Supramolecular Chemistry Synthesis Cucurbit[N]Uril

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Supramolecular Chemistry

and

Synthesis

Cucurbit[n]uril

Tim White (Student z9197557)

School of Chemistry, University College, Australian Defence Force Academy, University of New South Wales

CERTIFICATE OF ORIGINALITY I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, nor material which to a substantial extent has been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis.

I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.

Tim White

ii Dedication This work is dedicated to my fantastic, wonderful wife Amanda. Without your constant motivation, help and persistence this would not have been possible.

Thankyou for all of your patience and understanding while this has taken so long, but thank you most of all for your love and friendship.

iii Acknowledgements I would like to thank Drs Blanch, Day and Arnold for all of their guidance and support. Dr Blanch went above and beyond the call of a supervisor, donating much of his personal time to meet with me after hours. Without Dr. Day's work into cucurbit[n]uril this thesis would not have been possible.

Thanks to Dr. Paula Newitt, Prof. W. Greg Jackson and Danica Robinson for editorial comments on this thesis. Your help was invaluable. Thanks also to all of the staff at the School of Chemistry at the Australian Defence Force Academy. It has been a pleasure to work with you all.

A special thanks to all of my friends and family who have supported me with encouragement, finances, accommodation when I needed to spend time in Canberra and most importantly with an ear and a sympathetic shoulder when the stress kicked in!

ABSTRACT...... 1

INTRODUCTION ...... 3

Host-Guest Chemistry...... 13 Rotaxanes and Pseudorotaxanes ...... 16 Cucurbit[n]uril in the Literature...... 21 Templated Reactions...... 33 Potential Applications of Cucurbit[n]uril ...... 36

RESULTS AND DISCUSSION...... 40

SYNTHESIS AND SEPARATION OF CUCURBIT[N]URIL ...... 40 Separation of Cucurbit[n]uril by Fractional Crystallisation...... 47 Separation of Cucurbit[n]uril by Cation Induced Solubility ...... 49

SIZE-DEPENDENT BINDING OF CUCURBIT[N]URIL ...... 56 Group 1. Straight Chain and small alkyl amines ...... 85 Group 2. Tetra-alkyl ammoniums...... 86 Group 3. Aromatic Amines ...... 88 Group 4. Adamantane and Carborane based guests...... 93 Group 5. Bipyridyl derivatives ...... 96 Overall Observations From The Size-dependent Binding Experiments...... 100

TEMPLATED FORMATION OF CUCURBIT[N]URIL...... 110 Templates that inhibit the formation of cucurbit[n]uril...... 124 Impact of templates on the proportion of cucurbit[5]uril...... 128 Impact of templates on the proportion of cucurbit[6]uril...... 129 Impact of templates on the proportion of cucurbit[7]uril...... 130 Impact of templates on the proportion of cucurbit[8]uril...... 132

v General observations on the templated formation of cucurbit[n]uril ...... 133 Further Work ...... 140

NEW NANO-STRUCTURES FROM TEMPLATED REACTIONS ...... 142 Inverse Rotaxane...... 142 Inverse Pseudorotaxane...... 146

CONCLUSION ...... 150

EXPERIMENTAL PROCEDURES ...... 152

EXPERIMENTAL METHODS ...... 153 Synthesis of cucurbit[n]uril ...... 153 Synthesis of bis-ethyl-4-4'-bipyridyl (50)...... 155 Synthesis of bis-(4-4'-bipyridyl)-1,6-hexamethylene (48) ...... 156 Cucurbit[n]uril synthesis utilising differing cation solubilities to aid separation ...... 157 Size-dependent binding NMR experiments...... 159 Templated synthesis of cucurbit[n]uril...... 160 Molecular modelling of template reactions...... 165

BIBLIOGRAPHY...... 167

vi List of Figures

7 Figure 1. Cucurbituril (1). Structure minimised using HyperChem using AM1...... 3 Figure 2. Q[6] (rendered as tubes) with 1,6-hexane diamine (rendered 7 as space filling). Complex was minimised using HyperChem...... 8 Figure 3. Cyclotriveratrylene (CTV, shown as tubes) 'cavitand' complexed with o-carborane (shown as spacefilled). Complex minimised 7 using AM1 in the HyperChem package...... 13 Figure 4. The cyclic host complexes with the guest ...... 16 Figure 5. Some common host-guest complexes. (a) Pseudorotaxane; (b) Rotaxane (c) Catenane...... 17 Figure 6. The different schemes for rotaxane formation. (a) Clipping; (b) Threading; (c) Slipping...... 19 Figure 7. Kim and colleagues' have synthesised 'molecular necklaces' 53,57 using Q[6] rotaxanes ...... 28 Figure 8. Two and three dimensional polyrotaxane networks synthesised 60 by Kim et al...... 29 Figure 9. Q[10] has only been found encapsulating Q[5] as shown here, 13 this complex has been dubbed a 'gyroscane' ...... 32 Figure 10. Fujita's Coordination Nanotubes Templated by Rodlike 121 Guests ...... 35 Figure 11. 1H-NMR spectrum of cucurbit[n]uril mixture ...... 41 Figure 12. 13C NMR spectrum of cucurbit[n]uril reaction mixture...... 42 1 Figure 13. H-NMR spectrum of pure Q[6] in 0.1 M Na2SO4 solution...43 47 Figure 14. Potassium complexed Q[6] incorporating THF ...... 50 45 Figure 15. Cesium cation complexed Q[6] binds with THF ...... 51 42 Figure 16. Sodium lidded cucurbit[n]uril complex with THF ...... 52

vii Figure 17. Fast separation protocol for cucurbit[n]uril mixtures...... 54 Figure 18. The complex formation between 1,6-hexamethylene diamine (12) and Q[7] is an example of slow exchange. a) 1H-NMR spectrum of

1,6-hexamethylene diamine (12) in Na2SO4. and b) addition of Q[7]. Note the two sets of peaks, with the bound environment shifted upfield as marked...... 58 Figure 19. Diagram showing magnetic shielding regions. From top to centre there is a downfield shifting region (green), a zero shift region (red) and an upfield shift region (magenta)...... 84 Figure 20. A 2:1 complex of p-xylene diamine (32, shown as space filling) with Q[8] (shown as tubes). Complex minimised with the 7 HyperChem package , using the AM1 force field...... 89 Figure 21. Possible orientations of (21) complexed with a) Q[7] and b) Q[8]...... 90 Figure 22. Comparison of (a) 2-aminobenzimidazole (33) and (b) indol- 3-aldehyde (35) binding with Q[7]...... 92 Figure 23. 1H-NMR spectra of the N-adamantaneacetamide size- dependent binding series ...... 94 Figure 24. 1H-NMR spectra of bis-(4,4'-bipyridyl)-hexane a) complexed 112 with Q[6] b) in D2O/DCl ...... 97 Figure 25. Alkylamine binding with Q[6]. a) 1,6-hexane diamine b) 1- amino hexane. Complexes were minimised with the HyperChem 7 package , using the AM1 force field...... 102 Figure 26. 1H-NMR spectra of; a) p-Xylene diamine (32) b) cucurbit[7]uril complexed with p-xylene diamine c) cucurbit[8]uril complexed with p-xylene diamine. The unbound resonances are marked with solid shapes, the bound resonances are marked with the white shapes...... 106 viii Figure 27. 1H-NMR spectra of; a) 1-Adamantane methyl amine (40). b) cucurbit[7]uril complexed with 1-adamantane methylamine. The peaks are marked to illustrate the change in chemical shift...... 108 Figure 28. 1-Admantane methylamine complexed with Q[7]n showing regions of chemical shift change. The figure on the left was minimised 7 with the HyperChem package , using the AM1 force field...... 109 Figure 29: Sherman's carcerand forms 106 times faster in the presence of a pyrazine template (complexed in center). Complex minimised with the 7 HyperChem package , using the AM1 force field...... 112 Figure 30: Fujita's 'Cagelike' complex only forms in presence of a 139 template such as sodium adamantanecarboxylate. Complex minimised 7 with the HyperChem package , using the AM1 force field...... 113 Figure 31: 'Switchable molecular lock' complex synthesised by Fujita et al. forms in the presence of the sodium adamantanecarboxylate 140 7 template Complex minimised with the HyperChem package , using the AM1 force field...... 114 142 Figure 32. The 'softball' synthesised by Rebek et al. is an example of glycouril in supramolecular chemistry...... 118 143 Figure 33. Isaacs has used these C and S shaped glycouril dimers to investigate cucurbit[n]uril formation...... 119 10 Figure 34. Proposed reaction mechanism from Day et al...... 126 Figure 35. Proto-cucurbit[n]uril oligomer curving back on itself to form 10 a ring ...... 127 Figure 36. Cucurbit[n]uril formation using 3-propylamine-o-carborane as a template. 13C-NMR spectrum of dried reaction mixture dissolved in

D2O...... 134

ix Figure 37. Proposed cucurbit[n]uril formation around bis-(4,4'- bipyridyl)-'-p-xylene template. Complex minimised with the 7 HyperChem package , using the AM1 force field...... 136 Figure 38. bis-(4,4'-bipyridyl)--p-xylene (45) and bis-(4,4'- bipyridyl)-1,6-hexamethylene (48). Note the fixed angle through the rigid benzene in the centre of 45. Molecules were minimised with the 7 HyperChem package , using the AM1 force field...... 137 Figure 39. Cross section of Q[6] complexes, reproduced from Mock et 17 al...... 139 Figure 40: bis-(4,4'-bipyridyl)-1,6-hexamethylene (48) complexed with 7 Q[6]. Complex was minimised with the HyperChem package , using the AM1 force field...... 143 Figure 41: bis-(4,4'-bipyridyl)-,'-p-xylene (45) complexed with a) Q[6] (left) and b) Q[7] (right). Complexes were minimised with the 7 HyperChem package , using the AM1 force field...... 145 Figure 42. Propylamine-o-carborane (43, shown as space filling) complexed with Q[7] (shown as tubes). Complex minimised with the 7 HyperChem package , using the AM1 force field...... 146 Figure 43. o-carborane (shown as space filling) complexed with Q[7] 7 (shown as tubes). Complex minimised with the HyperChem package , using the AM1 force field...... 147

x List of Tables

3 Table 1. Structural Parameters for Cucurbit[n]uril (n = 5 - 8) ...... 4 Table 2. 13C NMR shifts (ppm) of the three carbons of the cucurbit[n]uril, n = 5-8 in D2O/concd DCl(1:1 v/v)...... 43 Table 3. 13C NMR spectroscopy integral correction factors for cucurbit[n]uril in 20-35% DCl...... 44 Table 4. Observed positive-ion ESMS peaks (m/z) of a CsCl solution of Q[n] (n = 5-8)...... 45 Table 5. Size-dependent binding NMR spectroscopy results...... 62 Table 6. Percentage by weight of cucurbit[n]uril obtained through 115 addition of cations to proto-cucurbit[n]uril oligomer ...... 116 Table 7. Percentage by weight of cucurbit[n]uril obtained under different reaction conditions...... 117 Table 8. Results from templated synthesis of cucurbit[n]uril ...... 121 Table 9. Templated formation of cucurbit[n]uril ...... 162 Table 10. Template effect modelling...... 166

xi Abstract

1-3 The recently discovered cucurbit[n]uril are a range of macrocyclic 4 5 hosts which have enormous potential in industrial , medical and academic applications. Cucurbit[n]uril have a rigid repeating structure of methylene bridged glycouril, which give cucurbit[n]uril their gourd like shape of a cavity with two carbonyl fringed portals.

In this thesis the host-guest binding abilities of three cucurbit[n]uril (n = 6, 7, 8) have been examined for a range of potential guests. These guests ranged from simple alkyl amines through globular alkyl and carboranyl amines to bipyridyl systems. In total 45 guest molecules where examined. Most of the guests examined where either cationically charged, capable of hydrogen binding, contained a substantial molecular dipole, or a combination of these. Furthermore, all of the potential guests examined had some solubility in an acidified aqueous sodium sulfate solution within which the host-guest properties were examined. It was generally found that the larger guests did have selectivity for the larger hosts. However, when the host became too large weaker complexes would form and for the range of materials examined here cucurbit[7]uril was found to be the 'best' host system. In one example, p-xylene diamine, a 2:1 complex with cucurbit[8]uril was observed. While not the focus of this work a new rapid purification method was developed for the cucurbit[n]uril using different metal ions to either solubilise or precipitate the different cucurbit[n]uril.

In the second part of this work these same guest molecules where used as potential templates in the synthesis of cucurbit[n]uril. Surprisingly the guests that bound strongly to an individual host did not seem to template

1 the cucurbit[n]uril synthesis at all. Rather these strong binders inhibited the reaction such that little or no cucurbit[n]uril formed under the reaction conditions studied. However, several examples provided excellent template results. Indeed the results indicate that guests which bound with intermediate rates of exchange are the best templates and using templates under these conditions we have been able to produce cucurbit[7]uril as 46% by mass of the total cucurbit[n]uril product. This is the highest yield ever recorded for cucurbit[7]uril and it is the first example of cucurbit[7]uril being the major product of this condensation reaction. In an another example cucurbit[8]uril formed 18% of the product an increase of 150% over the standard reaction conditions.

While studying both the template reactions and the host-guest binding properties of the cucurbit[n]uril a new supramolecular form, an 'inverse rotaxane' was discovered. Inverse rotaxanes are not held in place by large blocking groups, rather the molecular structure encapsulated by the cucurbit[n]uril host prevents decomplexation of the axle.

2 Introduction

When Mock, Freeman and Shih rediscovered the cyclic hexamer formed from the condensation of glycouril and formaldehyde, they gave it the 6 trivial namei of cucurbituril. This name comes from the resemblance of cucurbituril (Figure 1) to gourds or pumpkins, which have the family name cucurbitaceae.

1 Cucurbituril

7 Figure 1. Cucurbituril (1). Structure minimised using HyperChem using AM1.

8 Figure 1 shows the molecule first synthesised by Behrend et al. and 6 reinvestigated by Mock et al. Intrinsic in its shape is the symmetry and

i The IUPAC name for cucurbituril is 1H,4H,14H,17H-2,16:3,15-dimethano-5H,6H,7H,8H,9H,10H, 11H,12H,13H,18H,19H,20H,21H,22H,23H,24H,25H,26H 2,3,4a,5a,6a,7a,8a,9a,10a,11a,12a,13a,15, 16,17a,18a,19a,20a,21a,22a,23a,24a,25a,26a-tetracosaazabispentaleno[1''',6''':5'',6'',7'']cycloocta- [1'',2'',3'':3',4']pentaleno(1',6':5,6,7)cycloocta(1,2,3-gh:1',2',3'-g'h')cycloocta(1,2,3-cd:5,6,7-c'd') dipentalene-1, 4, 6, 8, 10, 12, 14, 17, 19, 21, 23, 25-dodecone6)Freeman, W. A.; Mock, W. L.; Shih, N. Y. J. Am. Chem. Soc. 1981, 103, 7367-8..

3 regularity of its ring structure. This structure is very conducive to binding guests, with the internal cavity of the cucurbituril being larger 6 (5.5Å across) than the carbonyl portals (4Å across).

While Mock et al. were the first to give a trivial name to cucurbituril, this naming scheme was later extended to include different sized rings by 9 Flinn et al. Flinn synthesised a cucurbituril using dimethyl-substituted glycouril and obtained a cyclic pentamer rather than hexamer. This was called decamethylcucurbit[5]uril and thus the original cucurbituril becomes cucurbit[6]uril. Cucurbit[n]uril (Q[n]) refers to any cyclic homologue where n is equal to the number of glycouril repeating units.

Recently several groups have synthesised different sized cucurbit[n]uril, 2,3,10 11,12 using both unsubstituted and substituted glycouril. The introduction of new sizes and substitutions has increased the range of potential uses of cucurbit[n]uril. These new cucurbit[n]uril have differing solubilities and cavity sizes. It will be shown here that the larger ring sizes allow binding of larger guests. The portal and cavity sizes for the 3 four cucurbit[n]uril where n = 5, 6, 7 and 8 are listed in Table 1.

3 Table 1. Structural Parameters for Cucurbit[n]uril (n = 5 - 8)

Q[5] Q[6] Q[7] Q[8] Portal diameter (Å) 2.4 3.9 5.4 6.9 Cavity diameter (Å) 4.4 5.8 7.3 8.8 Cavity volume (Å3) 82 164 279 479 Outer diameter (Å) 13.1 14.4 16.0 17.5 Height (Å) 9.1 9.1 9.1 9.1 The values in this table already account for the van der Waals radii of each atom.

4 Computer generated images of these four cucurbit[n]uril are shown below. It should be noted that there is no evidence of existence for Q[n] 13 smaller than Q[5]. Cucurbit[10]uril is the largest analogue yet isolated. While there is some NMR spectroscopy evidence for Q[9] and other Q[n] where n is larger than 10, these have not yet been isolated.

Cucurbit[5]uril (3) Cucurbit[6]uril (2)

Cucurbit[7]uril (5) Cucurbit[8]uril (4)

Whilst Mock et al. rediscovered and characterised Q[6], it was Behrend et al. who originally discovered Q[6] when they were studying the chemistry of glycouril and other substituted ureas. They synthesised an intractable material with limited solubility by reacting urea, glyoxal and formaldehyde in concentrated sulphuric acid. Although Behrend et al. could not establish the structure of the compound that they had produced, they were able to determine an empirical formula of C10H11N7O4. Whilst

5 this compound was not soluble in many common solvents, they noted the solubility of this material in ionic and acidic solutions. They also discovered that this compound formed complexes with amines and 6,8 dyes.

It wasn't until 1981 that Mock et al. determined the structure of Q[6] using X-ray crystallographic methods whilst reinvestigating the findings of Behrend. Mock was able to show the well defined ring structure of Q[6] with its repeating glycouril subunits separated by two bridging 6 methylenes as shown in Figures 1 and 2.

Mock and colleagues' further investigated the use of Q[6] as a complexing host. In particular their work showed that Q[6] is very good at binding alkyl amines in their protonated form. Mock showed Q[6]@amine complexes formed such that the alkyl chains are threaded into or through the inner cavity of Q[6]. This positions the protonated amine at the carbonyl portal of the Q[6], where it binds through ion- 1,14 dipole interactions. The breadth of these studies has shown that Q[6] will bind preferentially to certain amines, dependent on both the type of amine (1L, 2L or 3L) and more importantly the size and shape of the alkyl moiety. The chain length of the amine to bind with Q[6] should be complementary to the distance through the Q[6], such that for a monoalkylamine to bind it must entirely fit within the cucurbit[n]uril cavity. A dialkylamine should have amine functionality spaced at the inter-portal distance to bind effectively, such that the protonated amine is positioned near the carbonyl portal of the cucurbit[n]uril. If a guest is too large to fit through the carbonyl portal, that guest cannot bind internally to cucurbit[n]uril, although external or portal binding is possible.

Mock et al. determined that the best chain length for a diamine binding to Q[6] is around C5-C6 as shown in the complexes of Q[6] with 1,5- 15 pentanediamine.2HCl and 1,6-hexanediamine.2HCl. These two compounds 'thread' into Q[6] in acidic solutions in order to maximise the hydrophobic interaction of the alkyl chain with the cavity of the Q[6]. This hydrophobic effect couples with the ion-dipole interaction between the charged ammonium ion and the oxygen atoms in the Q[6] carbonyl portal to form a stable complex.

Mock and his colleagues have released several papers on the complex formation between alkyl/aryl amines and Q[6]. They provide dissociation 1,15-17 constants for many of these complexes. The range of dissociation constants they determined, obtained in a 1:1 mixture of H2O - 85% -2 HCO2H, went from the weakly bound NH3 (Kd = 1.2 x 10 ) to the -8 strongly bound spermine (Kd = 7.6 x 10 ). These dissociation constants compare favourably with those commonly obtained in cyclodextrin

-3 -4 18 complexes, which are in the range of Kd = 3.7 x 10 to 9.9 x 10 . Figure 2 shows an example complex of Q[6] with hexanediamine: notice the proximity of the portal oxygen atoms to the terminal ammoniums of the hexane diamine, it is believed that these ammoniums are bound to the 1,15,16 carbonyl oxygens through ion-dipole interactions.

Figure 2. Q[6] (rendered as tubes) with 1,6-hexane diamine (rendered as space filling). Complex 7 was minimised using HyperChem.

Mock and colleagues' pioneering work on Q[6] has paved the way for others to investigate the binding properties of Q[6]. Buschmann and Schollmeyer have studied rotaxane formation and strength of binding for a variety of Q[6] complexes, along with several patents detailing the synthesis of Q[6] and its use in the treatment of textile industry wastes.

Behrend and Mock et al. initially had yields in their synthesis of Q[6] at around 20%. Significantly, Buschmann and Schollmeyer developed a synthesis of Q[6] that increased the yield of Q[6] to around 90%. The

8 synthesis used to produce Q[n] in this work was optimised by Day et 2,10 al. Day et al. found that the reaction could be carried out in one pot using milder conditions than those reported by Mock et al., Buschmann et al. or Behrend et al.

9 Subsequent to Flinn's synthesis of decamethylcucurbit[5]uril in 1992 , some other groups have recently synthesised cucurbit[n]uril using substituted glycouril. Kim et al. have built on their extensive work on cucurbit[n]uril to produce two cucurbit[n]uril type compounds using 12 cyclo-hexanoglycouril. This is a ground breaking discovery as the subsequent cucurbit[n]uril were found to be soluble in both organic solvents and neutral water, which is not the case for any of the previous cucurbit[n]uril. Similarly Nakamura et al. have produced diphenyl Q[6] 11 from a mixture of diphenylglycouril and glycouril in 30% isolated yield. Both of these new substituted cucurbit[n]uril are important as they may lead to the development of cucurbit[n]uril attached to solid supports, which will be useful in separation, chromatography and detection.

A range of methodologies have been used to study the host-guest interactions of Q[6]. The main three of these are X-ray crystallography NMR spectroscopy, and UV-Vis spectroscopy. X-ray crystallography enables a researcher to determine the exact position of the guest in the Q[6] host. Mock et al. have shown that Q[6] bound guests show a change in their 1H-NMR spectroscopy upon complex formation. Guest protons inside the Q[6] cavity will experience an upfield shift, whilst guest protons outside the Q[6] carbonyl portal will show a downfield 1,15,16 shift. Guests with a UV absorbtion will often show a perturbation in 15,19,20 that absorbtion when complexed with Q[6].

Mock et al. have used both NMR and UV-Vis spectroscopy to determine the strength of amine complexes with Q[6]. They used UV-Vis spectroscopy to determine the strength of the complex between Q[6] and the 4-(methylbenzyl)ammonium ion. Using the relative binding of this 4- (methylbenzyl)ammonium ion and other amines, Mock et al. have 1,15-17,21,22 produced binding strengths for many compounds.

Fluorescent spectroscopy techniques have been used to study complexes of Q[6] with guests that have a fluorophore, which have shown similar results to complexes with the cyclodextrins. The fluorescence probe 1- anilino-8-napthalenesulfonate (1,8-ANS) has been studied by two groups simultaneously. Buschmann and Wolff studied complexes of 1,8-ANS 23 with Q[6], cyclodextrin and other hosts. Wagner and MacRae have also studied the complex of 1,8-ANS with Q[6], but at a much greater depth 24 than Buschmann. 1,8-ANS is sensitive to the polarity of the solvent. When an aqueous solution of 1,8-ANS is added to Q[6] the complex precipitates out of solution and the resultant solid is strongly fluorescent.

Wagner was able to obtain an X-ray crystal structure for this complex, which shows a 2:1 binding of 1,8-ANS to cucurbit[6]uril, contrary to the 1:1 complex assumed by Buschmann. This crystal structure shows that the 1,8-ANS is not bound internally, but forms instead a lattice inclusion compound with Q[6]. The 1,8-ANS is interspersed between the cucurbit[n]uril in the structure. Wagner proposes that the solid is highly fluorescent due to this spacing of the 1,8-ANS. The physical separation of the 1,8-ANS in the lattice prevents them from interacting with each other, thus increasing the fluorescence. Wagner proposes that this is in

10 essence a highly ordered solid solution of 1,8-ANS, with no excimer formation or energy transfer between the 1,8-ANS molecules.

With regard to the methods and results in this work which will be presented in a later chapter, Wagner shows that the Q[6]@1,8-ANS complex has no Na2SO4 present in the crystal structure, although this was in the solution from which the crystal precipitated. The reasoning given for this is that the complex with the 1,8-ANS displaced the Na+ cations from the Q[6], causing the precipitation of the Q[6]. This is relevant as a

Na2SO4 solution is used in this work for many host-guest binding experiments. The sodium ions are known to bind to the portal of Q[6], which could interfere with the binding of the amine guests used here. As will be shown later the Na+ ions apparently do not interfere with the amine binding and Wagner's result confirms that the Na+ ions don't interfere with 1,8-ANS binding.

Another technique that has been utilised for the study of cucurbit[n]uril complexes is that of micro-calorimetric titration. The small changes in heat due to complex formation may be measured, and from this measurement the binding constant may be calculated. This technique requires that the complex formation is essentially instantaneous, an assumption that may not always prove to be correct. The mathematical treatment of the data also relies on several other assumptions, such as the number of guests per host, which has been proven incorrect for some host-guest systems by other methods such as NMR spectroscopy or X-ray crystallography. This method is effective in the study of complexes with low solublility, as well as complexes with very low binding constants. Buschmann and colleagues' have predominately focussed on the removal of reactive dyes from the wastewater of textile plants. Many of these

11 dyes have amine functionality and so have some degree of affinity for cucurbit[n]uril.

12 Host-Guest Chemistry Host-guest chemistry is the name given to the study of the encapsulation of one compound (the guest) by a second compound (the host) through non-covalent interactions. As a general rule a host is chosen to be complementary to a particular guest, such that in solution a complex is formed spontaneously. It is the type and degree of binding that determines the nature of the complex, and this is reflected in the nomenclature. There exist a number of types of host-guest complexes; these include carcerands, cavitands, clefts, pseudorotaxanes and rotaxanes, along with others such as catenanes and knots. One example of a host-guest complex is the pseudorotaxane of 1,6-hexanediamine complexed with Q[6] shown in Figure 2. This is an example of internal binding, where the guest is 'threaded' through the host.

Figure 3. Cyclotriveratrylene (CTV, shown as tubes) 'cavitand' complexed with o-carborane 7 (shown as spacefilled). Complex minimised using AM1 in the HyperChem package. 13

A good example of a 'cavitand' style of host-guest complex is shown in Figure 3. This has o-carborane complexed with cyclotriveratrylene (CTV), utilising a weak interaction between the hydrogens of the o- 25 carborane and the benzene rings of the CTV to bind form the complex.

The extent of host-guest complex formation depends on various factors: S The affinity of the host for the guest. S The affinity of both the host and the guest for the solvent. S The rate of any closing (clipping/stoppering) reactions (if the complex formation relies on stoppering a pseudorotaxane). S The rate of complex dissociation.

Host-guest complexes may be synthesised in either aqueous or non-polar solvents, or indeed in the absence of solvent (depending on the system in question). Once the complex is formed it is the rule, rather than the exception, that the guest is in a unique environment. This environment is different from the bulk solution in which the complex is formed. The unique environment is extended to the part of the guest that is ensconced in the host and may be utilised in a number of ways. The unique environment that the encapsulated guest is in, is often reflected by changes in the guests' NMR, UV/Vis and other spectra. Host-guest complexes have also been shown to have unique electronic and charge 24,26-29 transfer properties in some instances.

Many techniques such as UV spectroscopy, voltammetry, fluorescence spectroscopy, micro-calorimetry and X-ray crystallography, have been used to investigate host-guest complexes. NMR spectroscopy is useful

14 because of the change in chemical shift that is often apparent when a complex is formed. It is common to find proton spectra in which a change in chemical shift of 1-2ppm is observed for the protons on a 1,15,16 guest. Many NMR techniques may be simply adapted to supramolecular studies, such as titrations and NOE experiments.

X-ray crystallography allows the chemist to view the exact orientation of a guest inside a host, something which can often only be inferred with other methods, like NMR spectroscopy. The technique does have shortcomings, not least of which is the difficulty in obtaining crystals of the complex being studied. Another shortcoming is that the structure obtained in the X-ray techniques is that of the complex in solid state, often with additional species co-crystallising. This may be different to the structure in solution: however, it is commonly accepted that this is close to the solution complex. Indeed other techniques like NMR spectroscopy are used to judge the effectiveness of results on the X-ray benchmark.

Other techniques like UV and fluorescence spectroscopy may also be successfully employed for determining the binding constant of the complex formed. These are useful if part of the complex has a chromophore or can fluoresce, as these properties have been shown to commonly change upon the binding of the guest by the host in 24,26 question.

Another commonly used technique is that of mass spectroscopy. A mass spectrum of a complex may show a complex ion, especially for a strongly bound complex. For cucurbit[n]uril compounds only electrospray mass

15 spectroscopy has proven itself as an acceptable technique due to its low energy ionisation process, which has been shown to successfully ionise Q[n] and their complexes without disrupting the complex.

Rotaxanes and Pseudorotaxanes Complexes such as those shown in Figure 2 and Figure 4 can be called host-guest complexes, although this name doesn't imply anything other than the existence of a complex. To further and more accurately describe the complex other nomenclature may be used. The name pseudorotaxane is given to a complex like that in Figure 2. This sort of complex may be stable for a relatively long period of time, but has no physical impediment to the dissociation of the complex. A rotaxane is a similar complex, but with a physical impediment to dissociation such as bulky end groups on the guest, to prevent 'de-threading'.

Guest Host Complex

Figure 4. The cyclic host complexes with the guest

Stoddart and co-workers performed much of the pioneering work into rotaxane formation and function. It was Stoddart who developed the nomenclature for rotaxanes, basing it on the nomenclature for carcerands proposed by Cram. In this nomenclature the number of rings, n, in a

16 rotaxane is indicated by: [n]rotaxane, whilst the number of interlocking rings, n, in a catenane is shown by [n]catenane.

Pseudorotaxanes and rotaxanes are similar structures, with one important difference. The complex formed as a pseudorotaxane has no physical barrier to decomplexation, so an equilibrium is formed between the 30 bound and unbound species. There are examples in the literature of these types of complexes which range from weakly to quite strongly bound. The robustness of a pseudorotaxane is attributed to several weak interactions between host and guest. Non-covalent bonds such as hydrogen bonding, van der Waals forces, or the hydrophobic effect, make up these weak interactions and can lead to very stable complexes.

Pseudorotaxanes are sometimes used as self-assembling precursors to rotaxanes. In these cases the complex is formed between the host and guest, after which the guest is reacted with 'stopper' groups to prevent the guest from de-complexing. This technique of rotaxane formation is quite common and is known as 'stoppering'.

Figure 5. Some common host-guest complexes. (a) Pseudorotaxane; (b) Rotaxane (c) Catenane

17 Rotaxanes can be formed by three different schemes; clipping, threading and slipping. The clipping method (Figure 6a) is different from the other two methods in that the host is formed around the guest as the complex- 31,32 forming step, either in a templated reaction or as a small addition to a 'C' shaped molecule to complete the ring. This method is less common, as success is usually forthcoming at higher yield with either threading or slipping. The threading scheme (Figure 6b) effectively involves forming a pseudorotaxane and then blocking the ends of the guest with bulky stoppers. In contrast, the slipping scheme (Figure 6c) involves the forcing of a guest into the host cavity through energy input, with the guest already containing the necessary stoppers. An important note on the different methods of rotaxane formation is that although the synthesis is different, the rotaxane that is obtained is equivalent. The choice of method will depend on both the host and guest.

Figure 6. The different schemes for rotaxane formation. (a) Clipping; (b) Threading; (c) Slipping.

A catenane (Figure 5c) is formed when the 'axle' of a pseudorotaxane or rotaxane is cyclised, resulting in two or more interconnecting rings. In order to enable the complex to form, hosts and guests with rigid geometries, such as bipyridyl compounds, are commonly used. There are also examples that utilise metal ions as geometry stabilisers during the catenane formation. These use organometallic complexes to maintain a

19 specific angle through the catenane rings. These organometallic complexes are chosen based on their geometry; for example square planar or tetrahedral. Similar in design are the knot compounds where, through use of specifically designed geometry or other templates, one or more 30,33 molecules are twisted through to form a knot.

Many of these complexes have now been identified, and it seems almost trivial to make a rotaxane between one of the known hosts and a molecule from one of the common families of guests. There is currently a great amount of research into rotaxanes currently being carried out, including new rotaxanes, kinetics and mechanics of formation as well as possible 15-17,30,33-35 uses for rotaxanes and other molecular structures. The detection of rotaxane formation is also reasonably straightforward. Often certain features of the guest's spectra are perturbed upon binding to the host. Stoddart et al. elucidated the first rotaxanes using NMR spectroscopy.

20 Cucurbit[n]uril in the Literature As mentioned earlier, Mock and co-workers re-investigated Q[6] throughout the 1980's. They were able to obtain a crystal structure for 6 Q[6] , which showed the cyclic nature, carbonyl portal and cavity of this macrocyclic host. Building from the observations of Behrend et al. from 8 1905 Mock used Q[6] to bind small amines in acidic solution. In these 1H-NMR spectroscopy experiments it was noticed that the Q[6] imparted a magnetic shielding on some of the protons of the alkyl amines with which it was complexed. Mock et al. were able to determine that when a guest is complexed with Q[6], the protons that are bound on the inside of the Q[6] cavity are shifted upfield in the 1H-NMR spectrum. Conversely any protons that are external to the carbonyl portals of the Q[6] are shifted downfield in the 1H-NMR spectrum. This observation may be used to help determine the orientation of compounds that are complexed with cucurbit[n]uril, as well as simply providing evidence that a complex has formed.

Mock et al. have studied the complex formation between Q[6] and a range of alkyl amines, alkyl diamines, cycloalkyl amines and aryl amines 1 in acidic solution. Of these they found that the straight chain diamines, with the amines orientated near the carbonyl portals, bind most strongly. Mock et al. found that it was possible for Q[6] to bind an alkyl chain that had a side methyl group, but not to a benzene moiety with methyl groups substituted ortho or meta to the amine. This restriction on aromatic rings 15 is due to the very tight fit of the benzene ring in the Q[6] cavity. Mock et al. also found that straight chains with 3 or more amines could complex more strongly than a simple diamine, possibly due to multiple binding sites.

Mock et al. have studied in detail the interactions between the alkylamine guests and Q[6]. Essentially they discovered that the carbonyl portal of Q[6] provides “a cation binding site, to which an ammonium ion may coordinate, with ion-dipole interactions facilitated by bipodal hydrogen 16 bonding”. The second contributory force that they determined in the complex formation is that once an alkylamine binds internally to the Q[6] it displaces the water molecules that would normally be encapsulated. This internal binding of a hydrophobic moiety inside the cavity provides 16 a beneficial hydrophobic effect to the stability of the complexes.

To form the complex the organic amine guest must pass through the 4 Å portal. This has been shown to impede the complex formation with guests that have a larger cross-section than 4 Å. This impediment to 17 formation is almost linear with the size of the guest up to the size of a benzene ring. A benzene ring with a side methyl group ortho or para to the amine functionality will not bind to Q[6] because it cannot fit through the portal. This impediment on the rate of formation of the complex does 16,17 not impact the rate of dissociation of these complexes.

While studying the competitive binding of the Q[6] with alkylamines, Mock et al. also determined that the guests have “considerable freedom 17 for re-orientation” inside the Q[6]. They measured the 13C spin-lattice relaxation time of some complexes to discover that the guests can spin freely at different rates to the Q[6]. In fact the guests are only marginally impeded when bound with Q[6], as compared to the guest in solution. They used this information to determine that the ability of the guests to move freely inside the Q[6] while bound does not impact upon the

22 dissociation constant of the complex. Mock et al. attributed this ability of the guest to move freely to the large internal cavity of the Q[6] compared to the portal, that is to say that the guest is only impeded by the portal and not by the entire Q[6].

When Behrend et al. first synthesised Q[6] in 1905 they noted that complexes were formed with both metal salts and dyes. Almost ninety years later another group of German researchers extended Mock and colleagues' research into Q[6] with respect to its binding capability of amines, metal salts and dyes. Buschmann, Schollmeyer and co-workers have contributed a great deal to the research of Q[6] as a host macrocycle, authoring many research papers and several patents in the area. The focus of this research group has been in the uses of Q[6] in the treatment of textile industry wastes. Buschmann et al. were able to optimise the reaction conditions for the synthesis of Q[6], to an isolated yield in excess of 85%, an increase from Mock and colleagues' yields of around 20%. 36 These synthetic changes produce Q[6] alone.

Buschmann's group has studied Q[6] complexes with a range of alkaline 4,36-41 and alkaline earth metal salts, along with other metal cations , which has been built upon in this work to provide a mechanism of separating individual cucurbit[n]uril from a reaction mixture. To study these complexes they utilised UV-Vis spectroscopy and micro-calorimetry. Buschmann et al. discovered that the UV-Vis absorbance of Q[6] increased upon complexing with alkaline metal salts. They use this absorption change to calculate the equilibrium constants for these Q[6] complexes.

23 Buschmann et al. have utilised micro-calorimetry to determine the heat produced in a complex's formation, which can be used to determine the enthalpy of formation of the complex. They have used this technique to determine binding constants for a range of guests, including organic amines, nitriles, alcohols and acids along with metal cations. This technique is very sensitive, which enables its use for studying very weak interactions. The technique does have some limitations – the data must be manipulated mathematically based on certain assumptions. The assumption that Buschmann et al. originally used for the complex with metal cations is that Q[6] would bind with one cation per portal. This has been shown to be dependent on the size of the cation used to bind with the Q[6]. For example, sodium cation complexed Q[6] has two sodium cations complexed per portal, at least in the crystals obtained by Kim et 42 al. Therefore the value of Buschmann et al.'s work is limited by this often incorrect assumption. This shortcoming aside, calorimetry is a useful technique if the mode of binding is known, or may be assumed with a good degree of certainty. Good examples of acceptable assumptions on the mode of binding in calorimetry studies may be found in Buschmann and colleagues' work on larger guest complexes with Q[6]. Buschmann et al. reinvestigated, using calorimetry, many of the guests studied by Mock et al.

As mentioned previously, Buschmann et al. have studied the complexes of Q[6] with many families of guest other than alkylamines. Using Mock and colleagues' work on the mechanism of complex formation, where they stated that hydrogen bonding was less important to complex formation than ion-dipole interactions, Buschmann et al. have complexed other compounds with hydrogen bonding capability (like organic acids) and compounds with no hydrogen bonding capability like bis-bipyridyl

24 compounds. These bis-bipyridyl compounds have been shown to bind to other macrocyclic hosts such as cyclodextrin. In this study most of the bipyridyl based compounds that Buschmann studied are re-investigated with the other cucurbit[n]uril. Buschmann et al. have also shown that bonding Q[6] to compounds which don't have an ion, such as alcohols and nitriles, is possible. The mode of bonding in these cases is obviously not ion-dipole interactions, but dipole-dipole interactions.

Once the existence of the different sized cucurbit[n]uril was known, Buschmann et al. have gone back and studied many of these interactions 19,20,43,44 with different sized cucurbit[n]uril, particularly Q[5].

One other group has provided as much, if not more, work on cucurbit[n]uril than those previously mentioned. This group is from Korea and is headed by Kimoon Kim. Kim et al. have synthesised many cucurbit[n]uril complexes, again using metal cations and amines. Kim has shown several rotaxanes and polyrotaxanes. Simultaneously with Day et al., Kim et al. discovered the different sized cucurbit[n]uril.

Kim has studied in depth several complexes of Q[6] with metal cations, 42 45 46 47 specifically with sodium , cesium , rubidium and potassium ions. Kim et al. obtained X-ray crystal structures for these complexes, each of which has a unique structure. Both the sodium and cesium complexes of Q[6] form a type of molecular container. Sodium complexes Q[6] such that there are two sodium cations complexed to each Q[6] portal, which Kim et al. call a 'lidded' cucurbit[6]uril. This container is able to bind THF reversibly, which is significant as this is the first example of a cucurbit[n]uril forming a complex with a compound that doesn't extend

25 past the cavity. The container formed with cesium is slightly different due to the larger ionic radius of cesium. Only one cesium cation is complexed per portal with Q[6], and upon binding with THF one of these cesium cations is displaced to give a complex containing one cesium, one Q[6] and one THF.

The complexes that are formed with both rubidium and potassium are much larger superstructures. Both rubidium and potassium bind on a 2:1 ratio with Q[6]. Each portal is bound to two cations, with each cation binding to two Q[6]. The resulting complex is a long chain of Q[6], portal to portal, with the cations bound to the portals. In each case the resulting long chains of complexed Q[6] pack together to form the superstructure. The two cations afford slightly different structures. In the case of potassium bound Q[6] the Q[6]-metal cation polymers are packed in columns, alternating columns having their portals at the height of their opposites' 'bulge'. That is to say the 'thin' point of one polymeric column is packed close to the 'fat' point of another polymeric column. The rubidium cations form a 'hexagonal, open framework'. In this case the Q[6] are still packed with a half Q[6] offset, although the packing is such that there is a 10Å channel between every six 'polymers'.

Kim et al. have also studied organic guests with cucurbit[n]uril. They have formed pseudorotaxanes, along with the first cucurbit[n]uril 48 49-51 rotaxanes and polyrotaxanes. A polyrotaxane is a structure very similar to a 'normal' rotaxane, except that the guest is a polymer. This was the first of many larger complexes that Kim's group has studied.

Following on from the work on the sodium lidded Q[6] 'container', Kim et al. have shown that Q[6] may also bind to neutral guests like xenon.

26 Q[6] was dissolved in aqueous Na2SO4 solution and xenon was bubbled through the solution. 129Xe-NMR spectroscopy was used to determine that a complex was formed. This clearly showed two peaks, one bound and one unbound.

Like many other supramolecular systems there are papers covering both simple complexes with cucurbit[n]uril hosts, as in the examples presented above, along with more complex structures as shown in Kim's 46,47,49,51-53 work . Indeed Kim et al. have provided the bulk of work dealing with the larger supramolecular complexes of cucurbit[n]uril.

Kim et al. have used Q[6] and alkylamines to make both rotaxanes and polyrotaxanes. They have investigated the use of cucurbit[6]uril 54 rotaxanes as molecular switches, one with kinetic control and another 55 56 with fluorescence signalling , extending from work done by Mock. Both of these rotaxane switches are based on having two locations for binding the Q[6], with the ability to turn 'on' or 'off' these binding sites, thus controlling where the Q[6] will bind.

53,57 Figure 7. Kim and colleagues' have synthesised 'molecular necklaces' using Q[6] rotaxanes

The bulk of complex work from Kim et al. is in reference to rotaxanes and polyrotaxanes formed from Q[6] pseudorotaxanes complexed with metal cations. Kim has merged cucurbit[n]uril chemistry with organometallic complexes to form very complex rotaxane and catenane networks. Usually they have used a secondary diamine to bind with the cucurbit[n]uril in its centre. The diamine then has functionality external to the carbonyl portal that is known to co-ordinate to the metal or organometallic complex. Depending on the relative angles of the cucurbit[n]uril guest and the metal complex, these polyrotaxanes have 49,51,58 formed one dimensional (straight chain) polymers , two dimensional 50,58,59 60 polymer 'nets' , three dimensional polyrotaxane 'networks' along with more discreet 'molecular necklaces' containing 3 or more Q[6] on a 52,53,57,61 circular guest.

60 Figure 8. Two and three dimensional polyrotaxane networks synthesised by Kim et al.

Kim's work on polyrotaxanes includes a subset of pseudopolyrotaxanes 62 where the Q[6] is complexed to a polymerised alkyl chain , or the Q[6] 63 is bound to alkylamine side chains of a polymer. Other research groups have released details of similar polyrotaxanes, essentially using 64-66 polymerised Q[6] guests.

Kim's group has strongly contributed to our knowledge of cucurbit[n]uril, with detailed work on both small and large complexes. The interested reader is referred to their papers and patents for further 3,5,12,27,28,42,45-53,55,57-63,67-83 details.

There have been other groups who have utilised cucurbit[n]uril in their inorganic complexes. Fedin et al. have several papers dealing with Q[6] 84-109 binding to various inorganic complexes. These have all been bound externally to Q[6] and some effort has been made to record X-ray crystal

29 data for these complexes. There has also recently been a tin chloro aqua 110 complex with Q[7] that was bound internally in Q[7].

Work on the other cucurbit[n]uril is not as prevalent as that undertaken for Q[6] and it mostly mirrors the work done for Q[6]. For example 111 binding studies of viologens and Q[7] are based on work with bipyridyl 112 based compounds complexing to Q[6]. This type of work has improved our knowledge of cucurbit[n]uril binding properties, and has cemented the hypothesis that cucurbit[n]uril binding is dependent heavily on size and shape for selectivity. This size selectivity is evident in the complex formation between decamethylcucurbit[5]uril and lead cations. 113 The host was shown to be very sensitive to lead cations.

Cucurbit[7]uril has been complexed successfully with viologen and 83,111 viologen derivatives. This follows on from work performed on 112 complexes with Q[6]. Cucurbit[7]uril has also complexed with a neutral guest, o-carborane. Carborane is an approximately spherical compound with formula of C2H12B10. The complex has only been formed in trifluoroacetic acid, as the carborane is not soluble in aqueous acid. This work is extended here with a water soluble o-carborane derivative forming water soluble complexes with Q[7] and Q[8].

Cucurbit[8]uril has proven to be significantly different in its complex formation, due to the larger cavity. Cucurbit[8]uril can hold much larger compounds than the smaller homologues and will even bind two other 75 macrocycles, cyclam and cyclen. Cyclam and cyclen are macrocycles that can bind metal cations. Binding these macrocycles with Q[8] increases the stability of the copper ligand when oxidised to CuI, whilst

30 simultaneously slowing the electron transfer. Kim et al. state that this is similar behaviour to redox centres that are encapsulated in the centre of proteins. Other electron transfer changes are seen in the complexes of Q[8] and charge transfer pairs based on viologens and aromatic compounds. These charge transfer complexes will form inside a Q[8], 27,28,71 such that the Q[8] complexes both the electron guest and donor. The complex formation actually increases the charge transfer interaction. Furthermore Kim et al. claim that the charge transfer interaction is a driving force in the formation of the complex. This is apparently the case as the aromatic, electron rich guest used by Kim et al. does not bind to 28 Q[8] without the corresponding viologen.

Cucurbit[10]uril has only been reported as complexed around Q[5]. It appears that this complex is formed in minor amounts in the reaction optimised by Day et al. The two parts of this Q[5]@Q[10] complex are able to rotate independently in solution, so this complex was coined a 13 gyroscane. Day et al. also state that it appears that the higher cucurbit[n]uril are unstable, and that Q[10] is obtained due to it being stabilised by forming a complex with Q[5]. Although it is possible that Q[10] is formed by a templated reaction around Q[5].

Figure 9. Q[10] has only been found encapsulating Q[5] as shown here, this complex has been 13 dubbed a 'gyroscane'

32 Templated Reactions Prior to the announcement of the other cucurbit[n]uril homologues, Buschmann et al. had optimised the reaction to produce Q[6] in good 114 yields. Mock and colleagues' reaction scheme, based on Behrend and colleagues' original reaction, only produces around 20% Q[6] due to substantial decomposition of glycouril. After the announcement of the 2 3 other cucurbit[n]uril homologues by both Day et al. and Kim et al. only 10,115 two other papers from Day et al. have described changes to the reaction designed to favour one size cucurbit[n]uril over another. In the first of these papers Day et al. describe the affect on the reaction by changing the temperature, concentration and acids used in the formation reaction. Part of this work lead to Day et al. postulating a reaction mechanism where a 'template' could be involved in the cucurbit[n]uril formation, by guiding or stabilising ring formation. In Day and colleagues' second paper about reaction conditions, the idea of templated formation of cucurbit[n]uril is developed through the addition of metal salt 'templates' to the reaction. Of these several were shown to make a marked difference to the distribution of products from the reaction, notably in the formation of the smaller rings, Q[5] and Q[6].

31 Templated reactions are not a new idea in macrocyclic chemistry. Both 116 117 anionic and cationic templates have been used in the formation of macrocyclic rings. These have been shown to make the macrocycle more stable during its formation. More relevant to parts of this work are the use of non-ionic templates in the formation of macrocycles and other supramolecular compounds. Several groups have successfully used organic templates to form or optimise the formation of larger compounds. Stoddart et al. have used templates in the formation of cyclobis(paraquat-

33 p-phenylene), a macrocycle that Stoddard et al. have used to form 118 rotaxanes and catenanes. Similarly Sherman et al. were able to prove 119,120 the template effect on the formation of their carcerand , which is a large 'container' compound formed from two 'bowl' shaped hemicarcerand molecules. The template in this case is a good guest for both the hemicarcerands and the carcerand. The formation of the carcerand from its halves involves the formation of four reversible inter-hemicarcerand bonds, which is normally a slow process. The template speeds the formation of the carcerand by increasing the stability of the intermediate.

Papers describing template effects like that in Fujita's rodlike complex (and references within) are useful in describing various uses for organic templates. Fujita et al. have shown that a rod-like compound can 121 template the formation of their rod-like host as shown in Figure 10. Without the biphenylene template their reaction made many products, whilst the addition of this template controlled the reaction such that after heating the desired product was the main product of the reaction.

121 Figure 10. Fujita's Coordination Nanotubes Templated by Rodlike Guests

The concept of templated formation of macrocycles will be utilised later, using cucurbit[n]uril guests as templates in an attempt to influence the product distribution of the cucurbit[n]uril formation reaction.

35 Potential Applications of Cucurbit[n]uril Cucurbit[n]uril has uses that extend beyond the purely academic sphere. The natural binding properties of cucurbit[n]uril mean that it may have uses in the waste industry, specifically to remove reactive dyes from wastewater.

It has been proven that Q[6] is adept at removing many dyes from the wastewater produced by the textiles industry by passing the dye containing wastewater over a column of Q[6]. Due to the resilience of Q[6] this column may then be rejuvenated with ozone or by flushing the 122 column with water. Day et al. have shown that Q[6] forms a complex with dioxane, a highly water soluble material produced as a by product in several manufacturing processes. Cucurbit[n]uril has also shown similar affinities to a range of small alkane and aromatic guests as 123 cyclodextrin , another macrocyclic compound capable of binding guests. This suggests that cucurbit[n]uril can be employed in many circumstances where cyclodextrin is currently used.

124 Mock and co-workers have shown Q[6] to act as a catalyst in a cycloaddition reaction. In this case both reactants are complexed with Q[6] and the reaction takes place in the internal cavity of Q[6]. This directed the orientation of the reactants and increased the reaction rate by several orders of magnitude.

56 55 Both Mock and Kim have also shown that the host-guest system may be controlled in such a way as to give cucurbit[n]uril multiple binding sites through the use of alkylamines with multiple amines. This in turn can be further refined to control the site at which cucurbit[n]uril binds

36 based on changes to the pH of the system. In effect this creates a 'switch' or 'shuttle', both on a molecular scale.

A portion of this thesis will be dedicated to examining a new form of rotaxane where the guest is completely trapped within the host, without the need for external stoppers. This may be thought of as a molecular 'ball and socket' joint.

Cucurbit[n]uril have traditionally had some problems with solublity in certain applications. Although cucurbit[n]uril can remove dyes from textile industry waste water, it is also soluble in this solution to varying degrees because of the ionic concentration of the waste water. Recently 11,12 synthesised substituted cucurbit[n]uril could lead to cucurbit[n]uril bound to a solid support to create a very effective treatment mechanism. Other applications of these substituted cucurbit[n]uril are to increase solubility in organic solvents, which makes cucurbit[n]uril more flexible than cyclodextrin as a host.

The other clear indication of potential practical application of cucurbit[n]uril is to note the number of patents in the area. At time of writing there were nine patents or applications, with seven of these 114 lodged after 2000. These are for the synthesis of Q[6] and the other 2 cucurbit[n]uril. There are also patents covering the formation of some 5,77,125 derivatised cucurbit[n]uril , along with some covering the use of 4,126-128 cucurbit[n]uril in various industrial applications.

The present work aims to take research performed on Q[6] and increase the scope to include other cucurbit[n]uril. This includes synthesis and separation of the different cucurbit[n]uril and a comparison of the host- guest chemistry of the different sized cucurbit[n]uril (where n = 6, 7 and 8). The work is presented in several discreet sections; these are summarised below:

Synthesis and Separation of cucurbit[n]uril In order to obtain the various cucurbit[n]uril needed for all of the size- dependent binding experiments, a cucurbit[n]uril synthetic scheme was adapted and a new separation methodology developed.

The effect of cucurbit[n]uril size on the host-guest binding properties of cucurbit[n]uril, or size-dependent binding In order to investigate and compare the binding properties of different cucurbit[n]uril certain well known cucurbit[n]uril guests, along with other proposed guests, were added to the cucurbit[n]uril, where n = 6, 7 and 8. The aim of this section was to investigate the differences in binding capability of the various cucurbit[n]uril.

The effect of templates on product distribution The guests used in the previous size-dependent binding section were added as templates to the reaction medium whilst forming the cucurbit[n]uril with the goal of altering the product distribution of the cucurbit[n]uril. The hypothesis here is that the forming cucurbit[n]uril could be bound to a guest template which causes a change in the product distribution by favouring a particular sized cucurbit[n]uril

38 New types of supramolecular structure Through the previous sections certain complexes stood out as being unique, due to unexpected binding or a different style of complex than has been seen to date. These are discussed in this section, including the distinguishing features of these new complexes and how they are formed.

39 Results and Discussion

Synthesis and Separation of Cucurbit[n]uril

6,8 Behrend et al. are credited with first producing Q[6] in 1905 , whilst examining the acid catalysed condensation reaction of glycouril and formaldehyde. The material produced was found to be a white intractable solid that was difficult to characterise. This compound was not reinvestigated for approximately another 70 years when Mock et al. found that the main product from this condensation was a new macrocycle, 1 which they named cucurbituril. Mock et al. found that cucurbituril (Q[6]) was highly symmetrical, with unique cavity shape. The internal equatorial diameter is larger than the two external portal diameters.

In 1997 Buschmann and co-workers published a procedure that enabled 114 the synthesis of Q[6] in much higher isolated yields (approximately 90%). Furthermore, under their reaction conditions no other sized 36 cucurbit[n]urils are produced. In 2000-2001 two groups published methods for the synthesis of cucurbit[n]uril where n = 5, 6, 7, 8 and 10 are produced in varied proportions depending on the reaction 2,3 conditions.

2 3 Both Day et al. and Kim et al. have also modified Behrend and colleagues' original reaction into steps with much milder reaction conditions, giving access to the range of cucurbit[n]uril where n = 5, 6, 7, 8 and 10 with almost quantitative conversion of glycouril to cucurbit[n]uril. This is an amazing yield for such a complex macrocycle. The high yield of cucurbit[n]uril is due to the final product being both a

40 thermodynamic and kinetic sink. Throughout this work cucurbit[n]uril 2 was prepared using the method published by Day et al.

Day et al. found that cucurbit[n]uril other than Q[6] were never formed 10 using the reaction conditions reported by Mock and Buschmann , because of decomposition of glycouril. Using the milder reaction conditions of Day et al. these cucurbit[n]uril (n = 5, 6, 7, 8 and 10) are apparent in both the proton and carbon NMR spectra, with very little 2 other non-cucurbit[n]uril species present. Both Day et al. and Kim et 3 al. reported these new cucurbit[n]uril homologues in 2000. These new cucurbit[n]uril have been fully characterised by NMR spectroscopy, ES- 2,3,5,10,13,77 MS and X-ray crystallography.

Figure 11. 1H-NMR spectrum of cucurbit[n]uril mixture

1H-NMR and 13C-NMR spectroscopy, used together, are an effective tool in the study of cucurbit[n]uril and cucurbit[n]uril complexes. Whilst the 1H-NMR spectrum of a mixture of cucurbit[n]uril shows the Q[n] peaks overlapping (Figure 11), the 13C NMR spectrum (Figure 12) presents the individual cucurbit[n]uril as clearly defined peaks. The cucurbit[n]uril

41 ions were also present in the mass spectrum of the reaction mixture, showing molecular ions for the Q[n] complexed with cations (either sodium or cesium). X-ray crystal structures for the cucurbit[n]uril, where 3,6,13 n = 5, 6, 7, 8 and 10, have now been published.

Figure 12. 13C NMR spectrum of cucurbit[n]uril reaction mixture.

The various Q[n] can be readily identified in the 13C NMR spectrum of the reaction mixture (Figure 12), where the resonances due to the methine and methylene carbons are in distinctively different, but characteristic, positions depending on the size of the ring. Figure 12 is a 13C-NMR spectrum of a reaction mixture containing both cucurbit[n]uril and the proto-cucurbit[n]uril oligomer. The oligomer presents itself as the large broad peak under the cucurbit[n]uril peaks. The cucurbit[n]uril resonances are listed in Table 2.

42 13 Table 2. C NMR shifts (ppm) of the three carbons of the cucurbit[n]uril, n = 5-8 in D2O/concd DCl(1:1 v/v) n methylene n – n-1 methine n – n-1 carbonyl 5 51.8 70.6 157.9 6 53.2 1.4 71.7 1.1 158.0 7 54.4 1.2 72.7 1.0 158.3 8 55.4 1.0 73.6 0.9 158.6

Unfortunately due to overlap of the cucurbit[n]uril resonances, the 1H NMR spectra cannot be used to determine the proportional product ratios in the reaction mixture. This is evident when comparing the 1H-NMR spectrum of a mixture of cucurbit[n]uril in Figure 11 with the 1H-NMR spectrum of pure Q[6] in Figure 13.

1 Figure 13. H-NMR spectrum of pure Q[6] in 0.1 M Na2SO4 solution.

10 Calibration of the 13C NMR spectrum using internal standards has allowed the product ratios to be determined from the integration of the

43 peak areas. The 13C-NMR response of individual carbons in the range of Q[n] will be different; as they will have different 1 and different NOE interactions with protons in the molecule. This means that the integration is not directly proportional to the relative concentration of the individual Q[n], therefore a correction factor needs to be applied. Table 3 gives the correction factors used in this work relative to Q[6] (in 20-35% DCl). It is important to note that these correction factors were developed and tested only on the particular instrument and settings used. The correction factor was determined by adding known amounts of the cucurbit[n]uril and comparing the relative peak integrations. These correction factors are applied to the integrals of the peaks for the different cucurbit[n]uril, to give the correct relative amounts present in solution.

Table 3. 13C NMR spectroscopy integral correction factors for cucurbit[n]uril in 20-35% DCl.

Q[n] Correction Factor 5 1.00 6 1.00 7 1.50 8 1.45 10 1.91 5 in 10 1.44

The cucurbit[n]uril species are also observed in electrospray mass spectrometry (ES-MS) where the compounds exist as their alkaline metal cation, dication and dication monohalide ions. Table 4 shows the data for 10 the ESMS peaks (m/z) of a CsCl solution of Q[5]-Q[8]. Note that no [P + H]+ ions were observed.

44 Table 4. Observed positive-ion ESMS peaks (m/z) of a CsCl solution of Q[n] (n = 5-8)

[P + Cs]+ [ P + 2Cs]2+ [P + 2Cs + Cl]+ n Parent ion, P (P + 132.9) (P + 265.8)/2 (P + 300.8)

5 C30H30N20O10 963.0 548.0 1131.0 (830)

6 C36H36N24O12 1129.1 631.0 1297.0 (996)

7 C42H42N28O14 1295.0 714.0 1463.0 (1162)

8 C48H48N32O18 1461.0 797.2 1628.9 (1328)

Electrospray mass spectrometry has proven to be a useful tool for cucurbit[n]uril study. Care is required with the choice of ions in solution. An example is KI, which is a good cucurbit[n]uril solubilising agent, but since KI has a mass of 166, it can be confused with the Q[n] repeating unit (glycouril and two methylene groups) which has the same mass. For example a [Q[8] + 2K + I]+ ion would be indistinguisable from a [Q[9] + K]+ ion at low resolution. Furthermore, if the ion concentration is too high the sample will be swamped.

The milder conditions proposed by Day et al. and used throughout this work have higher yield of cucurbit[n]uril through a two-step one pot reaction, compared to the yields reported by groups of Mock, Buschmann and Kim. The two steps are; S Formation of an oligomer gel of glycouril and formaldehyde in concentrated HCl at room temperature.

45 S Heating of this gel, which starts a series of reversible reactions which lead to the formation of cucurbit[n]uril as a family of thermodynamically stable species.

Day et al. report almost quantitative conversion of glycouril to Q[n] using 2,10 their procedure. This is again an increase on Buschmann and colleague's reaction which produces 85% Q[6]. The reaction published by Day et al. also produces the different sized rings, which aren't present 10 in Buschmann's reaction. The concentrations of glycouril and acid used in the reaction have been shown to have a large effect on the product distribution. At very low concentrations of glycouril, Q[5] is the only observed product (with considerable degradation of glycouril), while at higher concentrations of glycouril the proportion of larger cucurbit[n]uril is increased.

46 Separation of Cucurbit[n]uril by Fractional Crystallisation To isolate the individual cucurbit[n]uril species the reaction mixture as a whole was evaporated under vacuum and the solid obtained contained a mixture of Q[n] (n = 5, 6, 7 and 8). The next major step to using these cucurbit[n]uril was to separate the mixture into its component Q[n]. This was done using one of two different methods, each with its own benefits.

Cucurbit[n]uril are soluble in many aqueous acid solutions, particularly in strong acids. This is believed to be due to a complex forming between the portal oxygen atoms on the Q[n] and the hydronium ions in the acid 70 solution. The positively charged complex thus formed is then soluble in 70 the acid solution. Different Q[n] have different affinities for the hydronium ions and thus have the slightly different solubilities in acid. These differences in solubility allow the mixture to be separated by fractional crystallisation. Coupled with this it is also feasible that differences in crystallisation energies between the different cucurbit[n]uril could affect the differences in solubility.

The first method utilises fractional crystallisation. The crystallisations were repeated around 20-30 times by the following method: the solid obtained from evaporation of the reaction mixture was taken up in a minimum of hot concentrated hydrochloric acid and allowed to cool. The crystals formed were collected, washed with water and dried. The filtrate containing the remaining cucurbit[n]uril was evaporated and the recrystallisation process was repeated until the solid mass was negligible. Each of the fractions thus obtained were analysed by NMR spectroscopy. The first cucurbit[n]uril to crystallise by this method is Q[8], followed by Q[5], then Q[6] and finally Q[7]. This is only a generalised guide and

47 depends on the concentration of the cucurbit[n]uril in solution. Quite often Q[5] will become mixed with Q[8] and Q[6] will become mixed with Q[7], thus requiring further crystallisations to achieve separation.

This method of fractional recrystallisation requires careful examination of each fraction to determine the cucurbit[n]uril composition of that fraction. Unfortunately the composition of each fraction will vary from separation to separation due to factors such as the amount and temperature of acid used and the relative amounts of the different cucurbit[n]uril in the mixture. The solubilities of the different cucurbit[n]uril in concentrated HCl are very similar, which causes a certain percentage of 'wastage' of cucurbit[n]uril that is precipitated as a mixture, eg Q[8] mixed with Q[5], Q[7] mixed with Q[6]. These 'contaminated' fractions may then be added to the next batch of mixed cucurbit[n]uril to be separated. The number of repetitions, coupled with the wastage and need to analyse each fraction, makes this separation technique very time consuming.

The fractional crystallisation method has proven to be the best way of isolating the different cucurbit[n]uril in a pure form, without contamination from metal salts. However, the method is very time consuming due to the amount of evaporation of acid that is needed, coupled with the need to analyse each of the fractions obtained. It should be noted that cucurbit[n]uril is extremely difficult to isolate free from waters and acids of crystallisation due to the strength of hydronium ion complexes with cucurbit[n]uril. Water is also trapped inside Q[6] 129 crystals and this is likely to continue through the larger cucurbit[n]uril. Other separation methods have been investigated and used together with fractional recrystallisation they have proven to be effective in separating Q[n]. This method will be discussed below.

48 Separation of Cucurbit[n]uril by Cation Induced Solubility It has been shown that cucurbit[n]uril are soluble not only in acid but also 36,45,130 in aqueous ionic solutions. Several metal cations complex externally with cucurbit[n]uril through ion-dipole bonding to the carbonyl 36,37,39,45,46,98,113,130 oxygen portal. The mode of binding is somewhat similar to that of the crown ethers. A metal ion may be bound to the non- bonding electrons on the ether oxygens in a crown ether. With cucurbit[n]uril the metal cation will bind to the non-bonding electrons on the carbonyl oxygen atoms (Figure 14).

37,40,41,44-47,107,113,130 Several researchers have shown that certain metal cations will bind preferentially to Q[6], although only limited studies have been undertaken with a range of metal cations complexing to the 84,113 other cucurbit[n]uril. Cucurbit[6]uril complexes with both alkaline and alkaline earth metal cations have been extensively studied, along with 84 a study of lanthanide metal cations by Fedin et al. The metal cations Na+ and Cs+ bind strongly to Q[6], most likely due to a good size match between the Q[6] and the metal cation. Similarly lead ions will bind with 113 high specificity to decamethylcucurbit[5]uril.

Smaller cations like potassium and sodium can bind with more than one metal cation per carbonyl portal as shown in Figure 14.

47 Figure 14. Potassium complexed Q[6] incorporating THF

One reason given for this selective binding is the size of the metal cation in relation to the size of the carbonyl portal of the 5,36,37,41,45,113,115 cucurbit[n]uril. If the metal cation is an appropriate size to bind to multiple carbonyl oxygen atoms, then that metal will bind more strongly to the cucurbit[n]uril. If the strength of the metal cation – cucurbit[n]uril complexes depends on the relative size of the cation and the carbonyl portal, then the most strongly bound cations will change depending on the size of the cucurbit[n]uril.

The hypothesis is that this size-dependency on binding could be extrapolated to the different sized cucurbit[n]uril. This would mean that for each sized cucurbit[n]uril there is a metal cation that 'fits' the portal best, thus giving a cation that would bind strongly to that individual cucurbit[n]uril. This is different from the crown ether case, due to the rigidity of the cucurbit[n]uril ring when compared to the flexibility of the crown ethers. The flexibility of crown ether allows it to complex

50 131 effectively with a range of metal cations. The crown ether will twist and flex, allowing the oxygen atoms in the 'crown' to orientate into an appropriate position to bind with the metal cation. Cucurbit[n]uril do not have this flexibility, thus some metals bind much more strongly than others, depending on the size of the metal cation in relation to the size of the carbonyl portal.

Sodium and cesium metal cations have also been used as an aid to 42,45 complex formation between Q[6] and organic guests. Sodium “lidded” Q[6] will bind and hold the THF inside the Q[6], but the sodium does not complex directly with the THF molecule, as shown in Figure 42 16. The sodium acts as a 'stopper' to the internal binding of THF in Q[6]. Conversely cesium binds to Q[6] with only one cesium cation per portal due to the larger size of the cesium cation and incorporating only one molecule of water due to the depth of complex of the cesium. Figure 45 15 shows the cesium complexed Q[6] binding with THF. There is not enough room for the THF and two cesium cations, so one of the cesium cations disassociates from the Q[6]. The remaining cesium cation complexes simultaneously with the bound THF and the carbonyl portal.

45 Figure 15. Cesium cation complexed Q[6] binds with THF

42 Figure 16. Sodium lidded cucurbit[n]uril complex with THF

The phenomena of metal cations binding to cucurbit[n]uril preferentially also extends to the addition of metal cations to the reaction mixture in the synthesis of cucurbit[n]uril. Day et al. have shown that the addition of specific metal cations to the reaction will increase the yield of certain 115 Q[n]. The results (listed in Table 6) show a strong correlation between some metal cations and product distribution, particularly with regard to K+ influencing the production of Q[5] to 46% of the total yield, which is an increase of 84% over normal reaction conditions. The size of the metal cation is apparently a good match for the carbonyl portal of the Q[5], thus forming a strong complex. Another factor that influences the impact of the K+ cation is that Q[5] complexes with K+.Cl- are not very

52 soluble, so much of the Q[5] formed in the reaction precipitates out of solution.

Day et al. hypothesise that the addition of cations into the reaction 115 mixture causes a template effect on the formation of the cucurbit[n]uril. This means that the forming proto-cucurbit[n]uril must also be able to bind to cations in a similar fashion to the fully closed cucurbit[n]uril.

When the ability of various alkali and alkali earth metals cations to dissolve cucurbit[n]uril was investigated, it was found some of the cucurbit[n]uril were soluble in different metal salt solutions. The different solubilities of Q[n] in ionic solutions enabled the development of a fast separation protocol using these differences in solubility, as shown in Figure 17. This separation protocol isolates individual cucurbit[n]uril as their metal halide complex. Further purification by recrystallisation is needed for a cucurbit[n]uril sample free from metal salts. However, in many cases this was not necessary as an ionic solution was used in many of the NMR spectroscopy experiments (eg 0.1 M

Na2SO4). This solution allows the NMR spectroscopy experiments to be performed in a less acidic solution as both Q[6] and Q[7] are soluble in

Na2SO4.

Figure 17. Fast separation protocol for cucurbit[n]uril mixtures

After filtering the reaction solution to obtain any Q[8] crystallised during the reaction, the solution was evaporated under vacuum. The resultant solid was stirred in a 0.1 M sodium sulphate solution for 10 minutes. This was then filtered, which afforded Q[5]/Q[8] as the resultant solid and Q[6]/Q[7] dissolved in a sodium sulphate solution. Q[5] may be separated from Q[8] by simple recrystallisation using concentrated HCl. Barium sulphate may be used to separate Q[6] and Q[7], as Q[6] is not soluble in barium sulphate solution.

Metal salts are extremely difficult to remove from cucurbit[n]uril once bound, which is a disadvantage in using this method of separation (as opposed to fractional recrystallisation). Therefore this method of separation was used only when the metal salts did not affect the use of the cucurbit[n]uril obtained. Although the cucurbit[n]uril obtained in this fashion were contaminiated with metal salts, the organic purity was good. For the NMR spectroscopy experiments a standard environment was set up using slightly acidified sodium sulphate solution. As a major goal of

54 this work was to investigate differences in complexes of Q[6], Q[7] and Q[8] this medium was acceptable for many of the experiments. The sodium ions allow for dissolution of Q[6] and Q[7], the acidification of the solution allows the dissolution of Q[8]. The large ionic concentration of the reaction medium made it impractical to perform electrospray mass spectrometry on this work.

Cucurbit[n]uril of acceptable organic purity may be obtained from the ionic solution through multiple recrystallisations from HCl. This will drive most salts from solution, and also lead to the hydrochloride of cucurbit[n]uril. This process makes use of the low solubility of the metal salts in the highly ionic concentrated acid.

It is important to note that cucurbit[n]uril has not been isolated free from water and acids of crystallisation and will frequently sequester metal cations from glassware during ES-MS experiments. It is extremely difficult to remove all traces of hydronium salts, and cucurbit[n]uril will always contain several water molecules complexed internally. The difficulty in purification is due to the strength of the complexes between cucurbit[n]uril and cations like the hydronium and metal ions.

55 Size-dependent Binding of Cucurbit[n]uril The hypothesis in this size-dependent binding section of this thesis is that different sized guests will bind with discrimination to the different sized cucurbit[n]uril. To test for this size-dependent binding a range of potential guests were investigated. The guests chosen were alkyl and aryl amines with a range of different functionality, several bipyridyl derivatives and amides. These guests were chosen because either they, or their class of compounds, have shown complex formation with Q[6].

For example it was mentioned earlier that the compound bis-(4,4'- bipyridyl)-'-p-xylene (45) will not complex with Q[6] whilst the similar compound bis-(4,4'-bipyridyl)-hexane (48) will bind with Q[6]. This is due to the rigidity of both host and guest, but what happens if the host is larger? It is hypothesised that the guest bis-(4,4'-bipyridyl)-'-p- xylene will bind with a larger cucurbit[n]uril, because the larger cucurbit[n]uril has a larger portal and interior cavity and therefore the necessary room for the guest to thread through the host.

The host guest chemistry with cucurbit[n]uril, where n = 6, 7 and 8, was studied for each of the guests. This was accomplished by the addition of an excess of the individual cucurbit[n]uril to the guest in acidified 0.1M

Na2SO4 solution. Acidified 0.1M Na2SO4 solution was chosen as a solvent because it dissolves Q[6], Q[7] and Q[8] which were used in this investigation. 1H-NMR spectra were taken for each of these mixtures and compared to the spectra of the pure guest dissolved in the same solution. If an upfield change in chemical shift was apparent in the guests' spectra upon addition of cucurbit[n]uril that guest was belived to be internally 1,15,16 bound to the cucurbit[n]uril. Similarly a downfield shift for a guest

56 proton showed that that proton was just outside the carbonyl portal of the 1,15 cucurbit[n]uril .

For a sample to give an upfield change in chemical shift, with sharp peaks for both bound and unbound guest, the rate of decomplexation must be slow on the NMR time scale, as shown in Figure 18. This means that the complex is stable during each NMR transient. Some guests only give broadened peaks with an averaged change in chemical shift. This averaged change in chemical shift is due to the complex forming and dissociating in the time that it takes for one NMR transient. These guests are said to have complexed with cucurbit[n]uril with intermediate exchange. Fast exchange will give a peak that is sharp with a chemical shift averaged between the complexed and un-complexed chemical shifts. Several guests bind strongly (slow exchange) with one cucurbit[n]uril, then will bind with fast or intermediate exchange to a larger cucurbit[n]uril. This is most likely due to a weaker complex being formed with the larger cucurbit[n]uril because of the larger portal/cavity size. All of these results are listed in Table 5. For some of the guests that bind with slow exchange it was possible to work out dissociation 15 constants. Following the method used by Mock et al. , the relative amounts of host and guest in solution have been used to calculate dissociation constants and where available these are provided in Table 5.

Figure 18. The complex formation between 1,6-hexamethylene diamine (12) and Q[7] is an 1 example of slow exchange. a) H-NMR spectrum of 1,6-hexamethylene diamine (12) in Na2SO4. and b) addition of Q[7]. Note the two sets of peaks, with the bound environment shifted upfield as marked.

Often the amount of change in chemical shift for a guest varied depending on the cucurbit[n]uril with which it was bound. In these cases the guest was also added to an excess of two or more cucurbit[n]uril to determine the relative binding ability of the cucurbit[n]uril for each guest. Through comparison of the integration of the shifted guest peaks it was possible to determine which cucurbit[n]uril host has more guest bound. This enabled the determination of the preferred cucurbit[n]uril for many of the guests.

58 As mentioned earlier the guests were chosen based on prior examples of cucurbit[n]uril guests in the literature. These have been grouped as follows:

Group 1: consists of molecules that are either small or contain straight alkyl chains. These include smaller compounds such as acetamide, 8, through to the good Q[6] guest hexamethylene diamine, 12. These guests should have the capability to bind to each of the cucurbit[n]uril, as they are all relatively small compared to the guests in the following groups. Note that each of these potential guests contains at least one dipole or charged amine group to bind with the carbonyl portal oxygens.

Group 2: consists of tetra alkyl ammonium salts. This second group of guests were not expected to bind internally due to their bulky nature and the central positioning of their charged nitrogen. Of these compounds tetrabutyl ammonium, 14, was the largest, with tetramethyl ammonium, 17, being the smallest. These compounds have not been investigated as cucurbit[n]uril guests before now.

Group 3 contains aryl amines. Most of these compounds can bind with all three of the cucurbit[n]uril, although the complexes with Q[6] and benzene rings involves a level of distortion through the Q[6]. Therefore complexes between Q[6] and benzene rings have to balance the favourable complex formation energies with the 15 unfavourable stress-strain energy.

59 Group 4: Has the bulkiest groups that were combined with cucurbit[n]uril. The adamantane compounds, 38 - 41, and 3- propylamine-o-carborane, 43, each have a relatively large, approximately spherical moiety. These compounds were not expected to bind with Q[6], but possibly with Q[7] or Q[8].

Group 5: Contains the molecular systems that are based on bipyridyl. These include bis-bipyridyl compounds bridged with various length alkyl chains.

As noted earlier the solution used for these binding experiments was an acidified Na2SO4 solution. It must be highlighted that the cucurbit[n]uril would most likely be complexed to either the sodium ion or hydronium ion in this solution: it is this complex formation which enables the cucurbit[n]uril to dissolve in aqueous solution. This presents a competitive binding scenario for these size-dependent binding experiments. This should be of small effect, as it seems that the binding 24 of known Q[6] guests is unaffected. Other groups have used similar 111 solvents for cucurbit[n]uril host-guest experiments. Whilst the sodium and hydronium ions bind well with Q[6], it appears that the cucurbit[n]uril complexes with the guests are stronger than with the sodium ion. An example of this is the complex formed with sodium 'lidded' Q[6] and THF. Kim et al. found that upon addition of trifluoroacetic acid the THF became unbound. Initially this was thought to be due to the removal of the sodium cation 'lid' from the Q[6] due to 42 the affect of the acid. Later this dissociation of THF from Q[6] was found to be pH independent, with the researchers finding that the

60 trifluoroacetic acid actually competes with the THF for binding in the 72 cavity.

To investigate complex formation each guest was added to each one of the cucurbit[n]uril. Samples were then left for at least 24 hours to allow equilibrium concentrations of these complexes to form. Complex formation was ascertained through 1H-NMR spectroscopy, utilising the change in chemical shift of the guest that is apparent in inclusion 15,16 complexes with cucurbit[n]uril. Table 5 has the results from these size-dependent binding experiments, with the results ordered into the groupings above. For each guest the unbound chemical shift is given in ppm, along with the change in chemical shift in ppm. Upfield changes in chemical shift are given as plain numbers, downfield chemical shift changes are presented in parentheses. Certain of the guests proved to be useful templates for cucurbit[n]uril synthesis (presented later) and these are included in greyed boxes for completeness.

61 Table 5. Size-dependent binding NMR spectroscopy results

Chemical Shift Change (ppm)

Chemical Guest a Q[6] Q[7] Q[8] Shift (ppm) Comments

Group One Q[6] – Not bound. A 3.97 No Changes 0.40 Obscured O Q[7] – Internally bound with slow exchange. (C) (B) B 2.92 0.70 Peak Broadened -3 HH Kd = 1.2 x 10 M

SOHC 2.77 0.80 Peak Broadened H Q[8] – Binding is evident via (A) Templated yield peak broadening, NH 2 2 13%, up from Intermediate Exchange. 7% 6 cystine

Q[6] – Internally bound with S A 2.52 0.10 0.30 0.30 slow exchange

Q[7] – Internally bound with (A) Templated yield slow exchange. 41%, up from NH2 28% 7 thioacetamide Q[8] – Internally bound with intermediate exchange. Q[6] – Internally bound with O A 2.00 0.20 0.40 0.10 fast exchange.

Templated yield Q[7] – Internally bound with (A) 11%, up from fast exchange. NH2 7% 8 acetamide Q[8] – Internally bound with fast exchange

Guest

9 Br 2-amino-1-ethanesulfonic acid acid 2-amino-1-ethanesulfonic tetramethylethylenediamine H N 11 2 N 3-bromopropylamine A (B) (A) (A) 10 (Taurine) (B) N,N,N',N'- (C)

(A)

N SO NH 3 H

(B) 2

C B A B A B A Shift (ppm) Chemical 2.24 2.38 2.13 2.92 3.63 2.75 3.05

a No Changes No Changes No Changes No Changes 0.95 0.80 0.95 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) 28% from42%, up Templated yield No Changes No Changes 0.10 0.15 0.35 0.30 0.10

7% from13%, up Templated yield No Changes No Changes 0.20 0.20 0.25 0.20 0.25

exchange. fast with bound –Internally Q[8] exchange. fast with bound –Internally Q[7] bound. –Not Q[6] K peaks. Q[6]methylene inthe shifts slight and exchange slow with bound –Internally Q[6] peaks. methylene the Q[8] in shifts slight and exchange intermediate with bound –Internally Q[8] exchange. intermediate with bound –Internally Q[7] Comments bound. –Not Q[8] bound. –Not Q[7] bound. –Not Q[6] d = 1.9 x 10 x = 1.9 -4 M

Guest

H H 2 2 NN N (A) (A) 13 12 N-(2-aminoethyl)-1,3- 1,6-diaminohexane propanediamine (B) (B) C (C) (C) (C)

(A) b NH NH 2 2 C C B A B A Shift (ppm) Chemical 1.36 1.49 2.68 1.63 2.69 2.75

a No Changes No Changes Obscured 0.95 1.05 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) Broadened Peaks Broadened Broadened Peaks Broadened Peaks Broadened 0.60 0.55 0.55 No Changes No Changes Obscured 0.25 0.20

K slow exchange. with bound –Internally Q[7] solvent. by obscured peak 'A' exchange. slow with bound –Internally Q[6] 'B' obscured by solvent peaks. methylene theQ[8] of disorder and exchange slow with bound –Internally Q[8] Q[8] – Not bound. bound. –Not Q[8] exchange. intermediate with bound –Internally Q[7] bound. –Not Q[6] Comments d = 3.5 x 10 x = 3.5 -4 M

Two Group Guest

(D) (C) 15 14 (C) tetrapropylammonium bromide tetrapropylammonium (B) tetrabutylammonium iodide tetrabutylammonium (B) (A) (A)

N N

D C C B A B A Shift (ppm) Chemical 1.02 1.45 1.67 3.40 1.06 1.79 3.38

a 48% 56%,from up Templated yield No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) No Changes No Changes No Changes No Changes No Changes No Changes 0.25 0.13 0.13 0.15

Q[8] – Not bound. bound. –Not Q[8] bound. –Not Q[7] bound. –Not Q[6] intermediate exchange. exchange. intermediate with bound –Internally Q[8] bound. –Not Q[7] bound. –Not Q[6] Comments

Guest

17 16 tetramethylammonium chloride chloride tetramethylammonium tetraethylammonium chloride tetraethylammonium (B) (A) (A) N N

B A A

Shift (ppm) Chemical 1.27 3.27 3.20

No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) 28% 41%,from up Templated yield No Changes No Changes 0.13 0.25

No Changes No Changes 0.15 0.15

fast exchange. exchange. fast with bound –Internally Q[8] exchange intermediate with bound –Internally Q[7] bound. –Not Q[6] Q[8] – Not bound. bound. –Not Q[8] bound. –Not Q[7] bound. –Not Q[6] Comments

Three Group Guest

19 HO p- (dimethylamino)benzaldehyde (A) OH 18 p- aminophenol N (B)

NH 2

D C B A B A

Shift (ppm) Chemical 6.43 6.46 9.70 3.01 6.64 7.68

a No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm)

28% 34%,from up Templated yield 28% 43%,from up Templated yield Precipitated Precipitated No Change No Change 0.90 0.60 0.70

7% 15%,from up Templated yield Precipitated Precipitated No Change No Change Not Visible Not Visible 0.70 0.90

fast exchange. exchange. fast with bound –Internally Q[8] exchange. fast with bound –Internally Q[7] bound. –Not Q[6] occured. and Q[8] guest of precipitation guest of addition –Upon Q[8] occured. and Q[7] guest of precipitation guest of addition –Upon Q[7] bound. –Not Q[6] Comments

Guest

NH 2 C C B A B A Shift (ppm) Chemical 1.96 6.50 7.20 2.54 7.26 7.95

a No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm)

No Change No Change 0.90 0.80 1.00 0.93 0.95

Obscured (Solvent) Obscured (Solvent) Obscured 7% 11%,from up Templated yield (0.03) (0.03) 0.05 0.05 0.05 upfield by more than 0.5 ppm. ppm. 0.5 than more by upfield haveshifted peaks Obscured exchange. intermediate with bound –Internally Q[8] exchange. intermediate with bound –Internally Q[7] bound. –Not Q[6] fast exchange. exchange. fast with bound –Internally Q[8] Comments K exchange. slow with bound –Internally Q[7] bound. –Not Q[6] d = 3.5 x 10 x = 3.5 -5 M

Guest

23 2-amino-3-methyl benzoic acid benzoic 2-amino-3-methyl (A) (C) 22 OOH p- bromoaniline Br NH (B) 2 (A) (B) NH (D)

D C B A B A

Shift (ppm) Chemical 6.54 7.21 2.11 6.47 7.16 7.63

a No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm)

to a broad peak that to peak a broad Obscured (Solvent) Obscured A and B converge B converge A and is 0.38 upfield of of upfield 0.38 is the centre of the of the centre original AA'BB' AA'BB' original 28% 45%,from up Templated yield system. system. 0.35 0.35 0.50

7% 18%,from up Templated yield 7% 10%,from up Templated yield No Changes No Changes No Change No Change 0.75 0.20 0.30

exchange. intermediate with bound –Internally Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] Comments bound. –Not Q[8] exchange. intermediate with bound –Internally Q[7] bound. –Not Q[6]

Guest

HO 25 (A) (B) 26 H 24 4'-hydroxyacetanilide N aniline sulphate 3-amino-thiazol (B) NH S (A) H

2 (B) (C) (A) (C) NH NH

O C C B A B A B A

Shift (ppm) Chemical 1.987 1.987 6.45 6.75 6.64 6.73 7.12 6.69 7.35

a Peak Broadens Broadens Peak 48% 59%,from up Templated yield No Changes No Changes 0.75 0.40 0.15 0.10 0.15 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) Obscured (Solvent) Obscured 28% 34%,from up Templated yield No Change No Change 0.10 0.90 0.85 0.05 1.05 0.70

Obscured Solvent Obscured No Changes No Changes No Changes No Changes No Change No Change 1.10 K peaks. Q[6]methylene inthe shifts slight and exchange slow with bound –Internally Q[6] Q[8] – Not bound. bound. –Not Q[8] exchange. fast with bound –Internally Q[7] bound. –Not Q[6] Comments bound. –Not Q[8] exchange. fast with bound –Internally Q[7] exchange. fast with bound –Internally Q[6] slow exchange. exchange. slow with bound –Internally Q[8] exchange. slow with bound –Internally Q[7] d = 1.9 x 10 x = 1.9 -4 M

Guest

(B) (C) NH NH NH b

2 2 NH

C D C B A B A B A F

Shift (ppm) Chemical 2.25 6.47 6.49 6.56 7.01 2.23 6.58 6.95 6.38 6.50

a Peak Broadens Broadens Peak No Changes No Changes No Changes No Changes No Change No Change No Change Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) 28% 43%,from up Templated yield No Changes No Changes No Changes No Changes 1.10 0.80

system. AA'BB' original of centre from upfield 0.10ppm toonepeak merges system AA'BB' No Changes No Changes No Changes No Changes

Q[8] – Not bound. bound. –Not Q[8] bound. –Not Q[7] bound. –Not Q[6] Comments Q[8] – Not bound. bound. –Not Q[8] bound. –Not Q[7] exchange. intermediate with bound –Internally Q[6] slow exchange. exchange. slow with bound –Internally Q[8] exchange. slow with bound –Internally Q[7] bound. – Not Q[6]

Guest

(B) b

NH 2 C B A B A

Shift (ppm) 7.32 – 6.96 7.49 – 7.07 Chemical 2.32 3.80 3.84

a No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) No Changes No Changes 0.10 0.10

No Changes No Changes No Changes No Changes Comments Q[8] – Not bound. bound. –Not Q[8] bound. –Not Q[7] bound. –Not Q[6] Q[8] – Not bound. bound. –Not Q[8] exchange. fast with bound –Internally Q[7] bound. –Not Q[6]

Guest

(B) 33 H 32 2-aminobenzimidazole 2 (A) N p- xylenediamine (B) H N N NH (A) 2 b

NH 2 B A B A

Shift (ppm) Chemical 3.84 7.27 6.86 7.12

a No Changes No Changes 0.75 0.75 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) 28% 45%,from up Templated yield Precipitated Precipitated 0.95 0.39

Broadened Broadened broadened broadened 0.02 and 0.02 and 0.55 1.22

K exchange. slow with bound –Internally Q[7] bound. –Not Q[6] Q[ Comments system. AA'BB' original the of centre the from ppm 0.15 by upfield theguests for peak averaged bound. :1Q[8] 4Q[7]bound around with guest bound internally cucurbit[ cucurbit[ complex. K ina at once guests 2:1 two Binds exchange. slow with bound –Internally Q[8] Q[ exchange. intermediate with Q[8] – Bound occured. and Q[7] guest of precipitation guest of addition –Upon Q[7] exchange. slow with bound –Internally Q[6] d = 1.4 x 10 x = 1.4 n n ] mixture - The mixed mixed The - ] mixture mixed –The ] mixture n n ]uril sample gave an gave sample ]uril showed sample ]uril d = 8.3 x 10 8.3 x = -5 M -9 M 2

Guest

(I/J) (E) (G) (H) NH

2 G D C H E B A F J I

Shift (ppm) Chemical 3.22 3.24 3.59 6.90 7.37 7.38 7.49 7.50 7.84 8.36

a No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) No Change No Change Obscured (0.03) (0.03) (0.03) 0.25 0.25 0.30 0.30 0.25 0.6 7% 10%,from up Templated yield Obscured Obscured Obscured Obscured Obscured Obscured (0.40) (0.40) (0.40) 0.95 0.1

to that of the Q[8] sample. sample. theQ[8] of to that Q[ exchange. slow with bound –Internally Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] Comments mixed cucurbit[ n ] mixture – The spectra of of spectra –The ] mixture n ]uril is similar is similar ]uril

Guest

(F) (E) H H (C) 35 (D) H H indol-3-aldehyde 36 (B) N pyridine

N H b (C) (A)

H H (A) (B) O D C C E B A B A F Shift (ppm) Chemical 7.23 7.62 8.59 7.00 7.02 7.35 7.38 8.11 9.28

a 48% 62%,from up Templated yield No Changes No Changes (0.20) (0.20) (1.17) (1.17) (0.80) (0.80) 0.10 0.05 0.20 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6]

Chemical ShiftChange (ppm) Merged with Merged D with Merged C 0.10 Broad 0.10 Broad 0.05 0.05 0.05 0.20 0.70 0.95 No Changes No Changes (0.01) (0.01) (0.50) (0.05) (0.40) (0.10) 0.15 Q[ bound. –Not Q[8] exchange. fast with bound –Internally Q[7] bound. –Not Q[6] system. original of the centre to relative given is shift in change The peak. one to coalesce systems like AB two spectra encapsulated Q[7] In the 30% Q[7]. and Q[8] 70% is spectra mix 36 shows only Q[7] bound. bound. Q[7] only 36 shows Q[ exchange. slow with bound Q[8] – Externally exchange. slow with bound –Internally Q[7] exchange. slow with bound –Internally Q[6] Comments containing a mix of Q[ of mix a containing n n ] mixture – Spectrum –Spectrum ] mixture –.Cucurbit[ ] mixture n ] with ] with n ]uril ]uril

Guest

(D) (E) H H (F) (C) H H 37 2,2'-biquinoline (B) H N H (A) N

D C E B A F

Shift (ppm) Chemical 7.07 7.62 7.45 7.75 8.16 8.79

a No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) broad peak at 7.31 at7.31 peak broad a form F C through Broadened Peak Peak Broadened 28% 37%,from up Templated yield (2.05) Broad Broad (2.05) (0.12) Broad Broad (0.12) Broad (0.01) 0.30 Broad 0.30 Broad 0.30 Broad 0.13 Broad Obscured

Q[ exchange. intermediate with bound –Internally Q[8] exchange. intermediate with bound –Internally Q[7] bound. –Not Q[6] Comments guest. guest. bound andQ[8] ofQ[7] mix n ] mixture – Shows a 1:1 1:1 a –Shows ] mixture

Group Four Four Group Guest

39 38 (B) 1-adamantanamine.HCl 2-adamantanamine.HCl (A) (C) (D NH

) 2 (A) (C) (D) (B) NH

D C D C B A B A Shift (ppm) Chemical 1.70 2.06 2.16 8.31 1.91 1.91 2.01 2.16

a No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm)

No Change No Change 0.70 0.65 0.70 0.70 0.78 0.67 0.65

Slight broadening broadening Slight of each peak. peak. each of broadened broadened All peaks peaks All

Q[ exchange. intermediate with Q[8] – Bound environment. environment. bound unidentified another and bound Q[7] shows K peaks. methylene theQ[7] of distortion and exchange slow with bound –Internally Q[7] bound. –Not Q[6] K exchange. slow with bound –Internally Q[7] bound. –Not Q[6] Q[ exchange. intermediate with Q[8] – Bound Comments with Q[8]. most likely due to acomplex is environment bound extra This peaks. broad averaged of set withanother bound, cucurbit[ d d = 1.7 x 10 x = 1.7 = 9.8 x 10 x = 9.8 n n ] mixture – Spectrum –Spectrum ] mixture ] mixture – Mix of of –Mix ] mixture n ]uril is similar to Q[7] Q[7] to similar is ]uril -5 -3 M M

Guest

40 41 1-adamantane-methylamine N-(1-adamantyl)-acetamide HN (A)

(D) O (C) NH (B) (C) (B) (D) 2 (A)

D C D C B A B A Shift (ppm) Chemical 1.71 1.86 2.16 2.64 1.72 2.12 2.16 2.36

a No Changes No Changes No Change No Change Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm)

0.68 AB 0.68 AB System J=0.10 (0.20) (0.20) 0.25 0.75 0.65 0.75 0.70 0.76

Peak Broadened Broadened Peak Broadened Peak B & C broaden C broaden B & and coalesce and coalesce Broadened Broadened 0.60 Broad 0.60 Broad 0.45 Broad (0.10) (0.10)

K exchange. slow with bound –Internally Q[7] bound. –Not Q[6] K peaks. methylene theQ[7] of disordering and exchange slow with bound –Internally Q[7] bound. –Not Q[6] Q[ exchange. intermediate with bound –Internally Q[8] Q[ exchange. intermediate with bound –Internally Q[8] Comments 60:40 Q[8]:Q[7] complex. complex. Q[8]:Q[7] 60:40 bound. Q[7] only shows d d = 7.3 x 10 x = 7.3 10 x = 5.5 n n ] mixture – Shows around around –Shows ] mixture –Spectrum ] mixture -6 -5 M M

Guest

(A) 43 H 1-(propylamine)- (A) CC 42 (B) quinuclidine.HCl (C) N

o- (D) carborane (B) H (C)

C D C B A B A Shift (ppm) B-H broad broad B-H Chemical peak peak 1.94 2.15 3.32 1.73 2.24 2.83 4.24

a (0.50) (0.50) Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Broadened Broadened peaks

Chemical ShiftChange (ppm) upfield by around around by upfield B-H peak shifted shifted peak B-H Obscured 0.40 ppm 0.40 ppm for each. each. for (0.05) (0.05) (0.30) 0.20

upfield by around around by upfield B-H peak shifted shifted peak B-H 7% 16%,from up Templated yield No Changes No Changes No Change No Change 0.47 ppm 0.47 ppm (0.05) (0.05) 0.42 1.00

Comments Table 8. Table in data reaction the template to compared when interesting especially is This guest. bound andQ[8] ofQ[7] mix Q[8] – Not Bound Bound –Not Q[8] exchange. intermediate with Q[7] – Bound bound. –Not Q[6] Q[ exchange. slow with bound –Internally Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] n ] mixture – Shows a 50:50 50:50 a –Shows ] mixture

Group Five Five Group Guest

A (B) (A) N 45 (B) (D) bis-(4,4'-bipyridyl)- N (C) (A) 44 N

(F) + 4,4'-bipyridyl chloride (E)

b '- N

+ p- xylene N N

D C B A E B A F Shift (ppm) Chemical 4.98 6.59 7.50 7.50 8.00 8.13 7.53 8.74

a No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) 28% 35%,from up Templated yield No Change No Change Obscured (0.15) (0.15) (0.25) 0.13 0.50 1.09 0.10

No Changes No Changes No Change No Change 0.23 0.45 0.10 0.05 0.20 guest. guest. bound Q[7] and Q[8] between Q[ unbound. and bound Q[7] between averaged Comments Q[ exchange. slow with bound –Internally Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] Q[ bound –Not Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] n n n ] mixture is averaged averaged is ] mixture in peak –Bound ] mixture is peak –Bound ] mixture

Guest

47 (B) (B) 46 (D) (D) bis-(4,4'-bipyridyl)-1,3-propylene bis-(4,4'-bipyridyl)-1,2-ethylene N N (C) (C) (A) (A) chloride chloride N N (E)

(E)

+ +

(F) b b

N N + + N N

D C D C E B A E B A F Shift (ppm) Chemical 4.50 7.50 7.50 8.01 8.23 1.91 3.97 7.52 7.52 8.00 8.20

a No Changes No Changes No Changes No Changes Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) No Change No Change No Change No Change No Change Obscured (0.20) (0.20) (0.15) 1.13 1.13 0.20 0.91 0.55 No Changes No Changes No Changes No Changes Q[ bound. –Not Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] Q[8] – Not bound. bound. –Not Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] bound and unbound. unbound. and bound Q[7] between averaged Comments n ] mixture – Bound peak is is peak –Bound ] mixture

Guest

(B) (B) (D) (D) N N 48 49 (C) heptamethylene chloride heptamethylene (C) hexamethylene chloride hexamethylene (A) (A) bis-(4,4'-bipyridyl)-1,7- bis-(4,4'-bipyridyl)-1,6- N N (E)

(E)

+ + (F) (F) (G) (G)

(H) N N + + b b

N N G D C D C E B A E B A F Shift (ppm) Chemical 0.37 1.04 3.53 7.45 7.45 7.95 8.05 4.65 7.55 7.55 7.95 8.05

a (0.11) (0.11) (0.05) (0.55) (0.05) (0.05) (0.05) (0.30) (0.30) 0.91 0.84 0.20 0.05 0.05 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] Chemical ShiftChange (ppm) 28% 46%,from up Templated yield No Change No Change No Change No Change No Change Obscured (0.10) (0.10) (0.20) (0.05) 0.57 0.55 0.50 0.10

No Changes No Changes No Changes No Changes K exchange. slow with bound –Internally Q[6] Q[ bound. –Not Q[8] exchange. slow with bound –Internally Q[7] Q[ bound. –Not Q[8] exchange. slow with bound –Internally Q[7] change. shift chemical to with verybinds little Q[8] it that possible be It could with Q[6]. environment bound the like of instead unbound looks andQ[8] Q[6] of mix in the guest the Q[8], for changes shift nochemical are Q of tothat similar spectrum Comments K exchange. slow with bound –Internally Q[6] d d [ = 2.7 x 10 x = 2.7 10 x = 2.9 n 7 n ] mixture – Although there there –Although ] mixture ] a –Shows ] mixture bound bound g -5 -5 uest, but this is is this but uest, M M

results are included here for completeness. The Q[ The completeness. for here included are results chapter, later toa refers Yield' 'Templated Any chapter. later a in explained is which effect template regarding comments have guests Some Listed above is the change in chemical shift upon addition of thecucurbit[ of addition upon shift in chemical change the is above Listed

Guest Q[ chemical shift are all upfield, unless noted in parentheses. Some guest peaks were obscured by cucurbit[ obscured were peaks guest Some parentheses. in noted unless upfield, all are shift chemical

marked as 'Obscured'. Some guests precipitated with cucurbit[ with precipitated guests Some 'Obscured'. as marked

50 (D) n (C) ] of ~1.5 x 10 x ~1.5 ] of 40, 112) 20, 19, 17, 1,15, (Refernces: examined. previously been have compounds These b) a) The Spectral Data Base System Base Data Spectral The a) bis-ethyl-4-4'-bipyridyl chloride bis-ethyl-4-4'-bipyridyl + N ( A )(B) -4 molL

-1 . N + b

G D C H B A F 132 Shift (ppm) was used to assign assign to used was Chemical 1.26 4.40 8.45 8.98 0.25 0.25 1.00

n ] mixture contained equimolar amounts of Q[6] of amounts equimolar contained mixture ] a No Changes No Changes n 0.90 0.90 0.55 Q[6] Q[7] Q[8] Q[8] Q[7] Q[6] ]uril addition and no peaks are observed. These are marked with 'Precipitated'. 'Precipitated'. with marked are These observed. are no peaks and addition ]uril 1 H-NMR Chemical ShiftChange (ppm) n ]uril. All changes in chemical shift are listed in ppm. Changes in Changes ppm. in listed are shift chemical in changes All ]uril. 0.50 0.50 0.50 0.30 0.10 1.10

≈ Q[7] No Changes No Changes ≈ n Q[8] ]uril or solvent peaks. These are are These peaks. solvent or ]uril ≈ 0.5 x 10 0.5 x species. species. unbound with the averaged Comments bound. –Not Q[8] exchange. slow with bound –Internally Q[7] bound. –Not Q[6] -4 mmol, to give a total atotal togive mmol,

83 As mentioned previously, NMR spectroscopy is a useful tool for studying complexes of cucurbit[n]uril. When the complex has formed, a change in chemical shift is apparent due to the shielding/deshielding of the guest by the cucurbit[n]uril, as shown in Figure 19. This technique was used to determine whether a particular potential guest did in fact bind with cucurbit[n]uril, and if so what the mode of binding was. A shortcoming with 1H-NMR spectroscopy as an analytical tool for cucurbit[n]uril is that some complexes that are entirely external to the cucurbit[n]uril show no change in chemical shift. When a guest is complexed inside the cucurbit[n]uril, the cucurbit[n]uril provides an environment that is closer 29 to a non-polar solvent or gas phase than the polar bulk solution.

Figure 19. Diagram showing magnetic shielding regions. From top to centre there is a downfield shifting region (green), a zero shift region (red) and an upfield shift region (magenta).

The potential guests in Table 5 were split into five groups based on their general properties and shape. The five groups are: 1. Straight chain and small alkyl amines. 2. Tetra-alkyl ammoniums 3. Aromatic amines. 4. Adamantane and carborane based guests. 5. Bipyridyl derivatives.

Group 1. Straight Chain and small alkyl amines Some of these compounds are well known guests for Q[6], such as 12 (1,6-diaminohexane). This group was a mixed group with regards to hetero-atoms, which can have an adverse affect on the complex stability. All of the guests in Group 1 were expected to bind to at least one cucurbit[n]uril. This binding was expected due to the small nature of these guests, each of which should be small enough to 'fit' through the carbonyl portal and thus the internal Q[n] cavity. Each of these guests also has the required amine (or other dipole) to bind with the carbonyl portal.

Whilst only around half of the guests in Group 1 bound to Q[6], all except one of the guests bound to Q[7]. This can be explained by the larger cavity size, although fewer guests bound to Q[8] than Q[7]. This could be due to the cavity in Q[8] being too large to bind some of these smaller guests thus allowing for a very fast exchange. In fact this poor size complement could explain why so many more compounds bind with Q[7] compared to Q[8] throughout all of the groups used in this study. An example of this would be the guest 6, where the peaks are only

85 broadened when bound with Q[8]. When bound with Q[7] a distinct change in chemical shift is apparent for the guest.

Another feature of the guests in the first group is that none of them have any part external to the cucurbit[n]uril to which they are bound. This would be evident in the spectra as a downfield change in chemical shift for a proton just outside of the carbonyl lined portal. Throughout all five groups in this study there are only 8 guests that exhibit this downfield shift. These cases will be discussed later.

Group 2. Tetra-alkyl ammoniums The experimental evidence for this group shows three unexpected results. The first was that the tetrabutyl alkonium ion (14) binds to Q[8]. It was not expected that this would bind to any of the cucurbit[n]uril because of its large size. The second is that not only did 14 bind with Q[8] it does so internally as evidenced by the upfield change in chemical shift of the guest protons. The complex forms and dissociates at an intermediate rate on the NMR time scale, as evidenced by the resonances which are slightly broadened peaks with a chemical shift towards the bound state as explained earlier. However, it is not possible to determine the chemical shift of the bound state because the NMR signal is a time weighted average and the chemical shift change observed will depend on the difference between the bound and unbound states, the equilibrium constant and the rate of exchange. These cannot be determined in the experiments as described.

The bulky nature of these compounds and steric crowding of their charged amine, led to the expectation that this group would bind external

86 to the carbonyl portal if at all. It has generally been the case that anions and non-polar hydrocarbons can be encapsulated by cucurbit[n]uril, whilst cations are bound externally, to the carbonyl portals. These tetra- alkyl ammonium cations must be balanced between binding interally through hydrophobic effects with binding externally or remaining solvated.

The third unexpected result in this group is that 15 (tetrapropyl ammonium chloride) does not bind to any of the cucurbit[n]uril. It was expected that this compound would bind if 14 binds, as 15 is smaller than 14. This may be due to a balance of solvation effects and affinity for the cucurbit[n]uril. If the guest gets little energetic benefit from complexing internally to the cucurbit[n]uril then it is likely that it won't bind.

The next two tetra-alkyl ammonium ions follow the same pattern with the next largest, 16 (tetraethyl ammonium chloride), binding to both Q[7] and Q[8], whilst 17 (tetramethyl ammonium chloride) does not bind to any cucurbit[n]uril. Again the chemical shift change in the complexes of 16 may indicate fast exchange, due to the very low chemical shift change pointing toward a single, averaged signal for each resonance.

It is plausible that these compounds are binding such that one or two of the alkane 'arms' are complexing internally, with the other two outside of the portal. This could only be true if the amine was binding with a fast or intermediate exchange on the NMR time scale, so that the peaks are averaged. This orientation fits with the NMR spectroscopy results, which show an averaged signal for each of the amine protons. Computer modelling of the complex shows that it is possible for the entire tetrabutyl

87 ammonium ion to fit inside Q[8], with some ellipsoid distortion of the Q[8].

Group 3. Aromatic Amines Most of these compounds are benzenes substituted with amines and other functional groups. There are also some larger bicyclic aromatics. Many of the para-substituted benzenes should fit inside all three of the cucurbit[n]uril studied, with the meta and ortho substituted benzenes expected to only bind with the larger Q[n]. It should be noted from this study that many of these aryl amines do not bind with Q[6], whilst some of the much larger bicyclic compounds do. Mock and colleagues' noticed that the binding of Q[6] to benzene moities can distort the Q[6] into an ellipsoid when they examined the crystal structure of p-xylenediamine complexed with Q[6]. Therefore there is a balance between favourable complex formation energies and the stress-strain energy of the complex 15 formation.

Earlier it was put forward that guests will in general have different rates of exchange with Q[7] and Q[8]. 20 (p-aminoacetophenone) is a good example of this, in that it has a faster exchange with Q[8] than with Q[7]. This is due to the larger cavity and portal size of Q[8], which leads to both a weaker complex between Q[8] and 20, and a higher exchange rate of this guest. Previous examples of poor shape complement between a cucurbit[n]uril host and amine guest have been due to the guest being too large for the cucurbit[n]uril. In this example of poor size complement, the host is too large to bind the guest effectively.

This relative size complement can also lead to 2:1 complexes with the larger cucurbit[n]uril, particularly with Q[8]. Kim et al. have shown that 27,28,73 certain guests will bind in a 2:1 complex with Q[8]. When investigating the complexes formed between Q[8] and the guests in Table 5, it was clear that the complex between Q[8] and 32 (p-xylenediamine) also forms in a 2:1 ratio of guest:Q[8]. This complex has a very low dissociation constant of 8.3 x 10-9 M2. This 2:1 complex was apparent through the relative integrations of the bound and unbound guest. The integration of these peaks showed that the concentration of the bound guest was approximately double that of the Q[8], which can best be explained by a 2:1 complex shown in Figure 20.

Figure 20. A 2:1 complex of p-xylene diamine (32, shown as space filling) with Q[8] (shown as 7 tubes). Complex minimised with the HyperChem package , using the AM1 force field.

The guests 21 (p-aminoacetaldehyde) and 19 (p-(dimethylamino)- benzaldehyde) show the first examples in this study of guests which are internally bound with a part of the guest external to the Q[8]. In 21 the methyl group that is alpha to the carbonyl (marked C) is external to the carbonyl portal due to the orientation of the guest such that the nitrogen is bound to the carbonyl oxygens and the benzene moiety is encapsulated in the cucurbit[n]uril. This example unexpectedly shows that there is no change in chemical shift for this methyl peak when complexed with Q[7]. This is possibly due to the orientation of the guest such that the methyl is moved further away from the carbonyls than when bound with Q[8].

H2N H2N O N N (C) H H (B) (B) (A) (A)

a b

Figure 21. Possible orientations of (21) complexed with a) Q[7] and b) Q[8]

In the similar compound, 19 (p-(dimethylamino)benzaldehyde), the guest has two methyl groups directly attached to the amine, and there is no change in the chemical shift of these methyl protons. Therefore these methyl groups must either be positioned at the point close to the carbonyls where there is a cross-over from upfield to downfield shift, or significantly removed from the portal.

Guest 25 (4'-hydroxyacetanilide) shows another distinguishing feature in its 1H-NMR spectrum when bound with Q[7]. In the uncomplexed spectra there is an AA'BB' system from the two proton environments on the benzene ring. When the compound is complexed with Q[7] this AA'BB' system coalesces to a broad peak that is upfield from the original peaks. This is observed in some other guests in group 4, and is another clear example that the guests are bound internally to the cucurbit[n]uril. The environment that the protons are in is changed dramatically by the cucurbit[n]uril and this causes the coalescence of this AA'BB' system. Depending on the orientation of the guest molecule inside the cucurbit[n]uril, two previously coincident proton resonances may be shielded to different degrees, thus separating the signals for these protons. Like many other supramolecular systems this binding to cucurbit[n]uril changes the spectrum of the guest.

Another example of guest protons on the cusp of the shielding of cucurbit[n]uril is found in compounds with an amine directly off the benzene ring, such as 26 (aniline). The protons on the carbons adjacent to the amine are not shifted at all. This means that they must also be right on the cusp of the shielding/de-shielding effects of the cucurbit[n]uril.

An unexpected observation is that the cucurbit[n]uril do not bind well to aniline or benzylamine guests that have methyl groups para to the amino group. This is most likely due to the para methyl group orientated in the second carbonyl portal, although it was expected that these compounds could have orientated more favourably in the larger Q[n]. Having the para methyl group orientated at one of the carbonyl portals is unfavourable, hence this is a barrier to complex formation. Once the para group is removed the guest may bind, and if the para group is

91 replaced with an amine or methyl amine then the guest binds more strongly.

Experiments with the larger aromatics produced a few more unexpected results. Guest 33 (2-aminobenzimidazole) shows evidence of binding internally with all three of the cucurbit[n]uril studied. This is interesting as this compound was expected to only bind with the larger Q[n]. This compound is very similar to 35 (indol-3-aldehyde), and seems to bind in much the same way, although the orientation of 35 is slightly different. Figure 22 shows this slight difference in the binding so that the benzene moiety in 35 is closer to the portal, thus experiencing an upfield shift.

H H H H H N O

NH2 H H N H H H N H

a b

Figure 22. Comparison of (a) 2-aminobenzimidazole (33) and (b) indol-3-aldehyde (35) binding with Q[7]

Although 34 (N-(1-naphthyl)ethylenediamine) did not bind with Q[6], it was interesting to see all of the aromatic protons complexed internally to both Q[7] and Q[8]. Also unexpected was the amount of internal binding for Q[7] and Q[8] complexes of 37 (2,2'-biquinoline). These are interesting examples because the portion of the molecules that are internally complexed are much larger than expected. These are both

92 relatively bulky compounds and as such were expected to have much of the guest external to the carbonyl portal.

Group 4. Adamantane and Carborane based guests The adamantane and carborane compounds were chosen as they approximate a ball shape and are a much bulkier group than a benzene ring. These compounds don't bind to Q[6], although they bind well to Q[7] with slow exchange and show intermediate to fast (on the NMR time scale) exchanging complexes with Q[8]. All of these compounds bind to one or more cucurbit[n]uril such that their bulky groups are encapsulated in the cucurbit[n]uril cavity. The methyl group alpha to the carbonyl in 41 (N-(1-adamantyl)-acetamide) is external to the cucurbit[n]uril carbonyls as expected. Figure 23 shows the methyl peak as the left-most peak at around 2.3 ppm.

Figure 23. 1H-NMR spectra of the N-adamantaneacetamide size-dependent binding series

The complex of 40 (1-adamantane-methylamine) and Q[7] shows some distortion of the cucurbit[n]uril methylene peaks. The methylene peaks appear to be doubled, such that there are two distinct environments. This may be due to the adamantyl moiety being orientated further towards the second portal and causing a change in the portal and reflects a slight loss of symmetry in the host. It may also be due to a significant difference

94 between the bound and unbound cucurbit[n]uril. Mock et al. mention the ability of a guest to distort the Q[6], specifically the guest p-xylylene- 15 diamine. They obtained the crystal structure of this complex, which presents an ellipsoid distortion in the Q[6]. This distortion comes from the complex formation with the benzene that is almost too large for the cavity. To form this complex the favourable energies due to ion-dipole interactions and hydrophobic effect must compete with the unfavourable stress-strain energy from the distortion of Q[6].

Another guest that is similar in its spherical shape to the adamantyl guests is 43 (1-(propylamine)-o-carborane). This binds internally to both Q[7] and Q[8]. The propyl chain is orientated slightly differently in these two complexes, as evidenced by the two downfield shifts in the Q[7] complex, compared to the one downfield shift for the protons alpha to the amine in the Q[8] complex. This shows that the complex of 43 with Q[8] has the propylene chain orientated more deeply in the cavity than the complex between 43 and Q[7]. Two facts about this complex are:

1. The Q[7] complex is strong enough to enable ES-MS measurements. 2. Stirring a cucurbit[n]uril mixture with an aqueous solution of 1- (propylamine)-o-carborane will dissolve (as complexes) equal amounts of Q[7] and Q[8].

Both of these results are significant as they show the great affinity between the cucurbit[n]uril and this guest. The ability of the guest to solubilise the cucurbit[n]uril in water shows that the supramolecular complex can have distinctly different properties to the individual

95 constituents. In this case the guest has a good Q[7]/Q[8] binding moiety in the carborane, coupled with a water solublising moiety in the propyl amine chain. This is significant because the cucurbit[n]uril on their own are all reasonably insoluble in pure water, particularly Q[8].

Group 5. Bipyridyl derivatives Buschmann et al. have studied the guest properties of several bipyridyl 112 based compounds with Q[6]. They found that Q[6] would not bind paraquat (N,N'-dimethyl-4,4'-bipyridine) nor would it bind with 46 (bis- (4,4'-bipyridyl)-1,2-ethylene) or 47 (bis-(4,4'-bipyridyl)-1,3-propylene). Cucurbit[6]uril would however bind with N,N'-diethyl-4,4'-bipyridine (50) and bis-4,4'-bipyridyl compounds with more than 3 methylene groups separating the two bipyridyls. Their work was extended here, using Q[7] and Q[8]. Some discrepancies were found with the findings of Buschmann et al. in relation to their NMR spectroscopy results.

Buschmann et al. state that their NMR spectrum, reproduced in Figure

24, shows only a downfield shift for the HD peak, where it is quite apparent that there is also a small downfield shift for one of the HC or HB protons and a small upfield shift for the other upon complex formation with Q[6] (Figure 24a). The two larger peaks in Figure 24a are uncomplexed guest at their original chemical shift.

Figure 24. 1H-NMR spectra of bis-(4,4'-bipyridyl)-hexane a) complexed with Q[6] b) in 112 D2O/DCl

The other discrepancy is that in this study guest 50 (N,N'-bis-ethyl-4-4'- bipyridyl) is not observed to bind with Q[6]. It does however bind to Q[7] with a similar orientation to bipyridyl, such that the bipyridyl moiety is internally complexed.

The attempted complex formation of bipyridyl and Q[n] showed that a complex forms only for Q[7]. This is then reflected in the two smaller bis-bipyridyls (46 and 47) and the bis-ethyl-4,4'-bipyridyl (50), in that they bind only to Q[7]. The Q[7] binds over the bipyridyl moiety. The two longer chained bis-bipyridyls (48 and 49) bind both Q[6] and Q[7]. This is different to the case of the smaller bis-bipyridyls as the cucurbit[n]uril is orientated over the alkyl chain.

In the case of 45 (bis-(4,4'-bipyridyl)-'-p-xylene), complexes are formed with both Q[7] and Q[8] but not Q[6]. This is because the guest is too bulky and rigid to fit through the carbonyl portal of Q[6]. In this case the change in chemical shift of the guest shows that when bound, the Q[7] or Q[8] is orientated over the xylene moiety, with a certain amount of “shuttling” to become orientated over the bipyridyl. In this example the cucurbit[n]uril can bind in two locations, over the bipyridyl and over the xylene. This duality of binding sites can lead to a “shuttling” of the cucurbit[n]uril over the guest, between the two binding sites. This is evidenced by some of the bipyridyl resonances shifting downfield while the others shift upfield. The benzene moiety and methylene proton resonances shift upfield. This shows that for some of the time the benzene moiety is encapsulated (upfield shift), with the adacent bypridyl moiety protons external to the portal (downfield shift). At other times the Q[7] is orientated over the bipyridyl moiety, which leads to an upfield shift in some of the bipyridyl proton resonances. The amount of “shuttling” is increased in the complex with Q[8], as all of the resonances are shifted upfield, or not shifted. This shows that the Q[8] may be either bound over the bipyridyl or the benzene moieties.

This “shuttling” is evident in other cucurbit[n]uril complexes where there 55,56,79 are multiple possible binding sites. The “shuttling” accounts for the chemical shifts of each of the bipyridyl protons. If the Q[7] or Q[8] was orientated over only one site, not all of these protons would have a change in chemical shift. The Q[7] or Q[8] shuttles between each binding site quickly, as shown by the averaged sharp peaks at each site.

The complex formation between the longer alkyl bis-bipyridyls and Q[6] shows that the bipyridyl moiety can pass through the portal of Q[6]. It

98 was expected that the guest 44 (bipyridyl) should bind to Q[6]; the fact that it doesn't can be most likely attributed to its water solubility and lack of formal positive charges. If the target guest is very soluble in the solvent system used, it is less likely to bind as the energies for binding become less favourable. The orientation of any bipyridyl complex with Q[6] would have to have the bipyridyl straight through the centre axis of the Q[6], due to the 'tightness' of fit of 6 membered aromatic rings in the Q[6] cavity. The length of the bipyridyl, as well as its breadth and rigid nature, are likely to place one or more of the carbons that are alpha to the nitrogen outside of the portal. The bipyridyl complex with Q[7] may have slightly more flexibility with regards to the orientation of the guest due to the larger cavity and portal in Q[7]. Consequently the bipyridyl, when forming the complex with Q[7], may be able to orientate such that the bipyridyl can obtain maximum energy benefit from binding with Q[7], which it is unable to do in the attempted complex with Q[6].

Overall Observations From The Size-dependent Binding Experiments From the experiments listed above it is clear that cucurbit[n]uril binding does not necessarily get stronger or weaker as the ring gets larger, although larger cucurbit[n]uril can bind to larger guests. For a strong complex to form it appears that the host and guest need to be a complementary size. While a larger cavity could conceivably bind to all the ranges of guests that a smaller Q[n] can hold, the molecules that are smaller will not be restricted from dissociation which leads to a weaker complex. It was commonly observed that a guest would bind strongly to Q[7] without binding to Q[6]. It was expected that the binding ability of Q[8] would rival that of Q[7] but it was often Q[7] that formed the stronger complex, presumably reflecting the size range of the guests investigated. It would be interesting to repeat these experiments with larger guest molecules which would likely bind even more strongly with Q[8].

The stronger complex with Q[7] is most likely due to a better complement with the guests in question. Often the guests that formed slowly exchanging complexes with Q[7] would form fast or intermediate exchanging complexes with Q[8]. Cucurbit[8]uril has a much larger portal and internal cavity, leading to a faster possible rate of disassociation for many cucurbit[n]uril complexes. In fact it has been shown that Q[8] will internally complex two different bi-aromatic compounds, which would not be possible with any of the smaller 71 cucurbit[n]uril. Kim et al. showed that Q[8] will internally bind both halves of a charge transfer complex, such that both were threaded into the centre of the Q[8] cavity at the same time. This complexation with Q[8]

100 aided the stability of the charge transfer complex. Binding of two guests to Q[8] was evident in this study for the guest 32 (p-xylene diamine), which highlights the large cavity of Q[8].

Whilst the host-guest chemistry of Q[6] has been well studied over the 14 last 20 years , comparatively little work has been undertaken with regard to the other cucurbit[n]uril due to their relatively recent discovery. One of the aims of this study was to investigate the host-guest chemistry of the range of new, larger cucurbit[n]uril, particularly where n = 7 and 8, as well as comparing the complexes of both Q[7] and Q[8] with those of 133 Q[6]. Although Q[5] can complex small organics and inorganic gases , its small cavity size limited the number of guests that could have been investigated. Only one or two of the proposed guests could possibly have bound to Q[5], so Q[5] was not used in these size-dependent binding experiments.

As mentioned in the Introduction the host-guest chemistry of cucurbit[n]uril has to date been centred about guests with nitrogenous moities such as amines and bipyridyl based compounds. These compounds have two main factors driving complex formation. The charged ammoniums can form either hydrogen bonds or ion-dipole interactions with the oxygens in the carbonyl portals of the Q[n]. The other is the affinity of the hydrocarbon chain in these molecules to the hydrophobic cavity of the cucurbit[n]uril. Amines were chosen as the bulk of the guests for this study because of this selectivity of alkyl amines to Q[6]. Some of the other types of compounds which have shown 134 binding to cucurbit[n]uril include nitriles, alcohols, organic acids , 112 42 10 bipyridyls , THF , and dioxane.

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As mentioned previously, it is believed that alkyl amines bind well with cucurbit[n]uril due to two factors. Firstly the nitrogen at the oxygen portal is normally charged due to the protonation in the acidic conditions. The alkyl amines may contain one or more amines, the most strongly bound alkyl diamines often have one charged nitrogen positioned just outside each of the oxygen portals, allowing two fold complex stabilisation from dipole-dipole interactions. Figure 25 shows the binding of two alkyl amines to Q[6]. 1,6-diamino hexane is in Figure 25a, whilst the mono amine 1-amino hexane is in Figure 25b. Note the two amino groups in 1,6-diamino hexane are just at the carbonyl portals of the Q[6]. This enables the 1,6-diamino hexane to bind more strongly than the 1- 1 amino hexane in Figure 25b.

Figure 25. Alkylamine binding with Q[6]. a) 1,6-hexane diamine b) 1-amino hexane. Complexes 7 were minimised with the HyperChem package , using the AM1 force field.

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Another stabilising factor in cucurbit[n]uril complexes is the environment within the cucurbit[n]uril cavity. This cavity exhibits a hydrophobic environment, such that alkyl chains and other hydrophobic moieties will complex inside cucurbit[n]uril rather than remain in aqueous solution. 29 Nau and Marquez have studied the polarizability of Q[7] and have shown that the photophysical properties of their photo-probe in Q[7] are closer to gas phase than solution. This means that Q[7] has a very low polarizability. It is reasonable to assume that the other cucurbit[n]uril exhibit similar polarizability due to the similarities in change of spectra 24 upon binding, along with other effects like flourescence. This shows that the internal cavity of the cucurbit[n]uril is a similar environment to a non-polar solvent. In fact it has been shown that the hydrophobic cavity of Q[6] increases the complex stability by providing a barrier to decomplexation of charged species. Mock et al. proposed that this barrier to decomplexation is due to the interaction between the charged nitrogen 17 and the hydrophobic cavity. Mock et al. showed that for most Q[6] guests the differences in complex stability were due to changes in rates of complex formation rather than a difference in rates of complex 15-17 dissociation. Mock found that the rate of complex formation was very fast, with a much slower dissociation step determining the complex stability. One of the reasons given for the slow dissociation was the energy required to pass the charged nitrogen through the internal cucurbit[n]uril cavity.

It was initially believed that guests complexed to Q[6] through hydrogen 1 16 bonding , although this was later shown to be only partially correct. It has been shown that ion-dipole interactions can have a much larger bearing on the complex than any of the other stabilising forces. This has

103 led to other cucurbit[n]uril guests which show dipole-dipole interactions with cucurbit[6]uril, such as alcohols, nitriles and acids being studied by 134 Buschmann et al. These compounds all bind to cucurbit[n]uril even though they don't have a formal charge on the end group like the protonated amine does. This backs up Mock and colleagues' work where they state that the complexes are formed with several interacting forces, ion-dipole binding(or in these cases dipole-dipole binding), hydrogen bonding and the hydrophobic effects contributed by the cavity.

Other types of compound such as bipyridyl and bis-bipyridyl compounds 71,111,112 have also been shown to be good guests for cucurbit[n]uril. A study by Buschmann et al. showed that while 4,4'-bipyridinium and 1,1'- dimethyl-4,4'-bipyridinium are poor guests for Q[6], other bipyridine derivatives were good guests. These include 1,1'-diethyl-4,4'- bipyridinium along with bis-bipyridyl compounds containing bipyridyls separated by alkyl chains with a length of 5 or more carbons. The compound bis-(4,4'-bipyridyl)-'-p-xylene (45) does not form a complex with Q[6], however it does form a complex with Q[7]. It is believed that this complex does not form due to the rigidity of both the 112 Q[6] and bipyridyl species. This is a very good example of size- dependent binding.

The complex formation generalised above relies on the guest becoming bound within the cucurbit[n]uril. It is also conceivable that the guest may become complexed externally to the cucurbit[n]uril as shown by Wagner 24 et al. In Wagner's fluorescent solid, a complex of Q[6] and 1,8-ANS, the 1,8-ANS is associated with the Q[6], but entirely on the outside of the Q[6]. This is also the case in most of the metal cation complexes to date.

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This mode of binding is possible if the 'guest' has a charged moiety but is too bulky to fit in the cucurbit[n]uril, or as in the case of metal cations where there is no hydrophobic or solvation benefit for the species to bind internally. In these cases the 1H-NMR spectrum will not change significantly, although other methods such as calorimetry, fluorescence or UV-Vis absorption may be employed to determine these small interactions.

As mentioned earlier, NMR spectroscopy, and in particular 1H-NMR spectroscopy, may be utilised in determining complex formation. This is due to the shielding and de-shielding that the cucurbit[n]uril host effects on the guest. When the guest binds inside the cucurbit[n]uril there is a proton shielding effect from the cucurbit[n]uril which shifts the guests 15,16 internal protons upfield by 0.1 – 2.0 ppm. Conversely any guest protons that are positioned close, but external to the carbonyl portal are shifted slightly downfield. This combination of upfield/downfield shift enables the determination of the position of the guests in the cucurbit[n]uril complexes.

Figure 26 shows a simple example of this peak shifting. The guest 32 (p- xylene diamine) has only two 1H-NMR resonances, one at 7.27 ppm coresponding to the protons on the benzene and the second resonance at 3.84 ppm due to the para methylene groups. This example shows a guest which may bind with slow exchange to two different cucurbit[n]uril, the 1H-NMR spectra of the guest with a mixture of cucurbit[n]uril shows that Q[7] is the preferred host, with a 4:1 ratio of the guest bound in Q[7] compared to Q[8]. It is clear that both sets of peaks shift upfield upon addition of Q[7] and Q[8], as marked with the hollow diamond and circle.

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This is due to the shielding effect from the cucurbit[n]uril. Note that the change in chemical shift is different between the cucurbit[n]uril.

Figure 26. 1H-NMR spectra of; a) p-Xylene diamine (32) b) cucurbit[7]uril complexed with p- xylene diamine c) cucurbit[8]uril complexed with p-xylene diamine. The unbound resonances are marked with solid shapes, the bound resonances are marked with the white shapes.

Cucurbit[8]uril provides a greater shielding effect in this case. It is known that the degree of shielding inside a cucurbit[n]uril is not uniform.

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The initial belief that being closer to the side of the cucurbit[n]uril cavity and closer to the equator would provide the greatest shielding may not be the case, as it was expected that the complex with Q[7] would then provide a greater shielding. The increased shielding of the Q[8] could be due to a more favourable orientation of the guest inside the cavity, thus bringing the guest closer to the glycouril on the inside of the cucurbit[n]uril. It was indeed found that this guest binds in a 2:1 complex with cucurbit[8]uril, this configuration, shown in Figure 20, places the p- xylenediamine quite close to the cucurbit[8]uril.

Another example of the non-uniform nature of the shielding of the guest can be seen in the following example. Figure 27 shows the complex formation between Q[7] and 1-adamantane methylamine in aqueous

Na2SO4 solution. The AB system for the remote methylene position is clearly further separated in the host. Therefore, the degree of shielding is changing significantly over small distances inside the cucurbit[n]uril cavity.

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Figure 27. 1H-NMR spectra of; a) 1-Adamantane methyl amine (40). b) cucurbit[7]uril complexed with 1-adamantane methylamine. The peaks are marked to illustrate the change in chemical shift.

The methyl external to the adamantyl cage has the smallest change in chemical shift, showing that it is near the portal (but still in the cavity). Note the increase in the separation of the AB coupled protons marked with a white square. These protons have changed their magnetic environment upon encapsulation causing chemical shift change that affects the AB system. The non-uniformity of this change in chemical shift shows that one of the coupled sets of protons is in a region of the cavity that has a greater shielding effect . This is consistent with the model of the complex shown in Figure 28.

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Figure 28. 1-Admantane methylamine complexed with Q[7]n showing regions of chemical shift 7 change. The figure on the left was minimised with the HyperChem package , using the AM1 force field.

This section has shown that there are many different binding modes in the host-guest chemistry of cucurbit[n]uril. It is difficult to predict what guest will bind best to a particular cucurbit[n]uril due to the fine balance between ion-dipole, dipole-dipole, van der Waals contacts, solubility and hydrophobic effect, although it is possible to determine whether or not a particular guest will bind or not. As expected the larger cucurbit[n]uril generally act as better hosts for the larger guests, although this is not always the case. In the following section of work I have investigated the impact of the materials studied here as potential templates and compared this to their varied binding abilities.

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Templated Formation of Cucurbit[n]uril The synthesis of large macrocyclic compounds is generally very low in yield due to the diverse range of reaction products. In fact it is often the side products that form the majority of the reaction mixture. A good 135 example of this is the calixarenes that are formed as minor products in the bakelite reaction. Cucurbit[n]uril are an exception to this rule, with almost quantitative yields easily obtained. The main challenge in cucurbit[n]uril synthesis is the separation of the individual cucurbit[n]uril, along with reaction optimisation to target a particular ring size. The goal of this section of work is to examine the impact of reaction templates on the yield of individual cucurbit[n]uril.

An important part of the synthesis of a new supramolecular host is the optimisation of the synthesis parameters to maximise the yield of the target compounds. One way this may be achieved is through effective separation of the minor products from the bulk of the reaction mixture. Another approach is by designing a reaction that produces a higher yield of the target compound through reaction condition changes, self- assembly, template effects and other methods.

Cucurbit[n]uril may be produced in high yields due to several factors. All of the reaction steps leading to the formation of cucurbit[n]uril from glycouril/formaldehyde are reversible up to the final ring closure of the cucurbit[n]uril. This, coupled with the fact that the cucurbit[n]uril are apparently a thermodynamic sink, means that the final cucurbit[n]uril are formed without any major side products. With the exception of Q[6] and Q[5], which may be produced alone under appropriate conditions, the cucurbit[n]uril are all formed together in the same reaction. This means

110 that there is a significant separation process necessary to obtain pure Q[5], Q[7] or Q[8] from the cucurbit[n]uril mixture. The aim of this section of this work was to investigate ways to influence the product distribution to favour individual cucurbit[n]uril. Having a reaction that can increase the relative amount of a particular cucurbit[n]uril will aid in increasing the final recovered yield of that cucurbit[n]uril.

An example of a class of reactions that may make many more products in a similar yield are the new class of mixed substituted cucurbit[n]uril that are being produced by several different groups of researchers. These 'mixed' cucurbit[n]uril have some or all of their glycouril subunits replaced with 'extended' glycourils, with straight or cyclic aliphatic moieties replacing either (or both) of the hydrogens. Many of these mixed cucurbit[n]uril have substituents on alternate (or only one) glycouril. These 'mixed' reactions are capable of making a very large range of different cucurbit[n]uril in similar amounts due to the many 11,12 similarly favoured reaction steps.

One method of changing the product distribution of complex macrocyclic synthesis is to add a 'template' to the reaction. A template's role in the reaction is to change a product distribution in a favourable manner. This could mean increasing the amount of the target compound by only a small amount, or in some cases the target compound does not form without the 121 template. Templates have been used in a number of chemical fields, 136 137 138 including the synthesis of rotaxanes , polymers , macrocycles and 120 inclusion compounds (carcerands). An example of a templated supramolecular reaction similar to those attempted in this work is that of the templated formation of carcerands, some of which have been shown

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120 to favourably increase in yield with certain templates. Sherman et al. investigated the template effect on the yield and rate of reaction for the formation of a carcerand. Certain of the templates investigated were able to increase the yield dramatically, although not all templates studied were useful. Sherman et al. were able to show a 106 fold difference in template effect over the range of templates investigated. Figure 29 shows the template with the greatest effect on the reaction, pyrazine. Sherman states that the pyrazine is a good guest for the subunits, thus stabilising the forming carcerand.

Figure 29: Sherman's carcerand forms 106 times faster in the presence of a pyrazine template 7 (complexed in center). Complex minimised with the HyperChem package , using the AM1 force field.

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The results obtained by Sherman et al. clearly demonstrate that a compound with the correct size and electronic features to make a good guest, can potentially make a template in complex ring closure reactions.

Other investigations involving templates in the supramolecular field have found two hosts that will only form in the presence of templates. Fujita et al. have investigated the template effect or 'induced-fit' on the formation 139,140 of organo-metallic cages . Examples of these cage like complexes are shown in Figure 30 and Figure 31.

Figure 30: Fujita's 'Cagelike' complex only forms in presence of a template such as sodium 139 7 adamantanecarboxylate. Complex minimised with the HyperChem package , using the AM1 force field.

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Figure 31: 'Switchable molecular lock' complex synthesised by Fujita et al. forms in the presence 140 of the sodium adamantanecarboxylate template Complex minimised with the HyperChem 7 package , using the AM1 force field.

Most of the successful work involving templated reactions in supramolecular chemistry involve using a template that is a good 'guest' for the target macrocycle. This is so that the forming host may bind to a complementary molecule such that forming the host-guest complex is thermodynamically favourable. This may occur by increasing the thermodynamic stability of the forming host or lowering the barrier to reaction or by simply holding two or more components in close proximity and therefore increasing the probability of favourable reaction. The

114 template may bind in many ways including any combination of, but not limited to:

S formation of hydrogen bonds between host and guest S other types of weak bonds such as ion-dipole or dipole-dipole interactions or London dispersion forces S solvation effects

In the case of the reactions performed by Sherman et al. it could be argued that the affinity between the hemi-carcerand (the bowl shaped precursor to the carcerand) and the guest form a 2:1 bis hemicarcerand complex, therefore allowing for a longer period in which carcerand forming bonds are made. This would mean that the template would be a form of catalyst, by causing the reacting species to be together longer.

The aim of templating in this work was to change the amounts of the individual cucurbit[n]uril produced. This was studied through the addition of a large range of cucurbit[n]uril guests to the reaction mixture, so that the template would influence the series of reversible reactions in the forming cucurbit[n]uril to favour one size ring over another. It was anticipated that ion-dipole, dipole-dipole and hydrophobic effects would contribute to any templated formation of cucurbit[n]uril.

Day et al. and Kim et al. have shown that the percentage composition obtained from the cucurbit[n]uril formation is very dependent upon 10,70 concentration and type of acid. It has been hypothesised that the anion 10 plays some part in the reaction as a template. The hydronium ion is also believed to play a templating role, through the stabilisation of the proto-

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10,70 cucurbit[n]uril. Day et al. have shown that there is a templating effect on the formation of cucurbit[n]uril through the addition of different metal 115 cations. In this case the templating effect tends to favour the formation 115 of Q[5] and Q[7]. Day found that the addition of the cation to the cucurbit[n]uril formation reaction once the oligomer was already formed provided the best results. The results with Li+ and K+ cations were the most significant. These two metal cations provide a template effect for Q[5], increasing the yield of Q[5] to 40% and 46% of the reaction products respectively by weight when added to the reaction mixture. The + + + + + + + range of results for the cations H , Li , Na , K , Rb , Cs and NH4 are presented in Table 6.

Table 6. Percentage by weight of cucurbit[n]uril obtained through addition of cations to proto- 115 cucurbit[n]uril oligomer

+ + + + + + + H Li Na K Rb Cs NH4 Q[5] 25 40 31 46 33 19 25 Q[6] 51 36 41 38 45 56 47 Q[7] 20 18 21 13 19 19 21 Q[8] 4 5 7 3 3 6 7

Day proposed that these cations influenced the reaction by binding with portal carbonyls. This would then stabilise the forming ring such that the ring that best binds to a particular sized cation would be formed in higher yield than normal.

As stated earlier there are also effects on the product distribution from the 10 type of acid used, as well as from the concentration of reagents. Table 7

116 shows the percentage of cucurbit[n]uril by weight obtained in a variety of reaction conditions. Clearly the rate of ring formation is influenced by the concentration of glycouril and acid. Day et al. postulated that the anion counterpart to the acid also acts as a template, but on the inside of the internal cavity by complexing with the proto-cucurbit[n]uril.

Table 7. Percentage by weight of cucurbit[n]uril obtained under different reaction conditions. Weight %c Acida Q[5] Q[6] Q[7] Q[8]d

Conc. H2SO4 12 88 <1 <1 b Conc. H3PO4 8 51 35 6 Conc. HCl 17 48 28 7

50% HBF4 28 43 24 5

9 M H2SO4 23 44 25 8 9 M HCl 17 50 25 8 8 M HCl 16 52 27 5 7 M HCl 16 51 31 2 6 M HCl 10 53 32 5 5 M HCl 9 52 35 4 Conc. HCle 19 39 30 12 Toluene Sulfonic Acid 5 61 27 7 a. Reaction temperatures were at 100 LC over a 2-3 hr period and in all cases the reaction mixtures were homogenous throughout the entire process. b. After 18 hr the reaction was estimated to be >85% complete. c. Weight percentages were determined by 13C NMR spectroscopy, and include a correction factor. Percentages are calculated on a relative basis and are not absolute. d. Less than 1% of products that could be attributed to cucurbit[n]uril where n > 8.

e. Reaction was carried out at 50 LC over a period of 1 month and was estimated to be 85% complete. Other individual cucurbit[n]uril were present in proportions of <1% each.

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Rebek has a large body of work in the field of glycouril based supramolecular chemistry. He has developed a series of glycouril based compounds that self-assemble into different sized 'balls'. Rebek has 141 denoted these 'softballs', 'baseballs' or 'tennis balls'. One of the so- called 'softballs' is shown in Figure 32. These balls form in solution because of hydrogen bonding through the glycouril moieties. Once formed these balls may encapsulate smaller molecules. Compounds like this show the binding capabilities of non-cucurbit[n]uril glycouril based hosts.

142 Figure 32. The 'softball' synthesised by Rebek et al. is an example of glycouril in supramolecular chemistry.

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Other glycouril compounds have been synthesised seperately by Rebek et al. and Isaacs et al. These compounds have been shown to bind to certain guests through hydrogen bonding. The work by Isaacs et al. is particularly relevant to cucurbit[n]uril as they have synthesised model proto-cucurbit[n]uril. Examples of model dimers synthesised by Isaacs et al. are shown in Figure 33. Isaacs used the dimers as a way of 143 determining the mechanism of cucurbit[n]uril formation.

143 Figure 33. Isaacs has used these C and S shaped glycouril dimers to investigate cucurbit[n]uril formation

The proto-cucurbit[n]uril oligomer has been shown to bind more strongly 128 to certain known cucurbit[n]uril guests than Q[6]. This is likely due to the increased flexibility and open structure of the proto-cucurbit[n]uril in relation to the final cucurbit[n]uril, thus enabling the oligomer to accommodate the guest more effectively. This oligomer should be able to bind compounds in solution in a manner similar to that described by both Isaac and Rebek. The intermolecular bonding in these instances is likely to be a combination of ion-dipole or dipole-dipole interactions, along with a hydrophobic effect due the 'cleft' style complex. The proto-

119 cucurbit[n]uril oligomer could bind in a similar manner to the 'templates' used in this study.

The host-guest binding experiments just described provide a basis for the templated synthesis of cucurbit[n]uril developed in this work. The guests used in the previous size-dependent binding were added to the cucurbit[n]uril synthesis reaction. A guest that binds preferentially to one cucurbit[n]uril may well skew the distribution of cucurbit[n]uril by binding to the proto-cucurbit[n]uril oligomer and providing a template around which the cucurbit[n]uril could form. This template could then reduce the activation energies leading to the formation of a particular cucurbit[n]uril, thus increasing its percentage yield. Some guests can only bind with the larger cucurbit[n]uril due to the size or shape of the guest in relation to the cucurbit[n]uril. These guests should turn out to be successful 'templates' for the preferential formation of larger cucurbit[n]uril.

The templates investigated are listed in Table 8, and are all compounds studied in the size-dependent binding to cucurbit[n]uril (Table 5). These 'templates' were chosen based on the likelihood (and evidence above) of their cucurbit[n]uril binding capacity. The templates were expected to complex in a similar fashion as in the size-dependent binding experiments. It was anticipated that as the size of the templates increased, they would favour the formation of larger sized cucurbit[n]uril rings. All of the templates chosen had to be soluble and stable in the acidic reaction conditions, so that they could be in solution to bind to the forming cucurbit[n]uril. A successful template should also not react to form any side products.

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13C-NMR spectroscopy was used to measure the product distribution after reaction and the results are tabulated below. Table 8 lists both the percentage composition for each cucurbit[n]uril and the relative change in percentage yield for each of the cucurbit[n]uril, where n = 5-8, with marked differences from the normal percentage composition shaded.

Table 8. Results from templated synthesis of cucurbit[n]uril

Weight % of cucurbit[n]urila Q[5] Q[6] Q[7] Q[8] b Template (17%)c (48%)c (28%)c (7%)c 6d 51 30 13d 6 cystine (-65%) (7%) (6%) (86%)

11 58 26 5 51 ammonium hexafluorophosphate (-37%) (22%) (-7%) (-34%)

5 47 41 6 7 thioacetamide (-70%) (-1%) (47%) (-7%)

14 47 28 11 8 acetamide (-16%) (-2%) (0%) (54%)

14 44 29 13 9 taurine (-20%) (-8%) (5%) (81%)

3 47 42 9 10 N,N,N',N'-tetramethyldiaminoethane (-83%) (-3%) (49%) (26%)

11 3-aminopropylbromide.HBr No Cucurbit[n]uril formede

12 hexamethylene diamine No Cucurbit[n]uril formede

13 N-(2-aminoethyl)-1,3-propanediamine No Cucurbit[n]uril formede

52 tetrabutylammonium fluoride No Cucurbit[n]uril formede

12 53 30 5 53 tetrabutylammonium chloride (-30%) (11%) (7%) (-31%)

14 56 26 4 14 tetrabutylammonium iodide (-18%) (16%) (-7%) (-38%)

8 53 32 7 15 tetrapropylammonium bromide (-53%) (10%) (16%) (-1%)

7 44 41 8 16 tetraethylammonium chloride (-56%) (-8%) (45%) (9%)

17 tetramethylammonium chloride No Cucurbit[n]uril formede

18 p-aminophenol 11 31 43 15

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Weight % of cucurbit[n]urila Q[5] Q[6] Q[7] Q[8] b Template (17%)c (48%)c (28%)c (7%)c (-37%) (-35%) (55%) (109%)

6 54 34 6 19 4-dimethylaminobenzaldehyde (-63%) (12%) (21%) (-14%)

20 4-aminoactetophenone No Cucurbit[n]uril formede

10 51 28 11 21 p-acetamido-aniline (-41%) (7%) (0%) (52%)

9 28 45 18 22 p-bromoaniline (-49%) (-41%) (62%) (150%)

11 53 26 10 23 2-amino-3-methyl benzoic acid (-37%) (10%) (-6%) (47%)

24 3-amino-thiazol No Cucurbit[n]uril formede

3 59 34 4 25 4-acetamidophenol (-82%) (22%) (21%) (-36%)

26 aniline sulphate No Cucurbit[n]uril formede

27 p-toluidine No Cucurbit[n]uril formede

5 43 43 9 28 m-toluidine (-72%) (-10%) (55%) (25%)

29 o-phenylene diamine No Cucurbit[n]uril formede

30 4-methylbenzylamine No Cucurbit[n]uril formede

31 benzylamine No Cucurbit[n]uril formede

32 p-xylylenediamine No Cucurbit[n]uril formede

10 42 45 3 33 2-aminobenzimazol (-43%) (-12%) (59%) (-52%)

11 48 32 10 34 N-(1-naphthyl)ethylenediamine (-38%) (-1%) (13%) (45%)

5 62 30 4 35 indol-3-aldehyde (-69%) (28%) (6%) (-50%)

36 pyridine No Cucurbit[n]uril formede

12 47 41 0 54 4-phenylazoaniline (-30%) (-2%) (47%) (-100%)

6 48 37 8 37 2,2'-biquinoline (-63%) (0%) (33%) (20%)

38 2-adamantanamine.HCl No Cucurbit[n]uril formede

39 1-adamantanamine.HCl No Cucurbit[n]uril formede

40 1-adamantane-methylamine No Cucurbit[n]uril formede

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Weight % of cucurbit[n]urila Q[5] Q[6] Q[7] Q[8] b Template (17%)c (48%)c (28%)c (7%)c

41 N-(1-adamantyl)-acteamide No Cucurbit[n]uril formede

42 quinuclidine.HCl No Cucurbit[n]uril formede

10 54 32 4 55 blue tetrazolium (-42%) (13%) (14%) (-42%)

9 42 33 16 43 1-(propylamine)-o-carborane (-45%) (-13%) (18%) (125%)

44 4-4'-bipyridyl No Cucurbit[n]uril formede

45 bis-(4,4'-bipyridyl)-,'-p-xylene 18 38 35 9 chloride (7%) (-21%) (25%) (25%)

46 bis-(4,4'-bipyridyl)-1,2-ethylene chloride No Cucurbit[n]uril formede 47 bis-(4,4'-bipyridyl)-1,3-propylene chloride No Cucurbit[n]uril formede

48 bis-(4,4'-bipyridyl)-1,6-hexamethylene 5 43 46 6 chloride (-70%) (-10%) (63%) (-13%) 49 bis-(4,4'-bipyridyl)-1,7-heptamethylene chloride No Cucurbit[n]uril formede

50 bis-ethyl-4-4'-bipyridyl chloride No Cucurbit[n]uril formede a) Weight percentages were determined by 13C NMR spectroscopy, and include a correction factor. Percentages are calculated on a relative basis and are not absolute. b) The templates were all added to the cucurbit[n]uril reaction mixture prior to addition of glycouril in a ratio that would equal 1:1 with Q[6]; note that this was an arbitrarily chosen amount. All reactions contained 1mmol (142 mg) of glycouril, 60 mg of paraformaldehyde and 0.17 mmol of 'template' in 10 mL of conc. HCl. c) These are the percentages obtained from the reaction with no template added. d) Significant changes in the percentage of cucurbit[n]uril formed are highlighted e) No cucurbit[n]uril were formed in the two hour time scale of the reaction. At the end of two hours in these cases the reaction mixture usually contained a mixture of template and proto-cucurbit[n]uril oligomer.

It was found that several of the templates that were used did in fact alter the distribution of the Q[n] dramatically. In some cases the influence of the template on product distribution was even greater than that observed 10 by Day et al. in their manipulation of acids and reaction conditions.

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Significant changes in amounts of cucurbit[n]uril are highlighted in grey in Table 8. A significant change was said to be a greater than 40% change in amounts of Q[5] and Q[8], or greater than 20% change in Q[6] or Q[7].

Templates that inhibit the formation of cucurbit[n]uril It is evident that many of the proposed templates cause a negative impact on the cucurbit[n]uril formation. Of the fifty potential templates studied, twenty four of these completely inhibited the formation of cucurbit[n]uril over the reaction time (two hours). Comparing the results of these twenty four 'tempates' with their size-dependent binding experiments give the following; S Five did not bind with any cucurbit[n]uril S Two bound with cucurbit[6]uril S Eleven bound with cucurbit[7]uril S Six bound to more than one cucurbit[n]uril

Almost all of the above nineteen 'templates' which bind with cucurbit[n]uril bound with slow exchange, which is generally associated with a 'strong' complex. It would seem from this that the formation of cucurbit[n]uril in the presence of a strong binding guest can often inhibit the formation of the cucurbit[n]uril. In these cases where cucurbit[n]uril was not formed, the reaction mixture contained proto-cucurbit[n]uril oligomer. This oligomer may well be stabilised by a strong binding guest, such that forming the cucurbit[n]uril rings becomes less favourable. This is good evidence that a template can play a part in the cucurbit[n]uril formation reaction, as it appears that strong cucurbit[n]uril

124 binding guests may also bind strongly with the proto-cucurbit[n]uril oligomer.

Day et al. propose the reaction mechanism shown in Figure 34 that describes the formation of both an oligomeric pre-cursor and the 10 mechanism to move from the precursor to the final cucurbit[n]uril. The glycouril/formaldehyde condensation forms an ether bridge between two of the glycouril nitrogens. This glycouril ether may then react with another forming a glycouril dimer. This dimer will increase in length to form the oligomeric ribbon. If enough of these linked glycouril are in endo form, the ribbon will curve back upon itself, allowing the formation of the cucurbit[n]uril. It is at this point that a template would have its effect, with the oligomer forming around the template.

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10 Figure 34. Proposed reaction mechanism from Day et al.

Day et al. postulate that a template could help the oligomer chain curve back on itself through binding with the oligomer in some fashion as 10 shown in Figure 35. This presents the oligomer as a chain that has some cucurbit[n]uril properties, but is not yet entirely closed and therefore maintains a degree of flexibility.

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This flexibility allows the formation of cucurbit[n]uril in multiple sizes. The flexibility in the proto-cucurbit[n]uril is needed for the templated reactions to work as planned, as the forming cucurbit[n]uril would have to accommodate a greater percentage of larger rings. The degree of flexibility in the forming cucurbit[n]uril may well be a limiting factor in the effectiveness of the templated reactions.

10 Figure 35. Proto-cucurbit[n]uril oligomer curving back on itself to form a ring

It is possible that a strongly binding cucurbit[n]uril guest will bind the protocucurbit[n]uril oligomer so effectively that it impedes the reversible nature of the oligomer, thus slowing down the formation of the cucurbit[n]uril. If these templates had this effect then using longer reaction times at a greater temperature would speed the reaction up again,

127 although this is outside the scope of this work. As mentioned earlier it is the templates that were the most strongly bound cucurbit[n]uril guests which have impeded the cucurbit[n]uril formation, a very good indication that the templated reaction mechanism of Day et al. is correct.

Taketsuji et al. have provided an example of a use of the proto- 128 cucurbit[n]uril oligomer in their patent application. It has been known for some time that Q[6] is able to bind several common textile dyes from textile industry waste water. Taketsuji et al. use the proto-cucurbit[n]uril oligomer to greater effect at dye removal than Q[6] alone. This proves that the oligomer is able to bind to molecules in a manner similar to cucurbit[n]uril. Importantly this also shows that the mode of binding can be optimised by the oligomer, presumably through its flexibility and open structure, to provide a more optimum 'fit' to a range of guests. This is important because the oligomer must be able to be influenced by a bound template for the template to have an effect on the final cucurbit[n]uril distribution.

Impact of templates on the proportion of cucurbit[5]uril Day et al. have shown that cations can have a large template effect on the 115 formation of Q[5]. As expected there are no compounds in this study that cause a positive template effect for Q[5], as all of the compounds should be too large to bind internally to Q[5]. What is seen however, is a marked decrease in the percentage composition of Q[5] through several of the samples. This is reflected with an increase in the amounts of the larger Q[n], presumably because of a positive template effect with these

128 higher homologues as discussed below. In every case that there was a marked decrease in the amount of Q[5] produced, there was an increase in the amount produced of one or more of the higher cucurbit[n]uril homologues.

Impact of templates on the proportion of cucurbit[6]uril Whilst most of the template effect was seen in the larger two cucurbit[n]uril, some compounds exhibited a positive template effect for Q[6]. Notably these only achieved yields of 56-62%, up from 48%. This is significantly less than the easily obtainable 80-90% of Q[6] under 114 different reaction conditions. As with Q[5] many of the templates actually decrease the amount of Q[6] produced.

The templates that increase the amount of Q[6] formed are ammonium hexafluorophosphate, 4-acetamidophenol and indol-3-aldehyde. Of these it is most likely that the first acts as a template due to its counter ion. The hexafluorophosphate anion is large enough to exhibit an effect if it is complexed internally to the protocucurbit[n]uril. The ammonium cation has been studied separately, giving relative ratios of 25% Q[5], 47% 10 Q[6], 21% Q[7] and 7% Q[8]. If it were only the cation that had an effect on the proportions of the cucurbit[n]uril then the ammonium hexafluorophosphate template would produce the same proportions of cucurbit[n]uril as did the ammonium chloride used by Day et al. If the cation is complexed with the forming carbonyl portal then it is conceivable that the anion may bind in the cavity of the protocucurbit[n]uril. There have also been examples in the literature of anions complexing internally with the cucurbit[n]uril, such as the endoannular metal halide complex of cis-SnCl4(OH2)2 with

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13 cucurbit[7]uril. Therefore it is likely that the difference between the ammonium chloride example reported by Day and this work must be due to the hexafluorophosphate being encapsulated in the proto-cucurbituril and favouring the formation of the Q[6].

Both 4-acetamidophenol and indol-3-aldehyde bind with Q[6] as shown in the binding experiments. The results presented here support the hypothesis that a good template would be a good guest, as both of these compounds bound with Q[6] in the size-dependent binding experiments. Indol-3-aldehyde showed the strongest templating effect, increasing the proportion of Q[6] in the reaction product from 48% to 62%. In both of these cases there was a marked reduction in the amounts of Q[5] and Q[8] produced and a small increase in the amount of Q[7] produced.

Impact of templates on the proportion of cucurbit[7]uril Cucurbit[7]uril was the cucurbit[n]uril most positively affected by the templates. Thirteen of the compounds investigated proved to exhibit a significant template effect favouring the formation of Q[7]. A favourable effect was defined as one where the yield of Q[7] was increased by 20% or more. The strongest template effect recorded came from the template 48 (bis-(4,4'-bipyridyl)-1,6-hexamethylene), which increased the yield of Q[7] to 46%, making Q7 the major product. This is significantly higher than previous template or synthesis studies where the maximum 10 production of Q[7] was 35%. This is also an increase of 63% over the standard reaction conditions.

This and other similar templates gave some interesting results, which will be discussed later. The compounds bis-(4,4'-bipyridyl)-1,6-

130 hexamethylene, thioacetamide, 2-aminobenzimidazol and 4- phenylazoaniline all increased the proportion of Q[7] produced, whilst reducing the amount of the each of the other Q[n].

The compounds that templated Q[7] were; thioacetamide, p-aminophenol, N,N,N',N'-tetramethyldiaminoethane, tetraethylammonium chloride, 4- dimethylaminobenzaldehyde, p-bromoaniline, 4-acetamidophenol, m- toluidine, 2-aminobenzimidazol, 4-phenylazoaniline, bis-(4,4'-bipyridyl)- '-p-xylene, 2,2'-biquinoline and bis-(4,4'-bipyridyl)-hexamethylene.

Of these all but m-toluidine and 4-phenylazoaniline formed complexes with Q[7] in solution in the size-dependent binding experiments. This is an indication that a guest which forms a complex with a particular cucurbit[n]uril, may also prove to be a good template for that cucurbit[n]uril. It should also be noted that two of the templates complexed so well to Q[7] in the size-dependent binding experiments that the complex precipitated. It is worth noting however, that not all of the guests that bound to Q[7] exhibited a template effect of cucurbit[7]uril. In fact, as mentioned earlier, those that bind with slow exchange tended to cause no cucurbit[n]uril to be formed at all. Only bis-(4,4'-bipyridyl)- ,'-p-xylene (45), bis-(4,4'-bipyridyl)-1,6-hexamethylene (48) and thioacetamide formed complexes with slow exchange and templated the formation of Q[7]. This shows that the intermediate and fast exchanging 'templates' are preferable to use when trying to increase the proportion of Q[7].

Thioacetamide was an unexpected template for Q[7]. This is a relatively small molecule and although it complexes with Q[7], it was not anticipated to have a template effect. The addition of thioacetamide

131 increased the proportion of Q[7] in the product mixture from 28% to 41%, whilst simultaneously reducing the amounts of all of the other cucurbit[n]uril. Two possible explanations for the template effect of thioacetamide are that; S The relatively large sulphur atom is held in the forming carbonyl portal by the ammonium functionality and therefore it is templating around that which gives the observed effect. S The thioacetamide impedes the formation of smaller macrocycles by slowing down their formation. This would mean that thioacetamide has a negative template effect on Q[5], which indirectly benefits the formation of Q[7].

Impact of templates on the proportion of cucurbit[8]uril Some templates also increased the yield of Q[8]. These include cystine, acetamide, taurine, p-aminophenol (which also templated Q[7]), p- acetamidoaniline, p-bromoaniline (which also templated Q[7]), 2-amino- 3-methyl benzoic acid, N-(1-naphthyl)ethylenediamine and 1- (propylamine)-o-carborane. Both taurine and p-bromoaniline did not exhibit a complex with Q[8] in the size-dependent binding experiments. Of the others, all were complexed with fast or intermediate exchange, with the exception of N-(1-naphthyl)ethylenediamine and 1- (propylamine)-o-carborane which were complexed with slow exchange .

The most effective template for Q[8] is p-bromoaniline, increasing the amount produced from 7% to 18%. This result, along with the 16% yield of Q[8] for propylamine-o-carborane are good results, given the previously highest yield was 12% with a month long cucurbit[n]uril 10 reaction at 50 LC in conc. HCl.

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General observations on the templated formation of cucurbit[n]uril As mentioned earlier, the compounds that bind well with a particular cucurbit[n]uril often show a template effect for that cucurbit[n]uril. As a general rule this effect is negative, reducing the proportion of a Q[n] if the template is a strong binder to that Q[n]. Guests that bind with intermediate or fast exchange often showed a positive template effect. Both the negative and positive template effects are important observations, because they support the proposed templated reaction 10 mechanism.

Other than an affinity for a particular sized cucurbit[n]uril there does not appear to be any particular feature that a template should have to be effective. All of the groups had members that templated the size specific formation of cucurbit[n]uril to some degree. The only exception to this was the adamantyl compounds. These did not form any discernable cucurbit[n]uril. These are all strong binders with Q[7] and serve as a good example of 'templates' that bind too strongly with the proto- cucurbit[n]uril, slowing the reaction so that no cucurbit[n]uril was formed in the reaction time frame.

There were only a few templates which increased the amount of Q[8] that was formed. An example of this is the template 3-propylamine-o- carborane. This compound has a 'ball' like substructure, due to the o- 144 carborane. Unlike the un-substituted carborane used in previous work , 3-propylamine-o-carborane has the aliphatic amine as an additional binding moiety and to aid in aqueous solution solubility.

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Figure 36. Cucurbit[n]uril formation using 3-propylamine-o-carborane as a template. 13C-NMR spectrum of dried reaction mixture dissolved in D2O.

7 Molecular modelling using the HyperChem package shows that carborane has a very 'tight' fit with Q[7], and indeed Blanch et al. showed that o-carborane binds with Q[7], but not Q[6] in trifluoroacetic acid. Using propylamine-o-carborane as a template in this study extended those findings, with the propylamine-o-carborane capable of drawing both Q[7] and Q[8] into aqueous solution. Whilst Q[7] and Q[6] have been shown to be soluble in certain aqueous metal salt solutions, Q[8] has not to date been capable of being dissolved in these solutions. The reaction mixture for the template reaction with propylamine-o-carborane was evaporated and the solid obtained rinsed with water with the aim of removing excess propylamine-o-carborane. What was found instead was that the two cucurbit[n]uril, Q[7] and Q[8], were taken into the aqueous solution complexed around the carborane compound. The complex with Q[7] is so strong that it was able to withstand the conditions of ES-MS to give ions for the complex.

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13C-NMR spectra show that both Q[7] and Q[8] are taken up in solution in almost equal amounts. There is no Q[6] or Q[5] taken into solution, although either of those could bind externally (i.e. with the carborane moiety external to the cucurbit[n]uril) to the 3-propylamine-o-carborane. There are also ten distinct 3-propylamine-o-carborane carbon peaks, which show two separate propylamine-o-carborane environments, all different from the 13C-NMR spectrum of pure 3-propylamine-o- carborane. This shows that the 3-propylamine-o-carborane is bound strongly enough to exchange slowly over the NMR time scale. One set of five peaks are evident for each of the two cucurbit[n]uril complexes. The 1H-NMR spectrum of the reaction mixture is, as expected, a combination of the spectra obtained by mixing Q[7] and Q[8] with 3-propylamine-o- carborane.

The 1H-NMR spectrum of the reaction mixture also clearly indicates that the carborane moiety is encapsulated in the cucurbit[n]uril. The peaks for a proton inside a cucurbit[n]uril are shifted upfield, whilst the peaks for protons outside the cucurbit[n]uril are shifted downfield. Whilst the B-H protons are shifted upfield, the resonance for the methyl alpha to the amino group is shifted downfield. This means that this methyl is either external to the portal or at the actual portal itself.

Other clear examples of templated formation of cucurbit[n]uril from this reaction series are the products of the templated formation of cucurbit[n]uril with 45 (bis-(4,4'-bipyridyl)--p-xylene) and 48 (bis- (4,4'-bipyridyl)-1,6-hexamethylene). These bipyridyl based compounds both bound to Q[7], but only 48 bound to Q[6], 45 being too rigid to fit through the portal of Q[6].

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Both of these compounds provide template effects on Q[7] as well as binding Q[6]. Additionally these template reactions show almost equal amounts of both Q[6] and Q[7] being formed, 38% and 35% for 45, 43% and 46% respectively for 48.

Figure 37. Proposed cucurbit[n]uril formation around bis-(4,4'-bipyridyl)-'-p-xylene 7 template. Complex minimised with the HyperChem package , using the AM1 force field.

These results are important for the support of the templated reaction mechanism. The templates in the reaction medium must be capable of binding with the forming cucurbit[n]uril, otherwise 45 would not be bound to Q[6]. The only way for Q[6] to bind with this compound is for the Q[6] to form around the 'template', thus encapsulating it. This templated formation of Q[6] is shown in Figure 37. Note that the forming cucurbit[n]uril is a much more structured part of the oligomer; as the oligomer curves around through successive cis glycouril linkages the cucurbit[n]uril is closer to formation.

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The fact that both of these bipyridyl compounds act as templates, bringing both Q[6] and Q[7] to approximately the same final percentage composition, means that these tempates have a similar affinity for both Q[6] and Q[7]. To understand why this is so, it is helpful to consider the components of the templates, namely bipyridyl units and either a six membered alkyl chain or a p-xylene.

Each of these subunits should be able to pass individually through the portal of both Q[6] and Q[7], however when the subunits are joined to become the two templates, 48 is much more flexible than 45 due to the flexible hexamethylene chain in 48. The rigidity of 45 means that it is unable to thread through Q[6] and therefore it does not bind. The feature that is apparently restricting this molecule from threading is the angle through the methylene connecting the two relatively rigid aromatic systems. This rigidity also means that 45 doesn't disassociate from Q[6] once the templated reaction has taken place.

Figure 38. bis-(4,4'-bipyridyl)--p-xylene (45) and bis-(4,4'-bipyridyl)-1,6-hexamethylene (48). Note the fixed angle through the rigid benzene in the centre of 45. Molecules were minimised 7 with the HyperChem package , using the AM1 force field.

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Figure 38 shows the two bipyridyl compounds 45 and 48. Note the structural rigidity around the methylene in 45. The structural rigidity would not be an issue with the Q[6] binding were it not for the angle through the compound. This angle comes from the rigidity of the aromatic moities, with free rotation only possible on the two tetrahedral 'joining' methylenes. If this compound was planar, or more flexible like 48, it should be able to bind to Q[6] and the higher cucurbit[n]uril. The hexamethylene chain in 48 allows a degree of flexibility through the molecule, which allows the compound to bind with Q[6] effectively. Although 45 can not bind to Q[6] in solution due to the size and rigitiy of the guest, the complex is formed via clipping the Q[6] around 45. This complex will be discussed later.

Cucurbit[n]uril have very well defined and rigid structures due to their double ring structure and the rigid glycouril groups. This is different to many other good hosts, for example crown ethers, which have flexibility in their ring structure. This inflexibility means that for a guest to bind internally it should have a complementary structure to the cucurbit[n]uril 17 as shown in Figure 39.

For these templates to be effective they should bind internally to the proto-cucurbit[n]uril, due to solvation effects, shape and ion-dipole interactions. The internal cavity of cucurbit[n]uril is known to be hydrophobic in nature, although this cannot be assumed for all configurations of the forming cucurbit[n]uril. Examples of good cucurbit[n]uril guests may be found in Table 5. Many of these cucurbit[n]uril guests display hydrophobic alkyl or aryl moieties along with the hydrophilic charged end groups. A 'good' cucurbit[n]uril guest has these opposing functionalities as the charged moiety will tend to

138 associate with the carbonyl oxygens, whilst the hydrophobic chain will become bound in the internal hydrophobic cavity.

17 Figure 39. Cross section of Q[6] complexes, reproduced from Mock et al.

It is hypothesised that the internal binding of the template to the forming cucurbit[n]uril could increase the formation of the larger ring sizes. To understand the binding capabilities of the different sized cucurbit[n]uril it is appropriate to review what is known about the binding of guests to Q[6].

Mock et al. have studied a number of guests in Q[6] and have found some 15 common requirements for the formation of relatively stable complexes. Firstly, the guest can be either an alkyl or aryl amine of around 6 carbons in length. The guest should be terminated in acidified amino groups such that when encapsulated the amine is situated at the carbonyl portal. The chain may have methyl side groups and still bind, although larger side groups can prevent complex formation, especially for cyclic guests. While these general rules hold true for Q[6], the size-dependent binding experiments show that the larger cucurbit[n]uril can bind much larger

139 guests. Using this knowledge it is likely that the forming cucurbit[n]uril will also be able to bind to these larger templates. It is this binding effect that will determine the template effect.

Further Work The next step in this work should be testing of further common cucurbit[n]uril guests for their templating ability. However, based on this work it is likely that a good template is a molecule which only shows moderate binding to a particular cucurbit[n]uril host or target This template investigation could be undertaken with each newly discovered (especially larger) cucurbit[n]uril guest.

Several of the materials investigated here showed significant templating ability. The ability of these materials to template the forming cucurbit[n]uril should be further investigated by examining the impact of their concentration on product distribution. If binding of the proto- cucurbituril truly impacts the homologue formed by increasing the amount of a particular template it should be possible to push the reaction further in favour of the desired cucurbit[n]uril.

Further investigations into the host-guest properties of the model 143 oligomers produced by Isaacs et al. should also be undertaken. By investigating these ideal proto-cucurbituril we may better understand the binding modes and impact of potential templates. These dimers (Figure 33) are models of the forming oligomer which leads to the formation of cucurbit[n]uril. These dimers should also be good models for template binding, although the chain length may also have to be increased to 3 or 4 endo links so as to be better oligomer models. It may also be interesting

140 to compare the endo chain binding with exo chains. This may help us understand more of the stabilisation that templates can impart to the forming cucurbit[n]uril.

It is also important that we develop methods for the purification of the cucurbit[n]uril after the templated reactions have been performed. Ideally, a method which both purified the cucurbit[n]uril and recovered the template could be developed. This could rely on a mixture of recrystallisation, liquid chromatography and separation by solubility in ionic solutions. Potentially oxidative treatments such as ozonolysis could be used to degrade the template and free the desired cucurbit[n]uril.

141

New Nano-Structures from Templated Reactions Cucurbit[n]uril host-guest complexes with organic guests will often be in the form of rotaxanes (or pseudorotaxanes) and so the complexes form through the common mechanisms of rotaxane formation. These are 'slipping', 'threading' and 'clipping' as shown in the introduction (Figure 6). The first two methods are similar. In slipping the bulky guest is complexed internally to the host, and once complexed has a very high dissociation constant. This is not a very common mechanism for cucurbit[n]uril rotaxane formation. More common is threading, where a guest compound is 'threaded' through the host whereupon the guest is 'capped' in some manner to prevent disassociation of the resulting complex. This is the only way to date that cucurbit[n]uril rotaxanes have 48,52,54,55,145,146 been formed.

The bulk of the literature on the host-guest chemistry of cucurbit[n]uril deals with pseudorotaxane type complexes formed via the threading mechanism. Guests are drawn through the centre of the cucurbit[n]uril such that the charged end groups (often protonated amines) bind through ion-dipole interactions to the carbonyl portal of the cucurbit[n]uril.

Inverse Rotaxane By contrast, for the templated formation of cucurbit[n]uril to be a success a complex between host and guest will be formed by clipping. This is where the host actually forms around the guest. In other fields of research this has been accomplished with a ring closing reaction from two preformed parts, but this study involves the assembly of the entire ring structure around the template guest.

142

A good example of this is the Q[6] complex containing the compound bis-,'-bipyridyl)-p-xylene (45). This is a bulky compound and will not fit through the portal that Q[6] offers. A similar compound to 45 is bis-,'-bipyridyl)-hexane (48) which has a hexyl chain instead of a p- xylene in between the two bipyridyls. As mentioned previously this more flexible compound will complex with Q[6], and so it was postulated that the rigidity of the xylene bridged compound was the limiting factor in complexation with Q[6]. After a complex was successfully made between Q[7] and 45 in solution, a templating reaction was attempted using this compound.

Figure 40: bis-(4,4'-bipyridyl)-1,6-hexamethylene (48) complexed with Q[6]. Complex was 7 minimised with the HyperChem package , using the AM1 force field.

Unexpectedly this reaction produced a ratio of around 1:1 Q[6]:Q[7]. Upon closer investigation both species were bound to the bipyridyl

143 compound. Q[7] is bound to the 45, as expected from the size dependent binding studies undertaken earlier. Cucurbit[6]uril is also bound, which provides both proof that cucurbit[n]uril will form around favourably shaped molecules and an example of rotaxane formation via clipping in cucurbit[n]uril synthesis. This was found through evaporating the 1 reaction mixture and then dissolving the resultant solid in D2O. The H- NMR clearly shows two cucurbit[n]uril species, which were determined to be Q[6] and Q[7] through the addition of each of the cucurbit[n]uril to this NMR sample. Isolation proved difficult for the complex of Q[6] and 45, as Q[6] precipitates upon heating of the sample.

This is the first example of a clipping-based rotaxane with cucurbit[n]uril, and the only example that was found of a rotaxane of any type that is prevented from dissociation by the rigidity of the backbone of the axle, rather than a bulky end group. In other words the guest is not prevented from dissociating from Q[6] because of end functionality, but by the functionality that is enclosed by the Q[6]. This is shown in Figure 41, which compares the complexes of 45 with both Q[6] and Q[7]. There is just enough freedom in the complex with Q[7] to allow 45 to bind and dissociate, however the complex with Q[6] does not have this ability. Once the complex is formed between 45 and Q[6] by clipping it does not dissociate at room temperature.

144

Figure 41: bis-(4,4'-bipyridyl)-,'-p-xylene (45) complexed with a) Q[6] (left) and b) Q[7] 7 (right). Complexes were minimised with the HyperChem package , using the AM1 force field.

This complex has been denoted an 'inverse rotaxane', as the complex binding restriction is inside the host rather than external to the host. This is the inverse of a normal rotaxane where a bulky end group prevents dissociation.

Figure 41 clearly shows the restriction of the complex. In order for the guest to dissociate, one of the bipyridine units would have to move through the portal and centre of the cucurbit[n]uril. This is not possible due to the rigidity of both host and guest and so the complex persists. The complex with 45 and Q[7] that is formed in equal amounts in the templated reaction is a pseudorotaxane as the portal and cavity are slightly larger, allowing the disassociation of the complex.

145 Inverse Pseudorotaxane Another similar, 'inverse rotaxane', type complex is that formed between propylamine-o-carborane (43) and Q[7]. This strong complex is formed in aqueous solution with simple stirring of the guest and Q[7]. This complex might be pictured as an 'inverse pseudorotaxane'. The complex has the carborane 'ball' fully enclosed in the Q[7] cavity, with the alkyl chain feeding the amine to the carbonyl portal. This complex is stabilised by a combination of ion-dipole and hydrophobic interactions.

Figure 42. Propylamine-o-carborane (43, shown as space filling) complexed with Q[7] (shown as 7 tubes). Complex minimised with the HyperChem package , using the AM1 force field.

146 The ion dipole interaction comes from the complex of the protonated amine and the carbonyl portal. The hydrophobic driving force comes from the carborane cage, which is hydrophobic. Initial attempts to complex the o-carborane and Q[7] in aqueous acid were met with failure due to the lack of aqueous solubility of o-carboranes. This has been dealt with in two ways: in this study the water soluble propylamine-o- carborane (43) was used to get the carborane into solution, whilst a 144 previous study used trifluoroacetic acid to obtain both Q[7] and o- carborane in solution.

Figure 43. o-carborane (shown as space filling) complexed with Q[7] (shown as tubes)142. 7 Complex minimised with the HyperChem package , using the AM1 force field.

In both of these studies it is clear that the carborane moiety is encapsulated in the cucurbit[n]uril. The fact that it does so without any

147 ion-dipole interaction in the case of o-carborane in trifluoroacetic acid means that the hydrophobic effect alone is strong enough to drive the complex between the Q[7] and o-carborane. The o-carborane does have a significant dipole, however this is not utilised in the complex with Q[7] as the o-carborane does not bind to the carbonyl portal of the Q[7]. The hydrophobic effect comes from the relative 'solubility' of the carborane guest in both the trifluroacetic acid and the hydrophobic cavity of the cucurbit[n]uril, also water was often added. Indeed once formed the complex can be dissolved in aqueous acids and chromatographed with the complex staying intact

The reason that these carborane complexes may be considered as 'inverse rotaxanes' is that once again the binding is internal to the host, which is similar to the complex between 45 and Q[6] previously described. The difference here is that the guest is free to disassociate from the cucurbit[n]uril just like a normal pseudorotaxane. Hence 'inverse pseudorotaxane'.

A complex is also formed between Q[8] and 43. It was found in the templated reaction series that this complex is soluble in water, as is the complex between 43 and Q[7]. The reaction mixture from this templated reaction was evaporated and stirred with water in an attempt to remove any excess propylamine-o-carborane. Unexpectedly this dissolved almost equal amounts of the Q[7] and Q[8] complexed 43.

The complex with Q[8] cannot however be considered as an inverse pseudorotaxane. 1H-NMR shows that the complex of 43 with Q[8] is a deep inclusion complex, with no functionality of 43 extending out from

148 the carbonyl portal of Q[8]. This is another example of changing binding modes of the guests with the different sized cucurbit[n]uril.

149 Conclusion

The host-guest binding studies undertaken in this work clearly indicate the importance of 'fit' when looking for a good host guest system. As predicted the larger host systems of cucurbit[7]uril and cucurbit[8]uril did indeed bind larger guest molecules. However, if the host system became too large then a subsequent decrease in the strength of binding was observed. However, this is not always the case and in the case of p- xylene diamine it was found to bind strongly with cucurbit[8]uril forming a 2:1 complex with 2 guest molecules encapsulated in the one host. This 71 is similar to the observations made by Kim et al. and it may well be favourable stacking which encourages the formation of this supramolecular structure.

While not the main focus of this work, the size selectivity of the cucurbit[n]uril systems extends to the metal ion binding ability of the oxygen rich portals. This selective binding has been demonstrated by 113 others , but was exploited in this work to provide a rapid purification process to obtain each of the cucurbit[n]uril from the crude reaction mixture. By the use of sodium and barium salts the individual cucurbit[n]uril can be separated in around 5 steps. Previously, when fractional recrystallisation was used, as many as 20 steps were required to isolate all of the individual cucurbit[n]uril.

Attempts at templated formation of cucurbit[n]uril, using organic amines or other 'good' cucurbit[n]uril guests were successful. Several of the templates examined caused an increase in the amount of one or more cucurbit[n]uril produced, at the expense of the other cucurbit[n]uril. The templates had more positive influence on the larger cucurbit[n]uril, Q[7]

150 and Q[8]. These templated reactions gave the largest reported yields of both Q[7] (templated with bis-(4,4'-bipyridyl)-1,6-hexamethylene) and Q[8] (templated with p-bromoaniline), at 46% and 18% respectively. None of these templates was able to produce a single cucurbit[n]uril. Therefore there would still be a need to purify the cucurbit[n]uril thus obtained, both from other cucurbit[n]uril and from the template. From an academic perspective the successes in the templated reactions helps to confirm the mechanism of cucurbit[n]uril formation involving a template at the ring closure stage.

During both the template reaction and the size-dependent binding studies of cucurbit[n]uril, an 'inverse rotaxane' was discovered. Inverse rotaxanes are not held in place by large blocking groups, but rather the molecular structure encapsulated by the cucurbit[n]uril host prevents decomplexation of the axle. This 'inverse rotaxane' was found to be formed in the formation reaction of cucurbit[n]uril templated with bis- (4,4'-bipyridyl)-'-p-xylene. In this templated reaction a rotaxane is formed via the clipping of cucurbit[6]uril around the template.

151 Experimental Procedures

All chemicals used in the template and size-dependent binding experiments were of analytical grade or higher. They were all sourced from commercial suppliers with the exception of the compounds in the following few pages.

I would like to thank Dr. A. Day (School of Chemistry, University College, University of New South Wales, Australian Defence Force Academy, Canberra, Australia) for the gift of bis-(4,4'-bipyridyl)-'-p- xylene and Daniel Sheehy (from the same institution) for the gift of 1- (propylamine)-o-carborane, synthesised according to Quintana et al.'s procedure.147

152 Experimental Methods

Synthesis of cucurbit[n]uril

O O

HN NH N N HCl Formaldehyde HN NH N N

O O n

Experimental Description: Glycouril(27.9 g, 197 mmol) was dissolved in conc. HCl (129 mL). The solution was cooled to 0 °C and 40% formaldehyde (28 mL) was added. The solution was mixed and then allowed to gel. After 1 hour the mixture was heated at 100 °C for 3 hours. The mixture was allowed to cool to room temperature and then was evaporated to remove HCl. The mixture was stirred with water and again evaporated.

A fractional crystallisation was performed by dissolving the solid in a minimum of conc. HCl and then adding water until the solution started to precipitate. The mixture was left overnight and the precipitate collected. The filtrate was then evaporated and the recrystallisation steps repeated until all solid was collected. A total of 12 fractions were obtained.

153 The first cucurbit[n]uril collected was Q[8], which often precipitated from the reaction mixture. The next collected was Q[5], followed by Q[6] then Q[7].

The amount of cucurbit[n]uril collected was 30.8 g (95% Yield), which was distributed through Q[5] (17%), Q[6] 48%, Q[7] (28%) and Q[8] (7%).

1 Cucurbit[5]uril: H NMR 4.18 (d, 2 H, J = 15.5 Hz, CH2), 5.15 (d, 2 H, 13 J ) 15.5 Hz, CH2), 5.34 (s, 2 H, CH); C NMR 51.0 (CH2), 69.9 (CH), 157.0 (CO).

1 Cucurbit[6]uril: H NMR 4.10 (d, 2 H, J = 15.5 Hz, CH2), 5.17 (d, 2 H, 13 J ) 15.5 Hz, CH2), 5.30 (s, 2 H, CH); C NMR 52.0 (CH2), 71.0 (CH), 157.5 (CO).

1 Cucurbit[7]uril: H NMR 4.00 (d, 2 H, J = 15.5 Hz, CH2), 5.18 (d, 2 H, 13 J ) 15.5 Hz, CH2), 5.28 (s, 2 H, CH); C NMR 53.5 (CH2), 72.0 (CH), 157.5 (CO).

1 Cucurbit[8]uril: H NMR 3.97 (d, 2 H, J = 15.5 Hz, CH2), 5.21 (d, 2 H, J ) 15.5 Hz, CH2), 5.27 (s, 2 H, CH); 13C NMR 54.5 (CH2), 72.5 (CH), 158.0 (CO).

154

Synthesis of bis-ethyl-4-4'-bipyridyl (50)

+ N

Acetonitrile

N N

N +

Experimental Description: Bipyridyl (1.5 g, 9.5 mmol) was dissolved in acetonitrile (100 mL). An excess of bromoethane (1.5 mL) was added and the reaction mixture refluxed overnight. After cooling a yellow precipitate (3.2 g) was collected by vacuum filtration. Upon standing the yellow colour fades but returns when wet with acetonitrile.

This compound was found to be bis-ethyl-4-4'-bipyridyl, 90% yield.

1H NMR (ppm), 1.26 (m, 3H); 4.40 (m, 2H); 8.45 (m, 2H); 8.98 (m, 2H).

155 Synthesis of bis-(4-4'-bipyridyl)-1,6-hexamethylene (48)

Br Br

N +

+ N N

Experimental Description: An excess of bipyridyl(5 g, 31.6 mmol) was dissolved in acetonitrile (300 mL) and the reaction mixture was heated to reflux. 1,6-dibromohexane (1.63 mL, 10.6 mmol) was added over 30 minutes. After cooling a yellow precipitate (2.67 g) was collected by vacuum filtration. This compound was recrystallised from water.

This compound was found to be bis-(4-4'-bipyridyl)-1,6-hexamethylene, 45% yield.

1H NMR (ppm), 0.37 (bs, 2H); 1.04 (bs, 2H); 3.53 (m, 2H); 7.45 (m, 4H); 7.95 (m, 2H); 8.05 (m, 2H).

156 Cucurbit[n]uril synthesis utilising differing cation solubilities to aid separation

O O

HN NH N N HCl Formaldehyde HN NH N N

O O n

Experimental Description: Glycouril (67 g, 0.47 mol) was dissolved in Conc. HCl (300 mL) and stirred. This was cooled to 0 °C and 30% formaldehyde solution (67 mL) was added. This mixture was stirred until a gel formed and was allowed to stand for 3 hours. The mixture was then heated at 60 °C for 5 hours. An extra amount of 30% formaldehyde (50 mL) solution was added and the solution heated to 100 °C for 2 hours.

Upon cooling a small amount of Q[8] crystallised and was filtered. The remaining solution was evaporated and then the cucurbit[n]uril mix was suspended in an appropriate amount of 0.1M Na2SO4 solution. The solution was filtered.

The Na2SO4 solution was found to contain Q[6] and Q[7]. Upon addition small of amounts of a 0.1 M BaSO4 solution Q[6] was precipitated. This was then filtered to give solid Q[6]. The filtrate was evaporated to give

157 Q[7]. Both of these were taken up in the least amount of hot conc. HCl, which dissolves the cucurbit[n]uril but very little salt. These were filtered and then evaporated to obtain the cucurbit[n]uril in a more pure form.

The components of the original cucurbit[n]uril mixture that were not soluble in Na2SO4 solution were fractionally recrystallised from conc. HCl to obtain Q[8] and Q[5].

158 Size-dependent binding NMR experiments In order to determine the size dependant binding of cucurbit[n]uril with the various guests, NMR samples were made. Samples were made for each guest (~2.8 x 10-4 mmol to give ~3.7 x 10-4 molL-1) adding one drop of 35% DCl to 0.75 mL of an acidified 0.1M Na2SO4 solution in D2O. To this was added cucurbit[n]uril (~1.1 x 10-4 mmol) to give ~1.5 x 10-4 molL-1, leaving an excess of guest in solution. A sample was made in this fashion for each of the guests with individual cucurbit[n]uril (where n = 6, 7 and 8) as well as a mixed cucurbit[n]uril sample with the guest and an equal amount of each of the cucurbit[n]uril (Q[6] ≈ Q[7] ≈ Q[8] ≈ 0.5 x 10-4 mmol, to give a total Q[n] of ~1.5 x 10-4 molL-1).

These samples were left for at least 24 hours to form complexes before 1H-NMR spectra were taken using a Varian 400 MHz NMR at 25L C. The guest's spectrum taken in the presence of cucurbit[n]uril was compared to the spectrum taken without cucurbit[n]uril to determine any binding. The results of these experiments are listed in Table 5.

159 Templated synthesis of cucurbit[n]uril

O O

HN NH N N HCl Formaldehyde HN NH Template N N

O O n

Experimental Description: Cucurbit[n]uril was formed in the presence of another molecule. In all cases (except propylamine-o-carborane) the reaction was performed with 142.1 mg of glycoluril, 60 mg of paraformaldehyde, 5 mL of conc. HCl and 0.17 mmol of the 'template' compound.

In the reaction with propylamine-o-carborane the massess were; 0.394 g propylamine-o-carborane, 1.6 g of glycoluril, 1.5 mL of 35% formaldehyde solution and 5 mL of conc. HCl.

13C-NMR spectroscopy samples were made by taking approximately 0.25 mL of the reaction mixture and mixing it with an equal volume of deuterated concentrated HCl.

For each reaction 13C-NMR spectroscopy data were obtained listing both the percentage composition of the various cucurbit[n]uril and the percentage completion of the reaction. Table 9 lists this data; note that in some of the reactions there were no cucurbit[n]uril formed. These

160 reactions often had signs of the cucurbit[n]uril pre-cursor oligomer and some reactions showed other byproducts or dissociation of the reactants, all of which were taken into account in determining the percentage of reaction completion.

161 Table 9. Templated formation of cucurbit[n]uril

Mass (mg) Weight %

Template Glycouril Template Formaldehyde Q[5] Q[6] Q[7] Q[8] % Complete cystine 142 mg 41 mg 60 mg 6 51 30 13 99 ammonium hexafluorophosphate 142 mg 28 mg 60 mg 11 59 26 5 79 thioacetamide 142 mg 13 mg 60 mg 5 47 41 6 92 acetamide 142 mg 10 mg 60 mg 14 47 28 11 82 taurine 142 mg 21 mg 60 mg 14 44 29 13 90 N,N,N',N'-tetramethyldiaminoethane 142 mg 17 mg 60 mg 3 47 42 9 97 3-aminopropylbromide.HBr 142 mg 37 mg 60 mg #DIV/0! No Cucurbit[n]uril! hexamethylene diamine 142 mg 19 mg 60 mg #DIV/0! No Cucurbit[n]uril! N-(2-aminoethyl)-1,3-propanediamine 142 mg 20 mg 60 mg #DIV/0! No Cucurbit[n]uril! tetrabutylammonium fluoride 142 mg 0.17mL 60 mg #DIV/0! No Cucurbit[n]uril! tetrabutylammonium chloride 142 mg 47 mg 60 mg 12 53 30 5 88 tetrabutylammonium chloride 142 mg 47 mg 60 mg 12 53 30 5 88 tetrabutylammonium iodide 142 mg 63 mg 60 mg 14 56 26 4 82 tetrapropylammonium bromide 142 mg 45 mg 60 mg 8 53 32 7 84 tetraethylammonium chloride 142 mg 28 mg 60 mg 7 44 41 8 95 tetramethylammonium chloride 142 mg 19 mg 60 mg #DIV/0! No Cucurbit[n]uril! p-aminophenol 142 mg 19 mg 60 mg 11 32 43 15 83 4-dimethylaminobenzaldehyde 142 mg 25 mg 60 mg 6 54 34 6 100

162 Mass (mg) Weight %

Template Glycouril Template Formaldehyde Q[5] Q[6] Q[7] Q[8] % Complete 4-aminoactetophenone 142 mg 23 mg 60 mg #DIV/0! No Cucurbit[n]uril! p-acetamido-aniline 142 mg 26 mg 60 mg 10 51 28 11 99 p-bromoaniline 142 mg 29 mg 60 mg 9 29 45 18 78 2-amino-3-methyl benzoic acid 142 mg 26 mg 60 mg 11 53 27 11 96 3-amino-thiazol 142 mg 17 mg 60 mg #DIV/0! No Cucurbit[n]uril! 4-acetamidophenol 142 mg 26 mg 60 mg 3 59 34 4 100 aniline sulphate 142 mg 48 mg 60 mg #DIV/0! No Cucurbit[n]uril! p-toluidine 142 mg 18 mg 60 mg #DIV/0! No Cucurbit[n]uril! m-toluidine 142 mg 18 mg 60 mg 5 43 43 9 92 o-phenylene diamine 142 mg 31 mg 60 mg #DIV/0! No Cucurbit[n]uril! 4-methylbenzylamine 142 mg 21 mg 60 mg #DIV/0! No Cucurbit[n]uril! Benzylamine 142 mg 18 mg 60 mg #DIV/0! No Cucurbit[n]uril! p-xylenediamine 142 mg 23 mg 60 mg #DIV/0! No Cucurbit[n]uril! 2-aminobenzimazol 142 mg 23 mg 60 mg 10 42 45 3 97 N-(1-naphthyl)ethylenediamine 142 mg 44 mg 60 mg 11 47 32 10 92 indol-3-aldehyde 142 mg 25 mg 60 mg 5 62 30 4 99 pyridine 142 mg 13 mg 60 mg #DIV/0! No Cucurbit[n]uril! 4-phenylazoaniline 142 mg 33 mg 60 mg 12 47 41 0 54 2,2'-biquinoline 142 mg 44 mg 60 mg 6 48 37 8 82 2-adamantanamine.HCl 142 mg 32 mg 60 mg #DIV/0! No Cucurbit[n]uril!

163 Mass (mg) Weight %

Template Glycouril Template Formaldehyde Q[5] Q[6] Q[7] Q[8] % Complete 1-adamantanamine.HCl 142 mg 32 mg 60 mg #DIV/0! No Cucurbit[n]uril! 1-adamantane-methylamine 142 mg 28 mg 60 mg #DIV/0! No Cucurbit[n]uril! N-(1-adamantyl)-acetamide 142 mg 33 mg 60 mg #DIV/0! No Cucurbit[n]uril! quinuclidine.HCl 142 mg 25 mg 60 mg #DIV/0! No Cucurbit[n]uril! Blue tetrazolium 142 mg 124 mg 60 mg 10 54 32 4 96 1-(propylamine)-o-carborane 1.5 g 394 mg 1.5mL 9 42 33 16 95 4-4'-bipyridyl 142 mg 27 mg 60 mg #DIV/0! No Cucurbit[n]uril! bis-(4,4'-bipyridyl)-'-p-xylene 142 mg 111 mg 60 mg 18 38 35 9 100 bis-(4,4'-bipyridyl)-1,2-ethylene 142 mg 85 mg 60 mg #DIV/0! No Cucurbit[n]uril! bis-(4,4'-bipyridyl)-1,3-propylene 142 mg 87 mg 60 mg #DIV/0! No Cucurbit[n]uril! bis-(4,4'-bipyridyl)-1,6-hexamethylene 142 mg 95 mg 60 mg 5 43 45 6 74 bis-(4,4'-bipyridyl)-1,7-heptamethylene 142 mg 97 mg 60 mg #DIV/0! No Cucurbit[n]uril! bis-ethyl-4-4'-bipyridyl 142 mg 64 mg 60 mg #DIV/0! No Cucurbit[n]uril!

164 Molecular modelling of template reactions Each of the templates was modelled using HyperChem software. The modelling was performed as follows: the enthalpy of formation of the complex between the template and cucurbit[n]uril was compared to the enthalpies of formation of the uncomplexed species. The template was replaced with 3 water molecules in each instance (i.e. if the template was bound, the water was not and vice versa).

These systems were all modelled to AM1 level and the results are tabulated below where Hf refers to the difference in energy of the bound – unbound template. It was found that this level of modelling the guest binding was not adequate. Some of the guest binding was predicted, but some of the guest binding was not predicted by the modelling. Also the modelling predicted guest binding that did not occur in the experiments. Perhaps this could be improved by incorportating the correct solvent system into the model, but doing this would dramatically increase the computation time.

Although many of the calculated Hf values listed in Table 10 seem acceptable, several of the calculations seem to be orders of magnitude too large. As all of the calculations were performed with the same method, these large values put all of the values into doubt. The lack of faith in these calculations meant the they were not discussed, but they are presented here for completeness.

Although the modelling was not good at predicting the binding through computational methods, it was useful as a visualisation tool for possible 7 guests. The HyperChem package was used in a similar way that some

165 chemists use CPK models to 'see' if a particular guest would be suitable for cucurbit[n]uril.

Table 10. Template effect modelling

bound - unbound Template Q6 Q7 Q8 Cystine 217.8 18.6 -396.1 ammonium hexafluorophosphate -233.6 -10.9 -5.7 Thioacetamide -45.8 -54.7 -49.8 Acetamide -54.5 -55.6 -56.5 3-aminopropylbromide.HBr -269.8 -54.2 -53.9 N-(2-aminoethyl)-1,3-propanediamine -331.0 -114.1 -109.8 p-aminophenol -43.0 -53.0 -52.7 4-aminoactetophenone 445.3 -52.4 -50.8 p-bromoaniline -592.8 -49.5 -51.2 4-acetamidophenol -37.7 -53.9 -54.2 aniline sulphate -42.1 -49.7 -51.7 4-methylbenzylamine -7234.0 146.2 -49.9 Benzylamine -40.5 -250.9 -49.1 2-aminobenzimazol 509.1 -57.5 -53.6 4-phenylazoaniline -37.0 -48.8 -45.5 2-adamantanamine.HCl 2.2 -763.4 -48.8 1-adamantanamine.HCl -454.7 -42.2 -48.1 1-adamantane-methylamine 3.8 -760.7 -48.0 N-(1-adamantyl)-acteamide 9.2 -51.9 -119.6 quinuclidine.HCl -6.0 -35.1 -42.4 1-(propylamine)-o-carborane 35.9 691.9 4.6 4-4'-bipyridyl 28.0 721.5 7.0 bis-(4,4'-bipyridyl)-,'-p-xylene -59.7 -84.5 -267.5 bis-(4,4'-bipyridyl)-1,2-ethylene -67.6 17.6 -2.6 x 106 bis-(4,4'-bipyridyl)-1,3-propylene -531.3 66.3 61.2 bis-(4,4'-bipyridyl)-1,6-hexamethylene -69.2 -80.7 -2.9 x 106 bis-(4,4'-bipyridyl)-1,7-heptamethylene 294.4 -78.8 -77.8 bis-ethyl-4-4'-bipyridyl -60.7 -90.5 11.6

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