (8.5 mg, 18 %).

1 Data for 61 ( mixture of diastereomers): H NMR (250 MHz, CD 3OD) δ 7.72 (m, 11H), 7.19 (d, J = 7.5 Hz, 4H), 7.00-6.81 (m, 2H), 4.43 – 3.27 (m, 12H). ESI-MS (+ Ve): m/z (%) = 715.2 (100, [M-2H+2Na]+) , 693.3 (70, [M-H +Na]+), 693.3 (67, [M-3H +3Na]+).

Sodium cryptate [Na ⊂⊂⊂biph.bpy.bpy-Br]Br (Diast-62)

Br N N N Na HO Br N HO N N

Diast-62

Bromo macrocycle 36 (70.0 mg, 0.14 mmol, 1.0 equiv.) and Na 2CO 3 (157 mg, 1.48 mmol, 10 equiv.) were dissolved in acetonitrilee (100 ml) and refluxed for 30 min. Biphenol dibromide 30 (54.8 mg, 0.14 mmol, 1.0 equiv.) in aceteonitrile (100 ml) was added dropwise. The light yellow solution was refluxed for further 2 d. After filtration and removal of the solvent the

106

Experimental section

crude product was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 9: 1, detection:

UV, I 2) to give a yellow solid (47 mg, 43%)

1 Data for 62 ( mixture of diasteromers): H NMR (200 MHz, CDCl3): δ (ppm) 7.87 – 7.62 (m, 4H), 7.42 – 7.53 (m, 5H), 7.35 – 7.13 (m, 6H), 6.97 (t, J = 7.4 Hz, 2H), 4.96 – 3.46 (m, 12H). ESI-MS (+ Ve): m/z = 705.1 (100, [M] +).

Sodium cryptate [Na ⊂⊂⊂biph.bpy.bpy-NO 2]Br (Diast-63)

O N N 2 N N Na HO Br N HO N N

Diast-63

Under N 2, a mixture of nitro macrocycle 38 (55 mg, 0.12 mmol, 1.0 equiv.) and Na 2CO 3 (133 mg, 1.25 mmol, 10 equiv.) in acetonitrile (150 ml) was refluxed for 30 min. Biphenol dibromide 30 (46.5 mg, 0.12 mmol, 1.0 equiv.) in acetonitrile (150 ml) was added dropwise over 3 h. The light yellow solution was refluxed for further 2 d and the solvent was then removed. The crude product was chromatographed (SiO2, CH 2Cl 2/MeOH 9: 1, detection: UV,

I2) to give the product as a yellow solid (yield: 24 mg, 27 %).

1 Data for 63 ( mixture of diastereomers): H NMR (200 MHz, CDCl 3: δ (ppm) 8.22 – 7.71 (m, 3H), 7.71 – 7.58 (m, 3H), 7.54 – 7.24 (m, 5H), 7.21 – 7.15 (m, 3H), 6.99 – 6.90 (m, 2H), 5.23 – 3.16 (m, 12H). ESI MS: m/z (%) = 672.14 (100, [M +]).

Sodium cryptate [Na ⊂⊂⊂biph.bpy.bpy-NH 2]Br (Diast-64)

H2N N N N Na HO Br N HO N N

Diast-64

107

Experimental section

Under N 2, [NO 2-bpy.bpy.biph ⊂ Na]Br 63 (24 mg, 0.032 mmol) and Pd/C (3 mg) were dissolved in dry MeOH (2 ml). NaBH 4 (14.5 mg, 0.38 mmol, 12 equiv.) was added at 0 °C. After the gas evolution was ceased the reaction was allowed to stir at rt over night. The reaction was monitored with ESI-MS spectrum (+ ESI). After the filtration through Celite, the solvent was removed and the solid was dissolved once again in small amount MeOH and filtered to give the product as white solid (13 mg, 56 %).

1 Data for 64 (mixture of diastereomers): H NMR (200 MHz, CD 3OD: δ (ppm) 8.16 – 7.25 (m, 11H), 7.16 (d, J = 6.0, 4H), 6.88 (t, J = 7.5 Hz, 2H), 4.29 – 3.30 (m, 12H). ESI MS: m/z 642.7 (100, [M +]).

4- Carbomethoxy-6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine N,N ′-dioxide O

Br OMe N O O N Br

4-Carbomethoxy-6,6 ′-bis(bromomethyl)-2,2 ′bipyridine 53 (250 mg, 0.73 mmol, 1.0 equiv.) was dissolved in dry CH 2Cl 2 (5 ml) and cooled in an ice-bath. To this solution urea hydrogen peroxide (206 mg, 2.19 mmol, 3.0 equiv.) was added followed by dropwise addition of TFAA (0.25 ml, 1.82 mmol, 2.5 equiv.). The solution was stirred at rt over night. Dichloromethane (10 ml) and sodium thiosulfate (5 ml) were added and the mixture was stirred for additional

40 min. After extraction with dichloromethane (3 x 50 ml) and drying over MgSO 4, the solvent was removed. The crude product was chromatographed (SiO 2, CH 2Cl 2/MeOH 50:1) to afford the product as white solid (133 mg, 49 %).

1 Data for 65: H NMR (200 MHz, CDCl 3): δ(ppm) 8.20 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.8, 1.8 Hz, 1H), 7.52 (dd, J = 7.8, 1.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 13 1H), 4.70 (s, 2H), 4.68 (s, 2H), 3.93 (s, 3H). C NMR (50 MHz, CDCl 3): δ(ppm) 163.8, 148.4, 148.2, 143.7, 142.8, 128.1, 127.9, 127.8, 127.5, 125.3, 124.6, 53.1, 25.5, 25.2.

108

Experimental section

Sodium cryptate [MeOOC-bpyO2.bpy.bpy ⊂⊂⊂Na]Br ( rac-66)

N OMe N Br N N Na O O N N N N

A mixture of macrocycle 10 (120 mg, 0.30 mmol, 1.0 equiv.) and Na 2CO 3 (323 mg, 3.04 mmol, 10 equiv.) in acetonitrile (200 ml) was heated to reflux. At this temperature 6,6’- methylester dioxide 65 (131 mg, 0.3mmol, 1.0 equiv.) in acetonitrile (100 ml) was added and the mixture was refluxed for further 2 d. After removal the solvent the crude product was chromatographed (SiO 2, CH 2Cl 2/MeOH 9: 1, detection: UV, I 2) to give rac-66 as a white solid (90 mg, 39 %).

1 Data for rac-66: H NMR (250 MHz, CD 3OD) δ (ppm) 8.37 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.02 – 7.81 (m, 10H), 7.64 (t, J = 7.8 Hz, 1H), 7.54 – 7.41 (m, 4H), 4.31 (d J = 11.8, 2H), 3.97 (s, 3H), 3.94 – 3.79 (m, 4H), 3.60 (d, J = 12.9, 2H), 3.48 (m, 4H). ESI MS : m/z (%) = 687.31 (100, [M +]).

Sodium cryptate [ -OOC-bpyO2.bpy.bpy ⊂⊂⊂Na +] rac-67

N N O N N Na O O N N N N

rac-67

[MeCOO-bpy.bpy.bpyO 2⊂ Na]Br 66 (85 mg, 0.11 mmol) was dissolved in MeOH (10 ml).

To this solution NaOH (9.12 mg, 0.55 mmol, 5 equiv.) in H 2O (9 ml) was added dropwise. The Solution was heated at 40 °C for 2-3 h and the reaction was monitored with TLC (eluent:

MeOH/H 2O 2/1). After complete the reaction, the solvents were removed and the crude product was chromatographed with short column (SiO 2, eluent: MeOH/H 2O 2/1) to give the product as white solid (60 mg, 80 %).

109

Experimental section

1 Data for 67: H NMR (250 MHz, CD 3OD) δ (ppm) 8.25 (dd, J = 14.2, 2.3 Hz, 2H), 8.05 – 7.79 (m, 10H), 7.71 – 7.44 (m, 5H), 4.39 (d, J = 11.8 Hz, 2H), 3.94 (dd, J = 12.7, 7.9 Hz, 4H), 3.76 – 3.46 (m, 6H). ESI MS (+ Ve) m/z (%) = 687.1 (100, [M]+)

Synthesis of pivaloyl 68

O OH

68 Biphenol (2.00 g, 10.7 mmol, 1.0 equiv.) and triethylamine (3.24 g, 32.1 mmol, 3.0 equiv.) were dissolved in acetonitrile (60 ml). At 0 °C pivalyl chloride (1.41 g, 11.7 mmol, 1.1 equiv.) was added dropwise. The solution was then stirred for 4 h at room temperature. The reaction mixture was diluted with water (80 ml) and washed with 1 N HCl, saturated aqueous

NaHCO 3 and brine. The organic layer was dried over MgSO 4. After the solvent was removed the crude product was chromatographed (SiO 2, hexane/ethyl acetate 6:1) to give 37 as white solid (2.2 g, 76%).

1 Data for 68: H NMR (200 MHz, CDCl 3): δ (ppm) 7.40 – 7.25 (m, 1H), 7.27 – 7.17 (m, 1H), 7.19 – 7.07 (m, 2H), 6.99 (dd, J = 12.1, 4.7 Hz, 2H), 6.82 (dd, J = 12.0, 4.9 Hz, 2H), 4.90 (s, 1H), 0.93 (s, 9 H).

Synthesis of 69

O OH

O2N 69 Pivalate 68 (1.0 g, 3.7 mmol, 1.0 equiv.) was added to a mixture of conc. nitric acid (5 ml), ether (30 ml) and conc. sulphuric acid (2 ml) at 0 °C and the colour of the reaction mixture turned to yellow. After stirring for 2 h at 0 °C, the mixture was poured into a mixture of ether (30 ml) and water (30 ml). The organic phase was washed with water (30 ml, 4 times) and dried over MgSO 4. After removal of the solvent, the resulting residue was purified by column

110

Experimental section

chromatography (SiO 2, hexane/ethyl acetate 2:1) to give the product as a yellow solid (yield: 460 mg, 39 %).

1 Data for 69: H NMR (250 MHz, CDCl 3): δ (ppm) 8.17 (dd, J = 9.0, 2.8 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.57 – 7.46 (m, 1H), 7.43 – 7.31 (m, 2H), 7.18 (dd, J = 8.0, 1.1 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 5.80 (s, 1H), 1.05 (s, 9H).

2,2 ′-Dihydroxy-5-nitro-biphenol

OH OH

O2N 70

A mixture of 69 (460 mg, 1.46 mmol, 1.0 equiv.), KOH (296 mg, 5.28 mmol, 3.6 equiv.),

THF (20 ml), and water (20 ml) was stirred at 60 °C for 12 h under N 2. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1

M HCl, saturated NaHCO 3, water and brine. The organic layer was dried over MgSO4 and concentrated in vacuum to give 70 as a yellow solid (yield: 320 mg, 95 %).

1 Data for 70: H NMR (400 MHz, CDCl 3): δ (ppm) 8.21 (d, J = 8.8, 2H), 7.42 – 7.34 (m, 1H), 7.31 (d, J = 7.7, 1H), 7.15 – 7.07 (m, 2H), 7.00 (d, J = 8.1, 1H).

2,2 ′-dimethoxy-5-nitro-biphenol

OMe OMe

O2N 71

A mixture of nitro biphenol 70 (320 mg, 1.38 mmol, 1.0 equiv.), methyl iodide (786 mg, 5.54 mmol, 4.0 equiv.), potassium carbonate (1.07 g, 7.76 mmol, 6.0 equiv.), and acetone (300 mL) was refluxed for 24 h. After cooling to room temperature, the mixture was concentrated in vacuum and the residue was extracted with CHCl 3. The organic layer was washed with 111

Experimental section

brine and dried over MgSO 4. After removal of the solvent, the product was isolated clean as a white solid without any further purification (yield: 110 mg, 31%).

1 Data for 71: H NMR (250 MHz, CDCl 3): δ (ppm) 8.28 (dd, J = 9.1, 2.9 Hz, 1H), 8.20 (d, J = 2.9 Hz, 1H), 7.48 – 7.35 (m, 1H), 7.26 (dd, J = 7.5, 1.8 Hz, 1H), 7.09 – 7.01 (m, 3H), 3.91 (s, 3H), 3.81 (s, 3H).

[99] 5-Nitrosalicylaldehyde

OH O

NO2 77

Salicylic acid (2.00 g, 16.38 mmol, 1.0 equiv.) was dissolved in acetic acid (5 ml). At 0 °C nitric acid (fuming) (1 ml) was added slowly. The temperature was increased to about 60 °C, the colour changed to yellow and the reaction was completed. The mixture was added to crushed ice and the yellow precipitate was filtered and dissolved again in 50 ml NaOH (aq) (2.5 g in 75 ml H 2O) and the solution was heated until the colour turned to red-brown. The orange solid was filtered and re-crystallized from water to give the product as a yellow solid (yield: 850 mg, 31%)

1 Data for 77: H NMR (250 MHz, d 6-DMSO): δ = 10.06 (s, 1H), 8.21 (s, 1H), 7.78 (dd, J = 9.7, 3.3 Hz, 1H), 6.18 (d, J = 9.7 Hz, 1H).

3-bromo-2-hydroxy-5-nitrobenzaldehyde [100]

OH O Br H

NO2 78

5-Nitrosalicylic aldehyde (850 mg, 5.08 mmol, 1.0 equiv.) was dissolved in H2SO 4 (5 ml). At 60 °C N-bromosuccinimide (1.08 g, 6.06 mmol, 1.2 equiv.) was added in three portions each in 15 min. After complete addition, the reaction was stirred at 60 °C for 2 h. The solution was 112

Experimental section cooled down and poured into crushed ice, the yellow precipitate was filtered and re-dissolved in dichloromethane dried over MgSO 4 to remove the water and yield the product as a yellow solid (yield: 550 mg, 48%).

1 Data for 78: H NMR (250 MHz, CDCl 3): δ (ppm) 12.22 (s, 1H), 9.95 (s, 1H), 8.68 (d, J = 2.6 Hz, 1H), 8.52 (d, J = 2.6 Hz, 1H).

[101] 5-bromo-2-hydroxy-3-iodo-benzoic acid

OH O I OH

Br 81

To a solution of 5-bromo-2-hydroxybenzoic acid (1.0 g, 4.63 mmol, 1.0 equiv.) in DMF (15 ml) was added NIS (1.04 g, 4.63 mmol, 1.0 equiv.). The reaction was stirred at room temperature for ~ 20 h. Ethyl acetate (20 ml) was added and the solution washed with 0.1 M

HCl. The organic phase was washed with water and then dried over MgSO 4. After removal the solvent the product was obtained as red oil (1.41 g. 91%).

Data for 81: 1H NMR (200 MHz, DMSO): δ (ppm) 8.20 (d, J = 2.5 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H).

Methyl 2-methoxy-3-iodo-5-bromobenzoate

OMe O I OMe

Br 82

5-Bromo-2-hydroxy-3-iodobenzoic acid (770 mg, mmol, 1.0 equiv.) and potassium carbonate (778.3 mg, 5.63 mmol, 2.5 equiv.) in acetone (100 ml) was heated to reflux. At this temperature, dimethyl sulfate (597 mg, 4.73 mmol, 2.1 equiv.) was added dropwise and the mixture was refluxed for further 4 hr. The solution was filtered and the solvent was removed

113

Experimental section under reduced pressure to give the product as a orange solid (yield: 480 mg, 57%). The analytical data were in agreement with those reported using other procedure. [135]

1 Data for 82: H NMR (200 MHz, CDCl 3) δ = 7.98 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 2.88 (s, 3H), 2.80 (s, 3H). GC MS (70 eV, 15.058 min): m/z 370 [M+H] +.

2, 6-dibromo-4-methylanisole

OMe Br Br

A mixture of 2, 6-dibromo-4-methylphenol (2.00 g, 7.57 mmol), methyl iodide (1.28 g, 9.01 mmol, 1.3 eq), potassium carbonate (1.35 g, 9.84 mmol, 1.2 eq), and acetone (~125 mL) was refluxed for 24 h. After cooling to ambient temperature, the mixture was concentrated in vacuum and the residue was poured into a separatory funnel with dichloromethane and water. The organic layer was washed with brine and dried over MgSO4. After removal of the solvent, the residue was separated by column chromatography (SiO 2, hexane/ethyl acetate 2:1) affording the product 56 as a yellow powder (yield: 1.52 g, 72 %).

1 Data for 84: H NMR (250 MHz, CD 3OD): δ (ppm) 7.36 (d, J = 0.6 Hz, 2H), 3.81 (s, 3H), 2.27 (s, 3H).

Synthesis of boronic acid 85 and stannane derivative 86

OMe O X H

X= B(OH)2 85

X= SnBu3 86

To a stirred concentrated solution of n-BuLi (1.6 M in Hexane, 3.3 ml, 5.46 mmol, 1.0 equiv.) in Et 2O (7-8 ml) was slowly added a solution of 2,6-dibromo-4-methylanisole ( 1.52 g, 5.46 mmol, 1.0 equiv.) in Et 2O (7-8 ml) at -85 °C. The mixture was stirred for 30 min, followed by

114

Experimental section

the drop wise addition of B(OMe) 3 or Bu 3SnCl (1.0 equiv.). The resultant light yellow mixture was diluted with THF (10 ml) and stirred for ca. 30 min at -70 °C. n- BuLi (1.6 M in hexane, 3.7 ml, 5.92 mmol, 1.08 equiv.) was added to give slurry. The slurry was stirred for 30 min at 65 °C. At this temperature DMF (3.2 g, 43.7 mmol, 8.0 equiv.) was added and the mixture was stirred and warm up to 0°C. At this temperature sulphuric acid (1.5 M, 10 ml) was added, the organic phase was separated and washed with water. After removal of the solvent, dark red oil was obtained. The analytical data for both 85 and 86 indicated the existence of impurities which could not be removed. The isolated oil was used as it for next step and therefore, the yield could not be determined.

1 Data for 85: H NMR (250 MHz, CDCl 3): δ (ppm) 10.36 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 3.96 (s, 3H), 2.35 (s, 3H).

1 Data for 86: H NMR (250 MHz, CDCl 3): δ (ppm) 10.34 (s, 1H), 7.63 (d, J = 1.9, 1H), 7.45 (d, J = 2.3 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 1.71 – 1.45 (m, 6H), 1.31 – 1.18 (m, 6H), 1.20 – 1.03 (m, 6H), 0.94 (t, J = 7.2 Hz, 9H).

Synthesis of 88 OH

OMe

OMe Br O 88

Under N 2, a solution of methyl 2-methoxy-3-iodo-5-bromobenzoate 82 (190 mg, 0.51 mmol, 1.0 equiv.), 2-hydroxymethyl-5-tri-n-butylstannylfuran 113 (200 mg, 0.51 mmol, 1.0 equiv.) , bis(triphenylphosphine)palladium(II) chloride ( 0.035 mg, 0.05 mmol, 0.043 equiv.) and triphenylphosphine (0.02, 0.01 mmol, 0.017 equiv.) in degassed toluene (20 ml) was refluxed overnight. The resulting black solution was concentrated and extracted with ethyl acetate (3 x 70 ml). After removal of the solvent, the residue was subjected to column chromatography

(SiO 2, hexanes/ethyl acetate 4:1, detection: UV) to afford the product as dark yellow solid (130 mg, 75%).

115

Experimental section

1 Data for 88: H NMR (250 MHz, CDCl 3) δ 8.06 (d, J = 2.6 Hz, 1H), 7.75 (d, J = 2.6 Hz, 1H), 6.94 (d, J = 3.3 Hz,1H), 6.37 (d, J = 3.3 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H).

3-Bromo-3-chloro-2-hydroxybenzoic acid [101]

OH O Br OH

Cl 90

To a solution of 5-chloro-2-hydroxybenzoic acid 89 (1.0 g, 5.3 mmol, 1.0 equiv.) in DMF (15 ml) was added NIS (1.03 g, 5.7 mmol, 1.07 equiv.). The reaction was stirred at room temperature for ~ 20 h. Ethyl acetate (20 ml) was added and the solution washed with 0.1 M

HCl. The organic phase was washed with water and then dried over MgSO 4. After removal the solvent the product 90 was obtained as white solid (Yield: 1.5 g even after drying under vacuum at 60° C , NMR still indicated the existence of DMF) .

1 Data for 90: H NMR (200 MHz, d6-DMSO): δ 8.00 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H).

Synthesis of 91

OMe O Br OMe

Cl 91

To a solution 5-chloro-2-hydroxy-3-bromobenzoic acid 90 (1.52 g, 6.08 mmol, 1.0 equiv.) in DMF (40 ml) was added potassium carbonate (2.5 g, 18.08 mmol, 3.0 equiv.) and methyl iodide (5.17 g, 36.48 mmol, 6.0 equiv.) at room temperature. The reaction mixture stirred at

75 ºC for 18 h. After addition of H 2O, the mixture was extracted with ethyl acetate, washed with H 2O and brine, dried over anhydrous Na2SO 4, and concentrated in vacuum (yield: 900 mg, 41%).

116

Experimental section

1 Data for 91: H NMR (200 MHz, CDCl 3) δ 7.71 (dd, J = 5.3, 2.6 Hz, 2H), 3.93 (s, 3H), 3.91 13 (s, 3H). C NMR (50 MHz, CDCl 3): δ 164.44, 155.68, 136.52, 130.41, 129.57, 127.43, 119.78, 62.24, 52.66.

Sodium cryptate [Lys-bpy.bpy.bpyO 2⊂⊂⊂Na] (Diast-93)

NHFmoc O N HO N N H N N O Na O O N N N N

- + Under N 2, [ OOC-bpy.bpy.bpyO2 ⊂ Na ] (15 mg, 0.022 mmol, 1.0 equiv.) was dissolved in DMF (2 ml) and HATU (8.89 mg, 0.023 mmol, 1.05 equiv.) was added. The solution was stirred for 2 h at room temperature. Fmoc-L-Lys-OH (8.2 ml, 0.022 mmol, 1.0 eq) was added and the mixture was stirred over night. The solvent was removed and the yellow was dried well under vacuum. The crude product was chromatographed twice (SiO 2, CH 2Cl 2/MeOH 2/1) to offer the product as light yellow solid (4.0 mg, 18 %).

1 Data for 93 ( mixture of diastereomers): H NMR (250 MHz, CD 3OD) δ 8.36 (d, J = 4.3 Hz, 3H), 8.03 (d, J = 8.4 Hz, 4H), 7.95 – 6.85 (m, 18H), 4.58 – 3.26 (m, 13H), 1.90 – 1.12 (m, 7H). ESI-MS ( +Ve ): m/z (%) = 1023.54 (100, [M +]).

Sodium cryptate Na-16 [Lys-bpy.bpy.biph ⊂⊂⊂Na]

NHFmoc O N HO N N H N O Na HO N HO N N

94 - + Under N 2, [ OOC-bpy.bpy.bph ⊂ Na ] (8.5 mg, 0.012 mmol, 1.0 equiv.) was dissolved in DMF (1 ml) and HATU (5.3 mg, 0.014 mmol, 1.1 equiv.) was added. The solution was stirred for 2 h at room temperature. Fmoc-L-Lys-OH (4.67 ml, 0.012 mmol, 1.0 equiv.) was added

117

Experimental section and the mixture was stirred over night. The solvent was removed and the yellow solid was dried well under vacuum. The crude product was chromatographed (SiO 2, DCM/MeOH 2:1).

Data for 94: ESI MS : m/z (%) = 1021.29 (65, [M +]).

Synthesis of lanthanide cryptates 102a and 102b

+ + + N N N O O N O O N Ln O Ln O Ln O O O O O N O O O N N N N

Ln = Gd 95a Ln = Gd 96a Ln = Gd 97a

= Eu 97b

= Tb 97c

General procedure: A solution of sodium cryptate (1.0 equiv.), LnCl 3 ⋅ 6 H 2O (1.5 equivs.) and triethylamine (5.0 equivs.) in dry acetonitrile was heated under reflux overnight. The solvent was removed in vacuo . The remaining residue was dissolved in a minimum amount of

MeOH and the solution was layered with Et 2O. After storing the suspension at room temperature overnight, the precipitate was collected on a membrane filter (nylon, 0.45 µm), washed with Et 2O, and dried in vacuo to yield the lanthanoid complex as light-yellow powder.

95a: 8.3 mg (from 18.0 mg of 24 ) MS (ESI+): m/z (%) = 728.10 ([M] +), 764.1 (100, [M+H+Cl -]+ 96a: 9.7 mg (from 20 mg of 24 ) MS (ESI+): m/z (%) = 628.10 (89, [M] +), 664.0 (100, [M+H+Cl -]+ 97a: 1.8 mg (from 4.0 mg of 33 ) MS (ESI+): m/z (%) = 760.0 (38, [M] +), 796.0 (11, [M+H+Cl -]+ 97b: 3.2 mg (from 7.0 mg of 33 ) MS (ESI+): m/z (%) = 755.10 ([M] +). 97c: 3.7 mg (from 7.5 mg of 33 ) MS (ESI+): m/z (%) = 761.00 ([M] +).

118

Experimental section

+3 [Y ⊂⊂⊂bpy.bpy.bpyO 2] (rac-98)

3 N N N N X Y O O N N N N - . 2- X =Cl , (YCl5 6H2O)

[bpy.bpy.bpyO2 ⊂Na]Br 2 (117 mg, 0.16 mmol1.0 equiv.) and YCl 3. 6H 2O (75 mg, 0.24, 1.5 equiv.) were dissolved in acetonitrilee (50 ml, HPLC grade) and the mixture was refluxed overnight. TLC (SiO 2, CH 2Cl 2: MeOH 9:1) showed a spot corresponding to the sodium cryptate. Therefore, (9.7 mg, 0.2 equiv.) was added and the mixture was refluxed for further one day. The solvent was removed and the complex was isolated by dissolving in a minimum amount of MeOH and precipitated with diethyl ether (yield: 142 mg of a white solid).

1 Data for 98 : H NMR (200 MHz, CD 3OD) δ 8.52 (d, J = 8.0 Hz, 2H), 8.44 (d, J = 8.1 Hz, 2H), 8.38 – 8.14 (m, 10H), 7.73 (s, 2H), 7.69 (s, 2H), 4.80 (d, J = 15.1 Hz, 2H), 4.67 (d, J = 12.7 Hz, 2H), 4.24 (d, J = 10.9 Hz, 2H), 4.17 (d, J = 10.3 Hz, 2H), 3.95 (d, J = 12.7 Hz, 2H), 13 3.83 (d, J = 15.8 Hz, 2H, ). C NMR (63 MHz, CD 3OD): δ 159.1, 156.8, 155.9, 154.1, 150.6, 144.6, 143.1, 142.4, 136.1, 132.4, 131.0, 126.9, 126.7, 123.7, 123.3, 61.7, 60.7, 56.9. MS 2+ 3+ (ESI+): m/z (%) = 365.10 (100, [M+Cl] ), 231.70 (4, [M] ). Anal. Calcd. for C36 H30 BrN 8O2

Cl·YCl 5·6H2O: N, 10.14; C, 39.12; H, 3.83. Found: N, 10.23; C, 39.48; H, 4.54.

Synthesis of dialdehyde 106 O

H N

N H

O 106

Under N 2 and at −60°C, oxalyl chloride (452 mg, 0.30 mL, 3.56 mmol, 2.2 equivs.) was dissolved in CH 2Cl 2 (20 mL) and a solution of dry DMSO (556 mg, 7.12 mmol, 4.4 equivs.) in dry CH 2Cl 2 (5 mL) was added. The mixture was stirred for 5 min at this temperature before 119

Experimental section a solution of 6,6 ′-bis(hydroxymethyl)-2,2 ′-bipyridine 105 (350 mg, 1.62 mmol, 1.0 equiv.) in

CH 2Cl 2 (50 mL, with a minimum of dry DMSO necessary to dissolve everything) was added dropwise. After 15 min, dry NEt 3 (16.2 mmol, 1.63 g, 2.26 mL, 10 equivs.) was added and the mixture was allowed to reach room temperature over the course of a ca. 5 hours. Water (75 mL) was added, the phases were separated, and the aqueous layer was extracted with CH 2Cl 2

(2 × 50 mL). After drying the combined organic phases (MgSO 4), the solvent was removed under reduced pressure and the remaining light-brown solid was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 24:1, detection: UV). The product was isolated as a colorless solid (196 mg, 57%). The analytical data of the product were in agreement with previous reports using different synthetic procedures. [114, 115]

1 Data for 106: H NMR (200 MHz, CDCl 3): δ = 10.19 (s, 2 H), 8.85 −8.81 (m, 2 H), 8.07 −8.02 (m, 4 H) ppm.

Synthesis of macrocycle 108

N H N O

N O H N

108

Under N 2, anhydrous MgCl 2 (88 mg, 0.92 mmol, 1.0 equiv.) and 2,2 ′-bipyridine-6,6 ′- dicarbaldehyde 106 (196 mg, 0.92 mmol, 1.0 equiv.) were suspended in dry MeOH (20 mL) and the mixture was stirred at room temperature for 30 min. 1,8-Diamino-3,6-dioxaoctane 107 (137 mg, 0.92 mmol, 1.0 equiv.) in dry MeOH (2 mL) was added, stirring was continued for 1 h, and NaBH 4 (4.62 mmol, 175 mg, 5.0 equivs.) was added in small portions. After 20 h at room temperature, water (20 mL) was added to the clear solution, MeOH was removed under reduced pressure, and the aqueous phase was extracted with CH 2Cl 2 (3 × 35 mL). The combined organic layers were dried (MgSO 4) and concentrated. The crude product (280 mg, 93%) was obtained as a faintly yellow oil that appears to be slightly air-sensitive. It was therefore stored under inert atmosphere at 4°C and was used without further purification.

1 Data for 108: H NMR (250 MHz, CDCl 3): δ = 8.41 −7.06 (m, 4 H), 7.35 −7.06 (m, 2 H), 4.04 −3.85 (m, 4 H), 3.72 −3.52 (m, 8 H), 2.94 −2.74 (m, 4 H) ppm. 13 C NMR (62.9 MHz,

CDCl 3): δ =159.7, 159.1, 158.9, 156.6, 137.1, 137.0, 122.2, 122.0, 120.6, 119.3, 70.8, 70.6, 120

Experimental section

70.3, 64.2, 55.0, 54.9, 49.0, 48.8. MS (ESI+): m/z (%) = 351.13 (100, [M+Na] +), 329.18 (13, [M+H] +).

Sodium cryptate 102 + N N O N Na Br N N O N

102

Macrocycle 108 (132 mg, 402 µmol, 1.0 equiv.) was dissolved in CH 3CN (200 mL) and anhydrous Na 2CO 3 (426 mg, 4.02 mmol, 10 equivs.) was added. The suspension was heated to reflux and a solution of the 6,6 ′-bis(bromomethyl)-2,2 ′-bipyridine 56 (137 mg, 402 µmol,

1.0 equiv.) in freshly distilled CH 3CN (300 mL) was added under high-dilution conditions over 9 h. The mixture was heated under reflux for additional 20 h, cooled to ambient temperature, and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (SiO 2, gradient: CH 2Cl 2/MeOH gradient 24:1 →

9:1, detection: UV and I 2 vapor). The product was isolated as a colorless solid (42 mg, 17%).

1 Data for 102: H NMR (250 MHz, CDCl 3): δ = 8.03 −7.81 (m, 8 H), 7.43 −7.33 (m, 4 H), 3.97 (d, J = 14.0 Hz, 4 H), 3.82 −3.61 (m, 12 H), 2.72 (t, J = 5.2 Hz, 4 H) ppm. 13 C NMR (62.9

MHz, CDCl 3): δ = 158.8, 155.6, 138.7, 124.7, 120.8, 69.0, 66.1, 59.9, 53.3 ppm. MS (ESI+): + m/z (%) = 531.13 (100, [M] ). Rf = 0.17 (SiO 2, CH 2Cl 2/MeOH 9:1, detection: UV and I 2 vapor).

Synthesis of lanthanide cryptates 102a and 102b

3+ N N O N Ln N N O N

Ln = Gd 102a

= Eu 102b

121

Experimental section

General procedure: A solution of sodium cryptate 102 (1.0 equiv.) and LnCl 3 ⋅ 6 H 2O (1.05 equivs.) in dry acetonitrile was heated under reflux overnight. The solvent was removed in vacuo . The remaining residue was dissolved in a minimum amount of MeOH and the solution was layered with Et 2O. After storing the suspension at room temperature overnight, the precipitate was collected on a membrane filter (nylon, 0.45 µm), washed with Et 2O, and dried in vacuo to yield the lanthanoid complex as light-yellow powder.

102a : 5.1 mg (from 10.1 mg of 102 ) + MS (ESI+): m/z (%) = 735.94 ([M+2Cl] ); Anal. Calcd. (Found) for [C 30 H32 N6O2Gd](Cl) 3 ⋅⋅⋅

GdCl 3 ⋅⋅⋅ 8 H 2O (Mr = 1179.95): C, 30.5 (30.0); H, 4.10 (3.75); N, 7.12 (6.78). 102b : 1.4 mg (from 10.8 mg of 102 ) + MS (ESI+): m/z (%) = 730.93 ([M+2Cl] ); Anal. Calcd. (Found) for [C 30 H32 N6O2Eu](Cl) 3 ⋅⋅⋅

EuCl 3 ⋅⋅⋅ H 2O ⋅⋅⋅ 3 MeOH ⋅⋅⋅ Et 2O (Mr = 1213.52): C, 36.6 (36.9); H, 4.65 (4.79); N, 6.93 (7.34). . 2-Bromo-6-[(tert-butyldimethylsilyloxy)methyl]pyridine

O Br N Si

111

2-Bromo-6-hydroxymethylpyridine [125] (250 mg, 1.3 mmol, 1.0 equiv.), dry triethylamine (0.16 g, 0.27 ml, 1.58 mmol, 1.2 equiv.) and tert-butyldimthylsilyl chloride (0.20 g, 1.3 mmol,

1.0 equiv.) were dissolved in dry dichloromethane . 4-Dimethylaminopyridine (0.014 g, 0.11 mmol, 0.08 equiv.) was added and the mixture was stirred at room temperature over night. After addition of water, the organic layer was separated, washed with water and dried over

MgSO 4. The solvent was removed to give a colourless oil, which was subjected to column chromatography (SiO 2, CH 2Cl 2, detection: UV) to afford the product as white solid (250 mg, 91%). The analytical data of the product were in agreement with previous reports using different procedures [126, 127] .

1 Data for 111: H NMR (200 MHz, CDCl 3): δ (ppm) 7.61 – 7.42 (m, 2H), 7.36 – 7.21 (m, 13 1H), 4.80 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H) C NMR (50.1 MHz, CDCl 3): δ (ppm) 163.4, 141.1, 139.1, 126.1, 118.8, 65.6, 26.0, 18.4, -5.2. FAB +: m/z (%) = 302.0 (67, [M+H] +). Anal.

122

Experimental section

Calcd. for C 12 H20 BrNOSi.0.5H 2O: N, 4.50; C, 46.30; H, 6.80. Found: N, 4.91; C, 46.66; H, 6.46.

Synthesis of 114

O O N Si Si 114 O

Under N 2, a solution of 111 (1.45 g, 4.8 mmol, 1.0 equiv.), furane stannane 112 (2.40 g, 4.77 mmol, 1.0 equiv.), bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol, 0.01 equiv.) and triphenylphosphine (0.02 g, 0.1 mmol, 0.02 equiv.) in degassed toluene (30 ml) was refluxed overnight. The solvent was removed and the crude product was subjected to column chromatography (SiO 2, hexane/ethyl acetate 40:1, detection: UV) to give the product as yellow solid (600 mg, 29%).

1 Data for 114: H NMR (200 MHz, CDCl 3): δ (ppm) 7.69 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 6.8 Hz, 1H), 6.95 (d, J = 3.3 Hz, 1H), 6.34 (d, J = 3.3 Hz, 1H), 4.84 (s, 2H), 4.71 (s, 2H), 0.96 (s, 9H), 0.91 (s, 9H), 0.12 (s, 6H), 0.10 (s, 6H). 13 C NMR (50.1 MHz,

CDCl 3): δ (ppm) 161.3, 155.6, 148.4, 137.1, 118.1, 116.6, 109.4, 66.2, 58.5, 31.9, 29.4, 25.9, 22.7, 18.4, 14.1, -5.3. ESI-MS (+ Ve): m/z (%) = 334.26 (100, [M+H]+).

Synthesis of 115

HO O N O Si 115

Under N 2, a solution of 111 (347 mg, 1.15 mmol, 1.0 equiv.), 2-hydroxymethyl-5-tri-n- butylstannylfuran 113 (580 mg, 1.15 mmol, 1.0 equiv.) , bis(triphenylphosphine)palladium(II) chloride ( 0.035 mg, 0.05 mmol, 0.043 equiv.) and triphenylphosphine (0.02, 0.01 mmol, 0.017 equiv.) in degassed toulene (30 ml) was refluxed overnight. The resulting black solution was concentrated and extracted with ethyl acetate. The obtained yellow oil was purified by column chromatography (SiO 2, hexanes/ethyl acetate 4:1, detection: UV) to afford the product as orange solid (180 mg, 49%).

123

Experimental section

1 Data for 115: H NMR (200 MHz, CDCl 3): δ (ppm) 7.70 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 3.3 Hz, 1H), 6.39 (d, J = 3.3 Hz, 1H), 4.84 (s, 13 2H), 4.66 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H). C NMR (50.1 MHz, CDCl 3): δ (ppm) 161.4, 154.8, 153.5, 148.1, 137.1, 118.3, 116.8, 110.1, 109.2, 66.0, 57.7, 25.9, -5.3. ESI-MS (+ Ve): m/z (%) = 342.01 (100, [M+Na] +).

Synthesis of 115

O N OH 116 HO

From 114 : A solution of 114 (150 mg, 0.47 mmol) in THF/AcOH/H2O (9 ml: 9 ml: 3ml) was stirred for 6-7 d. The reaction was followed with TLC. The solution was diluted with dichloromethane, quenched with aqueous K 2CO 3 (30 ml, 1M) and anhydrous K 2CO 3 was added until gas evolution ceased. The organic layer was separated, washed with brine and dried over MgSO 4. After removal of the solvent the product was obtained as light yellow solid.

From 115 : A solution of 115 (250 mg, 0.577 mmol) in THF/AcOH/H2O (9 ml : 9 ml :3 ml) was stirred for 6-7 d and the reaction was followed with TLC (hexane/ethyl acetate 5:2). The solution was diluted with CH 2Cl 2 (60 ml) quenched with aqueous K 2CO 3 (30 ml, 1M).

Anhydrous K 2CO 3 was added cautiously until gas evolution ceased. The organic phase was separated, washed with brine and dried over MgSO 4. After removal the solvent the product was dried under vacuum at 60° C (110 mg, 93%).

1 Data for 116: H NMR (200 MHz, d 6-DMSO): δ (ppm) 7.84 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 3.3 Hz, 1H), 6.44 (d, J = 3.3 Hz, 1H), 5.40 (t, J = 5.8 Hz, 1H), 5.31 (t, J = 5.7 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.47 (d, J = 5.5 Hz, 2H). 13 C NMR (50 MHz, d6-DMSO): δ (ppm) 161.3, 155.9, 151.7, 147.0, 135.8, 117.6, 115.1, 109.1, 63.2, 58.6, 53.1. ESI-MS (+ Ve): m/z (%) = 227.9 (100, [M+Na] +), 205.9 (9, [M] +).

Anal. Calcd . for C 11 H11 NO 3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.35; H, 5.14; N, 6.53.

124

Experimental section

Synthesis of 117

Br N O 117 Br

Under N 2 and at 0° C, phosphorus tribromide (154 mg, 0.57 mmol, 1.2 equiv.) was added dropwise to a solution of dialcohol 116 (100 mg, 0.48 mmol, 1.0 equiv.) in dichloromethane (10 ml). The solution was stirred at room temperature overnight, before water was added. The organic layer was separated, dried over MgSO 4, and concentrated under reduced pressure to afford the product as yellow solid (90 mg, 56 %)

1 Data for 117: H NMR (250 MHz, CDCl 3): δ (ppm) 7.73 (t, J = 7.7 Hz, 1H), 7.63 (dd, J = 7.9, 1.0 Hz, 1H), 7.33 (dd, J = 7.6 Hz, 1.0 Hz, 1H), 7.12 (d, J = 3.4 Hz, 1H), 6.51 (d, J = 3.4 13 Hz, 1H), 4.57 (s, 2H), 4.56 (s, 2H). C NMR (62.9 MHz, CDCl 3): δ (ppm) 156.9, 153.8, 151.5, 138.2, 122.3, 118.3, 112.7, 33.6, 23.7.

Sodium cryptate [Na ⊂⊂⊂Fupy.2.1]Br ( rac-109)

N O N O Na Br O O N

rac- 109

Under N 2, Kryptofix 21 118 (60 mg, 0.27 mmol, 1.0 equiv.) and anhydrous sodium carbonate (290 mg, 2.7 mmol, 10 equiv.) were suspended in acetonitrile (300 ml) and the mixture was heated to reflux. To this mixture (90 mg, 0.27 mmol, 1.0 equiv.) 117 in acetonitrile (200 ml) was added dropwise to this mixture over a period of ca. 12 h. Heating was continued for additional 24 h. After filtration and solvent removal, the crude product was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 9:1, detection: I 2, UV) to afford the 108 as light yellow solid (65 mg, 54%).

125

Experimental section

1 Data for rac-109: H NMR (250 MHz, CDCl 3) δ (ppm) 7.60 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 6.26 (dd, J = 3.2 Hz, 1.2 Hz, 1H), 4.35 – 3.92 (m, 6H), 3.85 – 3.66 (m, 2H), 3.48 – 3.02 (m, 8H), 2.81 – 2.58 (m, 6H), 2.56 13 – 2.20 (m, 4H). C NMR (50.1 MHz, CDCl 3): δ (ppm) 157.0, 151.6, 150.3, 147.6, 137.7, 121.1, 116.7, 109.8, 109.7, 69.5, 69.4, 67.4, 67.4, 67.0, 66.8, 58.7, 54.1, 53.8, 52.2, 52.1, 50.9. ESI-MS (+ Ve): m/z (%) = 410.03 (100, [M] +).

Sodium cryptate [Na ⊂⊂⊂Fupy.bpy.2]Br ( rac-110)

N N O N Na N Br O O N

rac- 110

Under N 2, macrocycle 108 (65.0 mg, 0.19 mmol, 1.0 equiv.) and anhydrous sodium carbonate (308 mg, 1.97 mmol, 10 equiv.) were suspended in acetonitrile (200 ml) and heated to reflux. A solution of (65.5 mg, 0.19 mmol, 1.0 equiv.) 117 in acetonitrile (100 ml) was added dropwise overnight. The reaction mixture was additionally refluxed for further 24 h. After filtration and removal of the solvent, the crude product was subjected to column chromatography (SiO 2, CH 2Cl 2/MeOH 9:1, detection: I 2, UV) to afford the rac-109 as light yellow solid (19 mg, 17 %).

1 Data for rac-110: H NMR (200 MHz, CDCl 3): δ (ppm) 7.93 – 7.81 (m, 4H), 7.66 (t, J = 7.7 Hz, 1H), 7.49 – 7.30 (m, 3H), 7.11 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 3.3 Hz, 1H), 6.39 (d, J = 13 3.3 Hz, 1H), 4.00 – 3.39 (m, 16H), 2.92 – 2.50 (m, 4H). C NMR (50.1 MHz, CDCl 3): δ (ppm) 158.8, 157.8, 155.7, 152.6, 151.5, 149.5, 148.7, 138.8, 138.7, 138.1, 129.2, 125.0, 124.8, 122.1, 121.3, 121.2, 117.6, 110.8, 109.6, 69.3, 69.1, 66.5, 66.4, 59.7, 59.4, 52.8, 52.8, 51.4. ESI-MS (+ Ve): m/z (%) = 520.1 (100, [M] +).

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131

Appendix

7 Appendix

Table 4 . Crystal data and structure refinement for Pd-dimer.

Identification code pd-complex

Empirical formula C70 H 78 Br 2N2O2P2Pd 2Si 2

Formula weight 1470.08

Temperature 293 (2)

Wavelength 0.71073 A

Crystal system, space group Triclinic, P-1

Unit cell dimensions alpha = 80.222 deg. a = 13.492 (8) A b = 16.093 (8) A beta = 85.517 deg. c = 18.060 (5) A gamma = 69.838 deg.

Volume 3615 (2) A^3

Z, Calculated density 2, 1.351 Mg/m^3

Absorption coefficient 1.722 mm^-1

F(000) 1496

Crystal size 0.2 x 0.2 x 0.2 mm

Theta range for data collection 1.14 to 25.09 deg.

Limiting indices -12<=h<=15, -19<=k<=19, -19<=l<=21

Reflections collected / unique 12420 / 8971 [R(int) = 0.0595]

Completeness to theta = 25.05 99.8 %

Absorption correction Semi-empirical from equivalents

Refinement method SHELXL-97 (Sheldrick, 2008)

Data / restraints / parameters 12420 / 0 / 700

Goodness-of-fit on F^2 1.090

Final R indices [I>2sigma(I)] R1 = 0.0758, wR2 = 0.22315

R indices (all data) R1 = 0.1020, wR2 = 0.2478

132

Appendix

-1 E(T 1) = 22 240 cm

Figure 7.1: Low-temperature (77 K) steady state emission spectrum (black) of 101a in MeOH/EtOH (1:1, v/v) after excitation at λexc = 306 nm (cumulative fit function in red and individual gaussians in gray).

-1 E(T 1) = 22 230 cm

Figure 7.2: Low-temperature (77 K) steady state emission spectrum (black) of 102a in MeOH/EtOH (1:1, v/v) after excitation at λexc = 306 nm (cumulative fit function in red and individual gaussians in gray).

133

Appendix

-1 E(T 1) = 21 610 cm

Figure 7.3: Low-temperature (77 K) steady state emission spectrum (black) of 103a in MeOH/EtOH (1:1, v/v) after excitation at λexc = 306 nm (cumulative fit function in red and individual gaussians in gray).

134