Studies in Molecular, Supramolecular and Macromolecular Design · Laureate for Physics Richard P....

School of Chemistry and Physics

Discipline of Chemistry

Studies in

Molecular, Supramolecular

and Macromolecular Design

A thesis submitted for admission to the degree of

Doctor of Philosophy

by

Oscar Archer

B.Sc. (Hons)

2011

i

Declaration

This work contains no material that has been accepted for the award of any other degree

in any university or other tertiary institution. To the best of my knowledge, no previously

published material written by any other person has been included here-in, except where

due and clear reference has been made in the text.

I give consent to this copy of this work, when deposited in the University Library, being

available for loan and photocopying, subject to the provisions of the Copyright Act 1968.

I also give permission for the digital version of my thesis to be made available on the

web, through the University’s digital research repository, the Library catalogue and also

through web search engines, unless permission has been granted by the University to

restrict access for a period of time.

Oscar Archer / /

ii

Acknowledgements

First and foremost I want to thank my principle supervisor Stephen Lincoln for his great

guidance, encouragement and support through this doctorate. Thanks also to Simon Pyke

for more of the same, Kobas Gerber and Jacquie Cawthray for help with titrations, Phil

Clemens for all the NMR instruction, and of course to Bruce May for his ceaseless

support. And to the lab mates and other co-workers who helped in one way or another, or

simply made the days and nights more enjoyable.

Thanks must go to Paul Jensen at USyd for the resolution of x-ray crystal structures,

which could not have been easy.

I am grateful to my mum and dad for their ever-present encouragement over the years,

and, just as importantly, my past-housemates and friends: Tonja, Cassia, Ed, Jason, Ross,

Ange, Ali, Phoebe, Emma A., Matt and Janelle. Finally, biggest warmest thanks to my

partner and soul-mate Em, who has possibly anticipated this even more than I.

iii

Abstract

This thesis will be in three parts describing three projects which investigated different

areas of new materials science in the context of nanotechnological chemistry. The parts

include: the synthesis and characterisation of novel metalloporphyrin complexes with the

geometry of ‘molecular cogs’; physical analysis of simple, new cyclodextrin-based

inclusion compounds, and attempts to generate rotaxanes there-from; and analysis of the

behaviour of aromatic hydrophobically-modified water-soluble polymers as components

in supramolecular complexing complementary polymer systems.

A synthetic approach through a vinyl sulfone–modified Barton and Zard pyrrole was

successfully utilised. It was envisaged that this functionality could be extended further

into a cyclic spiro substituent: where the spiro functionality incorporated aromaticity, it

would constitute a planar, non-rotating substituent arranged orthogonally to the

macrocyclic plane. Symmetrical, tetraspiro annulated porphyrin systems including

indanyl and fluorenyl derivatives were synthesised and spectroscopically characterised.

The fluorenyl-derived zinc metalloporphyrin gave suitable crystals for X-ray

crystallographic analysis.

The design and synthesis of a series of cyclodextrin inclusion compounds incorporating

relatively simple amino-substituted biaryl axle was carried out. The pseudorotaxanes

were asymmetric in character, incorporating functionalised homo- and heteroaromatic

rings at either end, joined by an unsaturated linker. The heterocycle was an azine ring

(pyridine or pyrimidine), and therefore bore one or more nitrogen protonation sites; pKas

in water-methanol solutions were determined. Distinct inclusion in α-cyclodextrin was

observed and quantified in dilute basic aqueous solution by UV-visible spectroscopy.

Corresponding inclusion in concentrated acidic conditions was studied through 2D NMR

techniques, revealing a clear temperature dependence for the α-cyclodextrin/pyridine-

based axle, and site-exchange analysis was performed to determine the rate of inclusion

compound formation. Generation of corresponding rotaxanes was not achieved, most

iv

likely due to the reactivity of azine ring-bound amine groups in the necessary reaction

conditions.

The range of hydrophobically modified polymers was expanded by appending amide-

bonded aromatic side chains to poly(acrylic acid), to give phenyl-, diphenyl-, naphthyl-

and anthryl-type modification. This procedure allowed control over the molecular

weights of the polymer products, and a degree of direction of the amount of each new

polymer’s modification observed primarily through 2D NMR techniques, and

absorbance/fluorescence where applicable. It was generally found that aromatic

substituents lacked the tendency to aggregate in solution that is observed for long

polymer-bound alkyl groups. This is likely due to the relative length and rigidity of

aromatic species. For naphthyl and anthryl groups excimer emission would be a likely

consequence of aggregation but its absence suggests that π-CH hydrophobic association

between aromatic groups and the alkane backbone is more favoured. For the anthryl-

bearing polymer in particular this means that the likely form of substitution consistent

with the fluorescence data is not suitable for studying anthracene fluorescence behaviour

in an aqueous-polymer environment. The interactions of these modified polymers with

native α- and β-cyclodextrin and the corresponding cyclodextrin-modified PAAs in

aqueous solution were assessed with 2D NOESY NMR spectroscopy.

v

Abbreviations

AIBN 2,2′-Azobis(2-methylpropionitrile)

aq. aqueous

cat. catalyst

CD cyclodextrin

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC Dicyclohexylcarbodiimide

DMF N,N-dimethylformamide

EIMS electron impact mass spectrometry

Et ethyl

hr(s) hour(s)

IR infra red

lit. literature

MHz megahertz

min(s) minute(s)

m.p. melting point

NMP 1-methylpyrrolidin-2-one

NMR nuclear magnetic resonance

ppm parts per million

PTSA p-toluenesulfinic acid

Rf retention factor

sat. saturated

TFA trifluoroacetic acid

THF tetrahydrofuran

tlc thin layer chromatography

TMS tetramethylsilane

Tol p-toluene

UV-Vis ultraviolet–visible

w% weight percent

Contents

Declaration i

Acknowledgements ii

Abstract iii

Abbreviations v

CHAPTER 1: Introduction 1

1.1. Molecular Topology & Supramolecular Chemistry 1

1.2. Design at the Molecular and Supramolecular Scale 2

1.2.1. Molecular Gears 2

1.2.2. Host-Guest Inclusion Complexes 4

1.3. Design at the Macromolecular Scale Polymers and Hydrogels 5

1.4. Incorporation of Components into Nanotechnology 7

1.5 Aims 7

CHAPTER 2: Spiro-Annulated Porphyrins with “Molecular Cog” Morphology

2.1. Introduction 9

2.1.1. Porphyrins 9

2.1.1.1. Structure 9

2.1.1.2. Biology 11

2.1.1.3. Substitution 13

2.1.1.4. Conformation 14

2.1.2. Supramolecular Chemistry and Porphyrins 16

2.1.3. Porphyrin Synthesis 19

2.1.3.1. Synthesis from Pyrroles 19

2.1.3.2. Synthesis of Pyrroles 21

2.1.4. Recent Routes Facilitating Ring-Fused Spiro-Annulation 23

2.1.4.1. Synthesis of Vinyl Aryl Sulfones 23

2.1.4.2. Target Vinyl Bond-bearing Rings 23

2.1.5. Summary and Aims 24

2.2. Discussion 26

2.2.1. Retrosynthetic Details 26

2.2.2. Preparation of Spiro Cyclopentenes 27

2.2.2.1. Diallylation 27

2.2.2.2. Ring-Closing Metathesis 29

2.2.2.3. Preparation of Vinyl Sulfones 32

2.2.2.4. Preparation of Fused-Ring Pyrrole Carboxylates 33

2.2.3. Porphyrin Assembly 35

2.2.4. Analysis of Spiro-Annulated Porphyrins 36

2.2.4.1. Tetraspiro-annulated Indanyl System 36

2.2.4.2. Tetraspiro-annulated Fluorenyl System 38

2.3. Summary, Conclusion and Future Directions 41

CHAPTER 3: Asymmetric Pseudo-Rotaxanes as Switchable Molecular Systems

3.1. Introduction 43

3.1.1. Supramolecular Species 43

3.1.1.1. Pseudorotaxanes 43

3.1.1.2. Rotaxanes 45

3.1.2. Cyclodextrins 50

3.1.2.1. Cyclodextrins in Rotaxanes and Pseudo-Rotaxanes 52

3.1.2.2. Recently Studied Cyclodextrin Systems 57

3.1.3 Summary and Aims 61

3.2. Discussion 63

3.2.1. Targeted Axle Components 63

3.2.2. Syntheses of Axle Components 63

3.2.3. Analysis of [2]-Pseudorotaxanes 67

3.2.3.1. UV-Visible Spectroscopy 67

3.2.3.2. NMR Spectroscopy 72

3.2.4. Rotaxane Synthesis Attempts 80

3.2.5. Stilbene Homologue Comparison 83

3.2.5.1. UV-Visible Spectroscopy 84

3.2.5.2. NMR Spectroscopy 86

3.2.5.3. Stilbene-Derived Rotaxane Synthesis Attempts 88

3.3. Summary, Conclusions and Future Directions 91

CHAPTER 4: Hydrogels Consisting of Hydrophobe and Hydrophobe Receptor-

substituted Polymers in Aqueous Solution

4.1. Introduction 93

4.1.1. Hydrogel 93

4.1.1.1. Lower critical solution temperature (LCST) 94

4.1.1.2. Shear Viscosity 95

4.1.1.3. Drag Reduction 95

4.1.2. Aqueous Intra- and Intermolecular Supramolecular Assembly 95

4.1.2.1. Substituted Polymer Syntheses 99

4.1.3. Fluorescence Studies of Aqueous Polymers 100

4.1.4. Poly(acrylic Acid) 102

4.1.4.1. Poly(acrylic Acid) Substitutions 104

4.1.4.2. Recent Progress 106

4.1.5. Summary and Aims 108

4.2. Discussion 109

4.2.1. Target Poly(acrylic Acid) Substitution 109

4.2.2. Initial Hydrophobe Target Synthesis 109

4.2.3. Hydrophobic Amide Synthesis 110

4.2.3.1. Aryl Acetic Acids 110

4.2.3.2. Nitrophenol Aryl Acetates 112

4.2.3.3. Aminoethyl N-Aryl Acetamides 112

4.2.4. Aromatic Substituted Poly(acrylic Acids) 113

4.2.4.1. Substitution of Poly(acrylic Acid) 113

4.2.4.2. Cyclodextrin-Hydrophobe Complexation 115

4.2.5. Polyaromatic Substituted Poly(acrylic Acid) 125

4.2.6. Anthracene Substituted Poly(acrylic Acid) 127

4.2.6.1. Secondary Amine Synthesis 127

4.2.6.2. Poly(acrylic Acid) Substitution 129

4.2.6.3. Cyclodextrin-Anthryl Complexation 131

4.2.6.4. Effects on Fluorescence 131

4.2.7. Binary Poly(acrylate) Interactions 134

4.3 Summary and Conclusion 136

CHAPTER 5: Experimental

5.1. General Methods 138

5.2. Synthesis in Chapter 2 139



Appendix 159

A.1. X-ray Crystal Structure Data for Tetraspiro-annulated Fluorenyl

Porphyrin 2.11 159

A.1.1. Additional Refinement Details for 2.11 160

A.1.2. Non-Hydrogen Atom Coordinates, Isotropic Thermal Parameters and Occupancies

161

A.1.3. Anisotropic Thermal Parameters ( Å2) 163

A.1.4. Non Hydrogen Bond Lengths (Å) 165

A.1.5. Non Hydrogen Bond Angles (º) 167

A.2. Inclusion Complex UV-Visible Stability Determinations 172

A.2.1. Solution Preparation 172

A.3. Asymmetric Axle pH Titrations 177

A.3.1. Potentiometric Data Fitting 178

A.4. 2D NMR Spectra referenced in Section 4.2. 182

A.5. Public Presentations 188

References 189

Introduction

1

CHAPTER 1: Introduction

Most of King Coyote's books had to do with the secrets of atoms and how to put them

together to make machines. Naturally, all of them were magic books; the pictures moved,

and you could ask them questions and get answers.

– The Diamond Age, by Neal Stephenson

Nanotechnology is a relatively new field that has naturally amalgamated out of various

established areas of science since the early 1980s.1 First proposed broadly by Nobel

Laureate for Physics Richard P. Feynman2 in 1959, the field has attracted enormous

interest and activity in many countries within the last decade. Representing an overlap of

high-powered microscopy,3 physics,4 physical chemistry5 molecular biology,6 and

chemical synthesis,7 an essential ingredient has been an almost playful sense of

imagination, just as is invested in the molecular technology of Neal Stephenson’s

fictional post-industrial future.

1.1. Molecular Topology & Supramolecular Chemistry

In 1961 Frisch and Wasserman proposed the possibility of one or more macrocyclic

molecules forming topological isomers whilst specific atom number and order, bond

type, and rigid bond arrangements are conserved.8 Examples were based on the

“knotting” of single loops and the linking of two (or more) loops, into molecular species

such as trefoils (Figure 1.1, A) and catenanes9 (B), respectively. More exotic10 topology

such as Möbius strips was also conceived. The alteration of topology, but not chemical

structure, was nevertheless identified as a source of change of physical characteristics.

Although topological isomers were a consequence of essentially mechanical, and not

chemical, bonding, the mechanically-associative force is conceptually only as strong as

the weakest chemical bond of the component(s).

Introduction

2

A B

Figure 1.1. Schematic representation of intra- and intermolecular, mechanically-bonded

isomers: trefoil knot (A), catenane (B).8

Since this time, the topology of “mechanically bonded” multi-molecular complexes,

together with other non-covalent types of assembly, has been called supramolecular

chemistry, and its importance was recognised in 1987 by the awarding of the Nobel Prize

in Chemistry to Cram,11 Lehn,12 and Pedersen.13 This field of chemistry is largely

inspired by the kinds of non-covalent interactions and multi-molecular structures found in

natural biomolecular systems, where, for example, protein substrates and receptors are

the basis for control of many cellular processes. The scope of supramolecular chemistry

has grown vast in the intervening decades and only a small sample will be discussed

herein.

1.2. Design at the Molecular and Supramolecular Scale

1.2.1. Molecular Gears

Although not a binding interaction per se, the rotational fitting or meshing of a series of

similar bulky substituents is an appealing subject of research due to the obvious analogy

with meshing gears. The non-covalent force in this case does not contribute to molecular

assembly so much as the transfer of energy from one part of the system to the other.

Mislow et al. comprehensively described such molecular gear systems in 1988, using

triptycene substituents,14 flexibly bridged by methylene groups (Figure 1.2, A),

Correlated gearing of these three-toothed cog analogues was demonstrated using NMR

spectroscopy.

Introduction

3

NN

OCH3

OCH3

Hg

A B

Figure 1.2. Triptycene-based gear systems: methylene-bridged meshing gears14

(A) and

bipyridyl coordination-dependent molecular brake15 (B).

The potential of the triptycene geometry was investigated further by Kelly et al. As an

example, the “molecular brake”,15 featuring a 2,2’-bipyridine substituent, was activated in

solution by nitrogen lone pair coordination to Hg2+ (Figure 1.2, B): the resulting, rigid

substituent intercalated between triptycene “teeth” and halted rotation as shown by NMR

spectroscopy. Sequestration of Hg2+ by EDTA disengaged the brake. More recently,

similar molecular geometry has led to the design of a chemically powered rotating

molecular motor.16

The geometry of cogs has been further investigated in such systems as that displayed in

Figure 1.3a.17,18 Rapenne et al.19 observed a correlated rotation of the bromophenyl

substituents with the rotation of the trisindazoylborate ligand by NMR spectroscopy and

X-ray crystallography.

Introduction

4

a) b)

NN

NN

NN

Ru

BH

Br

Br

Br Br

Br

Figure 1.3. a) Ruthenium(II) pentaaryl cyclopentadienyl trisindazoylborate correlated

gears;17,18

b) decacyclene derivative rotor.20

The distinction between molecular cogs at rest and in rotational motion was elucidated by

Gimzewski et al.,20 Scanning tunnelling microscopy of a monolayer of the symmetrical

hydrocarbon “cog” (Figure 1.3b) deposited on a copper surface revealed a given

molecule to be stationary when engaged with adjacent molecules, and rapidly rotating

when disengaged. Transition between these states could be effected by manipulation with

the microscope tip.

The concept of utilising radially symmetrical molecules as analogues for gearing

components has been pursued for many years. Chapter 2 of this thesis will deal with the

design, synthesis and characterisation of metalloporphyrin-based molecular cogs

featuring symmetrical, spiro-annulated substitution.

1.2.2. Rotaxanes

A second type of topological isomer was also originally envisaged: a rod-like component

threaded within a macrocycle (Figure 1.4).8 Such a structure composed of a linear ether

featuring tertiary alkyl termini and an acyloin macrocyle was reported by Harrison and

Harrison in 1967,21 but it was Schill, with a species comprised of a bis(aminoalkyl)-

phenyl derivative complexed within a cyclic ketone, who introduced the term “rotaxane”

from the Latin rota and axis, for “wheel” and “axle”, respectively.22

NOTE: This figure is included on page 4 of the print copy of the thesis held in the University of Adelaide Library.

Introduction

5

Figure 1.4. Mechanically bonded axle and macrocycle “rotaxane”.8

By the mid-90s, a vast collection of supramolecular assemblies and syntheses featuring

widely varying chemistries existed,23 and rotaxanes featured prominently. The chemistry

and geometry of these systems has been deliberately designed and manipulated in order

to produce molecular analogues of shuttle systems,24,25 in which the rota component

preferentially rests at one or more sites of specific intermolecular compatibility

incorporated into the axle, and abaci,26 featuring one or more rotas per rotaxane that can

be directly slid along the axle component.

Further introduction to rotaxanes and their precursors is discussed in Chapter 3 of this

thesis, in which the background for the current project is also examined. This will be

followed by synthetic and analytical details of the project carried out with the aim of

generating simple asymmetric complexes and rotaxanes.

1.3. Design at the Macromolecular Scale: Polymers and Hydrogels

Polymers are macromolecules composed of repeating monomer units, and exhibit

physical properties not usually observed for smaller molecules. The chemistry of

macromolecules is affected by such factors as chain length, chain branching and cross-

linking. In particular, water soluble polymers provide an altered aqueous environment for

traditionally hydrophobic classes of chemical and physical molecular interactions.

In nature, the best example of the wide scope of polymer chemistry is DNA, and indeed

artificial derivatives have yielded various types of nanotechnological molecular

“devices”.6 Many other natural, comparatively simpler polymers exist,27 and form

solutions or suspensions in water that are known as hydrogels. Synthetic polymers have

Introduction

6

also been researched for decades in this capacity and the properties of this class of

material are exploited in such areas as gel permeation chromatography,28 tissue

engineering,29 ocular drug delivery30 and dermal regeneration.31

A

B

polymer backbone hydrophobe

intrastrandassociation

hydrophobe receptor

hydrophobe receptor-hydrophobe association

D

hydrophobeassociation

C

hydrophobe-single hydrophobe receptor association

single or molecular hydrophobe receptor-polymer hydrophobeinteraction

complimentarypolymer interaction

Figure 1.5. Substituted hydrogel supramolecular interactions: separate hydrophobe-

substituted water soluble polymer (A). Intra- and inter-strand association in solution (B).

Hydrophobe complexation by a small molecular hydrophobeb receptor removes inter-

polymer strand interaction (C). Complementary complexation a polymer substituted with

hydrophobe receptors and one substituted with hydrophobes produces a polymer network

(D).

Hydrogelating polymers present a platform for the incorporation of substituents to be

used as the basis of supramolecular complexes.7 Thus, substitution of polymers with

Introduction

7

either hydrophobes or hydrophobe receptors has enabled the manipulation of hydrogel

characteristics through either the mixing of one of each type of substituted polymer, or

mixing of either a small molecular ditopic hydrophobe or a ditopic hydrophobe receptor

with the corresponding substituted polymer to form hydrophobe receptor–hydrophobe

complexes and thereby inter-polymer strand cross-links.32-37 Chapter 4 of this thesis

describes research based on the concept of controlling the hydrogelation properties of

substituted water-soluble polymers as illustrated in Figure 1.5.

1.4. Incorporation of Components into Nanotechnology

Topological isomerism and other avenues of supramolecular assembly and interaction

provide the conceptual basis for the design of molecular devices in an emulation of the

machinery that functions within biological systems.6 It also facilitates the so-called

“bottom-up”2 approach to electronics and “smart” materials. The exercise of imagination

should be tempered, however, by consideration of the fundamental principles that govern

the behaviour of molecules, individually and, more critically, collectively. Molecular

behaviour is invariably an average of thermal motions and states in equilibrium, not a

matter of specific configurations of individual molecules. Applications arising from such

research are bound to offer significant redundancy of function, in addition to overall

simplicity of molecular design and motion.38 Incorporating designed molecular systems

into real-world usable devices will remain a field of interesting research for the

foreseeable future.

1.5 Aims

This thesis is concerned with investigations of the synthesis and analysis of several types

of molecules and molecular assemblies that fit within the three topics discussed above.

The general aim of each project was to generate new examples of these species to

potentially provide further information on molecular gears, hydrophobe receptor-

hydrophobe complexes and hydrophobically substituted polymers. The details of each

investigation comprise the following three chapters.

Introduction

8

The first chapter concerns porphyrin derivatives used as the basis of molecular cogs. This

project aimed to synthesise ring-fused porphyrins with the geometry of molecular cogs

through utilisation of planar spiro-annulated precursors, exploiting the planarity of the

porphyrin macrocycle and the orthogonal nature of the quaternary carbon spiro junction.

The planarity of the precursor was equally important, as this carbocycle forms the teeth

of the cog. The geometry of the spiro-annulated porphyrins produced are determined

through X-ray crystallography.

The second chapter is about the synthesis and characterisation of simple cyclodextrin

pseudorotaxanes that utilised asymmetric protonation sites in the axle component to

confer asymmetry to the complexes. Two species were synthesised and characterised in

terms of pKa and interaction with cyclodextrins in acidic and basic conditions. The

stability of the complexes, the consequences of asymmetry and the potential for forming

rotaxanes was studied.

The third chapter details the substitution of poly(acrylic acid) with a variety of aromatic

substituents. The modifications were randomly attached to low percentages of acrylate

carboxylate groups. The interactions between these polymers and both native

cyclodextrins and poly(acrylic acid)-bound cyclodextrins are investigated to assess the

switchability of viscosity properties, as well as spectroscopic properties.

Spiro Annulated Porphyrins

9

CHAPTER 2: Spiro-Annulated Porphyrins with “Molecular Cog”

Morphology

2.1. Introduction

2.1.1. Porphyrins

2.1.1.1. Structure

The porphyrin macrocycle is a cyclic tetramer of pyrrole units connected by methine

bridges. The structure is such that porphyrins, and the vast majority of derivatives

thereof, exhibit several important features:

• conjugated double bonds follow the Huckel rule and confer aromaticity.

The macrocycle of porphyrins exhibits a total of 22 π electrons which are all

conjugated, though only 18 of these are involved in a given delocalisation

pathway. This corresponds to a Huckel value, and hence aromaticity, making

porphyrins molecularly stable. A further consequence is characteristic intense

visible-spectrum absorption and colouration.

• the macrocycle is usually planar and mostly flat.

Porphyrins usually appear and behave as flat molecules, unless specific

substitution acts to introduce a different geometry. The major consequence is that

porphyrins present one of two faces during molecular interactions.

• the core nitrogens can be fully deprotonated and coordinate to a transition metal

ion centre.

Metalloporphyrins can be derived from free-base porphyrins by reaction with

appropriate metal salts. Optical and other properties can be greatly altered by this

modification. Naturally occurring porphyrinic systems are invariably ligands of

select metals.


10

"beta"

"meso"N

N N

N

M

b g

lq

b)

"alpha"

Figure 2.1. a) Free-base porphin. The systematic position and pyrrole labels correspond

to IUPAC nomenclature.39

b) The general structure of a metalloporphyrin, including

trivial labels for widely-functionalised sites and faces: the four meso methine positions,

the eight pyrrolic beta positions and the b,g,l,q edges pertinent to fused-ring substitution.

Porphyrins are aromatic when in the free-base state and when metallated, but the exact

nature of the aromaticity pathway has been the subject of decades of research. Two

extreme models40 describe the pathway as including the outer carbon-carbon bonds of

any two opposite pyrrole units (Figure 2.1a), and alternatively as following a route

through the inner edge of each pyrrole unit (Figure 2.1b). X-ray crystallography has been

used extensively to elucidate porphyrin-based structures, and has provided evidence for

both of these perspectives in porphin.41,42

N

NH N

HN N

N N

N

2H+

a) b)

Figure 2.2. a) The bridged diaza[18]annulene model; b) The tetraaza[16]annulene

model (the dianion charge is delocalised within the ring current).

The first model dictates a line of symmetry inherent in the macrocycle coupled with a

degree of tautomerism, and has been supported recently by molecular modelling.43 NMR

studies have provided further evidence: proton spectra showed a temperature dependent

coalescence for the beta-position hydrogen resonances, observed as distinct singlets at

193 K.44 The presence of a peak corresponding to the core N–H hydrogens is observed at

around –4 ppm for free-base porphyrins, indicating the rate of tautomeric exchange



11

between degenerate tautomers to be rapid on the NMR timescale. Carbon NMR spectral

data further supports this model as, for example, the chemical shifts corresponding to the

alpha and beta pyrrole carbons are consistent with nuclei lying within the same

delocalisation pathway.40 The tautomerism between degenerate delocalisation pathways,

as well as hydrogen-deuteron-triton exchange and isotope effects, have also been studied

in the liquid and solid state through dynamic NMR techniques.45,46

2.1.1.2. Biology

Porphyrins and porphyrin analogues are ubiquitous in the natural world. The first

isolation of a porphyrin involved treatment of iron-containing hemoglobin with aqueous

sulfuric acid, in 1871.47 This yielded the purple free-base protoporphyrin-IX (normally

four porphyrin rings linked at various positions) from heme, and German chemist Hoppe-

Seyler dubbed this substance hematoporphyrin from the Greek for blood and purple. The

intensity of colour is due to characteristic ultraviolet-visible absorptions which were

described for hemoglobin by Soret in 1883. The so-called Soret band, or (more formally)

“B” band appears, for all porphyrins, derivatives and related conjugated macrocycles, at

around 400 nm, with molar absorptivity typically in the order of 4 × 105 mol-1 cm-2

(Figure 2.3). The less intense “Q” bands (inset) occur at around 500–700 nm, and usually

number four for free-bases and two for metalloporphyrins.


12

0

0.5

1

1.5

350 450 550 650

wavelength (nm)

Abs

orba

nce

Q bands

0

0.1

485 565 645

free base

zinccomplex

Figure 2.3. UV-visible spectrum of tetraphenylporphyrin.

Besides heme, the active site of biological oxygen transport as well as the basis of

cytochrome enzymes, the central motif in the chlorophylls is chlorin, a derivative of

porphyrin with hydrogenation across one bond. Chlorophyll-a and b contain magnesium

ions and are responsible for most photosynthesis in plants and algae.47 An elucidation for

the biosynthesis of chlorophylls48 was proposed by Granick in 1951, and in 1960

Woodward et al. described the total synthesis of chlorophyll-a.49 Related systems include

chlorophyll-c and the bacteriochlorophylls. The other derivative of major biological

importance is vitamin B12 and its active coenzyme counterpart,47 which is a cobalt(III)-

binding corrin-based molecule that is responsible for specific chemical transformations in

the cell. Heme and chlorophyll derivatives, including vanadium(V) complexes, are

important trace constituents of crude fossil fuels.50

The medical roles of porphyrins as multigenerational photodynamic therapy agents51

have been researched in terms of their anticancer and antimicrobial properties.52,53

Initially, cellular toxicity was observed for hematoporphyrin derivative specifically after

irradiation with sunlight, and consequent work showed that the oligomeric substance


13

concentrated preferentially in tumour cells in animal models. It is generally accepted that

the electronic excitation of the porphyrin functionality results in the promotion of

molecular oxygen to the cytotoxic singlet state, which readily reacts with biological

substrates and interrupts cell function. Modern photodynamic therapy utilises the

porphyrin-based drug Photofrin®.

2.1.1.3. Substitution

N

NH N

HN

R1

R2 R0 R3

R4

R0

R5

R6R0R7

R8

R0

Figure 2.4. Common modes of porphyrin substitution.

Almost a century of investigation into the chemistry of hemes, chlorophylls and every

known related system has brought forth a wide understanding of the properties conferred

to porphyrins, etc., by the nature of the substitution around the macrocycle. Naturally-

derived porphyrins (not to mention chlorins and others already mentioned) display a

broad, often total, extent of substitution at the beta positions (Figure 2.4, R1-8 ≠ H),

combined with a large selection of possible groups, making for a vast number of

permutations in structure. For example, the etioporphyrins have an equal number of

methyl and ethyl substituents (Figure 2.4, etioporphyrin-III is R1 = R4 = R5 = R8 =

methyl, R2 = R3 = R6 = R7 = ethyl, R0 = H) and the UV-visible spectrum can be reliably

predicted as “etio-type”.47 The substitution pattern of protoporphyrin-IX (Figure 2.4, R1

= R3 = R5 = R8 = methyl, R2 = R4 = vinyl, R6 = R7 = 3-propionic acid, R0 = H) means that

this species also corresponds to this somewhat classical spectroscopic classification.

Of note are two synthetic porphyrins regarded as standard,54 namely tetraphenylporphyrin

and octaethylporphyrin (Figure 2.4, R1-8 = H, R0 = phenyl and R1-8 = ethyl, R0 = H,


14

respectively), for which preparative procedures have steadily improved as a facet of

research into porphyrins. As an example, Rothemund and Menotti’s original55 1941

synthesis of tetraphenylporphyrin was simplified by Alder et al. in 1967 with

significantly improved yield.56 A more recent report details optimisation of the yield

through careful management of reagent concentration.57

The other widely explored area of introduced substitution revolves around beta-beta ring

fusion, largely of an overall asymmetrical or partial nature (i.e., involving only one

corner of the ring). The outer edges of the pyrrole functions have been targeted as

dienophiles in studies to yield novel extended macrocycles, through reaction with various

ortho-quinodimethanes and other reactants such as pentacene (Figure 2.5a).58,59

N

a) c)

N

NH

N

NMe

b)

N

N

N

CN

CN

N

Figure 2.5. Examples of possible fused-ring porphyrin substitution.

Other studies have looked at the cycloaddition of azomethine ylids and the resulting

chlorin-type products (Figure 2.5b) as well as the subsequent bis- and trisadducts, with

the aim of developing potential photodynamic therapy agents. Other approaches have

been used to obtain quinoxaline-based ring-fused substitution60 (Figure 2.5c). Similar

modification but with more pronounced asymmetry includes the cyclisation of (typically

3,5-)substituents to obtain porphyrins with exocyclic rings.61,62

2.1.1.4. Conformation

The planarity of porphyrins is influenced by a variety of factors. For instance,

tetraphenylporphyrin retains planarity when it is metallated with tin,63 but

copper(II)tetraphenylporphyrin is geometrically distorted as the metal ion does not fit


15

well within the core and is coordinated slightly out of the plane of the macrocycle.64 The

complexation of metals as bulky as uranium and thorium has also been investigated,

resulting in such interesting non-planar structures as the thorium(tetraphenylporphyrin)2

sandwich.65

Steric crowding of covalent substituents is often involved in distortion of the plane.66 The

distortions have been classified broadly as being saddle-, ruffle-, wave- and dome-like.67

Importantly, interruption of the planarity of porphyrins and derivatives in biological

contexts, where the degree of deformation is often conserved among classes of

porphyrin-bearing proteins,68 is believed to be important in modulating chemical69 and

photochemical66 activity. Molecular mechanics simulation studies of porphyrin

conformations have recently been reviewed.70

In recent years porphyrin systems incorporating fused ring substitution at the beta

positions have been investigated for their anticipated degrees of non-planarity66 (Figure

2.6).

N

N N

N

X

XX

X

M

X = (CH2)n

Figure 2.6. Highly substituted and rigidly constrained fused-ring porphyrin derivatives.66


16

2.1.2. Supramolecular Chemistry and Porphyrins

Figure 2.7. β-Cyclodextrin dimer ligand chelating europium, forming a complex with

porphyrin guest molecule. The cyclodextrin hosts are denoted by the truncated cones (cf.

Section 3.1.2).72

Porphyrin derivatives have potential as components for molecular architecture and

examples exist for mechanical analogues as well as mimics of biological systems. One

reported system was a catenane featuring a 5,15 di-meso substituted octaethyl porphyrin

facing an aryl moiety, tethered by polyether links, and linked to a cyclophane

bisbipyridinium tetracation macrocycle.71 Diprotonation of the porphyrin resulted in a

geometrical elongation of the polyether chains to allow the cyclophane rotational

freedom localised opposite the porphyrin. Also of interest, the interactions of EDTA-

based β-cyclodextrin (cf. Section 3.1.2) dimer ligands with charge-bearing substituted

tetraaryl porphyrins was studied by Mulder et al., and found to have a flexibility-

dependent influence on the ligands’ chelation of europium (Figure 2.7).72

Arraying porphyrins into supramolecular materials has been approached from several

directions. The work of Goldberg led to collections of non-covalent, hydrogen bond-

associated tetraarylporphyrin networks.73 The facile coupling of 5,15-diaryl porphyrins at

the unsubstituted meso positions has led to covalently connected porphyrin arrays74 that

show promise as “molecular wires”. Such arrays can be dimensionally extended by


17

further meso coupling, such as the “windmill porphyrin arrays” of Aratani et al.,75 or be

synthetically manipulated to generate extraordinary fully-conjugated, planar fused

porphyrin materials with an extent of conjugation such that the lowest wavelengths of

electronic absorption lie in the infrared (Figure 2.8).

Figure 2.8. Fully conjugated porphyrin “strips”.75

The versatility and potential of porphyrin based oxidation catalysts is a considerable field

of research.76 To mimic the natural role of heme in cytochrome P450, Kuroda et al.

investigated the catalytic activity of an iron(II) tetraarylporphyrin sandwiched between

the primary faces of orthogonally tethered β-cyclodextrins.77 The presence of a

hydrophobic environment at the catalytic site had a pronounced effect on rates and yields

of hydrophobic alkene epoxidations.

Artificial photosynthetic models78 including systems based on charge separation in, for

example, covalently linked porphyrin-quinone,79 porphyrin-fullerene,80,81 and porphyrin-

anthracene82 combinations have been the subjects of study for over a decade. Of

particular consequence was the work of Steinberg-Yfrach et al.83 in which a synthetic

photo-reaction centre, a carotenoid-porphyrin-naphthoquinone triad (Figure 2.9), was

embedded in a liposomal bilayer, and upon irradiation at 430 nm a charge-separated

diradical species was generated which resulted in proton transport, by way of a mobile

lipid-soluble quinone shuttle, into the liposome interior. After one minute of irradiation a

measurable pH gradient could be detected. The same group continued this approach,

generating similarly constituted liposomes that also included the membrane-bound F0F1-

ATP synthase enzyme complex.84 The pH gradient was observed to supply sufficient



18

proton-motive force for the synthase-catalysed production of adenosine triphosphate,

effecting the creation of a self-contained artificial photosynthetic system. The exact

geometry of porphyrins and their derivatives has lately been manipulated to achieve other

biomimetic light-harvesting models.85

Figure 2.9. The artificial photoreaction centre triad of Steinberg-Yfrach et al.83

The possibility of incorporating porphyrins into metal sandwich-type photovoltaic cells

has also been investigated.86

2.1.3. Porphyrin Synthesis

2.1.3.1. Synthesis from Pyrroles

Pyrroles are the key components in porphyrin synthesis. Biologically, all porphyrins and

derivatives are formed from porphobilinogen,87 (Scheme 2.1) a ubiquitous substituted

pyrrole derived from aminolevulinic acid. Enzymatic cyclotetramerisation of the pyrrole

is followed by several enzyme-dependent substituent modifications. One major approach

to laboratory porphyrin syntheses parallels this formation in requiring 2-substitution of

the pyrrole ring. Species such as 2-dimethylaminomethylpyrroles88 and pyrrole-2-esters89

are commonly used because the substituent provides the bridge methine carbon. Also, an

alternative synthesis has proceeded through the 2-carboxylate oxime, which is converted

to the reactive aminomethylpyrrole in situ.90,91



19

N

NH N

HNNH

NH HN

HN

HN

HOOC COOH

NH2

COOHHOOC HOOC COOHPorphobilinogen

Protoporphyrinogen-IX Protoporphyrin-IX

Scheme 2.1.

The other widely used approach is the Rothemund92,93 synthesis which involves the

reaction of pyrroles with aldehydes to form 2-hydroxymethyl substituted intermediates

substituted at the 2 and 5 positions. Porphyrin formation from these pyrroles is essentially

a condensation reaction, and the substituent carbon provides the final methine bridge. The

advantage of this approach is the vast range of functionality possible at the porphyrin

meso position simply through choice of aldehyde.

Of more specialised use are “2+2” (dipyrrylmethanes)94-96 and “3+1”97,98 approaches,

which grant further control over the symmetry or asymmetry of the intended porphyrins,

e.g. for targeting chlorophyll-type exocyclic ring substitution.87 Alternatively, Diels-

Alder chemistry has been employed to introduce fused-ring functionality at the meso

position.99


20

NH

NH HN

HN

N

NH N

HN

N

NH N

HN

[O]

[O]

OR

RO

Cl

Cla)

b)

c)

ClOH

R

ROH

Cl

Figure 2.10. a) Porphyrinogen. b) Chlorin. c) R = Cl, p-chloranil; R = CN,

dichlorodicynoquinone (DDQ).

The cyclotetramerisation of pyrroles normally involves nonaromatic intermediates,

porphyrinogens (Figure 2.10a), which are spontaneously aromatised in the presence of

such mild oxidisers as air. In cases where the pyrrole precursors are tailored for

reactivity, addition of any oxidising agent may be unnecessary.100 Syntheses of beta

unsubstituted porphyrins such as those reported by Alder101 and Lindsey102 lead to trace

amounts of chlorin byproduct (Figure 2.10b) as a mixture with the desired product, and

further oxidation is most commonly affected with quinones such as p-chloranil and DDQ

(Figure 2.10c), which are readily reduced to their aromatic forms, to convert this by-

product to porphyrin.

2.1.3.2. Synthesis of Pyrroles

There are two popular routes to pyrrole products. The first is the Knorr pyrrole synthesis

(Scheme 2.2), normally involving condensation of an α-aminoketone with a β-


21

ketoester.90,96 The α-aminoketone is highly reactive and is first generated in situ from the

corresponding oxime in the presence of zinc and acetic acid. Normally, Knorr pyrroles

are fully substituted due to the nature of the reactants and require further preparative

treatment before their use as porphyrin components. In the related Paal-Knorr

synthesis,103 a 2,5-diketone is cyclised with an ammonium species providing the nitrogen.

In the reaction with dicarboxylates, 2- and 5-substitution can be avoided.

O R1

R2

O R1

R2 NOH

O R1

R2 NH2

O

R3O

OR4

HN

R1

R2 R3

OR4

O

+HONO Zn/AcOH

Scheme 2.2.9

Different desired substitution patterns can be obtained through other pyrrole syntheses,

such as the Hantzsch104 and the Piloty-Robinson reactions.105

The second popular method is the far more recent106 Barton and Zard pyrrole synthesis.

Those researchers observed the nucleophilic attack of nitroolefins by isocyanoacetate β-

anions, as had been similarly described in earlier research.107,108 Hydrogen abstraction

was concomitant with elimination of the nitro group, following cyclisation at the

isocyano carbon (Scheme 2.3). The final step involves [1,5]sigmatropic rearrangement to

the pyrrole product. The resulting functionality at the 2-position is potentially

synthetically useful in porphyrin formation, as explained above. Alternatively, generation

of the corresponding carboxylic acids allows facile decarboxylation and generation of

pyrroles unsubstituted at the 2 and 5 positions.


22

HN

R1 R2

O

OR

N

R1 R2

O

OR

N

R1 R2

O

OR

H

O2N

N

R1 R2

O

OR

H

O2NO2N N

C:

ORO

R2

R1NO2

R1

R2 N

ORO

C:+ base

baseH+

[1,5]

R = alkyl, aryl; R1 = H, alkyl, aryl; R2 = H, alkyl, aryl

Scheme 2.3.

Barton and Zard, and other workers since,109,110 found this methodology to be suitable for

a range of ester-, amide- and substituted aryl-functionalised starting materials. Moreover,

Ono et al. utilised it to obtain the 3,4[c] fused ring pyrrole-2-ethyl carboxylate from nitro-

1-cyclohexene, in order to generate the tetracyclohexenyl[b,g,l,q]porphyrin.111 This

demonstrated the potential for the Barton and Zard synthesis as a route to novel fused

ring porphyrins of more complex and interesting geometry.

Preparation of pyrrole-2-carboxylates was reported by Haake’s group in 1990 through

treatment of vinyl phenylsulfones,110 in place of nitroalkenes, with ethyl isocyanoacetate.

Almost simultaneously, Arnold et al. achieved comparable results through the use of

vinyl tosylsulfones.112 The modified Barton and Zard methods required somewhat

changed conditions, and initial yields were below fifty per cent. Details provided by

Arnold et al. include the use of hydride base to generate the initial carbanion to avoid

thermal side-reactions. The reaction proceeds to the dihydro-2H-pyrrole anion, with

acidic workup providing the conditions for the following steps which are analogous to

those described above. Both approaches were preceded by the use of conjugated vinyl

phenylsulfones in a specific pyrrole precursor synthesis as part of a natural products

strategy,113 although porphyrin synthesis was not involved. As will be detailed below,

obtaining vinyl sulfones is relatively trivial, and it is this route to novel pyrroles which

this work has focussed on.


23

2.1.4. Recent Routes Facilitating Ring-Fused Spiro-Annulation

2.1.4.1. Synthesis of Vinyl Aryl Sulfones

The chemistry of vinyl sulfones is well understood.114 In the broader picture of fused ring

porphyrin synthesis, arylsulfonyl groups are intended to stabilise the carbanion following

conjugate addition across the double bond and, more importantly, to subsequently

function as good leaving groups. Their utilisation, as an alternative to the nitroalkenes of

Barton and Zard, must necessarily offer comparative convenience. There exists a

spectrum of preparative methods, including 1,2-seleno-sulfonation-oxidation,115 boron

trifluoride catalysed selenosulfonation,116 chlorosulfenylation-dehydrochlorination,117

sulfonylmercuration and others.118 Inomata et al. provided a simplified protocol likely

involving an iodonium derivative of the vinyl reactant, with subsequent attack of the

intermediate by p-toluenesulfinate ion (Scheme 2.4). Abstraction of the α-hydrogen with

amine base and concomitant elimination of iodide regenerates the vinyl bond. The β-iodo

intermediate is relatively stable and its purification is not usually necessary.

R2

R1 R1

R2

IR1

R2 I

SO2Tol R1 SO2Tol

R2

I2 NaSO2p-Tol base

Scheme 2.4

2.1.4.2. Target Vinyl Bond-bearing Rings

The work of Pearce and Johnstone119 and others such as Vicente et al.120 covered the

synthesis of many fused-ring pyrroles from a diverse range of cyclopentenes,

cyclohexenes and vinyl functionalised heterocycles (Scheme 2.5).


24

X X X NH

SO2Ar

OOR

R = Me, Et, CH2Ph; Ar = Ph, p-Tol

X = NC6H4NO2, CMe2, OCMe2O, CH2OCMe2OCH2,

CH2CH2, SO2, C(CO2Me)2, C(CN)2, SiPh2, O,

OC

O .

Scheme 2.5.

The pyrrole-2-carboxylate-fused 3-sulfolene (Scheme 2.5, X = SO2) was synthesised as a

versatile precursor in annulated porphyrin synthesis.121 High-temperature extrusion of

sulphur dioxide in the presence of dienophiles yielded corresponding Diels-Alder

adducts. It was subsequently observed however that the conditions required for formation

of the potential tetrasulfolene annulated porphyrin led to degradation of this particular

pyrrole.119 Similar destruction of reagent was found for the other heterocyclic precursors

along with the non-alkyl functionalised cyclopentane pyrrole derivatives, where

attempted. Specifically, acid conditions with resulting protonation of the heteroatom

facilitated ring opening of the N-substituted pyrrolidinyl and furenyl moieties (Scheme

2.5, X = NC6H4NO2, O). Other precursors of interest such as the diphenyl-

silacyclopentene and dimethyl-dioxa-spiro-decene (Scheme 2.5, X = SiPh2, acetal)

homologues proved unstable and unsuitable as reagents in the synthetic methods

discussed previously. In the case of the acetal (which was intended as a protecting group),

the ultimate goal was to be a tetracyclopentaporphyrin system featuring symmetrical

carbonyl functionality at the “corners”.

2.1.5. Summary and Aims

Porphyrins, the syntheses and study of which reach back to the early 20th Century, have

had an impact in a huge range of areas from medicine to photovoltaic devices. As noted

by one author, porphyrins are attractive as the basis of molecular and supramolecular

systems as they can function as a highly functionalisable “platform”78 due to the inherent


25

relative planarity and aromatic stability, as well as other properties such as their

spectroscopic characteristics.

The synthesis of a free-base octamethyl tetracyclopentyl[b,g,l,q]porphyrin (Scheme 2.5,

X = CMe2) and its nickel metallated derivative has been reported.119 The vinyl sulfone–

modified Barton and Zard pyrrole was successfully utilised, most likely as the simple

annulated functionality presented no target for side-reactions compared to the more

complicated substitution and heterocyclic systems discussed above. It was envisaged that

this functionality could be extended further into a cyclic spiro substituent. Where the

spiro functionality incorporated aromaticity, it would constitute a planar, non-rotating

substituent arranged orthogonally to the macrocyclic plane. Symmetrical, tetraspiro

annulated porphyrin systems would be the result where this spiro functionality is

incorporated into the pyrrole precursors (Figure 2.11).

NNH N

HNNH

OOR

Figure 2.11. Planned porphyrin formation. Circles are a cartoon representation of the

planar spiro annulation, oriented orthogonally to the macrocyclic plane.

These structures would be entirely novel, introducing a new avenue of porphyrin

functionalisation to the literature. Also, they would have the physical geometry of

“molecular cogs”, and as such could potentially fill the role of analogous components

within supramolecular systems and nanotechnology.

In 2002, the initial synthesis of a tetraspiro indane annulated tetracylopentaporphyrin

(Figure 2.12) was attempted.121 The novel molecule was characterised by 1H NMR and

UV-Vis spectroscopy, and accurate mass spectrometry, but time constraints and the

limited amount of recovered material halted further study. However, from this initial


26

encouraging success it was anticipated that reproduction of this synthesis as well as

similar syntheses involving other aromatic group annulation would be easily achieved.

N

Figure 2.12. A representative subunit of the symmetrical, tetraspiro indane annulated

tetracylopentaporphyrin.

The aims of this project were therefore to obtain suitable spiro annulated cyclopentene

precursors which would be submitted to the previously optimised synthesis of

functionalised pyrroles suitable for porphyrin formation. This would include the synthesis

of the previously generated porphyrin for the purpose of further characterisation, if

possible. It would also ideally include the acquisition of crystal structures of the achieved

porphyrins in order to confirm that the concept of spiro annulation does confer

orthogonal geometry to the substituents relative to the macrocyclic plane.

2.2. Discussion

2.2.1. Retrosynthetic Details

N

N N

N

X X

XX

M

HN

X

OEt

O

X

TolO2S

X

X = spiro ring fusion

Scheme 2.6.


27

The retrosynthesis of annulated tetracyclopenta[b,g,l,q] porphyrin species is illustrated in

Scheme 2.6. Synthetic details of the synthesis of these novel porphyrins comprise the

majority of this sub-chapter and follow the procedures utilised by Pearce and Johnstone

in forming the methyl annulated homologue porphyrin directly from the pyrrole ester

through a reduced α-hydroxy pyrrole intermediate.119 The crucial step towards formation

of an annulated porphyrin is the formation of the corresponding functionalised pyrrole,

which proceeds readily in mild conditions in the presence of a variety of functionalities.

Fusing a pyrrole ring onto the spiro entity is the most direct approach in this regard. A

modified Barton and Zard pyrrole synthesis112 is likely to succeed in cases where

sulfonylation of the ring-closed spiro molecule is successful, and where there is no

functionality to lead to potential side reactions.

2.2.2. Preparation of Spiro Cyclopentenes

2.2.2.1. Diallylation

The approach to targets for ring-fused pyrrole formation began with diallylation of

purchased starting materials, 1,3-indandione and fluorene. The general mechanism for

allylation is a stepwise nucleophilic attack of a single carbanion upon two equivalents of

an appropriate allyl derivative. The reaction conditions and nature of the allyl reactant

can vary greatly, dependent on the acidity of the allylation site.

The first lead molecule, 1,3-indanedione, was diallyated in 84% yield by reaction with

allyl alcohol in the presence of boric oxide, triphenylphosphine and

tetrakis(triphenylphosphine)palladium(0) catalyst.122 The reaction follows the protocol

developed by Lu et. al. who optimised the facile allylation of a series of disubstituted

methylenes, where the substituents were combinations of acetyl, ester and cyano groups.

The mechanism is thought to involve a transient allylic borate, formed in situ, donating

an allyl species to a free coordination site of palladium(0), with simultaneous

deprotonation of the nucleophile by the resulting borate anion. Nucleophilic attack upon


28

the π-allylpalladium complex results in allylation of the acidic site and regeneration of

the catalyst (Scheme 2.7).

OO OO

OO

BO

3 OBO

2PdL2

PdL4

H

OO

PdL2

+ L2

2.1

Scheme 2.7.

Lu et. al. noted that excess triphenylphosphine ligand prevented palladium precipitation

from the tetrahydrofuran mixture, and also that excess boron oxide served to sequester

water generated by allyl alcohol consumption. 2,2-Diallylindane-1,3-dione (2.1) is a

known compound, however the details of its 1H NMR spectrum are noteworthy and will

be discussed below.

A comparatively direct approach was necessary for the synthesis of 9,9-diallylfluorene

2.2. The acidity of the fluorene methylene hydrogen, at pKa = 25,123 was far outside the

effective range of the neutral conditions utilised by Lu et al. Consequently, the starting

material required step-wise treatment with equimolar amounts of n-butyl lithium base at

–78°C before careful addition of allyl bromide to affect straightforward nucleophilic

attack of the allyl groups.


29

The symmetrical diallyl functionality of each of 2.1 and 2.2 provided a convenient 1H

NMR fingerprint (Figure 2.13) for identification which has not been summarised

elsewhere. The methylene protons display a simple doublet, however coupling to the

vicinal vinyl proton results in doublet-of-doublets-of-triplets splitting for the A resonance

of the double bond AMX system. The effect of JMX in this system is not observed at low

field strength, but the vicinal coupling of the terminal vinyl protons to the methylene

group is observed in these diallyl systems as multiplicity in the HM and HX doublets.

Identical coupling patterns were observed for several other diallylated molecules, used by

Kotha et. al. as model systems,124 in previous work.121 Coupling constants for each

species are provided in Section 5.2.

Figure 2.13. Diallyl indanedione 2.1 allyl resonances.

2.2.2.2. Ring-Closing Metathesis

The first use of ruthenium complexes in catalytic olefin metathesis was by Grubbs et al.,

involving ring-opening metathesis polymerisation catalysed by a dichlorobis-

triphenylphosphine-complexed conjugated ruthenium carbene.125 In 1993 the same


30

researchers reported the modification of the ruthenium system, specifically the

substitution of triphenylphosphine ligands with tricyclohexenylphosphines, and the ring-

closing metathesis (RCM) activity it exhibited.126 The ruthenium catalysts immediately

showed great promise127 for carbon-carbon double bond formation where tungsten-

titanium-128 and molybdenum-based129 catalysts offer less functional group tolerance or

comparative difficulty in handling and use.130 Robert Grubbs shared in the Nobel Prize

for chemistry in 2004 for this work in catalysis. Perhaps the most dramatic consequence

of this research is in the aerospace industry, where a specific autonomic Grubbs’ catalyst-

based polymer repair system now integrated within hull material.131

RuPCy3

PCy3

Cl

Cl Ph

RuPCy3

PCy3

Cl

Cl

RuPCy3

Cl

Cl Ph

RuPCy3

Cl

Cl

RuPCy3

Cl

Cl

RuPCy3

Cl

Cl

X

X

X

X

Ph

X

X

Ph

PCy3

Figure 2.14. Catalytic cycle involved in ring-closing metathesis: X = spiro carbon, Cy =

cyclohexenyl group.

The conditions for the RCM reactions through use of Grubbs’ catalyst (Figure 2.14) were

those reported by Kotha et al.124 The indanedione and fluorene spiro-cyclopentenes (2.3

and 2.4 respectively) were prepared in recovered yields of 61% and 99%, respectively, by


31

an easily effected flash chromatographic separation from residual starting materials. This

was assisted by the different hydrophobic affinity of long, mobile allyl groups compared

to the rigid cyclopentane ring. As with the diallylated species, the modified functionality

gives rise to useful 1H NMR signatures due to the cyclopentane symmetry. All spectra

exhibit a pair of broadened singlets at around 2.8 and 5.7 ppm, corresponding to the

methylene and vinyl protons, respectively, as exemplified in Figure 2.15. The spins of all

six of these protons constitute an AA’X2X2’ system (Figure 2.15, inset), but do not

resolve beyond broadened singlets with increasing field strength.

Figure 2.15. 1H NMR spectrum of the AA’X2X2’ cylcopentenyl system of 2.3, and (inset)

the symmetry of the hydrogens.

A sodium borohydride reduction used by He et al.132 was adapted to reduce the carbonyls

of the spiro indanedione product to methylenes over two steps in high yield (Scheme

2.8): 81% overall. Addition of ammonium fluoride worked to sequester oxidised

triethylsilane as the volatile fluoride133 and avoid contamination of the spiro product with

non-volatile silane by-products, such as hexaethyldisiloxane (b.p. 231°C/745 mmHg)

upon aqueous work-up. The novel spiro-functionalised indane species 2.5 displayed the

expected new singlet at 2.93 ppm in the 1H NMR spectrum; it was further characterised

by 13C NMR and IR spectroscopy, and accurate and fragmentation mass spectrometry.


32

O

O

OH

OH

NaBH4

MeOH CH2Cl2, CF3COOH

Et3SiH, NH4F

2.5

Scheme 2.8.

2.2.2.3. Preparation of Vinyl Sulfones

a)

X X I

SO

O

X

I

SO

OI I

b)

SO

OS

O

O

2.6 2.7

Scheme 2.9.

The arenesulfonylation of the cyclopentane double bond was achieved through a β-iodo

sulfone intermediate. Inomata et al. proposed a mechanism for the formation of this

species118 involving a symmetrical transient iodonium ion. The addition mechanism

necessarily directs exclusively trans addition (Scheme 2.9a). Where this synthetic step is

achieved the elimination of iodine and regeneration of the double bond is generally facile.

The mild, biphasic water-dichloromethane reaction conditions devised by Inomata et

al.118 and employed by Pearce119 for vinyl heterocycles were utilised for the derivation of

the product. Previous work121 highlighted limitations of this approach due to


33

functionality-allowed side-reactions, which previous studies114 of vinyl arene-

sulfonylation were not concerned with.

1,5-Diazabicyclo[5.4.0]undec-5-ene (DBU) was found to be the preferred hindered base

for vinylic regeneration121 in previous studies. Low temperature conditions were essential

for selectivity in deprotonation position as an unresolvable isomeric mix was generally

obtained at ambient temperature, due to competing deprotonation of the methylene

protons adjacent to the halogen-bearing carbon.

The identities of the novel vinyl sulfones 2.6 and 2.7 (Scheme 2.9b) were confirmed by

NMR. The spectrum of the spirocyclopenteneindanyl sulfone 2.6 (generated in 91%

yield) was recorded at 600 MHz. The signature tosyl aromatic AA’XX’ peaks and

deshielded methyl peak were observed. In addition, this substitution modified the

cyclopentenyl X2X’2 signal into a pair of symmetrical AB quartets centred about 3.0 ppm

at this field strength. This effect was evident in several annulated sulfones119 synthesised

by Pearce. The remaining beta vinyl proton resonance was shifted upfield from the initial

position of the AA’ portion of the spin system (observed for unsubstituted cyclopentane)

and appeared as a quintet (see Section 5.2). The spirocyclopentenefluorenyl sulfone 2.7

was isolated with a yield of 39%. The sulfone products were further fully characterised

with 13C NMR and IR spectroscopy, and EI mass spectrometry. Melting point and

microanalysis gave good results.

2.2.2.4. Preparation of Fused-Ring Pyrrole Carboxylates

Synthesis of pyrroles through conjugate addition of isocyanoacetate anion, generated in

situ, across the sulfone vinyl bond106 proceeded in mild conditions. Previous, extensive

utilisation of this approach has provided data on optimised methods for the synthesis of a

variety of novel, functionalised [3,4-c]pyrroles. The dimethylcyclopentenyl system

described in that research, which successfully led to a novel fused ring porphyrin,

presented a likely model for the pyrrole formations of interest. Previously synthesised119


34

ethyl isocyanoacetate was purified by Kugelrohr distillation and used exclusively for

subsequent reactions.

HN

O

OEtN

O

OEtTolO2S

XX

TolO2S

X

Na

i. ii.

i. Ethyl isocyanoacetate, NaH, THF, 0°C, 4 hrs. ii. Water.

Scheme 2.10.

The spiro indane (2.8) and fluorene (2.9) annulated pyrrole carboxylates were prepared in

70% and 71%, respectively, and isolated as white powders. Details of the 1H NMR

spectra for these pyrroles were consistent with previously characterised Barton and Zard

ethyl 2-carboxy pyrrole products.119,121 These included the unambiguous, deshielded N–H

peak near 9 ppm, the broadened doublet of the pyrrole C5 proton in the aromatic region,

and the two signals corresponding to the ethyl ester group further upfield. Both molecules

exhibited distinct methylene resonances around 3 ppm, separated by 0.2 ppm. A

confident assignment of these signals can be made on the basis of the greater extent of

resonance deshielding experienced by the methylene on the same edge as the ester group.

Furthermore, the spectrum of the spiro indane annulated pyrrole collected at 600 MHz

reveals a small degree of spin-spin splitting of the upfield methylene resonance that

corresponds to its coupling with the pyrrolic C5 hydrogen, demonstrating that they are on

the same edge. This 4J coupling is not observed for the pyrrolic hydrogen, however, due

to the proximity of the nitrogen quadrupole.

Pyrroles 2.8 and 2.9 were further characterised by melting point analysis, IR and 13C

NMR spectroscopy, and good peak matches were observed with accurate mass

spectrometry.


35

2.2.3. Porphyrin Assembly

N

NH N

HN

Figure 2.16. Annulated ring-fused porphyrin.121

In 1998 the novel 22,72,122,172 annulated porphyrin (Figure 2.16) was synthesised119 by

both classical Rothemund condensation of the decarboxylated pyrrole with

formaldehyde92 and cyclotetramerisation of the α-hydroxymethyl pyrrole derivative in the

presence of H+,134 in both cases followed by oxidation of the porphyrinogen intermediate.

It was noted at the time that the latter approach provided an appreciably higher yield

(10% versus 6%) over fewer, less time-consuming steps, and it was utilised exclusively

in the current porphyrin synthesis. The reactive α-hydroxymethyl pyrrole reaction

intermediates were obtained by reduction of each spiro annulated pyrrole with lithium

aluminium hydride, and subsequent protonation. The condensation step involved reflux

conditions in acetic acid, followed by stirring with excess p-chloranil (as a hydride

acceptor) while open to oxygen. The reaction was monitored by silica TLC, where

porphyrins exhibit distinct nonpolarity and a bright pink colour upon development with

vanillin/ethanol solution. As free-base porphyrins are prone to coordinating trace metals,

for example from chromatographic media, a step involving metallation with zinc was

included in the overall synthesis to conserve the yields of the desired products. This

approach is summarised in Scheme 2.11.


36

N

N N

N

X X

XX

Zn

HN

X

OEt

O HN

X

OH C C

X =

i. ii., iii.

2.10 2.11

i. LiAlH4, THF. ii. p-chloranil, AcOH, [O]. iii. Zn(OAc)2,

MeOH-CH2Cl2.

Scheme 2.11.

Rothemund-type porphyrin syntheses typically lead to a considerable amount of

polymerised, degradation by-product, and each final crude product resembled an entirely

opaque, black solution, and a black tar upon concentration. Following removal of the

solvent this material was chromatographed to isolate as much porphyrin product from the

by-products and excess reagents as possible. Each crude product was taken up in a 1:1

solution of methanol-dichloromethane and stirred at 70°C with an excess of zinc

acetate.119 The resulting metalloporphyrins were isolated in limited yields by elution

through plugs of flash silica and will be discussed separately in the next section.

2.2.4. Analysis of Spiro-Annulated Porphyrins

2.2.4.1. Tetraspiro-annulated Indanyl System

Previous work described the UV-visible and 1H NMR spectrometric properties of the

free-base indanyl porphyrin system, but had no further success in terms of

characterisation. The zinc-metallated homologue 2.10 was recovered in 6% yield as a

deep pink powder and displayed the characteristic collapse of the four porphyrin Q bands

in the visible spectrum into two peaks at 533 and 566 nanometres in tetrahydrofuran

(Figure 2.17a). The B band (Soret) was measured at 404 nanometres. Additionally, a

distinct peak was observed in the UV at 283 nanometres with a molar extinction

coefficient in the same range as the Q bands, and likely corresponds to the repeating

indane moieties. The 1H NMR spectrum in deuterated chloroform (Figure 2.17b)


37

consists of a singlet at 10.43 ppm for the very deshielded meso hydrogens, a narrow

multiplet, due to the aryl rings, between 7.39 and 7.29 ppm, and a pair of singlets at 4.16

and 3.55 ppm corresponding to the porphyrin and indane cyclopentane methylene

protons, respectively.

a)

0

1

2

3

4

240 340 440 540

wavelength (nm)

Abs

orba

nce

b)

Figure 2.17. Zinc indanyl spiro-porphyrin system 2.10: a) UV-Vis spectrum; b) 1H NMR

spectrum (300 MHz). Impurities are indicated by (*).


38

The 13C NMR spectrum, melting point and accurate mass data were also collected for this

novel porphyrinic system. Attempts at crystallisation of samples for x-ray crystallography

from a variety of solvent systems yielded microcrystalline precipitates at best.

2.2.4.2. Tetraspiro-annulated Fluorenyl System

The UV-visible characteristics in chloroform of the metallated fluorenyl porphyrin 2.11,

isolated in 2% yield, were more dramatic. In addition to the B (403 nanometres) and Q

bands (530 and 564 nanometres) was an intense absorbance at 293 nanometres due to the

fluorene groups with a molar extinction coefficient higher than that of the Soret band

(Figure 2.18a), most likely because of the effective molar ratio of four fluorenes to one

porphyrin ring.


39

a)

0

0.5

1

1.5

2

2.5

3

240 340 440 540

wavelength (nm)

Abs

orba

nce

b)

Figure 2.18. Zinc fluorenyl spiro-porphyrin system 2.11: a) UV-Vis spectrum; b) 1H

NMR spectrum (300 MHz). Impurities are indicated by (*).

Melting point analysis, 1H NMR spectroscopy and accurate mass spectrometry were also

carried out to characterise 2.11. The NMR spectrum (Figure 2.18b) featured a meso


40

hydrogen singlet at 10.13 ppm, a series of multiplets centred at δ 7.1–7.45 ppm

corresponding to the fluorene aromatic hydrogens, and the cyclopentenyl methylenes as a

singlet at 4.67 ppm. Unfortunately, a suitably concentrated sample could not be prepared

for 13C NMR spectroscopy. However, small reddish crystals were obtained by

precipitation from a refrigerated hexane-chloroform solution, and a peak match was made

by high resolution mass spectrometry.

A sample of this material was submitted for X-ray crystallographic analysis. The crystal

structure was refined as a 4:1 mixture of metallated and free-base spiro-annulated

porphyrin. Figure 2.19 shows the ORTEP plot for the zinc-containing portion of the

sample. As anticipated, the spiro-annulated fluorene moieties were arranged orthogonally

to the macrocyclic plane.

Figure 2.19. ORTEP plot of 2.11.


41

The geometry is most starkly seen in the stick model of the refined free-base species

component of the sample. From edge on in Figure 2.20a the result of the bend in the

cyclopentane bridges between macrocycle and spiro centres is a mixture of arrangements

of the flurorenes relative to the macrocylic plane. The porphyrin itself displays noticeable

distortion. Figure 2.20b gives the view down the central axis and shows the planar

“teeth” of the molecular “cog” model most clearly.

a) b)

Figure 2.20. Stick model of the free-base counterpart of 2.11.

2.3. Summary, Conclusion and Future Directions

Two products of ring-closing metathesis were utilised as the spiro annulated precursors

for porphyrin systems featuring orthogonal, planar substituents with axial symmetry.

Through an optimised synthesis the pyrrole derivatives were generated, by way of

reactive vinyl sulphone species. All new products were fully characterised. The pyrroles

were used as the components in the new porphyrins to generate

tetraspiro[,22,23,72,73,122,123,172,173-octahydro-21H,71

H,121H,171

H-tetracyclopenta

[b,g,l,q]porphyrinato-22,2’:72,2’’:122,2’’’:172,2’’’’-tetrakis([2]indane)] zinc and

tetraspiro[,22,23,72,73,122,123,172,173-octahydro-21H,71

H,121H,171

H-tetracyclopenta


42

[b,g,l,q]porphyrinato-22,9’:72,9’’:122,9’’’:172,9’’’’-tetrakis([9]fluorene)] zinc in limited

yields. The geometry of these porphyrins was confirmed spectroscopically, and in the

case of the latter was observed directly through the resolution of x-ray crystallographic

data. This “molecular cog” exhibited the anticipated “teeth” arrangement of the fluorene

spiro substituents, planar and orthogonal to the macrocylic plane.

N

N N

N

X X

XX

M

HN

X

OR

O HN

X

Ar

Ar

ArAr

Scheme 2.12.

It is anticipated that modifying the porphyrin formation step to decarboxylate a given

spiro annulated pyrrole, then react it with an aryl aldehyde (Scheme 2.12) such as

benzaldehyde would provide an extra four symmetrical “teeth” at the porphyrin meso

positions, as these substituents would likely assume an orthogonal conformation to the

macrocyclic plane due to steric crowding.

Asymmetric Pseudo-Rotaxanes

43

CHAPTER 3: Asymmetric Pseudo-Rotaxanes as Switchable

Supramolecular Systems

3.1. Introduction

3.1.1. Supramolecular Species

Biological macromolecules that agglomerate and transform energy into motion and

highly specialised chemical reactions are frequently cited as the epitome of

supramolecular chemistry and molecular machinery.1 As an example, eukaryotic DNA

replication consists of a conglomeration of specific proteins, requiring energy inputs and

conformational changes. These components fit together through specific, non-covalent

intermolecular associations which in many cases involve hydrophobic site interactions.137

This may be imitated by self-assembly of synthetic components to produce new

supramolecular chemistry.

3.1.1.1. Pseudorotaxanes

Pseudorotaxanes are formed in solution between a macrocyclic host and an appropriately

formed guest molecule when complexation of the latter within the former is energetically

favourable. The nature of the solvent and the complementarity of the components are

responsible for the strength of complexation, and are widely exploited in the rational

design of supramolecular systems.

The example in Figure 3.1, designed by Ballardini et al., is a [2]-pseudorotaxane

incorporating a functionalised dicationic diazoniapyrene axle within a dinaphtho

coronand, in acetonitrile.136 (The [2] indicates that two species form the [2]-

pseudorotaxane. Should two axles be complexed in one rota or one axle be complexed by

two rotas each is called a [3]-pseudorotaxane and so on. The orientation of aromatic

groups is depicted for clarity.) Complexation was observed to yield the [2]-

pseudorotaxane whose formation is attributed to the associative forces of π-π stacking


44

between the aromatic axle and the naphthyl groups of the macrocycle and the electron-

rich coronand component with the dication. A consequence of this design is that other

aliphatic species such as hexylamine associate with the diazoniapyrene group causing it

to “de-thread” from the [2]-pseudorotaxane. Acidification protonates hexylamine and

frees the axle to “rethread” within the macrocycle. This is an example pH control over

[2]-pseudorotaxane formation.

O O O O O

N

N

O OO O O

+2x CH3(CH2)5NH2-2x CH3(CH2)5NH3+

N

N

O O O O O

O OO O O

CH3(CH2)5NH2

NH2(CH2)5CH3

Figure 3.1. Alkylamine-controlled [2]-pseudorotaxane.136

A charge and hydrogen bond-dependant photo-converting “plug-and-socket” complex

has been reported137 which exhibited photoinduced energy transfer from the rota to the

axle, which engendered altered luminescence properties in dichloromethane solution.

Acidification of the axle amine group by triflic acid triggered its [2]-pseudorotaxane-like

association with the aromatic coronand, driven by hydrogen bond formation between the

amine hydrogens and the coronand oxygens. Addition of competing tributylamine

reversed the supramolecular association (Figure 3.2). The overall result was a reversible

chemical switch system that exhibited distinctly different fluorescence between

complexation states.


45

OO

O O

OO

O

OO

O O

OO

O

HN H2

N

hv

hv'CF3SO3H

n-Bu3N

Figure 3.2. Proton-activated photoinduced energy transfer complex.137

3.1.1.2. Rotaxanes

The synthesis and characterisation of rotaxanes has resulted in many such supramolecular

systems being reported in the literature.138-139 Rotaxanes are distinct from

pseudorotaxanes as the host is mechanically restricted from dethreading from the guest,

although the formation of pseudorotaxanes is a widely used route to their synthesis

(Figure 3.3, route A). In terms of nomenclature, a [2]-rotaxane is indicative of two

complexed molecular species.138 (Should two axles be complexed in one rota, or one axle

be complexed by two rotas, each is called a [3]-rotaxane, and so on.) Sometimes the

name polyrotaxane is used when one axle is complexed by many rotas.


46

Figure 3.3. Three rotaxane synthetic strategies.141

Route A involves the bonding of blocking groups or “stoppers” to the termini of the axle,

and is referred to as the threading method. Yields by this method mainly rely on the

stability of the pseudorotaxane complex under the reaction conditions. The blocking

groups must necessarily be too large to physically fit inside the rota, although rotaxane

synthesis is possible through the alternative route B, known as the slippage mechanism.

In this reaction the blocking groups are integral to the axle but can pass within the interior

of a sufficiently flexible rota. The third approach is route C, which again features

blocking groups attached to the axle but the rota is cyclised through chemical reaction

around the axle. This is called the “clipping” method.141

The non-covalent yet restrictive association of the rota and axle results in several widely-

observed characteristics. The rota is usually free to rotate around the axle, usually very

rapidly such that NMR characteristics are averaged. Sometimes the rota may shuttle from

one end of the axle to the other, but this may be restricted by the nature of the axle and

the blocking groups. Appropriate selection of the rotaxane components can lead to

control of this behaviour in a manner similar to that used in controlling the behaviour of

full-sized mechanical parts.


47

NN

NNN NO OO

O

2

2

O O

O O

O

O

O

O

O O

N N

N NCu

Figure 3.4. Bipyridine-bipyridium/crown ether-based [2]-rotaxane, and (inset)

bipyridine-copper complexation.142

[2]-Rotaxanes of the form shown in Figure 3.4 have been reported by Jiang et al.142 They

are formed by the slippage mechanism from bipyridine-based axles and the coronand-

based rota, and exhibited rapid shuttling in solution of the electron-rich coronand from

one electron-deficient bipyridinium “station” to the other. Addition of 0.5 mole

equivalents of a copper(I) salt to the [2]-rotaxane resulted in bipyridine metal

complexation between pairs of the [2]-rotaxane (Figure 3.4, inset), and asymmetry in the 1H NMR spectrum indicated that shuttling was mechanically restrained. The shuttling of

the rota could be re-established by treatment of the complex solution with ion-exchange

resin to remove the copper ion and break up the complex.

[2]-Rotaxanes of the type in Figure 3.5, consisting of phenol-based axles and a

tetralactam macrocycle rota, were synthesised by Ghosh et al.143 2D NOESY and

ROESY 1H NMR spectroscopy data showed that the rota shuttled freely between the

diamide stations at either end of the axle in deuterated dichloromethane solution. This

rapid motion was distinctly retarded upon phenolic deprotonation with phosphazene base

as a consequence of the conjugate anion electrostatically localised near the phenolate

(Figure 3.5, inset), acting as a physical barrier to rota shuttling. The result was a [2]-

rotaxane exhibiting a pH-controlled shuttling rate.


48

Figure 3.5. Phenol/tetralactam-based [2]-rotaxane, and (inset) phenolate-amide

interaction following deprotonation.143

Vignon et al. conducted work on [2]-rotaxanes of the type shown in Figure 3.6.144 This

[2]-rotaxane is asymmetric in that the two “station” moieties on the axle have different

affinities for the coronand-based rota. The 1H NMR spectrum in deuterodichloromethane-

deuteroacetone solution initially revealed that the rota was localised over the naphtho-

diimide moiety (state A). Upon addition of excess lithium perchlorate, the rota was

observed to move to the sterically less bulky pyromellitic diimide station to allow strong

coronand complexation of lithium ions (state B). State A was regained upon addition of

excess [12]-coronand-4 to sequester the lithium ions.


49

O(CH2)5

O

O

O

O

O

N N (CH2)5 N

O

O

O

O

N (CH2)5O

O

O

O

O

O

O

O

O

O

A

O(CH2)5 N N (CH2)5 N

O

O

O

O

N (CH2)5O

O

O

O

OO

O

O

O

O

O

O

O

O

OLi

Li

B

Figure 3.6. Diimide/coronand-based asymmetric [2]-rotaxane: (state A) pure in solution

and (state B) in presence of lithium ions.144

A photoisomerisation-controlled asymmetric [2]-rotaxane (Figure 3.7), reported by Perez

et al.145 features two amide-based stations as part of the axle around which the pyridine-

containing cyclophane rota localises in dichloromethane solution. An anthracene group

forms one blocking group adjacent to the station having lower binding affinity for the

rota. The rota is forced from the dominant position shown in Figure 3.7 (state A) upon

isomerisation of the double bond from the E- to the Z-form, taking up position at the

anthracene end (state B). A 200:1 intensity difference in fluorescence between states A

and B, respectively, is observed as a consequence of quenching by the macrocycle

pyridinium moieties in state B. Related rotaxanes have been utilised in atomic force

microscopy research on thin films,146 where they form uniform arrays with the potential

for lithographic data storage.


50

NH

HN

O (CH2)9 N

OHN

OPh

PhO

O

O

H

NH

NH

HN

NH

HN

HN

O O

OO

=

A

NH

HN

O (CH2)9 N

OO

O

O

OH

Ph

PhB

Figure 3.7. Carboxyanthracene/pyridinium cyclophane-based asymmetric rotaxane:

(state A) E-isomer, and (state B) Z-isomer.145

The above examples highlight the diverse range of molecular components available to fill

the various roles in rotaxane supramolecular chemistry. Further examples of asymmetric

rotaxanes feature relatively enormous metal-based blocking groups, such as titanium

dioxide147 and gold148 nanoparticles. These and other recently reviewed systems149

represent ways to tether rotaxanes onto surfaces and control their orientation.

3.1.2. Cyclodextrins

Cyclodextrins are natural macrocycles that have been studied for over a century, and have

relatively recently attracted sustained interest as components in supramolecular

chemistry.141,150,151 They are produced enzymatically from starch by Bacillus

macerans,152 and consist of chair-form glucose units connected in a circle by α-1,4

glycosydic bonds (Figure 3.8): the number of units mainly ranges from six for α-

cyclodextrin, through seven for β-cyclodextrin to eight for γ-cyclodextrin. Larger

cyclodextrins have also been characterized.153


51

Figure 3.8. The geometry of the common cyclodextrins.150

The orientation of the glucopyranose units dictates the unique properties of α-, β- and γ-

cyclodextrins. They have a truncated cone shape which is 7.9 Å high; the interior or

annulus is a hollow cavity ranging in width from 4.7-5.3, 6.0–6.5 and 7.5–8.3 Å

respectively; the uniform orientations of each glucose’s hydroxyl groups make the

outside surface largely hydrophilic and the annulus largely hydrophobic. As the primary

hydroxyl groups are arranged about the narrower end of the macrocycle, and the

secondary groups at the wider end, the ends are referred to as the primary and secondary

faces, respectively. Along with water solubility, the secondary hydroxyl groups can form

a circular hydrogen bonding network, to a greater or lesser extent, which confers some

rigidity to the cyclodextrin. The comparative hydrophobicity of the cyclodextrin annulus

provides an environment suitable for the complexation of suitably sized, shaped and

hydrophobic guest species to bind within.

Table 3.1. 1H NMR (D2O) chemical shifts (in ppm) observed for native cyclodextrins.154

cyclodextrin H-1 H-2 H-3 H-4 H-5 H-6a,b

α 4.60 3.19 3.57 3.08 3.39 3.44

β 4.68 3.26 3.58 3.19 3.47 3.49

γ 4.53 3.08 3.35 3.00 3.26 3.30

Table 3.1 provides the comparative 1H NMR data for the three common cyclodextrins in

D2O.157 The narrow chemical shift range of cyclodextrins, together with the spin-spin



52

splitting observed between neighbouring proton signals results in several overlapping

resonances (Figure 3.9).

Figure 3.9. 1H NMR spectrum of α-cyclodextrin (300 MHz, D2O, 293 K).

The extensive modification of cyclodextrins has been reviewed with respect to drug

delivery155 and photosensitisation156, industrial applications,157 catalysis of biomimetic

reactions158 and reaction mediation,159 and is the subject of books.150 Simple modification

can involve O-methylation of glucose units at one or more positions.152

3.1.2.1. Cyclodextrins in Rotaxanes and Pseudo-Rotaxanes

The complexation behaviour of cyclodextrins has lent itself to many aspects of aqueous

supramolecular chemistry, and their roles in forming rotaxanes160 and catenanes141 have

been comprehensively reviewed. Early examples of investigations into the suitability of

cyclodextrins as rota components complexed the [2]-pseudorotaxanes such as that in

Figure 3.10a.161 The terminal pyridinium ions provide a charge barrier to the dethreading

of the α-cyclodextrin from the [2]-pseudorotaxane, resulting in a complex stable enough

to be detected by 1H NMR spectroscopy.


53

(CH2)3O O(CH2)3XH3N NH3X

X- = Cl-, BPh4

-

b)

Figure 3.10. a) Cation-stabilised α-cyclodextrin [2]-pseudorotaxane.161

b) Diammonium

2,6-dimethylated-cyclodextrin [2]-pseudorotaxane.162

Early work by Rao and Lawrence involved the complexation of a biphenyl salt within

dimethylated β-cyclodextrin (Figure 3.10b, X- = Cl-),162 which acted to solubilise the

axle component in water. Addition of an excess of sodium tetraphenylborate produced a

stable, electrostatically stoppered species (X- = BPh4-) that resisted dissociation when

heated in acetone solution.

The formation of cobalt(III) complexes at the termini of axle components was the first

strategy employed for cyclodextrin-based rotaxanes by Ogino et al. (Figure 3.11).163

More recently, in-depth studies have been made into [2]-rotaxanes such as the α-

cyclodextrin-azine complex in Figure 3.11b, which both illustrate and exploit the use of

iron(II) complex blocking groups.164 Such [2]-rotaxanes may be readily obtained in

solution through the threading method and subsequent coordination of iron(II) complexes

to the pyridine nitrogens.



54

Figure 3.11. a) Early alkyl α-cyclodextrin [2]-rotaxane with attached cobalt(III)

complexes as stoppers.163

b) Ion(II) complex-stoppered pyridinecarboxaldehyde azine α-

cyclodextrin [2]-rotaxane.164

The need for control over the dynamic behaviour of cyclodextrin [2]-rotaxanes is a factor

in the design of the axle component. An example of this control is a stimulus that

localises the rota at one end or other of the axle, or impacts on the rate of shuttling.

Figure 3.12 shows a rotaxane165 that features a central azobenzene motif. Irradiation at

360 nm isomerises the covalently-stoppered axle from the E- to the Z-form, forcing the α-

cyclodextrin to move from over the azo moiety to a methylene ether group. Irradiation

NN

O

O

N

NN

N

NO2O2N

O2N NO2

ON

N

NO2O2N

N N

N

N

O2N NO2

O

λ

λ'

Figure 3.12. E- and Z-photoisomers of an α-cyclodextrin azobenzene [2]rotaxane:165

λ = 360 nm, λ’ = 430 nm.


55

with a wavelength of 430 nm converts the axle back to the E-isomer and returns the rota

to its previous location. In this way the shuttling behaviour is directly photo-controlled

and the [2]-rotaxane may be considered to be a simple “molecular switch”.

Recent work by Wang et al. produced the asymmetric [2]-rotaxane shown in Figure 3.13.

This example of a controllable molecular shuttle incorporates axle asymmetry,

photoisomerisation at the stilbene moiety, naphthalimide fluorescence, and pH-dependent

motion control of the rota.166 In state A α-cyclodextrin is positioned over the E-stilbene

bond, away from the naphthalimide group, and its rim hydroxyls formed hydrogen bonds

with the adjacent carboxylic acid substituents. Isomerisation to state C (X = CO2H) was

N

O

O

SO3

O3S

H2N

O

HO2C

CO2H

N

O

O

SO3

O3S

H2N

O

O2C

CO2

N

O

O

SO3

O3S

H2N

OX

X

λ' λ

OH

HA

B

C

Figure 3.13. pH-controlled photoisomerising asymmetric α-cyclodextrin rotaxane (λ =

335 nm, λ’ = 280 nm).166


56

not observed as a result of this configuration. Deprotonation by base disrupts the

hydrogen bonding, leading to state B in which α-cyclodextrin may shuttle to and fro.

Subsequent photoisomerisation to the Z-form in state C (X = CO2-) positions α-

cyclodextrin over the naphthalimide group, with a resultant enhancement in fluorescence

due to the proximity of the hydrophobic annulus of α-cyclodextrin.

FeN

NH

O

SO3

FeN

NH

O

SO3

Figure 3.14. Zwitterionic isomeric α-cyclodextrin rotaxane.167

The consequences of asymmetric axle components in rotaxane design were observed by

Isnin and Kaifer in early α-cyclodextrin [2]-rotaxane studies.167 Aqueous rotaxane

assembly yielded the isomeric forms shown in Figure 3.14 and observed by 1H NMR

spectroscopy, which revealed an approximate 6:4 ratio of isomers.

Recently, a relatively simple series of [2]-pseudorotaxanes was studied by Harada et al.,

specifically comprised of decamethylene-linked methyl-substituted pyridinium groups.168

Dimethyl substitution of the methyl-substituted pyridinium groups prevents threading

within α-cyclodextrin. However, the [2]-pseudorotaxane shown in Figure 3.15 is

produced in D2O from the threading of the corresponding asymmetric axle. At room

temperature, the isomer shown is initially the only one formed as observed by 1H NMR

spectroscopy over many days. This is attributed to a distinct facial selectivity for α-

cyclodextrin exhibited by the 2-methlypyridinium group. At elevated temperature the

selective threading is diminished and an equilibrium between the two [2]-pseudorotaxane

arrangements predominates. Consequently, this [2]-pseudorotaxane provides an example

of kinetic control at low temperature and thermodynamic control at high temperature.


57

NN

Figure 3.15. Dominant α-cyclodextrin [2]-pseudorotaxane.168

3.1.2.2. Recently Studied Cyclodextrin Systems

In 1999 Easton et al. reported on initial work169 involving the template-directed synthesis,

characterisation and behaviour of a stilbene axle-based [2]-rotaxane (Figure 3.16). This

[2]-rotaxane is formed through the corresponding [2]-pseudorotaxane intermediate,

which is thermodynamically favoured to assemble in aqueous conditions due to the

complimentary hydrophobicity of (E)-4,4’-diaminostilbene and the α-cyclodextrin

annulus. Upon addition of trinitrobenzene groups as blocking groups, the α-cyclodextrin

[2]-rotaxane is obtained. The β-cyclodextrin homologue is not observed, probably

because the β-cyclodextrin annulus is wide enough to allow dethreading over the

HN

NH

O2N

NO2

NO2

NO2

NO2O2N

Figure 3.16. Stilbene α-cyclodextrin [2]-rotaxane.169

trinitrobenzene blocking groups. For the [2]-rotaxane, the 1H NMR 2D ROESY spectrum

NOE cross-peaks reveal a dominant structure in which α-cyclodextrin is localised with

the secondary face overlapping one aryl moiety while the other aryl moiety is complexed

to a lesser extent within the primary face, giving rise to relatively weaker cross-peaks for

the pair of aromatic protons closer to the double bond.


58

NH

NH

O2N

NO2

NO2HNH

N

NO2

NO2

O2N

Figure 3.17. Stilbene hermaphrodite [2]-rotaxane.170

A hermaphrodite [2]-rotaxane was generated in subsequent work (Figure 3.17).170 There

the primary face of α-cyclodextrin was substituted at the C6A carbon with the stilbene

axle. Pairs of this substituted α-cyclodextrin acted as mutual rotas and axles which when

capped with trinitrobenzene in water gave the hermaphrodite [2]-rotaxane which

displayed distinct NOE interaction between the stilbene 1H NMR resonances and the

complex signals of the substituted α-cyclodextrin. This self-assembly was solvent-

dependent, as addition of trinitrobenzene blocking groups in N,N-dimethylformamide

resulted in recovery of mainly free monomer. Furthermore, the hermaphroditic dimer

formed exclusively over other possible arrangements such as trimers and “daisy chains”.

More recently the solid-state structure of this [1]-rotaxane was investigated along with

that of a homologue rotaxane with one methoxy-substituent ortho to each stilbene amino

group.171 The crystallographic analysis of these species reveals an end-to-end chain

arrangement of aligned axles and α-cyclodextrins reminiscent of coaxial cables. At the

same time, work relating to restriction of rotation of the α-cyclodextrin component of the

rotaxane was reported.172 Three rotaxanes were synthesised and characterised; all

involved an α-cyclodextrin functionalised at a single C-6 position with a succinamide

group, disrupting the symmetry of the α-cyclodextrin. A rotaxane was made of the

dimethoxy-substituted stilbene to afford a system resembling a “rachet tooth and pawl”

mechanism, and attachment of the succinamide to the stilbene amine afforded a new [1]-

rotaxane (Figure 3.18). While observation of NOEs in the 1H NMR 2D ROESY spectra

of the [2]-rotaxanes demonstrated free rotation of the modified α-cyclodextrin, the [1]-

rotaxane displayed relatively restricted rotation due to the barrier of methoxy group


59

HN

N

O2N

NO2

NO2

NO2

NO2O2N

HN

MeO

OMe

O

O

Figure 3.18. “Ratchet tooth and pawl” stilbene [1]-rotaxane.171

passage past the constraining succinamide linker. It was also evident, from a distinct

pattern of deshielding of specific α-cyclodextrin annulus protons in the corresponding 1H

NMR spectrum, that the stilbene, although still rotating, preferred to be oriented on a

plane roughly orthogonal to the linking group.

Recently a 4-tert-butyl-4’-hydroxystilbene axle complexed within a α- and β-cyclodextrin

dimer linked at the C6A of both primary faces through a urea moiety was utilised to

generate a new [2]-pseudorotaxane.173 1H 2D ROESY NMR spectroscopy revealed that

the guest was oriented in the asymmetrical host species in solution such that β-

cyclodextrin predominantly encompassed the tert-butyl group. When using the E-isomer

of the axle, the hydroxy end of the stilbene was complexed by α-cyclodextrin. Irradiation

at λ ≥ 300 nm photo-isomerised the stilbene to the Z-conformation such that the hydroxy

end no longer inhabited the annulus of α-cyclodextrin and the corresponding 2D ROESY

spectrum cross-peaks were seen to disappear. Heating in darkness reverted the stilbene to

the original fully complexed E-isomer. The potential of this novel, photo-thermal

controlled molecular device was demonstrated by simultaneous complexation of 4-

methylbenzoate in the α-cyclodextrin only, following the conversion of the E-stilbene to


60

O

NH

NH

O

λ∆

NH

NH

O

αβ

O

O

O

O

O

Figure 3.19. Photo-dependant behaviour of asymmetric stilbene bis(α,β-

cyclodextrin)urea-methylbenzoate switchable complex (λ = 355 nm).173

the Z-isomer, where 2D ROESY spectrum cross-peaks arose between the 4-

methylbenzoate and the annulus (Figure 3.19). The cross-peaks disappeared when the E-

stilbene rethreaded the α-cyclodextrin as a result of thermal isomerisation in darkness,

forcing 4-methylbenzoate to dissociate from the α-cyclodextrin annulus.

The 1H NMR spectrum of a 4-tert-butyl-4’-hydroxystilbene axle with one equivalent of

α-cyclodextrin (Figure 3.20, X = CH) in D2O solution displayed two distinct signals, one

corresponding to the chemical environment of the primary face of the α-cyclodextrin, and

the other the secondary face. Broadening and coalescence of these signals in variable

temperature 1H NMR studies allowed for lineshape analysis and the estimation of the

kinetic parameters that determined the observed equilibrium behaviour.174 One isomer

was shown to be dominant over the other in terms of stability. However, explicitly

assigning specific resonances to either of the two isomers was not possible.

XX O

XX O

X = CH, N

Figure 3.20. Asymmetric biaryl α-cyclodextrin [2]-pseudorotaxane equilibrium.175

In subsequent work, a series of [2]-pseudorotaxanes were prepared, comprised of a

structurally related azobenzene axle encompassed by either α- or β-cyclodextrin.175 As


61

with the preceding asymmetric stilbene, the process of threading and dethreading of one

equivalent of α-cyclodextrin (Figure 3.20, X = N) on and off the axle in aqueous solution

proved to be sufficiently slow on the NMR timescale that the 1H NMR spectroscopic

resonance of the terminal tert-butyl group appeared as two distinct signals. The bulky

tert-butyl group functioned as a blocking group; α-cyclodextrin was restricted to passing

over the hydroxyl end of the axle. Heating the sample increased the rate of exchange such

that the 1H NMR peaks were seen to coalesce and kinetic data was determined, again

showing that one isomer was favoured over the other, but not allowing the identification

of which one. The annulus diameter of β-cyclodextrin allowed passage of the tert-butyl

group when the other pseudorotaxane was formed, and no isomerisation in this system

was observed by 1H NMR.

3.1.3 Summary and Aims

Rotaxanes, pseudorotaxanes and other self-assembling host-guest systems have been

systematically tailored to exhibit particular physical properties and behaviours, and to

incorporate avenues of control over such attributes with various external stimuli.

Rotaxanes are considered to be prototypical systems in supramolecular chemistry, being

the most referenced class of mechanically interlocked species.160 Control over the

shuttling motion of the rota components in solution has been achieved in many recent

examples, and is a key consideration in contemporary molecular design.

The unique properties of water-soluble cyclodextrins lend themselves readily to

supramolecular design in general and rotaxane synthesis in particular. Their chiral nature

dictates the potential for asymmetric design and the generation of rotaxane and

pseudorotaxane isomers where isomerism is determined purely by the orientation of the

cyclodextrin on the assymetric axle.

The aims of this project were to design and synthesise a series of cyclodextrin complexes

incorporating relatively simple amino-substituted biaryl axle components of the type used

by Easton et al.169 The pseudorotaxanes would be asymmetric in character, incorporating


62

functionalised homo- and heteroaromatic rings at either end, joined by an unsaturated

linker. The heterocycle would be an azine ring such as pyridine and pyrimidine, and

therefore bear one or more nitrogen protonation sites. This was to provide a mode of pH-

control over the shuttling behaviour through the repulsion between charged sites and the

cyclodextrin annulus. The axle components involved would be assessed in terms of

complex stability as part of full characterisation. Stoppering of these systems would be

effected with appropriately substituted aromatic groups (Figure 3.21). Additionally, the

azine functionality would result in pseudorotaxane isomers, which could present

differences in 1H NMR spectra, given suitable dynamic behaviour.

NH2H2NNn

HN

HN

Nn

NH2H2NNn

XX

X

X X

X X

X

XX

HN

HN

Nn

XX

X

X X

X X

X

XX

LGX

X

X X

X+

+

Nn = azine nitrogen (n = 1, 2)

X = bulky substituent or H

LG = leaving group

= unsaturated linker

Figure 3.21. Schematic representation of the assembly of α-cyclodextrin [2]-rotaxane

isomers incorporating heteroaromatic asymmetry.


63

3.2. Discussion

3.2.1. Targeted Axle Components

An initial general synthetic target for the axle component was defined, consisting of two

aromatic rings, one of which was heterocyclic, with an unsaturated linkage and para-

substituted by amine groups. The advantage of such construction for this component was

largely that resonances in the 1H NMR spectrum would lie mainly in the aromatic region,

well downfield from where resonances due to cyclodextrins are typically observed.

3.2.2. Syntheses of Axle Components

A straightforward synthesis involving a Heck-type coupling of bromoaryl species with

styrene, utilising dichlorobis(tri-o-tolylphosphine)palladium(II) catalyst in aqueous

reaction media was available in the literature176 and adapted to generate a stilbene-type

asymmetric axle (Scheme 3.1). Unfortunately, no desired product was recovered from

this reaction.

H2N NBr

NH2

H2N

N

NH2

+

1.6M K2CO3(aq), DMF, PdCl2[P(o-Tol)3]2, P(o-Tol)3.

Scheme 3.1.

The second target to be focussed upon was of a disubstituted acetylenic type rather than

stilbenoid. 4-(2-(Trimethylsilyl)ethynyl)aniline was prepared in accordance with the

literature177 and deprotected to form the terminal alkyne reagent 3.1 and purified before

use.


64

N

N NH2

N

N NH2

IH2N

H2N

N

N NH2

+

i.

ii.

3.1 3.2 3.3

i. I2, DSMO, 373 K. ii. PdCl2(PPh3)2, CuI, CH3CN, NEt3, 343 K.

Scheme 3.2.

Iodination of 2-aminopyrimidine was facile and its purification trivial178 (yield: 76%).

Sonogashira coupling of 3.2 with the terminal alkyne 3.1, by treatment with palladium(II)

catalyst and copper iodide co-catalyst in triethylamine solvent, led to a novel asymmetric

di(aminoaryl)acetylene, 3.3, in 61% yield as a yellowish powder. The product displayed

poor solubility in most solvents except dimethyl sulfoxide and, to a lesser extent,

methanol. Protonation of the amine groups enabled solvation in water but raising pH

caused the precipitation of the product as an opaque suspension. The 1H NMR spectrum

in dimethyl sulfoxide-d6 is shown in Figure 3.22, and is fully assigned in Section 5.3. It

was further characterised by 13C NMR, IR and UV-Vis spectroscopy, melting point

analysis and accurate mass spectrometry. It proved sensitive to degradation in both air

and solution, e.g. unsealed samples rapidly darkened to a brown-black colour, and

degeneration in aqueous solution over several hours led to a complex mixture of olefinic

and aromatic signals in the 1H NMR spectrum.


65

Figure 3.22. 1H NMR spectrum of axle 3.3 (200 MHz, DMSO-d6, 298 K).

Similarly, 2-amino-5-iodopyridine 3.4 was synthesised and isolated by recrystallisation

from water in 22% yield. Coupling to the acetylenic reagent afforded the second

asymmetric axle 3.5 with 49% recovery, and characterisation was carried out as for the

pyrimidine derivative. Care in handling 3.5 was necessary as for 3.3 due to similar

instability

PdCl2(PPh3)2, CuI, THF, NEt3, 333 K.

Scheme 3.3.

NMR spectroscopic assignments were made with the sample dissolved in D2O, with the

acidity adjusted to pD ~ 1 to facilitate solubility. An AA’BB’ quartet corresponding to

the functionalised phenyl ring was observed, along with a set of three resonances


66

featuring multiplicity consistent with the arrangement of hydrogens around the pyridine

moiety as seen in Figure 3.23. (Full details are given in Section 5.3).

3.5 (acidified)

Figure 3.23. 1H NMR spectrum of the acidified axle 3.5 (300 MHz, D2O, pH ~ 1, 298 K).

To anticipate the degree of protonation of 3.3 and 3.5 in the solution conditions in which

they would be studied, the acid-base behaviour of each axle was investigated by

potentiometric titrations, and fitting of the data using the Hyperquad 2003 protocol.179

For axle 3.3 the pKas were determined as 3.24 and 6.04. The lower figure can be

attributed to protonation of the aniline amino group, which is known to have a lower pKa

than aminoazine rings.180 The pKas of axle 3.5 were determined to be 4.88 and 7.46.

Further protonation was not observed within the pH range of the equipment used.


67

3.2.3. Analysis of [2]-Pseudorotaxanes

3.2.3.1. UV-Visible Spectroscopy

The tendency of hydrophobic species to form complexes with cyclodextrins in aqueous

media is the primary driving force behind formation of cyclodextrin pseudo-rotaxanes.

The stability of these complexes may be determined from changes in the UV-visible

spectrum of axle components when cyclodextrins are added. By titrating with

cyclodextrin and observing the effect upon the axle absorption spectra, the necessary data

can be gathered for quantitative analysis of the stability of the pyrimidine and pyridine

derivative cyclodextrin complexes.

Each axle was maintained at constant concentration in ionic strength 0.10 M aqueous

sodium borate buffer at pH of 10.0 to ensure ring-bound nitrogens as well as amines

would not be protonated. α-Cyclodextrin concentration ranged from a fraction of the axle

concentration up to orders of magnitude excess. At 298 K the UV-vis spectrum of each

sample was recorded. The pyrimidine derivative 3.3 displayed a maximum absorbance at

302 nm, ε = 12500 dm3 mol-1 cm-1, that bathochromically shifted to 306 nm, ε = 12000

dm3 mol-1 cm-1, with a 50-fold molar excess of α-cyclodextrin present in solution (Figure

3.24).


68

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

220 240 260 280 300 320 340 360 380

wavelength (nm)

Abs

orba

nce

Figure 3.24. α-Cyclodextrin titrated against 5.6 × 10-5

mol dm-3

3.3 in aq. sodium borate

buffer, I = 0.10 mol dm-3

, pH 10.0, 298 K. Arrows indicate direction of absorbance

change with increasing α-cyclodextrin concentration. 3.3 λmax = 302 nm, log ε = 4.1; [2]-

pseudorotaxane λmax = 306 nm, log ε = 4.1; 1st λiso = 232 nm, log ε = 3.4; 2

nd λiso = 310

nm, log ε = 4.1.

The change in the 3.3 spectrum is related to solvatochromism, where the chromophore

experiences a change in the difference in its dipole moment between its ground and

excited states due to the varying polarity in the immediate environment, as the

concentration of α-cyclodextrin increases. The proportion of complexed axle increases

logarithmically to a plateau, and this relationship can be used to estimate the stability of

the [2]-pseudorotaxane.


69

Figure 3.25. Specfit-generated fit of [2]-pseudorotaxane simulated formation to UV-vis

data points of α-cyclodextrin titrated against 3.3 at 280 nm; α-cyclodextrin concentration

(mol dm-3

) vs [2]-pseudorotaxane molar absorptivity (dm3

mol-1

cm-1

). The best fit curve

was obtained by fitting the UV-vis data over the range 250–350 nm at 0.5 nm intervals.

The UV-visible spectral data variation was analysed with the Specfit program running in

Matlab.181 Axle concentration was maintained at 5.6 × 10-5 mol dm-3, and that of α-

cyclodextrin ranged from 4.8 × 10-6 to 2.4 × 10-3 mol dm-3. The stability constant for the

pyrimidine derivative-[2]-pseudorotaxane was estimated (Figure 3.25) to be 2.15 ± 0.10

× 103 dm3 mol-1.

A similar study of [2]-pseudorotaxane formation under acidic conditions was made. Axle

3.3 concentration was held at 2.4 × 10-5 mol dm-3 with α-cyclodextrin concentration

varied as for the corresponding basic conditions above. In 0.10 mol dm-3 hydrochloric

acid the UV-visible curve was very different from that in basic solution, and did not

display any appreciable change in the presence of 100-fold excess of α-cyclodextrin

(Figure 3.26), consistent with diprotonated 3.3 being weakly complexed at best. The

maximum absorbance was observed at 283 nm (ε ~ 26100 dm3 mol-1 cm-1).


70

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

220 240 260 280 300 320 340 360 380

wavelength (nm)

Abs

orba

nce

Figure 3.26. UV-Vis spectrum of 3.3, 2.4 × 10-5

mol dm-3

, 298 K, in 0.1 mol dm-3

aq.

hydrochloric acid solution (–––), and in the presence of excess α-cyclodextrin (----); λmax

= 283 nm, log ε = 4.4.

In a similar study the concentration of pyridine derivative axle 3.5 was maintained at

2.0 × 10-5 mol dm-3 with α-cyclodextrin present in concentrations between 4.0 × 10-6 and

2.0 × 10-3 mol dm-3 inclusively. Maximum absorption of axle alone in basic sodium

borate buffer solution was at 305 nm, ε = 37100 dm3 mol-1 cm-1, which increased to 307

nm, ε = 35600 dm3 mol-1 cm-1, with excess α-cyclodextrin present (Figure 3.27a). The

calculated stability constant for complexation of the pyridine derivative [2]-

pseudorotaxane (Figure 3.27b) was 4.76 ± 0.25 × 103 dm3 mol-1.


71

a)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

220 240 260 280 300 320 340 360 380

wavelength (nm)

Abs

orba

nce

b)

Figure 3.27. a) α-Cyclodextrin titrated against 3.5, 2.0 × 10-5

mol dm-3

in aq. sodium

borate buffer, I = 0.1 mol dm-3

, pH 10.0, 298 K. Arrows indicate direction of absorbance

change with increasing α-cyclodextrin concentration. 3.5 λmax = 305 nm, log ε = 4.6; [2]-

pseudorotaxane λmax = 307 nm, log ε = 4.5; 1st λiso = 232 nm, log ε = 3.8; 2

nd λiso = 315

nm, log ε = 4.5; b) Specfit-generated fit of [2]-pseudorotaxane simulated formation to

UV-Vis data points of α-cyclodextrin titrated against 3.5 at 280 nm; α-cyclodextrin

concentration (mol dm-3


mol-1

cm-1

). The

best fit curve was obtained by fitting the UV-vis data over the range 250–350 nm at 0.5

nm intervals.


72

A similar study of [2]-pseudorotaxane formation under acidic conditions was made. Axle

3.5 concentration was held at 2.0 × 10-5 mol dm-3 with α-cyclodextrin concentration

varied as for the corresponding basic conditions above. In 0.10 mol dm-3 hydrochloric

acid the UV-visible curve was very different from that in basic solution, and did not

display any appreciable change in the presence of 100-fold excess of α-cyclodextrin

(Figure 3.28), consistent with diprotonated 3.5 being weakly complexed at best.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

220 240 260 280 300 320 340 360 380

wavelength (nm)

Abs

orba

nce

Figure 3.28. UV-Vis spectrum of 3.5, 2.0 × 10-5

mol dm-3

, 298 K, in 0.1 mol dm-3

aqueous hydrochloric acid solution (–––), and in the presence of excess α-cyclodextrin

(----); λmax = 286 nm, log ε = 4.4.

3.2.3.2. NMR Spectroscopy

Due to the size range of the cyclodextrin annuli, appropriately stable complexes are

expected to exhibit nuclear Overhauser effects (NOEs) between the hydrogen nuclei of

the guest and those of the interior of the annuli. The interaction cut-off distance for these

spectroscopic techniques is generally 4 angstroms. However, the molecular mass of a

cyclodextrin plus a guest species is generally over 1000 and under 2000 daltons, which


73

causes cyclodextrin complexes to have tumbling times at which the laboratory-frame

NOE is approximately zero. This is due to cross-relaxation of the steady state of the

NOE.157 However, Rotating-frame Overhauser Effect SpectroscopY (ROESY) spin-lock

techniques may be used to visualise the NOEs of these complexes instead. In this study

samples were prepared in D2O with approximately 2 equivalents of hydrochloric acid (as

concentrated solution) added to aid the poor solubility of axles 3.3 and 3.5.

The 2D ROESY 1H NMR spectrum of the pyrimidine derivative axle 3.3 in the presence

of one equivalent of α-cyclodextrin each, in acidified D2O solutions displays cross-peaks

between the axle aromatic hydrogens and the H-3 and H-5 protons of the α-cyclodextrin

(Figure 3.29a). The interaction between the cyclodextrin annulus protons and the 3.5 B

hydrogens resulted in line broadening. The outermost phenyl group hydrogens (position

C) only show cross peaks with H-5 of the cyclodextrin annulus, suggesting that the

overall preferred conformation of this complex, under the studied conditions, is that

proposed in Figure 3.29b, with the primary face toward the phenyl moiety.


74

a)

b)

Figure 3.29. 2D ROESY 1H NMR spectrum of 1 w% diprotonated 3.3 with α-cyclodextrin

1:1 (600 MHz, D2O, pD = 1, 298 K). Non-interacting resonances are unlabeled. Relevant

cross-peaks are boxed. A probable orientation of diprotonated 3.3 with α-cyclodextrin in

the complex, in which there may be some movement to and fro along the axle, is shown.

An isomeric complex with the opposite orientation of α-cyclodextrin may also exist.

The corresponding spectrum of 3.3 interacting similarly with β-cyclodextrin showed

relatively weaker cross-peaks, indicating lower affinity for hydrophobic complexation, a

looser fit of guest within the larger β-cyclodextrin cavity, or both (Figure 3.30). This was


75

also evidenced by the lack of line broadening of aromatic resonances in the 1D

component of the spectrum. The absence of the mirror image cross peaks is an artefact of

processing to remove T1 noise.

Figure 3.30. 2D ROESY 1H NMR spectrum of 1 w% diprotonated 3.3 with β-cyclodextrin

1:1 (600 MHz, D2O, pD ~ 1, 298 K). Relevant cross-peaks are boxed. Non-interacting

resonances are unlabelled.


76

The complexation of the pyridine derivative 3.5 was observed to follow a similar trend to

that discussed above for 3.3. Complexation within the α-cyclodextrin annulus was

indicated by the cross-peaks in the 2D ROESY spectrum (Figure 3.31).

NND3D3N

H-3H-5

B A

E D CN

ND3D3N+

3.5 (acidified)

Figure 3.31. 2D ROESY 1H NMR spectrum of 1 w% 3.5 with α-cyclodextrin 1:1 (600

MHz, D2O, pD ~ 1, 298 K). Relevant cross-peaks are boxed. A probable orientation of

diprotonated 3.5 in the α-cyclodextrin annulus, in which there may be some movement to

and fro along the axle, is shown. A complex with the opposite orientation of α-

cyclodextrin may also exist.


77

The corresponding spectrum for β-cyclodextrin is shown in Figure 3.32. Cross-peaks

(solid box) were less distinct than for the interaction of 3.5 with α-cyclodextrin, and the

aromatic peaks showed no broadening. The correction of T1 noise lines resulted in the

obscuring of mirror image cross-peaks, as for axle 3.3 previously. However, distinct

residual COSY cross-peaks between peaks HA and HB, and HD and HE (Figure 3.32,

dashed boxes; cf. Figure 3.30) confirmed the assignment of the positions of these

hydrogens.

Figure 3.32. 2D ROESY 1H NMR spectrum of 1 w% diprotonated 3.5 with β-cyclodextrin

1:1 (600 MHz, D2O, pD ~ 1, 298 K). Relevant cross-peaks are boxed.


78

An interesting consequence of the complexation of 3.5 in α-cyclodextrin is seen in the 1D 1H NMR spectrum which shows temperature dependent line broadening and chemical

shift changes due to a chemical exchange process (Figure 3.33). At 278 K, the resonance

assigned to HE was distinctly split into a pair of peaks, one a sharp doublet and the other a

much broader peak, and the relative integrations represented a 1.00:0.43 ratio in

populations. The HD resonance appeared further downfield than that for HB: integration

of these peaks did not work out at approximately 2:1, suggesting that the HD resonance

was split similarly to HE at low temperature, however the corresponding small peak was

obscured by the HB peak. These split and broadened resonances indicate the presence of

either a pair of isomers or the free and complexed 3.5 axle, with the axle undergoing slow

exchange between two molecular environments at this low temperature. As complexation

could not be measured at much lower concentration in acidic conditions (c.f Section

3.2.3.1) it is more likely that the exchange between free and complexed 3.5 was

observed, with the complex shown in Figure 3.33 showing α-cyclodextrin positioned

over protons D and E of 3.5 consistent with the larger chemical shift differences shown

by them in the free and complexed 3.5. With increasing temperature the HD and HB

resonances were observed to broaden and shift, eventually appearing to reverse their

relative chemical shifts with HB further downfield at 323 K. Concurrently, coalescence

was observed for the pair of HE resonances into a single peak.

The peaks for HA and HC showed comparatively negligible change with temperature. This

indicated that there was less interaction between the pyridinamine end of the axle and α-

cyclodextrin, which was likely due to preferred association and dissociation of the

macrocycle at the aniline end, consistent with the temperature-dependent changes

discussed above. The presence of the duplicated peaks is most likely the result of

incomplete complexation of 3.5 within α-cyclodextrin, as evidenced by the lack of

measurable complexation at lower concentrations in acidic conditions (cf. Section

3.2.3.1).


79

NND3D3N

B A

H-3H-5E D CN

ND3D3N+

3.5 (acidified)

k1

k2

Figure 3.33. Representative variable temperature

1H NMR spectra of 1 w% diprotonated

3.5 aromatic region in the presence of α-cyclodextrin, 1:1 (600 MHz, D2O, pD ~ 1).

Spectra are plotted to a constant chemical shift scale, and relevant integrations are

indicated.

Complete lineshape analysis174,175,183 was carried out, utilising the coalescence of the HE

signal as the basis of a four-site (two molecular sites but four magnetic sites when spin-

spin coupling is taken into account) exchange process. At 298 K the estimated parameters


80

for site exchange were: k1 = 170 ± 8 s-1, ∆H1‡ = 68 ± 3 kJ mol-1, ∆S1

‡ = –30 ± 10 J K-1

mol-1, and k2 = 325 ± 15 s-1, ∆H2‡ = 52 ± 2 kJ mol-1, ∆S2

‡ = –22 ± 7 J K-1 mol- (subscripts

1 and 2 refer to the more and lesser populated magnetic environments, respectively). It is

likely that the more shielded HE resonance represents the complexed state of 3.5 due to

the environment within the cyclodextrin annulus, as well as the expected relative

instability of the complex. (The systematic change in the areas of the peaks due to free

and complexed 3.5 were extrapolated from lower temperatures into the temperature range

where peak coalescences occurred to allow for site population change in the fitting

procedure.)

3.2.4. Rotaxane Synthesis Attempts

The presence of amino groups as the termini of axle components was a part of the

rotaxane design strategy. In basic conditions a suitably activated phenyl ring undergoes

nucleophilic substitution with the amine lone pair electrons. Published research shows

that the reaction of amine axle termini with 2,4,6-trinitrobenzene-1-sulfonate provides

rotaxane blocking groups that are of sufficient bulk to mechanically restrain α-

cyclodextrin.169 It was also observed that a similar approach to forming the corresponding

β-cyclodextrin rotaxane merely yielded free axle with blocking groups probably due to

the wider β-cyclodextrin annulus allowing dethreading of the axle.

Others have utilised 2,4-dinitro-1-fluorobenzene, which is also too bulky to pass within

α-cyclodextrin,184 as a blocking grouping reagent.165,185 The synthesis of a rotaxane

utilising this blocking group and the pyrimidine axle 3.3 was attempted, following a

procedure adapted from previous research.169 The axle, dissolved in a little

dimethylsulfoxide, was introduced into a concentrated aqueous solution of α-cyclodextrin

with stirring and warming for a few hours before the addition of 2,4-dinitro-1-

fluorobenzene. A fine red suspension formed within an hour. As illustrated in Scheme

3.4, the product, recovered in 39% yield, was not the desired asymmetric rotaxane nor the

free, stoppered axle, but the “half stoppered” derivative 3.6. This new species was


81

characterised by 1H and 13C NMR spectroscopy, melting point analysis and accurate mass

spectrometry (cf. Section 5.3).

N

N

NH2H2N

N

N

HN

HN

N

N

NH2HN

NO2

O2N

NO2

O2N

O2N

NO2

N

N

HN

HN NO2

O2N

O2N

NO2

F

NO2

NO2

3.6

3.3

H2O, DMSO, pH 10, 313 K.

Scheme 3.4

The mass data and 1H NMR integration were consistent with a derivative of 3.3

incorporating only one dinitrophenyl group. To demonstrate that the substituent was

attached at the aniline end rather than the pyrimidinamine end, as proposed by the

structure of 3.6 in Scheme 3.4, the NMR sample (in dimethyl-sulfoxide-d6) was

submitted to a NOESY experiment (Figure 3.34). The resulting strong cross-peaks

between the HD resonance and the HE singlet confirmed that the amine resonance of

relative integration 1H was very close in space to the outermost hydrogens of the para-

substituted phenyl ring.


82

Figure 3.34. 2D NOESY 1H NMR spectrum of 3.6 (600 MHz, DMSO-d6, 298 K). Relevant

cross-peaks are boxed.

The formation of this product alone suggested that the pyrimidine-bound amine was too

poor a nucleophile to react with 2,4-dinitro-1-fluorobenzene under the conditions

required. This was likely to be a consequence of the electronegative nature of the


83

pyrimidine ring nitrogens, resulting in greater resonance withdrawal of the amine lone

pair electrons into the aromatic ring (Figure 3.35).

Figure 3.35. Pyridinamine group resonance structures due to ring nitrogen

electronegativity.

The solubility of derivative 3.6 was limited to polar organic solvents, in particular

acetone and dimethylsulfoxide. Preparation of aqueous solutions, even in the presence of

α-cyclodextrin, for NMR spectroscopic purposes, proved impossible. This insolubility in

water may have also contributed to the failure to react the blocking group reagent with

the pyrimidinamine end under a variety of solvent mixtures and reagent concentrations.

The reaction with 2,4,6-trinitrobenzene-1-sulfonate was not attempted based on these

limitations, and moreover, no other suitable blocking group reagent could be identified in

the literature.

As a test of the reactivity of 2,4-dinitro-1-fluorobenzene, two equivalents were added to

one equivalent each of aniline and 2-aminopyrimidine in the same aqueous conditions.

After 24 hours only one product was detected by silica tlc, and work up yielded 2,4-

dinitro-N-phenylbenzenamine in 96% yield as confirmed by 1H NMR spectroscopy and

electrospray ionisation mass spectrometry (cf. Section 5.3). No N-(2,4-

dinitrophenyl)pyrimidin-2-amine was detected by either method. This test was similarly

performed with 2-aminopyridine, with the same product recovered from the reaction in

98% yield, and with no pyridine derivative detected.

3.2.5. Stilbene Homologue Comparison

4,4’-Diaminostilbene, a symmetrical homologue of the heteroaromatic acetylenic

derivative axles 3.3 and 3.5, was also analysed in its capacity as a pseudo-rotaxane guest


84

component. Previous work185 has established it as an ideal small, covalent rotaxane axle.

However, specific data regarding the stilbene’s behaviour in solution, alone or in the

presence of cyclodextrin, had not been gathered.

The determination of the pKas of E-4,4’-diaminostilbene was attempted in the same

conditions as for the asymmetric axles, but failed due to the precipitation of material from

solution. It was determined that the solubility in these conditions was related to the

isomerism of the stilbene about the vinyl bond. In solution it was impossible to avoid at

least partial photo- or thermal isomerisation from the E- to the Z-form, with the result that

the stilbene was unsuitable for potentiometric titration with the equipment available.

3.2.5.1. UV-Visible Spectroscopy

The stability of the E-4,4’-diaminostilbene and α-cyclodextrin complex was assessed

under the same conditions as for 3.3 and 3.5. In sodium borate buffer at pH 10 and ionic

strength of 0.1 mol dm-1, axle concentration was maintained at 2.0 × 10-5 mol dm-3, with

α-cyclodextrin present at concentrations ranging from 4.0 × 10-6 to 2.0 × 10-3 mol dm-3. A

UV-visible bathochromic shift from a maximum of 335 nm, ε = 29700 dm3 mol-1 cm-1, to

339 nm, ε = 29000 dm3 mol-1 cm-1, was observed (Figure 3.36a). The Specfit calculation

(Figure 3.36b) yielded a stability constant for this complex of 1.23 ± 0.06 × 103 dm3

mol-1. Conversely, meaningful complexation data could not be derived under acidic

conditions, as was found for the asymmetric axles.


85

a)

0

1

250 270 290 310 330 350 370 390

wavelength (nm)

Abs

orba

nce

b)

Figure 3.36. a) α-Cyclodextrin titrated against 4,4’-diaminostilbene, 2.0 × 10-5

mol dm-3

in aq. sodium borate buffer, I = 0.1 mol dm-3

, pH 10.0, 298 K. Arrows indicate direction

of absorbance change with increasing α-cyclodextrin concentration. 4,4’-diaminostilbene

λmax = 335 nm, log ε = 4.4; [2]-pseudorotaxane λmax = 339 nm, log ε = 4.4; λiso = 341

nm, log ε = 4.4; b) Specfit-generated fit of 1:1 [2]-pseudorotaxane simulated formation

to UV-Vis data points of α-cyclodextrin titrated against 4,4’-diaminostilbene at 290 nm;

α-cyclodextrin concentration (mol dm-3


mol-1

cm-1

). The best fit curve was obtained by fitting the UV-vis data over the range

250–400 nm at 0.5 nm intervals.


86

The E/Z-isomerisation of 4,4’-diaminostilbene was also characterised. At a concentration

of 2.5 × 10-5 mol dm-3 in pH 10 sodium borate buffer, a fresh solution of the E-isomer

gave the UV-visible spectrum shown in Figure 3.37 by the solid curve, with a maximum

at 336 nm. Following 12 hours of sunlight the same solution gave the considerably less-

intense dashed spectrum corresponding to the Z-isomer, and the maximum shifted to 306

nm.

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

200 250 300 350 400 450

wavelength (nm)

Abs

orba

nce

Figure 3.37. 4,4’-Diaminostilbene, 2.5 × 10-5

mol dm-3

in aqueous. sodium borate buffer,

I = 0.1 mol dm-3

, pH 10.0, 298 K: fresh (──); sunlight, 12 hrs (----). E-4,4’-

diaminostilbene λmax = 335 nm, log ε = 4.5; Z-4,4’-diaminostilbene λmax = 306 nm, log ε

= 4.2; 1st λiso = 230 nm, log ε = 4.1; 2

nd λiso = 274 nm, log ε = 3.9.

3.2.5.2. NMR Spectroscopy

To confirm that this spectroscopic behaviour was due to photoisomerisation, a NMR

sample of E-4,4’-diaminostilbene in D2O was also prepared, and the corresponding 1H

NMR spectra were obtained under the same conditions (Figure 3.38).


87

D2N

ND2

D2N

ND2

AB C

Figure 3.38. 1

H NMR spectra of 4,4’-diaminostilbene E/Z-isomerisation in D2O (300

MHz, 298 K. a) The E isomer. b) After sunlight irradiation for 12 hours the spectrum is

dominantly that of the Z isomer. c) After warming at 333 K for one hour the spectrum

corresponded to a 1:1 E/Z isomeric mixture. The spectra are not plotted to constant

horizontal scale).


88

The phenyl and vinyl hydrogen resonances are clearly seen in the 1H NMR spectrum

(Figure 3.38, a)). Following irradiation, these resonances are nearly completely

depressed, with the occurrence of a new set of resonances consistent with the different

environment of the Z-isomer (b)). Subsequent warming of the sample leads to an

approximately 1:1 equilibration of these isomers (c)).

3.2.5.3. Stilbene-Derived Rotaxane Synthesis Attempts

The reaction of 4,4’-diaminostilbene with an excess of 2,4-dinitro-1-fluorobenzene in

water-acetone solution yielded 4,4’-bis(2,4-dinitrophenylamino)stilbene 3.7 which

spontaneously precipitated as a coloured powder. It was characterised by 1H and 13C

NMR spectroscopy, electrospray ionisation mass spectrometry, and melting point and

elemental analysis. Two separate reactions were carried out: the first involved the

reaction shielded from light, and the second involved a preliminary step in which the

stilbene reagent was exposed to sunlight in solution for 10 hours (Scheme 3.5).

i. 2,4-dinitro-1-fluorobenzene, H2O/acetone. ii. H2O, sunlight.

Scheme 3.5


89

The E-3.7 stilbene was recovered in 41% yield as a deep red powder, and a brown

powder determined to be 4:1 Z-3.7/E-3.7 by NMR integrations in 44% yield. The

isomeric forms were differentiated by their 1H NMR spectra in dimethylsulfoxide-d6

which paralleled the data for 4,4’-diaminostilbene. They also displayed differences in

their UV-Vis spectra. With 80 percent of 3.7 in the Z-form, at a concentration of 5 × 10-5

mol dm-3 in methanol, the absorption maximum was measured at 360 nm as shown in

Figure 3.39 by the dashed spectrum. The spectrum of E-3.7 under the same conditions

(solid curve) displayed less absorption and a maximum at 370 nm.

0

1

250 300 350 400 450 500 550

wavelength (nm)

Abs

orba

nce

Figure 3.39. Stilbene 3.7, 5 × 10-5

mol dm-3

in methanol, 298 K: 100% E-isomer (──);

80% Z-isomer (----).

Although E-3.7 did not convert to Z-3.7 to any significant degree through exposure to

sunlight, the reverse process occurred completely when UV-visible and NMR samples

were placed near a heat lamp for up to five hours. This is consistent with the degree of

steric crowding of the bulky dinitrophenyl moieties thermodynamically destabilising Z-

3.7 by comparison with E-3.7.


90

Repeated attempts to assemble the α-cyclodextrin rotaxane through previously optimised

methods169,171 were unsuccessful. Chromatography of the worked-up aqueous extracts

using Diaion HP-20 resin yielded trace degradation products as identified by tlc, but the

desired rotaxane was detected by 1H NMR spectroscopy or electrospray ionisation mass

spectrometry. Up to 31% of derivative 3.7 (as both isomers) was recovered from the

organic extracts, suggesting that formation of this byproduct was favoured in the aqueous

reaction conditions. It appears probable that the rate of amine nucleophilic attack of 2,4-

dinitro-1-fluorobenzene was slow enough that the dethreading of the [2]-pseudorotaxane

to α-cyclodextrin and the partially-stoppered axle occurred (Scheme 3.6). The failure to

increase the solubility of stilbene 3.6 in aqueous conditions in the presence of α-

cyclodextrin, as discussed previously, probably indicates that partially-stoppered axles of

this type do not interact significantly with α-cyclodextrin under the experimental

conditions.

NH

HN

O2N

NO2

NO2

NO2

3.7

H2N

NH2

H2N

NH2

H2N

HN

NO2

NO2

-cyclodextrin

-cyclodextrin

+

-

2,4-dinitro-1-

f luorobenzene

H2N

HN

NO2

NO2

2,4-dinitro-1-

f luorobenzene

-cyclodextrin

-cyclodextrin

+

-

2,4-dinitro-1-

f luorobenzene 2,4-dinitro-1-

f luorobenzene

No detectable product rotaxane

H2O, pH 10.

Scheme 3.6


91

3.3. Summary, Conclusions and Future Directions

The design of supramolecular species, exemplified by rotaxanes, requires the deliberate

choice or synthesis of an axle guest component of suitable size and shape, and desired

functionality; a rota component that features a cavity of suitable width and an affinity for

interaction with the axle; and bulky terminal blocking groups to mechanically restrict

dethreading of the rota from the axle of the rotaxane. Pseudorotaxanes represent a subset

of such systems, and ultimately depend on favourable forces of interaction between the

rota and the axle to form.

A pair of low molecular-weight axle components were designed and synthesised to

feature linearity, heterocycle-based asymmetry, and reactive termini for subsequent

coupling with blocking group reagents, based on geometry proven in previous, related

work.178 These axles were fully characterised; the basicity profiles for each axle in

methanol-water were investigated by potentiometric pKa determinations, and the

strengths of α-cyclodextrin complex formation were assessed qualitatively in acidic

conditions, through 2D ROESY NMR spectroscopy, and quantitatively in basic solution

through UV-visible spectroscopic titration. The corresponding complex formation of the

prototypical symmetrical stilbene axle was also assessed in basic conditions, and its

photoisomerisation behaviour was observed by NMR and UV-visible spectroscopy. The 1H NMR spectrum of the α-cyclodextrin-pyridine derivative [2]-pseudorotaxane in D2O

displayed temperature-dependent signal coalescence, which allowed for line-shape

analysis and estimation of the site exchange kinetic parameters of the [2]-pseudorotaxane.

Asymmetric rotaxane synthesis was obstructed by the unanticipated lack of reactivity of

the heterocycle-bound amino groups. Formation of the symmetrical stilbene-based

rotaxane under the same conditions also failed, probably resulting from a slow reaction

with the blocking group reagent. This indicated that a more reactive reagent was required

to successfully produce rotaxanes through this methodology. Moreover, the methodology

may be altered to incorporate different terminal groups on the axle component that would


92

offer reactivity with widely differing blocking group reagents, in other types of reaction

conditions.

Aqueous Polymer Hydrogels

93

CHAPTER 4: Hydrogels Consisting of Hydrophobe and Hydrophobe

Receptor-substituted Polymers in Aqueous Solution

4.1. Introduction

4.1.1. Hydrogels

Hydrogels are, broadly, gelatinous aqueous solutions of a hydrogelating agent. The added

reagent is often a water soluble polymer, although many low molecular weight

hydrogelators are known and are being studied.186 The hydrophilic polymer network of a

hydrogel has an extraordinary capacity for absorption of water from as low as 10 percent

up to many thousands of times the polymer dry weight. There are two types of polymer

hydrogels: chemical gels, in which the polymer networks are covalently cross-linked, and

physical gels in which the polymer networks are based on either molecular entanglement

or non-covalent associations.187 They have been widely investigated for use in tissue

engineering,27,29 drug delivery30 and release,188 organ replacement,189 cell

immobilisation190 and skin regeneration.31

Physical hydrogels, which are the subject of this study, are usually composed of

polymeric electrolytes composed of polar repeating units. The polymer matrix is not

homogenous and consists of clusters of polymer strands and dipole-dipole, ionic or

hydrophobic associations depending on the nature of the polymer. Polyelectrolytes form

ionotropic hydrogels when an oppositely charged multivalent ion is present to bridge the

ionic functionality: alginate (Figure 4.1a), derived from brown algae, gelates in aqueous

solution with calcium cations. This polyelectrolyte, mixed with poly(L-lysine) (Figure

4.1b) is an example of a polyion complex (a binary polymer system) which has been used

as a stabilising coating for microencapsulated islets to treat diabetes in rats.191


94

O OO OHO

OH

OHHO

ONH

H3N

O

OO

OO

a) b)

Figure 4.1. a) Alginate. b) Poly(L-lysine).

The macromolecular structures of hydrogels range from linear homopolymers to block

copolymers comprised of different monomers, and whose physical characteristics include

those of molded solids of contact lenses, powders for oral medicine delivery and

electrophoresis gels.187 The water in a hydrogel consists of bound water which is

associated with both hydrophilic and hydrophobic sites on the polymer and bulk water

that fills the elastic spaces and pores between the polymer network. At a sufficient level

of hydration these types of water are in rapid interchange.

The above examples are naturally derived, but much research has focussed on synthetic

polymer systems. These include poly(acrylic acid) and derivatives, poly(oxyethylene),

poly(vinyl alcohol), polyphosphazene and polypeptides.27 Synthetic hydrogels can be

used in tissue engineering where natural polymers are unsuitable. The main factors

determining their uses are biocompatibility which encompasses their potential to exist in

the human body benignly, and their ability to biodegrade.

4.1.1.1. Lower critical solution temperature (LCST)

This is a function of a particular polymer’s phase behaviour. Hydrogels that exhibit an

LCST form aqueous solutions at lower temperature but spontaneously precipitate at

higher temperature, resulting in a cloudy suspension (turbidity). The transitional

temperature is usually in a narrow range of less than a degree, an example being poly(N-

isopropylacrylamide) with an LCST of 273 K. This property is influenced less by

polymer concentration and molecular weight,192 than by solvent composition,193 the

presence and nature of salts and detergents194 and the nature of any copolymer

modification.195


95

4.1.1.2. Shear Viscosity

Viscosity is a rheological property of fluids, specifically the resistance of a sample to

stress-induced deformation. Shear viscosity measurements involve a constant temperature

(298.2 K) and shear rate (s-1), the rate of controlled deformation of the sample. These

parameters determine the observed viscosity η, expressed in mPa·s. For example, the

shear viscosity of an aqueous sample of poly(acrylic acid) (0.5 wt %, I = 0.1 M NaCl,

shear rate = 20 s-1) was measured as 3.9 mPa·s in recent work.32 For Newtonian materials,

the viscosity is proportional to sample concentration. In contrast the viscosity of semi-

dilute aqueous solutions of associating polymers increases more rapidly with increasing

concentration as a consequence of interpolymeric association.

4.1.1.3. Drag Reduction

Drag reduction is a decrease in the surface shear stress in turbulent liquid boundary

layers. In simple terms, it is an exchange of energy between the turbulence and the

polymer,196 such that the energy in the flowing liquid is absorbed by the elasticity of the

polymer. In optimised conditions, the overall result is a drop in pressure for a given flow

rate. Polymer additives may only be termed as drag reducing when their addition reduces

the friction of the solvent more effectively versus the increase in turbulence they cause.197

Drag reduction in aqueous and non-aqueous media is useful in oil production and has

been exploited to reduce hydraulic drag in oil pipelines,198 as well as in improving

injection of water into wells for enhanced recovery.199 The first example of the effect was

observed by Toms in monochlorobenzene, using polymethylmethacrylate.200 The

effectiveness of drag reduction is dependent on concentration, which is typically only in

the tens of parts per million.201

4.1.2. Aqueous Intra- and Intermolecular Supramolecular Assembly

Modification of water soluble polymers has been pursued for some time in order to

influence their physical behaviours. Tam et al. examined the effects of hydrophobic


96

hexadecyl end groups on the shear characteristics of a substituted poly(ethylene

glycol),202 and found that several polymer network structures which contributed to the

overall properties. Bokias et al. substituted poly(N-isopropylacrylamide) with varied

lengths and mole-percentages of quaternary ammonium-bearing alkyl chains, and found

that phase and rheological behaviour of such copolymers could be tuned in this way.203

Thus, the 5 mole-percent dodecyl-substituted polymer displayed a strongly temperature-

dependent reduction in viscosity when not under shear stress, but viscosity increased with

temperature under high shear stress.

Figure 4.2. a) The general formula for polyacrylamide copolymers.34

b) Phenylalanine-

and tryptophan-substituted polyacrylates.204

The concept of hydrophilic polymer modification as the basis of supramolecular

chemistry has been investigated extensively and recently reviewed by Hashidzume et

al.34 Initial work focussed on the interactions of cyclodextrins in solution with

hydrophobically substituted polyacrylamide. The polymer was substituted with various

alkyl groups at between 1 and 11 mole-percent substitution, as well as phenyl and

naphthyl groups at about 2 mole-percent substitution (Figure 4.2a). At sufficiently high

substitution, intermolecular interactions between hydrophobic groups are favoured over

intramolecular interactions, and these forces contribute to inter-polymer strand

association.204 It was observed using 1H NMR spectroscopy that α-, β-, and γ-

cyclodextrin (refer to Section 3.1.2 for details regarding cyclodextrins) complex the alkyl

substituents.34 Comparisons with the complexes formed by cyclodextrins with

corresponding model alcohols revealed a degree of selectivity for the polymer


97

substituents dependent on the steric effects of the polymer on their local environment.

Similarly, complexation of naphthyl substituents was observed by fluorescence emission

changes, where complexation in the hydrophobic cavity of β-cyclodextrin resulted in

greater emission than for the substituent in the uncomplexed state. The change in

fluorescence intensity was more pronounced for 2-substituted naphthalene by comparison

with 1-substituted naphthalene, since the long axis of the former arrangement is more

parallel to the axis of cyclodextrin. Unlike the alkyl substituents, the aromatic

substituents showed little evidence of polymer-dependent selectivity in complexation.

The phenylalanine- and tryptophan substituted methacrylates (Figure 4.2b) were studied

as a simple model for macromolecular recognition of proteins.204 Complexation of

tryptophan by β-cyclodextrin was observed by 1H NMR and fluorescence spectroscopy.

Both substituents were also observed to interact hydrophobically with methylene

segments of the polyacrylate backbone.

HO O O NH(CH2)11CH3 NN

OOC

COO

Fe COOH

A B

Figure 4.3. Dodecyl substituted poly(acrylate) with either α- or β-cyclodextrin and

competing guests.205

Competing hydrophobic interactions between interpolymeric alkyl substituents versus α-

and β-cyclodextrin can provided an avenue for control of the inter polymer strand

associations.205 Thus, in a ternary mixture of 5 mole-percent dodecyl substituted

poly(acrylate), equimolar amounts of either α- or β-cyclodextrin and a competing guest

species (Figure 4.3) hydrogel systems which may be switched between the gel and fluid

states may be formed. Complexation of the E-isomer of the azobenzene A with α-

cyclodextrin in solution was favoured in the presence of the substituted poly(acrylate),

with the result that hydrophobic dodecyl substituent aggregation lead to a high measured

viscosity and gel-like behaviour. UV irradiation largely converted the azobenzene A to


98

the Z-isomer which was a poor guest for α-cyclodextrin, which was then able to complex

the alkyl substituents of the substituted poly(acrylate). The decreased interpolymer strand

association caused a decrease in viscosity and the sample switched to solution-like

behaviour. This was shown to reverse upon photoisomerisation of the azobenzene A with

visible light irradiation, as well as switching between gel and solution states. Repetition

of this switching behaviour was demonstrated. A related ternary system incorporating β-

cyclodextrin and the ferrocenecarboxylic acid B, instead of the azobenzene A, exhibited a

redox-dependent gel to solution transition behaviour. of β-cyclodextrin-complexed B in

the ternary mixture. Oxidation of ferrocenecarboxylic acid B with sodium hypochlorite

rendered it cationic and less amenable to complexation by β-cyclodextrin which then

preferentially complexed the poly(acrylate) dodecyl groups and switched the system from

a gel to a solution state.

A pair of substituted poly(acrylates) with contrasting photo-dependent viscosity

characteristics has also been described.206 A combination of 3 mole-percent dodecyl-E-

azobenzene substituted poly(acrylate) and 2 mole-percent α-cyclodextrin C6-substituted

poly(acrylate) in water exhibited complex formation (Figure 4.4a and 4.4b) as indicated

by UV-visible absorption and 2D 1H NMR spectroscopy, as well as a viscosity value

several orders of magnitude higher than that of a poly(acrylate)/dodecyl-E-azobenzene-

substituted poly(acrylate) mixture. The 2D NOESY 1H spectrum indicated that α-

cyclodextrin complexed both the dodecyl and azobenzene moieties of the dodecyl-E-

azobenzene-substituents of 4.4a. Irradiation with UV light switched the azobenzene to

the Z-isomer (Figure 4.4b) and the dodecyl moiety of the dodecyl-Z-azobenzene-

substituents were then dominantly complexed by α-cyclodextrin as shown by 2D

NOESY 1H spectroscopy. This photoisomerization also resulted in a slight increase in

viscosity. Visible light irradiation converted the dodecyl-Z-azobenzene-substituents back

to dodecyl-E-azobenzene-substituents and reversed the association and the effect on shear

viscosity. The related system utilising 2 mole-percent α-cyclodextrin C3-substituted

poly(acrylate) (Figure 4.4c), spectroscopically and rheologically showed comparatively

weaker interpolymer interactions based on the selectivity of the α-cyclodextrin

substituent for the dodecyl-E-azobenzene substituent. Photo-isomerisation to the dodecyl-


99

E-azobenzene substituent resulted in a decrease in viscosity to almost equal that of the

free α-cyclodextrin substituted poly(acrylate) binary mixture.

HO O O NH(CH2)12NH

O

N N OHOOHN

a) c)

OHOOHN

HO O O NH(CH2)12NH

O

N

b)

N

OHO

O

HN

visible Uv

light light

Figure 4.4. a) Substituent E-azobenzene and C6-α−cyclodextrin substituted

poly(acrylates). b) Substituent Z-azobenzene and C6-α−cyclodextrin substituted

poly(acrylates). c) α-C3-cyclodextrin-substituted poly(acrylate).216

4.1.2.1. Substituted Polymer Syntheses

There are two widely used approaches to the substitution of water soluble polymers. One

is radical copolymerisation of a mixture of monomers, which optimally produces

polymers of random distribution of substituents in proportion to the ratio of initial

monomer reagents, and is widely applicable. The other involves reaction with an extant

polymer, exploiting the reactivity of particular side-chains. The degree of substitution in

this case is controlled by the amount of low molecular weight reagent used and its

reactivity. In the synthesis devised by Wang et al. the formation of amide bonds between


100

poly(acrylic acid) and hydrophobic amines is effected by dicyclohexylcarbodiimide

coupling.207 The authors noted that radical copolymerisation can present difficulties when

random distribution of modification is sought with monomers of widely varying

polarities, as well as a specific range of polymer molecular weight. Substitution methods

will be discussed further in following sections.

4.1.3. Fluorescence Studies of Aqueous Polymers

An early example of a fluorimetric study of polyelectrolytes in solution is exemplified by

that of Strauss and Vesnaver in 1975. They compared the fluorescence of 1-

dimethylamino-5-(β-aminoethyl)sulfonamidonaphthalene (referred to as the dansyl

probe) with dansylated methyl and butylvinyl ether copolymers of maleic anhydrides as a

function of pH in aqueous solution.208 Substitution of the dansyl entity onto the methyl

copolymer had little effect on the dansyl fluorescence characterised by emissions at 336

and 580 nm. However, substitution of the dansyl entity onto the butyl vinyl copolymer

resulted in a shift of the emission at 580 nm to 520 nm at low pH and its intensity was

higher than that of the dansyl probe alone. The wavelength of this emission increased and

its intensity decreased substantially as pH was increased and deprotonation of the

copolymer occurred. This was consistent with a tightly coiled conformation of the

substituted polymer at low pH providing a largely hydrophobic environment for the

dansyl substituents, which contrasted with the aqueous environment of the dansyl probe

alone. As the pH of the butyl vinyl copolymer solution was increased and ionization

increased a random coil conformation was assumed and the dansyl substituent

experienced an increasingly aqueous environment, so that its emission maximum

wavelength and intensity became similar to that of the dansyl probe alone.

Studies of (9-anthryl)methyl substituent bearing ionic polymers, or polyionenes, by

Suzuki and Tazuke show that polymer-bound anthryl groups aggregate and show excimer

fluorescence in aqueous solution consistent with hydrophobic interactions within the

polymer enhancing such aggregation.209,210 The same polymers show a much decreased

excimer fluorescence in methanol consistent with decreased hydrophobic interactions


101

within the polymer and consequently less aggregation of the anthryl substituents. In

contrast, small molecular weight species show little excimer activity in methanol or water

and thereby indicate the importance of the environmental factors affecting the polymer

conformation.

One avenue for the formation of fluorophore-substituted water soluble polymers is

illustrated by the substitution of pyrene onto the sugar fragment of oligonucleotides,

which were used as probes for specific nucleic acid sequence detection.211 Yamana et al.

studied the substitution the 2’ position of uridine with a pyrenylmethyl group (Figure

4.5a), incorporated the nucleotide into a sequence and observed the interactions with

complimentary DNA and RNA oligonuceotides.212 Fluorescence was enhanced by double

helix formation, aromatic intercalation, and DNA-DNA base pairing resulted in pyrene-

nucleobase exciplex emission. The same authors also investigated the excimer formation

of pyrenes attached to consecutive nucleotides such that the fluorophores are arrayed on

the outside of the duplex RNA.213 This DNA manipulation approach has been applied to

the study of ribozyme reaction214 as well as monitoring in vitro transcription.215 Pyrenes

were used as nucleotide surrogates by Langenegger and Häner in complimentary DNA

strands (Figure 4.5b), resulting in sandwiching of the pyrenes and strong excimer

emission.216 Pyrene is a favoured fluorophore in emission studies on the organisation of a

variety of substituted water soluble polymers.217


102

O

RO O

...XXXO N

NH

O

O

O

HN

O HN

OHN

O

HNO

O

O

O

...XXX

...XXX XXX...

XXX...nn

n n

a) b)

Figure 4.5. a) Pyrenylmethyl-substituted uridine (X = nucleotide).212

b) Stacked pyrene

nucleotide surrogates.216

4.1.4. Poly(acrylic Acid)

Poly(acrylic acid)s and their neutralised form, sodium poly(acrylate)s, are widely used

polymers, appearing in products ranging from transparent, breakage-resistant Plexiglas to

medical and household adhesives. The simplest of these polymers is poly(acrylic acid),

(Figure 4.6a), the polymer formed from acrylic acid monomer units, which was first

described in 1933.218 In 1967 Dow Chemical Company produced the poly(acrylate)

sodium salt of as a super absorbent hydrogel219 which is now contained in many domestic

products, in dry bead form, to absorb moisture.

R RRR RR R R R RCOOHn

Atactic Syndiotactic

a) b)

Figure 4.6. a) Poly(acrylic acid) monomer. b) The tacticity of poly(acrylic acid) (R =

COOH).237

Poly(acrylic acid) has a number of important features:

• it is a polyelectrolyte with high water solubility.

In a dry sample the carboxylic acid groups form non-covalent cross-links. Upon

initial hydration, water molecules first associate with these polar sites,

interrupting some polymer strand cross-linkage and allowing the solid network to


103

swell. Further volumes of less hydrophilic sites are consequently exposed which

provides space for more water to be accommodated by the polymer network.

After all of these sites are fully hydrated, water continues to be absorbed as the

polymer network is osmotically driven toward infinite dilution.

• the gel capacity is thousands of times the original mass.

The above-described absorption of water into the polymer matrix is opposed by

persistent cross-linking between carboxyl groups, which dictate an elastic network

structure within the non-solid, water-filled gel. This water that continues to absorb

and fill the spaces within the network is the ‘bulk water’. The gel can swell and

increase in mass several thousand times before passing an equilibrium level, after

which it will begin dissolving into the water.

• the tacticity of the polymer affects its physical behaviour.

Figure 4.6b displays the enantiomeric arrangements that are observed in

commercially available poly(acrylic acid). Atactic poly(acrylic acid) incorporates

each monomer with randomly arranged stereochemistry and is highly soluble in

water and dioxane. Contrastingly, syndiotactic poly(acrylic acid) is comprised of

a regularly alternating arrangement of monomer enantiomers and is comparatively

less soluble.220

Studies on poly(acrylic acid) have elucidated many of its chemical and physical

properties. Like other water-soluble polymers poly(acrylic acid) introduces a drag

reduction effect196 in solvent flow at low concentration, and Kim et al. observed a

conformational transition of a ultra-high molecular weight sample in water under shear

flow conditions that resulted in a decrease in drag reduction.221 (Shear is applied to a

sample placed between the stationary and rotating discs of a rheometer. The speed of

rotation may be varied to apply different degrees of shear force to the sample between the

discs.) This was due to a stable inter-polymer strand association, and the drag reduction

was observed to fully recover on addition of trace amounts of sodium chloride due to the

disruption of this association. The difference in these interactions, between sheared and

unsheared samples, was investigated by comparing the respective 23Na NMR spectra.

Line broadening and a measurably lower integrated intensity in the sheared sample


104

indicated relatively tighter binding of counterions to the poly(acrylic acid) carboxylate

groups. This broadening is a consequence of quadrupolar relaxation of the 23Na nuclear

spin being increased through interaction with the electronic environment of the binding

site such that the most strongly bound sodium ion 23Na resonances where so broad that

they did not significantly contribute to the overall 23Na resonance integration.

The intramolecular reactivity of substituted poly(acrylate) was investigated by Morawetz

and Zimmering.222 A model copolymer was prepared, incorporating 9 mole-percent 4-

nitrophenyl methacrylate substituents, and the hydration of this functionality was

observed to be much less dependent on solution pH than on the degree of polyelectrolyte

ionisation. When compared with 4-nitrophenyl trimethylacetate substituent hydrolysis in

similar conditions, the rate of loss of polymer-bound ester groups through hydrolysis was

observed to be orders of magnitude greater due to rapid attack by an adjacent carboxylate

anion of the poly(acrylate) backbone and the formation of a six-membered cyclic

intermediate (Figure 4.7), with a maximum between pH 5 to 7. Use of dioxane-water

mixed solvent retarded the intramolecular hydrolysis as the decrease in solvent polarity

reduced the extent of copolymer carboxylate deprotonation.

O O OO

NO2

Figure 4.7 Intramolecular hydrolysis in semi-esterified poly(acrylic acid).222

4.1.4.1. Poly(acrylic Acid) Substitutions

The importance of the complimentary binding sites of poly(acrylic acid) and polymeric

hydrogen bond acceptors such as poly(oxyethylene) (POE) and poly(vinyl pyrrolidone)

was initially studied by Chen and Morawetz.28 Poly(acrylic acid) was substituted with

dansyl fluorophores and interpolymer hydrogen bond association was found to maintain

dansyl fluorescence intensity in aqueous solution, which would otherwise quench dansyl


105

emission. Competitive complexation with the substituted poly(acrylic acid) backbone by

added poly(acrylic acid) resulted in a steady decrease in dansyl fluorescence. It was

subsequently shown that dissociation of the dansyl substituted poly(acrylic acid)-POE

complex could be controlled through raising pH and ionising the poly(acrylic acid)

carboxylate groups.37

Similarly, the fluorescence behaviour of poly(acrylic acid) substituted with 1.5 mole-

percent of 1-pyrene groups in different solvent environments and also in association with

other interacting polymers was also studied.223,224 Firstly, the extent of pyrene excimer

emission relative to monomer emission was observed to be much higher in water than in

N-methylpyrrolidin-2-one. This was considered to be due to the compact form that

poly(acrylic acid) assumes in the former environment, in which intramolecular pyrene

group interaction is favoured. Solvation by the aprotic organic solvent led to more open

of poly(acrylic acid) conformation and fluorophore interaction was diminished. A similar

result was observed in aqueous solution at high pH, where the charge repulsion of the

poly(acrylate) carboxylate anions caused chain expansion. Secondly, the strength of other

interacting polymer association was found to increase in the order of poly(oxyethylene) <

poly(vinylpyrrolidinone) < poly(vinylamine hydrochloride) as judged from the respective

increasing intensities of the corresponding pyrene excimer emission.223 Further, the

adsorption of the pyrene substituted polymer onto aluminium oxide slurry at varying pH

levels showed that the compact excimer emitting form was absorbed at low pH while

deprotonation of the carboxylates at high pH led to absorption of the extended excimer

deactivated form. Absorption onto tertiary ammonium-bearing cationic silica gel led to

negligible excimer emission independent of pH.224

A 0.319 mole-percent pyrene-substituted poly(acrylate) copolymer was studied by

Stramel et al.225 They observed significant pH-controlled structural changes in the

pyrene-substituted poly(acrylate), and fluorescence quenching upon addition of viologen

reagents. This indicated tight ion pairing between the pyrene fluorophore and the

viologen quencher, probably influenced by the pyrene-substituted poly(acrylate)

conformation.


106

4.1.4.2. Recent Progress

In 1988, a 3 mole-percent octadecylamide-substituted poly(acrylate) was synthesised

through amide coupling with poly(acrylic acid), which exhibited a hydrophobic

association of the substituents in aqueous conditions, in the order of ten to thirty groups

per junction, depending on the poly(acrylate) concentration.226 Recent work32 has studied

the influence of complexation by hydrophobe receptors on this hydrophobic association.

Thus, the viscosity of the substituted poly(acrylate) is steadily decreased to half of the

original with added α- or β-cyclodextrin, plateauing at an octadecyl/cyclodextrin ratio of

1:1. This implied comprehensive interruption of hydrophobic association. Further,

addition of an equivalent of sodium dodecyl sulfate to a 1:1 mixture of substituted

poly(acrylate) and α-cyclodextrin substantially increased the measured viscosity due to

competition for complexation with α-cyclodextrin.227 At two equivalents of sodium

dodecyl sulfate the viscosity equalled that of the substituted poly(acrylate) alone in

solution, but higher amounts of sodium dodecyl sulfate interrupted hydrophobic

aggregation of poly(acrylate) octadecyl substituents with a corresponding drop in

viscosity.


107

Viscosity

mPas

Figure 4.8. a) The disaggregation of interpolymeric octadecyl group aggregation and

complexation by a poly(acrylate) cyclodextrin substituent. b) Viscosity variation of an

aqueous 0.5% weight percent 3% octadecyl substituted sodium poly(acrylate) with added

3% α- or β-cyclodextrin substituted sodium poly(acrylate) (water, pH 7, I = 0.1 M NaCl,

25°C).227

Mixtures consisting of octadecyl substituted poly(acrylate) and cyclodextrin substituted

poly(acrylate) (Figure 4.8a) were investigated for the influence of hydrophobe receptor-

hydrophobe complexation on viscosity. The cyclodextrin substituted poly(acrylate)s

exhibited considerably less viscosity due to the bulkier nature of their substituents.

Models of associative polymers can be described theoretically,228,229 and these systems

behave predictably with viscosity maxima when the hydrophobe receptor : hydrophobe

substituent ratio is 1:1,32 as displayed in Figure 4.8b. Viscosity fell to lower levels past a

2:1 excess of cyclodextrin substituted poly(acrylate). The α-cyclodextrin substituted

poly(acrylate)/octadecyl substituted poly(acrylate) system was studied with increasing

concentration.227 Shear viscosity increased by nearly two orders of magnitude upon

increase of the binary substituted poly(acrylate) concentration from 1 percent to 2 by

weight. As the concentration was increased further to 4 percent, there was both a further

order of magnitude rise in viscosity, as well as shear thickening as shear rate increased.


108

4.1.5. Summary and Aims

Hydrogels consisting of substituted polyelectrolytes have potential application in areas

ranging from tissue engineering to pipeline flow efficiency. In terms of pure research,

they can provide simple models for biological polymeric systems. Molecular recognition

of substituents is the basis of a plethora of studied biological processes, as well as for the

design and construction of supramolecular assemblies based on macromolecular

components. Intentional adjustment of polymer properties, including polarity, flexibility,

steric bulk and percent occurrence of substituents, adjustment of sample pH, ionic

strength, concentration and temperature, as well as overall macromolecular weight and

conformation can be used to obtain new and improved hydrogel materials.

The aims of this project were to expand the range of hydrophobically substituted

polymers by appending amide-bonded aromatic side chains to poly(acrylic acid) through

the methods of Iliopoulos.226 This procedure provides control over the molecular weights

of the polymer products, and the extent of each poly(acrylic acid) or sodium

poly(acrylate) modification. The nature of the substituents was intended to parallel the

synthetic studies of Hashidzume which included phenyl- and naphthyl- substituted

polyacrylamide copolymers.205 It was intended to expand the range of substituted

poly(acrylates) with the aim of studying each rheologically. This would involve

interactions with native and poly(acrylate) cyclodextrin substituents as outlined in

previous work,227 observed primarily through 2D NMR and absorbance/fluorescence

spectroscopy where applicable. Additionally, it was anticipated that fluorescence changes

shown by aromatic substituents would provide insight into their hydrophobic

aggregation. The specific homologues to be studied were substituted with phenyl-,

diphenyl-, napthyl- and anthryl-substituents.


109

4.2. Discussion

4.2.1. Target Poly(acrylic acid) Substitution

Figure 4.9 illustrates the general formula of the proposed substituted poly(acrylates). In

this context, “x” is used to denote the mole percentage of amide substitution as

determined by comparative 1H NMR integration (cf. section 4.2.4.1). The procedure of

Iliopoulos et al.226 has consistently provided a method for polymer substitution that

ensures a predictable and random distribution of the substituent.32,230

Figure 4.9. Substituted poly(acrylate) general structure.

4.2.2. Initial Hydrophobe Target Synthesis

RO

NH2

CH2 CH2 CH2

RBr

HOCH2CH2NH2

NaH, DMF

R=

Scheme 4.1.

The initially planned series of hydrophobe substituents comprised simple aromatic groups

of incremental ring number: phenyl, naphthyl and anthryl. Using SN2 substitution to form

an ether provided an amino-alkyl linker which could be subsequently reacted with the

poly(acrylate) carboxyl groups to form an amide bond tethering the hydrophobe to the

poly(acrylate) (Scheme 4.1). It was anticipated that this approach would provide a single

step to the desired amine reagents from the bromides, however, in execution, it failed to


110

yield appreciable traces of product. The substitution of bromomethylbenzene was

attempted with varying excesses of ethanolamine but only yielded trace amounts of the

desired product as assessed from the 1H NMR spectrum of the reaction mixture. The

approach was abandoned and the synthesis of either of the other ethers was not

attempted.

4.2.3. Hydrophobic Amide Synthesis

Recent unpublished work has involved the substitution of adamantyl substituents onto

poly(acrylate), which affords a hydrophobe substituent for complexation by α- and β-

cyclodextrin substituents on poly(acrylate). The approach in this case utilises a facile

transformation of adamantane-1-carboxylate to the corresponding amide, featuring an

alkyl chain of variable length terminated with the necessary amine group. It can be

applied to any carboxylic acid, so a series of aryl acetic acids was prepared.

CH2 CH2 CH2R=CH

R OH

O

R O

ONO2

RHN

NH2

O

i. ii.

i. 4-NO2C6H4OH, DCC, CH2Cl2; ii. NH2CH2CH2NH2,

DMF.

Scheme 4.2.

4.2.3.1. Aryl Acetic Acids

Phenyl acetic acid 4.1 was obtained from benzyl bromide through the Grignard reaction

with carbon dioxide and was isolated as a white powder for which spectrometric

properties matched that in the literature. Spectroscopically pure 2-

(bromomethyl)naphthylene 4.2 was obtained by standard treatment of methylnapthylene


111

with N-bromosuccinimide and 2,2′-azobis(2-methylpropionitrile) (AIBN) under a

sunlamp with heating. The character of the slightly yellow material was confirmed by

melting point analysis and 1H NMR spectroscopy. However, generation of the

methylnaphthalene-derived Grignard reagent proved problematic and the corresponding

acid 4.3 was instead prepared through catalytic carboxylation by reaction of chloroform

and concentrated potassium hydroxide in the presence of bistriphenylphosphine

palladium dichloride.231

OH

O

i. NBS, AIBN, CHCl3

ii. PdCl2(PPh3)2, KOH, CHCl3, H2O

4.3

Scheme 4.3.

The anthryl homologue presented the most difficult challenge, as controlling the position

of bromination was impossible under a range of conditions. Literature methods are vague

at best and in some instances increase the difficulty in synthesising 2-

(bromomethyl)anthracene.232 An alternative preparation233,234 was carried out to give 2-

(bromomethyl)anthraquinone 4.4 in a yield of 47%, with the added benefit of being

readily recrystallised as pure product. 2-(Anthraquinone)acetic acid 4.5 was made with

the biphasic palladium catalysis route described above, and this was followed by a

reduction step to decarbonylate the anthraquinone to anthracene, involving treatment with

an excess of zinc dust in aqueous ammonia at 50°C. 2-(Anthracen-2-yl)acetic acid 4.6

was generated in a yield of 46%. In this way, using anthraquinone initially was a form of

“protection-deprotection” as bromination of the starting material was relatively facile in

the presence of the quinone functionality. However, the low yield of the initial acid was a

limiting factor in the effectiveness of this approach.

Diphenyl acetic acid was also investigated as its effects as a more sterically hindered

hydrophobic poly(acrylate) substituent were potentially interesting.


112

4.2.3.2. Nitrophenol Aryl Acetates

The starting acids were each treated with a slight excess of 4-nitrophenol in the presence

of DCC to generate the necessary activated esters 4.7 – 4.10 in yields mostly in excess of

70% (Table 4.1). These markedly stable esters were easily purified by chromatography,

and were easily handled. Each reaction was monitored by tlc, and plates developed by

exposure to ammonia vapour.

Table 4.1.

CHR1R2O

OO2N

R1, R2 phenyl, H

(4.7)

phenyl, phenyl

(4.8)

naphthyl, H

(4.9)

anthryl, H

(4.10)

Yield 78% 70% 80% 67%

The purities of 4.7 and 4.8 were ascertained by melting point analysis and 1H NMR

spectroscopy. Data for both species matched that in the literature. The new esters 4.9 and

4.10 were characterised by melting point analysis, 1H and 13C NMR spectroscopy and

accurate mass spectrometry.

4.2.3.3. Aminoethyl N-Aryl Acetamides

Table 4.2 gives the yields of the isolated target amides 4.11 through 4.13. Care was taken

to minimise the diamidation of diaminoethane by promoting collisions between the

nitrophenol ester and diamine starting materials: the ester was introduced to the reaction

as a very dilute solution and as slowly as practical, with the diamine stirred rapidly in at

least 25 equivalents excess. Isolation generally involved chromatography with basic

alumina of Brockman grade III, and generous flushing of the stationary phase with

dichloromethane-methanol to elute traces of amide product, which visualised as deep

purple streaks of very low retention factor on silica tlc plates with ninhydrin solution


113

staining. Each dried amide had the appearance of a white soapy solid to a greater or lesser

extent, in addition to a marked sensitivity to air, and was consequently difficult to handle.

Table 4.2.

CHR1R2HN

OH2N

R1, R2 phenyl, H

(4.11)

phenyl, phenyl

(4.12)

naphthyl, H

(4.13)

anthryl, H

Yield 17% 52% 53% –

The limitations of this synthetic step were most pronounced in the attempted preparation

of the anthryl acetamide homologue. In this case the steric bulk of the aryl moiety and its

role in non-favourable collisions may contribute to an overall retardation of the desired

nucleophilic attack, statistically allowing molecules of ester more time to mix with the

amide product and potentially form the unwanted diamide. The small amount of material

recovered appeared to be a mixture of products, and this, in addition to the poor yields of

several prior steps, lead to this approach to anthryl hydrophobic substituents being

abandoned.

4.2.4. Aromatic Substituted Poly(acrylic Acids)

4.2.4.1. Substitution of Poly(acrylic acid)

The substitution of poly(acrylic acid) was undertaken using the method established in

recent related work;32 specifically N,N’-dicyclohexylcarbodiimide (DCC) mediated

coupling of 3 mole percent of primary amine precursor relative to poly(acrylic acid) in

solution in 1-methyl-2-pyrrolidinone (NMP), as shown in Table 4.3 in which

poly(acrylate) is abbreviated to PAA for convenience in denoting specific substituted

poly(acrylates) as is also the case in the figures which follow. Reaction mixtures were

heated at 60°C and stirred for about four days, and consumption of amine reagent was

monitored by tlc with staining with ninhydrin solution. Care was taken in the addition of


114

NMP solutions of amine to each reaction, however the marked sensitivity to air shown by

these amines may have contributed, to a greater or lesser degree, to the observed

depression of final hydrophobic loading for some of the poly(acrylate) products. The

substitution on the poly(acrylate) backbone was random, but widely spaced on average

with substituents occurring at three out of every one hundred monomer units. Treatment

of the cooled reaction with concentrated aqueous sodium hydroxide solutions generated

carboxylate at the remaining acrylic acid units. The substituted poly(acrylate) product,

separated from the N,N’-dicyclohexyl urea (DCU) byproduct, was purified as its sodium

salt.

Table 4.3.

COO

x

100-x

NH

O

n

HN

O

CHR1R2

OH

O

m

H2N

HN CHR1R2

O

N C N

HN C

HN

O

+ +

+

60°CNMP

DCC

DCU

Amine precursor 4.11 4.12 4.13

Mstarting material (mg) 400.0 400.0 400.0

Mproduct recovered (mg) 90.8 203.9 378.9

% Loading (x) 1.5 2.7 3.0

Designation PAA1.5%Ph PAA2.7%Ph2 PAA3%Np

Dialysis of each product in SpectraPor 3 membranes (with a molecular weight cut-off of

3500 g/mol) against deionised water provided a convenient purification method to

separate the substituted polymer from residual solvent, ions and starting material. The

final product was freeze-dried for ease of handling. 1H NMR spectra of the products

isolated from this procedure displayed a diagnostic pair of broad signals between 1 and

2.2 parts per million due to the three protons on the secondary and tertiary carbons of the


115

poly(acrylate) backbone. Hydrophobic substituents generated relatively sharper

resonances downfield past 7 parts per million. This is exemplified by the naphthyl

homologue in Figure 4.10.

n

Figure 4.10. 1H NMR spectrum of PAA3%Np (600 MHz, D2O, 298 K).

The degree of substitution denoted by x of the carboxyl groups in poly(acrylate) by the

aromatic substituents is determined according to the following equation:

AAr/NArH substitution (x mol %) = –––––––– × 100 AAl/3

where AAr and AAl are the integrated areas of the substituent aromatic and poly(acrylate)

aliphatic signals, respectively, and NArH is the number of aromatic hydrogens. This

information also allows the abbreviated designation of the substituted poly(acrylates) in

the form of “PAAx%Ar”, where Ar denotes the type of aromatic substituent involved.

4.2.4.2. Cyclodextrin-Hydrophobe Complexation

The interactions of all hydrophobically substituted poly(acrylate)s with α- and β-

cyclodextrins were assessed through 2D 1H NOESY NMR spectroscopy. One equivalent

(relative to hydrophobe loading) of each cyclodextrin was added to 1 weight-percent

(w%) samples of each substituted poly(acrylate) in D2O, and cross-peaks were observed

where through-space interactions occurred between the hydrophobic substituent and


116

cyclodextrin annulus, indicating complexation. All spectral samples were prepared at

approximately pD 7.

Weak complexation was indicated in the spectrum of PAA2.7%Ph2 in the presence of α-

cyclodextrin (Figure 4.11). The low intensity of the boxed cross-peak, and absence of

mirror-image cross-peak distinguishable from T1 noise, is an indicator of the weak

complexation of the phenyl substituents by host. The lack of cross-speaks observed in the

case of PAA1.5%Ph as well as PAA3%Np supports the conclusion that despite the

tendency of α-cyclodextrin to form complexes with low-molecular weight phenyl and

naphthyl derivatives, it has a limited affinity for these hydrophobes in the aqueous

substituted poly(acrylate) environment.


117

Figure 4.11. 2D 1H NOESY NMR spectrum of PAA2.7%Ph2 with α-cyclodextrin (600

MHz, D2O, 298 K). Relevant cross-peaks are boxed.

Complexation was observed for the diphenyl substituted polymer PAA2.7%Ph2 in the

presence of β-cyclodextrin (Figure 4.12a, cross-peaks enclosed in solid boxes). The

amount of β-cyclodextrin added was 1 equivalent of the diphenyl moieties. It was

expected that complexation of a single phenyl group of a given diphenyl substituent

would occur as a consequence of the engendered steric hindrance to complexation by a


118

second β-cyclodextrin. This supposition was qualitatively supported by the addition of

two equivalents of β-cyclodextrin, which caused little change to the cross-peaks indicated

by solid boxes. A weak interaction between the diphenyl substituent and the

poly(acrylate) backbone appears to be indicated by a NOE cross-peak between the phenyl

groups and the polymer backbone (Figure 4.12a, dashed box). This interaction is

relatively weak judging by the lack of a mirror-image cross-peak in the spectrum. It is

likely that π-CH hydrophobic interactions are responsible for this association and that the

overall configuration is similar to that shown in Figure 4.12b. Addition of sodium

adamantane-1-carboxylate to the PAA2.7%Ph2 sample caused the disappearance of the

diphenyl substituent-β-cyclodextrin interaction and the appearance of cross-peaks due to

adamantane complexation by β-cyclodextrin.235


119

a)

b)

HN

ONH

O

n

Figure 4.12. a) 2D 1H NOESY NMR spectrum of 1 w% PAA2.7%Ph2 with β-CD (600

MHz, D2O, 298 K). Relevant cross-peaks are boxed. b) Schematic of the prevalent

substituent configuration.


120

Figure 4.13 shows the cross-peaks due to complex formation between the naphthyl

substituents of PAA3%Np and β-cyclodextrin. The relative strength of this complexation

was tested by the addition of an equivalent of sodium adamantane-1- carboxylate. This

resulted in the disappearance of the naphthyl-β-cyclodextrin cross-peaks and the

Figure 4.13. 2D 1H NOESY NMR spectrum of 1 w% PAA3%Np with β-cyclodextrin (600

MHz, D2O, 298 K). Relevant cross-peaks are boxed.


121

appearance of new cross-peaks corresponding to the complexation of adamantane-1-

carboxylate by β-cyclodextrin as seen in Figure 4.14.

Figure 4.14. 2D 1H ROESY NMR spectrum of 1 w% PAA3%Np, with β-cyclodextrin and

sodium adamantane-1-carboxylate (600 MHz, D2O, 298 K). Relevant cross-peaks are

boxed.

The complexation of the diphenyl substituent of PAA2.7%Ph2 by one equivalent of a

urea-linked β-cyclodextrin dimer236 produced NOESY cross-peaks (Figure 4.15, solid


122

boxes) and also caused the coalescence of the diphenyl 1H multiplet observed in the

absence of the β-cyclodextrin dimer (dashed box) into a single broad resonance. (A

similar coalescence was observed upon addition of one and two equivalents of free β-

cyclodextrin as seen in in Figure 4.12a.). These coalescences appear to be a result of

rapid site exchange of either phenyl group into the β-cyclodextrin annuli in both cases.

Figure 4.16. 2D 1H NOESY NMR spectrum of 1 w% PAA2.7%Ph2, with β-cyclodextrin

urea dimer (600 MHz, D2O, 298 K). Relevant peaks and cross-peaks are boxed.


123

When one equivalent of adamantane-1-carboxylate was introduced to the system, cross-

peaks in the 2D ROESY spectrum due to association with the β-cyclodextrin dimer were

observed (refer to Appendix 4, Figure A.4.1). The 2D NOESY spectrum (Figure 4.17a)

also displayed cross-peaks for PAA2.7%Ph2-dimer association (solid boxes), as well as

for adamantyl complexation (dashed boxes), despite the adamantane-1-carboxylate-urea

β-cyclodextrin dimer complex ordinarily being in the molecular mass range unsuitable

for detection by NOESY experiments. This indicated that some of the adamantane-1-

carboxylate-urea β-cyclodextrin dimer complex is probably also associated with the

diphenyl moiety (Figure 4.17b) such that the longer tumbling time of the poly(acrylate)

brings this complex into the NOESY timescale. Interestingly, comparatively weak cross-

peaks were evident between the phenyl and adamantyl 1H resonances (Figure 4.17a,

ovals). This appears to indicate a hydrophobic interaction between the two moieties,

probably as part of the site exchange process between the phenyl groups and the β-

cyclodextrin annulus. Evidently, the complexation of adamantane-1-carboxylate involves

some association with one of the diphenyl substituent phenyl groups.


124

a)

b)

HN

ONH

O

n

NH

NH

O

COO

Figure 4.17. a) 2D 1H NOESY NMR spectrum of 1 w% PAA2.7%Ph2, with β-

cyclodextrin urea dimer, sodium adamantane-1-carboxylate 1:1 (600 MHz, D2O, 298 K).

Relevant cross-peaks are indicated. b) Schematic of possible complexation arrangement.


125

Upon addition of a second equivalent of adamantane-1-carboxylate the β-cyclodextrin

dimer displaced from interaction with the substituted poly(acrylate) through dominant

complexation with adamantane-1-carboxylate, as evidenced by the disappearance of

phenyl-β-cyclodextrin cross-speaks in the 2D NOESY spectrum (Figure A.4.2)

Interestingly, this 2D ROESY spectrum is virtually identical to the NOESY spectrum.

This is unusual as the motional correlation time of a solvated molecule such as the 1:2 β-

cyclodextrin dimer-adamantane-1-carboxylate complex would normally be such that the

nuclear Overhauser effect was positive in the rotating-frame but nearly zero in the

laboratory frame, i.e. the NOE interactions would not be observed in the NOESY

spectrum. It appears that the motional correlation time of the 1:2 β-cyclodextrin dimer-

adamantane-1-carboxylate complex may be lengthened through dampening of the

complex’s molecular motion as a consequence of residual but less specific

hydrophobic/hydrophilic interaction with the substituted poly(acrylate) through the

interactions involved in the complexes directly detected.

4.2.5. Polyaromatic Substituted Poly(acrylic Acid)

The absorption and emission spectra of the polyaromatic substituted poly(acrylate)s were

also investigated. Naphthyl substituents absorb in the ultraviolet range with a maximum

at 224 nm, and appreciable emission was observed with a maximum at 334 nm. Solutions

were prepared by calculating the proportional mass of substituted poly(acrylate) to

provide a spectroscopically suitable amount of fluorophore. The effect of naphthyl

complexation was assessed based on work by Hashidzume et al. which involved the ratio

of 80 equivalents of cyclodextrin to fluorophore in the spectroscopic solution.237 The

spectra in Figure 4.18 indicate a negligible effect upon fluorescence in the presence of α-

cyclodextrin (blue line), consistent with the lack of complexation observed in the

corresponding 2D NOESY spectrum. The presence of β-cyclodextrin resulted in a distinct

increase in fluorescence intensity (red line), confirming naphthyl complexation. This

increase is due to the exclusion of water from the immediate fluorophore environment by

the β-cyclodextrin, which reduces the quenching of the napthyl excited state by the water

O–H oscillation. The increase is approximately 20 percent. Hashidzume observed a two-


126

fold increase in fluorescence in 2-methylnaphthyl-appended polyacrylamide copolymers,

and estimated a complexation constant of around 200 M-1. No evidence of hydrophobic

association of naphthyl groups was observed in that study, which is consistent with the

results presented here. Previous research by Tazuke and Banba characterised

naphthalene-substituted poly(ester)s.238 Excimer emission due to π-π stacking between

naphthyl groups was observed, consistent with both intra- and intermolecular association

of the polyester strands. However, these poly(ester)s were 100% substituted. All

measurements were carried out in tetrhydrofuran.

0

50

100

150

200

250 300 350 400 450 500 550

wavelength (nm)

Inte

nsit

y (a

.u.)

Figure 4.18. The fluorescence spectrum of (───) PAA3%Np, 1.0 × 10-6

mol dm-3

naphthyl groups; (───) with α-CD, 8.0 × 10-5

mol dm-3

; (───) with β-CD, 8 × 10-5

mol

dm-3

(water, pH 7, 293 K, λex = 224 nm).


127

4.2.6. Anthracene Substituted Poly(acrylic Acid)

4.2.6.1. Secondary Amine Synthesis

Nucleophilic attack at the brominated carbon of 4.4 by 1,2-diaminoethane in

dimethylformamide presented an alternative pathway towards an anthracene-based

substituent to that attempted in section 4.2.3, with both drawbacks and advantages. For

example, the envisaged hydrophobic substituent was an obvious departure from the

acetamide series, yet this approach removed two steps from the synthesis, including

removing the need to generate the substituted acetic acid, with the corresponding

conservation of overall yield.

O

O

O

O

NH

NH2NH

NH2i. ii.Br

4.4 4.12 4.13

i. NH2CH2CH2NH2, DMF; ii. Zn, NH4OH

Scheme 4.3.

Amination of the anthraquinone derivative 4.4 followed the same sequence as for the

synthesis of amides. The product 4.12 was similarly recovered by alumina

chromatography, but the yield of 18% reflects the persistent difficulty in avoiding

undesired side-reactions. It was anticipated that a secondary amide would be stable under

the subsequent reduction conditions, in contrast to an ether bond (the potential formation

of which, through reaction of 2-(bromomethyl)anthraquinone with ethanolamine, was not

attempted), which would be cleaved. The functionality proved stable after nearly a day of

heating, with the substituted anthracene 4.13 recovered in 72% yield. Both secondary

amines 4.12 and 4.13 were characterised by NMR (1H and 13C), melting point analysis

and accurate mass spectrometry.


128

The UV-vis spectrum (Figure 4.19) of the anthracene derivative in pH 10 sodium borate

buffer displayed a sharp absorbance peak at 254 nm. In a pH 1 solution of hydrochloric

acid the magnitude of this maximum was practically the same at a concentration of 2 ×

10-6 mol dm-3 (blue line) as for a 2.0 × 10-5 mol dm-3 solution in pH 10 sodium borate

buffer (black line). At low pH, protonated 4.13 is unlikely to aggregate due to charge

repulsion. At high pH there is no protonation and as a consequence π-π stacking can

occur, which leads to the large charge transfer band seen to extend up to approximately

320 nm.

0

0.2

0.4

0.6

0.8

1

1.2

200 220 240 260 280 300 320 340

wavelength (nm)

Abs

orba

nce

(a.u

.)

Figure 4.19. The UV-vis absorbance spectrum of 4.13. (───) 5.0 × 10-5

mol dm-3

, pH 10; (───) 5.0 × 10-6

mol dm-3

, pH 1 (water, 293 K). Baselines were

calibrated.

The fluorescence of 4.13 in aqueous solution is shown in Figure 4.20. At high pH

fluorescence was largely quenched through the interaction of the secondary amine lone

pair of electrons with the fluorophore excited state. At low pH (0.1 mol dm-3 hydrochloric

acid) characteristic anthracene fluorescence was observed as the nitrogens were

protonated such that intramolecular quenching did not occur.


129

0

50

100

150

200

250

300

350 400 450 500 550

wavelength (nm)

Inte

nsit

y (a

.u.)

Figure 4.20. Fluorescence spectrum of 4.13. (───) 5.0 × 10-7

mol dm-3

, pH 10; (───)

1.0 × 10-7

mol dm-3

, pH 1 (water, 293 K, λex = 254 nm).

4.2.6.2. Poly(acrylic Acid) Substitution

COO

x

100-x

NH

O

n

HN

Figure 4.21. PAA2.5%An substituted poly(acrylate).

The anthryl derivative 4.13 was substituted onto poly(acrylic acid) by the method

described in section 4.2.4.1, yielding 2.5 percent substituted sodium poly(acrylate)

(Figure 4.21) as a light yellow solid. The 1H NMR spectrum displayed the expected

resonances for the polymer backbone and the anthryl substituent, although the aromatic

peaks were notably broadened and spread over the region 6.5 to 7.5 parts per million. The


130

UV-vis absorption behaviour of this material was assessed in basic and acidic aqueous

media as described in section 4.2.5.1 and is shown in Figure 4.22. The absorbance in

borate buffer at pH 10 (black line) displays a maximum at 254 nm that is negligibly

greater than that for the same anthryl concentration measured at pH 1, indicating that the

pH effect on absorptivity is absent for the anthryl substituent. The bathochromic shift of

the absorption maximum wavelength from 254 to 257 nm at pH 2 (blue line) is the major

variation observed. The differences are very likely due to the presence of the polymer

backbone and the significant influence it has on the immediate environment, i.e.

protonation of the poly(acrylic acid) carboxylates results in a less hydrophilic

environment, causing the shift in absorbance maximum, relative to the high

hydrophilicity of the ionised poly(acrylate).

0

0.1

0.2

0.3

0.4

200 250 300

wavelength (nm)

Abs

orba

nce

(a.u

.)

Figure 4.22. The UV-vis absorbance spectrum of PAA2.5%An 1.0 × 10-6

mol dm-3

:

(───) pH 10; (───) pH 1 (water, 293 K).


131

4.2.6.3. Cyclodextrin-Anthryl Complexation

The interaction of the anthryl substituents with native and poly(acrylate) cyclodextrin

substituents was investigated by 1H NMR and fluorescence spectroscopies. As a degree

of hydrophobic association between the aromatic groups was anticipated this was

concurrently examined by observing differences in the fluorescence spectra.

An equimolar solution of α-cyclodextrin and anthryl substituents on PAA2.5%An

showed some complexation by α-cyclodextrin as indicated by a weak cross-peak in the

2D 1H NOESY spectrum (Figure A.4.3) in contrast to the stronger cross-peaks seen in

the 2D NOESY spectrum of an analogous solution of PAA2.5%An with β-cyclodextrin

(Figure A.4.4) consistent with stronger complexation in the latter case.

In the presence of an equivalent of adamantane-1-carboxylate the anthryl-β-cyclodextrin

cross-peaks disappeared and were replaced by those due to the complexation of

adamantane-1-carboxylate the by β-cyclodextrin (Figure A.4.5) consistent with the latter

complex being the more stable.

4.2.6.4. Effects on Fluorescence

The fluorescence of PAA2.5%An was investigated with the aim of assessing the

fluorescence behaviour of the anthracene substituent alone and in the presence of either

α- or β-cyclodextrin. The fluorescence spectra are shown in Figure 4.23 from which it is

seen that at pH 10 the PAA2.5%An anthryl substituent shows much stronger

fluorescence than that of its anthryl precursor 4.13 (Figure 4.20). This indicates that the

change of the anthryl substituent environment in PAA2.5%An substantially decreases

the quenching of the substituent fluorescence probably through interaction with the

poly(acrylate) backbone. This is unexpected as the anthryl substituent secondary amine


132

a) b)

0

100

200

300

400

500

350 400 450 500

wavelength (nm)

rel.

inte

nsit

y (a

. u.)

0

100

200

300

400

500

350 400 450 500wavelength (nm)

Figure 4.23. The fluorescence spectra of PAA2.5%An 2.0 × 10-7

mol dm-3

(───) a) λex

= 254 nm, λem max = 410 nm, pH 10; (───) with α-cyclodextrin 1.0 × 10-3

mol dm-3

;

(───) with β-cyclodextrin 1.0 × 10-3

mol dm-3

; b) λex = 257 nm, λem max = 412 nm, pH 1;

(───) with α-cyclodextrin 1.0 × 10-3

mol dm-3

; (───) with β-cyclodextrin 1.0 × 10-3

mol dm-3

; (water, 293 K).

should cause significant quenching of fluorescence as observed for the precursor 4.13.

One explanation is that for a significant portion of the substituted poly(acrylate) a second

amide bond is formed with the secondary amide as shown in Figure 4.24 which would

greatly decrease anthryl fluorescence quenching. Such a reaction would normally be

disfavoured, however the intramolecular reactivity of adjacent carboxyl groups noted by

Morawetz and Zimmering222 (as discussed in section 4.1.4) makes the formation of a

tertiary amide, subsequent to the DCC-mediated substitution, more likely in the reaction

conditions (60°C for four days).


133

NH

O

O

N

Figure 4.24. a) Adjacent amide substitution of poly(acrylate) in PAA2.5%An.

In the presence of excess α-cyclodextrin a small change is observed in the PAA2.5%An

anthryl substituent emission and a greater decrease in emission is observed in the

presence of excess β-cyclodextrin (Figure 4.23a) consistent with a greater extent of

complexation in the latter case.

In 0.1 mol dm-3 hydrochloric acid (Figure 4.23b), a fluorescence maximum occurred at

412 nm. Comparing the intensities relative to concentration of this spectrum of

PAA2.5%An to that of the anthryl substituent precursor 4.13 (cf. Figure 4.20) indicates

that the fluorescence of the anthryl substituent is increased by more than two-fold which

may also reflect the presence of a significant proportion of the anthryl substituent in the

diamide form as shown in Figure 4.24.

The differences in intensity of PAA2.5%An at pH 10 and pH 2 (Figure 4.23) most

probably indicates that the highly charged deprotonated PAA2.5%An at pH 10 assumes

a different conformation to that of the uncharged protonated form at pH 2. This likely to

change the hydration of the anthryl substituents and also their interaction with the

poly(acrylate) backbone and in turn the quenching of the anthryl substituent quenching

which is least at pH 10. The available data is insufficient to elucidate these effects in

more detail. However, the work of Chu and Thomas is relevant.239 They showed that a

pyrene-substituted poly(methacrylic acid) copolymer was tightly coiled below pH 3 but

exhibited a more open, flexible and random conformation when deprotonated above pH =

4. A similar principle may be at work in the pH-dependence of the slight fluorescence

changes observed in the described anthryl-substituted system.


134

4.2.7. Binary Poly(acrylate) Interactions

The interaction of the aromatic substituted poly(acrylates), PAA2.7%Ph2, PAA3%Np

and PAA2.5%An with α- and β-cyclodextrin- substituted poly(acrylate) (α-CDPAA and

β-CDPAA) in aqueous solution was studied with 2D 1H NOESY NMR spectroscopy.

The cyclodextrin-substituted poly(acrylate)s were 3% randomly substituted.32 The

presence of cross-peaks in the spectra between the aromatic and cyclodextrin substituent 1H resonances indicated the presence of binary substituted poly(acrylate) interaction,

shown schematically in Figure 4.25.

COO

x

100-x

NH

O

n

OOCHN

y

100-y

NH

O

m

Figure 4.25. Binary complexation between an aromatic substituted poly(acrylate) and a

cyclodextrin substituted poly(acrylate)(ovoid denotes aromatic substituent).

No binary poly(acrylate) interactions were observed for samples containing α-CDPAA.

The 2D ROESY spectrum in Figure 4.26 shows the cross-peaks arising from interactions

between the diphenyl substituents of PAA2.7%Ph2 and the β-cyclodextrin substituents of

β-CDPAA (solid boxes). However, cross-peaks also indicate interaction between the

diphenyl groups and either poly(acrylate) backbone (dashed boxes).


135

Figure 4.26. 2D 1H NOESY NMR spectrum of 1 w% PAA2.7%Ph2 with 1 w% β-CDPAA

(600 MHz, D2O, 298 K). Relevant cross-peaks are boxed.

The interaction of PAA3%Np with β-CDPAA results in small cross-peaks (Figure

A.4.6). No such interactions were observed in the corresponding spectrum of

PAA2.5%An despite the greater extent of hydrophobicity of the larger anthryl

substituent. This may be due to the diamide binding of the anthryl substituent to the

poly(acrylate) and consequently greater steric hindrance to the complexation by the β-

cyclodextrin substituent of β-CDPAA (cf. Figure 4.24).


136

4.3. Summary and Conclusion

Previous studies32 involving alkyl chain modification of poly(acrylates) and the effects of

complex formation with cyclodextrin substituents on poly(acrylate)s in binary systems

were extended to study the suitability of aromatic substitution in the same role. The

phenyl, diphenyl, naphthyl and anthryl substituents were synthesised and substituted

randomly on to poly(acrylates), and the interactions of each such poly(acrylate) with

various cyclodextrin species as well as α- and β-cyclodextrin-substituted poly(acrylate)s

were assessed principally with 2D 1H NMR spectroscopy. Fluorophore substituents were

investigated with UV-visible absorbance and fluorescence spectroscopies.

No tendency of the aromatic substituents to aggregate in aqueous solution similar to that

for long polymer-bound alkyl groups was observed.226 This is probably due to the

relatively short length and rigidity of the aromatic substituents, and also the shortness of

the tethers between them and the poly(acrylate) backbone. In the case of the anthryl-

substituted poly(acrylate) it is possible that its substitution to the poly(acrylate) through

two amide links may have further restricted its ability to aggregate and also to complex

with native cyclodextrins and their substituted poly(acrylate)s.

As a consequence of the generally poor interaction with cyclodextrin-substituted

poly(acrylate)s, it was decided to not proceed with rheology studies on the substituted

poly(acrylate)s systems studied in this project. The interactions may be enhanced in

future studies by use of a substantially longer alkyl linker, e.g. octyl instead of ethyl, or

by incorporation of more than one fluorophore at the site of substitution, attached end-to-

end as exemplified in Figure 4.27. This would provide substituent length comparable to

the alkyl chain-substituents successfully studied in previous work.32,227


137

COO

x

100-x

NH

O

n

m

Figure 4.27. Anthryl-substituted PAA system featuring two (m = 1) or more fluorophore

units.

Experimental

138

CHAPTER 5: Experimental

5.1. General Methods

Melting point ranges were determined using a Reichert hot stage apparatus, and are

uncorrected. FT-IR spectra were run variously on an ATI Mattson instrument, with the

WinFIRST (ver 2.10) interface, and a Perkin Elmer Spectrum BX instrument, running

Spectrum (ver 2.00) software. Electrospray fragmentation mass spectrometry was

performed with a Finnigans LCQ Classic instrument. Electron impact mass spectrometry

was performed with a VG ZAB 2HF machine operating at a 70 eV ionisation energy. MS

data is given as relevant peaks (percent abundance).

1D NMR spectra were obtained on Varian Gemini-2000 spectrometers operating at 200

(1H) and 60 (13C) MHz, or 300 (1H) and 75 (13C) MHz; temperature was maintained at

298 K and resonances referenced to trimethylsilane (0.0 ppm). 2D spectra were obtained

on an INOVA 600 spectrometer operating at 600 MHz. Deuterated solvents were

purchased from Lancaster, and are referred to by their label designations. Unless

otherwise stated, 13C NMR results were obtained under the same sample conditions as for

the corresponding 1H NMR data, and referenced to solvent chemical shifts (CDCl3 =

77.00, DMSO-d6 = 39.51 ppm).

Ultraviolet-visible data was obtained on Varian Cary 5000 UV-Vis-NIR and Cary 300

Bio Spectrometers, controlled with Carey WinUV software (ver 2.00). Matched pair

quartz cuvettes of 1 cm path length were used. Non-aqueous solvents were of

spectroscopic grade. Water was purified with a Waters Milli-Q millipore system.

Chromatography was performed with reference to Harwood and Moody.240 Basic

Alumina was deactivated to Brockman grade III. Thin layer chromatography was

performed with Merck silica gel 60 F254.

Experimental

139

For accurate mass spectrometry samples were dried at the pump and submitted to EIMS

performed by the Organic Mass Spectrometry Facility at the University of Tasmania,

Hobart. Microanalyses were performed at the University of Otago Chemistry

Department, Dunedin.

Complexation stability constants were calculated in Matlab (ver 4.2b) using the Specfit

program (Kurucsev, T., ver 950217)

Substituted PAA dialysis was performed with Spectra/Por 3 molecularporous membrane

tubing with a molecular weight cutoff of 3500 g mol-1, purchased from Spectrum Labs.

Starting materials not purchased directly from the suppliers indicated were purified

according to literature procedures before use.241 Fluorescence measurements were

conducted on a Varian Cary Eclipse fluorescence spectrophotometer with the Carey

interface (ver 02.00(25)).

5.2. Synthesis in Chapter 2

2,2-Diallylindane-1,3-dione 2.1 [CAS Reg No. 247040-83-1]

Tetrakistriphenylphosphine palladium(0) (501.2 mg, 0.43 mmol), triphenylphosphine

(240.6 mg, 3.86 mmol, Merck) and boric oxide (3.74 g, 53.74 mmol) were suspended in

tetrahydrofuran (100 cm3). Indandione (4.98 g, 34.10 mmol, Aldrich) and allyl alcohol

(4.1g, 70.59 mmol) were added and the mixture stirred under N2 atmosphere at 70°C for

2 hrs. The mixture was then washed through a plug of silica with dichloromethane,

concentrated and the residue submitted to flash chromatography (hexane-ethyl acetate

4:1). The yellow crude product was recrystallised from hexane to afford straw needles

(6.512 g, 84%): m.p. 41-43°C; 1H NMR (CDCl3) δ: 7.98–7.81 m (4H, ArH), 5.58–5.37

ddt (2H, J = 17.0, 10.0, 7.4 Hz, –CHA=CH2), 5.04 d (2H, J = 17.0 Hz, CH=CHMHX),

4.89 d (2H, J = 10.0 Hz, CH=CHMHX), 2.55 d (4H, J = 7.4 Hz, –CH2–CH=); 13C NMR δ:

203.5, 142.5, 135.9, 131.7, 123.2, 119.7, 58.5, 39.0.

Experimental

140

9,9-Diallylfluorene 2.2 [CAS Reg No. 14966-05-3]

To fluorene (2.3 g, 13.82 mmol, Aldrich) stirring in tetrahydrofuran (30 cm3) under N2

atmosphere at –78°C was added n-buytl lithium 2.2 mol/dm-3 in hexane (6.3 cm3,

Aldrich) dropwise over 15 min. As the solution was allowed to warm to 20°C, allyl

bromide (1.2 cm3, c.a. 14.0 mmol, BDH) was added dropwise. Following 1 hr stirring the

reaction was cooled to –78°C, further n-butyl lithium solution (6.3 cm3) was added over

15 min. Another amount of allyl bromide (1.4 cm3, c.a. 16.0 mmol) was added and the

reaction was allowed to warm again to 20°C and stirred for 15 hrs, then quenched with

water. The emulsion was washed with sat. ammonium chloride solution (2 × 25 cm3), the

aqueous portions extracted with hexane (3 × 25 cm3), then the combined organic fractions

were dried and concentrated to a green-yellow oil. Fractional distillation yielded

colourless oil (2.86 g, 84%): b.p. 138°C at 1.5 × 10-2 Torr; 1H NMR (CDCl3) δ: 7.72–

7.28 m (8H, ArH), 5.32–4.88 ddt (2H, J = 7.0, 11.0, 17.2 Hz, –CHA=CH2), 4.82 d (2H, J

= 17.0 Hz, CH=CHMHX), 4.75 d (2H, J = 11.0 Hz, CH=CHMHX), 2.70 d (4H, J = 7.0 Hz,

–CH2–CH=).

General method for ring-closing metathesis

To the diallyl reagent solution in dry toluene (c.a. 40 cm3 per mmol) was added Grubbs’

catalyst (c.a. 0.1 mol equivalent, Aldrich) and the reaction stirred at 110°C under N2

atmosphere for c.a. 5 days. Solvent was removed under reduced pressure and the residue

submitted to flash chromatography.

Spiro[cyclopent-1-ene-4,2’-indan-1’,3’-dione] 2.3 [CAS Reg No. 81055-89-2]

The crude product was recrystallised from hexane to afford spiro[cyclopent-1-ene-4,2’-

indan-1’,3’-dione] (527.0 mg, 61%) as white needles: Rf 0.24 (hexane-ethyl acetate 4:1);

m.p. 156-158°C (lit.242 m.p. 162-163°C); IR (nujol): 1738, 1698, 1591, 1266 cm-1; 1H

NMR (CDCl3) δ: 8.04–7.84 m (4H, ArH), 5.75 s, AA’ of AA’X2X’2 (2H, HC=CH), 2.78

Experimental

141

s, X2X’2 of AA’X2X’2 (4H, CH2–CH=); MS m/z (%): 198 (M+, 100), 169 (22), 141 (38),

104 (61), 76 (46).

Spiro[cyclopent-1-ene-4,9’-fluorene] 2.4 [CAS Reg No. 247040-84-2]

Product recovered as a spectroscopically pure yellow powder (4.35 g, 99%): Rf 0.85

(hexane-ethyl acetate 7:3); m.p. 72-75°C (lit.242 87-88°C); IR (nujol): 1H NMR (CDCl3)

δ: 7.72–7.26 m (8H, ArH), 5.99 s, AA’ of AA’X2X’2 (2H, HC=CH), 2.89 s, X2X’2 of

AA’X2X’2 (4H, 2 x CH2–CH=); 13C NMR δ: 154.6, 139.7, 130.5, 127.9, 127.2, 122.7,

119.8, 55.7, 46.5.

Spiro[cyclopent-1-ene-4,2’-indane] 2.5

A suspension of spiro[cyclopent-1-ene-4,2’-indan-1’,3’-dione] (1.4 g, 7.06 mmol) and

sodium borohydride (1.1 g, 28.62 mmol, Fluka) in methanol (50 cm3) was stirred

vigorously for 0.5 hr. Volatiles were removed under reduced pressure and the residue was

taken up in dichloromethane (10 cm3) to which was added triethyl silane (4.5 cm3, c.a.

28.3 mmol, Aldrich) and ammonium fluoride (1.1 g, 30.56 mmol). The mixture was

stirred at 0°C with trifluoroacetic acid (40 cm3) added dropwise over 10 min. Following 4

hr of stirring at 0°C the reaction was quenched with ice water (100 cm3), extracted with

dichloromethane (3 × 50 cm3); the organic fractions were combined and washed with

10% aq. sodium bicarbonate solution (150 cm3) and dried. The residue obtained by

removal of volatiles was eluted twice through flash silica (diethyl ether, then hexane) to

yield spiro indane product 14 (1.0 g, 81%) as a clear yellow oil: IR (neat): 3051, 2929,

2837, 1473, 1458, 1433, 1072, 741 cm-1; 1H NMR (CDCl3) δ: 7.21-7.12 m (4H, ArH),

5.72 AA’ of AA’X2X’2 (2H, HC=CH), 2.93 s (4H, Ar–CH2), 2.41 X2X’2 of AA’X2X’2

(4H, 2 x CH2–CH=); 13C NMR δ: 130.2, 126.3, 124.8, 50.8, 47.3, 46.3; MS m/z (%): 170

(M+, 74), 116 (100), 104 (75); Exact mass calcd for C13H14 m/z: 170.1096. Found m/z:

170.1095.

Experimental

142

Spiro[1-(4-methylphenyl sulfonyl)cyclopent-1-ene-4,2’-indane] 2.6

To spiro[cyclopent-1-ene-4,2’-indane] (c.a. 0.9 g, 5.4 mmol) in dichloromethane (50 cm3)

was added a solution of sodium p-toluenesulfinic acid (2.5 g, 14.1 mmol, Aldrich) in

water (50 cm3) with vigorous stirring for 5 min. Crushed iodine (1.8 g, 7.1 mmol, AJAX)

was added to the emulsion in portions over 2 min. Following stirring for 17 hr further

dichloromethane (50 cm3) was added and the mixture was washed with sat. aq. sodium

bicarbonate solution (80 cm3) containing 5% aq. sodium thiosulphate solution (20 cm3),

then sat. aq. sodium chloride solution (100 cm3). The organic phase was dried, all

volatiles removed under reduced pressure and the residue taken up in dichloromethane

(20 cm3) and stirred at 0°C with addition of 1,8-diazabicyclo(5.4.0)undec-7-ene (c.a. 1.0

g, 7.0 mmol, Aldrich) for 2.5 hrs. Volatiles were removed and the residue was eluted

through a squat column of flash silica by vacuum (hexane-ethyl acetate 7:3) to furnish the

vinyl sulfone as white crystals (1.6 g, 91%): Rf 0.35; m.p. 134-136°C; IR (nujol): 1613,

1298, 1145 cm-1; 1H NMR (CDCl3, 600 MHz) δ: 7.76–7.33 AA’BB’ (4H, TolH), 7.13 m

(4H, ArH), 6.71 quintet (1H, J = 2.4 Hz, –CH=), 2.88 AB q (4H, J = 15.0 Hz, Ar–CH2),

2.61 q (2H, J = 2.4 Hz, CH2–CH=), 2.55 q (2H. J = 2.4 Hz, CH2–CSO2), 2.45 s (3H, Ar–

CH3); 13C NMR δ: 144.3, 142.2, 141.2, 129.8, 128.0, 126.5, 124.7, 52.2, 46.4, 45.7, 43.7,

21.6; MS m/z (%): 324 (M+, 19), 167 (11), 139 (9), 116 (100), 104 (21); Anal calcd for

C20H20O2S C, 74.04; H, 6.21. Found C, 73.77; H, 6.18%.

Spiro[1-(4-methylphenyl sulfonyl)cyclopent-1-ene-4,9’-fluorene] 2.7

An emulsion of spiro[cyclopent-1-ene-4,9’-fluorene] (904.9 mg, 4.15 mmol) in

dichloromethane (30 cm3) and p-toluenesulfinic acid (1.93 g, 10.8 mmol, Aldrich) in

water (30 cm3) was vigorously mixed for 5 mins before iodine (1.39 g, 5.46 mmol,

AJAX) was added piecewise. The reaction was stirred for 24 hrs under N2 atmosphere at

20°C, then dichloromethane (50 cm3) was added and the organic layer washed with 10%

aq. sodium bicarbonate solution (30 cm3) and 5% aq. sodium thiosulfate solution (5 cm3),

then brine (20 cm3). The organic part was concentrated, with the residue being taken up

in dichloromethane (20 cm3) and stirred at 0°C with careful addition of 1,8-

Experimental

143

diazabicyclo(5.4.0)undec-7-ene (839.8 mg, 5.52 mmol, Aldrich). After 3 hrs reaction

under N2 atmosphere the mixture was concentrated under vacuum and eluted through

flash silica (hexane-ethyl acetate 49:1). The crude material was recrystallised from

ethanol to afford white needles (569.9 mg, 39%): Rf 0.80; m.p. 223-227°C; IR (nujol):

1714, 1625, 1591, 1312, 1155 cm-1; 1H NMR (CDCl3) δ: 7.86–7.64 AA’BB’ (4H, TolH),

7.38–7.20 m (8H, ArH), 6.99, t (1H, J = 1.8 Hz), 3.03 m (4H, C(–CH2)2), 2.45 s (3H, Ar–

CH3); 13C NMR: 151.5, 144.6, 144.4, 141.1, 139.2, 136.2, 129.9, 128.1, 127.9, 127.7,

122.2, 119.8, 56.2, 45.9, 43.4, 21.7; MS m/z (%): 372 (M+, 48), 217 (59), 216 (98), 215

(100), 178 (21); Exact mass calcd for C24H20O2S m/z: 372.1184. Found m/z: 372.1180.

Spiro{indane-2,5’-1’-ethoxycarbonyl-2’,4’,5’,6’-tetrahydrocyclopent[c]pyrrole} 2.8

A solution of spiro[1-(4-methylphenyl sulfonyl)cyclopent-1-ene-4,2’-indane]

(247.7 mg, 0.76 mmol) and ethyl isocyanoacetate (231.7 mg, 2.05 mmol) in

tetrahydrofuran (20 cm3) was added dropwise over 30 mins to a stirring solution of

hexane-rinsed sodium hydride (c.a. 55.6 mg, 2.3 mmol, Fluka) in tetrahydrofuran (15

cm3) at 0°C. The mixture was allowed to equilibrate to ambient temperature and was

stirred for 4 hr. Volatiles were removed under reduced pressure and the residue was taken

up in water (25 cm3) and extracted with dichloromethane (6 × 30 cm3). The combined

organic extracts were concentrated and the residue was submitted to flash

chromatography (dichloromethane-ethyl acetate 19:1) to furnish the title pyrrole (150.0

mg, 70%) as white powder: Rf 0.62; m.p. 136-138°C; IR (nujol): 3271, 1676, 1558, 1540,

1306, 1282, 1189, 1137 cm-1; 1H NMR (CDCl3, 600 MHz) δ: 8.71 brs (1H, N–H), 7.17 m

(4H, ArH), 6.60 d (1H, J = 3.0 Hz, =CH–NH), 4.27 q (2H, J = 7.2 Hz, CH2–CH3), 3.04

A of AB q (2H, J = 15.0 Hz, Ar–(CHA)2), 3.01 B of AB q (2H, J = 15.0 Hz, Ar–(CHB)2),

2.91 s (2H, CH2–C=C–), 2.71 d (2H, J = 0.6 Hz, CH2–C=CH), 1.31 t (3H, J = 7.2 Hz,

CH2–CH3); 13C NMR: 143.5, 136.8, 130.8, 126.5, 126.4, 124.9, 115.7, 115.4, 60.2, 59.1,

46.7, 39.9, 38.9, 14.8; Exact mass calcd for C18H19NO2 m/z: 281.1416. Found m/z:

281.1415.

Experimental

144

Spiro{fluorene-9,5’-1’-ethoxycarbonyl-2’,4’,5’,6’-tetrahydrocyclopent[c]pyrrole} 2.9

A solution of spiro[1-(4-methylphenyl sulfonyl)cyclopent-1-ene-4,9’-fluorene]

(339.4 mg, 0.91 mmol) and ethyl isocyanoacetate (205.0 mg, 1.81 mmol) in

tetrahydrofuran (30 cm3) was added with a dropping funnel to a suspension of hexane-

rinsed sodium hydride (57.9 mg, 2.41 mmol, Merck) in tetrahydrofuran (20 cm3) stirring

under N2 atmosphere at 0°C. After 40 mins the addition was complete and the

temperature brought to 20°C and the reaction was stirred for a further 3 hrs. The residue

obtained by concentration of the mixture under vacuum was dissolved in

dichloromethane (50 cm3), washed with water (50 cm3) then chromatographed through

flash silica (hexane-dichloromethane 1:9) to yield pyrrole ester as white powder (180.3

mg, 71%): Rf 0.52; m.p. 284-290°C; IR (nujol): 3295, 1685, 1155 cm-1; 1H NMR (CDCl3)

δ: 8.89 brs (1H, NH), 7.74 – 7.24 m (8H, ArH), 6.74 d (1H, J = 2.7 Hz, =CH–NH), 4.25

q (2H, J = 6.3 Hz, CH2–CH3), 3.32 s (2H, CH2–C=C–), 3.13 s (2H, CH2–C=CH), 1.26 t

(3H, J = 6.3 Hz, CH2–CH3); 13C NMR δ: 152.5, 139.4, 136.5, 130.7, 127.6, 127.3, 122.6,

119.7, 115.7, 115.3, 63.3, 60.1, 39.1, 38.1, 14.4; Exact mass calcd for C22H19NO2 m/z:

329.1416. Found m/z: 329.1417.

Tetraspiro[,22,23,72,73,122,123,172,173-octahydro-21H,71

H,121H,171

H-tetracyclo-

penta[b,g,l,q]porphyrinato-22,2’:72,2’’:122,2’’’:172,2’’’’-tetrakis([2]indane)]zinc 2.10

A solution of spiro{indane-2,5’-1’-ethoxycarbonyl-2’,4’,5’,6’-tetrahydrocyclopent-

[c]pyrrole} (234.0 mg, 0.83 mmol) in tetrahydrofuran (10 cm3) was introduced dropwise

into a suspension of lithium aluminium hydride (151.8 mg, 4.0 mmol, Aldrich) in

tetrahydrofuran (10 cm3) stirring at 0°C under N2 atmosphere. The reaction was allowed

to warm to 20°C and stirring continued for 4 hrs. Ethyl acetate (10 cm3) was added and

the crude intermediate washed with water (20 cm3). The organic part was dried and

concentrated under reduced pressure then taken up in acetic acid (20 cm3) and stirred

vigorously at 90°C for 15 hrs under N2 atmosphere. The reaction was unsealed, p-

chloranil (826.7 mg, 3.36 mmol, BDH) added and further stirred for 2.5 hrs. The solvent

was removed under reduced pressure and the crude material eluted through alumina

Experimental

145

(dichloromethane). The product was recovered as a maroon gum, which was taken up in a

mixture of dichloromethane (15 cm3) and methanol (15 cm3) with zinc acetate (182.8 mg,

0.83 mmol, BDH) and stirred at 70°C for 1 hr. The mixture was filtered through a plug of

flash silica (dichloromethane) and the metalloporphyrin (17.7 mg, 6%) was isolated as a

pink solid. Free base porphyrin: Rf = 0.72; m.p. 185-190°C dec.; 1H NMR (CDCl3) δ:

9.90 s (4H, meso H), 7.33 m (16H, ArH), 4.19 s (16H, 21,23,71,73,121,123,171,173 H),

3.53 s (16H, Ar–CH2), –4.30 brs (2H, N–H); UV-Vis λmax (CHCl3) (log ε): 397 (5.4), 495

(4.2), 526 (4.1), 564 (4.0), 617 (3.4), 633 (3.4) nm; Exact mass calcd for C64H54N4 m/z:

878.4348. Found m/z: 878.4366. Metalloporphyrin: Rf = 0.88; m.p. > 270°C (dec.); 1H

NMR (CDCl3) δ: 10.43 s (4H, meso H), 7.39–7.29 m (16H, ArH), 4.16 s (16H,

21,23,71,73,121,123,171,173 H), 3.55 s (16H, Ar–CH2); 13C NMR (600 MHz) δ: 169.6,

142.8, 140.8, 137.8, 126.8, 125.0, 60.1, 47.4, 41.3; UV-Vis λmax (THF) (log ε): 283 (4.6),

404 (5.4), 533 (4.4), 566 (4.2) nm; Exact mass calcd for C64H52N4Zn m/z: 940.3483.

Found m/z: 940.3472.

Tetraspiro[,22,23,72,73,122,123,172,173-octahydro-21H,71

H,121H,171

H-tetracyclo-

penta[b,g,l,q]porphyrinato-22,9’:72,9’’:122,9’’’:172,9’’’’-tetrakis([9]fluorene)]zinc

2.11

A solution of pyrrole (241.3 mg, 0.73 mmol) in tetrahydrofuran (25 cm3) was added

gradually over 10 mins to lithium aluminium hydride (81.4 mg, 2.15 mmol, Aldrich)

stirring in tetrahydrofuran (5 cm3) at 0°C under N2 atmosphere. After 5 hrs stirring at

20°C ethyl acetate (5 cm3) was added and the mixture washed with sat. aq. ammonium

chloride solution (25 cm3). The aqueous part was extracted thoroughly with ethyl acetate

(4 × 15 cm3). The combined organic layers were dried and the solvent removed, and the

residue was taken up in acetic acid (15 cm3) and stirred for 16 hrs at 90°C under N2

atmosphere. The reaction was unsealed and p-chloranil (710.7 mg, 2.89 mmol, BDH) was

introduced with stirring for a further 5 hrs. The residue obtained from concentration

under reduced pressure was chromatographed through alumina (dichloromethane), taken

up in solution in dichloromethane (20 cm3) and methanol (20 cm3). Zinc acetate (159.2,

0.73 mmol, BDH) was added and following stirring at 70°C under N2 atmosphere for 1 hr

Experimental

146

the mixture was concentrated under reduced pressure and eluted through silica

(dichloromethane-ethyl acetate 19:1) to afford a bright pink solid (14.1 mg, 2%),

recrystallised from chloroform: Rf 0.90; m.p. 220°C (dec.); 1H NMR (CDCl3) δ: 10.13 s

(4H, meso H), 7.88–7.21 m (32H, ArH), 4.67 s (16H, 21,23,71,73,121,123,171,173 H); UV-

Vis λmax (CHCl3) (log ε): 293 (5.3), 403 (5.2), 426 (4.5), 530 (3.9), 564 (3.9) nm; Exact

mass calcd for C80H52N4Zn m/z: 1132.3483. Found: 1133.3508.


4-(1-Ethynyl)aniline 3.1 [CAS Reg No. 14235-81-5]

A solution of 4-iodoaniline (2.43 g, 11.32 mmol, Fluka), dichlorobistriphenyl-phosphine

palladium cat. (73.2 mg, 0.18 mmol, Lancaster), copper iodide (37.1 mg, 0.20 mmol,

Aldrich) and trimethylsilyl acetylene (2 cm3, c.a. 14.15 mmol, Lancaster) in triethylamine

(20 cm3) and tetrahydrofuran (10 cm3) was stirred under a H2-N2 (c.a. 1:3) atmosphere at

20°C for 4 hours. The mixture was diluted with dichloromethane (40 cm3) and filtered

through a plug of flash silica, concentrated under vacuum and submitted to flash silica

chromatography (dichloromethane). The solvent was removed and recrystallisation of the

residue from hexane gave an off-white fibrous solid, which was taken up in a suspension

of potassium carbonate (7.0 g, 50.64 mmol) in methanol (20 cm3) and stirred for 12 hours

under N2 atmosphere at 20°C. The mixture was evaporated to dryness and taken up in

dichloromethane, and the solution was eluted through a plug of flash silica. Removal of

solvent under high vacuum afforded the spectroscopically pure title compound (0.97 g,

73%): m.p. 101-104°C (lit.243 102-104°C).

2-Amino-5-iodopyrimidine 3.2 [CAS Reg No. 1445-39-2]

A solution of 2-aminopyrimidine (178.8 mg, 1.88 mmol, Sigma) and iodine (1.0 g, 3.94

mmol, AJAX) in dimethylsulfoxide (5 cm3) was stirred under N2 at 100°C for 2 hr. The

cooled mixture was taken up into ethyl acetate (30 cm3), washed with brine (2 × 30 cm3)

then 5% aq. sodium thiosulfate solution (50 cm3). The combined aqueous layers were

Experimental

147

once more extracted with ethyl acetate (2 × 20 cm3). The organic extracts were combined,

dried, evaporated to dryness and the crude product recrystallised from ethyl acetate to

afford the title compound (315.2 mg, 76%) as yellow powder: m.p. 217-219°C (lit.178

m.p. 224-225°C).

2-Amino-5-iodopyridine 3.4 [CAS Reg No. 20511-12-0]

To a stirred solution of 2-aminopyridine (188.6 mg, 2.0 mmol, BDH) in

dimethylsulfoxide (10 cm3) was added iodine (521.6 mg, 2.06 mmol, AJAX) and

following 12 hrs the reaction mixture was heated to 100°C for 4 hrs under N2

atmosphere. The mixture was diluted with ethyl acetate (20 cm3) and washed with brine

(2 × 50 cm3) then 5% aq. sodium thiosulfate solution (40 cm3). The aqueous layers were

combined and extracted with ethyl acetate (40 cm3) before the combined organic

fractions were concentrated under reduced pressure. The crude material was

recrystallised from water to give straw flakes (96.1 mg, 22%): m.p. 128-130°C (lit.244

m.p. 132°C).

5-(2-(4-aminophenyl)ethynyl)pyrimidin-2-amine 3.3

4(1-Ethynyl)aniline (175.7 mg, 1.50 mmol), 2-amino-5-iodopyridinamine (331.5 mg,

1.50 mmol), dichlorobistriphenylphosphine palladium cat. (21.0 mg, 0.03 mmol,

Lancaster) and copper(I) iodide (2.8 mg, 0.01 mmol, Aldrich) were dissolved in

acetonitrile (6 cm3) under N2 atmosphere, triethylamine (1 cm3) was added and the

mixture stirred at 70°C under N2 atmosphere for 4 hrs. The residue was evaporated to

dryness and submitted to flash chromatography (ethyl acetate) to afford the title

compound (191.4 mg, 61%) as a deep red powder: m.p. 213-216°C; Rf 0.78; IR (nujol):

3445, 3292, 3169, 1662, 1609, 834 cm-1; 1H NMR (DMSO-d6) δ: 8.33 s (2H, pyrim.),

7.00 s (2H, pyrim. NH2), 6.84 (4H, AA’BB’); 13C NMR δ: 161.5, 159.6, 148.8, 132.2,

113.9, 108.7, 107.0, 93.1, 81.5; MS m/z (%): 210 (M+, 100), 192 (3); Exact mass calcd

for C12H10N4 m/z: 210.0905. Found: 210.0905.

Experimental

148

5-(2-(4-aminophenyl)ethynyl)pyridin-2-amine 3.5

To a mixture of 2-amino-5-iodopyridine (592.0 mg, 2.70 mmol) and 4-(1-ethynyl)aniline

(317.7 mg, 2.71 mmol) in triethylamine (15 cm3) and tetrahydrofuran (10 cm3) was added

dichlorobistriphenylphosphine palladium cat. (17.2 mg, 0.03 mmol, Aldrich) and copper

iodide (10.0 mg, 0.05 mmol, Aldrich), with stirring at 60°C for 6 hrs under N2

atmosphere. Solvent was removed and residue taken up in ethyl acetate (100 cm3),

washed with 10% aq. sodium bicarbonate solution (70 cm3). The organic fractions were

concentrated and the crude material eluted through flash silica (ethyl acetate) to furnish

orange powder (277.0 mg, 49%); m.p. 219-221°C; Rf 0.70; IR (nujol): 3448, 3376, 3288,

1614, 1513, 829 cm-1; 1H NMR (D2O) δ: 7.88 dd (1H, J4 = 2.1 Hz, J6 = 0.9 Hz, CH–N=),

7.81 dd (1H, J3 = 9.3 Hz, J4 = 2.1 Hz, –CH=CH–C–NH2), 7.41 (4H, AA’BB’), 6.87 dd

(1H, J3 = 9.3 Hz, J6 = 0.9 Hz); 13C NMR: 152.9, 145.8, 137.9, 133.1, 130.2, 123.5, 122.9,

114.1, 108.6, 90.0, 84.5; Exact mass calcd for C13H11N3 m/z: 209.0953. Found 209.0953.

Attempted assembly of [N2-(2,4-dinitrophenyl)-5-{2-[4-(2,4-dinitroanilino) phenyl]-

1-ethynyl}-2-pyrimidinamine]-[α-cyclodextrin]-[Rotaxane]

An aqueous (40 cm3) solution of α-cyclodextrin (1.87 g, 1.93 mmol, Nihon Shokuhin)

was stirred at 20°C and 5-(2-(4-aminophenyl)ethynyl)pyrimidin-2-amine (64.7 mg, 0.31

mmol) dissolved in dimethylsulfoxide (5 cm3) was added. 10% Aq. sodium bicarbonate

solution was added to raise the pH to pH 10, and the mixture was stirred for 2.5 hrs

before being warmed to 40°C, then 2,4-dinitrofluorobenzene (176.4 mg, 0.95 mmol,

Aldrich) was introduced. After 15 hrs further stirring the reaction was diluted with water

(200 cm3), extracted thoroughly with ethyl acetate (4 × 100 cm3) and the aqueous portion

concentrated under reduced pressure. No desired product was recovered. The organic part

was concentrated to yield red powder, 3.6 (45.5 mg, 39%): Rf 0.85 (methanol); m.p. 234-

236°C (dec); 1H NMR (DMSO-d6) δ: 10.15 s (1H, NH), 8.89 d (2H, J = 2.7 Hz, CH(–C–

NO2)2), 8.44 s (pyrim.), 8.25 dd (1H, J = 2.7, 9.6 Hz, CH–CH=C–NH), 7.61 BB’ (2H,

ArH), 7.43 AA’ (2H, ArH), 7.25 d (1H, J = 9.6 Hz, CH–CH=C–NH), 7.18 s (2H, NH2); 13C NMR δ: 162.0, 160.3, 145.8, 138.0, 136.9, 132.4, 132.1, 129.8, 125.2, 123.4, 120.3,

Experimental

149

117.5, 105.7, 91.2, 85.6; Exact mass calcd for C18H12N6O4 m/z: 376.0920. Found:

376.0923.

General method for reaction of 2,4-dinitro-1-fluorobenzene with arylamines

Aniline (60.0 mg, 0.63 mmol, AJAX), an equimolar amount of aminoazine compound (2-

aminopyrimidine: Sigma; 2-aminopyridine: BDH) and 2,4-dinitro-1-fluorobenzene

(246.5 mg, 1.32 mmol, Aldrich) were stirred in water-acetone (3:2 v/v, 40 cm3) with the

pH adjusted to pH 10 by addition of 10% aq. sodium bicarbonate solution for 5 hrs at

293 K. The acetone was removed under reduced pressure and the suspension filtered and

washed thoroughly with water. The spectroscopically pure bright orange product was

confirmed to be 2,4-dinitro-N-phenylbenzenamine [CAS Reg No. 961-68-2] by 1H, 13C

NMR and LCQ MS, recovered in yields no lower than 96%: Rf 0.65 (methanol); m.p.

149-152°C (lit.245 156-157°C). No other products were detected.

(E)-4,4’-Bis(2,4-dinitrophenylamino)stilbene 3.7

2,4-Dinitro-1-fluorobenzene (94.3 mg, 0.51 mmol, Aldrich) in solution in water-acetone

(3:2 v/v, 10 cm3) was introduced into a stirred solution of 4,4’-diaminostilbene

dihydrochloride (56.0 mg, 0.20 mmol, Aldrich) in water-acetone (3:2 v/v, 40 cm3) with

pH adjusted to pH 10 by addition of 10% aq. sodium bicarbonate solution. Following 30

hrs stirring at 20°C under N2 atmosphere acetone was removed under reduced pressure

and the suspension filtered and washed thoroughly with water. The brown crude product

was chromatographed twice (hexane-dichloromethane 1:1, then methanol) to afford the

deep red powder product (44.5 mg, 41%): Rf 0.30 (hexane/dichloromethane 1:2); m.p.

185°C (dec.); 1H NMR (DMSO-d6) δ: 10.18 s (2H, –NH–), 8.93 d (2H, J = 2.7 Hz, CH(–

C–NO2)2), 8.25 dd (2H, J = 2.7, 9.6 Hz, CH–CH=C–NH), 7.75 AA’ (4H, =CH–C(–

CH)2), 7.42 BB’ (4H, –NH–C(–CH)2), 7.36 s (2H, HC=CH), 7.23 d (2H, J = 9.6 Hz,

CH–CH=C–NH); 13C NMR δ: 146.2, 137.1, 136.4, 135.4, 131.5, 129.8, 129.6, 127.9,

125.8, 125.3, 117.1; MS m/z (%): 541 ([M-H]-, 100), 532 (6), 507 (13); Anal calcd for

C26H18N6O8 C, 57.57; H, 3.34; N, 15.49. Found C, 57.50; H, 3.61 N 14.88%.

Experimental

150

(Z)-4,4’-Bis(2,4-dinitrophenylamino)stilbene 3.7

An aqueous (5 cm3) solution of 4,4’-diaminostilbene dihydrochloride (51.0 mg, 0.18

mmol, Aldrich) was placed in sunlight for 10 hrs. It was added to stirring water-acetone

(3:2 v/v, 40 cm3) to which 10% aq. sodium bicarbonate solution was added until the pH

was raised to pH 10. 2,4-Dinitro-1-fluorobenzene (76.0 mg, 0.41 mmol, Aldrich) in

water-acetone (3:2 v/v, 3 cm3) was then added. The reaction was stoppered and stirred for

24 hrs. The solvent was removed under reduced pressure and the residue was

chromatographed through flash silica (hexane/dichloromethane 1:2) to afford a deep

brown powder (43.1 mg, 44%): Rf 0.30; 1H NMR (DMSO-d6) δ: 10.16 s (2H, –NH–),

8.90 d (2H, J = 2.7 Hz, CH(–C–NO2)2), 8.25 dd (2H, J = 2.7, 9.6 Hz, CH–CH=C–NH),

7.42 AA’ (4H, =CH–C(–CH)2), 7.34 BB’ (4H, –NH–C(–CH)2), 7.20 d (2H, J = 9.6 Hz,

CH–CH=C–NH), 6.75 s (2H, HC=CH); 13C NMR δ: 146.2, 136.9, 136.4, 135.1, 129.9,

129.8, 129.6, 127.7, 125.6, 125.3, 117.1.

Attempted synthesis of [(E)-4,4’-Bis(2,4-dinitrophenylamino)stilbene]-[α-cyclo-

dextrin]-[rotaxane]

4,4’-Diaminostilbene dihydrochloride (124.1 mg, 0.44, Aldrich) and α-cyclodextrin (2.47

g, 2.54 mmol, Nihon Shokuhin) were stirred in water (30 cm3), with the pH adjusted to

pH 10 by addition of 10% aq. sodium bicarbonate solution. Following 24 hrs stirring

under N2 atmosphere, 2,4-dinitro-1-fluorobenzene (681.5 mg, 3.66 mmol, Aldrich)

dissolved in methanol (5 cm3) was introduced with 24 hrs further stirring. The reaction

was filtered and the filtrate washed with ethyl acetate (5 × 20 cm3) then concentrated

under reduced pressure to c.a. 20 cm3 and submitted to a Diaion HP20 column. No

desired product was detected in the collected aqueous and aqueous-methanol fractions.

Experimental

151


Attempted synthesis of 2-(Benzyloxy)ethanamine [CAS Reg No. 38336-04-8]

To a stirred solution of ethanolamine (122.0 mg, 2.00 mmol, BDH) in N,N-

dimethylformamide (20 cm3) under N2 atmosphere was added hexane-rinsed sodium

hydride (77.4 mg, 1.9 mmol, Aldrich). Once all of the reagent was dissolved benzyl

bromide (325.0 mg, 1.9 mmol, Merck) was carefully added. After 2 hrs the solvent was

mostly removed by vacuum distillation. No appreciable amounts of desired product were

detected by NMR.

Phenylacetic acid 4.1 [CAS Reg No. 103-82-2]

A small amount of a solution of benzyl bromide (5.2048 g, 30.43 mmol, Merck) in fresh

ether (70 cm3) was dropped onto magnesium turnings (770.3 mg, 31.70 mmol, Aldrich)

under N2 atmosphere with addition of a crystal of iodine. After the mixture became

colourless the remaining reagent was added dropwise at a rate to maintain gentle reflux

and the reaction stirred for 2 hrs then poured onto dry ice. The crude emulsion was

washed with 5% aq. hydrochloric acid solution (30 cm3) then brine (40 cm3), then

extracted with 10% aq. sodium bicarbonate solution (100 cm3). The aqueous fraction was

washed with ether (50 cm3), acidified by dropwise addition of conc. aqueous

hydrochloric acid solution then extracted with ether (3 × 100 cm3). The organic fractions

were dried and concentrated under vacuum to afford white crystals (901.2 mg, 22%): Rf

0.20 (dichloromethane); m.p. 73-75°C (lit.246 m.p. 77-78.5°C).

2-(Bromomethyl)naphthalene 4.2 [CAS Reg No. 939-26-4]

A solution of 2-methylnaphthalene (2.5959 g, 18.26 mmol, Fluka), N-bromosuccinimde

(3.5782 g, 20.10 mmol, Aldrich) and a rice grain of 2,2’-azobisisobutyronitrile (TCI) in

carbon tetrachloride (60 cm3) was thoroughly degassed and stirred under N2 atmosphere

at 50°C under a sunlamp. After 1 hr the solution was allowed to cool, filtered and

Experimental

152

concentrated under vacuum. The crude product was eluted through a squat column of

flash silica (hexane-ethyl acetate 4:1) to yield spectroscopically pure powder (3.4477 g,

85%): Rf 0.44 (hexane); m.p. 51-53°C (lit.247 m.p. 51-54°C).

Attempted sysnthesis of 2-(Bromomethyl)anthracene [CAS Reg No. 31124-71-7]

A solution of 2-methylanthracene (476.5 mg, 2.48 mmol, K&K Labs), N-

bromosuccinimde (466.8 mg, 2.62 mmol, Aldrich) and two rice grains of benzoyl

peroxide (Aldrich) in carbon tetrachloride (120 cm3) was degassed and stirred at 19°C

under N2 atmosphere and a sunlamp for one hour. Following 30 hrs further stirring the

mixture was filtered, concentrated under vacuum to c.a. 10 cm3 and diluted with

dichloromethane (60 cm3) then washed with water (2 × 30 cm3). The organic layer was

dried, concentrated under vacuum and submitted to gravity column (hexane). Trace

amounts of target compound were detected by NMR in a mixture with inseparable side-

products.

2-(Bromomethyl)anthraquinone 4.4 [CAS Reg No. 7598-10-9]

A solution of 2-methylanthraquinone (2.1618 g, 9.73 mmol, BDH), N-bromosuccinimide

(1.7390 g, 9.77 mmol, Aldrich) and trace benzoyl peroxide (150 mg, Aldrich) in carbon

tetrachloride (50 cm3) was degassed and then stirred at 77°C under N2 atmosphere for 18

hrs. The resulting suspension was allowed to cool then was suction filtered and titurated

with methanol (50 cm3). This suspension was filtered and washed with methanol, and the

filter cake was recrystallised from ethyl acetate to afford light yellow solid (1.3739 g,

47%): m.p. 196-200°C (lit.248 m.p. 199-201°C).

2-(Naphthylen-2-yl)acetic acid 4.3 [CAS Reg No. 581-96-4]

To a mixture of chloroform (8 cm3) and 60% aq. potassium hydroxide solution (20 g) was

added 2-(Bromomethyl)naphthalene (1.7209 g, 7.78 mmol) with vigorous stirring.

Following degassing, bis(triphenylphosphine)palladium(II) chloride (48.6 mg, 0.07

Experimental

153

mmol, Alfa Aesar) was added and stirring was continued under N2 atmosphere at 20°C

for 20 hrs. The mixture was diluted with water (50 cm3) and washed with ether (2 × 20

cm3). The aqueous portion was acidified and extracted with ether (2 × 30 cm3), the

organic fractions were combined, dried and concentrated under vacuum to yield white

powder: 690.7 mg, 48%; m.p. 140-142°C (lit.231 m.p. 141-143°C).

2-(Anthraquinon-2-yl)acetic acid 4.5 [CAS Reg No. 76161-80-3]

To a mixture of chloroform (25 cm3) and 60% aq. potassium hydroxide solution (12 g)

was added 2-(Bromomethyl)anthraquinone (1.3676 g, 4.54 mmol). Following degassing,

bis(triphenylphosphine)palladium(II) chloride (63.4 mg, 0.09 mmol, Alfa Aesar) was

added and stirring was continued under N2 atmosphere at 20°C for 18 hrs. The mixture

was diluted with water (50 cm3) and washed with ether (2 × 40 cm3). The concentrated

crude material was taken up in 1 mol dm-3 aq. sodium hydroxide solution (100 cm3),

washed with dichloromethane (3 × 60 cm3), acidified and extracted into dichloromethane

(3 × 100 cm3). The organic portion was dried and solvent removed under reduced

pressure to give a light yellow powder (241.3 mg, 20%): m.p. 230-235°C (dec.).

2-(Anthracen-2-yl)acetic acid 4.6 [CAS Reg No. 92964-57-3]

To a solution of cupric sulphate pentahydrate(c.a. 10 mg, BDH) in water (40 cm3) was

added zinc dust (c.a. 1.0 g, Ace). After allowing the mixture to stand for 10 mins the

liquid was decanted and the residue taken up in conc. aq. ammonia solution (40 cm3), and

2-(Anthraquinon-6-yl)acetic acid (175.0 mg, 0.66 mmol) was added. The reaction was

stirred at 60°C under N2 atmosphere for 6 hrs, then water (50 cm3) was added, the

mixture filtered and washed with dichloromethane (3 × 50 cm3). The pH was adjusted to

around pH 1 and the aqueous phase was extracted with further dichloromethane (3 × 60

cm3). Organics were dried and concentrated under vacuum to furnish a light yellow

powder (72.5 mg, 47%): m.p. 226-229°C.

Experimental

154

General method for 4-nitrophenyl esterification of arylacetic acids

A solution of previously prepared arylacetic acid, 4-nitrophenol (1.1 mol equivalents,

BDH) and dicyclohexylcarbodiimide (1.1 mol equivalents, Merck) in dichloromethane

(c.a. 50 cm3 per mmol) was stirred at 20°C for up to 20 hrs. The mixture was filtered,

concentrated under reduced pressure and the residue eluted through a squat column of

flash silica to yield the ester product.

4-Nitrophenyl phenylacetate 4.7 [CAS Reg No. 3769-84-4]

Isolated as a white solid (275.7 mg, 78%): Rf 0.42 (hexane-dichloromethane 1:1); m.p.

60-62°C; 1H NMR (CDCl3) δ: 8.27–7.22 AA’BB’ (4H, ArH), 7.40–7.35 m (5H, ArH),

3.90 s (2H, CH2); 13C NMR δ: 169.2, 155.7, 145.9, 132.9, 129.5, 129.1, 127.9, 126.4,

122.6, 41.6.

4-Nitrophenyl 2,2-diphenylacetate 4.8 [CAS Reg No. 58241-10-4]

Isolated as a white powder (1.0685 g, 70%): Rf 0.34 (hexane-dichloromethane 1:1); m.p.

90-92°C; 1H NMR (CDCl3) δ: 8.27–7.23 AA’BB’ (4H, ArH), 7.41–7.28 m (10H, ArH),

5.29 s (1H, Ph2CH); 13C NMR δ: 170.3, 155.7, 145.7, 137.7, 129.1, 128.8, 128.0, 125.4,

122.5, 57.3.

4-Nitrophenyl 2-(naphthylen-2-yl)acetate 4.9

Isolated as a white powder (926.0 mg, 80%): Rf 0.20; m.p. 98-99°C; 1H NMR (CDCl3) δ:

8.27–7.24 AA’BB’ (4H, ArH), 7.90–7.48 m (7H, ArH), 4.07 s (2H, CH2); 13C NMR δ:

170.4, 155.6, 151.3, 137.7, 129.1, 128.8, 128.0, 126.7, 125.4, 122.5, 57.3; Exact mass

calcd for C18H13NO4 m/z: 307.0845, found: 307.0848.

Experimental

155

4-Nitrophenyl 2-(anthracen-2-yl)acetate 4.10

Isolated as a bright yellow powder (62.3 mg, 67%): Rf 0.40 (hexane-dichloromethane

3:7); m.p. 170-175°C; 1H NMR (CDCl3) δ: 8.44–7.46 m (9H, ArH), 8.28–7.26 AA’BB’

(4H, ArH), 4.10 s (2H, CH2); 13C NMR δ: 129.3, 128.5, 128.3, 126.8, 126.5, 126.3,

125.9, 125.4, 122.6, 41.9. Exact mass calcd for C22H15NO4 m/z: 357.1001, found:

357.1005.

General method for reaction of 4-nitrophenyl esters with diaminoethane

To vigorously stirring diaminoethane (c.a. 25 mol equivalents, AJAX) a solution of

arylacetic acid 4-nitrophenyl ester in N,N-dimethylformamide (20 cm3 per mmol) was

added dropwise over 30 mins. The reaction was further stirred for 24 hrs at 20°C under

N2 atmosphere and then concentrated by vacuum distillation of the solvent to c.a. 5 cm3.

The residue was taken up in dilute aq. hydrochloric acid solution (50 cm3), washed with

dichloromethane (2 × 40 cm3) then made basic and extracted with further dichloro-

methane (3 × 40 cm3). The combined organic extracts were dried and concentrated to

yield the desired acetamide.

N-(2-aminoethyl)-2-phenylacetamide 4.11 [CAS Reg No. 105070-17-4]

Isolated as a spectroscopically pure white gum (151.2 mg, 17%): Rf 0.15 (methanol);

m.p. 89-92°C; 1H NMR (DMSO-d6) δ: 8.00 brs (1H, CONH), 7.27–7.23 m (5H, ArH),

3.38 s (2H, CH2–CO), 3.02 dt (2H, CONH–CH2), 2.82 brs (2H, NH2), 2.54 t (2H, CH2–

NH2); 13C NMR δ: 170.0, 161.2, 136.5, 128.9, 128.1, 126.2, 42.4, 41.26.

N-(2-aminoethyl)-2,2-diphenylacetamide 4.12 [CAS Reg No. 49808-85-7]

Residue was eluted through a column of basic alumina to yield a pale yellow solid (409.5

mg, 52%): Rf 0.20 (dichloromethane-methanol 9:1); m.p. 142-145°C (lit.249 m.p. 125-

130°C); 1H NMR (DMSO-d6) δ: 8.24 brt (1H, CONH), 7.31–7.18 m (10H, ArH), 4.95 s

Experimental

156

(1H, Ph2CH), 3.12 brs (2H, NH2), 3.07 dt (2H, CONH–CH2), 2.56 t (2H, CH2–NH2); 13C

NMR δ: 170.9, 140.5, 131.9, 128.4, 128.1, 126.5, 56.5, 42.4, 41.2.

N-(2-aminoethyl)-2-(napthylen-2-yl)acetamide 4.13

The crude material was eluted through a column of basic alumina to yield fine white

powder (360.2 mg, 53%): Rf 0.2 (methanol); m.p. 131-133°C; 1H NMR (DMSO-d6) δ:

7.89 brs (1H, CONH), 7.86–7.41 m (7H, ArH), 3.58 s (2H, CH2–CO), 3.32 brs (2H,

NH2), 3.05 dt (2H, CONH–CH2), 2.56 t (2H, CH2–NH2); 13C NMR δ: 170.1, 134.3,

133.1, 131.8, 127.6, 127.5, 127.4, 127.3, 127.2, 126.0, 125.5, 42.6, 41.4; Exact mass

calcd for C14H16N2O m/z: 228.1263, found: 228.1264.

Attempted synthesis of N-(2-aminoethyl)-2-(anthracen-2-yl)acetamide

The residue was eluted through a squat column of silica (methanol) to give a trace white

powder (c.a. 20 mg) consisting of a mixture of products by 1H and 13C NMR

spectroscopic analysis.

2-((2-aminoethylamino)methyl)anthracene-9,10-dione 4.14

To thoroughly stirred diaminoethane (12.095 g, 201.30 mmol, AJAX), was added a

solution of 2-(bromomethyl)anthracene-9,10-dione (1.7886 g, 5.94 mmol) in N,N-

dimethylformamide (80 cm3) by dropping funnel over 6 hrs. The mixture was stirred

under N2 atmosphere for a further 18 hrs at 20°C, then most of the solvent was removed

by vacuum distillation. The residue was taken up in 5% aq. hydrochloric acid solution (50

cm3) and washed with dichloromethane (50 cm3). 60% Aq. sodium hydroxide solution

was added to the aqueous portion and it was extracted with dichloromethane (4 × 100

cm3). The organic fractions were combined and concentrated under vacuum and the crude

product eluted through basic alumina (dichloromethane-methanol 9:1) to yield an off-

white solid (296.4 mg, 18%): Rf 0.10; m.p. 163-167°C; 1H NMR (CDCl3) δ: 8.31–7.78 m

(7H, ArH), 3.98 s (2H, Ar–CH2), 2.88–2.71 m (4H, NH2–CH2–CH2–NH2); 13C NMR δ:

Experimental

157

183.6, 183.2, 148.0, 134.4, 134.3, 134.0, 133.8, 132.9, 132.6, 127.8, 127.5, 126.7, 53.6,

52.2, 41.9; Exact mass calcd for C17H17N2O2 (MH+) m/z: 281.1290, Found: 281.1301.

N1-((anthracen-2-yl)methyl)ethane-1,2-diamine 4.15

To an aqueous solution of cupric sulfate pentahydrate (30.0 mg, 0.12 mmol, BDH) was

added powdered zinc (7.00 g, 107.10 mmol, Ace), and the water was mostly decanted. A

suspension of 2-((2-aminoethylamino)methyl)anthracene-9,10-dione (278.3 mg, 1.00

mmol) in 22% aq. ammonia solution (100 cm3) was poured in and the mixture stirred

vigorously under N2 atmosphere at 60°C for 20 hrs, at which time the deep red colour had

faded. The mixture was decanted and the residue rinsed with dichloromethane (3 × 30

cm3). The layers were separated and the aqueous portion further extracted with

dichloromethane (2 × 50 cm3). The residue was taken up in 5% aq. hydrochloric acid

solution (200 cm3) and suction filtered. To the filtrate was added 60% aq. sodium

hydroxide until pH > 12 and the solution was extracted with dichloromethane (100 cm3).

The organic fractions were combined, concentrated under reduced pressure and submitted

to a basic alumina column (dichloromethane-methanol 4:1) to afford a cream powder

(171.6 mg, 72%): Rf 0.08; m.p. 150-154°C; 1H NMR (CDCl3) δ: 8.40–7.43 m (9H, ArH),

4.00 s (2H, Ar–CH2), 2.86–2.77 m (4H, NH2–CH2–CH2–NH2); 13C NMR δ: 132.1,

131.9, 131.8, 131.3, 128.6, 128.4, 128.3, 127.6, 126.6, 126.3, 126.2, 126.0, 125.5, 125.4,

54.3, 52.2, 42.0; UV-Vis λmax (H2O, pH 2.0) (log ε): 246 (4.8) nm; Exact mass calcd for

C17H18N2 m/z: 250.1470, Found: 250.1473.

General method for hydrophobic poly(acrylic acid) modification

To a 1-methyl-2-pyrrolidinone (25 cm3) solution of PAA (400 mg, Aldrich) at 60°C

stirred for 24 hrs, previously prepared aminoethyl hydrophobe (0.03 mol equivalents) and

dicyclohexylcarbodiimide (0.03 mol equivalents, Merck), each in c.a. 2 cm3 1-methyl-2-

pyrrolidinone solution, were added. The stoppered reaction was further stirred for 70 hrs

and then allowed to cool. 40% aq. sodium hydroxide solution was added and the

emulsion shaken then allowed to settle. Methanol (50 cm3) was added then decanted, and

Experimental

158

the polymer precipitate triturated with further methanol (30 cm3) then dried under

reduced pressure. It was dissolved in water (40 cm3) and dialyzed for 3 days, and the

resulting solution was filtered, concentrated to c.a. 20 cm3 and freeze dried. The loading

of hydrophobe modification was determined by 1H NMR (D2O) spectroscopic

integration.

Phenylacetamide-substituted Poly(acrylic Acid) PAA1.5%Ph

Substituted polymer was obtained as a white solid (90.8 mg). Loading of hydrophobic

substituent: 1.5%.

Diphenylacetamide-substituted Poly(acrylic Acid) PAA2.7%Ph2


substitutuent: 2.7%.

(Naphthylen-3-yl)acetamide-substituted Poly(acrylic Acid) PAA3%Np


substituent: 3.0%. UV-Vis λmax (H2O) (log ε): 225 (3.9) nm.

Anthracene amine-substituted Poly(acrylic Acid) PAA2.7%An

The reaction was scaled up to use 600 mg of poly(acrylic acid) starting material. The

substituted polymer (657.0 mg) was recovered as an orange solid, with a substituent

loading of 2.5% as determined by NMR spectroscopic integration; UV-Vis λmax (H2O, pH

2.0) (log ε): 257 (5.3) nm.

Appendices

159

Appendix

A.1. X-ray Crystal Structure Data for Tetraspiro-annulated Fluorenyl

Porphyrin 2.11

A red plate like crystal was attached with Exxon Paratone N, to a short length of fibre

supported on a thin piece of copper wire inserted in a copper mounting pin. The crystal

was quenched in a cold nitrogen gas stream from an Oxford Cryosystems Cryostream. A

Bruker-Nonius FR591 Kappa APEX II diffractometer employing graphite

monochromated MoKα radiation generated from a fine-focus rotating anode was used for

the data collection. Cell constants were obtained from a least squares refinement against

5756 reflections located between 4.54 and 48.84º 2θ. Data were collected at 150(2)

Kelvin with φ and ω scans to 50.74º 2θ. The data integration and reduction were

undertaken with SAINT and XPREP,250 and subsequent computations were carried out

with the X-Seed graphical user interface.251 An empirical absorption correction

determined with SADABS was applied to the data.252

The structure was solved in the space group P21/n(#14) by direct methods with SHELXS-

97,253 and extended and refined with SHELXL-97.253 Of the 103 non-hydrogen atom sites

in the asymmetric unit, 99 were modelled with anisotropic displacement parameters and

the rest were modelled with isotropic displacement parameters. A riding atom model with

group displacement parameters was used for the hydrogen atoms.

The structure was refined as 80% metallated and 20% free porphyrin disordered on the

same site. The two hydrogen atoms on the free porphyrin were refined as disordered

50:50 over the four porphyrin nitrogen atoms and therefore have occupancies of 0.10.

The site containing the chloroform molecule was refined at a total occupancy of 0.5 with

three positions at 0.22, 0.22, and 0.06. The minor position was modelled with isotropic

displacement parameters. The disordered hexane molecule was modelled (65:35) over

Appendices

160

two positions. Only half of the hexane atoms for each position are unique with inversion

symmetry generating the other half of the molecule. Bond distance restraints and

displacement parameter constraints were used during refinement of this disordered

solvent. An ORTEP254 depiction of the molecule with 50% displacement ellipsoids is

provided in Figure 2.19.

A.1.1. Additional Refinement Details for 2.11

A riding atom model was used for the H1, H2, H3, H4, H3A, H3B, H6, H7, H8, H9, H12,

H13, H14, H15, H17A, H17B, H20, H23A, H23B, H26, H27, H28, H29, H32, H33, H34,

H35, H37A, H37B, H40, H43A, H43B, H46, H47, H48, H49, H52, H53, H54, H55,

H57A, H57B, H60, H63A, H63B, H66, H67, H68, H69, H72, H73, H74, H75, H77A,

H77B, H80, H81, H81', H81", H82A, H82B, H82C, H83A, H83B, H84A, H84B, H82D,

H82E, H82F, H83C, H83D, H84C, H84D, sites.

The Zn1, H1, H2, H3, H4, C81, H81, Cl1, Cl2, Cl3, C81', H81', Cl1', Cl2', Cl3', C81",

H81", Cl1", Cl2", Cl3", C82A, H82A, H82B, H82C, C83A, H83A, H83B, C84A, H84A,

H84B, C82B, H82D, H82E, H82F, C83B, H83C, H83D, C84B, H84C, H84D, sites were

refined with partial occupancies.

The Zn1, H1, H2, H3, H4, C81, H81, Cl1, Cl2, Cl3, C81', H81', Cl1', Cl2', Cl3', C81",

H81", Cl1", Cl2", Cl3", C82A, H82A, H82B, H82C, C83A, H83A, H83B, C84A, H84A,

H84B, C82B, H82D, H82E, H82F, C83B, H83C, H83D, C84B, H84C, H84D, sites were

refined with occupancy constraints.

The C81, Cl1, Cl2, Cl3, C81', Cl1', Cl2', Cl3', C81", Cl1", Cl2", Cl3", C82A, C83A,

C84A, C82B, C83B, C84B, sites were refined with bond restraints.

The C81, Cl1, Cl2, Cl3, C81', Cl1', Cl2', Cl3', C82A, C83A, C84A, C82B, C83B, C84B,

sites were refined with rigid bond restraints.

Appendices

161

A.1.2. Non-Hydrogen Atom Coordinates, Isotropic Thermal Parameters and

Occupancies

atom x y z Ueq(Å2) Occ Zn(1) 0.53392(3) 0.251303(18) 0.313793(12) 0.02909(12) 0.80 N(1) 0.3393(2) 0.21918(10) 0.30317(7) 0.0331(5) 1 N(2) 0.5340(2) 0.26535(10) 0.24529(7) 0.0322(5) 1 N(3) 0.7269(2) 0.28532(10) 0.32414(7) 0.0323(5) 1 N(4) 0.5375(2) 0.23334(11) 0.38174(8) 0.0374(5) 1 C(1) 0.2660(3) 0.19357(12) 0.33578(9) 0.0334(6) 1 C(2) 0.1376(3) 0.17295(13) 0.31445(9) 0.0351(6) 1 C(3) 0.0157(3) 0.13708(13) 0.32578(10) 0.0384(7) 1 C(4) -0.0348(3) 0.10798(13) 0.27819(10) 0.0403(7) 1 C(5) 0.0353(3) 0.04440(13) 0.27000(9) 0.0387(7) 1 C(6) 0.1694(3) 0.03070(15) 0.26836(11) 0.0479(8) 1 C(7) 0.2068(3) -0.03151(16) 0.25887(11) 0.0521(8) 1 C(8) 0.1123(4) -0.07906(16) 0.25061(11) 0.0537(8) 1 C(9) -0.0243(3) -0.06549(15) 0.25205(11) 0.0504(8) 1 C(10) -0.0609(3) -0.00459(14) 0.26309(10) 0.0439(7) 1 C(11) -0.1934(3) 0.02267(15) 0.26778(11) 0.0502(8) 1 C(12) -0.3192(4) -0.00639(17) 0.26791(15) 0.0742(12) 1 C(13) -0.4293(4) 0.03134(19) 0.27239(18) 0.0925(15) 1 C(14) -0.4185(4) 0.09667(19) 0.27593(17) 0.0873(15) 1 C(15) -0.2927(3) 0.12528(16) 0.27743(14) 0.0649(10) 1 C(16) -0.1813(3) 0.08828(14) 0.27409(11) 0.0462(7) 1 C(17) 0.0071(3) 0.15908(14) 0.24380(10) 0.0424(7) 1 C(18) 0.1333(3) 0.18545(13) 0.26966(9) 0.0363(6) 1 C(19) 0.2605(3) 0.21422(12) 0.26209(9) 0.0325(6) 1 C(20) 0.3009(3) 0.23099(13) 0.22056(9) 0.0343(6) 1 C(21) 0.4259(3) 0.25432(12) 0.21226(9) 0.0320(6) 1 C(22) 0.4663(3) 0.27229(13) 0.16910(9) 0.0357(6) 1 C(23) 0.4088(3) 0.27342(16) 0.12014(9) 0.0432(7) 1 C(24) 0.5124(3) 0.31737(16) 0.09843(9) 0.0456(7) 1 C(25) 0.5332(3) 0.29874(16) 0.05024(10) 0.0472(8) 1 C(26) 0.5818(3) 0.24215(19) 0.03481(11) 0.0592(9) 1 C(27) 0.5902(3) 0.2348(2) -0.01151(12) 0.0662(10) 1 C(28) 0.5512(3) 0.2829(2) -0.04127(12) 0.0639(10) 1 C(29) 0.5019(3) 0.3397(2) -0.02661(11) 0.0607(10) 1 C(30) 0.4922(3) 0.34758(17) 0.01975(10) 0.0513(8) 1 C(31) 0.4432(3) 0.40034(17) 0.04537(10) 0.0497(8) 1 C(32) 0.3875(4) 0.45848(19) 0.03061(12) 0.0643(10) 1 C(33) 0.3481(4) 0.50035(18) 0.06243(13) 0.0685(10) 1 C(34) 0.3632(4) 0.48534(18) 0.10804(13) 0.0630(9) 1 C(35) 0.4189(3) 0.42725(17) 0.12289(11) 0.0550(9) 1 C(36) 0.4576(3) 0.38444(16) 0.09152(10) 0.0475(8) 1

Appendices

162

C(37) 0.6462(3) 0.31452(17) 0.13237(9) 0.0472(8) 1 C(38) 0.5944(3) 0.29334(13) 0.17559(9) 0.0359(6) 1 C(39) 0.6394(3) 0.28838(12) 0.22353(9) 0.0319(6) 1 C(40) 0.7639(3) 0.30708(12) 0.24509(9) 0.0323(6) 1 C(41) 0.8044(2) 0.30763(12) 0.29150(9) 0.0308(6) 1 C(42) 0.9284(2) 0.33336(12) 0.31375(8) 0.0310(6) 1 C(43) 1.0539(3) 0.36700(13) 0.30292(9) 0.0346(6) 1 C(44) 1.0972(3) 0.40239(13) 0.34923(9) 0.0368(6) 1 C(45) 1.0333(3) 0.46902(14) 0.34840(10) 0.0422(7) 1 C(46) 0.8986(3) 0.48617(16) 0.34281(12) 0.0541(8) 1 C(47) 0.8654(4) 0.55032(18) 0.34099(14) 0.0706(11) 1 C(48) 0.9638(4) 0.59657(19) 0.34462(16) 0.0807(12) 1 C(49) 1.0996(4) 0.57968(17) 0.35069(15) 0.0744(12) 1 C(50) 1.1328(3) 0.51558(15) 0.35246(11) 0.0515(8) 1 C(51) 1.2658(3) 0.48367(15) 0.35930(11) 0.0478(8) 1 C(52) 1.3950(4) 0.50889(18) 0.36614(13) 0.0658(10) 1 C(53) 1.5033(3) 0.46639(19) 0.37305(14) 0.0674(10) 1 C(54) 1.4837(3) 0.40195(17) 0.37288(11) 0.0562(9) 1 C(55) 1.3525(3) 0.37688(15) 0.36481(10) 0.0449(7) 1 C(56) 1.2452(3) 0.41811(14) 0.35805(9) 0.0384(7) 1 C(57) 1.0440(3) 0.35787(15) 0.38594(9) 0.0411(7) 1 C(58) 0.9245(3) 0.32756(13) 0.35888(9) 0.0344(6) 1 C(59) 0.7999(3) 0.29616(13) 0.36598(9) 0.0335(6) 1 C(60) 0.7597(3) 0.27885(14) 0.40750(9) 0.0381(6) 1 C(61) 0.6412(3) 0.24791(13) 0.41509(9) 0.0374(6) 1 C(62) 0.6027(3) 0.22767(15) 0.45794(9) 0.0418(7) 1 C(63) 0.6562(3) 0.22797(17) 0.50747(9) 0.0468(8) 1 C(64) 0.5208(3) 0.21906(16) 0.52972(10) 0.0448(7) 1 C(65) 0.4567(3) 0.28347(16) 0.53868(11) 0.0475(8) 1 C(66) 0.4192(3) 0.33214(17) 0.50887(13) 0.0617(9) 1 C(67) 0.3581(4) 0.38571(19) 0.52500(15) 0.0758(11) 1 C(68) 0.3349(4) 0.3903(2) 0.57019(16) 0.0771(11) 1 C(69) 0.3759(4) 0.34220(18) 0.60043(13) 0.0650(10) 1 C(70) 0.4373(3) 0.28860(16) 0.58463(11) 0.0510(8) 1 C(71) 0.4890(3) 0.23087(16) 0.60812(10) 0.0469(8) 1 C(72) 0.4947(3) 0.21366(19) 0.65341(11) 0.0591(9) 1 C(73) 0.5478(3) 0.1546(2) 0.66674(11) 0.0625(10) 1 C(74) 0.5935(3) 0.11412(19) 0.63588(11) 0.0619(9) 1 C(75) 0.5891(3) 0.13102(17) 0.59025(11) 0.0555(9) 1 C(76) 0.5370(3) 0.18966(15) 0.57674(10) 0.0447(7) 1 C(77) 0.4273(3) 0.18020(15) 0.49392(9) 0.0429(7) 1 C(78) 0.4792(3) 0.20160(14) 0.45065(9) 0.0404(7) 1 C(79) 0.4361(3) 0.20527(13) 0.40290(9) 0.0365(6) 1 C(80) 0.3117(3) 0.18669(13) 0.38132(9) 0.0352(6) 1 C(81) 0.6432(12) 0.0178(7) 0.3945(8) 0.088(4) 0.22 Cl(1) 0.7414(12) 0.0836(7) 0.3987(5) 0.161(6) 0.22

Appendices

163

Cl(2) 0.4880(7) 0.0349(4) 0.4100(5) 0.169(6) 0.22 Cl(3) 0.7153(13) -0.0433(7) 0.4256(11) 0.125(5) 0.22 C(81') 0.6432(15) 0.0240(6) 0.4072(6) 0.088(4) 0.22 Cl(1') 0.7202(11) 0.0953(4) 0.4045(4) 0.095(3) 0.22 Cl(2') 0.5335(10) 0.0256(5) 0.4471(4) 0.151(5) 0.22 Cl(3') 0.7545(14) -0.0362(6) 0.4193(9) 0.123(5) 0.22 C(81") 0.663(3) -0.0078(12) 0.3948(12) 0.119(5) 0.06 Cl(1") 0.812(2) 0.0281(14) 0.3882(9) 0.119(5) 0.06 Cl(2") 0.575(3) 0.0539(13) 0.4137(10) 0.119(5) 0.06 Cl(3") 0.696(4) -0.0624(15) 0.4369(15) 0.119(5) 0.06 C(82A) 0.2346(10) 0.0768(5) 0.0133(5) 0.167(3) 0.65 C(83A) 0.3507(10) 0.0602(5) -0.0110(4) 0.167(3) 0.65 C(84A) 0.4428(13) 0.0116(7) 0.0116(5) 0.167(3) 0.65 C(82B) 0.303(2) 0.1053(10) 0.0314(9) 0.196(5) 0.35 C(83B) 0.388(3) 0.0471(11) 0.0387(7) 0.196(5) 0.35 C(84B) 0.450(3) 0.0265(13) -0.0024(9) 0.196(5) 0.35

A.1.3. Anisotropic Thermal Parameters ( Å2)

atom U(1,1) U(2,2) U(3,3) U(1,2) U(1,3) U(2,3) Zn(1) 0.0297(2) 0.0362(2) 0.0212(2) -0.00704(15) 0.00186(14) 0.00123(16) N(1) 0.0349(12) 0.0350(13) 0.0293(12) -0.0021(10) 0.0026(9) -0.0003(10) N(2) 0.0335(12) 0.0347(13) 0.0280(12) -0.0014(9) 0.0013(9) 0.0008(10) N(3) 0.0320(12) 0.0373(13) 0.0273(12) -0.0031(9) 0.0026(9) 0.0018(10) N(4) 0.0354(12) 0.0463(14) 0.0302(12) -0.0061(10) 0.0028(10) 0.0016(11) C(1) 0.0340(14) 0.0327(15) 0.0343(15) -0.0024(11) 0.0069(11) -0.0026(12) C(2) 0.0354(15) 0.0325(15) 0.0375(16) -0.0031(11) 0.0044(12) -0.0011(12) C(3) 0.0364(15) 0.0378(16) 0.0415(17) -0.0049(12) 0.0065(12) 0.0000(13) C(4) 0.0373(16) 0.0397(17) 0.0433(17) -0.0047(12) 0.0017(12) -0.0001(14) C(5) 0.0446(17) 0.0363(17) 0.0348(16) -0.0034(12) 0.0026(12) -0.0021(13) C(6) 0.0452(18) 0.048(2) 0.0514(19) -0.0042(14) 0.0106(14) -0.0064(15) C(7) 0.0502(19) 0.056(2) 0.052(2) 0.0055(16) 0.0148(15) -0.0068(16) C(8) 0.072(2) 0.0432(19) 0.049(2) 0.0048(16) 0.0185(16) -0.0039(15) C(9) 0.060(2) 0.0401(19) 0.052(2) -0.0098(15) 0.0092(15) -0.0062(15) C(10) 0.0455(17) 0.0404(18) 0.0456(18) -0.0001(13) 0.0042(13) 0.0047(14) C(11) 0.0470(18) 0.0406(19) 0.062(2) -0.0054(14) 0.0003(15) -0.0012(15) C(12) 0.052(2) 0.045(2) 0.125(4) -0.0134(17) 0.009(2) -0.012(2) C(13) 0.044(2) 0.061(3) 0.172(5) -0.0155(18) 0.013(2) -0.027(3) C(14) 0.038(2) 0.055(2) 0.167(5) -0.0025(17) 0.006(2) -0.015(3) C(15) 0.048(2) 0.041(2) 0.104(3) -0.0038(15) -0.0010(19) -0.0074(19) C(16) 0.0395(17) 0.0411(18) 0.057(2) -0.0055(13) 0.0013(14) 0.0003(15) C(17) 0.0407(16) 0.0421(18) 0.0429(17) -0.0074(13) -0.0022(13) 0.0020(14) C(18) 0.0366(15) 0.0343(16) 0.0376(16) -0.0015(12) 0.0025(12) -0.0003(13)

Appendices

164

C(19) 0.0322(14) 0.0316(15) 0.0331(15) -0.0006(11) 0.0002(11) -0.0001(12) C(20) 0.0349(15) 0.0331(15) 0.0332(15) -0.0014(11) -0.0041(11) 0.0013(12) C(21) 0.0369(15) 0.0309(15) 0.0276(14) 0.0019(11) 0.0005(11) 0.0011(12) C(22) 0.0371(15) 0.0383(16) 0.0308(15) -0.0008(12) -0.0007(11) 0.0007(13) C(23) 0.0416(16) 0.0596(19) 0.0274(15) -0.0060(14) -0.0011(12) 0.0039(14) C(24) 0.0404(16) 0.066(2) 0.0293(16) -0.0071(14) 0.0004(12) 0.0041(15) C(25) 0.0404(17) 0.070(2) 0.0304(16) -0.0080(15) 0.0006(13) 0.0048(16) C(26) 0.0494(19) 0.084(3) 0.0426(19) -0.0005(17) -0.0007(15) -0.0003(18) C(27) 0.055(2) 0.101(3) 0.043(2) -0.0018(19) 0.0053(16) -0.009(2) C(28) 0.057(2) 0.100(3) 0.0362(19) -0.014(2) 0.0106(16) -0.009(2) C(29) 0.058(2) 0.090(3) 0.0334(18) -0.0191(19) 0.0053(15) 0.0077(18) C(30) 0.0456(18) 0.073(2) 0.0349(17) -0.0139(16) 0.0034(14) 0.0025(17) C(31) 0.0497(18) 0.064(2) 0.0352(17) -0.0160(16) 0.0028(14) 0.0112(16) C(32) 0.073(2) 0.074(3) 0.046(2) -0.016(2) 0.0066(17) 0.011(2) C(33) 0.083(3) 0.055(2) 0.067(3) -0.0132(19) 0.007(2) 0.011(2) C(34) 0.071(2) 0.061(2) 0.057(2) -0.0154(18) 0.0110(18) -0.0055(19) C(35) 0.061(2) 0.065(2) 0.0391(18) -0.0146(17) 0.0027(15) 0.0019(17) C(36) 0.0432(17) 0.066(2) 0.0327(17) -0.0158(15) 0.0030(13) 0.0009(15) C(37) 0.0388(16) 0.074(2) 0.0279(15) -0.0085(15) 0.0020(12) 0.0038(15) C(38) 0.0361(15) 0.0449(17) 0.0265(14) -0.0019(12) 0.0025(11) 0.0005(12) C(39) 0.0335(14) 0.0351(16) 0.0270(14) 0.0008(11) 0.0032(11) 0.0013(12) C(40) 0.0344(14) 0.0351(15) 0.0286(15) 0.0009(11) 0.0085(11) 0.0021(12) C(41) 0.0309(14) 0.0310(15) 0.0305(15) -0.0003(11) 0.0036(11) -0.0004(11) C(42) 0.0332(14) 0.0332(15) 0.0273(14) -0.0012(11) 0.0060(11) 0.0013(11) C(43) 0.0345(15) 0.0392(16) 0.0305(15) -0.0029(11) 0.0045(11) 0.0005(12) C(44) 0.0378(15) 0.0408(17) 0.0318(15) -0.0053(12) 0.0045(12) -0.0037(13) C(45) 0.0406(17) 0.0446(18) 0.0419(17) -0.0027(13) 0.0074(13) -0.0053(14) C(46) 0.0492(19) 0.047(2) 0.067(2) 0.0032(15) 0.0130(16) -0.0080(17) C(47) 0.061(2) 0.060(2) 0.092(3) 0.0123(19) 0.013(2) -0.010(2) C(48) 0.071(3) 0.049(2) 0.122(4) 0.013(2) 0.012(2) -0.008(2) C(49) 0.070(3) 0.039(2) 0.116(4) -0.0057(17) 0.016(2) -0.009(2) C(50) 0.0519(19) 0.0442(19) 0.059(2) -0.0032(14) 0.0082(15) -0.0057(16) C(51) 0.0465(18) 0.0428(19) 0.054(2) -0.0098(14) 0.0066(14) -0.0058(15) C(52) 0.054(2) 0.052(2) 0.091(3) -0.0169(17) 0.0071(19) -0.009(2) C(53) 0.041(2) 0.071(3) 0.091(3) -0.0173(17) 0.0049(18) -0.017(2) C(54) 0.0434(18) 0.063(2) 0.061(2) -0.0004(16) -0.0003(15) -0.0051(18) C(55) 0.0426(17) 0.0482(19) 0.0429(18) -0.0039(14) 0.0006(13) -0.0022(14) C(56) 0.0374(15) 0.0463(18) 0.0317(15) -0.0081(13) 0.0048(12) -0.0067(13) C(57) 0.0411(16) 0.0518(18) 0.0304(15) -0.0120(13) 0.0046(12) -0.0018(13) C(58) 0.0336(14) 0.0374(16) 0.0318(15) -0.0038(11) 0.0022(11) 0.0000(12) C(59) 0.0341(14) 0.0400(16) 0.0263(14) -0.0033(11) 0.0026(11) 0.0010(12) C(60) 0.0362(15) 0.0486(18) 0.0286(15) -0.0054(13) -0.0005(11) 0.0003(13) C(61) 0.0360(15) 0.0472(17) 0.0288(14) -0.0036(12) 0.0028(11) 0.0044(13) C(62) 0.0418(17) 0.0548(19) 0.0288(15) -0.0037(13) 0.0042(12) 0.0043(13) C(63) 0.0414(17) 0.068(2) 0.0302(16) -0.0044(14) 0.0017(13) 0.0076(15) C(64) 0.0426(17) 0.060(2) 0.0320(16) -0.0024(14) 0.0045(13) 0.0057(15)

Appendices

165

C(65) 0.0408(17) 0.056(2) 0.0443(19) -0.0086(14) -0.0003(13) 0.0015(16) C(66) 0.061(2) 0.061(2) 0.062(2) -0.0034(18) 0.0015(17) 0.0062(19) C(67) 0.080(3) 0.057(3) 0.088(3) -0.002(2) -0.006(2) 0.007(2) C(68) 0.082(3) 0.060(3) 0.088(3) 0.004(2) 0.004(2) -0.014(2) C(69) 0.068(2) 0.064(2) 0.063(2) -0.0008(19) 0.0049(18) -0.013(2) C(70) 0.0435(18) 0.059(2) 0.050(2) -0.0067(15) 0.0035(14) -0.0080(17) C(71) 0.0417(17) 0.063(2) 0.0364(17) -0.0040(14) 0.0052(13) -0.0003(15) C(72) 0.055(2) 0.087(3) 0.0360(18) -0.0015(19) 0.0097(15) -0.0057(18) C(73) 0.060(2) 0.096(3) 0.0329(18) 0.003(2) 0.0088(15) 0.0101(19) C(74) 0.063(2) 0.080(3) 0.043(2) 0.0124(18) 0.0080(16) 0.0159(19) C(75) 0.054(2) 0.072(2) 0.0417(19) 0.0105(17) 0.0088(15) 0.0049(17) C(76) 0.0396(16) 0.060(2) 0.0348(17) -0.0017(14) 0.0070(13) 0.0042(15) C(77) 0.0428(17) 0.058(2) 0.0282(15) -0.0036(14) 0.0058(12) 0.0071(14) C(78) 0.0419(16) 0.0483(18) 0.0313(16) -0.0042(13) 0.0052(12) 0.0033(13) C(79) 0.0390(15) 0.0417(17) 0.0299(15) -0.0040(12) 0.0081(12) 0.0014(12) C(80) 0.0379(15) 0.0386(16) 0.0303(15) -0.0051(12) 0.0095(12) -0.0003(12) C(81) 0.069(6) 0.103(6) 0.085(12) 0.019(4) -0.023(6) -0.082(7) Cl(1) 0.128(8) 0.246(11) 0.103(8) -0.100(9) -0.015(6) 0.074(9) Cl(2) 0.054(4) 0.057(4) 0.40(2) 0.002(3) 0.029(7) -0.068(8) Cl(3) 0.070(9) 0.098(6) 0.199(13) -0.011(5) -0.023(9) -0.068(6) C(81') 0.069(6) 0.103(6) 0.085(12) 0.019(4) -0.023(6) -0.082(7) Cl(1') 0.101(5) 0.082(4) 0.103(6) 0.035(3) 0.013(4) -0.022(4) Cl(2') 0.119(8) 0.094(6) 0.256(12) -0.026(5) 0.089(8) -0.083(8) Cl(3') 0.062(7) 0.106(7) 0.189(12) 0.033(6) -0.038(7) -0.091(8) C(82A) 0.135(5) 0.125(5) 0.253(8) 0.027(4) 0.068(5) 0.027(5) C(83A) 0.135(5) 0.125(5) 0.253(8) 0.027(4) 0.068(5) 0.027(5) C(84A) 0.135(5) 0.125(5) 0.253(8) 0.027(4) 0.068(5) 0.027(5) C(82B) 0.185(12) 0.167(12) 0.235(13) 0.029(9) 0.021(10) -0.020(11) C(83B) 0.185(12) 0.167(12) 0.235(13) 0.029(9) 0.021(10) -0.020(11) C(84B) 0.185(12) 0.167(12) 0.235(13) 0.029(9) 0.021(10) -0.020(11)

A.1.4. Non Hydrogen Bond Lengths (Å)

atom atom Distance atom atom Distance Zn(1) N(3) 2.044(2) Zn(1) N(4) 2.046(2) Zn(1) N(1) 2.046(2) Zn(1) N(2) 2.053(2) N(1) C(19) 1.379(3) N(1) C(1) 1.384(3) N(2) C(39) 1.381(3) N(2) C(21) 1.394(3) N(3) C(41) 1.386(3) N(3) C(59) 1.386(3) N(4) C(79) 1.380(3) N(4) C(61) 1.384(3) C(1) C(80) 1.384(4) C(1) C(2) 1.432(4) C(2) C(18) 1.350(4) C(2) C(3) 1.500(4) C(3) C(4) 1.568(4) C(4) C(16) 1.511(4)

Appendices

166

C(4) C(5) 1.537(4) C(4) C(17) 1.567(4) C(5) C(6) 1.374(4) C(5) C(10) 1.405(4) C(6) C(7) 1.394(4) C(7) C(8) 1.375(5) C(8) C(9) 1.398(4) C(9) C(10) 1.377(4) C(10) C(11) 1.461(4) C(11) C(16) 1.391(4) C(11) C(12) 1.396(4) C(12) C(13) 1.372(5) C(13) C(14) 1.377(5) C(14) C(15) 1.387(5) C(15) C(16) 1.369(4) C(17) C(18) 1.505(4) C(18) C(19) 1.445(4) C(19) C(20) 1.383(4) C(20) C(21) 1.386(4) C(21) C(22) 1.434(4) C(22) C(38) 1.346(4) C(22) C(23) 1.501(4) C(23) C(24) 1.574(4) C(24) C(36) 1.514(5) C(24) C(25) 1.518(4) C(24) C(37) 1.582(4) C(25) C(26) 1.379(5) C(25) C(30) 1.397(4) C(26) C(27) 1.394(5) C(27) C(28) 1.368(5) C(28) C(29) 1.376(5) C(29) C(30) 1.398(4) C(30) C(31) 1.457(5) C(31) C(32) 1.390(5) C(31) C(36) 1.400(4) C(32) C(33) 1.377(5) C(33) C(34) 1.381(5) C(34) C(35) 1.390(5) C(35) C(36) 1.378(5) C(37) C(38) 1.501(4) C(38) C(39) 1.447(4) C(39) C(40) 1.389(4) C(40) C(41) 1.391(4) C(41) C(42) 1.440(4) C(42) C(58) 1.348(4) C(42) C(43) 1.503(3) C(43) C(44) 1.578(4) C(44) C(56) 1.508(4) C(44) C(45) 1.534(4) C(44) C(57) 1.570(4) C(45) C(46) 1.383(4) C(45) C(50) 1.389(4) C(46) C(47) 1.385(5) C(47) C(48) 1.376(5) C(48) C(49) 1.393(5) C(49) C(50) 1.383(5) C(50) C(51) 1.480(4) C(51) C(52) 1.387(4) C(51) C(56) 1.389(4) C(52) C(53) 1.399(5) C(53) C(54) 1.365(5) C(54) C(55) 1.406(4) C(55) C(56) 1.373(4) C(57) C(58) 1.503(4) C(58) C(59) 1.442(4) C(59) C(60) 1.385(4) C(60) C(61) 1.388(4) C(61) C(62) 1.432(4) C(62) C(78) 1.343(4) C(62) C(63) 1.506(4) C(63) C(64) 1.580(4) C(64) C(76) 1.517(4) C(64) C(65) 1.529(5) C(64) C(77) 1.563(4) C(65) C(66) 1.375(5) C(65) C(70) 1.402(4) C(66) C(67) 1.388(5) C(67) C(68) 1.388(6) C(68) C(69) 1.381(5) C(69) C(70) 1.386(5) C(70) C(71) 1.462(5) C(71) C(72) 1.386(4) C(71) C(76) 1.393(4) C(72) C(73) 1.388(5) C(73) C(74) 1.363(5) C(74) C(75) 1.395(4) C(75) C(76) 1.377(4) C(77) C(78) 1.505(4) C(78) C(79) 1.436(4) C(79) C(80) 1.388(4) C(81) Cl(1) 1.687(8) C(81) Cl(3) 1.693(9)

Appendices

167

C(81) Cl(2) 1.701(8) C(81') Cl(1') 1.686(8) C(81') Cl(3') 1.694(8) C(81') Cl(2') 1.700(8) C(81") Cl(1") 1.694(9) C(81") Cl(2") 1.696(9) C(81") Cl(3") 1.699(9) C(82A) C(83A) 1.471(8) C(83A) C(84A) 1.481(9) C(84A) C(84A) 3_655 1.478(9) C(82B) C(83B) 1.485(10) C(83B) C(84B) 1.487(10) C(84B) C(84B) 3_655 1.491(10) Symmetry Operators (1) x, y, z (2) -x+1/2, y+1/2, -z+1/2 (3) -x, -y, -z (4) x-1/2, -y-1/2, z-1/2

A.1.5. Non Hydrogen Bond Angles (º)

atom atom atom angle N(3) Zn(1) N(4) 90.15(8) N(3) Zn(1) N(1) 178.78(9) N(4) Zn(1) N(1) 90.23(9) N(3) Zn(1) N(2) 89.72(8) N(4) Zn(1) N(2) 177.43(9) N(1) Zn(1) N(2) 89.95(8) C(19) N(1) C(1) 107.1(2) C(19) N(1) Zn(1) 126.83(17) C(1) N(1) Zn(1) 125.87(17) C(39) N(2) C(21) 107.5(2) C(39) N(2) Zn(1) 126.60(17) C(21) N(2) Zn(1) 125.91(17) C(41) N(3) C(59) 106.9(2) C(41) N(3) Zn(1) 127.04(17) C(59) N(3) Zn(1) 125.79(17) C(79) N(4) C(61) 107.3(2) C(79) N(4) Zn(1) 126.33(18) C(61) N(4) Zn(1) 126.40(18) N(1) C(1) C(80) 125.4(2) N(1) C(1) C(2) 108.9(2) C(80) C(1) C(2) 125.6(2) C(18) C(2) C(1) 107.8(2) C(18) C(2) C(3) 112.3(2) C(1) C(2) C(3) 139.5(3) C(2) C(3) C(4) 100.4(2) C(16) C(4) C(5) 101.7(2) C(16) C(4) C(17) 117.4(2)

Appendices

168

C(5) C(4) C(17) 109.3(2) C(16) C(4) C(3) 113.0(2) C(5) C(4) C(3) 111.9(2) C(17) C(4) C(3) 103.8(2) C(6) C(5) C(10) 119.6(3) C(6) C(5) C(4) 130.4(3) C(10) C(5) C(4) 109.9(2) C(5) C(6) C(7) 119.1(3) C(8) C(7) C(6) 121.4(3) C(7) C(8) C(9) 119.9(3) C(10) C(9) C(8) 118.8(3) C(9) C(10) C(5) 121.1(3) C(9) C(10) C(11) 130.7(3) C(5) C(10) C(11) 108.1(3) C(16) C(11) C(12) 119.7(3) C(16) C(11) C(10) 109.5(3) C(12) C(11) C(10) 130.8(3) C(13) C(12) C(11) 118.6(3) C(12) C(13) C(14) 121.6(3) C(13) C(14) C(15) 119.7(3) C(16) C(15) C(14) 119.5(3) C(15) C(16) C(11) 120.7(3) C(15) C(16) C(4) 128.8(3) C(11) C(16) C(4) 110.5(3) C(18) C(17) C(4) 100.8(2) C(2) C(18) C(19) 107.5(2) C(2) C(18) C(17) 111.4(2) C(19) C(18) C(17) 140.7(3) N(1) C(19) C(20) 125.0(2) N(1) C(19) C(18) 108.6(2) C(20) C(19) C(18) 126.3(2) C(19) C(20) C(21) 127.2(2) C(20) C(21) N(2) 125.1(2) C(20) C(21) C(22) 126.7(2) N(2) C(21) C(22) 108.1(2) C(38) C(22) C(21) 108.3(2) C(38) C(22) C(23) 112.8(2) C(21) C(22) C(23) 138.8(2) C(22) C(23) C(24) 102.0(2) C(36) C(24) C(25) 101.3(2) C(36) C(24) C(23) 110.8(2) C(25) C(24) C(23) 113.5(2) C(36) C(24) C(37) 112.8(3) C(25) C(24) C(37) 113.3(2) C(23) C(24) C(37) 105.3(2) C(26) C(25) C(30) 120.3(3)

Appendices

169

C(26) C(25) C(24) 128.6(3) C(30) C(25) C(24) 111.1(3) C(25) C(26) C(27) 118.9(3) C(28) C(27) C(26) 120.7(4) C(27) C(28) C(29) 121.3(3) C(28) C(29) C(30) 118.6(3) C(25) C(30) C(29) 120.2(3) C(25) C(30) C(31) 108.1(3) C(29) C(30) C(31) 131.8(3) C(32) C(31) C(36) 120.7(3) C(32) C(31) C(30) 130.3(3) C(36) C(31) C(30) 109.0(3) C(33) C(32) C(31) 118.5(3) C(32) C(33) C(34) 121.2(4) C(33) C(34) C(35) 120.4(4) C(36) C(35) C(34) 119.3(3) C(35) C(36) C(31) 119.9(3) C(35) C(36) C(24) 129.6(3) C(31) C(36) C(24) 110.5(3) C(38) C(37) C(24) 102.0(2) C(22) C(38) C(39) 107.7(2) C(22) C(38) C(37) 112.7(2) C(39) C(38) C(37) 139.6(2) N(2) C(39) C(40) 124.9(2) N(2) C(39) C(38) 108.3(2) C(40) C(39) C(38) 126.7(2) C(39) C(40) C(41) 127.3(2) N(3) C(41) C(40) 124.4(2) N(3) C(41) C(42) 108.9(2) C(40) C(41) C(42) 126.7(2) C(58) C(42) C(41) 107.7(2) C(58) C(42) C(43) 111.7(2) C(41) C(42) C(43) 140.5(2) C(42) C(43) C(44) 100.9(2) C(56) C(44) C(45) 101.6(2) C(56) C(44) C(57) 114.2(2) C(45) C(44) C(57) 112.4(2) C(56) C(44) C(43) 115.0(2) C(45) C(44) C(43) 109.9(2) C(57) C(44) C(43) 104.1(2) C(46) C(45) C(50) 120.3(3) C(46) C(45) C(44) 129.4(3) C(50) C(45) C(44) 110.3(2) C(45) C(46) C(47) 118.8(3) C(48) C(47) C(46) 121.0(3) C(47) C(48) C(49) 120.5(4)

Appendices

170

C(50) C(49) C(48) 118.5(3) C(49) C(50) C(45) 120.9(3) C(49) C(50) C(51) 130.7(3) C(45) C(50) C(51) 108.4(3) C(52) C(51) C(56) 120.9(3) C(52) C(51) C(50) 130.7(3) C(56) C(51) C(50) 108.4(3) C(51) C(52) C(53) 118.0(3) C(54) C(53) C(52) 121.4(3) C(53) C(54) C(55) 120.1(3) C(56) C(55) C(54) 119.0(3) C(55) C(56) C(51) 120.5(3) C(55) C(56) C(44) 128.4(3) C(51) C(56) C(44) 111.1(3) C(58) C(57) C(44) 100.9(2) C(42) C(58) C(59) 107.8(2) C(42) C(58) C(57) 112.6(2) C(59) C(58) C(57) 139.5(2) C(60) C(59) N(3) 125.3(2) C(60) C(59) C(58) 126.1(2) N(3) C(59) C(58) 108.7(2) C(59) C(60) C(61) 127.0(3) N(4) C(61) C(60) 124.7(2) N(4) C(61) C(62) 108.4(2) C(60) C(61) C(62) 126.8(3) C(78) C(62) C(61) 108.0(2) C(78) C(62) C(63) 112.2(2) C(61) C(62) C(63) 139.7(3) C(62) C(63) C(64) 100.3(2) C(76) C(64) C(65) 101.7(2) C(76) C(64) C(77) 114.1(2) C(65) C(64) C(77) 110.4(2) C(76) C(64) C(63) 115.0(2) C(65) C(64) C(63) 111.2(3) C(77) C(64) C(63) 104.6(2) C(66) C(65) C(70) 120.7(3) C(66) C(65) C(64) 129.3(3) C(70) C(65) C(64) 110.0(3) C(65) C(66) C(67) 118.5(4) C(66) C(67) C(68) 121.0(4) C(69) C(68) C(67) 120.5(4) C(68) C(69) C(70) 118.9(4) C(69) C(70) C(65) 120.3(3) C(69) C(70) C(71) 131.0(3) C(65) C(70) C(71) 108.7(3) C(72) C(71) C(76) 120.4(3)

Appendices

171

C(72) C(71) C(70) 130.7(3) C(76) C(71) C(70) 108.9(3) C(71) C(72) C(73) 118.8(3) C(74) C(73) C(72) 120.7(3) C(73) C(74) C(75) 121.1(3) C(76) C(75) C(74) 118.7(3) C(75) C(76) C(71) 120.4(3) C(75) C(76) C(64) 129.0(3) C(71) C(76) C(64) 110.6(3) C(78) C(77) C(64) 100.8(2) C(62) C(78) C(79) 107.9(2) C(62) C(78) C(77) 112.4(2) C(79) C(78) C(77) 139.7(3) N(4) C(79) C(80) 125.0(2) N(4) C(79) C(78) 108.4(2) C(80) C(79) C(78) 126.5(2) C(1) C(80) C(79) 127.0(2) Cl(1) C(81) Cl(3) 111.7(9) Cl(1) C(81) Cl(2) 110.2(8) Cl(3) C(81) Cl(2) 110.9(8) Cl(1') C(81') Cl(3') 112.3(9) Cl(1') C(81') Cl(2') 110.3(9) Cl(3') C(81') Cl(2') 108.9(9) Cl(1") C(81") Cl(2") 101.2(16) Cl(1") C(81") Cl(3") 106.3(17) Cl(2") C(81") Cl(3") 109.8(18) C(82A) C(83A) C(84A) 115.1(8) C(84A) 3_655 C(84A) C(83A) 119.2(12) C(82B) C(83B) C(84B) 113.6(12) C(83B) C(84B) C(84B) 3_655 118(2) Symmetry Operators (1) x, y, z (2) -x+1/2, y+1/2, -z+1/2 (3) -x, -y, -z (4) x-1/2, -y-1/2, z-1/2

Appendices

172

A.2. Inclusion Complex UV-Visible Stability Determinations

Samples of axle compounds 3.3 and 3.5 were each weighed into volumetric flasks,

spectroscopic grade methanol added and the solutions sonicated to ensure full dissolution.

The stock solutions were made up to the mark and aliquots measured from them to make

dilute spectroscopic stock solutions in pH 10 0.1 mol dm-1 sodium borate buffer and 0.1

mol dm-1 hydrochloric acid (BDH Convol®). Aliquots of known concentration solutions

of α-cyclodextrin at appropriate pH were weighed and added to 1 g aliquots of

spectroscopic stock solutions in volumetric flasks and made up to the marks with

appropriate buffer solutions. Flasks were stored in a water bath at 298 K and spectra run

in quick succession. Data was fitted with Matlab (version 4.2b, MathWorks Ltd.) using

the Specfit M file (version 950217, Kuruscev, T.), and erroneous data points were

discarded.

A.2.1. Solution Preparation

Masses of individual solutions used in sample solutions (in grams). Stock solution types

and concentrations of axle compounds and α-cyclodextrin are indicated (three

concentrations of α-cyclodextrin solutions were utilised for each experiment).

3.3 1.4 × 10-3

mol dm-3

,

borate buffer

α-cyclodextrin

1.2 × 10-2

mol dm-3

,

borate buffer total solution mass

1.0291 5.0852 25.0195

1.0188 4.0809 25.0107

1.0209 3.0663 25.0163

1.022 2.548 25.0174

1.0147 2.0521 25.0182

1.0155 1.5388 25.0141

1.0149 1.0694 25.0198

1.2 × 10-3

mol dm-3

1.0202 5.077 25.0192

Appendices

173

1.0198 4.5343 25.0143

1.0131 4.0387 25.0113

1.0084 3.5355 25.0149

1.0115 3.0601 25.0096

1.011 2.5441 25.0115

1.0216 2.0282 25.0113

1.0231 1.0308 25.0137

1.2 × 10-4

mol dm-3

1.0178 5.0812 25.0174

1.0089 4.0379 25.0093

1.0103 3.0573 25.0098

1.0145 2.022 25.0191

1.0177 1.0289 25.012

1.0193 25.0109

3.3 2.4 × 10-4

mol dm-3

,

HCl

α-cyclodextrin

1.2 × 10-3

mol dm-3

, HCl total solution mass

1.0164 5.0668 10.0117 1.031 4.0758 10.0134 1.0163 3.057 10.0175 1.0192 2.551 10.0072 1.0176 2.0443 10.0172 1.016 1.5442 10.0143 1.0126 1.0408 10.0133 1.2 × 10

-4 mol dm

-3 1.0154 5.0825 10.0139 1.0085 4.5478 10.0188 1.014 4.0446 10.0141 1.009 3.5272 10.0058 1.009 3.0376 10.0175 1.012 2.5318 10.0088 1.009 2.0301 10.0198 1.0115 1.0311 10.0137 1.2 × 10

-5 mol dm

-3 1.0181 5.0424 10.0085 1.0172 4.0479 10.0138 1.0171 3.0512 10.0168

Appendices

174

1.0186 2.0431 10.0093 1.0044 1.0342 10.0137 1.0127 10.0099

3.5 2.0 × 10-4

mol dm-3

,

borate buffer

α-cyclodextrin

4.0 × 10-3

mol dm-3

,


1.0092 5.0286 10.0117

1.0154 2.5296 10.0222

1.0163 1.5596 10.0142

1.0173 1.0463 10.0345

4.0 × 10-4

mol dm-3

1.0278 5.0612 10.0147

1.0104 4.0258 10.0138

1.0117 3.5415 10.0313

1.0137 3.0279 10.0295

1.0187 2.5378 10.0319

1.0215 2.0447 10.0266

4.0 × 10-5

mol dm-3

1.0102 5.0291 10.0348

1.0191 3.0242 10.016

1.0151 1.0275 10.0255

1.0202 10.0343

3.5 2.0 × 10-4

mol dm-3

,

HCl α-cyclodextrin

4.0 × 10-3

mol dm-3


1.0069 5.0642 10.021 1.0277 2.5434 10.0157 1.0294 1.5293 10.0243 1.0224 1.0221 10.019 4.0 × 10

-4 mol dm

-3 1.0255 5.0615 10.0201 1.0116 4.0537 10.0299 1.0177 3.5395 10.0297 1.0219 3.0452 10.0188 1.0241 2.5332 10.0282

Appendices

175

1.0214 2.0359 10.0163 4.0 × 10

-5 mol dm

-3 1.0204 5.041 10.0269 1.0152 3.0199 10.0191 1.0245 1.0237 10.0185 1.0193 10.017

4,4’-diaminostilbene

2.0 × 10-4

mol dm-3

,

borate buffer

α-cyclodextrin

4.0 × 10-3

mol dm-3

,


0.9868 5.079 10.0106 0.9934 4.0494 10.0114 0.991 3.0348 10.0164 0.9916 2.5274 10.0146 0.982 2.0343 10.0174 0.9988 1.5348 10.0098 0.9906 1.0213 10.0183 4.0 × 10

-4 mol dm

-3 0.9906 5.0613 10.0109 0.9983 4.5443 10.0175 0.9903 4.0141 10.0174 0.9892 3.5349 10.0189 0.9835 3.0446 10.0187 0.9863 2.5187 10.0182 0.9874 2.0168 10.011 0.9926 1.0208 10.0104 4.0 × 10

-5 mol dm

-3 0.993 5.0376 10.0173 0.9886 4.0331 10.0167 0.9849 3.0197 10.0157 0.9857 2.0174 10.0175 0.987 1.019 10.0151 0.9853 10.017

Appendices

176

4,4’-diaminostilbene

2.0 × 10-4

mol dm-3

, HCl α-cyclodextrin

4.0 × 10-3

mol dm-3


0.984 5.0563 10.0107 0.995 4.0675 10.0174 0.9948 3.0317 10.0186 0.984 2.5321 10.0156 0.994 2.0223 10.0142 0.9944 1.5481 10.0133 0.9882 1.0504 10.0158 4.0 × 10

-4 mol dm

-3 0.9901 5.0417 10.012 0.9906 4.54 10.0109 0.9895 4.0511 10.0136 0.9841 3.5511 10.0134 0.9865 3.0407 10.0149 0.9906 2.5634 10.0138 0.9945 2.0618 10.0182 0.9903 1.0559 10.014 4.0 × 10

-5 mol dm

-3 0.9942 5.0666 10.0095 0.9919 4.0295 10.0102 0.9842 3.036 10.0107 0.9931 2.0386 10.0153 0.9931 1.0536 10.0168 0.9846 10.0159

Appendices

177

A.3. Asymmetric Axle pH Titrations

Titrations used a glass electrode and titration vessel maintained at 298 K by water bath

and pump. Water was purified with a Millipore system, then boiled gently and sealed to

eliminate dissolved carbonate. 20% Methanol/aqueous stock 0.1 mol dm-3 sodium

hydroxide solution was prepared from Convol® stock solution (BDH) with water and

spectroscopic grade methanol measured by weight. It was titrated with potassium

phthalate solution to determine the exact basicity. Hydrochloric acid stock solution was

prepared from Convol® stock solution and used to make hydrochloric acid in 0.1 mol

dm-3 sodium chloride solution, determined to be approximately 0.13 mol dm-3 in

concentration. Solutions of axle molecules 3.3 and 3.5 of concentration 0.001 mol dm-3

were prepared by weighing (21.0 mg and 20.9 mg, respectively) samples into grade A

volumetric flasks, adding a calculated slight excess of acid stock solution and making the

solutions up to the line with I = 0.1 mol dm-3 20% methanol/aqueous sodium chloride

solution.

The glass electrode was equilibrated in 20% methanol/aqueous sodium chloride 0.1 mol

dm-3 solution, then calibrated each day by titration of hydrochloric acid stock solution

with sodium hydroxide stock solution. E0 and pKw values were calculated with the

calib.exe program. Titration curves were fitted with Hyperquad 2003 (version 3.0.43).

Appendices

178

A.3.1. Potentiometric Data Fitting

Axle 3.3 pKa Determination

Chi-squared = 11.07

Chi-squared should be less than 12.60 at the 95% confidence level

sigma = 0.2962

Value relative std devn

log beta

standard deviation

Beta 1 1 refined 1.5725E+03 0.1897 3.1966 0.0824 Beta 1 2 refined 9.6638E+05 0.1309 5.9851 0.0569 Beta 0 -1 constant 1.0715E-14 -13.9700

Appendices

179


Chi-squared = 8.00


sigma = 0.2253


log beta

standard deviation


pKa1 = (3.1966 + 3.2911)/2 = 3.244

pKa2 = (5.9851 + 6.0887)/2 = 6.037

Appendices

180


Chi-squared = 5.36


sigma = 0.1368


log beta

standard deviation


Appendices

181


Chi-squared = 4.62


sigma = 0.1812


log beta

standard deviation


pKa1 = (4.9065 + 4.8623)/2 = 4.8844

pKa2 = (7.5784 + 7.3487)/2 = 7.4636

Appendices

182

A.4. 2D NMR Spectra referenced in Section 4.2.

Figure A.4.1. 2D 1H ROESY NMR spectrum of 1 w% PAA2.7%Ph2, with β-cyclodextrin

urea dimer, sodium adamantane-1-carboxylate 1:1 (600 MHz, D2O, 298 K). Relevant

cross-peaks are boxed.

Appendices

183

Figure A.4.2. 2D 1H ROESY NMR spectrum of 1 w% PAA2.7%Ph2, with β-cyclodextrin

urea dimer, sodium adamantane-1-carboxylate 1:2 (600 MHz, D2O, 298 K). Cross-peaks

due to the adamantyl-β-cyclodextrin dimer complex are in solid boxes. The multiplet due

to the diphenyl substituent is in the dashed box, indicating that there is no interaction of

this substituent with the β-cyclodextrin dimer.

Appendices

184

Figure A.4.3. 2D 1H NOESY NMR spectrum of 1 w% PAA2.5%An, with α-cyclodextrin

(600 MHz, D2O, 298 K). Relevant cross-peaks are boxed. The 1D NMR aromatic region

is shown at increased amplitude for clarity.

Appendices

185

Figure A.4.4. 2D 1H NOESY NMR spectrum of 1 w% PAA2.5%An, with β-cyclodextrin


Appendices

186

Figure A.4.5. 2D 1H ROESY NMR spectrum of 1 w% PAA2.5%An, with β-cyclodextrin,

sodium adamantane-1-carboxylate 1:1 (600 MHz, D2O, 298 K). Relevant cross-peaks are

boxed.

Appendices

187

Figure A.4.6. 2D 1H NOESY NMR spectrum of 1 w% PAA3%Np with 1 w% β-CDPAA


Appendices

188

A.5. Public Presentations

“Discrete Mechanical Analogues in Chemistry.”

ADELAIDE SYNTHETIC CHEMSTRY SYMPOSIUM

School of Chemistry, Physics and Earth Sciences, Flinders University

The Department of Chemistry University of Adelaide

6th December, 2004

References

189

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