SYNTHESIS OF POLYROTAXANES
CONTAINING CUCURBITURIL
By
Donus Tuncel
A thesis submitted for the degree of Doctor of Philosophy at Imperial College of Science, Technology and Medicine
January 2000 Statement of Copyright
The copyright of this thesis rests solely with the author. No quotation from it should be published without the written consent of the author and information derived from it should be acknowledged.
Declaration
The work described in this thesis was carried out in the Department of Chemistry at the University of Cambridge between October 1996 and January 97, and in the
Department of Chemistry at Imperial College of Science, Technology and
Medicine between January 1997 and September 1999, the entire body of work is my own unless to the contrary and has not been submitted previously for a degree at this or any other University. Dedicated to Mehmet and Isil.
Ill Acknowledgements
Firstly I must thank my superviser, Dr Joachim Steinke for his constant help, enthusiasm and encouragement throughout the course of this project and also for giving me the opportunity working on this fascinating project.
I am particularly grateful to Dr Welham (University of London ULIRS Service) for
MALDI-TOF spectroscopy and RAPRA for GPC analysis. Prof David Williams and
Dr Andrew White (Imperial College) for X-ray crystallography.
I would like to thank all of the technical staff of Chemistry Department of Imperial
College for their friendly assistance, in particular R.Sheppard for NMR, J.Barton for
MS.
Many thanks must also go to the Steinke Group-past and present members- especially
Peter Cormack (Melville Lab, University of Cambridge), Laurence (also many thanks for DSC), Yi Ying, Kwok Tung, Clare, Alberto, Anne-Laure, Cam, Mohammed,
Gabriel, Gregor,
Finally, I must thank the EPSRC for their financial support.
IV Thesis Abstract
Synthesis of Polyrotaxanes Containing Cucurbituril
The abiUty of cucurbituril to catalyse 1,3-dipolar cycloadditions between alkyne and azido-substituted moieties has been extended to the synthesis of structurally well-defined polymers. We describe the first example of a polyrotaxane which contains a predictable number of threaded macrocycles per repeat unit due to the synthetic strategy of catalytic self-threading which has been employed. In order to adopt the catalysis of cucurbituril to the synthesis of polymers a variety of aromatic and aliphatic dialkyne and diazido monomers were synthesised.
Polymerisation was achieved only with the aromatic monomers. The resulting polymers were characterised using standard techniques and their molecular weights were determined by NMR, GPC and mass spectrometry (FAB, ES,
MALDI-TOF). Investigations into the polymerisation mechanism have produced a hypothesis, which explains the observed reactivity pattern. In the course of the mechanistic investigation a set of novel [2], [3] and [4] rotaxanes and pseudorotaxanes were also synthesised. The elusive aliphatic cucurbituril- containing polyrotaxanes were synthesised through post-threading of reduced nylons, in particular nylon 6, with cucurbituril. A series of polyrotaxanes with varying degrees of threading were synthesised and the effect of the degree of threading on solution and solid phase behaviour studied. Finally, a number of preliminary experiments were conducted to extend the architectural diversity of cucurbituril-containing polymers to hyperbranched and dendritic as well as sidechain polyrotaxanes via the catalytically self-threading concept. These syntheses require further work to establish a detailed picture of the molecular structures obtained. Abbreviations
NMR Nuclear Magnetic Resonance
6 Chemical Shift
ppm parts per million
Mn Number average molecular weight
GPC Gel Permeation Chromatography
QQ Cucurbituril
DSC Differential Scanning Calorimetry
DP Degree of Polymerisation
DSS 3-(TrimethyI silyl)-l-propanesulfonic acid, sodium salt
IR Infra red
Mw Weight average molecular weight
PDI Polydispersity Index
Tg Glass transition temperature lAA 2-t-Indoleacrylic acid
MALDI-TOF Matrix Assisted Laser Desorption lonisation Time of
Flight
ACVA 4,4'-Azobis(4-cyanovaleric acid)
Note: The counter ion chloride was omitted in some of the figures when ammonium ions were used.
VI Table of Contents
I. Introduction 1
1.1. Polyrotaxanes 2
1.1.1. Introduction 2
1.1.2. Definitions 3
1.1.3. Synthesis of Rotaxanes/Polyrotaxanes 4
1.1.4. A Brief Overview of the Synthesis of Rotaxanes 5
1.1.5. Classes of Rotaxanes/Polyrotaxanes 10
1.1.6. Main Chain Rotaxanes 11
1.1.6.1. Examples of Mainchain Polyrotaxanes 11
1.1.7. Side Chain Rotaxanes 25
1.1.7.1. Examples of Sidechain Polyrotaxanes 26
1.1.8. Branched/Dendritic Polyrotaxanes 30
1.1.9. Examples of Physical Properties of Polyrotaxanes 32
1.2. Cucurbituril 35
1.3. References 49
II. Results and Discussion 55
ILL Synthesis of Monomers 56
II.l.l .Introduction 56
11.1.2.Synthesis of Cucurbituril 1 58
11.1.3.Monomers Used in the Synthesis of Linear Polypseudorotaxanes 61
Vll 11.1.3.1. Synthesis of N', N®-bis(2-azidoethyl)-l,6-hexanediamine dihydrochloride 9 62
11.1.3.2. Synthesis of N', N^-bis(2-azidoethyl)-l,6-hexanedianiine dihydrochloride 12 63
II. 1.4. Monomers Used in the Synthesis of Linear Polyrotaxanes 65
II.1.4.1. Attempted Synthesis ofN-({10-[2-propynylamino)methyl]-9- anthryl}methylene)-2-propyn-l-amine 31 65
II. 1.4.2. Attempted Reduction of
5-^ert-butyl-JV'^^-di(2-propyny])isophthalamide 32b 67
II. 1.4.3. N- {2,4,6-trimethyl-3-[(2-propynylamino)methyl}benzyl}-2-propyn-1 - amine dihydrochloride 18 68
II. 1.4.4. Synthesis of N-(2-azidoethyl)-N-(3-{{(2-azidoethyl)amino]methyl}-
2,4,6-trimethylbenzyl)amine dihydrochloride 22 70
II. 1.5. Monomer Used in the Synthesis of Sidechain Polyrotaxanes 72
II.1.5.1. Synthesis of N-(3-butynyl)-N-(4-vinylbenzyl)amine hydrochloride salt 29 72
II.1.6. Monomers Used in the Synthesis of Hyperbranched Polyrotaxanes 73
II. 1.6.1. Syntesis ofNN-{2,4,6-trimethyl-3,5-bis[(2- propynyIamino)methyl]benzyl}-2-propyn-l-amine trihydrochloride 24 73
11.2.Synthesis of [n]Rotaxanes and Pseudo[n]rotaxanes 75
II.2.1. Introduction 75
II.2.2.Synthesis of [nJRotaxanes 77
II.2.2.1.Synthesis of [2]Rotaxane 33 77
Vlll 11.2.2.2. Synthesis of [3]Rotaxane 34 80
11.2.2.3. Synthesis of [3]Rotaxane 35 82 n.2.2.4. Synthesis of [4]Rotaxane 36 84
11.2.3. Synthesis of Pseudo[n]Rotaxanes 86
11.2.3.1. Synthesis of Senii[2]Rotaxane 37 86
11.2.3.2. Synthesis of Pseudo[2]Rotaxane 40 89
11.2.3.3. Synthesis of Pseudo[3]Rotaxane 42 91
11.2.3.4. Synthesis of Pseudo[4]Rotaxane 44 92
11.2.4. Dethreading of Pseudo[n]Rotaxanes 95
11.2.4.1. Synthesis of A^-{2-[l-(aminomethyl)-l/f-l,2,3-triazol-4-yl]ethyl}-A/^-(tert- butyl)amine 38 95
11.2.4.2. Synthesis of [l-(2-aminoethyl)-l//-l,2,3-triazol-4-yl]methylamine 41...97
11.2.4.3. Synthesis ofN-{[l-(2-aminoethyl)-l/f-l,2,3-triazol-4-yl]methyl}-N-{3-
[({[l-(2-aminoethyl)-l//-l,2,3-triazol-4-yl}methyl}amino)methyl]-2,4,6- trimethylbenzyl} amine 43 97
11.2.4.4. Synthesis ofN-{[l-(2-aminoethyl)-177-l,2,3-triazol-4-yl]methyl}-N-{3,5- bis[({[l-(2-aminoethyl)-l/f-l,2,3-triazol-4-yl}methyl}amino)methyl]-2,4,6- trimethylbenzyl} amine 45 99
II.3. Synthesis of Linear, Catalytically Self-Threading Polypseudorotaxanes and
Polyrotaxanes 101
11.3.1. Introduction 101
11.3.2. Attempted Synthesis of Linear, Catalytically Self-Threading
Polypseudorotaxanes 52 101
IX 11.3.2.1. Summary 109
II.3.3. Syntesis of Linear, Catalytically Self-Threading Polyrotaxanes 110
IL3.3.2. Determination of Mn by 'H-NMR 114
IL3.3.3. Other Characterisation Techniques 116 n.3.3.3.1. Matrix Assisted Laser Desorption lonisation Time of Fhght
Mass Spectrometry (MALDI-TOF) 116 n.3.3.3.2. Gel Permation Chromatography (GPC) 118
11.3.3.4. Conclusion 124
11.4. Synthesis of Catalytically Self-Threading Hyperbranced and Dendritic
Polyrotaxanes 127
IL4.1. Attempted Synthesis of Catalytically Self-Threading
Dendritic Polyrotaxanes 127
IL4.2. Conclusions 133
11.4.3.Synthesis of Catalytically Self-Threading
Hyperbranched Polyrotaxanes 133
11.5. Attempted Synthesis of Side Chain Polyrotaxanes 139
11.5.1. Attempted Polymerisation of n-(tert-butyl)-N-[2-(4-{[(4-vinyl benzyl)amino]methyl}-lH-l,2,3-triazole-l-yl)ethyl]amine hydrochloride salt-semi[2]rotaxane 139
11.5.1.2. Attempted Polymerisation of Semi[2]rotaxane 64 141
IL5.2. Synthesis of Polyrotaxanes via a Polymer-analogous Reaction 144
II.5.3. Conclusions 150
11.6. Synthesis of Linear Polypseudorotaxanes by Post-ThreadingMethod 151 11.6.1. Synthesis of Poly(iminohexamethylene) 76 151
11.6.2. Synthesis ofPolypseudorotaxanes 77 152
11.6.2.1. Evaluation of ^H-NMR Data, Calculation of the Degree of Threading and the Determination of Molecular weights (Mn) 155
11.6.2.2. Work-up of 77 155
11.6.2.3. Differential Scanning Calorimetry (DSC) 156
11.6.3. Conclusions 156
11.6.4. References
III. Experimental 161
References 219
XI I. INTRODUCTION I.l. Polyrotaxanes
1.1.1. Introduction
The total volume of synthetic polymers consumed is overtaking that of traditional materials such as iron and steel. There are reasonable economic reasons for the increasing use of synthetic polymers. They weigh less and are generally more corrosion resistant than metals. Like metals they are blended
(alloyed) to improve their properties. With increasing cost of energy, it is of particular importance that they can be manufactured and processed with lower energy input than either metals or glass.^
Consequently, the increasing demand for synthetic polymers has directed research to produce more versatile polymeric structures covering a wider range of properties with new polymeric architectures.^
Seeking architectural novel polymers^ led polymer chemist to synthesise numerous hyperbranched"^ and dendritic polymers.^ Finally even polycatananes and polyrotaxanes^"^ are starting to get attention from the polymer chemist as potentially interesting new materials.
In recent years, rotaxanes have attracted renewed interest in the field of supramolecular science because of their unique structures and properties and the potential utility as molecular materials for electron switching photo switching and for molecular sheathing. Mock et al.^^ reported a molecular switch based on cucurbituril, which will be discussed in section 1.2. 1.1.2. Definitions
Rotaxanes^'^ from the Latin words rota meaning wheel, and axis meaning axle, are comprised of a dumbbell-shaped component in the form of a rod and two bulky stopper groups, around which there are encircling macrocyclic component(s). The stoppers of the dumbbell prevent the unthreading of the macrocycle(s) from the rod. When these stoppers groups are absent from the ends of the rod, or if the bulky groups of it are insufficient size, Stoddart et a/.i4,i5 referred to the corresponding complex aspseudorotaxane 1.
• Pseudorotaxane Polypseudorotaxane 1 3
jzxO Macrocyde
linear segment —'"("O" Polyrotaxane 0 Rotaxane blocking group
Figure I.l.l: Schematic presentations of a pseudorotaxane 1, a rotaxane 2, a polyseudorotaxane 3 and polyrotaxane 4.
Polyrotaxanes^'^'^^ are molecular composites comprised of rings threaded by linear polymer backbones with no covalent bonds between the two components as shown in the generic structure 4 in Figure 1.1. 1.1.3. Synthesis of Rotaxanes/Polyrotaxanes
Polyrotaxanes can be prepared by statistical or directed (templated) synthesis.^
In the statistical approach, the interaction between the cyclic and linear species is weakly attractive, negligible or perhaps repulsive. The equilibrium for threading is thus primarily entropically controlled (AH ~0) and is subject to Le Chatelier's principle by use of an excess of macrocycle. The main advantage of the statistical approach is that the macrocycle and linear monomer need not complement each other in any interactive sense; thus the two components are independently variable and the methodology can be applied to common commodity types of polymer backbones. A disadvantage is that the equilibrium constant is usually small (0.05 to 5 1/mol); thus significant quantities of macrocycle are required to achieve a high proportion of macrocycle
C +
L incorporation.
^_g.(AG/RT)_^^y [L][C]
In K= -AG/ RT= -(AH/RT) + AS/R
Figure 1.1.2: General methodology of polypseudorotaxane synthesis by polymerisation of an equilibrium mixture of cyclic and linear species and the threaded assembly.^ The alternative approach uses templated or directed threading, and it involves an attractive interaction between the linear species and the macrocycle, such as metal chelation, charge transfer interactions, hydrogen bonding or the like.
Hence, the equilibrium (Figure 1.2) is enthalpically driven (AH < 0). The primary advantage of this approach is the high degree of threading that can be achieved. A major disadvantage is that complementarity of linear and cyclic species required, limiting its use to specialised systems.
1.1.4. A Brief Overview of the Synthesis of Rotaxanes
In 1960, Wasserman'^ reported the first synthesis of a [2]catenane. His approach consisted of conducting an acyloin ring closure in the presence of a macrocycle. During the ring closure process, a small fraction of diester was threaded to cycloalkane to form a [2]rotaxane as shown in Figure 1.1.3.
c-o OH A B -0-C' le- vy 1 [2]Catenane [2]Rotaxane
Figure 1.1.3: Acyloin ring closure, in the presence of cycloalkane yields [2]rotaxane and [2]catenane.'®
Some years later Harrison and Harrison'^ have prepared a rotaxane via a statistical threading. A macrocyle was bound to a Merrifield resin. The resin- bound macrocyle was treated with decane-l,10-diol and triphenylmethyl chloride in a solvent mixture to give threaded compound. To improve the total
yield, the treatment was repeated 70 times. Hydrolysis afforded a mixture
containing 6% rotaxane, which was purified by chromatography. They
suggested the name "hooplane" for the threaded compound (Figure 1.1.4).
The synthesis of rotaxanes via statistical threading afforded quite low yields.
Seeking for new strategies to improve the yield of rotaxanes directed the
research groups adopting templating approach in which host-guest chemistry
would be introduced to to the synthetic methodologies of rotaxane synthesis.
a)HO- (CH2)io—OH b) wash resin
c) repeat a) and b) 70 times cy^ (CH2)26
(CHzhe d) Na2C03 MeOH
(CHzke
Figure 1.1.4: Synthesis of a [2]rotaxane on a solid support.
Towards this end particularly Sauvage et have succeeded in the
preparation of rotaxanes and catenanes using a metal template approach in high
yields. Metal ions serve as a template to coordinate both cyclic and linear
moiety, forming the pseudorotaxanes and then catenanes by cyclisation, specifically using phenanthroline-based bisphenols and macrocycles in the presence of Cu(I) ions.
CU(CH3CN)4
Figure 1.1.5: Synthesis of a [2]rotaxane and a [2]catenane via a templating
strategy.
Cyclodextrins^'^^'20 (a-CD, 5, P-CD, 6, y-CD,. 7), crown ethers^-'^'^i and cyclophanes22.23 have been the most common macrocycles used in the preparation of rotaxanes/polyrotaxanes, mainly if not exclusively due to their availability. Recently, cucurbituril (QQ) has started to attract attention as a macrocycle and we have also used QQ in this function, which therefore is going to be reviewed in a separate section (Section 1.2). OH H
5, n=6 6, n=7 7, n-8
Figure 1.1.6: Schematic representation of cyclodextrins.
HgC N /) (A N—CH,
©/ — \ / — \© H2C N n N-CHg
n = 5, 30-crown-10 (30C10), 8 n = 7, 36-crown-12 (36C12), 9 n = 9, 42-crown-14 (42C14), 10 Figure 1.1.7: The structure of crown n = 11,48-crown-16 (48C16), 11 n= 15, 60-crown-20 (60C20), 12 ethers 8-12 and a cyclophane 13.
Ogina et al?-^ has prepared rotaxanes in relatively high yields by using the inclusion complex forming properties of cyclodextrins which selectively thread onto linear molecules containing diaminoalkanes coordinated to cobalt (III).
Along the same line of investigation, Rao and Lawrence^^ synthesised a rotaxane in water in 71% yield made from a diammonium salt and a B-CD derivative which was end-capped by tetraphenyl borate anions, the latter acting as a blocking group (Figure LB). 0"°\ © -NH3 eB,-\\ n
Figure 1.1.8: Synthesis of a [2]Rotaxane in water and end-capped in situ by tetraphenyl borate anions
Another elegant approach to form inclusion complexes is using charge transfer
or pi-stacked interaction between components.
This approach was initiated and developed extensively by Stoddart et <3/. 15,26-28
Complexes of a variety of dibenzo-crownethers and analogous macrocycles with small molecules such as [diquat]+2 (N, N'-dimethyl-2,2'-bipyridinium)
and [paraquat]+2 (N, N'-dimethyl-4,4'-bipyridinium) were studied. It was
found that due to electrostatic and charge transfer interactions with the electron- rich aromatic ether units in the crown ethers. X-ray crystal structural analysis
confirmed that the acceptor molecules were threaded through the macrocycle.
The use of a new concept of threading called "slippage" has also been
introduced by Stoddart et al. as shown in Figure 1.1.9. ^9,30 MeCN/SSoC/ IMays
Figure 1.1.9: Synthesis of a rotaxane via the slippage approach.
1.1.5 Classes of Rotaxanes/Polyrotaxanes
Rotaxanes can be divided into two major types, homorotaxanes and heterotaxanes. Homorotaxanes are composed of cyclic and linear species that are chemically related e.g., a polyrotaxane constructed from poly(ethylene oxide) and a crown ether. Study of such systems will allow the effects of the architecture itself to be distinguished from effects of changes in the nature of the chemical structure. Heterorotaxanes on the other hand, involve cyclic and linear species having different chemical structures, e.g., a polyrotaxane derived from poly(ethylene) and a-cyclodextrin, affording alternatives to classical copolymer architectures.
In principle there are many subclasses of polyrotaxanes differing in the nature and location of the covalent and physical linkages. They can be classified as main-chain, side-chain, branched and dendritic polyrotaxanes. In each of these
10 types there are two subgroups; the macrocycle may be an independent species hnked to the macrocycle only through threading or the macrocycle may be covalently attached to the macromolecule and threaded by another linear species.6
1.1.6. Main Chain Rotaxanes
There are at least five potential approaches to synthesise type 13 and 14 mainchain polyrotaxanes: cyclisation in the presence of linear macromolecules, polymerisation of monomeric materials, chemical conversion, threading of preformed linear macromolecules through preformed macrocycles, and production of linear macromolecule in the presence of preformed macrocyles or
13 14
0 d self-threading.
Figure I.l.lO: Schematic representations of mainchain polyrotaxanes.
1.1.6.1. Examples of Main Chain Polyrotaxanes
Oligomeric rotaxanes were prepared by Agam et al?^ from crown ethers and oligoethylene glycols. However, their purpose was simply to study the
11 efficiency of the threading process and they prepared polyurethanes by addition of diisocyanate simply to immobilise the rotaxanes as gels so that unthreaded macrocycles could be extracted; the polyrotaxanes were not characterised in any way.
In 1976 Ogato et alP reported the formation of poly [(ami de)-rotaxa-(p-CD)] by reaction of P-CD complexes of a,co-diaminohydrocarbons with diacid chlorides (Figure 1.1.11). The polymers were of low molecular weight as judged fi-om the reported specific viscosities. While no direct measures of either molecular weight or composition were made, solubility differences were dramatic; the polyrotaxanes were soluble in dipolar aprotic solvents, while the parent polyamides were not. Moreover, the polyrotaxanes showed no melting points, in contrast to the parent polyamide which is semicrystalline. Almost two decades later, this work was repeated by Bushmann et but this time cucurbituril was used as macrocyle (see Section 1.2. for details).
NHz + CI—- -NH--R
Figure I.l.ll: Synyhesis of a polyamide in the presence of cyclodextrins.
In 1977 Harrison first demonstrated that macrocycles could thread preformed polymer chains. For linear and cyclic alkanes fi-om CI4 to C35 gas chromatography on nonpolar silicone columns produced the theoretically expected linear relationship between the logarithm of retention time and carbon number. However, from gas chromatographic results on Carbowax 20 M
12 (poly(ethylene oxide), MW = 20.000) columns for the series of cycloalkanes
CI4 to C35 and the corresponding hnear alkanes, Harrison deduced that threading of the cychc species with the polymeric stationary phase occurred for
C26 and larger rings on the basis of their deviation (up to 33%) from such a relationship. The linear and smaller cyclic homologs behaved as expected.
Thus, the rationalisation was that when a large macrocyle passed through the column, threading of the macrocycle onto polymeric stationary phase took place and the vapour pressure of the macrocyle decreased, causing a delay in elution.
Maciejewski^^'^^ reported the synthesis of a polyrotaxane in 50% yield by radiation-induced polymerisation of the crystalline adduct of vinylidene chloride and P-cyclodextrin, and similarly by thermal polymerisation of the components in dimethylfbrmamide in low yield (Figure 1.1.12). The inclusion compound polymer had limited solubility and consisted of 80% by mass cyclodextrin. Its molar mass was 20 000 (method not reported). The crystal structure was essentially the same as that of cyclodextrin. No other properties were reported.
AIBN, DMF •
Figure LI.12: A polyrotaxane synthesised via free radical polymerisation.
Lipatova et al?'^ carried out thermal polymerisation of styrene in the presence of swollen (insoluble) cyclic urethanes (derived from di- and tri-ethylene glycols) and ZnCl2 to produce crystalline polyrotaxanes whose X-ray diffraction patterns
13 match those of the cychc urethanes; this indicates that the cyclic urethanes are aggregated, probably because of their incompatibility with polystyrene. The
Lewis acid is believed to promote formation of inclusion complexes, which are penetrated by the polystyrene. The number of rings in corporated varied from
0.05 to 0.14 per styryl unit. No other properties were reported.
Harada and Kamachi^^-^*^ reported that P- and y-cyclodextrins but not a- cyclodextrin form crystalline complexes with oligomeric propylene glycols.
The minimum degree of polymerisation for threading to occur was 4. A maximum yield of 96% was obtained at Mn= 1000 (n=17) with P-CD and in the case of y-CD 80% yield. It was found that two glycol units are sufficient to complex to one P-CD unit each producing a rotaxane structure. Similarly polyethylene glycols form crystalline complexes with a-CD but not P-CD.
Harada et al. also reported the linking of adjacent CD units in a polyrotaxane using an excess of epichlorohydrin to create a molecular necklace. Extraction of the linear oligomers resulted in an architecture called molecular tube (Figure
1.1.13). In this particular case poly(ethyleneglycol) (PEG) of molecular mass
1450 was used, because it had been established that a-CD forms complexes most efficiently when PEG chain is of a molecular weight between 600-2000.
The complexes formed are nearly stoichiometric (two ethylene glycol units: one
CD), which means that a-CDs are almost close-packed from end to end of the along the polymer chain. Such polyrotaxanes are soluble in water, dimethyl formamide (DMF) and dimethylsulfoxide (DMSO).
14 I NaOH T (25%) OH OH 0 0 0 0
MW 20000
Figure 1.1.13: Molecular tube was synthesised starting firom oligorotaxane in the presence of CDs.
Harada et al. showed the self- assembly of double-stranded inclusion complexes of PEGs with y-CD, in which two polymer chains are threaded through each macrocycle/^
More recently, they found that CDs form complexes not only with hydrophilic oligomers but also with hydrophobic oligomers, such as oligoethylene (OE) and polyisobuthylene a-CD forms complexes with OE, although P- and y-
CD did not. In contrast (3- and y-CD do form complexes with PIB,but not a-CD.
These complexes were obtained by adding PIB to a saturated aqueous solution
15 of either (3- or y-CDs under sonication. The solution became turbid and a crystalline precipitate of the desired polyrotaxanes was isolated. Table 1.1.1. shows the complex formation of three different hydrophobic oligomers/polymers with cyclodextrins.
OE, which has the smallest cross-sectional area, selectively forms a complex with a-CD (diameter of the cavity: 4.5 A) in high yield, while squalane, which has a larger cross-sectional are, selectively forms complexes with P-CD
(diameter of the cavity: 7.0 A) and y-CD (diameter of the cavity: 8.5 A). It is of interest that PIB, which has 1,1-dimethyl groups on its main chain, does not form complexes with a-CD but does so with y-CD. These results indicate that the relative sizes of the cavities of cyclodextrins and the cross-sectional areas of the polymer chains are essential in complex formation in the absence of non- hydrophobic effects.
The selectivity found in complex formation of polymers with cyclodextrins is different in the way they complex with low molecular weight compounds. A polymer chain has many binding sites and thus each CD has the opportunity to interact with each of these sites along the polymer backbone.
16 Table 1.1.1: Complex formation of hydrophobic oHgomers/polymers with CDs.
Polymer/ Structure Mol wt Yield (%) ohgomer a P y
OE -CH2CH2- 563 63 0 0
Squalene — CH2CH2CH2CH2— 423 0 62 24 CH2
PIB CHo -800 0 8 90 1 — CHoCHoCHo— 1 CHg
Complexes of y-CD with PIB are sparingly soluble in water. Solubilities are too
low to determine the solubility of inclusion compounds quantitatively. This is in
contrast to the complexes of poly(methylvinyl ether) (PMVE) and y-CD, which
are poorly soluble in water at RT but become more soluble upon heating. This
is owing to the fact that PIB is more hydrophobic than PMVE. The complexes
are also soluble in DMSO and DMF. X-ray powder diffraction studies show
that all complexes are crystalline, in spite of the fact that neat PIB is a liquid.
Thermogravimetric measurements of the complexes show that they decompose
above 320 °C, i.e. at a temperature higher than y-CD the one found on its own,
which melts and decomposes below 310 °C, indicating that complexation with
PIB is stabilising y-CD.
Again, Harada et al. reported that poly(s-caprolactone) forms crystalline
inclusion complexes with a-CD.'*^ The complexes are stoichiometric 1:1
(CD:monomer unit) compounds. The yields of the complexes decreases with an
increase in the molecular weight of the polymer.
17 Wenz et al. described the synthesis of polyrotaxanes of a generic structure 14 by threading preformed polyammonium ion 17, 18 (Fig. 14) through a-CD and the di-O-methyl derivative of P-CD.'*'^ The threading of a-CD was followed by
'H-NMR spectroscopy, in which significant downfield shifts of CD protons are observed as the polytrotaxane forms. The larger P-CD derivative is threaded several orders of magnitude more rapidly than the smaller a-CD. Similarly the structure and the molecular weight of the polyamines dramatically affect both threading and dethreading rate (17 more than two orders of magnitude faster than 18). Reaction of the amino groups with nicotinyl chloride gave stable polyrotaxanes with up to 0.67 a-CD units per amino group in the case of 17; this corresponds to 37 a-CDs per macromolecule or one a-CD for every backbone atoms.
• NH(CH2)xNH(CH2)y— + ( (( II •H NI-h~"Fq | R-
17, x=y=l 1, z=43 P-CD, a-CD 19, R = R'=
(CH2)n
18, x=10, y=3, z=23 20, R = (CHz)^,
R =
(CH2)3
Figure 1.1.14: Threading of a-CD onto Poly(iminoundecamethylene) 17 and poly(iminotrimethylene-iminodecamethylene) 18.
18 Wenz et al. also prepared water soluble poly[(amide)-rotaxa-CD]s by solid state polycondensations.'^^ a,co-Aminocarboxylic acids form microcrystalline compounds with a-CD. In these inclusion compounds cyclodexrins build up channel structures, in which the a,co-aminocarboxylic acids can be polycondensed at 200-240 °C. As the resulting polyamides are completely covered by CD rings they are readily water soluble. The dissociation of the polymeric inclusion compounds can be prevented by the introduction of bulky stopper within the polymer chain.
Wenz et al. recently described the photochemical synthesis of polyrotaxanes from stilbene polymers and a mixture of (3- and y-cyclodextrin in an aqueous solution."*^ In addition to stilbene units, the polymer contains quaternary ammonium centers, as well as hexa- and decamethylene chains
\/ \/ -N—(CH2)io—g—(CHzfe- 2Br6 0.87 (E)-2
{E)-l + (3-CD (Z)-2 + p-CD
Figure 1.1.15: Polyrotaxane formation by irradiation of P-CD-threaded stilbene polymers, leading to a mixture of (E) and (Z) isomers.
Upon irradiation of the supramolecular complex between CDs is irradiated at
312 imi for 30 hrs., a polyrotaxane, from which unthreading of the CD rings is prevented by the formation of the bulky tetraphenylcyclobutane groups was isolated.
19 The researchers claim that this is the first demonstration of a supramolecular catalysis of a polymer analogous conversion; that is a conversion of the repeat units without affecting the length of any polymer chain.
Figure 1.1.16: Photochemical synthesis of polyrotaxane,
"supramolecularcatalysis".
20 Gibson et al. have reported the synthesis of a variety of polyrotaxanes based on crown ethers, 8-12 (Figure 1.1.7.), as the cyclic moieties; linear backbones employed include polyesters 21, polyamides, polyurethanes 22 (Figure 1.1.17) and polystyrenes among others.^-
O crown ether
o - W
a. R= (CH2)io SOCIO a. 36C12 b. R= (CH2CH0)2CH2CH2 30C10 b. 42C14 c. R= (CH2CH0)2CH2CH2 60C10 c. 48C16 d. R= (CHz) SOCIO d. 60C20 e. R= (CH2)4 60C10
Figure I.1.I7: Poly[(ester)-rotaxa-crownether)]s 21 and poly[(urethane)-rotaxa- crownether)]s 22.
One of their first examples of polyrotaxanes synthesis was the preparation of poly[(alkylenesebacate)-rotaxa-(crownether)]s from sebacoyl chloride and a,
©-alkanediols using the crown ethers as solvent and they also studied the properties of these polyrotaxanes.'*^''^^
It was found that the average number of crown ether molecules (m) per repeat unit (n) in the polypseudorotaxane was a function of a) the ring size (degree of threading, m/n, increase nonlinearly with ring size) b) the stoichiometry of macrocycle to diol (the macrocycle content increases with increasing molar feed ratio up to 2, then becomes constant) but is independent of (i) the
21 equilibration time of diol and crown ether prior to addition of the diacid
chloride, (ii) the temperature of equilibration and polycondensation.
Dethreading from isolated polypseudorotaxanes is not significant on
experimental purification time scales, as demonstrated by long term dethreading
experiments. They concluded that the lack of the temperature dependence was
due to dethreading during the polymerisation, once the ester bond has formed there is no strongly attractive force between the linear and the cyclic species
and the low molecular weights of the growing oligomeric esters would permit relatively facile dethreading. Loss of macrocycles during the polymerisation can lead to a reduced degree of threading. In order to prevent macrocycles from dethreading, blocking groups are needed. Since the end capping of polymer
chains by monofunctional blocking groups is not efficient in the cases of high molecular polymers, difunctional bulky monomers are desirable. Based on this idea, a bulky tefraphenylmethane base bisphenol was employed to make a copolymer (1:4) with 1,10-decandiol; indeed, the purified polyrotaxane contained more than twice as much crown ether as the polypseudorotaxene from the linear diol, confirming that dethreading does occur during the polymerisation process.
A family of poly(urethane) rotaxane was synthesised from triethylene glycol and bis(p-isocyanatophenyl)methane (MID) using 36-crown-12, 42-crown-16 and 60-crown-20.^^ Using a constant feed ratio of 1.5 moles of crown ether per mole of glycol was employed. The amount of macrocycle incorporated into the polyrotaxane was Unearly dependent upon the ring size.
One of the first polymeric shuttle was also reported by Gibson et al, in which it is possible to control the locus of the crown ether rings in poly(urethane
22 rotaxanes) through the choice of solvent; in CDCI3 hydrogen bonding localises the rings on the urethane moieties, whereas in DMSO the crown ethers are localised over the portions of the backbone.^'
Gibson et al. also prepared poly[(aramides-rotaxa-(crownether)]s from isophthalic acid and bis(p-aminophenyl)ether using 30-crown-10 and 60-crown-
20. These polymers contain 9.1 % and 35% crown ether by weight respectively.
All the above examples were polycondensation chemistry but it also possible to prepare polyrotaxanes via chain growth (free radical) polymerisation. A family of poly(styrene rotaxanes)^^ and the corresponding poly(acrylonitrile rotaxanes)^^ were prepared using various crown ethers. In some cases an azo initiator containing triaryl-alkyl moieties was utilised in order to introduce blocking groups via the termination steps (recombination) in free radical chemistry.^"^ The threading efficiency was significantly increased using the blocking groups because the dethreading during polymerisation was eliminated.
Anionic polymerisation techniques have also been utilised to produce poly[(styrene)-rotaxa-(30-crown-10)].
A different approach was introduced for the synthesis of mainchain polyrotaxanes. In this approach, first the 23 (Figure 1.1.18) was prepared from bis(5-carbomethoxy-l,3-phenylene)32-crown-10 which had a Mn= 55700 (Da), a Mw= 133000 (Da) by GPC using polystyrene standards. This polymacrocycle
23 was used as a precursor to main chain polyrotaxane of type 15 and 16
(Figure 1.1.10). The vicosity of solutions of poly(estermacrocycle) 23'*^ with polystrene (PS) and poly(methyl methacrylate) (PMMA) increased as a ftinction of time, depending on the linear component (PS and PMMA) and its molecular weight also depending on relative and overall concentrations. This viscosity
23 increase is attributed to formation of polyrotaxanes. DSC traces of this material showed single glass transitions, whereas a brief solution blending of these components produced materials with two TgS because of their immiscibility.
They concluded that these polyrotaxanes are analogs to graft copolymers.
/OCHgCHzkO, \x .
^(OCHzCHz)^ PS or PMMA
Figure 1.1.19: Threading of preformed polyestermacrocycle 23 onto PS or
PMMA.
A fiirther example of this approach is the synthesis of polypseudorotaxanes which self-assemble through directed interaction. The threading of linear components of N,N'-bis(hydroxyethyl)-4,4'-bipyridinium hexafluorophosphate
26 through the cavities of in-chain cyclic units of a preformed poly(ester crown ether) 25^1 >55 occurred to yield a novel supramolecular polypseudorotaxane.
The principle mode of complex formation (threading) has already been established and demonstrated by Stoddart et al. when bis-phenylene-based crown ethers with bipyridinium salts.^^
24 (0CH2CH2)40
--C0(CH2)8C00CH
(0CH2CH2)40 25
Acetone
(0CH2CH2)4
--C0(CH2)8C00CH2
CH2)40
Figure 1.1.20: The threading of hnear component 26 through the cavities of in- chain cycHc units of of a preformed poly (ester crown ether) 25.
As would have been expected the m/n value of polypseudorotaxane 27 increased with increasing concentration of 26 as well as decreasing temperature.
Solubility of polypseudorotaxane 27 was found to be different to both starting materials. Polyrotaxanes with higher m/n have higher viscosities because of increased hydrodynamic volume and are more rigid as manifested by increased glass transition temperatures (Tg). Dethreading took place above Tg in the solid state, causing loss of colour (orange), a process potentially useful for temperature sensors.The design and preparation of the heteroditopic molecule to create linear oligo-and polymolecular arrays self-organised was reported in solution again by self-assemble of the host and guest^'^-ss. 'H-NMR, viscosity
25 experiments and mass spectroscopic studies supported the existence of the self- organised linear arrays.
All the examples were given so far for the synthesis of main chain polyrotaxanes containing cyclodextrins or crown ethers. Cyclophanes were employed as a macrocyle especially by Stoddart et al. but usually for the
synthesis of rotaxane. Hodge et alP extended their work in the polypseudorotaxane synthesis by threading cyclophane cyclobis(paraquat-p- phenylene) onto preformed polymer which have hydroquinol ether units linked by several ethylene oxide units in acetonitrile. Characteristic colour changed upon rotaxane formation was observed. 'H-NMR analysis of the reaction
solutions at -40 °C showed that the degree of threading in some cases even reached up to 0.94.
1.1.7. Side Chain Rotaxanes
There are at least six potential approaches to side chain polyrotaxanes such as
threading of preformed graft copolymer, grafting in presence of cyclic, grafting
of preformed rotaxane, polymerisation of macromonomer in presence of cyclic, polymerisation of macromonomeric rotaxane and chemical conversion. Figure
1.1.21 shows the schematic representations of subclasses of polyrotaxanes.
26 29
31
Figure 1.1.21: Schematic representations of subclasses of polyrotaxanes.^
1.1.7.1. Examples of Side Chain Polyrotaxanes
Ritter et al. described the synthesis of numerous side-chain polyrotaxanes and poly(tandem-rotaxane) via condensation of nucleophilic semirotaxanes on activated polymer side group.^9,6o One of the first examples for the poly(side chain-rotaxane) is that the mainchain is poly(methyl methacrylate) and the sidechain is comprised of 11-carboxamidodecamethyleneamide groups formed by aminolysis. They reported changes in behaviour of the rotaxane relative to the parent graft copolymer. Proton NMR signals exhibited chemical shift changes and broadening attributable to the rotaxane structure. Solubility was dramatically increased in a good solvent for the macrocycle. The viscosity of the polyrotaxane was lower than that of the parent polymer, presumably because of reduced intermolecular amide-amide hydrogen bonding.
27 NH (CH2)io NH,
Figure 1.1.22: A p-CD based sidechain polyrotaxane by Bom and Ritter.^^
Then, they described the synthesis of a new side-chain polyrotaxane containing
(3-dimethylcyclodextrin rings. The rotaxane side groups are attached via amide functions at an aromatic polysulfone. Some characteristic of the polyrotaxane are compared with those of a corresponding guest model compound. For example it was found that the non-covalently anchored cyclodextrin rings significantly influence the Tg of the side chain polypseudorotaxane, solubility in chloroform and acetone, the 'H-NMR spectrum and the elution time found in the GPC trace.
The polyrotaxane shows a significantly increased Tg value of 135 °C compared with about 110 °C of the model compound. Obviously, the CDs lower the mobility of the polysulfone chain in the condensed state. Viscosity measurements of polyrotaxane and the model compound have been preformed in chloroform. It was observed that the anchored CDs influence the solvent interaction and probably the inter- and intramolecular H- bond formation
28 between the amide groups. This effect strongly depends on the concentration of the polymer.
The model polymer is not soluble in acetone whereas the polyrotaxane was found to be soluble in this solvent. This also proves the influence of the non- covalently attached CD on the solubility of the polymer. GPC measurements, which have been performed in THF as solvent, indicate a higher coil volume of the polyrotaxane compared with the model polymer. As a result, CD influences the solubility, and coil dimension and lowers the mobility of the polymer in the condensed state.
Ritter et al. reported later that the synthesis of new tandem polyrotaxanes, in which each branched polymeric side chain, has a noncovalently bound cyclodextrin at either end of the side chain.^^
The synthesis and NMR spectroscopic characterisation of the topological arrangements of new side-chain polyrotaxanes bearing about 80% of peracetylated CDs in the side chains of a functionalised polyethersulfone is described. The characterisations have been conducted in relation to a similar model compound bearing no CDs. The result strongly indicates that the CDs are uniformly located on the side chains, with the bigger opening over the aromatic anilide components of the blocking group. The Tg of the polyrotaxane is significantly higher than the model polymer. Thus, the non-covalently attached ring molecules seem to lower the mobility of the whole system.
29 Very recently, the same group described the synthesis of a new water soluble
semi-rotaxane monomer consisting of threaded 2,6-dimethyl-P-CD on a 3-0-
(11-acryloylaminoundecanyl) cholic acid guest component. Since this new
monomer complex is completely soluble in water, the polymerisation could be
carried out in water using K2S2O8/KHSO3 as free radical redox initiator. Two
main fractions of the resulting polymeric product were isolated by extraction
with water. In the main fraction (49 wt.%), a non-water soluble polymer was
obtained, which contained about 40 mol % (calculated from ^H-NMR data) of
non-covalently anchored CD with regard to the amount of side chain.
Additionally, a smaller water-soluble fraction with a significantly lower degree
of polymerisation (DP=6) was isolated bearing nearly one CD on each side
chain unit.®^
Takata et al.^^ reported the synthesis of side chain polyrotaxane via free radical
polymerisation of semirotaxane which assembled from polymerisable
methylacrylate skeleton with a crown ether macrocycle stabilised by secondary
ammonium ion. Degree of threading can be controlled by the reaction
conditions such as solvent polarity and the feed ratio of the macrocyle and the
monomer.
CH,
o ro
O \ O. AIBN, 60 ^C, 20 ©NHg Q y ?••• •' X " o
Figure 1.1.23: The synthesis of side chain polyrotaxane via radical polymerisation.
30 1.1.8. Branched/Dendritic Polyrotaxanes
Significant advances in the area of polyrotaxane synthesis have been made very recently. These involve particularly in the close understanding of the fomiation mechanism, which helps the development of new materials such as branched/dendritic and network or croslinked polyrotaxanes.
Branched/Dendritic 36 Network/Crosslinked 37
Fig 1.1.24: Schematic presentation of branched, dendritic, network and crosslinked polyrotaxanes.
One of the first examples to physically branched and cross-linked polymeric rotaxanes was synthesised by Gibson et al. These materials were produced by rotaxane formation during the reaction of a pendant group of a preformed macromolecule.^'''^^. The rotaxane structure is believed to form from a hydrogen-bonded bimolecular complex of 5- (hydroxymethyl)-l ,3-phenylene-
r,3'-phenyIene-32-crown-10 38 by esterification of the hydroxy group of one macrocycle through the cavity of the second in its reaction with poly(methacryloyl chloride) (Figure LI.25). Increasing the concentration in the
31 reaction of 38 with poly(niethacryloyl chloride) led to the formation of a gel
fraction along with a high molecular weight sol fraction; the gel represents a novel network structure based on mechanical interlocking via rotaxane
structures. 2D NOESY NMR experiments clearly demonstrated the rotaxane
structure as manifest in the through-space correlation of the benzylic protons of the "thread" with the intra-annular protons of the "bead".
=Q n /(OCHgCHzl^O Pyridine -o. CI ^(OCHzCHzkc/ g 5 I §
Figure 1.1,25: Preparation of branched and network polyrotaxanes by esterification of poly(acid chloride) with macrocyclic alcohol.
Self association of macrocyclic diol 40 (Figure 1.1.26) prior to reaction with a
diisocyanate resulted in the rotaxane formation on the urethane linkages.2'. gy
variation of the proportion of macrocyclic diol in copolymers with
tetra(ethylene glycol) in diglyme solution the extent of branching can be
controlled. However, DMSO rotaxane formation is prevented. The authors
concluded that concentration and solvent are important variable for systematic
design of the final polymer's structure.
Another example of the synthesis of polyesters by self-threading of a
macrocylic diol 40 has been provided by Gibson and his coworkers. Bis(5-
hydroxymethyl-m-phenylene)32-crown-10 was reacted with sebacoyl chloride
in a bulk polymerisation process to produce an insoluble elastomer.
32 Self assembly of hydrogen bonded complexes of the macrocyclic diol allows endo esterification, which produces the rotaxane linkages.
(OCH^CHzkO^
3H R(C0CI)2 \(0CH2CH2),0/ or R(NC0)2 :ORCO~
40
Figure 1.1.26: Branched and crosslinked polyurethane and polyester rotaxanes as a result of association of crown ether diols.^i
Even dendritic polyrotaxanes have been reported.A self-organising dendritic pseudorotaxanes synthesis in which 1:3 pseudorotaxane complexes between a triply charged ammonium salt and substituted dibenzo [24]crown-8 units make up the core portions of the dendritic architectures. 'H-NMR confirmed the formation of the self-organising dendritic pseudorotaxanes as a result of a simple recognition between the secondary ammonium salt moieties and dibenzo[24]-crown-8 units at the focal points of the dendron units. Mass spectrometry was also used to characterise the resulting dendritic pseudorotaxanes.
33 1.1.9. Examples to Physical Properties of Polyrotaxanes
Gibson et al. have synthesised poly[(ester)-rotaxa-crownether]s''^'®'' 21 (Figure
1.1.17) and studied their properties. Their work is comprehensive and in itself complete therefore this can serve as an excellent example to highlight the property- structure relationship and to show the differences between conventional polymer and polyrotaxanes. a) Intrinsic viscosity as a function of solvent
The solution behaviour of polyrotaxanes depends on the differential solvation of the cyclic and linear species of polymers. The differential solvation effect could in the extreme case cause either the macrocycle or the linear backbone to be fully expanded or to collapse into a 6 state. A good solvent for both the
cyclic and linear species would lead to expansion of both components. A good
solvent for the linear macromolecule but a poor solvent for the cyclic species
should lead to an expanded backbone but collapsed macrocycle. A poor solvent
for the linear backbone but a good solvent for the macrocycle should provide a collapsed state of the linear component and expanded state for the rings. A poor
solvent for both components affords collapsed conformations of both. It should be noted that for polypseudorotaxanes these factors would be very important in determining the rates of threading and dethreading.
The intrinsic viscosity of the polyrotaxanes, which is higher than that of the backbone species due to increased hydrodynamic volume, has been shown to be a function of the solvent, increasing significantly in a good solvent for the crown ether component because of changes in conformational mobility. Thus,
34 rotaxanation has the potential to increase the intrinsic viscosity of linear macromolecules; this could be advantageous in some applications.
b) Thermal properties ofpoly[(ester)-rotaxa-crownether]s
A different phase transition behaviour compared to their parent polyesters was observed. Melting temperatures were changed and in some cases the macrocycles were able to crystallise without dethreading. In cases of high loading of crown ether two distinct crystalline phases were detected by DSC: one due to the polyester backbone and one due to crown ether; glass transition temperature was also observed for the crown ether component of the polyrotaxanes.
All of these polyrotaxanes are able to complex metal ions and extract them from aqueous solutions by interaction with the crown ether components.
The melt viscosity has been measured to be lower than that of the unthreaded polymers of equivalent molecular weight, the presence of the threaded macrocycles reduces the degree of chain entanglement.
In summary polyrotaxane architecture provide polymer scientists with the ability 1) to alter solubility properties, 2) to control the sohd state phase behaviour, including the introduction of crystalline phases derived from the cyclic species, 3) to increase and manipulate through differential solvation the intrinsic viscosity, 4) to reduce the melt viscosity, and 5) to bring about metal complexation of linear macromolecules (depending on the chemistry of the macrocycle).
35 1.2, Cucurbituril
In 1905 Behrend et reported a variety of products from the acidic
condensation of glycoluril with an excess of formaldehyde. The initial product
obtained in this way is amorphous and insoluble in all common solvents. In
seeking a more tractable material from this precipitate, the chemists resorted to
treatment with hot, concentrated sulphuric acid, which eventually dissolved the
substance. When such solution is diluted with cold water, filtered, and
subsequently boiled, a crystalline precipitate is obtained, which Behrend
characterised as CioH; 1N7O4.2H2O. A remarkable chemical aspect of the
structure is that all of its 19 rings are held together entirely by aminal linkages.
o A. HN NH HCI, H2O „ conc.HzSOA + Precursor ^ HN NH H H 110-120°C UN N-^_^ HI \ fl ^ O O Cucurbituril 1 Equation 1.2.1: Synthesis of cucurbituril.
Although no structure for this compound was proposed, the substance proved
exceedingly stable toward a number of potent reagents. Also, a series of
crystalline complexes incorporating a surprising variety of metal salts and dye
stuffs was prepared.^^'
Mock et al?^ repeated the preparation (Equation 1.2.1) and the spectral
characterisation of the product was carried out. It was immediately apparent
that the imidazolone ring of glycoluril remained intact (IR, 1720 cm"') and the
NMR spectrum, consisting of only three signals of equal-intensity, indicating a
36 highly symmetrical, non-aromatic structure; 6 5.75 ppm (singlet, from glycoluril nucleus), 4.43, 5.97 ppm (doublets, formal-derived).
That prompted an X-ray crystallographic investigation revealing the hexameric nonadecacyclic structure of the composition C36H36N24O12 now known as cucurbituril (Figure 1.2.1)."^° The designated trivial name derives from the general resemblance of models of the molecule to a gourd or a pumpkin of botanical family Cucurbitaceae.^o It has a relatively rigid structure, with an internal cavity of approximately 5.5 A diameter. This cavity is accessible by two carbonyl fringed portals with 4 A diameter and the distance between the portals is 6 A.
Q
Figure 1.2.1; X-ray crystal structure of inclusion complex of cucurbituril with 1,6-diaminohexane dihydrochloride salt.
While some development work on the synthesis has been carried out, the procedure of Behrend et al.^^ has not been substantially improved upon. So far a
37 detailed preparation of cucurbituril has not been published. It is believed that the material obtained in the first step (see Experimental Section ILL) is an irregular macromolecular condensation product. Most likely cucurbituril is the product of an acid-induced, thermodynamically controlled rearrangement of an initially formed product. In view of the subsequently elaborated cation-binding properties of cucurbituril through carbonyl fringed "occuh", Mock et suggested that a template synthesis is likely to be involved, with hydronium ions at this locus providing nuclei for assembly of the convex structure. That would explain why only the cyclic hexamer is produced; oligomers with greater or fewer glycoluril units have not been detected in the standard synthesis. Also, as we confirmed, molecular modelling suggests that this cyclic hexamer has
almost strain-free structure and is therefore thermodynamically more favourable. Pentameric and heptameric models are highly strained in comparison with hexameric model. However, Stoddart et alP^ have synthesised a cyclic pentamer under milder acidic conditions with formaldehyde and dimethylglycoluril. The dimethylated glycoluril forces to the reaction to yield a
smaller macrocycle for steric reasons. Information on the host-guest chemistry of this pentameric cucurbituril-derivative have not been described.
A unique aspect of cucurbituril as a molecular receptor is its structural rigidity.
Because of its polycychc nature, it cannot easily conform itself to the shape of incorporated small molecules. This leads to exceptional specificity in complexation and thereby provides an opportunity to probe systematically the factors involved in non-covalent binding.
The straightforward synthesis of cucurbituril, its rigid structure, and its capability of holding guest molecules inside its cavity renders cucurbituril an
38 unique molecular sructure. One severe drawback of cucurbituril, however, is its extremely poor solubility in all common solvents except strongly acidic aqueous solution. Its host-guest chemistry, therefore, has been studied only in strongly acidic solutions. Most work has involved aliphatic and aromatic ammonium ions, which show exceptional affinity towards cucurbituril primarily due to strong electrostatic interactions between the ammonium ions and the carbonyl oxygen atoms at the portal of cucurbituril.Although the carbonyl groups at the portal of cucurbituril should also provide interesting metal ion binding sites for a variety of metal ions, only a few detailed studies on this topic are known, although the metal ion binding phenomena of cucurbituril was already mentioned even in the original report by Behrend et al.^^
Recently Bushmann et alJ'^ studied complexation of alkaline metal ions such as
Na^, K"^, Rb^, Cs"^, Ca^"^ to cucurbituril by UV-vis spectroscopy. The complex formation constants were measured in the presence of alkaline metal salts in the range of 1x10"^ to 5x10^ M. Usually complexes of cucurbituril to alkaline metal ions (1:2) were observed. They suggested that, due to the stronger interactions of carbonyl oxygen atoms with cations compared with ether oxygen atoms, cucurbituril does form stronger complexes than classical crown ethers, such as
18-crown-6. The cations interact with the carbonyl oxygen atoms at the portals.
Thus in contrast to the cryptants, these ions are not encapsulated inside a cavity due to their hydrophilic nature but located on the outside.
Kim et alJ^ also studied complexation of alkaline metal ions to cucurbituril and observed that cucurbituril dissolves appreciably in aqueous solution of alkaline metal salts, in particular sodium sulphate solutions. They succeeded in obtaining a crystal structure of cucurbituril in the presence of sodium sulphate.
39 The X-ray crystal structure of this complex reveals that the molecule has a center of symmetry and two sodium ions are coordinated to each portal of cucurbituril. They made another very interesting observation. Two sodium ions and five water molecules are effectively covering each portal of cucurbituril like a 'lid' on a 'barrel'. However, this observation contradicts the observation of Bushmann et alJ^ who assumed that only one metal ion is bound to each portal of cucurbituril in all cases.
As discussed earlier the cavity inside cucurbituril can hold small organic molecules due to its hydrophobic nature. This has been established crystallographically, and is easily investigated in solution by NMR
spectroscopy. Although some simple purely aliphatic molecules do bind, most work has been done with alkylammonium ions, which show exceptional ligand receptor affinities as shown in Table 1.2.1.'^^
40 No. Ammonium ion ligand KKrel)" No. Ammonium ion ligand KKrel)' 1 NH3 0.25 diammonium ions: simple alkyl substituents: 25 NH2(CH2)3NH2 2.8 2 CH3NH2 &25 26 NH2(CH2)4NH2 480 3 CH3CH2NH2 0.3 27 NH2(CH2)5NH2 7600 4 CH3(CH2)2NH2 37.6 28 NH2(CH2)6NH2 8600 5 CH3(CH2)3NH2 307 29 NH2(CH2)7NH2 135 6 CH3(CH2)4NH2 74 30 NH2(CH2)8NH2 28 7 CH3(CH2)5NH2 7.0 31 NH2(CH2)9NH2 1.5 8 CH3(CH2)6NH2 0.3 32 NH2(CH2)IONH2 0.3 9 (CH3)2CHCH2NH2 67 arene-containing substituents 10 (CH3)2CH2(CH2)2NH2 109 33 C6H5CH2NH2 0.8 11 (CH3)2CH2(CH2)3NH2 13 34 P-CH3C6H4CH2NH2 1.0 12 6.0 35 (2-C4H3S)CH2NH2 710 CH3CH2CH(CH3)CH2NH2 13 3.5 36 (2-C4H30)CH2NH2 350 CH3CH2CH(CH3)(CH2)2NH2 cyc/o-alkyl substituents: miscellaneous: 14 C3;C/O-(CH2)2CHCH2NH2 45 37 (CH3)C(CH2)2NH2 <0.1 15 cyclo- 1130 38 CH3(CH2)3NHCH3 340 (CH2)3CHCH2NH2 1040 39 CH3(CH2)3N(CH3)2 2.3 16 cyclo- 1.2 40 H0(CH2)6NH2 3.6 (CH2)4CHCH2NH2 17 cyc/o-(CH2)2CHNH2 18 C>;C/o-(CH2)3CHNH2 9.2 41 HCCCH2NH2 4.8 19 cyc/o-(CH2)4CHNH2 19.5 42 N3CH2CH2NH2 1.2 thioether-containing 43 4200 substituents NH2(CH2)4NH(CH2)3NH2 20 CH3S(CH2)2NH2 52 44 21 CH3CH2S(CH2)2NH2 105 NH2(CH2)3NH(CH2)4NH(C 40 000 22 CH3S(CH2)3NH2 27 H2)3NH2 23 CH3CH2S(CH2)3NH2 2.3 24 cyclo- 1810 (CH2S)2CHCH2NH2
Table 1.2.1: Affinity data for ligand-receptor complexes of cucurbituril ( = Formation constant relative to No.34, for which the absolute value of Kd= 3.1 mM in aqueous formic acid at 40 °C).^
41 Induced 'H-NMR chemical shifts were observed upon inclusion complex formation between cucurbituril and a series of alkanediammonium ions which are summarised in Figure. It may be seen that the shielding region extends for approximately 4.5 methylene units, or 6 A which coincidentally is the interatomic distance between carbonyl oxygens axially spanning the cavity of cucurbituril. Evidently the interior of cucurbituril comprises a proton-shielding region relative to the aqueous medium employed for solvating the host species.
The induced shift probably arises fi-om a cumilative effect of the 12 urea residues of cucurbituril, each of which presents a face to the interior of the cavity.^^
H2N -CH2 -CH2 -CH2 -NH2 (not bound internally) H2N -CH2 -CH2 -CH2 —CH2 -NH2 (+0.83) (+1.08) (+1.08) (+0.83) H2N -CH2 -CH2 -CH2 —CH2-CH2 -NH2 (+0.44) (+1.00) (+1.00) (+1.00) (+0.44) H2N -CH2 -CH2 -CH2 —CH2-CH2 -CH2 -NH2 (+0.04) (+1.01) (+0.83) (+0.83) (+1.01) (0.04) H2N -CH2 -CH2 -CH2 —CH2-CH2-CH2-CH2-NH2 (-0.08) (+0.49) (+0.87) (+0.87) (+0.87) (+0.49) (-0.08) H2N -CH2 -CH2 -CH2 —CH2—CH2-CH2-CH2-CH2 -NH2 (-0.07) (+0.25) (+0.60) (+0.73) (+0.73) (+0.60) (+0.25) (-0.07)
Shielding region
Figure 1.2.2: 'H-NMR induced shifts (ppm) of methylene groups of aUcanediammonium ions upon complexation with cucurbituril (D2O-
HC00H).76
42 Cucurbituril is not only an exceptional molecular receptor, it also is a catalyst for 1,3-dipolar cycloadditions.
Alkynes undergo 1,3-dipolar cycloaddition with certain substituted azides, yielding substituted triazoles^'^-'^^ In the particular case of propargylamine and azidoethylamine, the reaction proceeds slowly when carried out in a common organic solvent solvent, yielding a pair of regioisomeric adducts in equal amount. However, Mock et aASO found that a catalytic amount of cucurbituril accelerated the reaction 10^ fold and at the same time rendered it regiospecific, yielding only the 1,3-disubstituted product as shown in Fig. 1.2.3. This result is explained by formation of a transient ternary complex between the reactants and receptor. Simultaneous binding of both the alkyne and the azide, with one primary ammonium ion coordinated to each set of carbonyls and with the substituents extending into the interior of cucurbituril, results with an alignment of reactive groups within the core of the receptor so as to facilitate production of the 1,3-disubstituted triazole. The presence of one reactant within the interior of cucurbituril diminishes the thermodynamic affinity of the second reactant for cucurbituril. This implies that the cavity within cucurbituril is slightly undersized for optimal binding. Therefore, the substrates have to experience strain when they are incorporated simultaneously, i.e. they are compressed inside the cavity. Previous examination of macroscopic pressure effects in 1,3- dipolar cycloadditions, as well as common sense, indicate that the increasing release of the strain energy tends to promote the reaction.
43 Y HC00H/H20 "-A- @\ + — 1.3-dipolar " \ — cycloaddition 1 g- =0 \ Na H
o-
Oz
Cucurbituril 1 Figure 1.2.3: 1,3-dipolar cycloadditions are catalysed in the presence cucurbituril.
Another interesting application of cucurbituril is to be part of a molecular switch as shown by Mock et alM A molecular switch is defined as a ligand receptor system which has the capacity to exist in more than one state, contingent upon some controlling element, i.e. trigger. A triamine ligand
(C6H5NH(CH2)6NH(CH2)4NH2 was specifically designed and prepared so as to be capable of binding in two distinct ways to cucurbituril as shown in Figure
1.2.4. The important feature of the guest is that the pair of aliphatic nitrogen atoms not connected directly to a benzene ring ought to be 10^-fold more basic than the one which is directly connected to the ring. The other piece of relavent piece of information is that the relevant affinities of the n-hexanediammonium
(8600), n-butanediamonium (480) and anilinium (16) towards cucurbituril (see
Table 1.2.1).
Therefore in acidic solution cucurbituril adheres to the ligand by spanning the hexanediamine portion, but at pH of > 6.7 it coordinates to the butanediamine
44 end. So long as the aniline nitrogen remains protonated, binding is favored across the six carbon site, upon deprotonation of the aniline nitrogen, the receptor translocates to the four carbon site of the ligand. While binding with a butanediammonium ion may be intrinsically less favorable, it is superior to that of an n-hexyl(mono)ammonium ion (7.0).
Figure 1.2.4: Presentation of a molecular switch based on cucurbituril and
(C6H5NH(CH2)6NH(CH2)4NH2 in acidic and alkaline aqueous solution.
Cucurbituril as a host molecule in the synthesis of rotaxanes/polyrotaxanes
Although cucurbituril 1 was recognised as a unique receptor similar to CDs or crown ethers, so far there have only been described a very limited number of polymers containing this macrocycle.
Mock et al attempted to synthesise a polymer from bispropargylamine and bisazidoethylamine using catalytic amounts of cucurbituril.They assumed that cucurbituril would act as a catalyst so that an alternating coplymer would form as shown in Fig. 1.2.5. However, in practise bond forming reaction shut down
45 after one or two cycloadditions. This is Ukely to be due to the fact that the triazole moiety adheres too firmly to the interior of cucurbituril. In order to form a second triazole ring apparently cucurbituril would have to move over on the bound guest, so that one of its portals is free to complex with a second propargyl (or azidoethyl) ammonium ion, finally undergoing the second cycloaddition with the already encapsulated azide (or propargyl) group.
0=1 + "3 ^3 + Hz
Fig. 1.2.5: Mock's hypothesis of how cucurbituril would catalyse the reaction of of bis-(2-azidoethyl)ammmonium and dipropargylammmonium in order to form a poly aromatic polymer.^^
Very recently, work on the syntheis of polyrotaxanes based on cucurbituril has been reported by Kim et al. ^ They synthesized a rotaxane and pseudorotaxane based on cucurbituril and spermine which were characterised by various spectroscopic tecniques and X-ray diffraction methods.The
construction of a rotaxane was achieved in one step in high yield by threading
46 QQ onto spermine and then attaching dinitrophenyl groups to both ends of spermine molecule to prevent dethreading. Then both ends of the spermine thread are converted to carbamates to yield a pseudorotaxane. Although the size of the terminal carbamate group may not be large enough to function as a stopper, but its negative charge seems to prevent dethreading effectively.
Interestingly they observed that the carbamate group of each pseudorotaxane molecule forms strong hydrogen bonds to neighbouring pseudorotaxane molecules. The strong intermolecular hydrogen bonds between the terminal groups of the sperminedicarbamate threads link them head-to-tail to form an 1-
D 'polymer' in the solid state. They suggests that this solid state structure may be viewed as a 'polyrotaxane' in which cucurbituril beads are threaded by
'poly(sperminedicarbamate)'. However, any physical properties of this polymer have yet to be reported.
Kim et al. followed their initial success with a coordination polyrotaxane containing cyclic component in every repeat unit.^^ The synthesis of this polyrotaxane was achieved in one step by threading cucurbituril molecules with
N,N'-bis(4-pyridylmethyl)-l,4-diaminobutane dihydrochloride and then allowing the resulting psuedorotaxane to react with Cu(N03)2 to form a coordination polymer (Figure 1.2.6). This polyrotaxane was structurally characterised by a single-crystal X-ray crystallography. It revealed that cucurbituril 'beads' are threaded on the coordination polymer, which is composed of alternating copper ions and N,N'-bis(4-pyridylmethyl)-l,4- diaminobutane dihydrochloride repeat units.
47 L = H20 Figure 1.2.6: A coordination polyrotaxane based on cucurbituril, N,N'-bis(4- pyridyknethyl)-1,4-diaminobutane dihydrochloride and Cu(N03)2 85
Extending this approach, they subsequently reported another unprecedented polyrotaxane this time a 2D coordination polymer networks containing
cucurbituril as cyclic beads. The 2D polyrotaxane network is fully interlocked;
therefore they claimed that it represents the first example of a polycatenated polyrotaxane net (Figure 1.2.
48 4+
0= ©/
L = H20 AgNOa ,Ag(CH3C6H4S03)
lA/NA Agn "/
Figure 1.2.7: An example of polycatanated polyrotaxane based on
cucurbituril.
Buschmann et al. reported the first synthesis of mono-,oligo- and polyamide rotaxanes using cucurbituril as a macrocycle by inter facial condensation of the complex of cucurbituril with 1,6-hexanediammonium ions and either aromatic or aliphatic diacid chlorides in 70-80% yield. The characterisation of the mono-, oligo- and polyrotaxane were not complete due to solubilty problem but the existence of the rotaxane structure was confirmed with by IR, DTA, 'H-
NMR.and elemental analysis. The degree of threading was calculated from C/N ratios varying from 0.5 to 0.95. They also noted that the choice of diacid chloride determines the motion and content of the threaded cucurbituril. DTA
49 curves showed that the crytalhnity of the polyamide had changed if cucurbituril
threaded onto polymer.^^' 3*
interfacial LiOH
CI
0 HaN. s,® NHo
interfacial LiOH CI
Figure 1.2.8: The first synthesis of rotaxane and polyrotaxane using
cucurbituril as a mmacrocycle in solution by interfacial condensation.^^
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56 II. RESULTS AND DISCUSSION
57 II I. Synthesis of Monomers
II.l.l. Introduction
Cucurbituril 1 as discussed in Section 1.2 is a rigid cavitand possessing a hydrophobic interior and two carbonyl-fringed portals of hydrophilic character. It can bind ammonium ions, diammonium ions and metal ions with high affinity. One of its most remarkable features is its abihty to catalyse 1,3-dipolar cycloadditon between aliphatic alkynes and aliphatic azides, provided a suitably placed ammonium ion is present in each molecule. Its straightforward synthesis, rigid structure and high association constants for certain types of guest molecules make cucurbituril a useful candidate for becoming the 'threaded bead' in rotaxane and polyrotaxane syntheses, as has been shown by Kim et a/.' for the solid state and
Buschmann et al^'^ in solution.
In order to utilise the exceptional properties of 1 in the synthesis of polymers our approach is to polymerise a^ido- and alkyne- substituted moieties via a self- threading approach in which rotaxane formation occur simultaneously to yield a perfectly threaded polyrotaxane due to the presence 1. This polyaddition reaction is expected to be either linear, hyperbranched, dendritic or sidechain polyrotaxanes depending on the type of monomer(s) used and the kind of synthetic strategy employed. The synthesis of linear polyrotaxanes requires the preparation of Ag type monomers both as dialkynes and diazido compounds. AB type monomers are also a possibly and of interest, whereas the synthesis of hyperbranched polyrotaxanes requires either AB], or A] (diazide or dialkyne) plus Bg (trialkyne or triazide) type monomers. Sidechain polyrotaxanes require the synthesis of a polymer backbone where a suitable azido or alkyne functional group is set up for the self-threading rotaxane formation.
58 The use of cucurbituril imposes certain structural criteria into the design of suitable monomers. Mock et al. have established these structural requirements in much detail.For optimal molecular recognition the alkyne group has to be separated from the amine that acts as recognition site by one methylene group. The azide moiety on the other hand should ideally be separated by two methylene units from the amine functionality. Only protonated primary and secondary amines, but not tertiary amines bind strongly to the carbonyl-fringed portals of 1, which also has to be allowed for.
The poor solubility of cucurbituril in most solvents means that reactions such as 1,3- dipolar cycloaddition have to be carried out either under acidic conditions as has been shown in the literature^- ^ or potentially in a neutral alkali salt solution.^
Although the latter is without precedent to allow QQ act as a catalyst. For these reasons it is important that the selected monomers are sufficiently stable under aqueous and at least moderately acidic conditions. Therefore monomers were designed and prepared taking into account all established design criteria.
59 II I.2. Synthesis of Cucurbituril lio n
The precursor for the synthesis of cucurbituril was obtained as an amorphous powder by acid condensation of the glycoluril and excess formaldehyde (Scheme 11.1.1).
This amorphous material is only soluble in hot conc. H2SO4.
HCI, H2O conc.H2S04 )—( + U Precursor — HN NH H^H 110-120 C
O
Solution • Solution — • Cucurbituril 1 0-10% n ^6 O Scheme II.l.l. Synthesis of cucurbituril.
It is very important to dry the precursor well before going to second step since the
success of the latter depends on the dryness of the precursor. For the second step, the precursor was heated in conc. H2SO4 (2.2 ml per gram of precursor) until
dissolved. The temperature should be carefully adjusted to 110-120 °C since
exceeding 120 °C may slow down the reaction; e.g. problem in the ring closure.")
The resulting brown coloured viscous syrup was cooled down to r.t. and then ice
cold water (22 ml per gram of precursor) was added. A very small amount of flaky precipitate was filtered off rapidly. The filtrate was heated upon which white crystals formed.
Sometimes even before heating, crystals can be observed or in some cases before the formation of crystals the solution became cloudy upon heating. In this case, it is better to cool down this cloudy solution and heat it up again until all is dissolved then leave it to cool. This procedure is best repeated 2-3 times and finally the
60 cloudy mixture is put aside at ambient temperature for 1-2 days to allow cucurbituril to crystallise out.
Cucurbituril was further purified using a number of slightly different methods. In method 1, cucurbituril was dissolved in hot (-60 °C) conc. HCl, stirred for 30 min and filtered hot (~60 °C). After the filtrate had cooled to r.t. water was added to induce the precipitation of cucurbituril. In method 2, cucurbituril was dissolved in a hot formic acid/water mixture (50/50, v/v), refluxed for 30 min, and again filtered hot. After cooling, addition of distilled water induced cucurbituril to precipitate in crystalline form. In method 3, cucurbituril is suspended in hot (~ 80 °C) conc.
HCOOH and stirred at 80 °C for 20 min to dissolve all impurities because cucurbituril is insoluble under these conditions, and then crystalline colourless cucurbituril was filtered off If crude cucurbituril with a yellow tinge is used, those dissolve when suspended in the hot media with which crystals being left behind. In all cases the precipitate was washed with distilled hot and then cold water after filtration.
In the course of this project it has been avoided to wash the crystals with organic solvents since ^H-NMR shows QQ to form inclusion complex with them and removal of these solvent molecules from QQ is difficult. Elemental analysis of dried crystals shows the presence of an average of 2.5 water molecules. Also molecular weight of cucurbituril (996.84) experimentally determined to be 997.51 using FAB-MS. This is accordance with the protonated ligand, [QQ + H]^.
The infrared spectrum confirms a broad carbonyl band at 1738 cm"'. The 'H-NMR spectrum in DCl (aqn. 35%, v/v) shows three signals of equal intensity:
61 5 5.75 (s, 12 H, He), 5.54 (d, 12H, %h = 15.6 Hz, Ha) and 4.46 (d, 12H, %h = 15.6
Hz, Hb). The '^C-NMR spectrum also shows three signals: 5 51.55 (-CH), 71.60 (-
CH2) and 158.1 (C=0). All spectral data are in agreement with proposed structure of cucurbituril.
II.1.3. Monomers Used in the Synthesis of Linear Polypseudorotaxanes
Aliphatic diazide 9 (A2) and aliphatic dialkyne 12 (B2) were synthesised to be used in synthesis of linear polypseudorotaxanes. These momomers were chosen for the synthesis of polyseudorotaxanes because they contain flexible aliphatic spacer which will render the resulting polyrotaxanes more soluble, they are expected to bind to cucurbituril with high affinity and allow the possibility of dethreading after polyseudorotaxane formation to obtain a model polymer and finally for their straightforward synthesis. (See section 11.3. for a discussion of their polymerisation chemistry).
62 ILl.3.1. Synthesis of N\ N^-bis (2-azidoethyl)-l,6-hexanediamine
hydrochloride salt 9^^
N\ N^-bis (2-azidoethyl)-l,6-hexanediamine hydrochloride salt 9 was synthesised
in four steps according to the synthetic Scheme 11.1.2.
HO—\ "CI + ^NH,
(iv)
9 Scheme II.1.2. Synthesis of N',N^-bis (2-azidoethyl)-l,6-hexanediamine hydrochloride salt 9.(i) Neat, 20 min at 120-130 °C then 6 hrs 150-160 °C, 57%, (ii) SOCI2, 60 °C, 100 min, 65%, (iii) NaNa, H2O, 75 °C, 16 hrs, 60%, (iv) IN HCl in EtiO, r.t, 84%.
The first step is an N-alkylation of ethanolamine with 1,6-dichlorohexane. In order to minimise the formation of tertiary amines, the dialkylhalide was added dropwise to an excess of ethanolamine at 120-130 °C. After work-up and then subsequently recrystallisation from ethanol, N',N^-bis(2-hydroxyethyl)-l,6-hexanediamine 6 was obtained as a white microcrystalline powder in 57% yield. Conversion of the hydroxy groups to chloride using SOCI2 gave a dark brown coloured solid which was recrystallised once from isopropanol to yield a light brown powder in 65% yield as
N\N^-bis(2-chloroethyl)-l,6-hexanediamine dihydrochloride 7. It was used without further purification in the next step.
63 N^-bis (2-azidoethyl)-l,6-hexanediamine 8 was isolated as a crude material by
another substitution reaction between 7 and sodium azide in water and the resulting
light yellow oil 8 was directly converted to its dihydrochloride salt by adding a IN
solution of HCl in diethylether. Recrystallisation of this salt from a mixture of
ethanol/toluene yielded the light yellow microcrystalline product 9 in 84% yield.
Compounds 6, 7, 8 and 9 were all characterised by 'H-NMR and '^C-NMR
spectroscopy and MS. Elemental analysis was only carried out for the target
monomer 9 and was found to be in good agreement.
II.1.3.2. N\ N^-di(2-propynyl)-l,6-hexanediamme dihydrochloride 12^3
It was attempted to prepare 12 directly from 1,6-diaminohexane and propargyl
bromide both in water and in methanol as described in the literature, but without
success. A mixture of mono, di- and tri- substituted compounds were obtained and
attempts to purify the compound by column chromatography were unsuccessful.
11a ^ lib o
X„A O N •v°x — 11c
Scheme II.1.3. Synthesis of N\ N^-di(2-propynyl)-l,6-hexanediamine dihydrochloride 12. (i) [(CH3)3C02]20, dioxane, r.t., 48 hrs, (ii) BrCHaCCH, DMF, NaH, r.t,, 18 hrs, (iii) IN HCl in diethylether, r.t., 4hrs.
64 Therefore a different route was chosen via t-BOC protected'"* 1,6-diaminohexane which was obtained in 60% yield after recrystallisation from dichloromethane.
N',N^-bis(tert-butylcarbonyl)-l,6-diaminohexane lib was treated with 2.5 equivalents of propargylbromide and 2 equivalents of NaH in DMF. After stirring the mixture at r.t. for 18 hrs, the solvent was removed under reduced pressure and the residue was purified by column chromatography using the mixture of CHCI2,
MeOH and hexane (30:40:30, (v/v/v)) as eluent to obtain 11c (Scheme II. 1.3).
Hydrochloride salt 12 was prepared by dissolving 11c in ethanol and adding a IN solution of HCl in diethyl ether. The overall yield is only moderate (36%) but very little time was invested to optimise yields in any of the reaction steps. 'H-NMR,
MS and elemental analysis data are in accordance with the proposed structure.
II.1.4. Monomers Used in the Synthesis of Linear Polyrotaxanes
As will become clear from Section II.3.3. in which the polymer chemistry of these monomers is discussed it proved necessary to substitute the flexible monomers 9 and 12 with monomers that are sufficiently bulky so that they do not slip through the cavity of cucurbituril. With this in mind diazide 22 (A2) and dialkyne 18 (B2) were synthesised as shown in Scheme II. 1.5 and Scheme II. 1.9. For the synthesis of the required bulky dialkyne compound a number of different synthetic routes were explored such as reductive amination and reduction of a diamide using a number of different reducing agents. But in the end direct N-alkylation of propargylamine with a dihalide proved to be the most useful and successfiil route.
65 ILl.4.1. Attempted synthesis of
N-({10-[2-propynyIammo)methyl]-9-anthryl}methylene)-2-propyn-l-amine
3115
Firstly bis-imination of 9,10-anthracenedicarboxaldehyde with two equivalents of propargylamine was carried out in chloroform in the presence of 4 A molecular sieves. The reaction was complete in 2 hrs, as confirmed by TLC and 'H-NMR.
Bis-imine 30 was dissolved in THF and treated with an excess of sodium borohydride. After 3hrs reflux and stirring overnight at r.t., the solvent was removed.
(i)
H
// (ii)
HoN®
Scheme II.1.4. The attempted reductive amination of 9,10- anthracenedicarboxaldehyde. (i) CHCI3, 4A molecular sieves, HCl, 2 hrs, 60 "C, (ii) NaBILt, THF, 2 hrs at 50 °C then 16 hrs at r.t.
The orange solid residue was dissolved in water and NaOH pellets were added to bring the pH to ~ 10. The solution was extracted several times with chloroform.
66 The organic phase was collected, dried and evaporated to dryness. The resulting oil was analysed by 'H-NMR and IR spectra. The desired compound could not be identified.
II I.4.2. Attempted reduction of
5-te/^-butyl-V^^-di(2-propynyl)isophthalamide 32b
Compound 32b was chosen as an alternative route into the required bulky dialkyne compound. To this end amidation of 5-tert-butylisophthalic acid with propargylamine was carried out using 1,1-carbonyl diimidazole as the activating agent. The reaction went smoothly in a 75% yield. It was then attempted to reduce bisamide 32a to bisamine 32b with a number of different reducing agents. The reduction step however proved difficult. Which was not necessarily unexpected since no literature procedure could be found for this transformation. At least with the reagents and conditions tried, this will remain to be case. It was hoped that the carbonyl group would help to direct reducing agent the desired location on the substrate, but it appears that the alkyne group did interfere after all. Protection group chemistry on the triple bond was not employed since in the end a simpler route was identified.
67 o NH, (i) N N V
(ii)
32a 32b
Scheme IL1.5, Attempted reduction of 32a to 32b with a number of different reducing agents, (i) THF, 60 °C, 3 + 3 hrs, 75%, (ii)
An attempt to reduce 32a with hthium aluminiumborohydride in THF was
unsuccessful. After two days of reflux, TLC showed the reduction not to have
occurred only starting material being present. 'H-NMR did not show any signal
indicative of benzylic protons.
Another reduction attempt was carried out with borane in THF. More than one
product was observed by TLC, but the 'H-NMR spectrum gave no indication of the
desired product being formed. Further attempts were not made and it remains
unclear what reaction took place instead of the intended carbonyl reduction.
68 11.1,4.3. Synthesis of
N-{2,4,6-trimethyl-3-[(2-propynylamino)methyl}benzyl}-2-propyn-l-amine dihydrochloride 18
N-alkylation of 2,4-bis-(chlonnethyl)-l,3,5-tri-methylene benzene with excess propargylamine gave the desired compound 18 in 86% yield. Again no dialkylation of propargylamine could be detected ortho-placed benzylic methyl groups act as
steric protecting groups, rendering it impossible to obatin dialkylation. This
synthesis only became viable as our main synthetic route into bulky dialkyne monomer through the efficient recovery of the solvent (propargylamine) by
distillation. Compound 17 was isolated as a crude material in a quantitative yield
and without further purification it was directly converted into 18 by adding a IN
solution of HCl in diethylether to the solution of 17 in chloroform.
(i). (ii)
18
Scheme II.1.6. Synthesis of 18 via N-alkylation of dichloride. (i) Neat, 0 °C r.t., 16 hrs, 100% (crude), (ii) IN HCl in Et^O, 86%.
18 was characterised by 'H-NMR, '^C-NMR, MS and elemental analysis. All analytical data are consistent with the expected compound.
69 11.1,4.4. Synthesis of N-(2-a2idoethyl)-N-(3-{{(2-azidoethyl)ainino]methyl}
-2,4,6-trimethylbenzyl)amine dihydrochloride salt 22
N-(2-azidoethyl)-N-(3-{{(2-azidoethyl)amino]methyl}-,4,6-trimethylbenzyl)amine dihydrochloride 22 was synthesised via a 4 step reaction sequence in a similar fashion as diazide 9 as shown in Scheme II. 1.5.
HoN©
Scheme II.1.7. Synthesis of N-(2-azidoethyl)-N-(3- {{(2-azidoethyI)amino]methyl}- 2,4,6-trimethylbenzyl)amine dihydrochloride 22. (i) Neat, 5hrs, 150-160 °C, 66%, (ii) SOCI2, CHCI3, 5hrs, r.t., 70 %, (iii) NaNs, H2O, 75 °C, 16 hrs, 87%, (vi) IN HCl in Et20, r.t., 96%.
70 Again the syntheses involves a sequence of nucleophilic substitution reactions starting off with the amination of the commercially available starting material 2,4- bis-(chloromethyl)-l,3,5-tri-methylene benzene using excess ethanolamine. Because of the excess ethanolamine only monosubstitution was observed leading to secondary amine species 19 in 66% yield. Diol 19 was converted into dichloride 20
(70% yield) using thionyl chloride and finally 20 was reacted with excess sodium azide in water at 75 °C for 16 hrs to yield diazide 21 as a crude oil in 87% yield.
The resulting pale yellow oil 21 was directly converted to its dihydrochloride salt by adding a IN solution of HCl in diethylether. The resulting yellow powder was recrystallised from ethanol to afford 22 as a pale yellow microcrystalline powder in
96% yield. Spectroscopic data of all intermediates are in agreement with the proposed structures. Target compound 22 was confirmed by 'H and NMR, mass spectrometry and elemental analysis.
71 II I.5. Monomer Used in the Synthesis of Side Chain Polyrotaxane
A useful monomer for the synthesis of a self-threading side chain polyrotaxanes has to contain the following features: A polymerisable functional group and a second functional group (in our case) azide or alkyne moiety that can be reacted with the appropriate corresponding alkyne or azido compound in the presence of QQ. N-(3- butynyl)-N-(4-vinylbenzyl)amine hydrochloride salt 29 fulfils these requirements.
II.5.1. Synthesis of N-(3-butynyl)-N-(4-vinyIbenzyl)amine hydrochloride salt 29
The title compound 29 was synthesised according to Scheme ILL 9 in two steps in
77% yield.
(i) (ii) \ 6 NHc 6 © CI" HN' HoN'
28 29
Scheme II. 1. 8. Synthesis of 29. (i) Dioxane, 0 °C —>• r.t., 48 hrs, 98% (crude), (ii) IN HCl in EtzO, r.t., 77%.
4-Vinyl benzylchloride was reacted with an excess of propargylamine in dioxane to yield crude 28 in almost quantitative yield and 28 was converted in situ into its hydrochloride salt 29 by adding a IN solution of HCl in diethyl ether. 'H-NMR, ^^C-
NMR spectra and MS of 29 confirm its proposed structure.
72 II I.6. Monomers Used in the Synthesis of Hyperbranched Polyrotaxanes
Monomers with more than two polymerisable groups lead to branched polymers or
polymer networks. Trialkyne (B3) 24 was prepared exactly for this reason, to be
employed in the synthesis of (hyper)branched polyrotaxanes (see Section 11.4. for
the discussion of the polymerisation chemistry).
II.1.6.1. Synthesis of
N-{2,4,6-trimethyl-3,5-bis[(2-propynyIamino)methyl]benzyl}-2-propyn-l-amine
trihydrochloride 24
Analogous to the synthesis of 18, 2,4,6-tris-(chloromethyl)-mesitylene and an
excess of propargylamine gave the anticipated product in 88% overall yield.
Conversion of free amine 23 to its hydrochloride salt 24 was again achieved by
adding a IN solution of HCl in diethylether to the solution of the crude
intermediate.
^ (i),(ii) ^ NH2
Scheme II.l.lO. Synthesis of 24. (i) Neat, 0 C -> r.t., 60 C, 16 hrs, 100% (crude), (ii) IN HCl, in EtzO, r.t., 88%.
'H-NMR and '^C-NMR spectra confirmed the formation of the anticipated product
24. This was further supported by FAB+ve MS and elemental analysis.
73 At this stage it should be noted that the presence of flanking methyl groups next to an aromatic chloromethyl functionality allows to use an excess primary amine without having to fear overalkylation of the latter. The steric shielding resulting from the ortho-positioned CH3 group is sufficient to stop the reaction at the mono alkylation stage. The selectivity avoids completely the use of protecting chemistry usually employed to mono-alkylated primary amines.
74 II. 2. Synthesis of [n]Rotaxanes and Pseudo[n]rotaxanes
II.2.1. Introduction
The abihty of cucurbituril to catalyse 1,3-dipolar cycloadditions will be utilised in the synthesis of rotaxanes. Therefore this feature will be discussed here in more detail.
Alkynes undergo 1,3-dipolar cycloaddition with substituted azides, yielding substituted triazoles. In the particular case of propargylamine and azidoethylamine, the reaction proceeds slowly when carried out in a standard solvent, yielding a pair of triazole regioisomers in almost equal amount as shown in Scheme II.2.1. Previous investigations of this type of transformation have shown it to be a typical concerted peri cyclic reaction.'^'
-NHa 'NHs X Hay Hatr"
®,%N' G- -NH, 7 %H3 NHa
Scheme II.2.1: 1,3-Dipolar cycloaddition between the hydrochloride salts of propargylamine and azidoethylamine.
Mock et alJ found that a catalytic amount of cucurbituril accelerated the reaction
10^ fold and at the same time rendered it regiospecific, yielding only the 1,3- disubstituted product and none of the other isomer. This result is explained by the formation of a transient ternary complex between the reactants and the receptor
75 (QQ). Simultaneous binding of both the alkyne and the azide, with each R-NHs^ coordinated to one set of carbonyls and with the acyclic substituents extending into the interior of cucurbituril, results in the alignment of the reactive groups within the core of cucurbituril so as to facilitate the formation of the 1,3-disubstituted triazole^
(see Section 1.2. for details).
The reason for this catalytic effect is due to the presence of one reactant within the interior of cucurbituril, which diminishes the thermodynamic affinity of the second reactant for cucurbituril. This in turn implies that the cavity within cucurbituril is
slightly undersized for optimal binding. Therefore, the substrates experience a strain when they are simultaneously incorporated, which tends to compress them together.
Previous examination of macroscopic pressure effects in 1,3-dipolar cycloadditions,
as well as common chemical sense indicates that the release of strain energy promotes the reaction.
The aim of this project is the synthesis of polyrotaxanes. However, we thought it would be wise to start with model reactions involving the synthesis of rotaxanes to
optimise reaction conditions and to establish rehable molecular characterisation data.
As will become clear in due course is that the collection of analytical data will help us to establish a "data bank" which will be valuable in the analysis of the more
complex polymeric structures.
76 II.2.2. Synthesis of [n]rotaxanes
11.2.2,1. Synthesis of [2]rotaxane 33
The rotaxane 33 was synthesised by Mock et al^ almost two decades ago. We modified their preparation slightly and fully characterised the resulting [2]rotaxane by 'H and ^^C-NMR, mass spectrometry and elemental analysis.
0= H H 6N HCI gAb Av'' RT, 72 hrs H2 0= -0H2 N3 QQ, 71% c
33
O- o N N QQ O: -O N. ,N
Cucurbituril 1
Scheme II.2.2: Synthesis of 33.
The rotaxane 33 was prepared by reacting equimolar amounts of 3 and 5 in the presence of cucurbituril in 6N HCI at r.t. for 72 hrs (Scheme II.2.2). After workup and purification by precipitation into acetone, a white powder was obtained with
71% yield. 33 is soluble in water at r.t. and its melting point exceeds 300 °C.
FAB +ve mass spectrometry revealed molecular ions at 1251 and 1287 corresponding to [33-2Cl]^ and [33-Cl]"^ respectively. Elemental analysis also confirmed the expected rotaxane. If one allows for 9 H2O molecules to be associated with the rotaxane as a reflection of its hygroscopic nature.
77 The reaction was followed by 'H-NMR to observe the triazole ring formation. As soon as the reaction was started a signal at 6.5 ppm has appeared and its intensity increased over time and after 24 hrs the intensity reached its maximum. This signal was assigned the proton located on triazole ring that is further confirmed by preparing a model free triazole species (see Section II.2.4.1). This proton shifted ~
Ippm up field due to QQ's shielding effect which was well documented by Mock et.al}^ (Also see Figure 1.2.3). The interior of QQ comprises a proton shielding region relative to the acidic aqueous medium employed for solvating the QQ. The induced shift probably arises from a cumulative effect of the 12 urea residues of QQ, each of which presents a face to the interior of the cavity. 18, 19
Table 11.2.1: ^H-NMR data for the starting material 3, 5 and [2]rotaxane 33.
' H-NMR (ppm) t- a b d butyl 3 1.35 3J2 3.7 5 5 1.45 4.25 33 1.61 3^6 3.8 4.26 1.64 7
^H-NMR spectrum of 33 was recorded after work-up and purification. Spectral data were summarised in Table 11.2.1. As can be seen from the Table II.2.1, all protons of
33 are shifted downfield relative to its starting materials (3 and 5) upon rotaxane formation.
78 Another observation was the change in the spUtting pattern of QQ. Free QQ exhibits signals at 4.43 ppm, 5.75 ppm and 5.97 ppm due to Hy a 12H-doublet, Ha a 12H doublet and He a 12H singlet respectively but in 33 these signals shifted resonating at 4.26 ppm (12H double doublet), 5.49 (12H singlet) and 5.71 ppm (12H double doublet) for Hy, Ha and He respectively. The splitting within the complex arises because the cation (ammonium ion) coordinated to a set of six urea carbonyls surrounding a portal of 1 creates a different magnetic environment for nearby methylene residues, as compared with that provided for the remaining half of the host molecule. In other words, reflection symmetry perpendicular to the six-fold axis of 1 is destroyed upon complexation with different cation binding site ^
The '^C-NMR gives rise to two signals due to the triazole ring at 124.29 ppm
(-C=CH-) and 142.65 ppm (-C=CH-). No significant shielding effect is observed in the '^C-NMR of the encapsulated triazole ring. Signals for QQ in 33 are different to firee QQ. Whereas uncomplexed QQ gives three equally intense signals at 51.55 ppm
(CH2), 71.60 ppm (CH) and 158.1 ppm (C=0) those are split into five different signals resonating at 54.18 ppm and 54.34 ppm (CH2); 73.20 ppm (CH) and 159.50 ppm and 159.54 ppm (C=0). This finding also suggests that each set of carbonyl rim in QQ experiences a different chemical environment.
After the exchange of counter ions chloride for tetrafluoroborate according to a reported method by Stoddart et rotaxane, 33, became soluble in DMF and
DMSO. Even GPC in DMF was performed although the outcome was not very informative probably due to polar solvent column interaction.
When carrying out GPC with polar solvents, there is always a risk of strong interactions between the sample polymer/oligomer/monomer and column packing.
79 The weight molecular average (Mw) has found to be as 1950 (Da) and number molecular average (M^) as 1890 (Da), which is higher than expected.
II.2.2.2. Synthesis of [3]rotaxane 34
[3]Rotaxane 34 was prepared in 6N HCl by stirring two equivalents of 5 and one equivalent of 17 in the presence of two equivalents of cucurbituril at r.t. for 72 hrs
(Scheme 11.2.3). The removal of solvent under reduced pressure gave a light yellow coloured film, which was scraped off the wall of the flask and the resulting powder was suspended in methanol. A white precipitate was isolated and further purification was carried out in order to remove excess QQ by dissolving this solid in hot water
(~80 °C) and stirring for 20 min. After filtration, the filtrate was evaporated to dryness to yield 34 as an off-white powder in 88% yield. 34 is readily soluble in water and appeared to be hygroscopic. Elemental analysis was performed after 34 being dried in vacuo over P2O5 for a week and the result is agreement with the structure if one assumes 21 H2O molecules still to be present, complexed to the rotaxane. Already in the case of QQ itself is it known from the literature^^ the removal of the traces of complexed water is extremely difficult to achieve.
80 V®
17 Hj 0- N:^N =0 K O- Hz 6N HCI H2 'g r.t., 72 hrs, 4^" =0 -N'H 2 QQ, 88% ®\ 34 5 N3
Scheme II.2.3: Synthesis of [3]Rotaxane 34 from 17 and 5 in the presence of 1.
The reaction was monitored by 'H-NMR using two signals as references. One signal is the triazole proton at 6.5 ppm and the other is the phenyl proton at 7.2 ppm. A ratio of 2 to 1 (triazole:phenyl) is indicative of full conversion which was observed after 72 hrs.
After work-up and purification similar to 33, ^H-NMR of 34 spectrum was obtained and the results have been summarised in Table 11.2.2. Upon rotaxane formation, practically all protons are shifted to downfield relative to the starting materials 5 and
17.
' H-NMR spectrum shows no free cucurbituril after hot filtration was carried out.
This was also confirmed by recording ^H-NMR spectra before and after hot filtration
81 Table IL2.2: 'H-NMR data for the starting material 5,18 and [2]rotaxane 34.
' H-NMR (ppm) t-butyl a b e f g 5 1.35 122 3J5 18 4.09 230 2.40 34 1.68 3jU 4.03 4.30 2.68 2.98
Signals due to compexed QQ showed a splitting pattern similar to that formed for 33.
A broad hump was observed at 7.10 ppm, which may be due to a protonated triazole ring nitrogen since upon addition of NaOH it disappeared. Also some other changes have been observed in the ^ H-NMR spectrum upon addition of NaOH protons due to
QQ appeared at 4.22 (d, ^Jhh= 15.2 Hz), at 5.43 (s) at 5.72, 5.78(d,d) and
6.48(triazole), 7.05 (phenyl). This is not a surprising observation since the complex is pH dependent.
ES-MS spectra showed molecular ions at 2536.5 and 2573.1 which correspond to [34-
4C1]^ and [34-301]"^ respectively.
With the exchange of counter ions from chloride to tetrafluoroborate, as decribed earlier [3]rotaxane becomes soluble in DMF, DMSO and DMAC where before it was only soluble in water. Taking advantage of this solubility change, GPC in DMF was carried out but the result is not very reliable it is believed that due to specific interaction behaviour sample to column, different runs produced three slightly different results. The weight average molecular weight was calculated to be 2510,
2410 and 2610 and number average molecular weight was 2310, 2240 and 2430 respectively. This data is in good agreement with the calculated molecular mass and that recorded by mass spectrometry.
82 IL3.2.3. Synthesis of [3]Rotaxane 35
[SjRotaxane 35 was synthesised by reacting two equivalent of 3 and one equimolar of
22 in the presence of two equivalent of QQ in 6N HCl at r.t. for 72 hrs as shown in
Scheme 11.3.4. Work-up and purification were carried out in a similar fashion as for
34. It was obtained as an off-white powder in 80% yield and dried in vacuo over P2O5 for a week.
6NHCI 22 r.t.. 72 hrs. b = 0 H; 2 QQ, 80% -kL. 3 —
Scheme II.2.4: Synthetic scheme for 35.
As discussed for 34, thre reaction was followed by ^H-NMR making use of the triazole and phenyl proton. After 72 hrs rotaxane formation was complete with the intensity ratio of triazole to phenyl to reach 2:1.
Table II.2.3: 'H-NMR data for the starting material 3, 22 and [2]rotaxane 35.
'H-NMR, ppm
t-butyl a c d e f g
3 1.45 4.25
22 3.81 336 4.39 2.42 132
35 L48 4.85 3.77 145 4.17 2.92 2.59
83 Protons due to i resonate at 5 1.48 very similar to the starting material 3 which resonate at 51.45 ppm and significantly different than from those in 34 which give rise to a signal at 5 1.68. A 2H triplet and a 2H singlet appear at 5 3.74 (almost overlapping) which were assigned as protons d and a. Moreover protons c and e gave rise signals at 5 3.98, (2H triplet) and 4.85, (2H singlet) respectively (Table II.2.4)
QQ give rise slightly different splitting pattern than 34 resonating at 5 4.17-4.26, 24H double doublet; 5.46, 12H singlet; 5.67, 12H triplet.
ES-MS shows a molecular ion at 2572.50 which corresponds to [35- 3C1]^.
11.2.2.4. Synthesis of [4]rotaxane 36
Reacting one equivalent of 24 with three equivalents of 5 in the presence of three equivalent of QQ in 6N HCl at r.t. for 72 hrs afforded 36 with a 89% yield (Scheme
II.2.5). 36 is readily soluble in water. Precipitation in a polar solvent and filtration removed most of the excess QQ but not all.^^C-NMR shows that there is still some excess QQ.
84 t
HzN© 24
6NHCI
r.t, 72 hrs. 3 QQ, 89%
+ 3-
Scheme II.2.5: Synthesis of 36 via 1,3-dipolar cycloaddition between 24 and 5
catalysed by 1.
Once again, the reaction was followed by 'H-NMR. In this case the triazole proton at
6.5 ppm and due to lack of phenyl proton t-butyl at 1.64 ppm were chosen as reference signals. The intensity ratio after 72 hrs was 1:9 as can be expected. All other 'H-NMR data are in a good agreement eith the expected compound. T-Butyl protons resonate at 1.60 ppm as a one sharp 9H singlet whereas starting material 5 gives rise a signal at 1.35 ppm as a 9H singlet, which is shifted to downfield. This suggests that QQ is located near the t-butyl group as a result of steric crowding.
Protons f, e and c are also shifted downfield to 3.58, 3.86 and 4.51 ppm respectively compared to the starting materials 5 and 24 as listed in Table 11.2.4.
85 Table II.2.4: 'H-NMR data for the starting material 5, 24 and [2]rotaxane 36. * Proton
c probably overlapped with D2O signal (4.75 ppm).
' H-NMR (ppm)
t-butyl a b c e f
5 1.34 3.75 322
24 2.49 4.54 4.04
36 L60 3.11 4.51 * 3.86 3.58
Protons due to complexed QQ (in 36) gave rise similar chemical shifts and spHtting pattern to earlier rotaxanes.
'^C-NMR spectrum shows 6 resonances at 54.12-54.34 ppm (CH2), 73.08-73.16 ppm
(CH), 159.18 - 159.52 ppm (C=0). These pattern can be explained by assuming that both portals of cucurbituril find themselves in a slightly different chemical environment as explained earlier.
MALDI-TOF gives a molecular ion at 3910 which corresponds to [(36-2C1) + Na]"^.
86 IL2.3. Synthesis of Pseudo[n]rotaxanes
After having synthesised cucurbituril containing [2], [3] and [4]rotaxanes in very good yield, we extended our synthesis to the analogous pseudo[n]rotaxanes. One purpose of this work was to establish the scope of rotaxane synthesis involving cucurbituril, the second one, more importantly, was to synthesise non-threaded model compounds.
With these model structures assignment NMR spectra of polyrotaxanes would be greatly aided.
And finally these experiments would also help us to understand in more detail the interactions which are involved in the molecular recognition event.
11.2.3,1. Synthesis of Semi[2]rotaxane 37
Two isomeric semi[2]rotaxanes , 37a and 37b were prepared as shown in the Scheme
11.3.8. in a similar fashion to that already described in Section 11.2.2.1.
Hot filtration from insoluble material followed by reprecipitation ensured the removal of all unreacted monomer and QQ as confirmed by 'H-NMR analysis.
An additional benefit of preparing two isomeric semi[2]rotaxanes 37a and 37b was to investigate the preference of QQ towards secondary and primary ammonium ions when acting as encapsulant. We assumed that this can be determined by comparing the
^H-NMR spectra of both isomers.
87 H 0=1 I N'H O -N' -H 6N HCI, r.t., 72 hrs d © ®\ ^ + N ^ -\@,H N3 NH3 QQ, 75% H 25 H 37a
0= pN e 6N, HCI, r.t., 72 hrs H^@ B "NH3 QQ, 75%
26 37b
Scheme 11.2.6: Synthesis of semi[2]rotaxanes 37a and 37b.
Table II.2.5: Summmary of 'H-NMR data for pseudo[2]rotaxanes 37a and 37b and the starting materials 5 and 25; 3 and 26.
' H-NMR (ppm) t-butyl a b c d 5 1.34 122 3J5 25 4.02 3 1.45 4.25 26 3.07 178 37b 1.70 3.40 3.99 &56 4.34
Protons a, b and d of 37a and 37b are shifted downfield upon complexation relative to the starting materials as observed in formation.of rotaxanes too. Table 11.2.5. lists the
'H-NMR data of 37a, 37b and that of the starting materials 5 and 25 as well as 3 and
26.
88 '^C-NMR spectrum of 37b reveals two signals at 123.17 and 142.37 ppm corresponding to both triazole carbons (-CH=C-) and (CH=C-). Also QQ give rise to 5 different signals at 5 54.13 and 54.13 (CH2), 159.24 and 159.49 (C=0) suggesting that upper and lower rims of QQ experiencing different environments which was also confirmed by ^H-NMR spectroscopy.
Also FAB +ve mass spectroscopy gave a molecular ion at 1194 for [37b-2HCl]^.
If we make a comparison between the 'H-NMR spectra of 37a and 37b, we can see the differences in chemical shifts. Protons due to a, b, c and d of 37a resonate at 6 3.74, 4.12,
6.50 and 4.05 whereas these protons appear at 5 3.40, 3.99, 6.56 and 4.34 for a, b, c and d of 37b suggesting that QQ has higher affinity towards to primary ammonium ions.
89 II.2.3.2, Synthesis of Pseudo[2]rotaxane 40
Pseudo[2]rotaxane 40 was synthesised by reacting stoichiometric amount of 25, 26
and cucurbituril in 6N HCl at r.t. for 72 hrs as shown in Scheme 11.2.1.
H H 6N HCl
\ ®\ = RT, 72 hrs. H I o Ns QQ, 65% H \ ^ H 26 25 40
Scheme II.2.7: Synthesis of pseudo[2]rotaxane 40.
Elemental analysis was carried out on a sample, which has been dried in vacuo over
P2O5 for a week. The result has shown a hydrous salt suggesting 9 H2O molecules. 40 is readily soluble in water at r.t.
The characteristic triazole signal appeared at 5 6.53 with right intensity as a IH singlet. Signals due to a, b and d showed up at 6 3.55, 4.15 and 4.15 respectively as a
2H-triplet (a and b) and a 2H singlet (d). These signals were shifted to downfield upon complexation when they compared to signals due to starting materials which resonate at 5 3.07, 3.75 and 3.90 for a, b and d as a 2H triplet (a and b) and 2H doublet (d) (see
Table II.2.6).
90 Table II.2.6: Summmary of 'H-NMR data for pseudo[n]rotaxane 40 and the starting materials used. ' H-NMR (ppm)
a b c d
25 4.02
26 3.07 3J8
40 155 4.15 6.53 4.12
Protons due to QQ resonate at 4.25 a double-doublet, 5.48 a singlet and 5.70 a double doublet giving similar splitting pattern as earlier examples.
FAB +ve mass spectrometry revealed a molecular ion at 1138 corresponding to [40-
2C1]^. Further confirmation came from MALDI-TOF measurements showing a molecular ion at 1138.
91 II.2.3.3. Synthesis of Pseudo[3]rotaxane 42
Scheme II.2.8. shows the reaction between azide 26 and dialkyne 18 in the presence
of an equimolar amount of cucurbituril under our standard reaction conditions.
:0 f. 18 Ha O- 6N HCI Ncrk H3
•« r.t., 72 hrs. r„«. 0=1 l=o QQ, 60% g 2 ©\ 42 26 Nj
Scheme II.2.8: Synthesis of pseudo[3]rotaxane 42.
The rotaxane 42 is readily soluble in water at r.t. Elemental analysis was performed after drying 42 in vacuo over P2O5 for a week. The result shows a hydrous salt of 42 with a calculated number of associating water molecules of 31. It was not possible to overcome the extremely hygroscopic nature of this pseudorotaxanes as discussed for rotaxanes.
Signals due to a, b, d and e resonate at 6 3.37, 3.94, 4.49 and 4.63 respectively as 2H triplet (a and b) and 2H singlet (d and e) (Table II.2.7). Once again these signals were shifted to downfield in rotaxane formation.'H-NMR reveals signals at 6.5 ppm and
7.12 ppm which corresponds to triazole and phenyl protons respectively. The intensity ratio between these protons is two to one (triazole/phenyl) as required.
92 Table II.2.7: Summmary of 'H-NMR data for pseudo[n]rotaxanes and the starting materials used. ^ H-NMR (ppm) c a b d e f g h
26 3.07 178
18 4.09 4.44 7.15 42 3.37 3.94 6.51 4.49 4.63 2.75 3.06 7.12
A molecular ion at 2420 was identified by MALDI-TOF corresponding to [42-4Cl]"^
11.2.3.4. Synthesis of Pseudo[4]rotaxane 44
Three equivalents of 26 and one equivalent of 24 and three equivalents of 1 were
reacted in 6N HCl solution at r.t. for 72 hrs. The clear solution was precipitated into
ethanol to yield off-white powder, which was further purified in the same way as
described for other rotaxanes.
93 6N HCI
r.t., 72 hrs. QQ, 78% 3 H-N^H ®\ 26 Nj
H,N©
Scheme 11.2.9: Synthesis of pseudo[4]rotaxane 44
'H-NMR revealed a signal resonating at 6.52 ppm which is characteristic of triazole proton as discussed earlier. The intensity of this proton corresponds to three protons. A
9H-singlet resonates at 3.12 ppm due to f (CH3). The protons a (6H-triplet), b (6H- triplet), c (6H-singlet), d (6H-singlet) resonate at 5 3.42, 3.95, 4.60, 4.75 respectively.
Signals due to a, b, d and e in starting materials 24 and 26 reveal at 5 3.07, 3.75, 4.04 and 4.54 respectively (Table 11.2.8)
94 Table IL2.8: Summmary of 'H-NMR data for pseudo[n]rotaxane 44 and the starting materials used.* Signal which overlaps with solvent (D2O). 'H-NMR (ppm)
a b c d e f
26 3.07 3J8
24 4.04 4.54 2.49
44 3.42 3.95 &52 4.75 4.60 3.12
This time protons of QQ show different splitting pattern in which a 36H triplet at 4.30 ppm, a 36H singlet at 5.55 ppm and a 36H triplet at 5.75 ppm. This pattern is clearly different than the former examples and also of course free QQ.
'^C-NMR shows two signals as before due to triazole ring at 6 122.87 (-CH=C-) and
142.02 (-CH=C-).
QQ give rise this time 6 different signals at 54.10 and 54.37 ppm (-CH2-), 73.08 and
73.27 ppm (-CH-) and 159.19 and 159.24 ppm (C=0). The difference is the extra signal at 73.08-73.27 ppm since [2] or [3]rotaxanes or, pseudo[2], or [3]rotaxanes normally show one signal in this region. This different splitting was also observed for
[4]rotaxane 36.
MALDI-TOF produced a molecular ion at 3567, which is close to molecular ion
(3569) of [44-6HCl]^
95 IL2.4. Dethreading of Pseudo[n]Rotaxanes
Solutions of pseudo[n]rotaxanes 37b, 40, 42 and 44 were prepared separately in
D2O and heated to 90 °C for one week in order to observe any dethreading. 'H-
NMR spectra were recorded at regular intervals and showed no indication of dethreading at all.
Another way to encourage dethreading of these pseudo [n]rotaxanes is to change the pH. We know from the literature" and from our own experience that the interaction between QQ and the ammonium ions are mainly ion-dipole interaction and hydrogen bonding.
It means QQ should release the guest if one can deprotonate the ammonium ions of these pseudorotaxanes therereby producing free amines. When this happens ion- dipole interactions between host and guest is not available anymore. Hydrogen bonding on the other hand is still operational but as a weaker attractive contribution.
Once the guest has decomplexed, the presence of an organic solvent will "capture" free triazole and thus will make it unavailable for rebinding to QQ.
II.2.4.1. Synthesis of N-{2-[l-(ammomethyl)-lH-l,2,3-triazol-4-yl]ethyl}-N-
(tert-butyl)amine 38
Dethreading of 37a was accomplished by adding two molar equivalents of a IN
NaOH solution to 37a dissolved in water. After extraction into chloroform and washing with brine, a clear oil was recovered in 65% yield and has not been purified further.
96 Scheme II.2.10: Synthesis of 38 via dethreading of 37a.
^H-NMR, ^^C-NMR were recorded in CDCI3 'H-NMR shows a peak at 7.53 ppm due to free triazole shifted by about Ippm downfield since it is free from QQ's shielding effect.
Protons due to a and b resonate as two separate triplets at 5 3.02 and 4.37 respectively. Whereas they appeared at 5 3.74 (a) and 4.12 (b). Protons due to d come to resonance at 5 3.96 which was shifted -0.1 ppm up ft eld compared to 37a.
'H-NMR of 38 was also recorded in DCl and of course strong downfield shifts were observed in the spectrum such as the triazole proton was shifted from 7.53 ppm to
8.6 ppm. Also protons due to a, b and d come to resonance at 3.85, 5.15 and 4.62 respectively, which in all cases are significant downfield shifts.
^^C-NMR spectrum exhibits two signals due to triazole ring resonating at 5 123.30 and 142.35 (-CH=C-) and (-CH=C-).
II.2.4.2. Synthesis of [l-(2-amiiioethyl)-lH-l,2,3-triazol-4-yl]methylamine 41
Dethreading of 40 was accomplished by adding two molar equivalents of a IN
NaOH solution to 40 dissolved in water in a method similar to that used for 37a.
After extraction into chloroform and washing with brine, a clear oil was recovered in 69% yield and which was not been purified further.
97 Scheme 11.2.11: Synthesis of 41 via dethreading of 40.
^H-NMR shows the triazole proton at 7.53 ppm shifted downfield by about Ippm compared to 40 similar to what has been discussed for 37a. Two triplets appeared at
3.17 and 4.42 respectively due to a and b. Protons d gave a singlet at 3.97. A broad signal at 1.48 ppm was assigned to the NH proton.
II.2.4.3. Synthesis of N-{[l-(2-ammoethyl)-lH-l,2,3-triazol-4-yl]methyl}-N-{3-
[({[l-(2-aminoethyl)-lH-l,2,3-triazol-4-yl}methyl}ammo)methyI]-2,4,6- trimethylbenzyl}amine 43
Dethreading of 42 was performed treating the aqueous solution of 42 with four equivalents of a IN NaOH solution. After the mixture was stirred and the organic phase was extracted with chloroform, colourless oil was recovered in 59% yield.
Basic NH, + 1
Scheme II.2.12: The compound 43 was synthesised via threading of 42 changing the
pH.
98 No further purification was undertaken prior to characterisation. The characterisation was performed in order to compare the 'H-NMR and '^C-NMR data of bound and free triazole hosts.
Protons a, b, d and e resonate at 5 3.17 (2H-triplet), 4.36 (2H triplet), 3.76 (2H singlet) and 4.03 (2H singlet) respectively. In 42 protons due to a, b, d and e appeared at 5 3.37(2H triplet), 3.94 (2H triplet), 4.49 (2H singlet) and 4.63 (2H singlet) ppm respectively. The triazole proton absorbed at 7.54 ppm similar to 38.
The phenyl proton resonates at 6.81 ppm and the ratio of the integrals of triazole and phenyl protons is two to one as required.
'^C-NMR also provided useful information. The characteristic triazole signals appear at 122.23 ppm and 147.14 ppm. Carbon signals at 130.16, 134.41, 135.83 and 136.34 ppm belong to the aromatic ring.
It was attempted to get mass spectrometry data (EI and FAB +ve) none of these produced a molecular ion for 43.
99 II.2.4.4. Synthesis of N-{[l-(2-ammoethyl)-lH-l,2,3-triazol-4-yl]methyl}-N-
{3,5-bis [({[l-(2-aminoethyl)-l H-1,2,3-triazoI-4-yl} methyl} amino)methyl]-2,4,6- trimethylbenzyl} amine 45
An aqueous solution of 44 was treated with 6 equivalents of an aqueous IN NaOH solution and the aqueous layer was extracted with chloroform. After washing the organic layer with brine and removal of the solvent under reduced pressure a viscous pale yellow coloured oil was obtained in 55% yield. No further purification was carried out since only a very small quantity of sample was recovered.
N—N
basic
Scheme 11.2.13: Synthesis of 45 via dethreading of 44.
The 'H-NMR spectrum of 45 exhibits some unidentified impurities and also a significant amount of water. However, the expected spectrum of 45 can be extracted from this data without difficulties.
Protons a and b resonate at 5 3.19 (triplet) and 4.39 (triplet). Protons f, e, d absorb at 5 2.39 (singlet), 3.81 (singlet) and 4.05 (singlet).
100 Triazole proton absorbs again at 7.57 ppm. Protons a, b, c, d, e and f were observed at 3.19, 4.39, 7.57, 4.05, 3.81 and 4.05 ppm respectively in 44.
As discussed in Section II.2.4.3, molar mass determination by mass spectrometry both (EI) and (FAB +ve) were attempted but none of these produced a suitable molecular ion consisted with 45.
101 II. 3. Synthesis of Linear, Catalytically Self-Threading Polypseudorotaxanes
and Polyrotaxanes23
IL3.1. Introduction
As discussed in Section I.L, many polyrotaxanes^'^ and polypseudorotaxanes^^'^^ have been synthesised to date adopting a variety of methods such as statistical and templated threading incorporating different kinds of macrocycles such as cyclodextrins, crown ethers and cyclophanes. QQ also has been used in polyrotaxane syntheses but only in a handful of examples.
Here we would like to introduce a new approach in which polymerisation and rotaxane formation occur simultaneously due to the presence of cucurbituril, a macrocycle that catalyses 1,3-dipolar cycloadditions (see for discussion of rotaxanes
Section 11.2) applied to the synthesis of perfectly threaded polyrotaxanes.
II.3.2. Attempted Synthesis of Linear,
Catalytically Self-Threading Polypseudorotaxanes
The polyaddition reaction between diazide 9 and dialkyne 12 in the presence of cucurbituril should in principle lead to a linear polypseudorotaxane 52 of well- defined structure as shown in Figure 11.3.1. The mechanism is believed to involve the following steps:
First, the reactive functionalities, alkyne and azide group will enter the cavity of cucurbituril and in this process solvent molecules are displaced. Then the geometry of the ternary complex inside the cavity of 1 leads to a catalysed 1,3-dipolar cycloadition forming a 1,3-disubstituted triazole regiospecifically.
For this reaction, monomers 9 and 12 have been prepared containing aliphatic hexamethylene spacer. One of the reasons for choosing aliphatic spacers is to
102 improve the solubihty of resulting polyrotaxanes in organic solvents. Another one is to be able to obtain the corresponding dethreaded polymer after the removal of cucurbituril.
Figure II.3.1: Proposed synthetic scheme of catalytically self-threading
polypseudorotaxanes in the presence of g cucurbituril.
A series of reaction were carried out as listed in Table II.3.1. varying reaction conditions such as time, temperature and molarity of monomers. All reactions were carried out inert atmosphere using standard conditions established for rotaxane formation in Section II.2.
103 Table 11.3.1: Reactions conditions for the attempted syntheses of Unear, catalytically self-threaded polypseudorotaxane 52. The ratio x/y is the ratio of the intensity of the central methylene protons x (c + d + 4 + 5, (16H)) versus the intensity of triazole proton (y) (^H-NMR). DP is the degree of polymerisation. Molar Ratio (Mol) Solvent: 6N HC (mg) Entry [Azide] [Alkyne] QQ t T Ratio DP (A:) (B:) (h) (°C) x/y A 1 1 1 24 20 none 0 &84 7.98 322 B 1 1 2 192 20 none 0 4.92 3.99 322 C 1 1 3 120 20 none 0 2.19 1.77 2&0 D 1 1 2 384 90 16/1.0 2 4.92 3.99 322 E 1 1 3 384 90 16/0.8 1.8 2.19 1.77 2&0 F 1 1 4 384 90 16/0.7 1.7 2.46 1.99 30.0 G 1 1 0 384 90 16/0.8 1.7 &84 7.98
For an infinite polymer chain, the ratio between the central methylene units (4 + 5,
8H and d + e, 8H) and the triazole proton should be 16 to 2. The reason for using these protons as a reference is that they appear in a region of the ^H-NMR spectrum
(0-2 ppm) wliich is well separated from the other NMR resonances and thus can be easily identified and integrated. What is more the methylene protons are only present in this region when an inclusion complex has been formed. It was therefore possible
104 to follow the reaction by 'H-NMR spectroscopy and degree of polymerisation. A
detailed discussion on the latter can be found in section II.3.3.
Entry A in Table II.3.2 shows the outcome of the reaction between equimolar
amounts of dialkyne 12 and diazide 9 and 1. The reaction was stirred in 6N HCl at r.t.
for 24 hrs.
No triazole proton was observed in the proton NMR spectrum, neither at 6.5 ppm
(triazole encapsulated by 1) nor at approx. 8 ppm as free (but protonated) species.
Two multiplets at 0.45 (e) and 0.75 (d) ppm, however provide evidence for the
unreacted inclusion complex 46 between QQ and and 9 as shown in Figure II.3.2.
Table 11.3.2. lists the ^H-NMR data of monomer 9 and its inclusion complex 46 with
QQ. Only one of the monomer was included since only one equivalent of QQ is
present in the reaction mixture.
It can be concluded that inclusion complex 46 has formed but no polymerisation took
place either because of steric effects, that inhibit catalysis, or because the amount of
uncomplexed QQ is very small. In order to establish the reason(s) for this behaviour a
number of reaction parameters have been varied (Entry B to G) in Table II.3.1.
105 0= =0 -O c © © No © -N. -N. "N' N Hz Hz, Hz n- -O
46 47
Figure 11.3.2: Inclusion complexes 46 and 47
Table II.3.2: A comparison of chemical shifts before and after inclusion complex formation between 9 + 1 (46) and 12 + 1 (47).
' H-NMR (ppm)
a b c d e
9 3J5 3.15 3.05 1.65 1.35
46 3j# 335 2.95 0.75 0.45
1 2 3 4 5
12 2.90 3.90 3.15 1.65 1.35
47 3.15 4.15 2.95 0.75 0.45
First the molarity of QQ was increased to two equivalents with simultaneously increasing the reaction time. This had no effect at all and only signals for the inclusion complexes of 12 and 9 with QQ (Figure II.4.3) were seen at 0.45 ppm
(e+5) and 0.75 ppm (d+4) in the 'H-NMR spectrum. Triazole resonances were not detected. Adding two equivalents of QQ was probably not sufficient.
Therefore the amount of QQ was raised to three equivalents (Entry C) with no change in the reaction outcome. Since it had been ensured that sufficient molar equivalents of
106 free QQ were available for the self-threading process one has to consider the possibility that the formation of the ternary complex may be inhibited by the possibility that the monomeric inclusion complexes are too bulky to allow the third
QQ molecule to bring together two of these monomers for subsequent threading.
Increasing the temperature is another measure that can be taken, to shift the equilibrium of the inclusion complexes towards the free species. A number of polymerisations have been carried out identical to those just discussed with the difference of increasing the temperature from 20 to 90 °C (Table 11.3.1.)
'H-NMR spectrum of Entry D exhibits a signal at 8.55 ppm which is characteristic for an unbound triazole proton and also upfield shifts of methylene resonances at 0.45 ppm and 0.75 ppm indicating inclusion complex formation were observed. This data suggests that this time 1,3-dipolar cycloaddition was observed even at under ratio of monomers to QQ of 1:1!
The intensity ratio of the integrals of methylene protons (4+5 and d+e) is only 1 to 16 which means that every two monomers must have reacted together to form a triazole ring as shown in Figure 11.3.4.
107 Figure II. 3. 3: ^H-NMR of Entry D suggests formation of a dimers.
By having extended the reaction time already from 192 to 384 hrs, it is believed that extending them further will not change the outcome to any significant extend.
If anything at all than an increase of QQ to 3 or even 4 equivalents (Entry E and F) reduces the amount of dimer formation somewhat, which can be explained by an an inhibitory mode of action when excess QQ presents.
A possible explanation as to why polymerisation does not take place, is based onto a steric arguments derived from the inclusion complexes of QQ with both monomers.
An additional inhibitory effect of using excess QQ where conversion to triazole was less when QQ was present in 3 and 4 fold in excess could be considered given the fact that the formation of dimer was observed even in the absence of QQ under identical conditions (90 °C, 384 hrs) (Entry G).
108 Figure II.3.4: Proposed reaction scheme to synthesise poly(triazole).
The progress of the reaction (Entry G) was followed by ^H-NMR and a signal at 9.02 ppm was observed due to unbound triazole proton. The intensity ratio of triazole proton to protons 4 +5 and d + e was found to be 16 to 0.8 which suggests formation of 80% of dimer with the rest remaining monomers. Longer reaction time did not changed this ratio to any significant extent. The 'H-NMR spectrum also showed additional signals at 4.95, 5.85 and 0.15 ppm with poorly resolved which do not correspond to the expected structure. These signals are most likely the result of decomposition products from the original monomers. This could also explain why the reaction did not go beyond that of dimer formation. The decomposition of monomers during the 1,3-cycloaddition reaction upsets the stoichiometric balance. This in return leads to a lower degree of "polymerisation".
Especially aliphatic azides are known from the literature not to be very stable under these harsh conditions. Therefore decomposition is not surprising after all.
In summary it became apparent that a different set of monomers had to be designed so as to favour the catalytical self-threading process. A vital feature of these re-designed monomers should be a spacer unit with an affinity towards QQ lower than that of
109 either propargyl or ethyl azide species. It could simply be a bulky spacer to fit at all into the cavity of QQ.
At least in that way the formation of inclusion complex can be prevented with certainity. Polymerisation chemistry involving these bulky monomers is discussed in
Section 11.3.3.
IL3.2.1. Summary
QQ does not catalyse the reaction between propargyl and azidoethyl groups substituted with 1,6-diammonium hexane. Once it forms a thermodynamically stable complex with the hexyl spacer, the dissociation of this complex is very slow process.
Whereas this process needs be faster than formation of inclusion complex to catalyse the reaction as seen for the rotaxanes discussed in Section II.2.
Although triazole formation has been observed (only at elevated temperature) this is very unlikely to be a result of the catalytic effect of QQ since the same amount of triazole formation was observed under identical conditions in the absence of QQ.
110 11.3.3. Synthesis of Linear Polyrotaxanes via Self-Threading Method^^
As discussed in the previous section polypseudorotaxane formation with monomers 9 and 12 did not proceed. The most hkely reason was seen in the design of the monomers, especially the spacer which separates the two ammonium groups on each monomers turned out to be crucial. The spacer group has to be chosen such that it has a lesser affinity to QQ than either propargyl ammonium and azidoethyl ammonium species, but still threads through the cavity of cucurbituril or it has to be bulky enough not to fit inside the cavity of QQ.
It was decided to pursue the latter. The cavity of cucurbituril has dimensions close to the size of para-disubstituted benzene ring. Therefore the spacer has to be bulkier than this; i.e. no complex formation between 1,3 or 1,2-disubstituted benzene ring and QQ.19
Based on this analysis, monomers 18 and 22 were chosen and the synthesis has akeady been discussed in Section ILL
111 Figure II.3.5: Synthesis of hnear catalytically self-threading polyrotaxanes using
"stoppered" monomers.
In a typical polymerisation experiment, QQ was dissolved in 6N HCl solution followed by addition of azide 22 to obtain a pale yellow solution, which was stirred for 10 min at r.t. before alkyne 18 was added. Polymerisation conditions of each polymerisation are summarised in Table II.3.4.
For work-up, the solution was precipitated into acetone/ethanol (50/50 (v/v)) to yield a white solid. To remove any excess of QQ from the precipitated polymer, the polymer was dissolved in hot water (80 °C) and stirred for 1-2 hrs followed by hot filtration. This operation ensured the removal of any excess and unreacted QQ.
Finally the solvent was evaporated to dryness under reduced pressure to yield a colourless film. All polyrotaxanes listed in Table II.3.4 are soluble in water at r.t. up to 80 °C .
Before work-up had been undertaken, reactions were closely monitored by ^H-NMR taking the newly formed triazole (6.5 ppm) and the phenyl proton (7.2 ppm) as discussed in the Section 11.2. on rotaxane synthesis. The intensity ratio between these
112 proton signals became 1:2 (triazole:phenyl) after 24 hrs suggesting dimer formation and it increased to a ratio close to 1:1 after further 24 hrs at r.t.
Also that the triazole proton located inside the cavity of cucurbituril is further confirmed through the model [2] and [3]rotaxanes (Figure 11.3.6). In an unprotonated triazole model 38 the same proton appears at 7.5 ppm and it is shifted even further downfield in the same compound 39 at 8.56 when it is protonated (Table II.3.3).
Table II.3.4: Comparison of triazole chemical shifts in 'H-NMR and '^C-NMR spectra. 'H-NMR, 5 '^C-NMR, 6 Triazole Triazole -CH=C- -CH=C- [2]Rotaxane 33 6.5 124.3 142.7
[3]Rotaxane 34 6.5 122_9 143.4 Polyrotaxane 55 6.5 122.7 142.2 Free triazole species 38 7.5 123.3 142.4 Protonated 38 or 39 8.6
After we established an appropriate way to follow the reaction, naturally a series of experiments were carried out as shown in the Table 11.3.4. to optimise the yield, molecular weight and to gain an understanding of the mechanistic details of the polymerisation
113 Table 11.3.1.2: Polyrotaxanes with variable reaction conditions, yield, degree of polymerisation (DP) and Mn values. * Reaction was carried out a 0.2 N solution of NaS04, ^ Reactions (Entry K and Q) were only conducted on a 'H-NMR scale and no work-up was carried out. Ratio (Mol) Solvent: 6N HCl 'H-NMR Entry [Azide [Alkyn( QQ t T Yield Mn DP (%) (A:) (B2) (h) (°C) (Da) A 1 1 2 48 20 68 13000 10 B 1 1 2 72 60 78 17000 11 C 1 1 2 72 + 20 + 40 75 28000 21 24 D 1 1 2 120 60 68 39000 29 E 1 1 2 144 80 91 29000 21 F* 1 1 2 192 20 79 21000 16
G 1 1 250 144 20 73 7000 5 H 1 1.12 236 144 20 72 12000 9 I 1 1.20 2.48 144 20 71 12000 9 J 1 1 225 144 20 84 12000 9
K' 1 1 1 192 90 3400 2.5 L 1 1 2 144 20 82 25000 19 M 1 1 2 144 90 86 18000 13 N 1 1 2 336 20 75 30000 22 0 1 1 2 336 90 79 25000 19 P 1 1 0 192 20 0 No 0 polymer Q' 1 1 0 192 90 Dimer 2
114 II.3.2.1. Determination of Mn by H-NMR:
Most informative region in the ^H-NMR spectrum is the region between 6.0 and 7.5 ppm because one can calculate from the intensity ratio between triazole proton and phenyl proton the number average molecular weight value (Mn value) by applying
Carothers equation.
DP = l/Up
Figure II.3.6: Carothers equation, DP is degree of polymerisation and p monomer
conversion.
In our calculation, the ratio between triazole proton to phenyl proton allows the
calculation of the value for the monomer conversion p. Mn values for all polymers
shown in Table 11.3.4. are calculated in this manner.
115 i-
triazole =C-H
Polyrotaxane
[3jRotaxane
[2]Rotaxane ' I I I—!~-i—I I ~i I r J I I I V y' I I I' ' —r—r- 7.5 7.0 6.S 6.0 S.5
Figure II.3.6: 'H-NMR overlay of the triazole and phenyl region of the polyrotaxane 55, [Bjrotaxane 34 and [2]rotaxane 33.
116 11.3.3.3. Other Characterisation Techniques
'H-NMR proved to be a useful tool for the molecular weight analysis but we also characterised these polyrotaxanes by other methods to obtain additional information on their molecular weight. Therefore some attempts were made to characterise polyrotaxanes 55 also by MALDI-TOF and GPC.
However, probably due to the polyelectrolyte nature of these polyrotaxanes we have encountered some difficulties in this task.
II.3.3.3.1. Matrix Assisted Laser Desorption lonisation-Time of Flight Mass
Spectrometry (MALDI-TOF)^^
MALDI-TOF is very sensitive technique for determining molecular weight and end- groups of polymers with molecular weights of 5000-50000.28
The matrix can be prepared in various ways and is crucial to the success of the MS experiment. The polymer sample is first dissolved together with aromatic acids of various kinds the solvent is evaporated to leave behind a solid matrix of acid molecule surrounding the polymer molecule.
It is also possible to load a polymer sample on top of an acid group containing matrix.
In each case the sample is irradiated with a laser at a wavelength at which the matrix but, ideally, not the polymer will absorb.
The energy 'from' the laser is transferred via the excited matrix molecules onto the polymer, which then vaporises intact (the ideal situation).
During the volatilisation of polymer the matrix also confers a positive charge on to the polymer sample via a proton transfer or ion transfer process. The latter is the case when aromatic acid salts are used.
117 A number of spots of the sample are made up on a plate and loaded into the spectrometer. The matrix is vaporised along with the polymer causing little or no fragmentation. The laser is focused on the spot and pulsed. The polymer is then analysed using time of flight mass spectrometry. An average spectrum is obtained by summing over a series of shots.
1.1P1 * IK' i -iKi i hcl a.imu J. iKI
j. lU : y. IK] 2.11a Z iU Ml IJ .S.la.1 J.IU :i. inj
i. lEJ -edit ri/wj'j T.biB jaitt' itXt-j Ma: ilCki ibcc- l Figure 11.3.7: MALDI-TOF of Entry D.
As shown in Fig II.3.1.3 MALDI-TOF spectrum which was produced using trans- indoleacryhc acid (lAA) as matrix showed very broad peak clusters and the reason for this is not known. Peak maxima are spaced by about m/z 1350 (molar masses of the repeat units are 1324.14 and 1386.17) with the molecular weight number average value close to 6000.
18 II.3.3.3.2. Gel Permeation Chromatography (GPC)
GPC (also known as size exclusion chromatography) is a technique based to determine polymer molecular weights and polydispersities. The apparatus typically uses two columns, which packed with cross-linked polystyrene with a controlled pore size distribution (separation by size only, no interaction). The wide distribution in pore sizes in the gel causes the separation by molecular size only. The larger molecules dissolved in the solvent carrier cannot diffuse into the pores, and are rapidly eluted, while the smaller ones penetrate further with decreasing size and are retarded accordingly. Thus the larger molecules elute first and the smaller molecules last because they travel a much longer path. In order to relate size to molecular weight, the columns are calibrated using poly(styrene) standards (or PMMA). A calibration curve is calculated and the elution time is related to the molecular weight of the polymer standards.
Other methods also known, particularly universal calibration and triple detector
GPCs, but for the solvent systems used and keeping in mind the unusual polyrotaxane architecture, these methods were not available to us or of Httle value. Static light scattering was attempted but establishing the dn/dc value has so far proven to be difficult.
In an attempt to change the solubility pattern of polyrotaxane (only soluble in water and acidified water) the chloride counterions were exchanged for hexafiuorophosphate in order to render the polymer soluble in organic non-protic polar solvents.
119 Counter ion chloride of polyrotaxane (Entry D, Table) was exchanged for [PFe]" according to a procedure by Stoddart et al. to produce a material, which dissolves in
DMF, DMSO and DM Ac.
The sample was then analysed by RAPRA using DMF as eluent at 80 °C, using a column set suited to the analysis of high and medium molecular weight polymers and which was calibrated with poly(methyl methacrylate) and all of the results are expressed as the "PMMA equivalent" molecular weights. Sample solutions were prepared by adding 10 ml of solvent to 20 mg of sample, then warming for 20 minutes to dissolve. After thorough mixing, the solutions were filtered through a 0.2 micron
PTFE membrane prior to the chromatography. The data has been collected and analysed using Polymer Laboratories 'Caliber' software.
Figure 11.3.8.shows the GPC traces of this polyrotaxane (Entry D) with Mn and Mw values which were calculated as 5100 and 9000 respectively.
But it should be noted that the GPC system used for this work was calibrated with poly(methyl methacrylate) and all of the results are expressed as "PMMA equivalent" molecular weights. There could be a considerable difference between these PMMA equivalents and the actual molecular weights of the samples.
Also the potential for unwanted (also specific binding) interactions with the column packing should be kept in mind. There is always significant potential for such interactions when working with polar polymers and salts, such as ammonium acetate is added to the eluent to minimise the possible non-steric interactions. This analysis has been carried out based on the assumption that purely a size exclusion mechanism is operating. It should be noted that this remains unproven. Possible non steric interactions are poorly understood with the consequence that PMMA equivalent molecular weight is likely to be lower than the actual molecular weight of the sample.
120 Polymers K and L were treated in the same way as described above and after
exchange for the tetrafluoroborate ion. They became soluble in DMF, DMSO and
DMAC. However the GPC analysis of these samples was unsuccessful and an
explanation can not be provided at this time.
Rl Chromatograms
5t / Df91001.020
/ Df91001.021
M 3- 0c 1 2-
10 15 20 25
Minutes
Figure II.3.8: GPC of polyrotaxane with counter ion [PFg]' in DMF.
121 The influence of reaction time on molecular weight can be seen from entries A, L and
N (Table II.3.5). At 20 °C molecular weight increased from 13000 to 25000 when the reaction time increased from 48 hrs to 144 hrs. However beyond 144 hrs no significant difference was observed.
Table II.3.5: Influence of reaction time on yield and molecular weight of polyrotaxane 55. Ratio (Mol) Solvent: 6N ^H-NMR HCl Entry [Azide] [Alkyne] QQ t T Yield M„ (Da) DP (A:) (Bi) (h) (°C) (%) (NMR) A 1 1 2 48 20 68 13000 13 L 1 1 2 144 20 82 25000 18 N 1 1 2 336 20 75 30000 22
Changing reaction time from 20 °C to 90 °C had also an effect on molecular weight.
Raising the temperature yielded lower molecular weight (entries L, M, N and O)
(Table 11.3.7) when compared to the identical reaction time at 20 °C instead.
122 Table II.3.6: Influence of reaction time and reaction temperature on yield and molecular weight of polyrotaxane 55.
Ratio (Mol) Solvent: 6N HCl 'H-NMR Entry [Azide] [Alkyne] QQ t T Yield Mn (Da) DP (Az) (Bz) (h) (°C) (%) L 1 1 2 144 20 82 25000 18 M 1 1 2 144 90 86 18000 13 N 1 1 2 336 20 75 30000 22 0 1 1 2 336 90 79 25000 18
Again an increase in reaction time entry L and M and entry N and O leads to an increase in molecular weight. Yields on the other hand were not effected to any significant extent.
High molecular polyrotaxanes can be obtained increasing the reaction time. Reactions can be accelerated at elevated temperature but temperature higher than 80 °C is likely cause the decomposition of monomers limiting the accessable molecular weight.
Exact stoichiometry between three components is essential to obtain a high molecular weight polyrotaxanes as would be expected from a polyaddition polymerisation. In this case the stoichiometry of the catalyst/cyclic unit is equally important since a subequimolar amounts limits the molecular weight obtainable according to Carothers
Equation whereas an excess inhibits further dipolar addition reaction through complexation thus upsetting the stoichiometric balance again. Table II.3.5 compares the molecular weight of the polyrotaxane (Entry L) with an exact stoichiometry with polyrotaxanes prepared being different stoichiometric imbalances (entry H, I, J).
123 Table IL3.7: Influence of stoichiometry on yield and molecular weight of polyrotaxane
55.
Ratio (Mol) Solvent; 6N H( 'H-NMR Entry [Azide] [Alkyne] QQ t T Yield Mn DP (A2) (B2) (h) (°C) (%) (Da) H 1 1.12 236 144 20 72 12000 9 I 1 1.20 248 144 20 71 12000 9 J 1 1 225 144 20 84 12000 9
L 1 1 2 144 20 82 25000 18
IL3.3.4. Conclusions
All results suggest that the mechanism is a step growth reaction polymerisation for
which stoichiometric balance of all components is very important.
Step growth reaction polymerisation can be summarised as following to understand
better the similarities in reactions in the Table 11.3.4.
1. Linear polymer are synthesised either from difunctional monomers of AB type or
from a combination of A] or difunctional monomers. We have used A2, diazide
(22) and B2 dialkyne (18) for the synthesis of polyrotaxanes.
2. Network polymers are formed from monomers having a functionality greater than
two.
3. Polymers retain their functionality as end groups when polymerisation is
complete (No proof from 'H-NMR is available for the propargyl and ethylazide end
groups).
4. A single reaction (or reaction sequence) is responsible for all steps contributing to
polymer formation (in contrast to initiation, propagation and termination in chain
reaction polymerisation).
124 5. Molecular weight increases slowly even at high level of conversion (Carothers
Equation).
6. A high yielding reaction and exact stoichiometric balance are necessary to obtain high molecular weight linear polymer. Polyrotaxanes were synthesised in high yields but it is extremely difficult to provide the exact stoichiometric balance because in our case three components are involved in the polymerisation process. Moreover, all three are highly hygroscopic. For all these reasons, it is difficult to obtain a high molecular weight linear polyrotaxane also decomposition of monomers even small amounts at low temperature.
Another set of experiment was carried out to establish the catalytic nature of QQ. One polymerisation at 20 °C is compared with one at 90 °C both are reacted for 192 hrs.
The former reaction at lower temperature did not proceed at all but in the latter case triazole formation was observed indicating a degree of polymerisation close to 2 (but no polymer was formed as in the case when QQ is present).
Some ^H-NMR signals, which in the reaction at 90 °C can be attributed to decomposition products of the monomers used and could thus explain that only dimeric species. More important is the fact that the self-threading process is indeed catalytical, since without QQ present no reaction takes place at room temperature. At
90 °C on the other hand one can still attribute involvement of QQ in the polymerisation process either still as catalyst or as an encapsulant which protects
functional groups from side reaction and just upholding the stoichiometric balance.
125 II. 4, Synthesis of Catalytically Self-Threading Hyperbranched and Dendritic Polyrotaxanes
11.4.1. Attempted Synthesis of Catalytically Self-Threading Dendritic
Polyrotaxanes 57
Dendrimers^^ are perfectly branched monodisperse macromolecules. They display unusual physical properties as a consequence of their unique topology. These properties differ from those of linear polymers or any other known polymeric architecture.
Dendrimers can be synthesised mainly by two methods, the so called divergent^o and the convergent^' approach. Recently, a synthetic approach based on self-organisation was introduced by Zimmermann et al.^^ and which was followed by Gibson et in the synthesis of dendritic pseudorotaxane. The preparation of dendrimers often involves numerous protection, deprotection and purification steps, which are costly and time consuming.
We attempted to synthesise dendritic polyrotaxanes using the divergent method. A3 type monomer 24 was chosen as a core. For the synthesis of the first generation an excess of Bz-type monomer 22 (4 or 6 equivalents) in the presence of excess cucurbituril (4 or 5 equivalents) was added to the core molecule (24) in an attempt to generate the first generation, [4]rotaxane 57 exclusively. The [4]rotaxane 57 would be purified (removal of excess reagents) and the subsequently second generation can be synthesised by addition of excess A3 monomer (24) (4 or 6 equivalents) and excess
QQ (4 or 5 equivalents). This process is then meant to become iterative until the starburst limit is reached as shown in Figure II.4.1.
126 22
0 H,Nf>
57 Generation 0.5
First Generation excess B3, 24 excess QQ followed by purification
Generation 1.0
Figure II.4.1. Synthetic strategy for catalytically self-threading
polyrotaxane dendrimers.
Table II.4.1. summarises our attempts to synthesise generation 0.5. in this way. For
Entry A and B (Table 11.4.1), 5 equivalents of QQ were dissolved in 6N HCl and one
equivalent of alkyne 24 was added. The resulting solution was stirred at r.t. for 15 min before the addition of excess azide 22. The solution with a very small amount of fine particles was stirred at r.t. for 24 hrs and for 72 hrs for Entry A and Entry B
127 respectively. Undissolved fine particles were filtered off with a 0.45 p.m membrane filter before the filtrate was precipitated into ethanol to form a white solid, which turned into an off-white sticky solid during filtration.
Again the triazole signal at 6.5 ppm (Tr) and phenyl signal 7.2 ppm (Ph) signals were taken as reference in the ^H-NMR spectrum. Foe a perfect generation 0.5 polyrotaxane ([4]rotaxane 57) the integrals of triazole to phenyl should be exactly 1:1
(Figure II.4.1), but in our case the ratios were 1.0:1.4 (Tr:Ph) for both Entry A and B.
This results suggest either presence of generation 0.5 besides with inclusion complex between QQ and excess 22 or the product is a simply statistical mixture of [2], [3],
[4]rotaxanes and (hyper)branched polyrotaxane. Further information could not be gleamed fi'om the ^H-NMR spectrum since it was very complex indeed.
MALDI-TOF of Entry A shows no sensible molecular ions which corresponds to desired compound. The peaks are quite low in intensity and mostly due to QQ (996), or some form of dimer QQ (1994). The reason for this is still unknown. However the
MALDI-TOF spectrum of the product formed in Entry B provided some useful information. Molecular ions are found at 3075 with 100% intensity and at 4592 with
65 % intensity, former corresponds to [3]rotaxane 56 (Figure II.4.2) with the loss of
3HC1 (calc. molar mass: 3093.75) and latter [4]rotaxane 57 (Calc. Molar mass:
4589.33). There are additional signals with molar mass up to 20000, although with very low intensity is very weak after 4592 and also peaks are not sharp but more looks like a noise.
128 The method which Entry A and B were employed seemed to be not efficient.
Therefore procedure for Entry C and D (Table II.7.1) was slightly changed. In that a
6N HCl solution of four equivalents QQ and alkyne 24 was stirred at r.t. for 24 hrs before six equivalents of azide 22 was added. Entry C differs from D in that in the latter case 6N HCl has been replaced by a 0.2 N solution of Na2S04 as a solvent.
The working was identical to that mentioned above.
The intensity ratio between triazole and phenyl proton became 1.0:2.1 in ^H-NMR spectrum for Entry C and D. One can speculate from this result that either excess azide 22 could not be removed from the product since it formed an inclusion complex with QQ and that's why the intensity ratio of phenyl proton is high relative to triazole or a mixture of [2], [3], [4] and polyrotaxane has formed as mentioned earlier for Entry A and B. It was not possible to tell the product(s) from 'H-NMR spectrum.
Table II.4.1: Reaction conditions and selected NMR data for the attempted synthesis of generation 0.5 ([4]rotaxane 57). * Reaction was carried out in a 0.2N solution of
Na2S04.
Molar Ratio of Monomers 'H-NMR Entry 22 24 QQ t T Ratio [azidej [alkyne] (h) (°C) Tr:Ph A 4 1 5 24 20 1.0:1.4
B 4 1 5 72 20 1.0:1.4
C 6 1 4 48 20 1.0:2.1 *D 6 1 4 48 20 1.0:2.1
129 MALDI-TOF spectra of Entry C and D revealed a broad molar mass range between
3000-23000 (Da) with clusters of molecular ions.
None of the two methods yielded the desired compound 57 exclusively (generation
0.5). 'H-NMR and MALDI-TOF suggest the formation of more than one compound.
Assuming, the presence of an inclusion complex between excess QQ and excess azide 22 in the isolated solids of Entry A, B, C and D, further purification was attempted. This purification was mainly based on the idea of disrupting the ion- dipole interaction between QQ and excess azide 22 by deprotonation.
Solid 57 (Entry C) was dissolved in water and a O.IN solution of NaOH was added drop wise to bring the pH to ~10. Upon addition of base, solution became cloudy and it was further stirred at r.t. for 2 hrs before the addition of CHCI3. Addition of CHCI3 resulted a gel like mixture which was left stand at r.t. for 24 hrs. However, no phase
separation was observed in the mixture therefore it was evaporated to dryness under reduced pressure to yield a slightly yellow solid which was suspended in methanol
and stirred at r.t. for 24 hrs. An off-white sticky solid was obtained in 68% yield.
'H-NMR spectrum of purified product is essentially the same as before the purification indicating that purification was unsuccessful.
130 11.4.2. Conclusions
Attempts to synthesise dendritic polyrotaxanes via the divergent approach seem to have potential but are hampered by difficulties at the purification stage.
The evidence accumulated is not conclusive with regards to the formation of the generation 0.5 polyrotaxane dendrimer. A suitable purification method has to be found in order to expand this strategy to higher generations. It is also likely that the reaction conditions employed were not optimal, which may have complicated matters even further.
11.4.3. Synthesis of Catalytically Self Threading Branched Polyrotaxanes
Hyperbranched polymer are structurally less perfect than dendrimers but can still exhibit physical properties similar to that of dendrimers and different to their linear polymer analogous. For the synthesis of hyperbranched polymers including hyperbranched polyrotaxanes, ABx (x >1) type monomers are required. There are a few examples for branched^''and dendritic polyrotaxanes^^ to date mainly through work carried out by Gibson et al.
Since our effort for the synthesis of dendritic polyrotaxanes was unsuccesful, instead of dendritic polyrotaxane we wanted to synthesise hyperbranched polyrotaxanes in which all the monomers can react in one pot.
First we intended to use monomers 22 (A2) and 24 (B3) which were in hand to synthesise mixture of B3, AB2, A2B, A3 monomers and to isolate the individual rotaxanes from the reaction mixture by fractional precipitation as shown in the
Figure 11.4.2.
131 58 Figure II.4.2: [3]rotaxane 56 (A2B) and [2]rotaxane 58 (AB2). Two monomers suitable for the synthesis of hyperbranched polyrotaxanes.
Once they are prepared, the polymerisation of these monomeric rotaxanes in the presence of additional quantities of cucurbituril would be carried out. Reaction conditions for the reaction of 22 and 24 with cucurbituril are summarised in Table
11.4.2.
Table II.4.2: Synthesis of monomeric rotaxanes.
Molar ratio 1-NMR Entry 22 24 QQ Time/h Temp/°C Ratio Mn azide alkyne Ph: Tr (Da) A 1 1 1 48 20 to 50 1:1 1800 B 1 2.5 2 48 20 1:2 3200
D 1 3 0.8 192 20 1.0:0.8 1800
132 'H-NMR spectrum of Entry A before the addition of azide 22 was recorded which has shown that -CCH proton is shifted upfield by 0.45 ppm in the presence of cucurbituril. The addition of azide 22 to the solution of QQ and 24 in DCl produced a spectrum like a signals of forest which possibly indicative of the statistical mixture of 16.6% A] (57), 33.3% A2B (56) and 33.3 AB2 (58), 16.6% AB3 type monomers.
The intensity ratio between phenyl and triazole protons is close to be on to one.
Hence it is quite difficult to separate these monomeric rotaxanes from each other, an excess amount of B3 and limited amount of Aa and QQ were reacted as shown in
Table II.4.2 for Entry D, however, ^H-NMR did not show a single product but a complex mixture could not be analysed. The MALDI-TOF spectrum shows a molecular ion at -1700 but also higher under masses molecular weight up to 10000
(Da) with a very weak intensity.
As a result, it has been shown that AB2 and A^B type monomer can be obtained by the method described but separation and purification of product remains an unresolved challenge.
The synthesis of hyperbranched polyrotaxanes using monomeric AB2 or A2 B precursor was not successful. Therefore an alternative approach has been investigated which is the one pot reaction between an A2 and B3 monomer in the presence of QQ were reacted together.
133 Table 11.4.3: Synthesis of hyperbranched polyrotaxanes.
Molar Ratio 'H-NMR Yield (%)
Entry 22 24 QQ T T Ratio Mn (Az) (Bs) (h) (°(:) Tr :Ph (Da) [azide] [alkyne] A 1 1 2 96 + 24 20 to 60 1.51: 1.00 4600 80
B 1.5 1 3 72 20 1.86: 1.00 21500 70
C 1.5 1 3 96 20 1.91: 1.00 32000 75 D 1 1 3 144 60 1.92: 1.00 34000 78
Reactions were carried out by dissolving QQ in 6N HCl followed by the addition of
alkyne 24 then azide 22 as listed in Table II.8.2. Reaction conditions are hsted in
Table II.4.3. The work-up involved precipitation of the reaction mixture into
acetone/ethanol from which a white precipitate was obtained in all cases. During the
subsequent filtration the precipitates formed yellow and sticky (78% yield).
Polyrotaxanes (Entry A-D) are readily soluble in water at r.t.
The characteristic triazole and phenyl protons (see Figure II.4.3. for full spectrum)
were taken as reference once again to calculate the number average molecular
weight Mn based on CBrothers equation as already discussed in Section 11.3.
134 H,N®
0= N=N r 0=:
Figure II.4.3. A (Hyper)branched polyrotaxane 63
These molecular masses are number average molar masses which can give no indication about the degree of branching. Entry A-D produce MALDI-TOF spectra showing molecular ions clusters in the range between 3000-23000 (Da).
Exchange of counterions from chloride to haxafluorophospate made the polymers partially soluble in DMSO and DMF but GPC runs in DMF (by RAPRA) did not provide useful data. Due to nature of this polymerisation approach an end group analysis (including the ratio of unreacted alkyne and azido goups) in the polymer product would principally allow to determine the degree of branching. In our case this is an ongoing endeavour mainly hampered by the limited spectral resolution of the recorded 'H-NMR and '^C-NMR spectra. The use of higher fields and elevated temperature should help to overcome this problem.
135 Int
CRT
&0 74 50 40 30 20 LO (ppm)
Figure IL4.4: 400 MHz ^H-NMR spectrum (in D2O) for catalytically self-threading hyperbranched polyrotaxanes, intensity ratio of Tr(triazole) proton at 6.5 ppm to Ph
(phenyl) proton at 7.2 ppm 11.5 to 6.0, translating into Mn.- 34000.
34000
136 II.5. Attempted Synthesis of Sidechain Polyrotaxanes
There are at least six approaches for the synthesis of sidechain polyrotaxanes^^"-^^ as discussed in the Section LI (Figure LI.21) such as tlireading onto a preformed graft
copolymer, grafting in presence of cychc, grafting of a preformed rotaxane, polymerisation of macromonomer in presence of cyclic, polymerisation of macromonomeric rotaxane and finally chemical conversion.^"^ Here we have
explored two methods for the synthesis of sidechain polyrotaxanes.
The first approach involves the synthesis of a polymerisable rotaxane and the second
approach involves the synthesis of a preformed polymer will be (self)-threaded onto
which the macrocycle as a side chain. The second synthetic variation is a polymer-
analogous polyrotaxane formation.
II.5.1. Attempted Polymerisations of
N-(tert-butyl)-N-[2-(4-{[(4-vinylbenzyl)amino]methyl}-7if-l,2,3-triazoIe-l-
yl)ethyl]amine hydrochloride salt- semi[2]rotaxane 64
The vinyl-rotaxane monomer was synthesised as shown in Figure IL6.1. Equimolar
amounts of monomers 5 and 29 were stirred in the 6N HCl in the presence of one
equivalent of cucurbituril at r.t. for 72 hrs. Work-up involved precipitation into
ethanol/acetone (50/50, (v/v)) to yield white precipitate. Similar to an earlier
structurally related example the white precipitate change colour to become an off-
white powder during filtration (62% yield).
137 0 o IL Jl 6N HCI. RT. 72 hrs ^ ° HzN^ ^ 62% \T T/ H2N© o o
29
A 64 \Jhh, o'^
Figure II.6.1: Synthesis of vinyl-rotaxane 64.
Vinyl-rotaxane 64 was characterised by 'H-NMR spectroscopy and showed the characteristic triazole signal at 6.56 ppm with an intensity of one proton.
The aromatic protons in the styrene moiety give rise to four doublets at 7.55, 7.63,
7.83 and 7.85 ppm whereas in 29 only the two doublets can be observed. This can be explained by the fact that QQ can exist in two different conformations, one where it binds to the benzylammonium group, the other where it is situated closer to the other ammonium ion attached to the t-butylgroup in the molecule.
The double doublet at 6.86 ppm and the two sets of double doublets at 5.40 and 5.92 ppm characteristic of the vinyl group remain at similar chemical shifts compared with starting material 29. However, all methylene groups (a, b, c, d) have shifted downfield relative to their free components 3 and 29. Protons a have shifted downfield from 4.35 to 4.50ppm; b from 3.92 to 4.27 ppm; c from 3.74 to 4.19 ppm and d from .3.22 to 3.80.
138 Protons of QQ give rise to a different splitting pattern relative to the free cucurbituril at 4.27 ppm as a triplet, at 5.52 ppm as singlet and at 5.72 ppm as a double doublet.
However, this observation is not new since QQ has shown similar splitting pattern in rotaxane formation due to experiencing different magnetic environments as discussed in Section 11.2.
II.5.1.2. Attempted Polymerisations of Semi[2]rotaxane 64
Now that the styrenic rotaxane monomer was in hand its free radical polymerisation was investigated.
The reaction was carried out in water (limited solubility of monomer) and therefore
4, 4'-azobis(4-cyanovaleric acid) (ACVA) as water-soluble azo initiator was used.
After three freeze-thaw cycles which is essential to remove oxygen, the solution was heated to 60 °C for 18 hrs. It was precipitated into THF to obtain an off-white solid in %70 yield.
139 HOgC 60 °C, 18hrs/ -Np 11
A 64
Figure 11.6.2: Attempted polymerisation of vinyl rotaxane 64 via free radical polymerisation.
Characterisation of this solid by 'H-NMR spectroscopy revealed complete recovery
of starting material clearly indicating that radical polymerisation was in some way
unsuccessful.
A purely thermally initiated polymerisation was also carried out, this time without the use of a radical initiator.
It is known from the literature that some monomers polymerise slowly on heating, they autopolymerise. In such cases, free radical initiating species are generated in
situ by mechanisms that are usually not, well understood. Styrene undergoes thermal polymerisation more rapidly than the other commercially available vinyl monomers.
The mechanism involves initial formation of a Diels-Alder dimer 66, which
abstracts a hydrogen atom from the monomer to form styryl radical 68 and benzylic radical 67 (Figure 11.6.3). This is an example of what is referred to as molecule-
140 induced homolysis- the rapid formation of radicals by reactions of nonradical
species. 39,40
66 Figure II.6.3. Mechanism of the thermal polymerisation (autopolymerisation) of
styrene. The reaction proceeds via a Diels-Alder intermediate which subsequently
induces homolysis.
Semi[2]rotaxane 60 was dissolved in water and after three freeze-thaw cycles the
solution was heated at 80 °C for 18 hrs. It was precipitated into an acetone/ethanol
mixture. Off-white solid was obtained in quantitative yield.
It could be immediately seen from the 'H-NMR that the vinyl protons had
dissappeared and some additional well-resolved signals had appeared at 1.30 and
1.46 ppm as a multiplet in each case. The aromatic protons on the other hand became broader with overlapping some additional well-resolved signals.
This result may possibly suggest that radical formation took place but based on the well-resolved signalsindicative of a "small molecule" one has to infer that
termination occurred directly after initiation via a radical combination reaction. One
could hypothesise that this may be due to steric and/or electrostatic repulsion between monomers, favouring termination over propagation.
141 Because of limited time no further experiments were conducted to establish the reaction mechanism in more detail.
II.5.2. Synthesis of Polyrotaxane via Polymer Analogous Reactions
Since the polymerisation of semi[2]rotaxane 64 was unsuccessful therefore we explored a polymer-analogous strategy. Here a polymeric precursor is synthesised which later will be turned into a side chain polyrotaxanes.
Monomer 29 was prepared from N-alkylation of proparylamine with 4- vinylbenzylchloride in 77% yield as discussed in Section II. 1 on monomer synthesis.
It was polymerised free radically in water in the presence of ACVA. Polymer 69 was obtained after precipitation in 36% yield.
f n
ACVA, HgO bl^b 6 75 °C, 36% /c H,N© HoN®
29 69
Figure II.6.4. Free radical polymerisation of 29.
^H-NMR spectroscopy revealed broadened signals for all the protons in the polymer structure. The aromatic protons were found at 7.15 and 6.85 ppm due to the ortho- and meta protons. Vinylic protons were absent, which is a good evidence for the polymer formation. Protons due to c, d and e reveal at 4.35, 3.82 and 3.05 ppm as
142 broad singlets. Protons f and g give rise to extremely broad signals at 2.12 and 1.52 ppm respectively.
For the purpose of molecular weight determination, polymer was deprotonated by treating it with aqueous NaOH solution. Resulting free base polymer analogous is soluble in THF and CHCI3; unfortunately, the attempt to run GPC in CHCI3 (by
RAPRA) was unsuccessful. The reason for this not known.
MALDI-TOF spectrum of this polymer shows a sharp peak at 2377 (Da) besides not well-resolved other peaks up to 4500 (Da).
Since ^H-NMR spectroscopy provided a good evidence for the desired polymer formation, the next step was the synthesis of side-chain polyrotaxanes via self- threading method as shown in the Figure II.9.5.
For the polymer-analogous reaction equal amounts of 69, 5 and 1 were dissolved in
6N DCl upon gentle heating. The resulting viscous solution was stirred at r.t. and the reaction was followed by 'H-NMR in the usual way (triazole formation). 'H-NMR spectrum after 24 hrs showed no triazole signal but an upfield shift of the alkyne proton from 3.05 to 2.20 ppm (relative to the starting material) indicating encapsulation by QQ. The polystyrene backbone was almost invisible in the 'H-
NMR spectrum, which can be rationalised by slowed down conformational changes flexibility and a decrease in tumbling frequency of the polymer backbone due to the complexation of QQ.
143 After 48 hrs the triazole proton was identified as a shghtly broad singlet at 6.48 ppm. The alkyne proton at 2.20 ppm on the other hand disappeared. Signals for the polystyrene backbone only presents as very broad humps essentially spread out along the baseline of the spectrum. The result suggests the rotaxanation must have been succesful.
The experiment was repeated on a large scale and by heating it to 70 °C for 5 days followed by precipitation. A slightly yellow solid was obtained in 88% yield. 'H-
NMR spectrum (see Figure 11.5.6) of the solid revealed the characteristic but broad triazole signal at 6.56 ppm. Cucurbituril signals were not well-resolved with peaks overlapped by well-defined resonances. Protons belonging to the t-butyl group gave rise to a sharp single. Very very broad aromatic protons of the polystyrene backbone are seen in the region of 7.26-7.67 ppm.
Obviously the'H-NMR spectrum contains very broad and overlapped signals and this made the structural analysis difficult.
I 6N HC.70°C 120 hrs, 88% H,N® W 17 o o
Figure II. 6.5. Self-threaded side chain polyrotaxane 65
144 As far as we can calculate from the intensity ratios the degree of threading which is the number of macrocyle per repeat unit, is close to one. It means every side chain
(alkyne group) was threaded to form a rotaxane containing the expected triazole ring.
'^C-NMR spectrum revealed only some of the expected carbon signals which were assigned as f (28.26 ppm), j (42.83 ppm), g (50.34 ppm), (C(CH3)3 (60.87 ppm), c
(61.76 ppm), h (123.77), Ar (131.19 ppm) and carbon signals of QQ (54.37, 73.09 and 159.2 ppm) (Figure 11.5.7). Rest of the signals either under the noise or simply they are not present. Even running '^C-NMR for a longer period of time at higher field did not change the outcome.
MALDI-TOF of this compound did not produce useful information. The spectrum shows basically not well-resolved clusters with molecular weights up to 3000 (Da).
145 D.Tuncel- IH orDTl-73-74 in D20 «l iOOMHt
Figure II.5.6: 400 MHz ^H-NMR spectrum (in D2O) for catalytically self- threading side chain polyrotaxane 65.
D. Tuned • 13C of iyr3-73-74 in DM on WUC-WO.
mm
Figure 11.5.7: 100 MHz ^^C-NMR spectrum (in D2O) for catalytically self- threading side chain polyrotaxanes 65.
146 II.5.3. Conclusions
Initial results, in synthesising self-threading sidechain polyrotaxanes are suggesting that semi[2]rotaxane 64 can not be polymerised radically. It is possible that QQ acts as a radical inhibitor but another explanation may be that steric and electrostatic reasons suppress propagation and termination (after initiation) becomes the dominant process.
Threading of the sidechain using a preformed polymer 69 (polymer analogous reaction) gave rather encouraging results. Triazole ring formation was observed
(indicative of rotaxane formation) although the polystyrene backbone was only seen as an extremely broad signal.
Unfortunately time did not allow carrying out one more synthetic variation as shown in Figure 11.2.8. In this case sidechain poly(semirotaxane) 70 would form. It is possible to dethread the polymer by changing pH. The dethreaded polymer 71 is expected to be soluble which would facilitate the analysis of MW and degree of rotaxane formation.
29 + H3N- + 1 + 1
Figure II.6.8. Proposed reaction for the synthesis of non-threaded side chain polymer
71.
147 II.6. Synthesis of Linear Polypseudorotaxanes via a Post-Threading Method
The self-threading approach was successfully applied in the synthesis of structurally well-defined polyrotaxanes but nevertheless it was failed so far in the synthesis of the corresponding polypseudorotaxanes using the discussed current monomer system (Section II.3). For this reason, we have chosen to use a post- threading approach in order to synthesise novel pseudorotaxanes with a particular intention to investigate the threading behaviour of QQ along a linear unstoppered polymer. Inspired by the work of Wenz et al. in which nylon 3/11 and nylon 11 were reduced to the corresponding polyamines and subsequently threaded with cyclodextrins. We decided to reduce Nylon 6/6 to form poly(iminohexamethylene) and then to thread QQ onto this preformed polymer in acidified water.
One of the reason for choosing nylon 6/6 (it could have been nylon 6 as well) is that
QQ forms a very stable inclusion complex with 1,6-diaminohexane dihydrochloride salts as demonstrated recently by Bushmaim et al.^ in polyrotaxane synthesis.
Nylon 6/6 is readily available and in the longer term its low cost may be an added advantage.
IL6.1. Synthesis of Poly(iminohexamethylene) 76
Poly(iminohexamethylene) was prepared by the reduction of nylon 6/6 with
BH3.Me2S in THF.'^'' The reaction was performed in heterogeneous system because nylon 6/6 is insoluble in aprotic solvent like THF. Reaction was complete in 20 hrs. After the workup and purification by extracting with CHCI3 in a soxhlet apparatus, white powder was obtained in 66% yield.
148 H BH3.Me2S ^ -NJ THF, 66% 75 76 Figure II.6.1: Reduction of nylon 6/6 with BH3.Me2S.
The isolated polymer is soluble in diluted HCl and CHCI3 at r.t. Reduction of nylon
6/6 was confirmed by IR and NMR. In IR no signal corresponds to C=0 was observed. '^C-NMR only shows two signals at 27.55 ppm corresponding to the central methylene groups and at 49.79 ppm for the amine-substituted methylene groups.
The 'H-NMR spectrum shows broad signals at 1.42 and 1.68 ppm due to the central methylene protons (b+c) and at 3.01 ppm for terminal methylene protons (a). The spectrum also contained additional signals presumably due to the presence of some non-reduced nylon 6/6. However, those account for less than 3%.
Molecular weight of polymer was determined by GPC in CHCI3 with Mn- 20100,
Mw= 55000 which translates into degree of polymerisation of 200.
11.6.2. Synthesis of Polypseudorotaxanes 77
Poly(iminohexamethlene) 76 was in hand, the next step the threading of QQ onto this polymer backbone. For the synthesis of polypseudorotaxanes, QQ was dissolved in DCl (20%, (w/w)) and stirred for 30 min before the addition of poly(iminohexamethylene). Individual solutions were prepared in NMR tubes by transferring aliquots via a syringe. The progress of the threading reaction was
149 monitored by collecting ' H-NMR spectra at selected time intervals run at different temperatures (20 °C, 60 °C or 90 °C) as summarised in Table II.6.1.
4 + .t c a
76 77
Figure 11.6.2: Synthesis of polypseudorotaxane 77 via the post-threading approach.
150 Table II.6.1: Table summarises the reaction conditions, degree of threading (m/n) and molecular weights (Mn) of the linear polypseudorotaxane 77. m/n: degree of threading m: macrocycle; n: repeat unit
Entry 1 2 3 4 5 6
QQ/n 5/1 1/1 0.5/1 0.3/1 0.2/1 0.1/1 (mol) 200/19E 100/9.9 100/19.9 100/29.8 100/49.7 100/99.4 QQ/n (mg 5 0 5 5 9 T: r.t. m/n m/n m/n m/n m/n m/n 48 hrs 0.05 0.02 0.027 0.024 0.02 0,02 72 hrs 0.09 0.03 0.029 0.03 0.03 0.02 216 hrs 0.11 0.04 0.040 0.03 0.03 0.03 Mn (Da) 41000 28000 28000 27000 27000 26000
T: 60 °C m/n m/n m/n m/n m/n m/n 48 hrs 0.08 0.11 0.1 0.1 0.08 0.04 144 hrs 0.11 0.17 0.16 0.13 0.10 0.04 216 hrs 0.18 0.21 0.18 0.16 0.13 0.05 552 hrs 0J4 026 0.22 0J2 0.05 Mn (Da) 105000 89000 72000 64000 44000 30000 T: 90 °C m/n: m/n m/n m/n m/n m/n 48 hrs 0.18 0.16 0.16 0.16 0.09 0.04 144 hrs 0.41 0.34 0.27 0.20 0.10 0.05 216 hrs 0.51 0.36 0.32 0.23 0.12 0.05 384 hrs O.JP &2J 0.12 0.05 Mn (Da) 139000 97000 89000 66000 44000 31000
151 IL6.2.1. Evaluation of H-NMR Data, Calculation of the Degree of Threading and Molecular Weights (Mn) Determination
When QQ and poly(iminohexamethylene) were reacted in DCl, the 'H-NMR revealed signals which were up field at 0.49 and 0.71 ppm which are characteristic of methylene protons situated inside the cavity of QQ. The degree of threading
(m/n) which is the number of macrocyles (m) per repeat unit (n) was calculated using the ratio of the intensities from b' + c' (which are threaded by QQ) to protons b + c which are un-threaded). Results are summarised in Table 11.6.1.
The number average molecular weight Mn of polyseudorotaxanes 77 were calculated according to the following formula.
(y + molar mass of QQ) + Mn of 76 - 77
(m/n) X (DP)= y
Where y is the number of QQ threaded onto 77.
II.6.2.2. Work-up of 77
Only the work-up of third series the one heated at 90 °C was carried out because it gave the highest degree of threading. For a typical work-up, the solution was precipitated into large excess of propan-2-ol. White precipitate which turned into a slightly off-white and partly sticky solid during filtration was isolated in quantitative yield. However, no further purification was carried out to remove the excess QQ from the polymer. The solid was dried in vacuo for one week.
152 IL6.2.3. Differential Scanning Calorimetry (DSC)
The glass transition temperature (Tg) is the point at which the polymer chains have enough energy to be mobile. The sample changes from being glassy and becomes soft and rubberlike.
TgS are most commonly measured by differential scanning calorimetry (DSC), differential thermal analysis (DTA), or thermomechanical analysis (TMA). We used
DSC to investigate the relationship between the degree of threading and the TgS of polypseudorotanes 77.
Each samples (5-10 mg) of 77, 76 and QQ were sealed in aluminium pans before analysis and heated up to 250-300 °C at a rate of 10 °C/min after coohng down to -
35 °C.
Thermal behaviour of hydrated and anhydrous QQ using DSC was well-documented by Buschmann et They observed three different transitions in the DSC trace.
The first (broad) transition is between 30 °C-150 °C. It is a broad endothermic peak corresponding to the various degrees of hydration of QQ. The second one is a very weak hump around 250 °C indicating that QQ is starting to decompose and the third oneshows that the total decomposition of QQ is taking place around 425 C°.
Sample 76 showed crystallisation transition at 91 °C, which is consistent with literature (94 °C). However, no melting point or Tg was detected in the DSC traces for the sample of 77. Only broad endothermic effect at around 50-150 °C similar to
QQ was observed which is probably the loss of solvent molecules (water).
153 IL6.3. Conclusions
For all ratios of m/n the results show that threading is a very slow process at 20 °C.
Even using a large excess of QQ did this not increase the ratio. An increase in temperature relates directly to the degree of threading which reaches to a maximum at 90 °C.
Another interesting observation is that the concentration of QQ did not make a huge difference in degree of threading meaning that the maximum degree of threading can be achieved with this system is only around 0.5. In other word, every second repeat unit contains one QQ, which also explains why we were not able to synthesise polyseudorotaxanes using aliphatic diazides and aliphatic dialkynes. As documented very well by Mock et aliphatic diammonium ion have a very high binding constant with QQ because of the presence of second ammonium ion in the molecule.
In order to improve the solubility of 77 in aprotic solvents for characterisation purpose, 77 was dissolved in an aqueous IN solution of camphorsulphonic acid followed by the addition of QQ. A suspension formed which was heated at 60 °C for
24 hrs. However heating did not facilitate dissolution of QQ to any noticeable degree.
Time did not allow to investigate further the threading behaviour of QQ with reduced polyamides other than nylon 6/6.
154 II.7. References
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157 III. EXPERIMENTAL
158 III.l. General
III.l.l. Experimental Techniques
All manipulations of air and moisture sensitive compounds were performed under an atmosphere of nitrogen.
Infrared spectra were recorded on a Perkin-Elmer 1710 and 1725 series FTIR spectrometer using KBr plates. Absorptions are abbreviated as follows: vs (very strong), s (strong), m (medium), w (weak), br (broad), sh (shoulder).
NMR spectra were recorded on the following instruments at the listed frequencies,
Bruker DRX400 (400 MHz 'H; 100 MHz '^C), Bruker AC250 (250 MHz ^H; 62.5
MHz '^C). The following abbreviations are used to classify the NMR signals, s
(singlet), d (doublet), t (triplet), q (quartet), sept (septet), m (multiplet), br (broad), vbr (very broad). Chemical shifts quoted as 5 in ppm relative to the appropriate reference. Reference compounds for NMR and their chemical shifts were, CDCI3 (^H
7.26 ppm; '^C 77 ppm), D2O ('H 4.75 ppm), D2SO4 ('H 10.42 ppm), CD3SOCD3,
DSS ('H 0 ppm; 0 ppm).
Atoms in molecules are labelled with small letters (or numbers), which are used to indicate protons in the case of 'H-NMR and carbons in the case of '^C-NMR. Where
(?) indicates unidentified signal in NMR spectra, 'h and '^C-NMR signals that could not be assigned with certainty have not been specified.
GPC analysis was performed by RAPRA on a Polymer Laboratories GPC-210 with a refractive index detector using DMF with ammonium acetate as eluent. Columns are
Plgel 2 X mixed bed-B, 30 cm, 10 microns with a flow-rate of 1.0 ml/min (nominal).
The columns were calibrated with PMMA standards.
159 MALDI-TOF mass spectroscopy analysis was carried out by the ULIRS (University of London Intercollegiate Research Service) on a Fisons (Manchester, UK) TofSpec using a 337 nm nitrogen laser. The mass spectrometer was operated at 28kV accelerating voltage.
Differential scarming calorimetry was conducted by Dr.L.Puech on a Perkin Elmer
Pyris 1 in the Department of Chemical Engineering at Imperial College. Samples of between 5-10 mg were sealed in aluminium pans before analysis and heated at a rate of
10 °C/min. Purge gas was nitrogen.
Elemental analyses were carried out by the Analytical Service of University of North
London.
Note: The counter ion chloride was omitted in some of the figures when ammonium ions were used.
III.1.2. Solvents and Reagents
NMR solvents were obtained commercially and used as received unless stated otherwise: d4-methanol (Aldrich Chemicals), de-DMSO (Aldrich Chemicals), d2- water (Apollo Scientific), dz-sulphuric acid (Apollo Scientific), DCl (35% aqueous solution (w/w)) (Aldrich Chemicals) and DCl (20% aqueous solution (w/w)) (Apollo
Scientific).
The following solvents were dried by prolonged reflux over a suitable drying agent
(in brackets). They were distilled and degassed prior to use: tetrahydrofuran (sodium metal and benzophenone), dichloromethane (calcium hydride) and diethyl ether
(lithium aluminium hydride), ethanol (4A molecular sieve), chloroform (P2O5).
The following reagents were obtained commercially as highest purity available and were used as received unless otherwise stated:
160 These following chemicals were purchased from Aldrich Chemicals:
Chloroacetonitrile, 1,6-diaminohexane, 1,6-dichlorohexane, 1,12-diaminododecane, ethanolamine, IN ethynlmagnesium solution in THF, nylon 6/6, glycoluril, propargylamine, propargyl bromide in Toluene, tert-butyl amine, 2-(N-tert- butylamino)ethanol, 2,4,6-tris-(bromomethyl)-mesitylene, 5-tert-butylisophthalic acid, 4-vinylbenzyl chloride (Aldrich Chemical).
Thionylchloride (Fluka), sodium azide (Avocado), 2,4-bis-(chlormethyl)l,3,5- trimethylene benzene (Lancaster), 9, 10-Antracenediacarboxaldehyde (Acros) etc.
161 III.2. Experimental Details for the Synthesis of Monomers
IIL2.1. Preparation of Cucurbituril
Glycoluril (7.0 g, 49 mmol), formaldehyde (10.5 ml of a 37% w/w aqueous solution
150 mmol), conc.HCl (16 ml) and water (35 ml) were placed in a round bottom flask and heated to reflux until all solid had dissolved. A few minutes later the reaction mixture turned cloudy and a precipitate was formed. The contents of the flask was poured into 350 ml of ice-cooled water and a white powder precipitated. This was filtered off and subsequently washed with water (10 ml), ethanol (10 ml) and diethyl ether (10 ml). The white powder was dried in vacuo over P2O5 for a week to yield the precursor for 1. (Longer drying times better the results).
Yield: 5.42 g (42%). (See discussion, Section ILL).
The well dried solid was placed into a conical flask and conc.H2S04 (2.2 ml of acid per gram of solid) was added carefully. The mixture was heated under vigorous stirring to 110-120 °C until all solid had dissolved. Initially the reaction mixture turned into a brown suspension but subsequently became a brown viscous solution with some fine particles. After cooling to r.t., the mixture was poured into ice cold- water (22 ml per gram of starting material). A small amount of precipitate was filtered off rapidly with suction through sintered glass fiinnel by suction. The light brown coloured filtrate was heated gently to yield a slightly brown coloured crystals
(sometimes white crystals can be obtained).
Purification of cucurbituril (QQ) can be carried out via either method 1 or method 2:
Method 1: Crude QQ is dissolved in formic acid/water (1:1 (v/v)) mixture and heated to reflux for about Ihr. The resulting solution is filtered hot by suction. Through a sintered glass funnel Filtrate was allowed to cool down to r.t.
162 Water (twice the volume of the filtrate) was added to yield a white powder. This white precipitate is washed with hot distilled water and dried over P2O5 under vacuum at
least for a week and stored in a desiccator over P2O5.
Method 2: Crude QQ is suspended in hot conc. HCOOH and heated at 80 °C for ~ 20
min under vigorous stirring. If the crude QQ is coloured, a slightly brown coloured
suspension with white precipitate is obtained. Clearly the impurities are dissolved in
conc. HCOOH but not QQ. colourless crystals is filtered, washed with water and dried
over P2O5 under vacuum at least for a week and stored over P2O5 in a desiccator at all.
Yield; 1.81 g (21%)
M.p: > 300°C3
IR (KBr, Nujol mull, cm"'): 3469 (NH-), 2998 (C-H), 1738 (C=0).
1A Cucurbituril
'H-NMR (250 MHz, DCl) = 6 4.46 (d, 12H, %h = 15.6 Hz, Hb), 5.54 (d, 12H,%h =
15.6 Hz, Ha), 5.75 (s, 12H, He).
'^C-NMR (62.5 MHz, DCl, 35% aq.soln, w/w) = 6 51.55(CH2), 71.60(CH),
158.1(C=0).
Molar Mass of C36H36O12N24 : 996.8418
FAB +ve m/z: 997 [M + H]^, 1019 [M + Na]", 1035 [M + K]+.
Elemental Analysis of C36H36O12N24 • (2.5H2O)
Calc.: C, 41.50; H, 3.96; N, 32.26 Found: C, 41.38; H, 3.93; N, 30.56
163 III.2.2. Preparation of N-(tert-butyl)propargyIamine hydrochloride salt S'*
A solution of propargyl bromide in toluene (80% w/w) (5.0 ml, 45 mmol) was added dropwise to an ice-cooled solution of tert-butyl amine (47.7 ml, 450 mmol) in methanol (175 ml) over a period of 15 min. The clear solution was left at r.t. overnight and then heated at 50°C for 5 hrs. Methanol was removed under reduced pressure to
1/5 of the initial volume. The concentrated solution was treated with NaOH pellets
(3.80 g) and kept for 3 hrs at 0°C by stirring. Precipitated NaBr was filtered off and the resulting mixture was extracted with diethylether (3x50ml). The organic layers were combined and subsequently dried first over potassium hydroxide (~2hrs) then anhydrous potassium carbonate (~1 hrs) and finally molecular sieves (4A) (overnight).
The solvent was removed under reduced pressure and the remaining oily liquid was distilled by bulb to bulb distillation to yield N-(tert-butyl)propargylamine 2.
B.p. 122-125 °C (found), 125 °C (literature) 5
Yield: 2.2 g, 40%.
3 was prepared in cooled methanol (0°C) by adding dropwise a solution of conc.HCl in methanol (50:50 (v/v)). Colourless crystals were formed and they were filtered and dried in vacuo. Recrystallisation firom methanol-toluene (20:80 (v/v)) afforded the title compound 3.
M.p.: 195-198°C (found), 192-196°C (literature)^ m. (Nujol mull, KBr, cm '): 3310 (s), 2359 (w), 2122 (w).
'H-NMR (250 MHz, D2O): 5 1.45 (s, 9H), 3.18 (t, IH, = 2.2 Hz,), 4.25 (d, 2H,
%h = 2.2HZ).
164 III.2.3. Synthesis of (N-tert-butyl)chloroethylamine hydrochloride 4^
A solution of thionyl chloride (6.00 ml, 8.40 mmol) was added dropwise to a stirred solution of freshly distilled 2-(N-tert-butylamino)ethanol (7.26 g, 6.00 mmol) in dry chloroform (55 ml) while keeping the temperature at -10°C. After addition was complete, the resulting white suspension was allowed to warm to r.t. and then was heated to reflux during which the suspension became homogeneous. Precipitate appeared after 60 min. After reflux had continued for another 45 min, the suspension became light yellow in colour and a precipitate was formed. Methanol (5ml) was
added. The reaction mixture was stirred for 10 min. Removal of the solvent under reduced pressure yielded a light yellow solid. Recrystallisation from ethanol-acetone
(80:20 (v/v)) gave 4 as colourless crystals.
Yield: 6.5g(61%)
M.p. 200-204 °C (lit.m.p: 202-203°C)6
'H-NMR (250 MHz, D2O): 5 1.35 (s, 9H, CH3), 3.42 (t, 2H, ^Jhh= 5.77 Hz, NCH2),
3.85 (t, 2H, %H=5.77 Hz, CH2CI).
NMR (62.5 MHz, D2O): 5 27.4 (CH3), 42.5 (CH2CI), 45.8 (NCH2), 60.4
(C(CH3)).
IIL2.4. Preparation of N-(tert-butyl)azidoethyIamine hydochloride
N-(tert-butyl)chloroethylamine hydrochloride salt 4 (5.02 g, 29.20 mmol) and sodium
azide (2.28 g, 35.00 mmol) were dissolved in 50 ml of water and heated at 75 °C
overnight. A solution of sodium hydroxide (7.3N, 4ml) was added and the product was steam distilled. Sufficient hydrochloric acid (6N) was added to adjust the pH to
165 1-2. The acidified reaction mixture was evaporated to dryness under reduced pressure.
A white solid has formed which was recrystallised from ethanol-toluene (20:80 (v/v)) to yield colourless crystals.
Yield: 2.13g(41%)
M.p: 126-128 °C (found), 126-129 (literature).^
'H-NMR (250 MHz, D2O) - 5 1.34 (s,9H, CH3), 3.22 (t, 2H, ^Jhh = 5.11 Hz, -
NCH2CH2N3), 3.75 (t, 2H, ^Jhh= 5.11 Hz, NCH2CH2N3).
'^C- NMR (62.5 MHz, D2O): 5 27.6 (CH3), 43.4 (NCH2CH2N3, 50.3 (NCH2CH2N3),
60.3 (C(CH3)).
FAB +ve m/z: 143 [M-HCl]^
III.2.5. Synthesis of N\ N^-bis(2-hydroxyethyl)-l,6-hexanediamine 6*
1,6-Dichlorohexane (10 g, 64 mmol) was added dropwise to ethanolamine (25 ml,
414 mmol) at 120-130 °C under vigorous stirring over a period of 20 min. The
mixture was further heated at 150-160 °C for 6 hrs, cooled down to r.t., treated with a
methanohc solution of sodium hydroxide (125 ml, 0.05 N) and kept for 4-5 hours at 0
°C. The precipitated sodium chloride was filtered off and methanol was removed
under reduced pressure. Ethanolamine was distilled off under vacuum at 40°C (1mm
Hg) and the remaining light yellow solid was recrystallised from ethanol to yield
white microcrystalline 6.
Yield: 7.25 g (57 %)
166 'H-NMR (250 MHz, D2O): 5 1.45, (m, 4H, e), 1.65 (m, 4H, d), 3.05 (t, 4H, ^Jhh= 7.1 Hz , c), 3.15 (t, 4H, ^Jhh= 5.4 Hz, b) and 3.75 (t, 4H, ^Jhh^ 5.4 Hz, a).
'^C-NMR (100 MHz, D2O); 6 28.09 (e), 28.13 (d), 50.23 (c), 51.86 (b), 59.49 (a).
MS E.I. m/z; 202 [M-2H].
III.2.6. Synthesis of N\ N®-bis(2-azidoethyl)-l,6-hexanediamine dihydrochloride
Salt 98
N\ N^-bis(2-hydroxyethyl)-l,6-hexanediamine 6 (2.5 g, 12.2 mmol) and thionyl
chloride (25 ml) were heated to reflux for 100 min. The reaction mixture was cooled to r.t. and excess thionyl chloride was removed under reduced pressure. The resulting
dark brown residue was washed with 2-propanol. The dark coloured powder was
filtered off and recrystallised from isopropanol to yield 7 as a light brown solid, which was used in the next step without further purification.
Yield: 2.5 g, 65%.
c Ho5 - N d © a 7
^H-NMR (250 MHz, D2O): 51.40, (m, 4H, e), 1.65 (m, 4H, d), 3.05 (t, 4H, %h =
7.14 Hz, c), 3.45 (t, 4H, ^Jhh = 5.4 Hz, b) and 3.80 (t, 4H, =5.4 Hz, a).
7 (1.73 g, 5.54 mmol) and sodium azide (1.00 g, 15.4 mmol) were dissolved in water
(25 ml). The light yellow solution was heated to 75°C under vigorous stirring
167 overnight. Sodium hydroxide pellets (0.50 g, 12.5 mmol) were added and the solution was stirred for Ihr. The precipitated salt was filtered off and the filtrate extracted with diethylether (4 x 25 ml) and the combined organic phase was washed with sat. NaCl solution (30 ml). The organic layer was dried over anhydr.MgS04. N', N^-bis(2- azidoethyl)-l,6-hexanediamine 8 was isolated as a pale yellow oil after the solvent had been removed under reduced pressure.
Yield: 0.66 g (60%)
8 was dissolved in ethanol (5 ml) and a IN solution of HCl in ether was added dropwise. After three hours stirring at RT the precipitated white solid was filtered off.
Recrystallisation fi-om ethanol/toluene (50:50 (v/v)) yielded a light yellow, microcrystalline product, 9.
Yield: 0.75 (84%)
" H2A ^3 ^ g a 9
IR (Nujol mull, KBr, cm"'): 3585(w), 3392(m), 3158(m), 2438(m), 2105(s), 2088(vs).
NMR (250 MHz, D2O): 51.35 (m, 4H, e), 1.65 (m, 4H, d), 3.05 (t, 4H, %h= 7.14 Hz, c), 3.15 (t, 4H, 5.40 Hz, b), 3.75 (t, 4H, ^Jhh= 5.40 Hz, a).
"C-NMR (100 MHz, D2O): 6 28.07 (e), 28.11 (d), 49.08 (c), 49.76 (b), 50.39 (a).
Mw of C10H24CI2N8 : 327.26
E.I. m/z: 256(M-2C1).
Elemental analysis: Calc.: C, 36.70; H, 7.39; N, 34.24; found: C, 36.81; H, 7.52; N,
34.50
168 III.2.7. Synthesis of ({6-[(cyanomethyl)amino]hexyl}amino) acetonitrile dihydrochloride salt lOb^
1,6-Diaminohexane (5.81 g, 0.05 mol), triethylamine (10.10 g, 0.10 mol) and chloroacetonitrile (4.60 ml, 0.10 mol) were dissolved in ethanol (60). The clear solution was heated to reflux for 4 hrs. The solvent was removed under reduced pressure and the yellow residue dissolved in chloroform (50 ml). The organic layer was washed with water (3x50 ml) and dried over anhydr. MgS04.
The solvent was removed under reduced pressure and a light yellow coloured oil was obtained as ({6-[(cyanomethyl)amino]hexyl}amino)acetonitrile 10a.
Yield: 2.94 g (31%).
The oil 10a was dissolved in ethanol (15 ml) and a IN solution of hydrochloride in ether was added dropwise. After 5 hrs the precipitated light yellow solid was filtered off and recrystallisation from ethanol/toluene (70:30 (v/v)) yielded a white powder.
Yield: 2.85 (70%)
b c e d H2 . N
H2 d e c b ®
10b
IR (Nujol mull, KBr, cm '): 3397(w), 3155(w), 2423(s), 2231(w), 2033(w).
'H-NMR (250 MHz, CDCLS):^ = 1.30 (m, 4H, e), 1.35 (m, 4H, d), 2.55 (t, 4H, ^Jhh =
4.2 Hz, c), 3.45 (s, 4H, b).
13,C-NMR(62. 5 MHz, CDCl3):5 = 26.73(e), 29.21(d), 37.25(c), 48.58(b), 118.06(a).
169 III.2.8. Preparation of N\ N^-di(2-propynyI)-l,6-hexanediainme dihydrochloride
N', N^-di(t-butoxycarbonyl)-l,6-hexanediaminell (2.08 g, 6.32 mmol) was dissolved in DMF (15 ml) to which NaH (0.50 g, 60%wt dispersion in oil, 12.64 mmol) was added slowly. The mixture was stirred for 1 hr at r.t. before propargyl bromide (1.90 g,16.0 mmol ) was added. Stirring was continued for 18 hrs. The solvent was removed under reduced pressure and the remaining brown residue was purified by flash chromatography (CHaCb/MeOH/hexane, 30:40:30, (v/v/v)).
The resulting light brown oil was dissolved in dry ethanol and a solution of anhydrous hydrochloric acid in ether was added dropwise under vigorous stirring.
After 4-5 hrs, the light yellow precipitate was formed. It was filtered and dried in vacuo to yield 12.
Yield: 60 mg (36%)
b ® c e d §
12
IR (Nujol mull, KBr, cm '): 3417(vw), 3227(w), 2590(w), 2424(w), 2327(vw),
2126(w)
'H-NMR (250 MHz, D2O): 5 1.35 (m, 4H, f), 1.65 (m, 4H, e). 2.90 (t, 2H, = 2.2
Hz, b), 3.15 (t, 4H, %H=7.5 Hz, d), 3.90 (d, 4H, %h= 2.2 Hz, c).
Molar Mass of C12H22CI2N2: 265.22
FAB +ve m/z: 193 [M-2HC1]^ 229 [M-HCl]"".
Elemental analysis of C12H22CI2N2: Calc.: C, 54.34; H, 8.36; N, 10.56; found: C,
54.60; H, 8.52; N, 10.85
170 III.2.9. Synthesis of N-{2,4,6-triniethyl-3-[(2-propynylamino)methyl}benzyl}-2- propyn-l-amine dihdrochloride salt 18
2,4- Bis-(chloromethyl)-l,3,5-trimethylene benzene (0.51 g, 2.3 mmol) was added to the excess propargylamine (2.0 ml, 40.6 mmol) at 0 °C. When the addition was complete, a light brown solution was obtained which has started to solidify within 5 min. This solid was heated to dissolve then refluxed for 4 hrs. The yellow- brown
solution further stirred overnight at r.t. The excess propargylamine was distilled off at
ambient pressure. The brown solid residue was dissolved in water (5 ml). Sodium hydroxide pellets (0.2 g, 5.0 mmol) were added and stirred for 2-3 hrs. The aqueous
layer was extracted with chloroform (4x5 ml) and the combined organic layers were
then washed with sat. NaCl solution (10 ml). The isolated organic phase was dried
over magnesium sulphate and the solvent was removed under reduced pressure to yield a light brown sohd, 17.
Yield; 0.55 g (100%) (crude).
17
^H-NMR (250 MHz, CDCI3); 5 2.29 (t, 2H, = 2.5 Hz, a), 2.35 (s, 6H, e+f), 2.45
(s, 3H, d), 3.49 (d, 4H, ''Jhh = 2.5 Hz, b), 3.84 (s, 4H, c), 6.86 (s, IH, g).
Crude 17 (0.55 g) was dissolved in chloroform (5 ml) and 1 N solution of HCl in
diethylether (4.5 ml) was added dropwise. A dark yellow precipitate was formed
immediately and the suspension was stirred overnight. The yellow precipitate was
171 collected by filtration and washed with chloroform (5ml) and diethylether (10 ml).
Recrystallisation from ethanol/toluene (80:20 (v/v)) gave 18 as a light yellow powder.
Yield: 0.60 g (86%)
^H-NMR (250 MHz, D2O): 5 2.30 (s, 6H, e), 2.40 (s, 3H, d), 3.05 (t, 2H, ^Jhh = 2.5
Hz, a), 4.09 (t, 4H, %h - 2.5 Hz, b), 4.44 (s, 4H, c), 7.15 (s, IH, f).
'^C-NMR (100 MHz, D2O, DSS): 5 18.43 (d), 22.13 (e), 39.80 (b), 47.87 (c), 76.06
(a), 81.46 (-CCH), 129.52 (Ar, C4), 134.39 (Ar, CI), 141.45 (Ar, C2 + C6), 143.62
(Ar, C3 + C5).
Molar Mass of C17H24CI2N2: 327.29
FAB +ve m/z: 255 [M-2HC1]^, 291 [M-HCl]^.
Microanalysis for C17H26N2CI2O: calc.: C, 59.13; H, 7.59; N, found: C, 59.46; H,
7.61; N, 8.79
III.2.10. Synthesis of N-(2-hydroxyethyl)-N-(3-{{(2-hydroxyethyI)ammo]methyI}-
2,4,6 trimethylbenzyl} amine 19®
2,4-Bis-(chloromethyl)-1,3,5-trimethylene benzene (1.0 g, 4.6 mmol) was added portionwise under vigorous stirring at 120-130 °C to ethanolamine (5.6 ml, 92.0 mmol) over a period of 20 min. The mixture was further heated at 150-160 °C for 6 hrs, allowed to cool to r.t. and then treated with a 0.05 N methanolic solution of
NaOH (20 ml). Then solution was cooled to 0 °C and stirred for several hours at this
172 temperature. The precipitated sodium chloride was filtered off, methanol was removed under reduced pressure. Excess ethanolamine was distilled off under vacuum at 50 °C (0.8 mm Hg) and the remaining white solid was recrystallised from ethanol to yield 19 as a white powder.
Yield: 0.80 g (66%)
'H-NMR (250 MHz, DzO): 6 2.25 (s, 6H, e), 2.30 (s, 3H, d), 2.80 (t, 4H, ^Jhh = 7.5
Hz, b), 3.54 (t, 4H, ^Jhh = 7.5 Hz, a), 3.77 (s, 4H, c), 6.95 (s, IH, f).
'^C-NMR (100 MHz, D2O): 5 18.64 (e), 22.24 (d), 41.77(c), 48.23 (b), 51.83 (a),
129.43 (Ar), 134.44 (Ar), 141.50 (Ar), 143.60 (Ar).
Molar Mass of C15H26N2O2: 266.38
FAB +ve m/z: 267 [M+H]"^
III.2.11. Synthesis of N-(2-chloroethyl)-N-(3-{(2-chloroethyl)amino]methyI}-
2,4,6-trimetbylamine dibydrochloride salt 20^
19 (2.22 g, 8.37 mmol) was dissolved in chloroform (25 ml) and cooled to -10°C.
Thionyl chloride (2.50 ml, 34.0 mmol) was dissolved in chloroform (10 ml) and added dropwise under vigorous stirring over a period of 15 min. The resulting white suspension was allowed to warm to r.t. and then heated to reflux for 3 hrs.
During this time the solution became first light yellow in colour and then a precipitate formed. The mixture was allowed to cool to r.t. and methanol (10 ml) was added and
173 the reaction mixture was stirred for 15 min. Removal of the solvent under reduced pressure yielded a light yellow solid. Recrystallisation from ethanol/ acetone (60:40
(v/v)) gave 20 as a white powder.
Yield: 1.76 g (70%)
20
'H-NMR (250 MHz, D2O): 5 2.37 (s, 6H, e+f), 2.43 (s, 3H, d), 3.58 (t, 4H, ^Jhh =
5.5 Hz, b), 3.91 (t, 4H, ^Jhh = 5.5 Hz, a), 4.55 (s, 4H, c), 7.14 (s, IH, g).
"C-NMR (100 MHz, D2O): 6 18.36 (e), 22.10 (d), 48.18 (a), 52.08 (c), 59.08 (b),
129.88 (Ar), 134.28 (Ar), 141.28 (Ar), 143.29 (Ar).
Molar Mass of C15H26N2CI4: 374.09
E.I. m/z: 302 [M-2HC1]
111.2.12. Synthesis of N-(2-azidoethyl)-N-(3-{{(2-azidoethyl)ainino]methyI}-
2,4,6-trimethylbenzyl)amine dihydrochloride salt 22
21 (1.39 g, 4.60 mmol) and sodium azide (1.19 g, 18.4 mmol) were dissolved in
water (50 ml). The light yellow solution was heated at 75 °C under vigorous
stirring overnight. Sodium hydroxide pellets (0.81 g, 20 mmol) were added neat
and the solution was stirred for 2 hrs. The light yellow oil was extracted with
chloroform (4 x 30 ml) and the organic phase was washed with sat. NaCl (30 ml)
solution and dried over anhydr.MgS04. A pale yellow oil of 21 was obtained after
the solvent was removed under reduced pressure.
174 Yield: 1.02 (87 %).
IR (film, KBr, cm '): 3328 (br), 3006(s), 2922(s), 2101 (vs), 1667(m), 1451 (s).
'H-NMR (250 MHz, CDCI3): 5 2.33 (s, 6H, e), 2.42 (s, 3H, d), 2.90 (t, 4H, =
5.6 Hz, b), 3.46 (t, 4H, ^Jhh = 5.6 Hz, a), 3.77 (s, 4H, c), 6.95 (s, IH, f).
Freebase 21 was dissolved in dry methanol (5 ml) and a solution of anhydrous 1 N
HCl in diethyl ether (6.5 ml) was added drop wise under vigorous stirring at 0 °C
over a period of 20 min. Afterwards the yellow reaction mixture was stirred at r.t.
for 5 hrs. The solvent was removed under reduced pressure to yield a yellow solid
which was recrystallised from ethanol to yield 22 as a pale yellow microcrystalline powder.
Yield: 1.20 g (96%)
'H-NMR (250 MHz, D2O): 5 2.32 (s, 6H, e ), 2.42 (s, 3H, d), 3.36(t, 4H, ^Jhh = 5.6
Hz, b), 3.81 (t, 4H, ^Jhh = 5.6 Hz, a), 4.39 (s, 4H, c), 7.15 (s, IH, f).
"C-NMR (100 MHz, D2O): 6 18.50 (d), 22.15 (e), 48.32 (c), 49.28 (b), 49.38 (a),
129.54 (Ar), 134.37 (Ar), 141.36 (Ar), 143.46 (Ar).
Molar Mass of C15H26N8CI2: 389.33
175 FAB +ve m/z: 317 [M-2HC1]\ 353 [M-HCl]".
Elemental analysis of CtsHzeNgClz: calc.: C, 46.28; H, 6.73; N, 28.78; found: C,
46.26; H, 6.71; N, 28.70
III.2.13. Synthesis of
N-{2,4,6-trimethyl-3,5-bis[(2-propynylamino)methyl]benzyl}-2-propyn-l-amine trihydrochloride salt 24
2,4,6-Tris-(bromomethyl)-mesitylene (1.0 g, 2.5 mmol) was added portionwise to propargylamine (3.4 ml, 50.0 mmol) at 0 °C over the period of 30 min. After the addition was complete, a dark red solid was obtained. It was brought to r.t. and was then heated to reflux at 50-60 °C for 24 hrs.
The excess propargylamine was distilled off at ambient pressure. The dark red residue was suspended in chloroform (5 ml) and IN NaOH solution (8 ml) was added. The reaction mixture was stirred for 3-4 hrs and extracted with CHCI3 (4 x
5ml). The organic layer was washed with sat. NaCl solution and dried over anhydr.
MgS04. The solvent was removed under reduced pressure to yield 23 as a red- brown oily residue.
Yield: 0.90 g (100%) (crude).
176 ^H-NMR (250 MHz, CDCI3): 5 1.06 (br, 3H, NH), 2.36 (t, 3H, %n = 2.5 Hz, a),
2.45 (s, 9H, d), 3.50 (d, 6H, %h = 2.5 Hz, b), 3.86 (s, 6H, c).
The crude 23 was dissolved in dry CHCI3 (5 ml) and a solution of anhydr.lM HCl in
diethylether (11 ml) was added dropwise over a period of 15 min. The brown
coloured reaction mixture was stirred overnight. The light brown precipitate was
filtered off and washed with diethylether (10 ml). Recrystallisation from
ethanol/toluene (80:20 (v/v)) gave a light orange solid of 24.
Yield: 0.95 g (88%)
24
^H-NMR (250 MHz, D2O): 6 2.49 (s, 9H, d), 3.06(t, 3H, %n = 2.5 Hz, a), 4.04 (t, 6H,
%n = 2.5 Hz, b), 4.54 (s, 6H, c).
'^C-NMR (100 MHz, D2O): 5 19.53 (d), 39.98 (b), 48.25 (c), 75.99 (a), 81.70 (-CCH),
131.02 (Ar, CI + C3 + C5), 144.06 (Ar, C2 + C4 + C6).
Molar Mass of C21H31N3CI4: 429.15
FAB +vem/z: 322 [M-3HC1]^, 358 [M-2HC1]'".
Elemental Analysis for C21H31N3CI4: calc.: C, 58.54; H, 7.02; N, 9.75; found: C,
58.38; H, 6.93; N, 9.73
177 III.2.14. Synthesis of N-(3-butynyl)-N-(4-vinylbenzyl)amine hydrochloride salt
29
Propargylamine (2.3 ml, 32.8 mmol) was dissolved in dioxane (15 ml) and 4- vinylbenzyl chloride (1.0 g, 6.6 mmol) was added drop wise at 0 °C under vigorous stirring over the period of 20 min. The light yellow solution was stirred for 2 days at r.t. A Sodium hydroxide solution (5 ml, 1.5 M) was added dropwise and the reaction mixture was stirred for Ihr. The yellow suspension was extracted with diethylether
(2x 15 ml), chloroform (15 ml x2) and sat. NaCl solution (20ml). The organic layers were dried over anhdyr.MgS04. The solvent was removed under reduced pressure to yield a light yellow oil of 28.
Yield: 2.14 g (98%) (Crude)
28
^H-NMR (250 MHz, CDCI3): 5 1.62 (br,lH, NH ), 2.27 (t, IH, ^Jhh - 2.7 Hz, h), 3.44
(d, 2H, %H = 2.7 Hz, g), 3.87 (s, 2H, c), 5.24 (d, IH, = 12.5 Hz, f), 5.76 (d, IH,
%H - 18.4 Hz, e), 6.72 (dd, IH, ^Jhh = 10.8,17.5 Hz, d), 7.28-7.39 (m, 5H, a+b+?)
This yellow oil 28 was dissolved in dry chloroform (10 ml) and IN HCl solution in
diethylether (7 ml) was added dropwise. The yellow-orange precipitate which was
178 formed was filtered off and washed with diethylether (10 ml), followed by acetone
(10 ml). Recrystallisation from ethanol/toluene (70:30 (v/v)) gave 29 as a pale yellow
powder.
Yield: 2.59 (77%)
29
'H-NMR (250 MHz, D2O): 5 2.97 (t, IH, ^Jhh = 2.7 Hz, h), 3.85 (d, 2H,%h = 2.7 Hz, g), 4.26 (s, 2H, c), 5.33 (d, IH, %h = 12.5 Hz, f), 5.89 (d, IH, %h = 18.4 Hz, e), 6.80
(dd, IH, ^Jhh = 10.8, 17.6 Hz, d), 7.37 (d, 2H, ^Jhh = 8.2 Hz, b), 7.53 (d, 2H, ^Jhh =
8.2 Hz, a).
'^C-NMR (100 MHz, D2O): 5 23.5 (g), 38.4 (c), 52.5 (h), 75.5 (-CCH), 118.5
(C=CH2), 129.8 (C=CH2), 132.5 (Ar), 133.2 (Ar), 138.7 (Ar), 141.5 (Ar)
FAB+vem/z: 172 [M-Cl]^
III.2.15. Attempted Synthesis of
N-({10-[2-propynylamino)methyl]-9-anthryl}methylene)-2-propyn-l-amine 3V^
9,10-Antracenedicarboxaldehyde (1.0 g, 4.3 mmol) was dissolved in chloroform (100 ml). Propargylamine and 4A molecular sieve (20 g) were added. The reaction mixture
179 was heated to reflux. Within Ihr, the clear yellow solution became cloudy and a yellow precipitate formed. The suspension was heated to reflux. After refluxing Ihr, the solvent was removed under reduced pressure to yield an orange residue.
Recrystallisation from THF yielded 30 as a light yellow crystalline powder.
Yield: 0.95 g (64%)
'H-NMR (250 MHz, DMSO): 5 3.58(br, 2H, a), 4.82(br, 4H, b), 7.64(m, 4H, d),
8.49(m, 4H, e), 9.66(s, 2H, c).
Note: Some of the signals in 'H-NMR spectrum are not well-resolved.
Molar Mass of C22H16N2: 308.376
E.I. m/z: 308.131
Free base 30 (0.38 g, 1.62 mmol) was dissolve in dry THF (15 ml) with gentle heating. NaBH4 (0.45 g, 16 mmol) was added portionwise at r.t. and the reaction mixture was heated to reflux for 2 hrs; stirred at r.t. overnight. The solvent was removed under reduced pressure. The remaining brown solid was dissolved in water
(10 ml), sodium hydroxide pellets (0.13 g) were added and the solution was extracted with dichloromethane (5x 4ml). The organic phases were combined and dried over
180 anhydr.MgS04. After removal of the solvent, a red oil was obtained. The product could not be identified through its 'H-NMR and IR spectra.
IIL2.16. Synthesis of 5-fert-butyl-A^'^^-di(2-propynyI)isophthalamide 32a
5-Tert-butylisophthalic acid (2.0 g, 9.0 mmol) was dissolved in dry THF (150 ml) and heated to 60°C. 1,1-Carbonyldiimidazole (2.92 g, 18.0 mmol) was added. The clear solution was heated for 3 hrs, cooled down to r.t. and propargylamine (1.5 ml, 20 mmol) was added dropwise. The yellow coloured clear solution was heated at 60 °C for 3 hrs. The solvent was removed under reduced pressure to yield a yellow oil which was washed with water several times to obtain 32a as a white crystalline powder.
Yield: 1.90 (75%).
32a
^H-NMR (250 MHz, CDCI3): 5 1.35 (s, 9H, tert-butyl), 2.32 (t, 2H, %h = 2.5 Hz, a),
4.30 (q, 4H, %H = 2.5 Hz, b), 6.62 (br, 2H, NH), 8.05 (s, 3H, c).
Molar Mass of C18H20O2N2: 296.1525
FAB +ve m/z: 297.1603 [M+H]^.
181 IIL3.1. Preparation of Rotaxanes
III.3.1.1. Synthesis of [2]rotaxane 33^
Cucurbituril, 1, (200.0 mg, 200.0 p.mol) was dissolved in 6N HCl (5 ml) and stirred at r.t. for 30 min. Tert-butyl-azidoethylamine hydrochloride salt 5 (36.0 mg, 200.0
|j,mol) was added under vigorous stirring and followed by tert-butyl-propargylamine hydrochloride salt 3 (30.0 mg, 200.0 jiimol). The clear solution was stirred at r.t. for
72 hrs. After removal of the solvent under reduced pressure a white solid was left behind which was suspended in hot water (5 ml, -80 "C) for 1 hr. Undissolved cucurbituril was removed by filtration. The filtrate was precipitated into a large excess of acetone upon which a white precipitate was formed. It was filtered off, washed with acetone (10 ml) and dried in vacuo over P2O5 for one week to afford 33.
Yield: 190 mg (71%)
Hz 0=
33
'H-NMR (250 MHz, D2O): 6 1.61 (s, 9H, e or f), 1.64(s, 9H, e or f), 3.56 (t, 2H,
= 6.3 Hz, a), 3.87 (t, 2H, ^Jhh = 6.3 Hz, b), 4.26 (dd, 12H, ^Jhh = 15.6 Hz, QQ + s, 2H, d), 5.49(s, 12H, QQ), 5.71 (dd, 12H, = 15.6 Hz, QQ), 6.50(s, IH, c).
"C-NMR (100 MHz, D2O, DSS): 5 28.40 (f or e), 28.86 (f or e), 39.47 (a), 43.41 (b),
50.33 (d), 54.34 (QQ), 61.23 (€(%)]), 62.12 (€(%)]), 73.20 (QQ), 124.29 (Tr,
CI), 142.65 (Tr, C2), 159.54 (QQ)
Molar Mass of Ci3H29N5Cl2.(C36H360i2N24): 1323.16
FAB +ve MS m/z; 1251 [M-2C1]\ 1287[M-C1]+
182 Elemental analysis of C, 3H29N5CI2. (CseHseO 12N24) x 9H2O
Calc.: C, 40.24; H, 5.16; N, 27.81, Found: C, 40.11; H, 5.56; N, 27.68
Calc.: C, 44.48; H, 4.95; N, 30.70 (Anhydrous 33).
IIL3.1.2. Synthesis of [3]rotaxane 34
Cucurbituril 1 (150.0 mg, 151.0 ^mol) was dissolved in 6 N HCl (4 ml) and 5 (27.0 mg, 151.0 lamol) was added under vigorous stirring, followed by N- {2,4,6-trimethyl-
3-[(2propynylamino)methyl}benzyl}-2-propyn-l-amine dihydrochloride salt 17 (21.9 mg, 75.0 )j.mol). The yellow coloured clear solution was stirred at r.t. for 72 hrs. The solvent was removed under reduced pressure to yield a light yellow film, which was scraped off the wall of the flask. The resulting powder was suspended in MeOH and stirred at r.t. for 3 hrs. The undissolved residue was filtered off, washed with methanol (3 ml), acetone (5 ml) and dried in vacuo. The isolated solid was suspended in hot water (5 ml) at 80 °C and stirred for 1 hr before filtered to remove excess cucurbituril. The solvent was removed under reduced pressure to yield 34 as an off- white powder which was dried in vacuo over P2O5 for a week
Yield: 175 mg (88%)
Hz O- =0 ^ h N Hz =0 ® g 34
'H-NMR (250 MHz, D2O) : S 1.68 (s, 18H, h), 2.68 (s, 6H, f), 2.98 (s, 3H, g), 3.81 (t,
4H, = 7.9 Hz, a), 4.03 (t, 4H, ^Jhh = 7.7 Hz, b), 4.30 (dd, 24 H, QQ + s, 4H, d),
4.85 (s, 4H, e), 5.59 (s, 24H, QQ), 5.73 (t, 24H, QQ), 6.54 (s, 2H, c), 7.29 (s, IH, h).
183 Molar Mass of C29H54NioCl4.(C36H360i2N24)2' 2678.32
ES-MS m/z: 2536.50 [M-4Clf, 2573.10 [M-3Clf
Elemental analysis of C29H54NioCl4.(C36H360i2N24)2 x 2IH2O
Calc.; C, 39.42; H, 5.39; N, 26.91; found; C, 39.69; H, 5.54; N, 26.58
Calc.: C, 45.29; H, 4.74; N, 30.33 (Anhydrous 34)
III.3.1.3. Synthesis of [3]rotaxane 35
Cucurbituril 1 (150.0 mg, 151.0 |a.mol) was dissolved in 6N HCl (4 ml) and 22 (29.8 mg, 75.0 mmol) followed by 3 (4.0 mg, 151.0 |j,mol mmol) were added under vigorous stirring and stirred at r.t. for 72 hrs. The solvent was removed under reduced pressure to yield a yellow film, which was scraped off the wall of the flask. The resulting powder was suspended in MeOH (3 ml) at r.t. and stirred for 3hrs. The undissolved residue was filtered and washed with MeOH (3 ml) followed by acetone (5 ml). To remove excess of cucurbituril, the precipitate was dissolved hot water (5 ml) at ~80 "C and stirred for 1 hrs. Undissolved particles were removed by filtration. Removal of the solvent under reduced pessure afforded 35 as an off-white powder which was dried in vacuo over P2O5 for one week
Yield: 160 mg (80%)
0=
H2 0% Hz O
'H-NMR (250 MHz, D2O); 5 1.48 (s, 18H, i), 2.59 (s, 6H, g), 2.92(s, 3H, f), 3.45 (br,
4H, d ), 3.77 (br, 4H, c), 4.17 (dd, 24 H, QQ + s, 4H, e), 4.85 (s, 4H, a), 5.48 (48H,
QQ), 6.54 (s, 2H, b), 7.29 (s, IH, h).
184 Molar Mass of C29H54NioCl4-(C36H360i2N24)2: 2678.32
ES-MS m/z: 2572.50 [M-3C1]\
IL3.1.4. Synthesis of [4]rotaxane 36
Cucurbituril 1 (150.0 mg, 151.0 |amol) was dissolved in 6N HCl (4 ml) and stirred at r.t. for 30 min. Compound 24 (21.7 mg, 50.3 p.mol) followed by 5 (27.0 mg, 151.0 p.mol ) were added under vigorous stirring to obtain a clear solution which was further stirred at r.t. for 72 hrs. The solvent was removed under reduced pressure to yield a light yellow film which was suspended in hot water (4ml) at 80 °C and stirred for 1 hr. Undissolved excess cucurbituril was removed by filtration. Filtrate was precipitated into acetone (10ml) and white precipitate was collected by centrifugation.
It was dried in vacuo over P2O5 for one week to afford title compound 36.
Yield: 177.4 mg (89%)
@NH, a
H,Ne
36
^H-NMR (400 MHz, D2O): 5 1.60 (s, 27H, g), 3.11 (s, 9H, a), 3.58 (m, 6H, f), 3.86
(m, 6H, e), 4.30 (m, 36H, QQ), 4.5l(s, 6H, b), 5.53 (s, 36H, QQ), 5.74 (t, 36H, QQ),
6.49 (s, 3H, d).
185 "C-NMR (100 MHz, D2O): 8 20.32 (a), 27.56 (?), 28.19 (?), 28.41 (g), 42.91 (?),
43.33 (f), 49.95 (-NCCCH])]), 54.12(QQ), 54.34 (QQ), 62.15 (b), 72.24 (c), 72.45
(e), 73.08(QQ), 73.16(QQ), 123.95(Tr), 130.99 (Ar), 142.33 (Tr), 146.04 (Ar),
159.18 (QQ), 159.52 (QQ).
Molar Mass of C39H75N]5Cl6.(C36H360]2N24)3 •' 3957.38
MALDI-TOF m/z: 3910 [(M-2C1) + Na]+ (?)
III.3.1.5. Preparation of semi[2]rotaxane 37
1 (100.0 mg, 100.0 i^mol) was dissolved in 6N HCl (3ml) and stirred vigorously at r.t. for 30 min. After adding 25 (17.9 mg, 100.0 p,mol) followed by 5 (19.1 mg, 100.0
|i,mol) a clear solution was obtained. The clear solution was further stirred at r.t. for
72 hrs. The solvent was removed under reduced pressure to yield white solid which was suspended in hot water (3 ml) at 80 °C and stirred for 10 min. Undissolved excess
QQ was removed by filtration and the filtrate was precipitated into ethanol (15 ml). A white precipitate was collected; washed with ethanol (3ml) followed by acetone (3ml) and dried in vacuo over P2O5 for one week to yield 37.
Yield; 105 mg (77%).
e 3 N H2 Oc 37
'H-NMR (400 MHz, D2O): 5 1.58 (s, 9H, e), 3.74 (t, 2H, ^Jhh = 7.5 Hz, a), 4.05 (s,
2H, d), 4.12 (t, 2H, ^Jhh = 7.5 Hz, b), 4.23 (dd, 12H, QQ), 5.49 (s, 12H, QQ), 5.65
(dd, 12h, QQ), 6.50 (s, IH, c).
186 '^C-NMR (100 MHz, D2O, DSS): 5 28.82 (e), 39.46 (a), 41.18 (d), 49.14 (€(^3)3),
54.13 (QQ), 54.35 (QQ), 60.92 (b), 73.18 (QQ), 123.17(Tr), 142.37 (Tr), 159.24
(QQ), 159.49 (QQ).
Molar Mass of (C36H36N24012).C9H21CI2N5: 1267.05
FAB +ve m/z: 1194 [M-2HC1]^
III.3.1.6. Synthesis of N-{2-[l-(aminomethyl)-lH-l,2,3-triazol-4-yl]ethyl}-N-(tert- butyl)amine 38
Semirotaxane 37 (105 mg, 83 p.mol) was dissolved in water (5 ml) and a 0.1 N NaOH solution (2 ml) was added. The mixture was stirred for 30 min and then extracted with chloroform (3x3 ml) and sat. NaCl solution (5 ml). The combined organic layers were dried over anhydr.MgS04 and the solvent was removed under reduced pressure to yield 38 as a clear viscous oil.
Yield: 11.6 mg (71%) (crude).
N^d
^H-NMR (250 MHz, CDCI3); 5 1.04 (s, 9H, e), 1.48 (br, 3H, NH), 3.03 (t, 2H, ^Jhh =
6.2 Hz, a), 3.96 (s, 2H, d), 4.37 (t, 2H, ^Jhh = 6.3 Hz, b), 7.53 (s, IH, c).
^H-NMR (400 MHz, D2O); 5 1.58 (s, 9H, e), 3.74 (t, 2H, ^Jhh = 7.5 Hz, a), 4.05 (s,
2H, d), 4.12 (t, 2H, ^Jhh = 7.5 Hz, b), 4.23 (dd, 12H, QQ), 5.49 (s, 12H, QQ), 5.65
(dd, 12h, QQ), 6.50 (s, IH, c).
'^C-NMR (100 MHz, D2O, DSS): 5 28.82 (e), 39.46 (a), 41.18 (d), 49.14 (€(^3)3),
54.13 (QQ), 54.35 (QQ), 60.92 (b), 73.18 (QQ), 123.17(Tr), 142.37 (Tr), 159.24
(QQ), 159.49 (QQ).
187 Molar Mass of (C36H36N240,2).C9H21CI2N5: 1267.05
FAB +ve m/z: 1194 [M-2HC1]^
III.3.1.6. Synthesis of N-{2-fl-(aminomethyl)-lH-l,2,3-tnazol-4-ylJethyl}-N-(tert-
butyl)amine 38
Semirotaxane 37 (105 mg, 83 p.mol) was dissolved in water (5 ml) and a 0.1 N NaOH
solution (2 ml) was added. The mixture was stirred for 30 min and then extracted
with chloroform (3x3 ml) and sat. NaCl solution (5 ml). The combined organic
layers were dried over anhydr.MgS04 and the solvent was removed under reduced
pressure to yield 38 as a clear viscous oil.
Yield: 11.6 mg (71%) (crude).
N^d
'H-NMR (250 MHz, CDCI3): 5 1.04 (s, 9H, e), 1.48 (br, 3H, NH),
3.03 (t, 2H, ^Jhh = 6.2 Hz, a), 3.96 (s, 2H, d), 4.37 (t, 2H, ^Jrh = 6.3 Hz, b), 7.53 (s,
IH, c).
"C-NMR (62.5 MHz, CDCI3): § 29.05 (e), 38.10 (a), 42.55 (d), 51.76 (€(^3)3),
67.20 (b), 123.30 (Tr), 142.35 (Tr).
111.3.1.7. N-{2-[l-(aminomethyl)-lH-l,2,3-triazol-4-yl]ethyl}-N-(tert-butyl)
amine dihydrochloride 39
'H-NMR (250 MHz, DCl, DSS): 6 1.45 (s, 9H, e), 3.85 (t, 2H, ^Jhh = 6.2 Hz, a), 4.62
(s, 2H, d), 5.15 (t, 2H, ^Jhh = 6.3 Hz, b), 8.80 (s, IH, c).
188 III.3.2. Synthesis of Pseudorotaxanes
III.3.2.1. Synthesis of pseudo[2]rotaxane 40
Compound 26 (18.4 mg, 150.0 pmol) and 25 (13.7 mg, 150 i^mol) were dissolved in water (3 ml) under vigorous stirring. Cucurbituril 1 (150.0 mg, 150.0 fimol) was dissolved in 6N HCl solution (5 ml) and added to the former solution. The resultant clear solution was stirred further at r.t. for 72 hrs and it was added to ethanol (25 ml).
A white precipitate was filtered and dried in vacuo. The white solid was dissolved in hot water (3ml) at 80 "C and stirred for 10 min. Undissolved excess cucurbituril was removed by filtration. Filtrate was added to ethanol (20 ml) and white precipitate was collected by centrifugation and dried in vacuo over P2O5 for one week to afford 40 as a white crystalline powder.
Yield: 115 mg (65%).
0—
H3 40
^H-NMR (250 MHz, D2O): 5 = 3.55 (t, 2H, ^Jhh = 6.3, a), 4.12-4.15 (s and t overlapped, 4H, b,d), 4.25 (dd, 12H, 15.6 Hz, QQ), 5.48(s, 12H, QQ), 5.69
(dd, 12H, %H= 15.6 Hz, QQ), 6.53(s, IH, c).
Molar Mass of C5HiiN5.(C36H360i2N24). 2HC1: 1210.94
FAB +ve MS m/z: 1138 [M-2HC1]^
MALDI-TOF m/z: 1138 [M-2HC1]^
Elemental analysis of C5H, ]N5.(C36H360i2N24).8H20
Calc.: C, 36.34; H, 4.84; N, 29.98; Found: C, 36.38; H, 4.69; N, 28.65
Calc.: C, 40.67; H, 4.08; N, 33.54 (Anhydrous)
189 1113.2.2. Synthesis of [l-(2-aminoetJiyl)-lH-l,2,3-triazol-4-yl]methylamine 41
Rotaxane 40 (100 mg, 80 jiimol) was dissolved in water (3 ml) and a 0.1 N NaOH solution (2 ml) was added to obtain a cloudy solution which was stirred at r.t. for 30 min. Aqueous phase was extracted with chloroform (3x 4ml). The combined organic layers were washed with sat. NaCl solution (4 ml) and then dried over anhydr.
MgS04, the solvent was removed under reduced pressure to yield a colourless viscous oil.
Yield: 8.25 mg (69%).
'H-NMR (250 MHz, CDCI3): 5 1.48 (br, 3H, NH), 3.17 (t, 2H, ^Jhh = 6.2 Hz, a), 3.97
(s, 2H, d), 4.42 (t, 2H, ^Jhh = 6.3 Hz, b), 7.53 (s, IH, c).
IIL3.2.3. Synthesis of Pseudo[3]rotaxane 42
Compound 26 (36.9 mg, 300.0 pmol) and 18 (49.2 mg, 150.0 pmol) were dissolved in water (5 ml) under vigorous stirring. A solution of 1 (300.0 mg, 301 p.mol) dissolved in 6N HCl (7 ml) was added. The clear solution was stirred at r.t. for 72 hrs.
Precipitation into ethanol (40 ml) gave a white solid, which was filtered off, washed with ethanol (5 ml). Off-white solid was dissolved in hot water (3 ml) at 80 °C and stirred for 20 min. After hot filtration the filtrate was added to ethanol (15 ml). A white precipitate formed, which turned off-white during filtration was filtered and dried in vacuo over P2O5 for one week to afford title compound 42.
Yield: 230 mg (60%)
190 'H-NMR (250 MHz, D2O) ; § = 2.75 (s, 6H, f), 3.06 (s, 3H, g), 3.37 (t, 4H, ^Jhh= 6.5, a), 3.94 (t, 4H, ^Jhh= 6.5, b), 4.17-4.28 (dd, 24H, QQ), 4.49(s, 4H, d), 4.63 (s, 4H, e),
5.48 (s, 24H, QQ), 5.61-5.75 (t, 24H, %n= 16.1, QQ), 6.51 (s, 2H, c), 7.12 (s, IH, h).
'^C-NMR (100 MHz, D2O, DSS): 5 19.40 (g), 22.74 (f), 41.14 (a), 46.39 (b), 49.26
(d), 50.59 (e), 54.12 (QQ), 54.37 (QQ), 73.16 (QQ), 122.92 (Tr), 129.86 (Ar),
133.82 (Ar), 142.04 (Ar), 143.44 (Ar), 143.97 (Tr), 159.24 (QQ), 159.37 (QQ).
Molar Mass of C2iH38NioCl4.(C36H360i2N24)2:2566.10
MALDI-TOF m/z: 2420 [M-4HC1]^
Elemental Analysis of C2iH38NioCl4.(C36H360i2N24)2 x 3IH2O
Calc.: C, 35.62; H, 4.73; N, 26.12; Found: C, 35.75; H, 5.55; N, 26.00
Calc.: C, 43.53; H, 4.32; N, 31.66 (Anhydrous)
III.3.2.4. N- {[1 -(2-aminoethyl)-l H-1,2,3-triazol-4-yl] methyl}-N-
{3-[({[l-(2-ammoethyl)-lH-l,2,3-triazoI-4-yl]methyl]amino]methyI]-2,4,6-
trimethylbenzyl}amine 43
Compound 42 (148.1 mg, 58.0 jimol) was dissolved in water (3 ml) and as soon as a
0.1 N NaOH solution (2.4 ml) was added a cloudy mixture was obtained. Stirring
continued for 2 hrs after which the suspension was extracted with CHCI3 (4x5 ml).
The organic phases were washed with sat. NaCl solution (5 ml) and dried over
anhydr. MgS04. The removal of solvent afforded 43 as a colourless viscous oil.
Yield: 19.5 mg (59%) (Crude)
191 H,N2' ^ ^ A. ,, N-'^\ b
^H-NMR (400 MHz, CDCI3): 5 = 1.23 (br s, 6H, NH), 2.27 (s, 6H, f), 2.38 (s, 3H, g), 3.17 (t, 4H, %H= 6.5, a), 3.76 (s, 4H, d), 4.03 (s, 4H, e), 4.36 (t, 4H, ^Jhh= 6.5, b),
6.81 (s, IH, h), 7.54 (s, 2H, c).
'^C-NMR (100 MHz, CDCI3): 5 = 19.63 (f), 22.68 (g), 42.04 (a), 45.11 (b), 47.69 (d),
53.35 (e), 122.23 (Tr), 130.16 (Ar), 134.41 (Ar), 135.83 (Ar), 136.34 (Ar), 147.14
(Tr).
IIL3.2.5. Synthesis of Pseudo[4]rotaxane 44
Compound 26 (36.9 mg, 300.0 ^mol) and 24 (43.3 mg, 100.0 |amol) were dissolved in water (5 ml) under vigorous stirring. A solution of 1 (300.0 mg, 301.0 |j,mol) dissolved in 6N HCl solution (7 ml) was added. The resulting clear solution was stirred at r.t. for 72 hrs. Precipitation into ethanol (40 ml) gave an off-white precipitate which was filtered off and washed with ethanol (5 ml). The isolated solid was dissolved in hot water (3 ml) at 80 °C and stirred for 20 min. After hot filtration, the filtrate was added to ethanol (20 ml). An off-white powder precipitated and was collected by centrifugation. It was dried in vacuo over P2O5 for one week.
Yield: 297 mg (78%).
192 a^NHj
©NH, O
'H-NMR (250 MHz, D2O): 6 = 3.12 (s, 9H, f), 3.42 (t, 6H, ^Jhh= 6.5, a), 3.95 (t, 6H,
^Jhh= 6.5, b), 4.30 (t, 36H, QQ), 4.60 (s, 6H, e), 4.75 (s, 6H, c, (overlapped with solvent peak)), 5.55 (s, 36 H, QQ), 5.75 (t, 36 H, QQ), 6.52 (s, 3H, c).
"C-NMR (100 MHz, D2O, DSS); S 20.34 (f), 41.13 (a), 46.80 (b), 49.18 (e), 51.34
(c), 54.10 (QQ), 54.37 (QQ), 73.08 (QQ), 73.27 (QQ), 122.87(Tr), 126.42 (Ar),
130.99 (Ar), 142.02 (Tr), 159.19 (QQ), 159.24 (QQ).
Molar Mass of C27H45N15: (C36H360i2N24)3 x 6HC1: 3789.05
MALDI-TOF; Calc. 3569.92 [M-6HC1]^; Found: 3567 [M-6HC1]^
IIL3.2.6. Synthesis of N-{[l-(2-aminoethyl)-lH-l,2,3~triazol-4-yl]methyl}-N-{3,5- bis[({[l-(2-aminoethyl)-lH-l,2,3-tnazol-4-yl}methyl}amino)methyl]-2,4,6- trimethylbenzyl}amine 45
Compound 44 (145 mg, 38 p,mol) was dissolved in water (4 ml) and a suspension formed as soon as 0.1 N NaOH solution (2.5 ml) was added under vigorous stirring.
Chloroform (4 ml) was added after Ihr and stirring continued for another hour. Fine particles were filtered off before the organic layer was isolated and dried over anhydr.
193 MgS04. Removal of solvent under reduced pressure afforded 45 a viscous pale yellow oil.
Yield: 13 mg (55%) (crude)
Tr iT ". '2 c
Since no further purification was carried out, the product contains unidentified impurities therefore only selected data, which is consistent with 45 are given below
(See results and discussion Section 11.2.3)
^H-NMR (400 MHz, CDCI3): 5 2.39 (s, 9H, f), 3.19 (t, 6H, ^Jhh= 5.8 Hz, a), 3.81 (s,
6H, e), 4.05 (s, 6H, d), 4.39 (t, 6H, ^Jhh= 5.6 Hz, b), 7.57 (s, 3H, c).
IIL3.2.7. Synthesis of Pseudo[3]rotaxane 42 in 0.2 M Na2S04 solution
Compound 18 (39.0 mg, 100.0 |amol) and 26 (18.2 mg, 200 pmol) were dissolved in water (5 ml) and stirred for 15 min at r.t. to obtain a light yellow coloured solution. A solution of 1 (200 mg, 200.0 ^mol) dissolved in a 0.2 M solution of NaS04 (5 ml) under vigorous stirring was added. The resulting homogeneous mixture was stirred at
40 °C for 120 hrs before the solvent was removed under reduced pressure to yield 42 as a pale yellow solid
Yield: 254 mg, (100%, crude)
'H-NMR (D2O, 250 MHz): (The same as 42)
194 42 (208 mg, 81 |imol) was dissolved in water (10 ml). A 0.1 N NaOH solution (3.5 ml) was added and stirred for 3 hrs. The clear solution was extracted with chloroform
(4x7 ml). The combined organic layers were washed with sat. NaCl solution (6 ml) and dried over anhydr. MgS04. The solvent was removed under reduced pressure to yield 43 as a colourless oil.
Yield: 28.2 mg, (60%) (crude).
43
'H-NMR (CDCI3, 250 MHz): 6 1.66 (br, 6H, NH), 2.16 (s, 6H, f), 2.26 (s, 3H, g),
3.17 (t, 4H, ^Jhh= 7.5 Hz, a), 3.74 (s, 4H, e), 3.94 (s, 4H, d), 4.43 (t, 4H, ^Jhh= 7.5
Hz, b), 6.82 (s, IH, h), 7.51 (s, 2H, c).
IIL3.4. Counter Ion Exchange for [n]Rotaxane: Chloride to Tetrafluroborate
General Procedure:
An [nJRotaxane was dissolved in a minimum volume of water and a saturated solution of sodium tetrafluroborate was added dropwise until no further precipitation occurred. The resulting suspension was stirred for another 2 hrs. Any precipitate was collected by filtration and dried in vacuo.
[nJRotaxanes with [BF4] ~ as counterion dissolve in DMF and DMSO at r.t.
GPC analysis of [n]rotaxanes was carried out in DMF.
33. [BF4]', Mn: 1890, M^: 1950
34. [BF4]', M^: 2310, 2240, 2430, Mw: 2510, 2410, 2610
195 III.4. Linear Polyrotaxanes
III.4.1. Attempted Preparation of Linear, Catalytically Self-Threaded
Polypseudorotaxanes 52
12 9 \=.0
(A2) (B2)
Table IIL4.1. Reaction conditions for the attempted syntheses of polypseudorotaxane
52. The ratio x/y is the ratio of the intensity of the central methylene protons x
(4+5+6+7+d+e+f+g (16H)) versus the intensity of triazole proton y (^H-NMR).
Molar Ratio (Mol) Solvent: 6N (mg) HCl Entr [Azide [Alkyn QQ t T Ratio DP ] y e] (h) (°C) x/y (Az) (B2)
A 1 1 1 24 20 none 0 9.84 7.98 32.2 B 1 1 2 192 20 none 0 4.92 3.99 32.2 C 1 1 3 120 20 none 0 2.19 1.77 20.0
D 1 1 2 384 90 16/1.0 2 4.92 3.99 32.2 E 1 1 3 384 90 16/0.8 1.8 2.19 1.77 20.0 F 1 1 4 384 90 16/0.7 1.7 2.46 1.99 30.0 G 1 1 0 384 90 16/0.8 1.7 9.84 7.98
196 IIL4.1.1. General Procedure for the Preparation of 52
1 (32.2 mg, 31.0 pmol) was dissolved in DCl (1ml) and stirred for 30 min. 9 (4.9 mg,
15.5 pmol) was added and the solution was stirred vigorously at r.t. for another 10 min before the addition of alkyne 12 (4.0 mg, 15.5 pmol). The resulting solution was stirred at the temperature and for the length of time as specified in Table III.4. The course of each reaction was followed by 'H-NMR.
III.4.1.1.1. General Spectroscopic data for Entry A, B, C:
'H-NMR (250 MHz, D2O): 6 = 0.45(m, 8H, 5+6+e+f), 0.75 (m, 8H, 4 +7+d+g),
2.95(t, 8H, ^Jhh = 6.5 Hz, 3+8+c+h), 3.15(t, 2H, 1, 10), 3.35(t, 4H, ^Jhh = 5.5 Hz b+j), 3.85(t, 4H, ^Jhh = 5.5 Hz, a+k), 4.15(d, 2H, = 2.5 Hz, 2+9), 4.43 (d, 24H,
QQ), 5.55(s, 12H, QQ), 5.75(d, 12H, QQ).
'H NMR absorption at 6.5 ppm (bound i.e. inclusion complex) and 8-9 ppm
(unbound, fi-ee) is characteristic of triazole proton in acidic media.
'^C-NMR (62.5 MHz, D2O): S = 27.99 (5+6), 28.06 (e+f), 28.67 (4+7), 29.16 (d+g),
39.13 (?), 49.07 (c+h), 49.43 (3+8), 49.76 (b+j), 50.22 (2+9), 50.38 (a+k), 50.59
(1+10), 50.98 (-CCH), 54.38 (QQ), 73.26 (QQ), 159.19 (QQ)
Also ^^C-NMR absorption at - 120 ppm (bound) and -140 ppm (unbound, free) is also characteristic of triazole formation.
197 III.4.1.1.2. Spectroscopic data for Entry D:
O- Hz O- -O 11 3^® ^5^ -N 9\@ N3^'V®V- .5 4, 3 ^2^10''^ ^ N=N Mo Ho o
53
^H-NMR (250 MHz, D2O): 6 = 0.44 (br s, 8H, 5), 0.70 (br s, 8H, 4), 3.05 (br s, 8 H, 3),
3.63 (s, IH, ?), 3.88 (br, 2.7H, 1+?), 4.5 (br, 1.3H, ?), 4.33 (d, 24 H, QQ), 4.55(s,
2.7H, 9 + ?), 5.20 (b, 2H, 7), 5.55 (s, 24 H, QQ), 5.62 (dd, 24 H, QQ). 8.55 (s, IH, 8).
III.4.1.1.3. Spectroscopic data for entry E:
^H-NMR (250 MHz, D2O); S = 0.46 (br m, 8H, 5), 0.72 (br m, 8H, 4), 2.95 (br t, 8H,
3), 3.10 (br, IH, 11), 3.35 (t, 2H, 2), 3.88 (br m, 6H, 1, 5,10 overlapped), 4.33 (d, 36H,
QQ), 4.52 (s, 1.5H, 9), 5.10 (b, 1.5H, 7), 5.52 (s, 36 H, QQ), 5.62 (q, 36 H, QQ), 8.51
(s, 0.7H, 8).
IIL4.1.1.4. Spectroscopic data for entry F:
'H-NMR (250 MHz , D2O): 5 = 0.48 (bs, 8H, 5), 0.75 (bs, 8H, 4), 3.05 (bs, 8 H, 3 and
IH, 11), 3.40 (t, 2H, 2), 3.63 (s, IH (?)), 3.88 (t and d overlapped, 6H, 1, 5, 10), 4.33
(d, 48H, QQ), 4.50 (s, 1.6H, 9), 5.10 (b, 1.6H, 7), 5.52 (s, 48 H, QQ), 5.62 (q, 48 H,
QQ). 8.51 (s, 0.8 H, 8).
See result and discussion.
III.4.1.2. Procedure for entry G:
Ha
N3 19 © 18 16 14 N H2 N=N Ho 54
198 Alkyne 12 (4.1 mg, 15.5 pmol) and azide 9 (5.1 mg, 15.5 ^mol) were dissolved in DCl
(20% aquoeus, w/w) (0.7 ml) and stirred while heating gently to facilitate the dissolution. After Ihr, the solution was transferred to a NMR tube and heated at 90 °C for 336 hrs. Reaction was monitored by 'H-NMR
IIL4.1.2.1. Spectroscopic data for entry G after heating 336 hrs
'H-NMR (250 MHz, D2O): 6 = 1.48 (b, 8H, 5+6+15+16), 1.85 (b, 8H, 4+7+14+17),
3.35 (m, 8H, 3+8+13+18), 3.62 (s, 4H, 2+12), 4.10 (m, 4H, 19+20), 4.78 (s, IH, 9),
4.95 (s, 0.18H, ?), 5.32 (br, 2H, 11), 5.45 (br, 0.3H, ?), 5.85 (s, 0.15H, ?), 6.82 (s,
0.24H, ?), 9.02 (s, 0.82H, 8).
'H-NMR suggests the formation of 54 with other unidentified compounds.
199 IIL4.2. Preparation of Linear, Catalytically Self-Threading Polyrotaxanes 55
Table III.4.2. Reaction conditions, yield, degree of polymerisation (DP) and Mn
values. * Reaction was carried out an 0.2 N aqoueus solution of Na2S04, ^reactions
(Entry K and Q) were conducted on a only 'H-NMR scale and no work-up was carried
out.
Ratio (Mol) Solvent; 6N HCl 'H-NMR Entry [Azide] [Alkyne] QQ t T Yield Mn DP (%) (Az) (Bz) (h) (°C) (Da) A 1 1 2 48 20 68 13000 10 B 1 1 2 72 60 78 17000 11 C 1 1 2 72 + 20 + 75 28000 21 24 40 D 1 1 2 120 60 68 39000 29 E 1 1 2 144 80 91 29000 21 F* 1 1 2 192 20 79 21000 16
G 1 1 2.50 144 20 73 7000 5 H 1 1.12 236 144 20 72 12000 9 I 1 1.20 2.48 144 20 71 12000 9 J 1 1 2.25 144 20 84 12000 9
K" 1 1 1 192 90 3400 2.5 L 1 1 2 144 20 82 25000 19 M 1 1 2 144 90 86 18000 13 N 1 1 2 336 20 75 30000 22 0 1 1 2 336 90 79 25000 19 P 1 1 0 192 hrs 20 0 No 0 polymer Q' 1 1 0 192 hrs 90 Dimer 2
200 III.4.2.1. General Procedure for the Preparation of 55
ro =0
55
Cucurbituril 1 (200.0 mg, 200 |imol) was dissolved in 6N HCl (4 ml) and stirred for 30 min. Azide 22 (39.1 mg, 100 |amol) was added and stirred vigorously at r.t. for another
10 min. With the subsequent addition of alkyne 18 (32.3 mg, 100 (j.mol) was obtained a clear solution. Individual reaction times and temperatures, yields and molecular weights for each polymerisation are summarised in Table III.4.2.
The solution was precipitated into a large excess of acetone/ethanol (50/50, v/v) to yield a white sohd, which turned into yellow-white during filtration. To remove excess
1, each solid was dissolved in hot water (~ 80 °C) and stirred for 1-2 hrs. Undissolved material was filtered off. The solvent was removed under reduced pressure to a yield colourless film which was dried in vacuo over P2O5 for one week.
Reaction conditions, yield and molecular weight are summarised in the Table III.4.2.
III.4.2.1.1. General spectroscopic data for Entry A to P
'H-NMR (400 MHz, D2O): 6 2.75 (s, 6H, g), 3.35 (s, 3H, f), 3.81 (br, 2H, d), 4.02 (br,
2H, c), 4.31 (t, 12H, QQ), 4.52 (s, 2H, e), 4.65 (s, 2H, a), 5.55-5.95 (m, 24H, QQ),
6.54 (s, IH, b), 7.21 (s, IH, h).
201 '^C-NMR (100 MHz, D2O+DSS): 6 18.96 (f), 19.09(f), 22.65 (g), 22.77 (g), 54.15
(QQ), 54.33 (QQ), 73.16 (QQ), 122.73 (Tr), 129.86 (Ar), 130.17 (Ar), 133.01(Ar),
142.17 (Ar), 143.52 (Tr), 159.28- 59.38 (QQ).
MALDI-TOF (See Results and Discussion).
III.4.2.1.2. Selected spectroscopic data for Q
'H-NMR (250 MHz, DCl): §= 2.50 (br, 18H, f+g), 5.35 (br, 2H, a), 5.85 (d, 0.25, ?),
6.80 (s, d, 0.25H, ?), 8.95 (br, 0.75H, b).
Spectrum indicates a mixture of more than one product besides the starting material. It is quite difficult to assign all the peaks with certainty.
IIL4.2.2. Counter Ion Exchange for Polyrotaxane 55D From Chloride to
Hexafluoroph osph ate
Polyrotaxane 55D (Table 111.4.2) (50 mg) was dissolved in water (3 ml) to which a saturated solution of ammonium hexafluorophosphate was added dropwise. The clear solution turned into cloudy just after the addition had started. Addition continued until no further precipitate occurred. The mixture was stirred at r.t. for 3-4 hrs. Filtration proved to difficult, therefore the solvent was removed under reduced pressure and the resulting solid was washed with water (3 ml) to remove excess salt. The resulting pale yellow sticky solid was dried in vacuo. The counter ion exchanged polyrotaxane was soluble in DMF, DMSO and N, N'-dimethylacetamide.
GPC was performed in DMF (refractive index detector)
Mw = 9020, Mn = 5160
202 IIL4. Synthesis of Hyperbranced and Dendritic Polyrotaxanes
III.4.1. Attempted Synthesis of Dendritic Polyrotaxanes 57
IIL4.1.1. General Procedure for Entry A and B (see Table III.4.1)
QQ 1 (115 mg, 115 pmol) and 24 (10 mg, 23 pmol) were dissolved in 6N HCl (5 ml)
and the yellow coloured solution was stirred for 15 min before the addition of 22 (38 mg, 92 jj,mol). The final solution with a very small amount of very fine particles was
further stirred at r.t. for 24 hrs (Entry A) and 72 hrs (Entry B). Undissolved particles were filtered off with a 0.45 jam membrane filter from the final solution and the filtrate was precipitated into ethanol (20 ml) to form a white precipitate which became off- white sticky solid upon filtration. It was dried in vacuo over P2O5 for 24 hrs to yield
57.
Yield: 129 mg (80%).
^H-NMR spectrum was recorded (see results and discussion for 'H-NMR analysis
Section 11.4).
It was attempted to further purify this solid as follows;
57 (100 mg) was dissolved in water (4 ml) and a solution of 0.1 N NaOH was added dropwise to reach pH ~ 10. The solution became cloudy as soon as the addition of
NaOH solution commenced. This mixture was stirred at r.t. for 2 hrs before the addition of CHCI3 (5 ml). The resulting gel like mixture was left to stand at r.t. for 24 hrs. However, no phase separation was observed even after this time. Therefore the solvents was evaporated to dryness under reduced pressure to yield a yellow to white sticky solid which subsequently was suspended in methanol and stirred at r.t. for 24 hrs. An off-white sticky solid was collected and dried over P2O5 in vacuum for 24 hrs.
Yield: 95 mg
203 See results and discussion for H-NMR, MALDI-TOF, ES-MS.
IIL4.1.1. General Procedure for Entry C and D
Because this preparation procedure is slightly different it is described separately.
However, the work-up is the same as A and B (Table II.4.1).
24 (10 mg, 23 |imol) and QQ 1 (92 mg, 94 pmol) were dissolved in 0.2 N Na2S04 solution (3 ml) (for Entry D) or 6N HCl (3 ml) (for Entry C). Each of the clear solutions was stirred at r.t. for 24 hrs before the addition of 22 (53.68 mg, 0.138 mmol). After stirring at r.t. for another 72 hrs, the solution was precipitated into ethanol (15 ml) separately. Off-white sticky solids were obtained in both cases. Purification was identical to previous samples.
See results and discussion for 'H-NMR, MALDI-TOF, ES-MS.
Table 111.4.1. Reaction conditions for the attempted synthesis of polyrotaxane. * The reaction was carried out in a 0.2 N aqueous solution of Na2S04.
Molar Ratio of Monomers ^H-NMR
Entry 22 24 QQ t T Ratio
[azide] [alkyne] (h) (°C) Ph: Tr
A 4 1 5 24 20 1.4:1.0
B 4 1 5 72 20 1.4:1.0
C 6 1 4 48 20 2.2:1.0
*D 6 1 4 48 20 2.2:1.0
204 IIL4.2. Synthesis of Catalytically Self-Threading Hyperbranched Polyrotaxane 59
General Procedure for Entry A-G
(This example is for Entry G. All other experiments were carried out in an identical fashion. Reaction conditions are summarised in Table II.4.2).
1 (300 mg, 0.300 mmol) was dissolved in 6N HCl (5 ml) under vigorous stirring and alkyne 24 (43.10 mg, 0.100 mmol) was added to yield a yellow coloured solution which was stirred at r.t. for Ihr before the addition of azide 22 (38.9 mg, 100 p,mol).
The resulting solution was heated at 60 °C for 192 hrs. The solution was precipitated into acetone/ethanol (25 ml, 50/50, (v/v)) to form a white precipitate which became a white-yellow sticky solid upon filtration. It was dried in vacuo over P2O5 for one week.
Yield: 308 mg, 78%.
See results and discussion for 'H-NMR, MALDI-TOF, ES-MS.
205 Table III.4.2: Reaction condition and Mn of catalytically self-threading hyperbranched polyrotaxanes.
Molar ratio 'H-NMR
Entry 22 24 QQ Time Temp Ratio Mn (Ai) (Ba) (h) (°C) Ph:Tr (Da) [azide] [alkyne] A 1 1 1 24 +24 20 to 50 1:1 1800
B 1 2.5 2 48 20 1:2 3200
C 1 3 0.8 192 20 1.0:0.8 1800
D 1 1 2 96 + 20 to 60 (178: (153 4600
24
E 1.5 1 3 72 20 0.39 : 0.21 21500
F 1.5 1 3 96 20 0.21 : 0.11 32000
G 1 1 3 144 60 11.5 : 6.0 34000
206 IIL6. Synthesis of Side Chain Polyrotaxanes
III.6.1. Attempted Polymerisations of Semi[2]rotaxane 60
III.6.1.1, Synthesis of N-(tert-butyl)-N-[2-(4-{[(4-vinylbenzyl)amino]methyl}-i^-
1,2,3-triazole-l-yl)etbyl]amine hydrochloride salt - semi[2]rotaxane 60
QQ 1 (300 mg, 300 ^imol) was dissolved in 6 N HCl (10 ml) and N-(3-butynyl)-(4- vinylbenzyl)amine hydrochloride 29 (65.1 mg, 300 |j.mol) was added under vigorous stirring to obtain a yellow suspension. After the addition of tert-butyl-propargylamine hydrochloride salt 5 (55.1 mg, 300 jamol) was complete, the yellow suspension was heated gently in a water bath (~ 40 °C) for 2-3 min. to obtain a clear solution under vigorous stirring which was continued at r.t. for 72 hrs. The solution was precipitated into a large excess of ethanol/acetone (50/50, v/v) to yield a white precipitate. The latter turned into pale yellow sticky solid during filtration.
Yield; 257 mg (61 %).
'H-NMR (400 MHz, D2O); 5= 1.64 (s, 9H, 1), 3.80 (t, 2H, ^Jhh = 6.33 Hz, k), 4.19 (t,
2H, m, ^Jhh = 6.36 Hz, j), 4.27 (t, 14H, QQ + g), 4.50 (s, 2H, c), 5.40 (d, IH, \n =
11.5 Hz, e), 5.52 (s, 12H, QQ), 5.92 (d, IH, ^Jhh = 18.4 Hz, f), 6.56 (s, IH, h), 6.86
207 (dd, IH, = 18.2, 10.8 Hz, d), 7.55 (dd, 2H, ^Jhh = 8.08 Hz, a), 7.83 (dd, 2H, ^Jhh =
8.09 Hz, b).
IIL6.1.2. Attempted Free Radical Polymerisation of Semirotaxane 60
Semirotaxane 60 (50.0 mg, 36.0 )J.mol) and 4,4'-Azo-bis(4-cyano-valeric acid) (0.3 mg,
1.2 |j.mol) were dissolved in water (5ml) under vigorous stirring. The solution was freed from oxygen with three freeze-thaw cycles and brought to r.t. After heating at 75
°C for 24 hrs, the solution remained colourless. It was concentrated to % of its initial volume under reduced pressure and the solution was precipitated into THF (30 ml).
The off-white precipitate was collected by filtration under suction and dried in vacuo for 5 hrs.
Yield: 35 mg (70%).
'H-NMR (400 MHz, D2O): 5= 1.57 (d, IH), 1.69 (s, 9H, f), 2.76 (s, 0.2H, ?), 2.90 (s,
0.2H, ?), 3.78 (s, 0.5H, ?), 3.85 (t, 2H, %h - 6.33 Hz, j), 4.24 (t, 2H, m, = 6.36
Hz, i), 4.33 (dd, 14H, QQ), 4.36 (br s, IH, ?), 4.56 (s, 0.5H, ?), 5.57 (s, 12H, QQ), 5.76
(dd, 12H, QQ), 6.62 (s, IH, h), 7.59 (d,lH, ^Jhh = 8.08 Hz, a), 7.68 (br s, IH, a), 7.91
(d, IH, %H = 8.09 Hz, b), 8.13 (br m, IH, b).
208 IIL6.1.3. Attempted Thermal Polymerisation of Semirotaxane 60
Semirotaxane 60 (50 mg, 36 pmol) was dissolved in water (3ml) under vigorous stirring. The clear solution was freed from oxygen with three freeze-thaw cycles and brought to r.t. After heating at 80 °C for 24 hrs, the solution was precipitated into acetone/ethanol (20 ml, 50/50 (v/v)). The off-white precipitate was collected by filtration under suction and dried in vacuo for 5 hrs.
Yield: 47 mg (94%).
^H-NMR (250 MHz, D2O): 6= 1.20 (s, 0.2H, ?), 1.30-1.46 (m, 5H, ?), 1.57 (s, 9H, f),
3.15 (s, 0.2H, ?), 3.85 ( br t, 2H, j), 4.05-4.25 (m, 16H, QQ and c), 4.43 (br t, IH, ?),
5.42 (s, 12H, QQ), 5.61 (dd, 12H, QQ), 6.49 (s, IH, h), 7.43-756 (brm, 4H, a+b), 7.76
(d, 1.3H, ^Jhh = 8.09 Hz, a+b).
III.6.2. Synthesis of a Side Chain Polyrotaxane via a Polymer Analogous Reaction
IIL6.2.1. Synthesis of poly(vinylbenzyl-propargylamine) 69a and its hydrochloride salt 69b
Compound 29 (200.0 mg, 960.0 p^mol) was dissolved in water (10 ml) and 4,4'-azo- bis(4-cyano-valeric acid) (13.5 mg, 48.0 jimol) was added under vigorous stirring. The solution was freed from oxygen with threefreeze-thaw cycles. The reaction mixture was brought to r.t. before it was heated to 90 °C for 24 hrs. The solvent was removed from the brown solution under reduced pressure. A brown, oily suspension remained, which was dissolved in ethanol (5 ml) and precipitated into acetone (50 ml). A white precipitate formed which during filtration turned dark yellow. It was washed with acetone and dried in vacuo for 6 hrs to yield 69b.
Yield: 72 mg (19%).
209 HpN©
'H-NMR (250 MHz, D2O): 5 1.65 (br s, 2H, f), 2.15(vbr s, IH, g), 3.05(vbr s , IH, e),
3.82 (vbr s, 2H, d), 4.35(vbr s, 2H, c), 6.70-7.35(vbr m, 4H, a, b).
Polymer 69b (130 mg, 630 mmol) was dissolved in water (5ml) and a 0.5 M NaOH solution (5 ml) was added dropwise. The solution was extracted with chloroform (3 x
15 ml) and a brine solution (15 ml). The combined organic layers were dried over anhydr.MgS04. The extract was concentrated under reduced pressure and precipitated into toluene (30 ml). The precipitate formed white at first but turned into a yellow powder after filtration and washing with toluene (3 ml). It was dried in vacuo for 5-6 hrs to yield 69a.
Yield: 97 mg (59%).
III.6.3.1. Attempted Synthesis of 65 via Side Chain Threading: NMR Scale
Cucurbituril 1 (20.0 mg, 19.0 jamol) was dissolved in DCl (2 ml). 63 (4.0 mg, 19.0
|imol) and tert-butyl-azidoethylamine hydrochloride salt 5 (3.7 mg, 19.0 pmol) were added under vigorous stirring to obtain a suspension which was heated at 50 °C for 10 min. The resulting viscous solution was further stirred at r.t. and the course of the
210 reaction was followed by 'H-NMR over time to monitor especially the triazole formation.
(See results and discussion for 'H-NMR spectrum)
III.6.3.2. Attempted Synthesis of Sidechain Polyrotaxane 65 via Sidechain
Threading:
Large Scale
Polymer 69b (43.4 mg, 190.0 p,mol) and tert-butyl-azidoethylamine hydrochloride 5
(37.2 mg, 190.0 jamol) were dissolved in 6 N HCl (10 ml) and stirred under nitrogen for 1 hr. 1 (200.0 mg, 190.0 p.mol) was added and the suspension was heated to reflux.
Within an hour a light yellow solution formed with heating to continue at 70 °C for 120 hrs. The solution was concentrated to 1/3 of its initial volume and precipitated into ethanol/acetone (40 ml, 50:50, (v/v)). Upon filtration the precipitate had changed colour from white to shghtly yellow and became a sticky solid. It was dried in vacuo over P2O5 for 24 hrs.
Yield: 246 mg (88%).
The 'H-NMR spectrum contains its very broad and overlapping signals and thus made the structural analysis very difficult (see results and discussion for the full ^H-NM spectrum).
'H-NMR (400 MHz, D2O): 6 1.29-1.95(m, 16H, d+e+f), 3.04 (t, 5H, ^Jhh= 7.2 Hz, ?),
3.67 - 4.57 (br m, 23H, QQ and c-i-g-t-i4-j), 5.56-5.79 (m, 30H, QQ), 6.56 (br s, IH, h),
7.26-7.67 (vbr m, 4H, a-Kb).
Not all the signals due to expected polymer were seen in the '^C-NMR spectrum.
'^C-NMR (100 MHz, D2O): 5 28.26 (f), 42.83 (j), 50.34 (g), 54.37 (QQ), 60.87
(C(CH3)), 61.76 (c), 73.09 (QQ), 73.22 (QQ), 123.77 (h), 131.19 (Ar), 159.23 (QQ).
211 III.7. Preparation of Linear Polypseudorotaxanes via a Post-Threading Approach
IIL7.1. Reprecipitation of Nylon 6/6
Granulated nylon 6/6 (3g) was dissolved in conc.HCOOH (20 ml) and precipitated into methanol (100 ml). After adding water (100 ml) the polyamide was filtered and washed several times with hot water. The white solid was suspended in toluene (50 ml) and water was removed by azeotropic distillation with stirring. After filtration, the polymer was first dried by itself in vacuo at 50 °C for 4-5 hrs and afterwards over P2O5 for 48 hrs.75 was obtained as a colourless powder.
Yield: 2.5 g (83%).
III.7.2. Reduction of Nylon 6/6 ^^,14
Nylon 6/6, 75, (1.55 g, 6.86 mmol) was suspended in dry THF (20 ml) under nitrogen and heated to gentle reflux. Under vigorous stirring a solution of 2M borane/dimethyl sulfide in THF (15.80 ml, 31.56 mmol) was added dropwise over a period of 30 min.
After about 20 min the mixture became a swollen gel. The mixture was diluted with another portion of THF (20 ml) and heated to reflux for an additional 20 hrs. THF and dimethylsulfide were distilled off. By careful addition of 6N HCl (20 ml) and further heating to reflux for 2hrs, excess borane and any borane amine complex were destroyed.
The viscous solution was cooled to r.t. and added to a large excess of a 5N NaOH solution (150ml). The precipitated polymer was filtered under suction and washed with water until it became neutral. It was dried in vacuo over P2O5 for 24 hrs and extracted with chloroform (30 ml) in a Soxhlet apparatus. The extract was added dropwise to
212 diethylether (200 ml). The precipitated polymer was collected by filtration and dried in vacuo over P2O5 for about 3 days to yield 76 as a white powder.
Yield: 0.95 g (66%).
76
'H-NMR (250 MHz, DCl); 5 1.42 (br m, 4H, c), 1.74 (br m, 4H, b), 3.01 (t, 4H,
^JHH=7.51 Hz, a).
'^C-NMR (62.5 MHz, D2O, DCl, DSS): 6 27.55 (b+c), 49.79 (a).
GPC (Conventional calibration (polystyrene), RI detector in CHCI3)
Mn: 20,000 Da, Mw: 55,000 Da, Mz: 66,000 Da, DP: 202
III.7.3. Preparation of Linear Polypseudorotaxane 77 via a Post-Threading
Approach
General Procedure: QQ was dissolved in DCl (2ml) and the solution was stirred vigorously for 30 min at r.t. Poly(iminohexamethylene) 76 was added. After stirring at r.t. for another hour (to ensure complete dissolution) individual solutions were prepared in NMR tubes by transferring aliquaots via a syringe. The course of threading reaction was monitored by collecting NMR spectra at selected time intervals with reaction temperature for each set of experiments to be set to either 20 °C, 60 °C or 90
°C (see Table 111.7.1. for details).
213 III.7.3.1. General Work-up for Polyseudorotaxane 77
The clear solution from III.7.3. was added to a large excess of isopropanol to form a white precipitate which turned into a slightly off-white and partly sticky solid during filtration. It was dried over P2O5 in vacuo for one week.
'H-NMR (250 MHz, DCl): 5 0.49 (c'), 0.71 (b'), 1.42 (s, 4H, c), 1.68 (s, 4H, b), 3.01 (t,
4H, ^JHH=7.51 Hz, a,a'),.
IIL7.4. Calculation of Molecular Weight (Mn) of 77(See Table III.7.1)
The degree of threading (m/n) is the number of macrocycles (m) per repeat unit (n). m/n was calculated taking the ratio of the intensity of the protons b'+c' which are threaded by QQ versus protons b+c which are not threaded in the ' H-NMR spectra.
Mn's of 77 is calculated as following:
(y X Molar Mass of QQ) + M„ of 76 ~ M„ of 77
(m/n) X (DP) = y
Where y is the number of QQ threaded onto 76.
Mn of 76= 20000, Degree of Polymerisation (DP) of 76 = 202.
214 Table III.7.1 Table summarises the reactions conditions, degree of threading (m/n) and molecular weights (Mn) of the linear polypsuedorotaxane 77.
m/n: degree of threading m: macrocycle; n: repeat unit
Entry 1 2 3 4 5 6
QQ/n (mol) 5/1 1/1 0.5/1 0.3/1 0.2/1 0.1/1 QQ/n (mg) 200/3.98 100/9.95 100/19.90 100/29.85 100/49.75 100/99.49
T: r.t. m/n m/n m/n m/n m/n m/n 48 hrs 0.05 &02 0.03 0.02 0.02 0.02 72 hrs 0.09 0.03 0.03 0.03 0.03 0.02 216 hrs 0.11 0.04 O.OJ 0.03 O.Oj Mn (Da) 41000 28000 28000 27000 27000 26000
T: 60 °C m/n m/n m/n m/n m/n m/n 48 hrs 0.08 0.11 0.1 0.1 0.08 0.04 144 hrs 0.11 0.17 0.16 0.13 0.10 0.04 216 hrs OJg 0.27 oja OJj 0.0 J 552 hrs 0.420 0.34 0.26 0.22 0.12 0.05 Mn (Da) 105000 89000 72000 64000 44000 30000
T: 90 °C m/n: m/n m/n m/n m/n m/n 48 hrs 0^8 0.16 0.16 0.16 0.09 0.04 144 hrs 0.41 &34 0.27 &20 0.10 0.05 216 hrs 0.51 036 0J2 0.23 0.12 0.05 384 hrs &JP OJV 0.23 0.12 0.05 Mn (Da) 139000 97000 89000 66000 44000 31000
215 III. 7.5. Attempted Counter Ion Exchange Reactions of 69
Attempt 1;
Poly(iminohexamethylene) 76 (20.0 mg, 200 |imol) was dissolved in an aqueous IN solution of camphorsulphonic acid (3 ml). When 1 (40 mg, 40 jimol) was added a suspension formed which was heated at 60 °C for 24 hrs. However, heating did not facilitate dissolution of 1, to any noticeable degree.
Attempt 2:
Poly(iminohexamethylene)76 (20.0 mg, 200 jxmol) was dissolved in an aqueous IN solution of camphorsulfonic acid (3 ml) and stirred for 2 hrs before the solvent was removed under reduced pressure to yield a white solid. This salt was redissolved in water (3 ml) and 1 (20 mg, 20 pimol) was added portionwise under vigorous stirring. A suspension formed which was heated at 60 °C for 24 hrs but without showing any sign of dissolution of 1.
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217