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TOWARDS THE SYNTHESIS OF FUNCTIONALISED MACROCYCLIC RECEPTORS A dissertation submitted to the University of Manchester for the degree of Master of Science by Research in the Faculty of Engineering and Physical Sciences 2012 IMAN RAJABI SCHOOL OF CHEMISTRY 1 Table of Contents Abstract.................................................................................................. 4 Declaration ............................................................................................ 5 Copyright statement ............................................................................. 5 Acknowledgements ............................................................................... 6 List abbreviations ................................................................................. 7 INTRODUCTION ................................................................................ 8 1 Introduction.................................................................................... 9 1.1 Supramolecular chemistry ......................................................... 9 1.1.1 Host-Guest Chemistry ........................................................................................................... 9 1.2 Macrocycles ............................................................................... 10 1.2.1 Crown Ethers ...................................................................................................................... 12 1.2.1.1 Synthesis of crown ether .................................................................................................. 14 1.3 Mixed-donor Macrocycles ....................................................... 15 1.3.1 Templating Effects .............................................................................................................. 17 1.3.2 The Caesium Effect ............................................................................................................. 19 1.4 Macrocycles as Catalysts.......................................................... 20 1.4.1 Application of crown ethers (single/mixed donor) .............................................................. 24 1.4.1.1 Miscellaneous applications of crown ethers in synthesis ................................................. 25 2 Results and Discussion ................................................................ 28 2.1 Pyridine-based Macrocycles .................................................... 28 2.1.1 Introduction......................................................................................................................... 28 2.1.2 Aims and Objectives ............................................................................................................ 31 2.2 Discussion of Results................................................................. 32 2.2.1 Preparation of Bromo-ditosylate ........................................................................................ 33 2.2.1.1 Esterification of chelidamic acid ...................................................................................... 36 2.2.1.2 Preparation of bromide 78 ................................................................................................ 36 2.2.1.3 Reduction of bromo-diester ............................................................................................. 38 2.2.2 Preparation of macrocycle 82 ............................................................................................. 40 2 2.2.2.1 Attempted synthesis of macrocycles using different spacers ............................................ 41 2.2.3 Oxidation of Macrocycle ..................................................................................................... 42 2.2.4 Oxidation of bromo-ditosylate 81 and the synthesis of a crown-N-oxide ............................. 43 2.2.4 Attempted Pd-Coupling reaction......................................................................................... 45 3. Conclusion ................................................................................... 45 3.1 Future Work................................................................................ 46 EXPERIMETAL................................................................................. 47 4 Experimental ................................................................................ 48 4.1 General Experimental .............................................................. 48 4.2 Cross-linkers ............................................................................. 49 4.3 Macrocycles ............................................................................... 56 4.4 Unsuccessful attempts at the synthesis of three further macrocycles.......................................................................................... 58 5. References ....................................................................................... 61 Appendix .............................................................................................. 63 3 Abstract A practical route to the synthesis of two new macrocyclic thio-crown ethers, 13bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene, 82, and 13bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13-triene-15-oxide, 84, is described. Both macrocycles were fully characterised using elemental analysis, 1H NMR, 13C NMR, and mass spectroscopy. The solid-state structure of 82 was also determined using X-ray crystallography. During these investigations it was shown that Cs+ can be replaced by K+ as an effective template in the pivotal macrocyclisation reaction. An operationally simple route to the synthesis of 4-bromo-2,6- bis((tosyloxy)methyl)pyridine 81, the key intermediate to both macrocycles, starting from chelidamic acid 75 has also been developed which will facilitate the synthesis of other macrocycles using this scaffold. The attempted functionalisation of 82 using a Heck reaction is described. 4 Declaration No portion of the work referred to in the dissertation has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning. Copyright statement i. The author of this dissertation (including any appendices and/or schedules to this dissertation) owns any copyright in it (the “Copyright”) and s/he has given The University of Manchester the right to use such Copyright for any administrative, promotional, educational and/or teaching purposes. ii. Copies of this dissertation, either in full or in extracts, may be made only in accordance with the regulations of the John Rylands University Library of Manchester. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made. iii. The ownership of any patents, designs, trade marks and any and all other intellectual property rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of copyright works, for example graphs and tables (“Reproductions”), which may be described in this dissertation, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property Rights and/or Reproductions. iv. Further information on the conditions under which disclosure, publication and exploitation of this dissertation, the Copyright and any Intellectual Property Rights and/or Reproductions described in it may take place is available from the Head of School of Chemistry. 5 Acknowledgements I’ll like to take this opportunity to express my appreciation to the people who have been influential in successful completion of this project. I would like to show my gratitude to my supervisor and mentor, Dr. Peter Quayle for giving me the opportunity to be part of the Quayle group and for his endless support and valuable advice through out the past year. It was a pleasure to learn from him and to work in his group. I would like to thank every single member of the Quayle group for their help and assistance. Especially, Omer Rasheed, Mark Little and Andreas Economou. My appreciation also goes to all technical and administrative staff from the Chemistry Department. Last but not least, I would also like to thank my dear parents, brothers and lovely fiancée for encouraging me to study harder and supporting me through out. 6 List abbreviations br.s Broad singlet mCPBA 3-Chloroperoxybenzoic acid d doublet DCM Dichloromethane DMAP 4-(Dimethylamino)pyridine DMF N,N-Dimethylformamide EtOAc Ethyl acetate HPLC High pressure liquid chromatography HRMS High resolution mass spectrometry IR Infrared spectroscopy m multiplet MeOH Methanol MS Mass spectrometry NMR Nuclear magnetic resonance NRO Nucleophilic ring opening q quartet quin. quintet RuAAC Ruthenium mediated azide-alkyne cyclisation s singlet t triplet TBAB Tetrabutylammonium bromide TEA Triethylamine THF Tetrahydrofuran TLC Thin layer chromatography TsCl Tosyl chloride 7 INTRODUCTION 8 1 Introduction 1.1 Supramolecular chemistry Jean-Marie Lehn described supramolecular chemistry as an interdisciplinary field of science covering the chemical, physical and biological features of highly complex chemical species involving two or more molecules held together by noncovalent interactions.1 Therefore, two factors which are important in determining the use of this chemistry are the nature of the molecular components and types of interactions which hold them together. These interactions include; Van der Waals forces, hydrogen bonding, metal ion coordination, electrostatic, - interactions and hydrophobic forces.2 Non-covalent interactions play a key role in a lot of biological processes, such as protein folding and substrate binding by enzymes or receptors.3 Supramolecular chemistry impinges on numerous, cognate, areas of research although those which are most germane to this discussion are host-guest chemistry and self-assembly. 1.1.1 Host-Guest Chemistry Host-guest chemistry is related to complexes that are made up of two or more molecules or ions held together by interactions other that full covalent bonds. To form a complex, the host compound identifies and incorporates the guest into the molecules. In this case the guest can be a specific molecule, atom or ions. 4-7 Different types of interactions are involved in formation of these complexes. They includes; hydrogen bonding, hydrophobic interactions, ion-dipole, , and ionion. According to Cram the host compound is a molecule or ion whose binding sites converge in the complex and the guest compound is any molecule or ion whose binding sites diverge in the complex.5 9 Figure 1-1. Examples of two typical host-guest complexes. One classic example of host-guest chemistry is enzyme-substrate interaction. The chemical reaction starts with the binding of the substrate to the active site on the enzyme which is specific to that substrate. In 1894, Emil Fischer postulated the lock and key analogy for the active site and enzyme. In this analogy the lock is the enzyme (host) and the key is the substrate (guest).6 Figure 1-2. Lock and key analogy 1.2 Macrocycles The synthesis of the first macrocycle dates back to mid 1930s were the synthesis of 1,4,8,11-tetraazacyclotetradecane was reported.8 However, in early 1960s the field began to develop through the work of Busch and Curtis.9 The first macrocycles were synthesised to copy biologically occurring macrocycles such as chlorins, corrins and corphins. By the late 1960s another area of macrocyclic synthesis was developed. This time the initial idea was towards modelling biological processes such as ion transport.10 10 Petersons’ oxygen-based crown ethers and the mixed oxygen-nitrogen bicyclic cryptands of Lehn were among the first10,11 synthetic macrocycles to exhibit high selectivity towards alkali and alkaline earth metal ions. The macrocyclic ring structure allows the host molecule to achieve a degree of structural pre-organisation.12 This enables key functional groups to interact with a host within the binding sites thereby minimising entropic loss. Overall these properties can result in certain macrocycles having both a high binding affinity as well as high selectivity for specific guest species.13 Macrocycles are not rigid molecules: they can reorganise in a way to hold their structural pre-organisation and at the same time have adequate flexibility to stitch to a target surface and increase binding interactions. This can result in high affinity and selectivity for targets, while keeping enough bioavailability to reach intracellular locations.12-13 Despite all these benefits, applications as drug candidates stemming from the pharmaceutical and drug discovery sectors have been somewhat limited, although there are specific exceptions as illustrated below (Figure 1-3). 11 1.2.1 Crown Ethers In 1967 Pederson reported the synthesis of crown ethers and commented upon their ability to selectively complex metal cations.14-15 Since these seminal reports many crown ethers have been synthesised and their binding to metal cations has been studied in detail. A crown ether has been defined as a compound with multiple oxygen atoms incorporated in a monocyclic backbone and the name “crown” derives from the actual cavity shape of the macrocycle, which in many cases adopts the topology of a crown.17 Representative examples of crown ether are shown below (Figure 1-4). Due to the oxygen lone pairs in the structure, the cavity of the crown ether is electron rich. This is where the cation binds. The electric potential surface is a measure of charge distribution. Red indicates regions of negative charge, green shows the neutral area, blue shows the region of positive charge. We can see from the image that the positive charge is distributed over a very large area and that the centre of the crown ether is negatively charged. [Image from: http://www.chem.ucla.edu/harding/crownethers.html] 12 In order for a given ligand set embedded within a crown ether to bind effectively to its “guest”, the cavity size of the crown ether is very important. For example, Bordunov et al. revealed in 1996 that when the 5-chloro-8-hydroxyquinoline (CHQ) group was attached to the ring via position 7 (9), it was selective for Mg2+ compared to other alkali and alkaline earth metals. On the other hand if the CHQ was attached via 2 position (8), it became selective for K+ over other alkaline metals and Ba2+ over other metal ions.18 The study of crown ethers and its definition has expanded dramatically over the years following the synthesis of other macrocycle compounds containing nitrogen (aza-crown ether) and sulphur (thiacrown ether). The interest in the synthesis of aza-crown compounds is continuing to grow. Their complexation properties lie between those with all oxygen atoms in which they complex alkali and alkaline earth metal and those crown with all nitrogen atoms in which complexes heavy metal cations. Therefore, these mixed properties make aza-crown ethers very interesting for researchers. Examples of both crowns are shown (Figure 1-5). 13 According to Pederson, crown ethers can exhibit excellent binding strength and selectivity towards alkali and alkaline earth metals.14 These properties make crown ethers an excellent synthetic compound to mimic many of the naturally occurring cyclic antibiotics. Alkaline and alkaline earth metals are an important part of biological system and crown ethers are important ligands in the study of chemistry of these metal ions. Crown ethers are used in areas such as biological mimics, reaction catalysts, sensors, recovery/removal of specific species and separations.19 Reports have shown that derivatives of crown ethers have potential in anti-tumour agent. 1.2.1.1 Synthesis of crown ether The Williamson ether synthesis is commonly used in the synthesis of macrocyclic polyethers. This classic reaction involves the SN2 displacement of an alkyl halide with an alkoxide anion21 when a diol and dihalide are reacted together in presence of a base. Recently it was reported that the halide leaving group could be replaced by a much more reactive tosylate or mesylate leaving group.20 Generally in these reactions, sodium hydride or potassium tert-butoxide is used as a base together with a strongly co-ordinating dipolar, aprotic, solvent such as DMF or THF, which facilitates the SN2 reaction mechanism. 14 The synthesis of macrocycle 16 typifies the general strategies used for the synthesis of cyclic polyethers. In this case, monoprotection of hydroquinione 12 afforded 13 which could then be capped with a di-tosylate 14 affording ether 15. Catalytic hydrogenolysis of 15 unmasked the corresponding bis-phenol which was again reacted with a di-tosylate 14 in the presence of sodium hydride as base resulting in the isolation of the crown ether 16 in 31% yield.23 1.3 Mixed-donor Macrocycles The synthesis and properties of mixed-donor macrocycles has attracted a lot of attention in recent years. These types of compounds could be suitable for a wide range of applications, from molecular recognition to chromatographic separation of metal cations. Previously, the importance of crown ethers and their ability to bind alkali and alkaline earth metal ions was reviewed and discussed. However, one factor which needs to be mentioned is their limited ability to bind transition metal ions. Transition metal ions such as iron, copper and zinc are vital for everyday life. On the other hand, some transition metal ions such as cadmium and mercury are toxic. It’s known that transition metal ions play a role in some neurological diseases such as Alzheimer’s diseases. Therefore, the ability of these mixed donor macrocycles to complex transition metal ions and selectively detect and possibly remove such ions could be useful in various areas and widespread potential uses in water treatment, environmental monitoring, animal and human health.22-24 The synthesis of mixed-donor macrocycles has broadened the chemistry of crown ethers. One advantage of mixed-donor macrocycles over the single-donor macrocycles lies in their ability to offer the coordination of both hard sigma-donor N-ligands and soft sigma-donor and possibly -acceptor S-ligands.22 In 1969, Busch24 reported that thioether-based ligands could coordinate metals and since then different complexes was synthesised by Danks and Lindoy in 1998 and 2010 respectively.54,55 15 Much research has been conducted with a view to establishing the factors which determine the strength of metal-ligand interactions and also the geometry of the complexes which result from such interactions. In 1997, Bradshaw et al.26 reported that 1,10-dithia-18-crown-6 formed higher affinity complexes with Hg2+ and Ag2+ compared to 18-crown-6. However, the results were vice versa for alkali metal cations. Vögtle et al. first reported the use of crown-type polyethers as transport mimics. These workers were able to prepare a number of crown ethers in order to replicate ion transport across membranes present in biological systems.27 In 1976, E. Weber and F. Vögtle28 reported the synthesis of new cyclic neutral ligands of different ring sizes and of new heteroatom sequences. The synthesis of macrocycles 19 and 20, which proceeded in moderate yields when conducted under high dilution conditions, employed KOH in ethanol as base in order to promote the cyclisation over polymerisation reactions. Curiously benzene was also employed as a co-solvent in such reactions. Interestingly, attempted synthesis of macrocycle 21 resulted in an unexpected ring contraction to afford the macrocycle 19 (Scheme 1-2). 16 1.3.1 Templating Effects When it comes to the synthesis of macrocylic molecules it’s important for chemists to choose the appropriate methods to obtain the desired structure. Synthesis of macrocyclic compounds involves reactions of multifunctional monomers. If the correct conditions are not chosen, there is the possibility of competition between macrocyclisation and polymerisation. In the example below (scheme 1-3), triethylamine or KOH is used as a base. This would either afford the crown ether 26 or the polymeric compound 27. The presence of K+ ion in pathway A is the difference in the two pathways. The K+ ion allows the reactant to arrange itself into a cycle like intermediate 24 that is pre-organised to form the crown ether. The potassium ion is therefore considered as the template for the reaction and this is known as the template effect.22-29 17 Notably, when this reaction is performed in the absence of a potassium counter ion derived from the base, cyclisation does not occur. Frequently therefore polymerisation is the result of such reactions when organic bases such Et3N are used in these cyclisation reactions. The base selection is therefore very important for synthesis of crown ethers. It was originally documented that potassium ions have a templating effect which enables cyclisation to proceed in favour of polymerisation. Subsequently many studies have shown that a range of cationic species (such as alkali and alkaline earth metal, transition metals and lanthanides) can also act as templating agents. Such an effect was reported by the Bailey group who observed that the presence of the Cs+ ion was pivotal to the synthesis macrocycle 30. 18 1.3.2 The Caesium Effect In the last two decades the use of caesium salts in many synthetic conversions has received a lot of interest. Caesium is used in variety of organic synthesis. For example, palladium catalysed coupling reactions like Suzuki coupling or the Buchwald amination.30 It’s also been used in more straightforward nucleophilic substitution reactions. The use of caesium salts in macrocyclisation reactions has been shown to have a positive effect on cyclisation. In the mid 1980s, Kellogg31 carried out a macrocyclisation reaction forming a C-O bond using a variety of carbonate salts (Figure 1-6). It was found that use of a caesium ion was superior to other alkali metal counterparts with respect to yields. Since then, a lot of research has been done into the full extent of this principle. Furthermore, use of caesium ions was found to have an effect on reaction time and most such conversions proceed under mild conditions. Caesium bases have shown to control chemo-selectivity and have been shown to be compatible with a wide range of functional groups. The improved reactivity has been defined as the ‘caesium effect’. The exact cause of the caesium effect is still not known. Different types of caesium reagents have been used in macrocyclisation reactions.32 Due to the low solubility of caesium fluoride, it’s less desirable for cyclisation in comparison to caesium carbonate or the hydroxide analogue. Between the two, caesium carbonate is preferred over caesium hydroxide, because it’s less hydroscopic and therefore easier to handle. 19 1.4 Macrocycles as Catalysts During 2001 the Bailey group began to investigate the possibility of creating a new type of enantioselective catalyst or enzyme mimic.22-33 The group’s initial studies began with the development of a general strategy for the synthesis of novel peptide-derived macrocycles. The macrocyclic pyridine derivative 33 was identified as an initial target, because the macrocyclic ring substituent might be used to alter the chemistry of the pyridine nitrogen. It was important structurally to position the source of asymmetry within the compound close to the pyridine nitrogen, but leaving enough space for chemical reactions to take place at the pyridine nitrogen. Alpha-amino acids were therefore used as a source of this chirality. These macrocycles are all C2-symmetric. Ensuring similar chiral environment of both side of the macrocycle, regardless of the direction of approach taken by incoming species e.g. nucleophile (Figure 1-7). Recently, Sethi reported the potential binding of macrocyclic compounds with organic guests such as glycine amide, acetyl L-alanine, L-alanine amide and acetyl glycine. One example is the triethylene glycol-base macrocycle 36. The results indicated that binding of such organic guests to the host are entropically driven. The most stable binding was acetyl L-alanine and the least stable with L-alanine34 (Scheme 1-6). 20 Chiral crown ether macrocycles have been identified as potential “nucleophilic asymmetric catalysts”, in that they comply with requirements delineated by Fu et al. where the presence of an electron rich donor group and steric hindrance are required for high selectivity in reactions catalysed in this manner. In order to validate the use of nucleophilic catalysis in epoxide ring-opening reactions, Bailey synthesised the pyridine N-oxide macrocycle 41. Reaction of 37 with SiCl4 afforded 2-chloro-2-phenylethanol 39 in high yields, and in preference to 40. In order to confirm that the epoxide ring-opening was facilitated by the presence of 41, a number of control reactions were carried out as it was thought that the byproduct HCl could also ring open the epoxide. In these blank reactions it was observed that, in the absence of 41, ring opening of 37 was wholly none-selective and afforded an equimolar mixture of 39 and 40. The optical purity of the product 39 produced in this reaction has yet to be established (Scheme 1-7). In 2011, Veitía’s group35 synthesised two series of chiral azapyridinomacrocycles, containing a pyridine N-oxide as a key structural feature and alpha-amino acid were used as a readily available source of this chirality (Figure 1-8). 21 In this study, azapyridinomacrocycles were used as organocatalysts in the asymmetric allylation of p-nitrobenzaldehyde 46 with allyltrichlorosilane 47 (Scheme 1-8). The 12-membered ring azapyridinomacrocycle N-oxides PyCyN-OX[12]N4 (42) and (43) were tested first and the results were negative. Only 48% of conversion rate and 12% of ee were reported. No major differences were observed between the two functionalised 12-membered macrocycles and only slight improvements in conversion rate were seen when DCM or THF were used as solvent respectively. Next, the 15-membered macrocycle PyCyN-OX[15]N5 (44) and (45) was used as possibly better catalysts. The results reported (Table 1-1) shows good improvement in reaction rate and asymmetric conversion. 22 Table 1-1: Allylation of p-nitrobenzaldehyde with allyltrichlorosilane catalyzed by 15-membered azapyridinomacrocycles N-oxides Entry Catalyst No Temp/ °C Time/h Yield (%) ee (%) confiq 1 36a 20 72 28 10 (S)-(-) 2 36b 20 72 48 2 (R)-(-) 3 36b 0 72 27 3 (R)-(-) 4 36c 20 48 60 5 (R)-(-) 5 36c 0 48 42 6 (R)-(-) 6 37a 20 24 83 13 (S)-(-) 7 37a 0 24 72 8 (S)-(-) 8 37a -38 24 58 14 (S)-(-) 9 37a -38 24 43 40 (S)-(-) 10[e] 37a -38 24 65 5 (S)-(-) 23 1.4.1 Application of crown ethers (single/mixed donor) As discovered previously, crown compounds are used in many field e.g. extraction. However, their application in organic synthesis has shown great progress. Crown ethers are capable to make inorganic alkali metals and salts soluble even in nonpolar solvents. Crown ethers are therefore used as catalysts by chemists. Sharghi et al. looked into using different types of crown ethers as catalysts in the ring opening of epoxides (Scheme 1-9). The reaction was carried out under mild conditions using 0.01 mol% of catalyst (49a-c). The catalysts 49a-c were synthesised by the Sharghi group. They have also carried out these experiments with available crown ethers (50-52), in order to compare the differences.36 The outcome of the reaction was positive and gave over 90% regioselectivity. For reactions in which the modified catalysts (49a-c) were used, the reaction times ranged from 25-90 minutes, resulting in 90% yield for 49a and 55% yield for 49c respectfully. Use of the other modified catalysts was not much success. Furthermore, for the crown ether 50-52 reaction times ranged from 60 – 90 minutes and yields varying from 55 – 70%. The catalyst 49a was found to be the most effective in this reaction. Therefore, further epoxide ring opening reactions were carried out and regioselective thiocyanate products were obtained with over 75% yield for ten different epoxides. 24 1.4.1.1 Miscellaneous applications of crown ethers in synthesis Crown ethers have found application in the promotion of Michael addition reactions under the conditions of phase transfer catalysis. The advantages of using crown ethers in this particular reaction are high yields and more importantly high stereoselectivity37 (Scheme 1-10). Potassium permanganate is a strong oxidising agent. Its ionic character makes it insoluble or partially insoluble in organic solvents. Therefore, a solubilising agent is required. In the presence of crown ethers the reaction can be performed in nonpolar organic solvents38 (Scheme 1-11). Using crown ethers as phase transfer catalysts in condensation reactions, it was observed that the reaction rates were increased by 102~105 times.39 25 Reduction of 4-methyl-cyclohexane can result in formation of both isomers. The use of crown ethers in this reaction however resulted in much higher yields and better selectivity towards the trans-isomer40 (Scheme 1-13). 26 RESULTS AND DISCUSSION 27 2 2.1 Results and Discussion Pyridine-based Macrocycles 2.1.1 Introduction Previous work carried out in the Quayle group has focused on the synthesis of novel macrocyclic receptors which have potential application in asymmetric synthesis and in the interrogation of molecular recognition phenomena. In particular, the synthesis of chiral macromolecules such as 66 and 72 has recently been accomplished with a view to invocating their application as nucleophilic catalysts. The synthesis of macrocycles 66 and 72 is shown below (schemes 2-1 and 2-2). 28 In a related area, recent work within the Quayle group has also been directed toward the synthesis of molecular sensors for the detection and determination of metabolites or specific metal ions in biological systems. Here we wish to develop a modular approach to the synthesis of receptor molecules which can sense the presence of, for example, heavy metals in various organs within the body. In this approach we wish to attach a “recognition/transport domain” to a “reporter” domain such that interaction of a metal ion with the receptor can be reported to an observer. In practice our “first generation sensors” are to be derived from azo-dyes which are to be attached to a macrocycle (recognition domain) which are also decorated with carbohydrates as the “carrier” domain. 29 Scheme 2-3: Possible route to the synthesis of complex 76 Validation of this design concept is now in progress, where we have shown that macrocyclic species can be attached to suitable spacers via “click” chemistry (Scheme 2-4). Scheme 2-4: CuSO4.5H2O, sodium ascorbate, EtOH /H2O (3:1), rt, 12 hrs, 19 %.51 More recently we have also shown that azo-dyes can also be attached, again using “click chemistry” to macrocyclic “recognition” domains, as exemplified in Scheme 2-5 30 Scheme 2-5: CuSO4.5H2O, sodium ascorbate, THF /H2O (3:1), 50 °C, 12 hrs, 57 %.51 The next phase of this programme of research requires that the sensing domain (e.g. an azo-dye) be attached, with direct electronic interaction, to the recognition domain, such that complexation of the macrocycle to a metal ion results in a change in the chromophore of the dye. 2.1.2 Aims and Objectives In the current project we wished to establish: whether a viable route to functionalised pyridine-containing macrocycles such as 84 could be developed, and that macrocycles such as 84 and 104 could be conjugated with functionalised azo-dyes using Heck, Stille or related cross-coupling reactions. 31 Scheme 2-6: Planned route to functionalized azo-dyes. We reasoned that the target pyridine-containing macrocycle 84 could itself be prepared from the diol 89, which itself should be accessible from chelidonic acid 87 (Scheme 2-8). Although the preparation of 86 from chelidonic acid is reported in the literature, previous work within the group indicated that this seemingly simple set of transformations was, in reality problematic, hence providing the impetus for the present study. Scheme 2-7: Proposed route to macrocycle 84 2.2 Discussion of Results During this programme of research we developed an effective method for synthesis of the ditosylate 91, which proved to be a useful surrogate for the tri-bromide 86 in subsequent alkylation reactions leading to the desired macrocycle 84 (Scheme 2-8). 32 Overall Scheme of synthesis of macrocycle 84 Scheme 2-8: a) Na, MeOH, diethyl oxalate, acetone. b) 37% aqueous ammonia, 48h, rt. c) SOCl 2, MeOH, rt, 24h. d) TBAB, P 2O5, toluene, 4h, 110 °C. e) NaBH4, EtOH, 24h, 80 °C. f) TsCl, CH2Cl2, KOH, 0 °C, 1h. g) 2,2-thiodiethanethiol, KOH, toluene/EtOH. h) 37% HBr/AcOH, rt. 2h. 2.2.1 Preparation of bromo-ditosylate 90 To prepare macrocycles, it’s important to have a very useful building block to start with. One of those useful starting materials is 4-bromo-2,6-pyridinedimethyl ditosylate 90. Since the bromo-ditosylate 90 is a very useful building block, a general method for its preparation is important. To start its synthesis, we begin with the preparation of chelidonic acid 87. Chelidonic acid 87 was prepared by addition of dry acetone and diethyl oxalate to sodium ethoxide solution (Scheme 2-9). After addition, the reaction was refluxed and HCl/water was added. Crude chelidonic acid was produced in 42% yield. Unfortunately when the crude product from this reaction was recrystallised (from water) the overall yield was much reduced, affording only a 10-15% yield of purified material. Given the relatively low yield of this reaction, initial investigations focussed upon the optimisation of this classic, aldol- cyclisation 33 process. As the crude compound was fairly clean, it was decided to carry on to the next stage with the crude compound. A number of workers have reported the synthesis of chelidonic acid 87 using very similar methods but the one factor which was different was the timing of acetone addition. We have tried to add the acetone after the addition of diethyl oxalate to the sodium ethoxide solution. This approach didn’t go very well, resulting in a very low yield. The next factor which was looked at was the solvents. In order for the reaction to work, it was important to use dry and fresh solvents. Both solvents were dried using molecular sieves. The reaction was run using dry solvents prepared 48 hours prior to the experiment and good improvements were seen in terms of yield. Another reaction was run using solvents dried 24h prior to the experiment and the results showed further improvements in yield. One further reaction was carried out using solvents dried 12-15 hours prior to the experiment. Again further improvement in yield was seen and 42% yield was the highest which was achieved. It is clearly evident in this reaction that the quality of the dry solvents had a major impact on yield (Scheme 2-9). Scheme 2-9: Synthesis of chelidonic acid 87 Once obtained in a pure state chelidonic acid 87 was efficiently converted into chelidamic acid 91 merely by reaction with concentrated aqueous ammonia for 2 days, resulting in the isolation of the pure product in 70% yield (Scheme 2-10). Scheme 2-10: Synthesis of chelidamic acid 91 34 The synthesis of dimethyl chelidamate 92 was first achieved by refluxing chelidamic acid 91 with thionyl chloride overnight then adding MeOH. This method gave very poor yields42. Therefore, an alternative method reported by Pellegatti41 was investigated. Thionyl chloride was reacted with methanol at low temperature and then chelidamic acid was added and the reaction was refluxed overnight resulting in dimethyl chelidamate 92 in near quantitative yield (Scheme 2-11). After much experimentation we discovered that diester 92 was best converted to bromo-diester 88 using P2O5 in the presence of TBAB in 64% isolated yield (Scheme 2-11). This reagent combination proved to be far superior to other, more common used reagents such as phosphorus pentabromide53, which generally afforded complex reaction mixtures and involved more complex work-up and purification procedures. In the next step, the bromo-diester was reduced to bromodiol 89 using sodium borohydride in ethanol46 as solvent. Scheme 2-11: Route to the synthesis of diol 89 from chelidamic acid 91 On occasion this reaction could also prove to be problematic, as removal of boronresidues could be difficult to achieve (Soxhlet extraction can be used to remove the impurity). Recrystalisation of the crude product of this reduction reaction from water afforded diol 89 in a high state of purity, in reproducible yields of ca. 74%. 35 2.2.1.1 Esterification of chelidamic acid Scheme 2-12: Mechanism of esterification Chelidamate ester 92 was synthesised in near quantitative yield and the formation of the ester confirmed by 1H NMR. Figure 2-1: 1H NMR of chelidamate ester 92 in MeOD 2.2.1.2 Preparation of bromide 88 Conversion of chelidamate methyl ester into the 4-bromopyridine derivative 88 is usually carried out under harsh conditions using PBr3, PBr5 or POBr353. Use such of reagents does, however have drawbacks such as handling of hazardous reagents, 36 production of hydrogen bromide and reaction-temperature control. Therefore, a more useful method was used using P2O5 and tetrabuylammonium bromide (TBAB). For bromination of chelidamate ester, the P2O5 will form the leaving moiety and tetrabutylammonium bromide as a source of bromide ion. Chelidamate ester 92 was reacted with excess of TBAB in hot toluene for 4 hours in presence of P 2O5. After workup, bromo-ester was afforded in 76% yield. This operationally simple reaction could be carried out on a multi-gram scale, thereby facilitating Figure 2-2: 1H NMR of bromo-diester in CDCl3 37 2.2.1.3 Reduction of bromo-diester Scheme 2-13: Mechanism of reduction The bromo-diester 88 was reduced to bromo-diol 89 using sodium borohydride. This approved reaction is favoured over other methods, because it can be run under mild conditions. Sodium borohydride is easier to use and handle compared to the powerful reducing agent lithium aluminium hydride. The reduction of the diester is proceeding slowly at first. After that the mothoxy leaving group reacts with sodium borohydride to form sodium methoxyborohydride. The sodium methoxyborohydride is a much stronger reducing agent, therefore forcing the completion of the reduction. 38 Given that the Quayle group had, in the recent past, used the dibromoether 65 in the synthesis the macrocycle 66, the synthesis of 4-bromo-2,6- bis(bromomethyl)pyridine 86 was next attempted. In the parent system, this transformation can be accomplished by heating the diol 89 in 37% HBr-acetic acid. Unfortunately, in our hands repeating this reaction on the bromo-diol 89 merely afforded a mixture of products, consisting of the dibromide and starting material, which could not be driven over to the desired tri-bromide 86. Therefore, conversion of the diol 89 into the tosylate 90 was attempted, as it was considered that ditosylate of this compound would also act as a suitable alkylating agent in the macrocyclisation reactions.46,47 Tosylation of the diol 89 using tosyl chloride in the presence of KOH as base, afforded the desired di-tosylate 90, a crystalline solid, in reproducibly good yields (ca. 70%) on a multigram scale (Scheme 2-14). Scheme 2-14: Synthesis of ditosylate 90 Figure 2-3: 1H NMR of ditosylate 90 in CDCl3 39 2.2.2 Preparation of macrocycle 84 The synthesis of the novel macrocycle 84 was accomplished using a modification of the procedure reported earlier by Weber and Vögtle28. Reaction of bromoditosylate 90 with commercially available 2,2-thioethanethiol 93 using KOH as base in an ethanol-toluene solvent system cleanly led to the formation of the desired thia-crown 84 in 48% yield as an off-white coloured crystalline solid. The structure of the crown 84 was confirmed spectroscopically and also by way of a single crystal Xray analysis (Figure 2-4). The Xray structure of 84 revealed that, in common with many thio-crowns which possess [–S-CH2-CH2-S-]n units, that the S-C-C-S torsion angles are all close to 180° (see Appendix), in order to maximise lone pair-lone pair repulsion. Figure 2-4: Crystal structure of crown ether 84 Scheme 2-15: Synthesis of macrocycle 84 40 Figure 2-5: 1H NMR of macrocycle 84 in CDCl3 2.2.2.1 Attempted synthesis of macrocycles using different spacers Cyclisation of three different macrocycles was attempted with various thiol spacers using KOH and ethanol. However, 1H NMR spectrum revealed no reaction was taken place (scheme 2-15, 2-16 and 2-17). Scheme 2-16: Synthesis of macrocycle 96 and 97 41 Scheme 2-17: Attempted synthesis of macrocycle 99 2.2.3 Oxidation of Macrocycle Bailey group’s previous experience on macrocycle derivatives leads them to investigate the use of 4-dimethylaminopyridine (DMAP) derivatives (e.g. 100) in acyl-transfer catalysis instead of the unfunctionalised pyridine ring. It was found, due to the presence of the 4-dimethylamino group, the ring becomes susceptible to intramolecular cleavage. This may be caused by the attack of the nitrogen lone pair at the ester carbonyl. In 2001, Fu and his co-workers experimented in oxidising the pyridine to form the electron rich N-oxide. This could act as a ligation site. Recently, the Quayle group carried out the oxidation of the macrocycle using mCPBA in DCM at room temperature for 48 hours. 42 Scheme 2-18: Synthesis of macrocycle 102 2.2.4 Oxidation of bromo-ditosylate 90 and the synthesis of a crown-N-oxide It was decided within the group to convert the di-tosylate 90 into the N-oxide 103 first, then taking it forward to form the macrocyclic N-oxide 104 as oppose to oxidising the macrocycle itself. Oxidation of di-tosylate 90 was cleanly accomplished using m-CPBA in methylene chloride at room temperature for 48 hours, affording the N-oxide 103 in 64% yield after recrystallisation from methylenechloride–petrol (Scheme2-19). Scheme 2-19: Synthesis of macrocyclic N-oxide 104 43 Figure 2-6: 1H NMR of N-oxide 103 Conversion of di-tosylate 90 to the N-oxide 103 was accompanied by characteristic changes in its 1H NMR spectrum. The signal for the H-2 moved downfield from 7.37 ppm to 7.60 ppm after oxidation, the 4-proton signal shifted downfield from 4.95 ppm to 5.18 ppm, the 3,7 and 4, 6-proton signals both doublets shifted downfield by 0.12 ppm and the 9-proton signal have has also shifted downfield from 2.38 ppm to 2.48 ppm. Mass spectrometry also confirmed the synthesis of the N-oxide 72 (m/z [M+H]+ = 542). Comparing the 1H NMR spectrum of macrocycle 84 to the 1H NMR spectrum of macrocyclic N-oxide 104, few changes were observed. The signal for the 1-proton shifted downfield from 7.49 ppm (84) to 7.57 ppm (104) after oxidation, the 2proton signal shifted downfield from 3.79 ppm to 4.00 ppm, and the 3-proton signals also shifted downfield from 2.52 ppm to 2.75 ppm. Mass spectrometry also confirmed the synthesis of the macrocyclic N-oxide 104 (m/z [M+Na]+ = 374). 44 2.2.4 Attempted Pd-Coupling reaction The conjugation of the functionalised macrocycle 84 with phenylacetylene 105 using Heck chemistry was also briefly examined but proved to be unsuccessful. The reaction was carried out by reacting macrocycle 84 with phenylacetylene 105, palladium catalyst and copper iodide under nitrogen and then adding Pri2NH followed by THF. It is not clear why this reaction failed – this may possibly be due to the presence of the thioether moities which are able to deactivate, in some manner, the palladium catalyst. This aspect of the project will be the subject of future research. Scheme 2-20: Synthesis of macrocycle 106 3. Conclusion In conclusion, a practical route to the synthesis of bromo-ditosylate 90 and N-oxide 103 was developed from chelidonic acid 87. Both cross-linkers were taken forward to produce macrocyle 84 and macrocyclic N-oxide 104 successfully in respectable yields. Attempts were made to synthesis macrocycles 96, 97 and 102 by applying the same method, but all three reactions failed. This may suggest that the use of a tosylate leaving group in these reactions is not optimal: in situ conversion of the tosylate to the bis-halide (Finkelstein reaction) should provide a solution to this impasse. 45 3.1 Future Work Future work will necessarily concentrate upon the development of a coupling procedure which will enable conjugation of the functionalised crown ethers such as 84 with suitable dyes or fluorescing agents. Once this has been achieved ligand binding studies with various metals ions (e.g. Cu2+, Zn2+) will be investigated in order to generate proof of principle that co-ordination of the receptor to the host results in a change in the UV/fluorescence spectrum of the complex. It is envisaged that a library of complexes, e.g. based upon structures such as 107 can be prepared using this modular approach in order to develop a sensor for specific metal ions in biological systems. 46 EXPERIMENTAL 47 4 4.1 Experimental General Experimental All reactions were carried out in clean and dry glassware under nitrogen atmosphere, unless stated otherwise. Acetone, EtOH, and MeOH were dried over molecular sieves. THF was distilled from sodium wire and benzophenone. Dried toluene was obtained from the PureSolv MD solvent Purification System. All reaction temperatures are given in degrees Celsius (ºC), when a temperature is not given, the reaction was therefore carried out in room temperature. All chemicals obtained from supplier were used without further purifications, unless stated otherwise. Petrol refers to the fraction of petroleum ether that has a boiling point between 40 – 60 ºC. The melting point of compounds was obtained by Sanyo Gallenkamp apparatus. Infra red were recorded on a Genesis FTIR machine and quoted in cm-1. Deutorated chloroform was used as a solvent to record Nuclear Magnetic Resonance (NMR), unless stated otherwise. 1H NMR was recorded on Bruker 300 (300 MHz) and Bruker 400 (400 MHz) spectrometers. Signal splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qn), broad singlet (br. s) or multiplet (m). Chemical shifts are shown in parts per million (ppm). Carbon NMR spectra were recorded on a Varian INOVA unity 300 spectrometer at 75 MHz or Bruker spectrometer 125 MHz. Micromass Trio 200 spectrometer was used to record low resolution mass spectra and for high resolution spectra a Kratos Concept IS spectra was used. Single crystal X-ray structure determinations were carried out by the school of chemistry x-ray structure services using AXS SMART Apex Bruker. Glass plates coated with Merck HF 254/366 silica gel were used for thin layer chromatography (TLC). Flash column chromatography was carried out using silica gel 60H (40-60 nm, 230-3-00 mesh) for Merck. 48 4.2 Cross-linkers Synthesis of 4-Oxo-4H-pyran-2,6-dicarboxylic acid 43 A solution of sodium ethoxide was prepared by dissolving sodium (2.4 g, 0.1 mol) in 36 mL of dry ethanol. To this mixture was added a mixture of dry acetone (4 mL, 0.05 mmol) and diethyl oxalate (14.5 g, 0.11 mol). During the addition of two mixtures a yellow precipitate formed. The reaction was stirred for an hour at 60 °C to complete the reaction, then 20 mL of 37% of HCl and 10 mL of water was added and it was left to stir for one day at 50 °C. Excess ethanol was removed under reduced pressure, and then 30 mL of water and 5 mL of HCl was added and was left to stir at ambient temperature for a further period of 3 – 4 days. The crude product which had been deposited was removed by filtration, washed with water and then acetone to afford the title compound as a brown-coloured solid (11.54 g, 42%). 1 H NMR: (MeOD, 300 MHz) δ/ppm 7.01 (2H, s, ArH) 13 C NMR: (MeOD, 300 MHz) δ/ppm 119.96 (C2), 156.97 (C3), 162.44 (C4), 182.84 (C1) IR υmax (film): 1229 (s), 1583 (m), 1633 (m), 1742 (s), 2560 (w), 3078 (w) cm-1 Melting point: 245 – 248 °C (Lit: 157 °C43) MS (ES+): m/z [M+H]+ 185; [M+Na]+ 207 Accurate Mass: [C7H4O6-e] requires 184.0008 found 184.0021 49 Synthesis of 1,4-Dihydro-4-oxo-2,6-pyridinedicarboxylic acid 43 Aqueous ammonia (80 mL of a 35% aqueous solution) was added to chelidonic acid (7.91 g, 42.9 mmol) dropwise at 0 °C. Upon completing the addition the reaction mixture was stirred for two days at room temperature. Excess ammonia was removed under reduced pressure and the solid was boiled with 80 mL of water together with 1.6 g of charcoal for 5 minutes. The mixture was filtered and the cold solution was acidified with 37 % aqueous HCl to about pH 1. The white crystals were filtered off and washed with ice cold water 3 times to give 5.53 g (70%) of the desired product. 1 H NMR: (MeOD, 300 MHz) δ/ppm 6.95 (2H, s, ArH) 13 C NMR: (MeOD, 300 MHz) δ/ppm 117.29 (C2), 145.37 (C3), 165.95 (C4), 184.44 (C1) IR υmax (film): 1336 (s), 1392 (s), 1460 (m), 1609 (s), 1710 (m), 2498 (m), 3120 (w), 3446 (w), 3605 (m) cm-1 Meting point = 253 - 255 °C (lit: 248 °C44) MS (ES+): m/z [M+H]+ 183; [M+Na]+ 205 Accurate Mass: [C7H6NO5-e] requires 184.0246 found 184.0241 50 Synthesis of 2,6-Pyridinedicarboxylic acid, 1,4-dihydro-4-oxo-, 2,6-dimethyl ester 41 Thionyl chloride (22.3 mL, 306 mmol, 8 eq) was added dropwise to methanol (70 mL) cooled at -10 °C. Chelidamic acid (7 g, 38.2 mmol) was also added to the mixture. The solution was left to stir for 24 hours at room temperature and then heated at reflux for an additional 2 hours. The excess of thionyl chloride and the solvent was removed under reduce pressure to give the compound 92 as a white solid (7.85 g, 97%). 1 H NMR: (MeOD, 300 MHz) δ/ppm 3.99 (6H, s, CH3), 7.78 (2H, s, ArH) 13 C NMR: (MeOD, 300 MHz) δ/ppm 54.85 (C5), 117.74 (C2), 145.6 (C3), 161.65 (C4), 174.71 (C1) IR υmax (film): 1187 (s), 1348 (s), 1478 (m), 1558 (s), 1724 (m), 3106 (m), 3307 (m) cm-1 Meting point = 162 - 165 °C (Lit: 169 – 170 °C45) MS (ES+): m/z [M+H]+ 212; [M+Na]+ 234 Accurate Mass: [C9H10NO5-e] requires 212.0552 found 212.0554 51 Synthesis of 2,6-Pyridinedicarboxylic acid, 4-bromo-, 2,6-dimethyl ester 49 Phosphorus pentoxide (42.5 g, 147.2 mmol), tetrabutylammonium bromide (38.3 g, 118.9 mmol) and dry toluene (150 mL) was introduced into one flask and heated for an hour at 80 °C. 4-hydroxy-2,6-pyridine-dicarboxylic acid dimethyl ester 92 (5.0 g, 23.7 mmol) was dissolved in toluene and added slowly to the reaction. The mixture was left to stir for 4 hours at 110 °C. After cooling the mixture to room temperature, the supernatant was taken aside while the remaining oily residue was triturated with toluene for an hour. Both organic phases were poured into water and stirred for 2 hours. Water was separated and the organic phase was dried over Mg2SO4 and concentrated in vacuo to give 4.15 g (64%) white beige solid. 1 H NMR: (MeOD, 300 MHz) δ/ppm 4.06 (6H, s, CH3), 8.49 (2H, s, ArH) 13 C NMR: (MeOD, 300 MHz) δ/ppm 53.48 (C5), 131.3 (C2), 135.11 (C1), 149.13 (C3), 164.03 (C4) IR υmax (film): 1146 (s), 1246 (s), 1263 (m), 1326 (s), 1442 (m), 1714 (m), 2951 (w) 3077 (w) cm-1 Meting point = 153 - 156 °C (155 – 156 °C50) Microanalysis: Found: C, 39.07; H, 3.09; N, 5.12; Br, 29.07 %. C9H8BrNO4 requires C, 39.44; H, 2.94; N, 5.11; Br, 29.15 %. 52 Synthesis of 4-bromo-2,6-pyridinedimethanol 46 Bromo ester 88 (5.0 g, 18.2 mmol) was dropped into dry EtOH (130 mL) and the mixture was cooled to 0 °C. To this suspension, NaBH4 (3.33 g, 88 mmol) was added and the mixture stirred at 0 °C for a hour, at room temperature for another hour and at reflux temperature for 1 day. Acetone (85 mL) was added and the mixture refluxed for an extra hour. The solvent was removed in vacuo and the waxy residue was triturated with saturated aqueous Na2CO3 solution (55 mL) and stirred for 1 hour. The solvent was removed in vacuo and then the residue recrystallised from water to give 2.95 g (74%) of pale white solid. 1 H NMR: (DMSO, 500 MHz) δ/ppm 4.53 (4H, s, CH2), 7.52 (2H, s, ArH) 13 C NMR: (MeOD, 75 MHz) δ/ppm 63.61 (C4), 121.04 (C2), 133.20 (C1), 163.19 (C3) IR υmax (film): 1305 (s), 1361 (m), 1403 (s), 1566 (s), 1566 (s), 2763 (w), 3093 (w), 3344 (m) cm-1 Meting point = 152 - 156 °C (Lit: 158 – 160 °C46) Microanalysis: Found: C, 38.39; H, 3.86; N, 6.13 %. C7H8BrNO2 requires C, 38.56; H, 3.7; N, 6.42 %. 53 Synthesis of 4-bromo-2,6-bis(tosyloxymethyl)pyridine 47 To a pre-cooled mixture of CH2Cl2 (18 mL) and KOH (8.3 g) in water (10 mL), bromo diol 89 was added. Tosyl chloride (2.67 g, 14 mmol) was also added and the resulting mixture was stirred vigorously for a few minutes. The resulting emulsion was stirred at 0 °C for about an hour. The mixture was poured into water (35 mL) and extracted with CH2Cl2 (35 mL). The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from hexane and ethyl acetate to give bis-tosylate as white flakes in 45% yield. 1 H NMR: (CDCl3, 300 MHz) δ/ppm 2.38 (6H, s, CH3), 4.95 (4H, s, CH2), 7.27 (2H, d, J = 8 Hz, ArH), 7.37 (2H, s, ArH), 7.73 (2H, d, J = 8 Hz, ArH) 13 C NMR: (MeOD, 75 MHz) δ/ppm 21.67 (C9), 70.39 (C4), 124.50 (C2), 128.07 (C6), 130.01 (C7), 133.0 (C1), 145.39 (C5, C8), 154.91 (C3) IR υmax (film): 1122 (s), 1172 (s), 1291 (m), 1303 (s), 1359 (m), 1367 (m), 1447 (m), 1571 (m), 1596 (w), 2950 (m) cm-1 Melting point: 107 – 110 °C (Lit: 110 – 111 °C48) MS (ES+): m/z [M+H]+ 526; [M+Na]+ 548 Accurate Mass: C21H20BrNO6S2-e requires 525.9985 found 525.9988 Microanalysis: Found: C, 48.3; H, 4.05; N, 2.94; Br, 15.49; S, 11.35 %. C21H20BrNO6S2 requires C, 47.91; H, 3.83; N, 2.66; Br, 15.18; S, 12.18 %. 54 Synthesis of 4-bromo-2,6-bis((tosyloxy)methyl)pyridine 1-oxide 22 To a solution of bis-tosylate 90 (1 g, 1.9 mmol) in dry dichloromethane, m-CPBA (1.64 g, 9.5 mmol) was added and the reaction stirred at room temperature for 48h. The reaction was quenched by addition of 0.1 M solution of NaOH (2 x 100 mL) and the organic phase dried over MgSO4. Solvent was removed in vacuo and crude compound recrystallised from dichloromethane and petroleum ether to give compound 103 (0.66 g, 64%). 1 H NMR: (CDCl3, 300 MHz) δ/ppm 2.39 (6H, s, CH3), 5.09 (4H, s, CH2), 7.3 (2H, d, J = 7.9 Hz, ArH), 7.52 (2H, s, ArH), 7.77 (2H, d, J = 8.3 Hz, ArH) 13 C NMR: (MeOD, 300 MHz) δ/ppm 21.72 (C9), 64.45 (C4), 125.75 (C1), 128.17 (C2), 130.22 (C6), 131.93 (C7), 145.83 (C5, C8), 146.27 (C3) IR υmax (film): 1122 (s), 1172 (s), 1294 (s), 1304 (s), 1371 (m), 1407 (m), 1437 (m), 1573 (m), 1596 (w), 3049 (m), 3107 (m) cm-1 Melting point: 118 – 120 °C MS (ES+): m/z [M+H]+ 542 Accurate Mass: C21H20BrNO7S2-e requires 541.9947 found 541.9938 55 4.3 Macrocycles Synthesis of 13-bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13triene 28 To a stirred solution of 4-bromo-2,6-bis(tosyloxymethyl)pyridine 90 (1.11 g, 2.11 mmol) in toluene (25 mL), 2,2-thiodiethanethiol (0.28 mL, 2.11 mmol), and KOH (0.24 g, 4.22 mmol) in ethanol/H2O 50:1 (25 mL) was added and stirred at room temperature for 24 hours. Solvent was removed in vacuo, the residue dissolved in DCM and washed with water (6 times). The organic phase was dried over MgSO4 and solvent removed in vacuo. The crude compound was further purified by column chromatography (DCM:Pet) to afford 0.341 g, 48% of pure compound. 1 H NMR: (CDCl3, 400 MHz) δ/ppm 2.52 (8H, s, CH2), 3.79 (4H, s, CH2), 7.49 (2H, s, ArH) 13 C NMR: (CDCl3, 100 MHz) δ/ppm 30.07 (C6), 31.00 (C5), 35.39 (C4), 125.68 (C2), 158.67 (C3) IR υmax (film): 1187 (s), 1348 (s), 1478 (m), 1558 (s), 1724 (m), 3106 (m), 3307 (m) cm-1 MS (ES+): m/z [M+H]+ 336 Accurate Mass: [C11H14BrNS3-e] requires 335.9547 found 335.9545 Microanalysis: Found: C, 39.16; H, 4.17; N, 3.82 %. C11H14BrNS3 requires C, 39.28; H, 4.2; N, 4.16 %. 56 Synthesis of 13-bromo-3,6,9-trithia-15-azabicyclo[9.3.1]pentadeca-1(15),11,13triene 15-oxide 28 To a stirred solution of compound 103 (0.5 g, 0.92 mmol) in toluene (12 mL), 2,2thiodiethanethiol (0.12 mL, 0.92 mmol), and KOH (0.1 g, 1.84 mmol) in ethanol/H2O 50:1 (12 mL) was added and stirred at room temperature for 24 hours. Solvent was removed in vacuo, the residue dissolved in dichloromethane and washed with water (6 times). The organic phase was dried over MgSO4 and solvent removed in vacuo. The crude compound was further purified by column chromatography (DCM:Pet) to afford compound 104 (0.23 g, 32%). 1 H NMR: (CDCl3, 400 MHz) δ/ppm 2.75 (8H, s, CH2), 4.00 (4H, s, CH2), 7.57 (2H, s, ArH) 13 C NMR: (CDCl, 400 MHz) δ/ppm 27.39 (C6), 31.54 (C5), 31.90 (C4), 128.63 (C2), 151.66 (C3) MS (ES+): m/z [M+Na]+ 374 Accurate Mass: [C21H14BrONS3-e] requires 351.9498 found 351.9494 57 4.4 Unsuccessful attempts at the synthesis of three further macrocycles General methods To a stirred solution of 4-bromo-2,6-bis(tosyloxymethyl)pyridine 90 (1 eq.) in toluene (12 mL/mmol), thiol spacer (1 eq.), and KOH (2 eq.) in ethanol/H2O 50:1 (12 mL/mmol) was added and stirred at room temperature for 24 hours. Solvent was removed in vacuo, the residue dissolved in DCM and washed with water (6 times). The organic phase was dried over MgSO4 and solvent removed in vacuo. The crude compound was further purified by column chromatography (DCM:Pet) to afford the desired compound. Attempted Synthesis of 13-bromo-6-oxa-3,9-trithia-15azabicyclo[9.3.1]pentadeca-1(15),11,13-triene Using general method mentioned above, 4-bromo-2,6-bis(tosyloxymethyl)pyridine (0.5 g, 0.95 mmol) in toluene (12 mL), 2,2-thiodiethanethiol (0.12 mL, 0.95 mmol), and KOH (0.11 g, 1.9 mmol) in ethanol/H2O 50:1 (12 mL). Examination of the crude reaction mixture by 1H NMR indicated that none of the desired macrocycle 96 had been formed. 58 Attempted synthesis of 16-bromo-6,9-dioxa-3,12-dithia-18azabicyclo[12.3.1]octadeca-1(18),14,16-triene Using general method mentioned above, 4-bromo-2,6-bis(tosyloxymethyl)pyridine (0.5 g, 0.95 mmol) in toluene (12 mL), 2,2′-(Ethylenedioxy)diethanethiol (0.15 mL, 0.95 mmol), and KOH (0.11 g, 1.9 mmol) in ethanol/H2O 50:1 (12 mL). Examination of the crude reaction mixture by 1H NMR indicated that none of the desired macrocycle 97 had been formed. Attempted synthesis of 19-bromo(4S,14S)-4,14-Dimethyl-3,15-bis-(toluene-4sulfonyl)-6,9,12-trithia-3,15,21-triaza-bicyclo[15.3.1]henicosa-1(20),17(21),18triene Using general method mentioned above, 4-bromo-2,6-bis(tosyloxymethyl)pyridine (0.5 g, 0.95 mmol) in toluene (12 mL), spacer 101 (0.55 g, 0.95 mmol), and KOH (0.11 g, 1.9 mmol) in ethanol/H2O 50:1 (12 mL). Examination of the crude reaction mixture by 1H NMR indicated that none of the desired macrocycle 102 had been formed. 59 Attempted synthesis of 13-(phenylethynyl)-3,6,9-trithia-15azabicyclo[9.3.1]pentadeca-1(15),11,13-triene Macrocycle 84 (0.5 g, 1.49 mmol), phenylacetylene (0.16 mL, 1.49 mmol), Pd(PPh3)2Cl2 (0.021 g, 0.03 mmol) and CuI (0.012 g, 0.0623 mmol) were placed under nitrogen atmosphere. Dry degassed THF (10 mL) and Pri2NH was added and the reaction was left to stir for 24 hours in a dark room. The dark brown solution was filtered and dried in vacuo and the crude compound was purified by column chromatography, unfortunately none of the desired product 106 could be isolated. 60 5. References 1. J. M. Lehn, Science (New York, N.Y.), 1993, 260, 1762–3. 2. J.-M. Lehn, Polymer International, 2002, 51, 825–839. 3. F. Vögtle, Supramolecular Chemistry, 2nd edn., John Wiley & Sons., Chichester, 1993. 4. J. D. van der Waals, Over De Continuiteit van den Gas- en Vloeistoftoestand (On the Continuity of the Gaseous and Liquid States), PhD Thesis, University of Leiden, 1873. 5. S. Ahmadi, Macroheterocycles, 2012, 5, 23–31 6. E. Fischer, Ber. Dtsch. Chem. Ges., 1894, 27, 2985-2993 7. M. Xue, J. Mater. Chem., 2012, 22, 17644-17648 8. J. Van Alphen, Recl. Trav. Chim. Pays-Bas, 1936, 55, 835. 9. M. C. Thompson and D. H. Busch, Chem. Eng. News, 1962, 57. 10. C. J. Pedersen, J. Am. Chem. Soc., 1967, 89, 7017 11 B. Dietrich, J.-M. Lehn, and J.-P. Sauvage, Tetrahedron Lett., 1969, 2889. 12. 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Champness and M. Schröder, Coord. Chem. Rev., 1998, 174, 417- 468. 55. L. F. Lindoy, I. M. Vasilescu, H. J. Kim, J.-E. Lee and S. S. Lee, Coord. Chem. Rev., 2010, 254, 1713-1725. Appendix Table 8. Crystal data and structure refinement for crown ether 82 63 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges s3707ma C11 H14 Br N S3 336.32 180(2) K 1.54178 Å Orthorhombic Pbcn a = 13.0722(6) Å b = 7.8927(4) Å c = 25.4406(12) Å 2624.8(2) Å3 8 1.702 Mg/m3 8.498 mm-1 = 90°. = 90°. 1360 0.21 x 0.20 x 0.16 mm3 3.47 to 72.29°. -13<=h<=16, -9<=k<=9, -27<=l<=31 Reflections collected Independent reflections Completeness to theta = 66.60° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] 15382 2585 [R(int) = 0.0710] 99.8 % Semi-empirical from equivalents 0.3434 and 0.206104 Full-matrix least-squares on F2 2585 / 0 / 145 1.083 R1 = 0.0383, wR2 = 0.0984 R indices (all data) Largest diff. peak and hole R1 = 0.0401, wR2 = 0.0999 0.711 and -0.936 e.Å-3 64 Table 9. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for s3707ma. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. __________________________________________________________________ ______________ x y z U(eq) __________________________________________________________________ ______________ Br(1) C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) 6418(1) 6378(2) 6153(2) 6109(2) 5836(2) 4125(2) 3517(2) 4385(2) 4645(2) 1670(1) 3004(3) 4716(3) 5607(3) 7454(3) 6825(3) 5218(4) 3176(3) 1649(3) 2754(1) 2137(1) 2164(1) 1693(1) 1688(1) 1038(1) 1124(1) 342(1) 677(1) 37(1) 20(1) 20(1) 19(1) 25(1) 28(1) 32(1) 23(1) 23(1) C(9) 6742(2) 2476(3) 678(1) 21(1) C(10) 6525(2) 3233(3) 1211(1) 17(1) C(11) 6556(2) 2226(3) 1659(1) 20(1) N(1) 6299(2) 4894(3) 1222(1) 17(1) S(1) 4460(1) 7836(1) 1660(1) 29(1) S(2) 3179(1) 4160(1) 516(1) 32(1) S(3) 5880(1) 739(1) 513(1) 26(1) __________________________________________________________________ ______________ 65 Table 10. Bond lengths [Å] and angles [°] for s3707ma. _____________________________________________________ Br(1)-C(1) 1.891(3) C(1)-C(11) 1.382(4) C(1)-C(2) 1.384(4) C(2)-C(3) 1.392(4) C(2)-H(2) 0.9500 C(3)-N(1) 1.346(3) C(3)-C(4) 1.501(3) C(4)-S(1) C(4)-H(4A) C(4)-H(4B) C(5)-C(6) C(5)-S(1) C(5)-H(5A) C(5)-H(5B) C(6)-S(2) C(6)-H(6A) 1.825(3) 0.9900 0.9900 1.512(4) 1.826(3) 0.9900 0.9900 1.814(3) 0.9900 C(6)-H(6B) C(7)-C(8) C(7)-S(2) C(7)-H(7A) C(7)-H(7B) C(8)-S(3) C(8)-H(8A) C(8)-H(8B) C(9)-C(10) 0.9900 1.515(4) 1.812(3) 0.9900 0.9900 1.816(3) 0.9900 0.9900 1.509(3) C(9)-S(3) C(9)-H(9A) C(9)-H(9B) C(10)-N(1) C(10)-C(11) C(11)-H(11) 1.824(3) 0.9900 0.9900 1.344(3) 1.389(4) 0.9500 C(11)-C(1)-C(2)120.9(2) C(11)-C(1)-Br(1)118.6(2) C(2)-C(1)-Br(1)120.5(2) C(1)-C(2)-C(3) 117.3(2) 66 C(1)-C(2)-H(2) 121.3 C(3)-C(2)-H(2) 121.3 N(1)-C(3)-C(2) 123.2(2) N(1)-C(3)-C(4) 116.3(2) C(2)-C(3)-C(4) 120.5(2) C(3)-C(4)-S(1) 113.31(19) C(3)-C(4)-H(4A)108.9 S(1)-C(4)-H(4A)108.9 C(3)-C(4)-H(4B)108.9 S(1)-C(4)-H(4B)108.9 H(4A)-C(4)-H(4B)107.7 C(6)-C(5)-S(1) 111.5(2) C(6)-C(5)-H(5A)109.3 S(1)-C(5)-H(5A)109.3 C(6)-C(5)-H(5B)109.3 S(1)-C(5)-H(5B)109.3 H(5A)-C(5)-H(5B)108.0 C(5)-C(6)-S(2) 113.0(2) C(5)-C(6)-H(6A)109.0 S(2)-C(6)-H(6A)109.0 C(5)-C(6)-H(6B)109.0 S(2)-C(6)-H(6B)109.0 H(6A)-C(6)-H(6B)107.8 C(8)-C(7)-S(2) 113.53(19) C(8)-C(7)-H(7A)108.9 S(2)-C(7)-H(7A)108.9 C(8)-C(7)-H(7B)108.9 S(2)-C(7)-H(7B)108.9 H(7A)-C(7)-H(7B)107.7 C(7)-C(8)-S(3) 112.64(18) C(7)-C(8)-H(8A)109.1 S(3)-C(8)-H(8A)109.1 C(7)-C(8)-H(8B)109.1 S(3)-C(8)-H(8B)109.1 H(8A)-C(8)-H(8B)107.8 C(10)-C(9)-S(3)112.85(17) C(10)-C(9)-H(9A)109.0 S(3)-C(9)-H(9A)109.0 67 C(10)-C(9)-H(9B)109.0 S(3)-C(9)-H(9B)109.0 H(9A)-C(9)-H(9B)107.8 N(1)-C(10)-C(11)123.2(2) N(1)-C(10)-C(9)116.5(2) C(11)-C(10)-C(9)120.3(2) C(1)-C(11)-C(10)117.5(2) C(1)-C(11)-H(11)121.2 C(10)-C(11)-H(11)121.2 C(10)-N(1)-C(3)117.8(2) C(4)-S(1)-C(5) 101.41(13) C(7)-S(2)-C(6) 101.16(13) C(8)-S(3)-C(9) 101.46(12) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table 11. Anisotropic displacement parameters (Å2x 103) for s3707ma. The anisotropic displacement factor exponent takes the form: - 2[ h2 a*2U11 + ... + 2 h k a* b* U12 ] __________________________________________________________________ ____________ U11 U22 U33 U23 U13 U12 __________________________________________________________________ ____________ Br(1) 56(1) 35(1) 19(1) 9(1) 4(1) 16(1) C(1) 22(1) 21(1) 18(1) 3(1) -1(1) 2(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) 25(1) 21(1) 37(1) 34(1) 38(2) 29(1) 31(1) 26(1) 18(1) 18(1) 15(1) 13(1) 22(1) 28(2) 22(1) 20(1) 20(1) 17(1) 16(1) 21(1) 24(1) 28(1) 31(2) 19(1) 19(1) 17(1) 17(1) -4(1) -3(1) -3(1) 7(1) -3(1) 0(1) -1(1) -3(1) -2(1) 1(1) 0(1) 1(1) -2(1) 13(1) 2(1) 1(1) 3(1) 0(1) 0(1) -2(1) -3(1) 4(1) 0(1) -2(1) -6(1) 1(1) -1(1) C(11) N(1) 23(1) 21(1) 15(1) 15(1) 21(1) 16(1) 0(1) 0(1) -1(1) 1(1) 1(1) -2(1) 68 S(1) 39(1) 20(1) 28(1) -2(1) 6(1) 10(1) S(2) 25(1) 34(1) 37(1) -2(1) -1(1) -1(1) S(3) 38(1) 15(1) 24(1) -7(1) -1(1) 1(1) __________________________________________________________________ ____________ Table 12. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for s3707ma. __________________________________________________________________ ______________ x y z U(eq) __________________________________________________________________ ______________ H(2) H(4A) H(4B) H(5A) H(5B) 6033 6163 6115 3717 4758 5260 7998 7994 7623 6555 2491 1380 2009 823 842 24 30 30 33 33 H(6A) H(6B) H(7A) H(7B) H(8A) H(8B) H(9A) H(9B) H(11) 2883 3924 4358 4938 4109 4647 7456 6679 6695 5497 4433 2822 4025 777 1990 2055 3372 1047 1319 1344 -31 377 631 1052 672 408 1638 39 39 28 28 28 28 25 25 24 __________________________________________________________________ ______________ 69 Table 13. Torsion angles [°] for s3707ma. ________________________________________________________________ C(11)-C(1)-C(2)-C(3) 0.3(4) Br(1)-C(1)-C(2)-C(3) -178.28(18) C(1)-C(2)-C(3)-N(1) -1.7(4) C(1)-C(2)-C(3)-C(4) 178.0(2) N(1)-C(3)-C(4)-S(1) 92.9(2) C(2)-C(3)-C(4)-S(1) -86.8(3) S(1)-C(5)-C(6)-S(2) -179.40(15) S(2)-C(7)-C(8)-S(3) S(3)-C(9)-C(10)-N(1) S(3)-C(9)-C(10)-C(11) C(2)-C(1)-C(11)-C(10) Br(1)-C(1)-C(11)-C(10) N(1)-C(10)-C(11)-C(1) C(9)-C(10)-C(11)-C(1) C(11)-C(10)-N(1)-C(3) C(9)-C(10)-N(1)-C(3) -177.67(13) -121.4(2) 58.2(3) 1.5(4) -179.88(18) -2.2(4) 178.2(2) 0.9(3) -179.5(2) C(2)-C(3)-N(1)-C(10) 1.1(4) C(4)-C(3)-N(1)-C(10) -178.6(2) C(3)-C(4)-S(1)-C(5) -60.8(2) C(6)-C(5)-S(1)-C(4) 109.2(2) C(8)-C(7)-S(2)-C(6) 74.1(2) C(5)-C(6)-S(2)-C(7) 76.7(2) C(7)-C(8)-S(3)-C(9) 63.3(2) C(10)-C(9)-S(3)-C(8) 47.7(2) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table 14. Hydrogen bonds for s3707ma [Å and °]. __________________________________________________________________ __________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) __________________________________________________________________ __________ 70 X-ray crystal structure of Macrocycle 82 71