Crystal Engineering of Bicyclo[3.3.0]Octane Derivatives

Crystal Engineering of Bicyclo[3.3.0]octane Derivatives

This thesis is submitted in fulfilment of the degree of

Doctor of Philosophy

Jiabin Gao

Supervisors:

Prof. Roger Bishop Dr Mohan Bhadbhade

School of Chemistry The University of New South Wales Sydney, Australia

March 2013 Acknowledgements

I am so blessed in my life that I have received so much more love, support and help than I really deserve. I am heartily grateful to all those kindness from so many kind people and it will never be enough no matter how much I try to pay them back.

Firstly, I would like to thank my parents for giving me the life and raising me up, without which nothing is possible. They are the most unique parents I have even seen who nurtured me in a special way that is: never go astray on the road of life as a human being, focus on main things and forget trivialities, never lose the appetite of leaning. They have been so insightful and supportive during this long journey of study with their unconditional love. I want to thank my dad, an example I have been following, for the toughness, responsibility, diligence and persistence he demonstrates. He is the man that made me a man as I am.

Secondly, I would like to thank most influential females in my life, my grandmas from both sides, who shaped my soft side and made my whole. They have given me so much care, tenderness and love, which made me feel how great the love is, and therefore, I am able to return it to the people I love.

Thirdly, I would like to thank my co-supervisor, Dr Mohan Bhadbhade, who has taught me so much about crystallography and instrumentations. He helped enormously with my data collection and structure refinement. In addition to that, he is also being so gentle, supportive and helpful as a supervisor and a friend.

Last but not least, I would like to thank my supervisor, Professor Roger Bishop, who has been with me for the last four years in and out of my research work, for his continuous encouragement, patience, forgiveness and guidance. It has been my great honour to work with Roger and to be supervised by him. I admired him so much as a noble person and as an unparalleled mentor. He showed me the great passion he has for the research, vast and profound knowledge in chemistry and incomparable virtues as a human.

My special thank also go to Chris Marjo for his kind help and excellent ideas.

I also want to thank all my friends, Ren, Samuel, Kitty, Caroline, Hu for their help, support and company. Whoever is missed here will be always remembered in my heart.

Originality Statement

‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’

Signed ……………………………………

Date……………………………………….

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Abstract

The concept of awkward shape has been proved to be a powerful tool in deliberately designing and obtaining alternative crystal forms. Awkward shape stands for a type of relatively rigid molecular configuration which does not allow the molecule itself to pack efficiently, leaving more energetically favoured crystal forms possible, such as solvate, hydrate and co-crystal. The bicyclo[3.3.0]octane ring structure is a typical example with a dish-like awkward shape.

Bicyclo[3.3.0]octane derivatives were finely designed and have been successfully synthesized in our lab. Different crystallisation behaviour of all these compounds were explored by growing X-ray quality crystals simply by changing the recrystallization solvent at room temperature and pressure (except one case). In chapter 2, the racemic compound 2,4,6,8-tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene-3,7-diol (tetraester) yielded a second apohost polymorph from methanol at 0Ԩ. We also have obtained a family of closely related inclusion compounds. In addition, tetraester also shows unique properties when mixed solvents were applied as recrystallization solvent. In chapter 3, mono-, di-, trimethylated compounds have lost their potential of forming multiple crystal forms. The tetramethyl tetraester was found to adopt four apohost polymorphs in which C-H…O interactions dominate. In chapter 4, di-n-butyl, dibenzyl and dinaphthyl compounds yielded only one solvent free crystal form. The dipyridyl compound adopts five crystal forms including two apohost polymorphs, two hydrate polymorphs and a benzene solvate. The dithienyl compound exclusively includes small alcohols as co- crystals. In chapter 5, a family of V-shaped molecules has been designed and successfully synthesized as host compounds affording the property of including guest

iv solvents. They exhibit completely different crystallisation behaviour compared to their structural isomers.

It is demonstrated here that supramolecular awkwardness can be used as a powerful tool for designing compounds that are prone to yielding more than one crystal forms, but prediction of the exact crystal packing is still a challenge beyond our current understanding.

Table of Contents

Acknowledgements ...... i Originality Statement ...... iii Abstract ...... iv Table of Contents ...... vi

CHAPTER 1 ...... 1 Introduction ...... 1 1.1 Overview ...... 1 1.2 Supramolecular Chemistry ...... 2 1.3 Crystal Engineering ...... 5 1.4 Supramolecular Synthon ...... 9 1.5 Intermolecular Interactions ...... 12 1.5.1 Hydrogen Bonding (strong and weak) ...... 13 1.5.2 Halogen Bonding ...... 16 1.5.3 Other Interactions ...... 18 1.6 Crystal Forms ...... 20 1.7 Inclusion Chemistry ...... 22 1.7.1 The Formation of Clathrate Compounds ...... 22 1.7.2 Development of Inclusion Chemistry ...... 23 1.8 Polymorphism ...... 32 1.9 Hydrates ...... 36 1.10 Co-crystals ...... 37 1.11 Aims of the Project ...... 39 CHAPTER 2 ...... 40 Multiple Crystal Forms of Bicyclo[3.3.0]octane Tetraester ...... 40 2.1 Introduction ...... 40 2.2 Synthesis ...... 42 2.3 Crystal Structures of Tetraester 15 ...... 43 2.3.1 The Apohost Structure of Tetraester 15 (Form 1) ...... 45 2.3.2 The New Apohost Structure of the Tetraester 15 (Form 2)...... 48 2.3.3 The Major Inclusion Crystal Form of the Tetraester 15 (Form 3) ...... 50

2.3.4 Crystal Structure of (15)2·(THF) (Form 4) ...... 55 2.3.5 Discussion ...... 56 2.3.6 Inclusion Compounds of Tetraester 15 From Solvent Mixtures ...... 59 2.4 Conclusions ...... 65 CHAPTER 3 ...... 66 Methyl Derivatives of the Tetraester ...... 66 3.1 Introduction ...... 66 3.2 Synthesis ...... 68 3.3 Crystal Structures of the Methylated Compounds ...... 73 3.3.1 Polymorph 1 of Monomethyl Tetraester 18 ...... 76 3.3.2 Polymorph 2 of Monomethyl Tetraester 18 ...... 81 3.3.3 Discussion on Polymorphs 1 and 2 ...... 84 3.3.4 Crystal Structure of trans-Dimethyl Tetraester 19 ...... 87 3.3.5 Crystal Structure of cis-Dimethyl Tetraester 20 ...... 92 3.3.6 Crystal Structure of Trimethyl Tetraester 21 ...... 95 3.3.7 Polymorph 1 of Tetramethyl Tetraester 22 ...... 98 3.3.8 Polymorph 2 of Tetramethyl Tetraester 22 ...... 101 3.3.9 Polymorph 3 of Tetramethyl Tetraester 22 ...... 105 3.3.10 Polymorph 4 of Tetramethyl Tetraester 22 ...... 109 3.3.11 Discussion on the Polymorphs of Tetramethyl Tetraester 22 ...... 113 3.4 Conclusions ...... 116 CHAPTER4 ...... 117 Bicyclo[3.3.0]octane Diols with Aromatic Substituents ...... 117 4.1 Introduction ...... 117 4.2 Synthesis ...... 119 4.3 Crystal Structures of Bicyclo[3.3.0]octane Diols ...... 121 4.3.1 Crystal Structure of Di-n-butyl Diol 28 ...... 124 4.3.2 Crystal Structure of Dibenzyl Diol 29 ...... 127 4.3.3 Crystal Structure of Dinaphthyl Diol 30 ...... 129 4.3.4 Apohost Polymorph 1 of Dipyridyl Diol 31 ...... 132 4.3.5 Apohost Polymorph 2 of Dipyridyl Diol 31 ...... 135 4.3.6 Monohydrate Polymorph 1 of Dipyridyl Diol 31 ...... 138 4.3.7 Monohydrate Polymorph 2 of Dipyridyl Diol 31 ...... 140 4.3.8 Solvate Structure of Dipyridyl Diol 31 ...... 143 vii

4.3.9 Discussion of the Dipyridyl Diol 31 Crystal Structures ...... 146 4.3.10 Apohost Structure of Dithienyl Diol 32 ...... 153 4.3.11 Alcohol Co-crystals of Dithienyl Diol 32 ...... 155 4.4 Conclusions ...... 158 CHAPTER 5 ...... 159 Diquinoline Derivatives of Bicyclo[3.3.0]octane ...... 159 5.1 Introduction ...... 159 5.2 Synthesis ...... 161 5.3 Crystal Structures of Diquinoline Derivatives ...... 163 5.3.1 Crystal Structure of Diquinoline 43 ...... 167 5.3.2 Apohost Structure of Dibromodiquinoline 44 ...... 169

5.3.3 Crystal Structure of (44)·(CCl4) ...... 171

5.3.4 Crystal Structure of (44)2·(benzene) ...... 174

5.3.5 Crystal Structure of (44)2·(toluene) ...... 176

5.3.6 Crystal Structure of (44)2·(1,4-dioxane) ...... 179 5.3.7 Crystal Structure of (44)·(pyridine) ...... 181

5.3.8 Crystal Structure of (44)2·(1,1,1-trichloroethane) ...... 183

5.3.9 Crystal structures of (44)2·(acetone) and (44)2·(dichloromethane) ...... 185

5.3.10 Crystal Structure of (44)2·(ethanol) ...... 189

5.3.11 Crystal Structure of (46)2·(benzene) ...... 191

5.3.12 Crystal Structure of (46)2·(diethyl ether) ...... 195 5.4 Conclusions ...... 199 CHAPTER 6 ...... 200 Experimental ...... 200 6.1 General Conditions and Instrumentation ...... 200 6.2 X-Ray Diffraction and Crystallography ...... 201 6.3 Synthetic Procedures ...... 202 Publications and Conference Papers ...... 223 Journal Publications ...... 223 Conference Presentations ...... 224 References ...... 225

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CHAPTER 1

Introduction

1.1 Overview

The ability to predict and then control the crystal structure for a given compound is the ultimate goal in crystal engineering.[1,2]Crystal engineering has been defined as “the understanding of intermolecular interactions in the context of crystal packing and the utilisation of such understanding in the design of new solids with desired physical and chemical properties”.[3] This subunit of supramolecular chemistry is of both fundamental and practical importance.[4] It has broad applications, particularly in the pharmaceutical and pigments industries where different polymorphic forms are different materials with different properties and patentabilities.[5,6] Understanding the intriguing correlation between molecular shape, symmetry and the nature of intermolecular forces is therefore the key for successful design of crystalline materials.[7] One of the most powerful techniques in structure determination is X-ray crystallography.[8] Recent advances in both the X-ray diffraction and computer areas have been continuously boosting the overall growth of crystal engineering.[9]

1.2 Supramolecular Chemistry

As defined by Nobel Prize winner Jean-Marie Lehn, supramolecular chemistry, or chemistry beyond the molecule, is the chemistry of the intermolecular bond, covering the structures and functions of the entities formed by associations of two or more chemical species.[10-12] More specifically, It is based on the theme of mutual molecular recognition,[13] bearing on the assembled entities of higher complexity resulting from the associations of two or more chemical species held together by intermolecular forces.[10]

Supramolecular chemistry, as a concept relative to molecular chemistry, evolves using all resources of molecular chemistry combined with manipulation of noncovalent interactions. Molecular chemistry is the chemistry of the covalent bond and focuses on discovering, understanding and mastering the laws that govern the structures, properties and transformations of molecules.[14] It is reasonable to state that supramolecular chemistry is to molecules and intermolecular bonding what molecular chemistry is to atoms and covalent bonding.

Molecular associations have long been recognised[15] and studied, and the term supermolecule was introduced in the mid-1930s.[16] The partners of a supramolecular species can be named as molecular receptor and substrate[17], and molecular recognition[18-20], transformation and translocation are three basic functions of supramolecular species, as shown in Scheme 1.[10]

Scheme 1 The comparison of molecular chemistry and supramolecular chemistry.[10]

The concept of molecules and chemical bonding are fundamental to chemistry. The idea of the molecule as a chemical entity was not accepted until organic chemistry became a separate subject, which is marked by the Friedrich WÖhler synthesis of urea from ammonium cyanate in 1828.[21] The definition of the chemical bond, also termed covalent bond, was formulated in detail by Linus Pauling during the 1930s.[22]

Based on the establishment of important concepts and theories in molecular chemistry, supramolecular chemistry for the first time could be viewed as a potential subject in the big family of chemistry. After the Emil Fisher enunciation of the lock-and-key principle to explain the functioning of enzymes and Paul Pfeiffer’s description of the first molecular complexes in the 1890s, formal supramolecular thinking can be said to have begun and supramolecular chemistry as a new discipline commenced.[23]

In 1948, H. M. Powell reported the structure of clathrates of hydroquinone 1 and described their crystal structure as a network in a holistic perspective.[24] In this supramolecular point of view, it stressed that what is important is not just the molecule itself but the topology and arrangement of molecules. In other words, the whole is more

3 than the sum of every part in a supramolecuar entity. It also demonstrates that different molecules can produce the same network.[13]

1 The first example came from the crystal structure of adamantane-1,3,5,7-tetracarboxylic acid 2. This crystal structure is the topological equivalent of the diamond lattice where the C-C bond has been replaced by the O-H…O hydrogen bond.[25]

2 After decades of hard work by chemists from various subareas, supramolecular chemistry become fully recognised when the Nobel Prize in chemistry was awarded in

1988 to Jean-Marie Lehn, Donald Cram and Charles Pedersen for their major contributions in the field of supramolecular chemistry.

Today, supramolecular chemistry has been studied by many research groups all over the world and it has further extended its applications throughout the full spectrum of chemistry-related subjects such as material science[26], medicine, catalysis[27] and has been applied to many other devices and functions.[28,29]

1.3 Crystal Engineering

The supramolecular concept successfully drew together the organic, inorganic, organometallic and biological chemists with its holistic principle and dissolved some barriers among these subdivisions of chemistry. This supramolecular perception of chemistry generated a “paradigm shift”, a phrase used by Dario Braga[30], meaning that many chemists shifted their attention from atoms and covalent bonds between atoms, to molecules and intermolecular interactions.

The awareness that a crystal can be considered as a supramolecular entity, like the

Dunitz statement that “the crystal is, in a sense, the supermolecule par excellence”,[31] brought crystal engineering into the mainstream of supramolecular chemistry.[32]

Although, it is clear that the term ‘crystal engineering’ was first used by Ray

Pepinsky[33] in 1955, the formal origin of crystal engineering in its current sense can be traced to the pioneering work of Schmidt and Cohen at the Weizmann Institute of

Science in the 1960s.[34, 35]

Along with other achievements, they developed possibly the first rule of crystal engineering that the photoreactivity of certain organic molecules in the solid state was more controlled by their immediate stereochemical vicinity than by intrinsic electronic properties.[36] Schmidt studied 2+2 photocycloaddition by using substituted trans- cinnamic acid as a research candidate. The cinnamic acids do not usually dimerise in solution, and even when they do under certain conditions, many isomeric products occur and the conversion rate of dimerization is low. Cinnamic acid itself crystallises into three different forms: α, β, γ. The solid α and β forms react in 2+2 photocycloaddition to give cyclobutanes in high conversion efficiencies and regiospecificities while the γ form is photostable. Obviously, the formation of the mirror

5 symmetry truxinic acid results from the β form and the inversion symmetry product from the α form,[35] as shown in Figure 1.1. Cinnamic acid derivatives whose crystal structures contained molecules separated by about 4 Å now could be predicted to be photoactive, where cases with greater separations would not usually react in the solid state. Starting from this successful explanation of outcome in solid state reactions, the relationship between crystal structure and their properties attracted more and more attention.

Figure 1.1 The photoreactions of three different crystal forms of substituted cinnamic acid.[35]

In the last two decades of the 20th century, many branches of chemistry, including medicinal, environmental, computational, pharmaceutical, material and supramolecular chemistry, came into prominence. Crystal engineering is also one of these new branches of chemistry which takes ideas from organic, inorganic, physical, and many other chemistry related subjects and especially from X-ray crystallography. Several other factors also contribute to the evolution of modern crystal engineering. It became easier to determine the crystal structure of small organic molecules due to advances both in instrumentation and computation. The second was the establishment of the Cambridge

Structural Database as a data storage and mining research tool.[37] It for the first time became possible to analyse and identify recurring structures, which in return helps researchers to design similar structures using different molecules or completely new crystal patterns. There was also the increasing realisation that crystal engineering should not be confined to solid state reactivity.

The book authored by G. R. Desiraju and entitled Crystal Engineering: The Design of

Organic Solids, marked a milestone in the development of modern crystal engineering.

In this book, he presented some important thoughts as follows[13]:

(1) Crystal engineering is an interdisciplinary subject and it has a wide-ranging applications. It should be applied in a scope that is beyond the topochemical photoreactivity of organic solids.

(2) Directional interactions such as the hydrogen bond and halogen bond are anisotropic in nature and they induce deviation from close packing. Hydrogen bonding exists in strong and weak varieties.

(3) Study of multiple component molecular crystals is an activity of great importance in modern crystal engineering.

(4) Polymorphism, the existence of different crystal packing from the same molecular content, was labelled as the nemesis of crystal engineering.

Since then, a large number of papers in widely different areas have been published.

Desiraju and Gavezzotti categorised crystal structures of polynuclear aromatic hydrocarbons.[38] Papers by Etter focused on utilising hydrogen bonding as a design tool and she also invented a widely used method of classifying and labelling hydrogen bond networks.[39]

Crystal engineering also expanded to encompass organometallic crystal structures.

Robson extended the work on inorganic extended solids to coordination compounds and called these coordination polymers. The structure reported by Robson of compound

Ι + [40] [Cu {C(C6H4CN)4}] in 1989 has a diamond network, as seen in Figure 1.2.

Ι + [40] Figure 1.2 Diamond-like network in [Cu {C(C6H4CN)4}] .

Crystal engineering was originally concerned with the design of more efficient topochemical reactions, but has since then changed to the deliberate design and synthesis of crystals with desired properties and functions.[41] It consists of two main tasks, analysis and synthesis, so that it resembles classical organic chemistry in a sense.[42]Therefore, a good synthetic strategy was needed for efficiently and conveniently synthesizing crystal structures on demand. Supramolecular retrosynthesis and the term supramolecular synthon were subsequently introduced in 1995.[43]

1.4 Supramolecular Synthon

The organic crystal is a typical example of a nearly perfect three dimensional assembly of numerous molecules which are held together by medium and long range noncovalent interactions.[44] An organic crystal can be treated as a supermolecule, therefore a further analogy can be made that crystal engineering, the design and synthesis of crystalline solids, is a supramolecular equivalent of organic synthesis. Table 1.1 below shows the analogies between organic chemistry and crystal engineering.

Table 1.1 Analogies between organic chemistry and crystal engineering.

Organic chemistry Crystal engineering

Atom Molecule

Covalent bond Intermolecular bond

Molecule Crystal

Organic synthon Supramolecular synthon

Isomer Polymorph

Transition state Nucleus

Reaction Crystallisation

In order to synthesize crystals in a logical and controllable manner, Corey’s retrosynthesis theory[45] was extended by Desiraju in 1995 to describe non-covalently bonded supramolecular subunits, termed as supramolecular synthons.[43]

Supramolecular synthons are different spatial arrangements of intermolecular interactions that play a similar role in supramolecular synthesis to that of the organic synthons in organic synthesis.

A supramolecular synthon is a pattern that shows the major manner by which molecules are connected in a supramolecular system. In a crystal, various supramolecular synthons might be identified and these may repeat in other crystal structures containing similar functional groups. For instance, all molecules containing the C-H group and CΞN group can potentially form a C-H…NΞC hydrogen bond. Reliable supramolecular synthons can be disconnected by dissolving the crystal and can also be regained upon crystallisation. As a result, we may predict the crystal structure of some molecules that are prone to forming common supramolecular synthons.[13]

Some commonly encountered supramolecular synthons are shown in Figure 1.3.[46]

Most of these involve traditional hydrogen bonding, such as O-H…O, N-H…O interactions. Hydrogen bonding has been studied for nearly 100 years and therefore we have accumulated a considerable amount of understanding and knowledge compared to that of other intermolecular interactions. Hydrogen bonding involves relatively strong and directional forces, and it is also most reliable interaction that has been used extensively as the key for molecular recognition amongst organic molecules. At present, more and more efforts are being devoted to the study of other weaker interactions including C-H…O, C-H…N, halogen bonding, dipolar interactions, C-H…Pi (EF) and

Pi…Pi (OFF) interactions.

Figure 1.3 Some commonly used supramolecular synthons.[46]

1.5 Intermolecular Interactions

A molecular crystal is a periodic assembly of molecules that are held together by intermolecular interactions. These intermolecular forces are usually weaker than the covalent bonds. Two goals of crystal engineering are understanding the intermolecular interactions in the context of crystal packing and manipulation of these intermolecular interactions to achieve desired crystal packing and properties. The design of crystal structures with specific properties requires a correct assessment of the energetic and spatial features of the intermolecular interactions, and it is therefore essential to comprehend the nature of intermolecular interactions.

Most covalent bonds have bond energy of 75-125 kcal mol-1 while the majority of intermolecular interactions lie in the range of 0.5-15 kcal mol-1. Many interactions that are important in crystal packing lie in the lowest range of energies between 0.5 and 5 kcal mol-1.[47] Weak interactions like these may have a considerable effect on crystal packing due to their dominating number in quantity. Extremely weak interactions such as C…C, C…H and H…H are numerous. When taken as a whole, they account for a significant amount of crystal stabilisation and other characteristics such as solubility, density and melting point.

1.5.1 Hydrogen Bonding (strong and weak)

The hydrogen bond is one of the most thoroughly investigated interactions and it plays a significant role in controlling and directing the structure of molecular assembly in supramolecular chemistry.[48,49]

The typical hydrogen bond can be represented as an interaction between a donor X-H and an acceptor Y. The hydrogen bond is then written as X-H…Y with three dots signifying the bonding interaction.[50] An electron deficient hydrogen atom is formed when it is covalently bonded to a more electronegative atom, such as N, O, F, P, Br, etc., and it is most likely that this electron poor hydrogen atom will form a hydrogen bond with other electron rich atoms.

Unlike C…C, C…H and H…H interactions, the hydrogen bond is much stronger and also exhibits directionality. Generally, hydrogen bonds can be formed in three distinct manners: simple, bifurcated and trifurcated, as illustrated in Figure 1.4.

Simple hydrogen bond Bifurcated hydrogen bond Trifurcated hydrogen bond

Figure 1.4 Common hydrogen bonding geometries found in crystal structures.

Hydrogen bonds can also be categorised into three types: strong hydrogen bond, moderate hydrogen bond and weak hydrogen bond as proposed by Jeffrey.[51] As described in the Table 1.2, moderate hydrogen bonds resemble those between water molecules or in carbohydrates with their bond energies in the range of 4-15 kcal mol-

1.[52] 13

Table 1.2 Numerical data of strong, moderate and weak hydrogen bonds.[52]

Bruno pointed out that the hydrogen bond preferentially points toward the lone pair of its partner heteroatom,[53] and so the tendency for all hydrogen bonds is towards linearity. The third general property of the hydrogen bond is its distance dependence.

Many non-directional intermolecular interactions have approximate inverse sixth power dependence (r-6) while hydrogen bonds have inverse distance dependence (r-1).[54]

Hydroxy groups, with the hydrogen atom acting as hydrogen bond donor, and oxygen as acceptor, often assemble in a variety of arrangements, including infinite (O-H)n chains, four membered (O-H)4 cycles and six-membered (O-H)6 cycles, as shown in Figure 1.5.

Figure 1.5 Some typical hydrogen bonding arrangements.

Weak hydrogen bonds are typified by C-H…O, C-H…N, O-H…halogen, O-H…Pi and

N-H…Pi interactions, where the hydrogen atoms can be aliphatic or aromatic.[55,56]

These weak interactions have been studied extensively due to their importance both in chemical[57,58] and biological systems[59,60].

1.5.2 Halogen Bonding

Although crystal engineering is still dominated by hydrogen bonding and coordination interactions, halogen bonds have become a hotspot of modern crystal engineering.[61]

Halogen bonding has been applied to a range of areas, from formation of co-crystals,[62] anion binding,[63] molecular capsule assembly[64], and molecular conformation control[65], to membrane permeability improvement[66].

Halogen bonding, signified as XB, is commonplace in crystals. However, the nature of this short contact was not clear. Recently, it has been found that these halogen bonds arise from polarization.[67] A halogen atom, covalently bonded to a carbon atom, is polarized positively in the region that is furthest away from carbon atom. The equatorial region is therefore negatively polarized, as shown in Figure 1.6. In this way, a halogen atom has the potential of forming an electrostatic contact with a negatively polarized or electronegative species. In short, halogen bonding is the attractive interaction between an electrophilic region on a halogen atom and a nucleophilic region of a molecule or molecular fragment.[68]

Figure 1.6 The polar region of a halogen atom covalently bonded to a carbon.

As illustrated in Figure 1.7, halogen bonds can be categorised into two different types.

In type 1, C-X bonds in the interactions C-X…X-C are exactly or nearly parallel. In type 2, two C-X bonds are perpendicular to each other.

Type 1 Type 2

Figure 1.7 Two types of typical halogen bonding arrangements.

The first report on molecular complexes controlled by halogen bonding can be traced back to Colin’s work on the iodine-ammonia reaction in 1814.[69] The product purified

[70] and formulated as NH3·I2 was described by Guthrie in 1863. In 2001, the concept article entitled “Halogen Bonding: A Paradigm in Supramolecular Chemistry” was published and proposed that electrophilic behaviour of halogen atoms as a general phenomenon.[71] In 2008, after exponential growth of research into halogen bonding, the first book specifically covering this interaction and its applications appeared.[72]

At present, there is a increasing realisation that fluorine, under some circumstances, can also act as an XB donor in chemical and biological environments.[73] In the coming years, XB will probably see its application extended to further areas, especially the biosciences. Conformational control of biomolecules such as peptides and polynucleotides[74,75] and optimization of small drug molecule-protein interactions will be two particularly promising areas.[76,77]

1.5.3 Other Interactions

Apart from well-known hydrogen bonding and halogen bonding, many other interactions also participate in determining crystal structures. One that is often overlooked is the dipolar interaction which has a ubiquitous presence in many small molecules and most protein structures.[78,79] As enunciated by Allen, the contributions of these dipolar interactions to the supramolecular recognition process are comparable to those of the medium strength hydrogen bonds. Based on the research on small molecules, Maccallum’s conclusion[80,81] was confirmed that C=O…C=O dipolar interactions are of significance in stabilising protein secondary structural motifs.[82]

There are two types of dipolar interactions in these crystal structures, as depicted in

Figure 1.8. In type 1, two C=O groups are parallel to each other. In type 2, the C=O groups are in the orthogonal or near-orthogonal orientation.

Type 1 Parallel dipolar interaction Type 2 Orthogonal dipolar interaction

Figure 1.8 Two types of carbonyl…carbonyl dipolar interactions.

Like the halogen atoms, sulphur has large polarizability and it forms short directional contacts of the type S…N, S…S and S…Cl.[83] Similarly, intermolecular interactions formed with Se and Te have been identified.[84,85]

Metal interactions have also been examined in crystals. In particular, the Au…Au interaction has been well documented and its use as a design method reported.[85] Metal

18 atoms can also act as hydrogen bond acceptors. Halogen atoms attached to metal atoms can be strong hydrogen bond acceptors.[86]

1.6 Crystal Forms

Crystal engineering is all about the design and synthesis of crystals with desired properties and functions.[87,88] Different crystal forms have different structures and accordingly, different properties. More and more resources and effort are being applied to screening and predicting possible crystal forms of a given compound. There is an increasing awareness that a molecule frequently can have more than one crystal form and it is widely accepted that there are four major types of crystal forms.

Solvates or clathrates: There is inclusion of one or more guest molecules in a cavity formed by the original host molecule.

Polymorphs: The same crystal contents are present, but there is a different packing of the molecules in the crystal.

Hydrates: There is inclusion of water by the original molecule.

Co-crystals: Two or more different molecules hydrogen bond together, and the terms host and guest are no longer relevant.

Solvates, hydrates and co-crystals are multi-component crystals. It is generally difficult to have a particular system of classification and nomenclature for all multi-component crystals (solvate, hydrate and co-crystal). Thus, the terms clathrate, solvate, and inclusion compound tend to be used interchangeably. All stable crystals represent free energy minima, which means that the free energy of a multi-component crystal is probably lower than that of any single component crystal. The formation of multi- component crystals is the outcome of either enthalpic or entropic minimisation.[89]

Generally, enthalpy driven multi-component crystals are characterised by distinctive intermolecular interactions and have a definite composition of each component. Entropy 20 driven ones are usually solid solutions in which that the stoichiometry of the molecular components varies.[13]

1.7 Inclusion Chemistry

1.7.1 The Formation of Clathrate Compounds

Originally, clathrate compounds were discovered by happy accident due to the enormous difficulty in understanding and controlling weak intermolecular interactions in crystal engineering.[90] In many cases the included molecules, usually solvents, result in unstable crystals or introduce disorder difficulties in structure refinement.[91]

Structures with large empty voids or channels are generally energetically unstable so that there is a strong need such crystals to have solvent inclusion in order to stabilise itself both structurally and energetically.[92]

Solvent molecules in the clathrate compounds have essentially three different functions.[93,94]

(1) as space fillers due to the spatial requirement of molecular packing or caging which results in inclusion without a specific host-guest interaction being required.

(2) as participants in hydrogen bonding networks.

(3) as ligands completing the coordination around a metal ion.

The formation of clathrate compounds that result from intermolecular interactions between the host and guest molecules is therefore more complicated and less predictable.

The channels or cavities in the clathrate compounds are formed by supramolecular assembly of certain number of host molecules. Therefore this type of clathrate compound should not be confused with the inclusion complexes formed from preformed host molecules, such as crown ethers,[95] cryptands,[96] calixarenes[97] and cyclodextrins[98].

1.7.2 Development of Inclusion Chemistry

The boiling stone discovered by Axel Cronstedt in 1756 and the anomalous ice compound prepared by Joseph Priestley probably represent the first two inclusion materials that are described scientifically.[99] Since then, many further case of inclusion compounds were found accidentally during the next two centuries, for example

Hofmann clathrates, phenol inclusion compounds, Dianin’s compound, urea tubulates, the choleic acids and the interpenetrated hydroquinone inclusion compounds.[100,101]

This term was first introduced by Powell to describe the X-ray structure of these inclusion compounds.[24] Until this work, the nature of the molecular inclusion had been a mystery, but now X-ray diffractometry could be used to demonstrate what was happening.

However, serendipitous findings will never satisfy scientists who aim to manipulate the inclusion phenomenon at their wish. Based on the establishment in 1962 of the fundamental topologies adopted by inclusion compounds[102] and the categorisation of host-guest structural types proposed by Weber in 1983[103], a significant number of new inclusion compounds have since been designed and synthesized by research groups all over the world.[104] MacNicol[105,106], Wuest[107], Moore[108,109], Toda[110], Weber[111],

Aoyama[112,113], Atwood[114], Zimmerman[115], Nassimbeni[116], Caira[117], Bishop[118-122] and their co-workers are amongst outstanding examples of this research work.

In Bishop’s recent comprehensive review on synthetic clathrate systems, he classified these clathrates into families of closely related materials depending on their host structures and behavioural properties.[90] This big family includes classic clathrate hosts[123,124], Dianin’s compound and its derivatives[125], inclined aromatic planes[126], multi-legged hosts[127,128], helical tubuland diols[118-122], highly porous organics[129,130],

23 hosts with trigonal symmetry[131] and halogenated diheteroaromatic hosts[132-135]. A brief selection of examples from some of these sub-families will be discussed in detail.

Bile acids

The bile acids are a group of natural compounds produced in the liver. They are also able to form inclusion compounds named collectively as choleic acids. The steroidal skeleton of the bile acid cholic acid 3has a dish-like topology with two angular methyl groups and an alkyl side chain extended from its convex face. Around 17 of these steroidal compounds have been shown to act as inclusion host molecules. The dish-like host molecules have a strong tendency to pack concave face to concave face through interaction of their polar groups. A bilayer structure is therefore produced and guest molecules occupy the void spaces. One inclusion compound, (3)·(ethyl acetate), is shown in Figure 1.9.[136]

Figure 1.9 Part of the structure of (3)·(ethylacetate) showing a typical host bilayer assembly with enclathrated guest molecules. Colour code: H, light blue; O, red; host C, green; guest C, purple or orange crystallographically independent guest molecules.

Host–host hydrogen bonding is indicated by dashed lines.[136]

Dishes in the kitchen are stacked in a concave face to convex face manner. Therefore

Bishop proposed that dish-like shaped molecules display supramolecular awkwardness if they do not pack in this way. Molecules exhibiting supramolecular awkwardness are prone to adopting more than one crystal form and forming inclusion compounds.

Bicyclo[3.3.0]octane derivatives 4, 5, 6 have a shallow dish-like shape and have been proved to behave as good hosts in earlier work by the Bishop group. The compounds 5,

6 also crystallise in multiple crystal forms.[137-139]

5 6

V-shaped diquinoline systems

The design of new crystals with specific properties is made simpler by using relatively strong and directional intermolecular forces such as hydrogen bonding[140] and coordination interactions[141].These processes have been widely studied and are well understood. However, much less is known by us about how the weaker intermolecular interactions can be utilised in the design and synthesis of new crystals with desired properties and functions.[142] Interactions such as Pi…Pi (OFF), C-H…Pi (EF), and halogen…Pi are three well-known examples, illustrated in Figure 1.10 that we would like to utilise in such work.

Figure 1.10 Pi…Pi (OFF), C-H…Pi (EF), Halogen…Pi interactions.[142]

A concept for designing new clathrate systems was devised by Bishop several years ago.

The host molecules are constructed from three subunits, as shown in Figure 1.11, all of which play indispensable functions in achieving the ultimate goal.[57]

Figure 1.11 The generic structure of designed V-shaped hosts compounds showing three subunits.

(1) The central linkage is a small bicyclic ring that imparts actual or pseudo-C2 symmetry to the host, which therefore can be investigated as either the racemate or the chirally pure compound. Additionally, the linker also gives a degree of conformational freedom to the host so that it can adjust itself to accommodate guest molecules of differing sizes, shapes and functionalities.

(2) The two aromatic rings promote the C-H…Pi and Pi…Pi interactions.

(3) Introduction of halogen substituents, either on the aliphatic bicyclic ring or on the aromatic wings reduce the three dimensional propagation of the aromatic interactions and generate the awkwardness.

This principle[90] deliberately avoids traditional strong interactions and provided a pure environment for probing the roles of weaker interactions in crystal formation. A group of host compounds, some of which are shown in Figure 1.12, have been synthesized

27 based on this principle and eighteen out of nineteen compounds produced clathrate products (a 95% success rate).

7 8

9 10

11 12

Figure 1.12 Some host compounds synthesized following the designing principle.

As the first compound obtained in this study, the structure of (7)·(CHCl3) involves an edge-edge (EE) aryl C-H…N dimer (Figure 1.13) packing mode.[143] Hosts 8 and 9 also produced clathrate compounds adopting edge to edge aryl C-H…N dimers but in a modified manner.

Figure 1.13 The centrosymmetric aryl edge–edge (EE) C–H…N dimer interaction formed between two enantiomers of 7.[143]

V-shaped diquinoline compounds preferentially adopt a host-host arrangement termed the parallel 4-fold aryl embrace (P4AE) by Dance and Scudder.[144,145] This centrosymmetric motif comprises two EF interactions and one OFF interaction between two opposite enantiomers. A guest molecule can slip in between if the two molecules are pulled apart, and then a molecular pen is formed, as shown in Figure 1.14.[142] This penannular motif dominates the structure of all inclusion compounds yielded by

10.[57,146]

Figure 1.14 P4AE packing motif with and without a guest molecule between two host molecules.[142]

Apart from the EE C-H…N dimer, a different bifurcated C-H…N interaction connects adjacent layers in clathrates formed by 10 (Figure 1.15).

Figure 1.15 The bifurcated Ar-H…N EE interaction that links layers of molecular pens in the clathrate compounds formed by 10.[142]

Compound 11 (X=Br or I) employs a slightly different packing mode with respect to host-host associations: The two EF interactions are replaced by four Br…Pi interactions, as shown in Figure 1.16. This host-host arrangement is the named Pi…halogen dimer

(PHD) interaction.[134]

Figure 1.16 The Pi…halogen dimer (PHD) is formed in all inclusion compounds formed by 11.[134] 30

Most of these V-shaped molecules are not capable of differentiating the guest molecules they include and a wide range of guests are trapped. An exception is 12 that exclusively traps small aromatic molecules, such as benzene and toluene, but excludes all other types.[147]

Inclusion chemistry has now reached a level of maturity and at present attention is mainly focused on applicable properties and functions which are directly related to crystal structure. Host compounds with the ability of selective absorption and release under specific conditions, both in chemical and biological domains, are in the spotlight of current research.

1.8 Polymorphism

Polymorphism is the phenomenon in crystals where the same chemical substance exhibits different arrangements of molecules. Sharma has defined polymorphs as being

“different crystal forms, belonging to the same or different crystal systems, in which the identical units of the same element or the identical units are packed differently”.[148]

[149] The first organic polymorph discovered by WÖhler and Liebig was benzamide. With the advancement of our understanding in crystallography and also in the development of analytical techniques, this once unusual and mysterious phenomenon has become an important area in crystal engineering. The phenomenon is still difficult to understand, and more so to predict, but it is of great importance in legal and commercial aspects of drug manufacture.[150]

People have become more aware that it is not so unusual for organic compounds to produce polymorphs. Compounds like naphthazarin, thiourea and 2-thiobarbituric acid generate more than 10 polymorphs each.[13] Does every compound tend to yield polymorphs? This is not always the case. Urea, naphthalene and benzoic acid are three examples that have never yielded a second crystal form despite enormous research efforts during last two decades.[151] In this sense, you cannot predict the occurrence and frequency of polymorphism in organic compounds. In 1970, McCrone made a stimulating statement that “every compound has different polymorphic forms and the number of forms known for a given compounds is proportional to the time and energy spent in research on that compound”.[152] It is the source of much current discussion to what extent this provocative assertion is true. It is interesting that McCrone did not restrict his comment with respect to temperature and pressure. The majority of crystallisation studies are conducted close to laboratory temperature and pressure.

Calculation shows that for a given organic compound there could exist theoretically a large number of potential polymorphs. Each polymorph of a given compound is expected to be close in energy such that around 100-150 crystal structures might be identified within 2 kcal mol-1 from the global minimum.[153]

Crystallisation of polymorphs is difficult to control due to the competing outcomes both kinetically and thermodynamically during the whole crystal growth process. Due to the extreme complexity of crystallisation, incidents of obtaining unwelcomed crystal forms can happen. This is therefore of major concern in the pharmaceutical industry as such new polymorphs can impact heavily on the marketing and patenting of drugs. An approximate 30-50 % of pharmaceutically important compounds in the market are known to exhibit polymorphism.[153] A well-known case is from the drug company,

Abbott, who were not able to reproduce the original form of the HIV medicine

Ritonavirin 1998 due to the emergency of a second polymorph which is less effective and can also convert the original form into its own type.[154] Thus, drug companies attempt to identify all the possible polymorphs with a view to securing wider patent coverage. There are also some worse cases where the initially isolated crystal form cannot be reproduced. This once obtained polymorph is called a disappearing polymorph.[155] Additionally, different polymorphs are different materials and so always display different morphologies, shelf life, solubilities and bioavailabilities. Morphology is of paramount importance in manufacturing processes such as filtration, drying, tableting.[156]

Organic polymorphs can be classified into three different groups: conformational, packing and tautomeric polymorphs.

In conformational polymorphism, just as the name implies, each crystal polymorph contains a different conformation of the same molecule. Some parts of a molecule are inclined to adopt different orientations, such as ester, amide and phenyl groups, due the free rotation of σ bonds which leads to a different conformation in the solid state.[157-160]

Muscle relaxant metaxalone is a good example, as shown in Figure 1.17.

13 Figure 1.17 (left) Chemical diagram of metaxalone. (right) conformational comparison of metaxalone13 from its three polymorphs.[160]

Packing polymorphism, also named orientational polymorphism, is caused by the differences in the mutual arrangement of the same molecule in different crystals. In packing polymorphs, there is no conformational difference between molecules in each crystal form.[161]

Tautomeric polymorphism is apparently triggered by tautomerism. Tautomers generally equilibrate in solution at the temperature at which the solid forms are obtained. An example is shown in Figure 1.18 by the drug omeprazole.[162]

14 Figure 1.18 The tautomerism of omeprazole 14.[162]

In addition to pure chemical compounds, polymorphs can also be formed by solvates, co-crystals and hydrates. It still remains challenging to predict the occurrence of polymorphism or control the formation of a particular polymorph.[163,164]

1.9 Hydrates

Hydrates, the inclusion of water in the molecular solid, are reactively common substances. The hydrate isolated and described as a loose addition compound of chlorine and water by Humphry Davy in 1811 was the first case whose host-guest stoichiometry was clearly determined.[165] We understand today that water molecules can act either as host or guest entities. Due to its small size and superb hydrogen bonding potential, water plays a critical role in many crystal structures.

In clathrate hydrates, water behaves as the host by forming water cages in which the guest molecules are trapped. Combustible ice, a clathrate hydrate of methane formed in the deep sea under high pressure and low temperature is an abundant source for natural gas.[166]

More generally, the water molecule performs as the guest of an organic host. When an organic molecule contains more hydrogen bonding acceptors than donors, water can often participate as a hydrogen bonding donor to balance the number of two-centred hydrogen bonds.[138]

1.10 Co-crystals

According to our definition here, a co-crystal consists of two or more hydrogen bonded molecular species. In the past decade, increasing attention and effort have been drawn to this continuously expanding area.[167-170]

In 1844, WÖhler reported the first organic co-crystal composed of quinone and hydroquinone in the ratio 1:1.[171] A CSD survey has demonstrated that most co-crystals form preferentially using heterosynthons rather than homosynthons. Two of the most common families of hydrogen bonded compounds, carboxylic acid and primary amide are excellent examples, as illustrated in Figure 1.19.[172] Acid-amide heterosynthons occur more frequently between two different components than the remaining two homosynthons.

acid-acidhomosynthon amide-amide homosynthon acid-amide heterosynthon

Figure 1.19 Homosynthons and heterosynthons formed by carboxylic acids and primary amides.[172]

Co-crystals have found a valuable role in the pharmaceutical industry, primarily because of their ability to modify physiochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API).[173-176]

Currently, crystal engineers apply a variety of strategies in order to adjust the properties of APIs, namely, the formation of solvates, polymorphs, hydrates, co-crystals and salts.

(Figure 1.20)[167]

Figure 1.20 The four most common strategies for API modification.[167]

However, there are limitations such as that some compounds may not be able to form solvates/hydrates, extreme conditions might be needed to yield polymorphs and the lack of ionisable sites may prevent salt formation. In such cases, the use of co-crystals provides an alternative method to fine-tune API properties, such as melting point, chemical and physical stability, solubility, dissolution and bioavailability.

1.11 Aims of the Project

The bicyclo[3.3.0]octane ring has a shallow dish-like shape and it is also able to bend or twist to some degree.[138] This shape of the bicyclic ring can therefore be utilized to generate the supramolecular awkwardness which can result in multiple crystal forms.

Synthetic methods were applied to modify the functional groups on the periphery of the ring so that desired intermolecular interactions will be employed in the crystal.

Many compounds contain this ring skeleton, but almost no work has been carried out on their crystal engineering properties. This project focuses on revealing crystallization properties of families of bicyclo[3.3.0]octane derivatives, and also on understanding further how different crystal forms can be achieved. We also hope to gain deeper insight into the prediction and control of crystal structures with our compounds.

CHAPTER 2

Multiple Crystal Forms of Bicyclo[3.3.0]octane Tetraester

2.1 Introduction

The ability of a given compound to produce more than one crystal form is a topic of much contemporary interest both in the academic research and industrial fields. It is becoming more and more widely accepted that solid state diversity is far more frequent than was once believed. Hence, it should not be too surprising to obtain multiple crystal forms from just one single compound. In order to test our design concept that molecules packing awkwardly in their pure state are likely to crystallise in more than one crystal form, the racemic compound 2,4,6,8-tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene-

3,7-diol 15 was chosen as a candidate to be thoroughly examined with respect to its crystal engineering properties.

15 What exactly is meant by awkwardness in this context? In order to achieve high packing efficiency and low energy, molecules may adopt alternative crystal packing modes by including guests, as frequently seen in protein structures. On the other hand, a molecule as simple and highly symmetrical as hydroquinone 1 produces several different crystal forms, one of which has 54 hydroquinone molecules in its unit cell.[177] This shows to us that supramolecular awkwardness must also be taken into account. Not merely the shape

40 of the molecule but also the requirements imposed by the intermolecular forces, are of the utmost importance.

In the first structure of tetraester 15 reported by Escobar et al.[178], molecules of the racemic tetraester 15 adopt a dish-like shape and pack using a concave face to concave face double-dish unit. This packing mode is considered to be anti-intuitive and awkward, as dishes in the kitchen would preferentially stack in a concave face to convex face manner. Multiple crystal forms are expected to be possible where awkwardness exists.

2.2 Synthesis

The racemic tetraester 15 was synthesized using the Weiss reaction which is a condensation of one equivalent of glyoxal 16 with two equivalents of dimethyl 3- ketoglutarate 17, as shown below.[179]

16 17 15 Scheme 2.1 Synthesis of the racemic tetraester 15 following the Weiss reaction.

2.3 Crystal Structures of Tetraester 15

The first apohost structure, designated as Form 1, was first obtained from acetone by

Escobar et al.[178] This structure shows indications of inefficient packing where the concave face to concave face double-dish unit prevails. Due to our long-standing interest in the crystal structure of alicyclic diols and especially those with potential of adopting multiple crystal forms, we believed that the crystallisation properties of tetraester 15 were worthy of closer examination.

Further screening proved our assumption and gave us another three crystal forms, including a second apohost structure (Form 2), a big family of essentially isostructural inclusion compounds (Form 3) and a tetrahydrofuran (THF) inclusion solvate (Form 4).

More interestingly, the crystallisation of this host compound from mixed solvents showed unique correlations as to the requirements for obtaining inclusion crystal Form

3. Crystallisation from small polar solvents (chloroform, methanol, dichloromethane, acetonitrile, acetone) or hydrocarbons (cyclopentane, cyclohexane, cycloheptane, cyclooctane) merely yielded solvent-free crystal Form 1. However, a mixture of solvents from each group produced inclusion crystals with varying guest ratios. This unusual phenomenon will be presented and discussed later in this chapter.

Numerical details of the solution and refinement of the crystal structures are presented in Table 2.1.

Table 2.1 Numerical details of the crystal structures of 15.

THF apohost apohost p-xylene clathrate, crystal form polymorph 1, polymorph 2, clathrate,

Form 1 Form 2 Form 3 Form 4 (15) · [178 2 compound 15 ] 15 (15)2·(THF) (p-xylene)

(C16H18O10)2· (C16H18O10)2· formula C16H18O10 C16H18O10 (C6H6) (C4H8O) formula mass 370.3 370.30 423.38 402.83 crystal system, Monoclinic, Monoclinic, Triclinic, P-1 Monoclinic Cc space group P21/n P21/c temperature (K) 294 150 150 150 12.261 (6), 7.2550 (2), 11.0883 (5), 22.9208 (17), a, b, c (Å) 12.555 (5), 9.2807 (3), 8.5689 (3), 17.0618 (15), 12.522 (6) 13.0344 (4) 21.5332 (9) 21.6623 (17) 90 77.359 (1), 90 90 α, β, γ (°) 114.50 (2) 78.816 (1), 93.104 (1) 99.580 (2) 90 88.811 (1) 90 90 V (Å3) 1754 (1) 839.87 (4) 2042.97 (14) 8353.3 (12) Z 4 2 4 16 Radiation type Mo Kα Mo Kα Mo Kα Mo Kα μ (mm−1) 0.11 0.12 0.11 0.11 0.20 × 0.20 × 0.23 × 0.20 × 0.46 × 0.44 × 0.30 × 0.29 × crystal size (mm) 0.15 0.19 0.37 0.22

Tmin, Tmax 0.973, 0.977 0.951, 0.960 No. of measured, independent 2568, 2441, 11935, 2945, 14126, 3587, 28710, 12355, and observed [I > 2σ(I)] 1097 2743 3242 4682 reflections Rint 0.021 0.041 0.045 0.048 0.047, 0.055, 0.033, 0.089, 0.037, 0.142, 0.098, 0.332, R [F2 > 2σ(F2)], wR(F2), S 1.67 1.05 1.20 1.70 no. of reflections 1097 2945 3587 12355 no. of parameters 142 247 276 1029 no. of restraints 0 0 0 2 −3 Δρmax, Δρmin (e Å ) 0.68, −0.62 0.23, −0.22 0.31, −0.22 1.57, −0.44

2.3.1 The Apohost Structure of Tetraester 15 (Form 1)

As reported, crystallisation of racemic tetraester 15 from either methanol or acetone at room temperature produced X-ray quality single crystals in space group P21/n that are free of included solvent. Highly crystalline material of the same structure as Form 1 was also obtained from cyclopentane, cyclohexane, dichloromethane or t-butylbenzene at room temperature.

As seen in Figure. 2.1, the molecules of tetraester 15 adopt a shallow dish-like shape with a handle. Although tetraester 15 has C2-symmetry in solution, this is not carried through to its solid state where one non-conjugated ester group is oriented differently and occupies a protruding position. There is intramolecular hydrogen bonding between each enol group and the carbonyl oxygen of its adjacent conjugated ester group. The

O…H distance for both intramolecular hydrogen bonds is 1.911 and 1.885 Հ respectively. This motif persists even though the polar solvent methanol with a strong hydrogen bond donor group had been used its recrystallisation.

Figure 2.1 The molecular conformation adopted by tetraester 15 in crystal Form 1. The intramolecular hydrogen bonding is indicated by dashed lines. Atom code: C green, O red, H grey.

There is no strong intermolecular hydrogen bonding in Form 1 and only weak interactions such as C-H…O and orthogonal C=O…C=O contacts operate. The protruding ester group, together with the hydrogen atoms on the bridgehead carbons, prevent the molecules of tetraester 15 stacking in a concave face to convex face manner.

On the contrary, two molecules of the opposite handedness associate to form a centrosymmetric double-dish unit by means of C-H…O interactions, as shown in Figure

2.2.

Figure 2.2 The centrosymmetric double-dish unit formed by opposite enantiomers of tetraester 15 in crystal Form 1. Opposite enantiomers are indicated by light and dark green.

The double-dish unit constitutes an awkwardly shaped molecular combination, but the complete crystal structure is generated through the repetition of these units.

Enantiomers of the same handedness from each unit, linked by C-H…O interactions, surround 21 screw axes and the resulting helices of opposite enantiomers are connected using orthogonal C=O…C=O interactions which have a C…O distance of 2.962 Հ.

Figure 2.3 shows five double-dish units projected on the bc plane. This illustrates the C-

H…O interactions linking the homochiral molecules of 15 and also the dipolar carbonyl interactions between the helices.

Figure 2.3 Partial structure of the tetraester 15 in crystal Form 1 projected on the bc plane. The C-H…O interactions are indicated by thin black dashed lines and the orthogonal C=O…C=O interactions by thick blue dashes.

2.3.2 The New Apohost Structure of the Tetraester 15 (Form 2).

Crystallisation of racemic 15 from methanol at 0 Ԩ gave a new apohost crystal structure in space group P-1, which is a polymorph of crystal Form 1.

Crystal Form 2 has a rather simple structure where molecules of the same chirality are translated along both a and b directions. The molecules along b form hydrogen bonded chains using a cyclic motif (OH)2(CO)2 that includes two intramolecular and two intermolecular hydrogen bonds. Each hydroxy hydrogen atom acts as a donor to two carbonyl oxygens and each carbonyl oxygen acts as an acceptor for two hydroxy hydrogens, as shown in Figure 2.4.

Figure 2.4 Part of a hydrogen bonded chain along b in crystal Form 2 of tetraester 15.

A homochiral molecular layer is simply generated through the repetition of hydrogen bonded chains running along a. These chains of the same chirality are connected by C-

H…O and near-orthogonal C=O…C=O interactions, as shown in Figure 2.5. Layers of opposite handedness alternate along c and are joined by dimeric C-H…O weak interactions.

Figure 2.5 Part of the structure projected on the ab plane showing the interactions that connect the homochiral hydrogen bonded chains. (C=O…C=O is indicated by thick blue dashed lines and C-H…O by thick black dashed lines).

Figure 2.6 Part of the Form 2 structure projected on the bc plane showing the layers of alternating chirality. The opposite enantiomers are coloured light or dark green.

2.3.3 The Major Inclusion Crystal Form of the Tetraester 15 (Form 3)

Crystallisation screening of tetraester 15 at room temperature also revealed a big family of essentially isostructural inclusion compounds in space group P21/c (Form 3). These compounds include the guests: diethyl ether, toluene, trifluoromethylbenzene, carbon disulfide, o-, p-, m-xylene, n-hexane, chlorobenzene, 1,4-dioxane, butan-2-ol, 1,4- dichlorobenzene, cyclohexanol and methylcyclohexane. All these inclusion compounds share the same host-guest ratio 2:1 and only (15)2·(p-xylene) will be discussed in detail.

In Form 3, only strong intramolecular hydrogen bonding with O…H distances of 1.948 and 2.003 Հ is observed, which is similar to that adopted in crystal Form 1. As illustrated in Figure 2.7, hosts of the same handedness associate by surrounding a 21 screw axis along the b direction. In order to avoid steric hindrance from the protruding bridgehead hydrogen atoms, the host molecules are assembled around this screw axis in a concave face to convex face manner by means of two different C-H…O and two different near-orthogonal C=O…C=O interactions (2.956 and 3.096 Հሻ.

Figure 2.7 Part of the structure of (15)2·(p-xylene) showing the helical assembly of homochiral host molecules around a 21 screw axis along the b direction. C-H…O interactions are indicated by thin black dashed lines and near-orthogonal C=O…C=O interactions by thick blue dashed lines.

As shown in Figure 2.8, these 21 helices pack parallel to each other as homochiral assemblies in the ac plane. Layers of alternating chirality pack along c. Parallel channels running along the b direction are generated between four neighbouring helices and are occupied by the guest molecules. Each channel has the cross-sectional area of approximately 5.0Χ6.1 Հ2. The molecules of p-xylene are well ordered and anchored at each end by means of C-H…O interactions between guest methyl hydrogen atoms and host enol oxygens.

Figure 2.8 Part of the structure of (15)2·(p-xylene) projected on the ac plane. Opposite enantiomers are coloured light or dark green.

The only significant difference between the inclusion compounds of Form 3 lies in their host-guest interactions. All the guest molecules except p-xylene are disordered over at least two positions in the channel. Here we present the rest of the inclusion compounds obtained (Figure 2.9-2.15). Only one disorder component is shown for clarity.

Figure 2.9 Part of the structure of (15)2·(diethyl ether) and (15)2·(toluene) projected on the ac plane.

Figure 2.10 Part of the structure of (15)2·(trifluoromethylbenzene) and (15)2·(carbon disulfide) projected on the ac plane.

Figure 2.11 Part of the structure of (15)2·(o-xylene) and (15)2·(m-xylene) projected on the ac plane.

Figure 2.12 Part of the structure of (15)2·(THF) and (15)2·(n-hexane) projected on the ac plane.

Figure 2.13 Part of the structure of (15)2·(chlorobenzene) and (15)2·(1,4-dioxane) projected on the ac plane.

Figure 2.14 Part of the structure of (15)2·(2-butan-ol) and (15)2·(1,4-dichlorobenzene) projected on the ac plane.

Figure 2.15 Part of the structure of (15)2·(cyclohexanol) and (15)2·(methyl cyclohexane) projected on the ac plane.

2.3.4 Crystal Structure of (15)2·(THF) (Form 4)

Another crystal form (Form 4) in space group Cc was obtained when tetraester 15 was recrystallised from pure tetrahydrofuran (THF) under ambient conditions. The unit cell dimensions are a=22.9 b=17.1 c=21.7 Հ compared to a=11.0 b=8.6 c=21.5 Հ in Form 3

(p-xylene). Apparently, two dimensions of the unit cell in Form 4 have been doubled while the third dimension remains unchanged. This also reflects, to some extent, the high similarities between these two crystal structures.

If we have a close look at one repeat unit in Form 4, as shown in Figure 2.16, we can observe that tetrahydrofuran (THF) molecules are stacked on top of each other along the channel. Due to its relatively small molecular size compared to that of guests in Form 3,

THF molecules in Form 4 are not able to establish sufficient interactions with the host, which also explains why the guest THF molecules have low occupancy in the structure.

Notably, THF molecules are orientated in a nearly parallel position to the cross-section of the channel.

Figure 2.16 Part of the crystal structure in (15)2·(THF) (Form 4) where the hydrogen atoms and extra disordered positions of THF are omitted for clarity.

2.3.5 Discussion

The calculated densities of the three main structures are 1.401g cm-3 (Form 1), 1.464 g cm-3 (Form 2), 1.377 g cm-3 (p-xylene compound, Form 3). It is notable that both apohost crystal forms were obtained from methanol solution, but at different temperatures. The density of form 2 (obtained at 0 Ԩ) is considerable higher than of form 1 (obtained at 20 Ԩ). The packing coefficients of Forms 1-3 are 67.7%, 70.4% and

68.7%. These values indicate that Form 2 has a better packed structure than Form 1.

Conformational change is one of the means by which a molecule can achieve alternative crystal forms. As shown in Figure 2.17, the conformations adopted by the three main crystal forms are generally similar apart from the orientation of one ester group, which results in significant changes in molecular shape. The ester group protrudes outwards like a handle in Form 1 while it adopts more compact orientation in

Form 3 simply by rotating the ester group in Form 1 by 180°. The Form 2 is closer in overall shape to Form 1 than Form 3.

Figure 2.17 Left: Side view of tetraester 15 in three crystal forms: Form 1 (orange),

Form 2 (blue), Form 3 (p-xylene) (magenta). Right: Overlap of the three conformations of tetraester 15.

The Forms 1 and 3 show some structural similarity with both containing molecules of

15 arranged around twofold screw axes. Helices of opposite handedness alternate along c in Form 1 and leave no space for guest inclusion. However, in Form 3, the opposite helices are separated through the insertion of guest molecules. All three forms undergo a considerable degree of enantiomer separation into homochiral layers and helices during their crystal formation, as shown in Figure 2.18.

Figure 2.18 Left: Part of the structure in Form 1 projected on the bc plane. Right: The inclusion compound containing p-xylene (Form 3) also in the bc plane. Colour code: molecules of 15 green (opposite enantiomers dark or light green), p-xylene blue.

2.3.6 Inclusion Compounds of Tetraester 15 From Solvent Mixtures

Approximately half the test solvents yielded the apohost crystal Form 1, and the remainder the inclusion Form 3. All the experiments were conducted at room temperature and pressure (apart from Form 2) and therefore the crystallisation outcome relies solely on the solvent. There appears to be little correlation between outcome and solvent polarity or functionality. On the other hand, it was observed that methylcyclohexane is included by the host while cyclohexane is not; o- and m-xylene are disordered over two positions to achieve better interactions with the host; and smaller molecular solvents such as methanol, acetone, dichloromethane and chloroform only gave the solvent-free crystal Form 1. Therefore the molecular size of the guest plays a key role.

We were then wondering what if a two-component mixture solvent were used for crystallisation? Could the combination of cyclohexane with chloroform give rise to inclusion where both their pure individual components fail. Surprisingly, the inclusion

Form 3 crystals were obtained from this purposely mixed solvent, although only chloroform was included in a highly disordered and low occupancy state.

A thorough study of crystallisation of the tetraester using solvent mixtures was then commenced. As cyclohexane has a close structure to methylcyclohexane, a mixture of chloroform and cyclohexane (1:1 v/v) was used first as crystallisation solvent and inclusion crystal Form 3 was obtained. In this case, both cyclohexane and chloroform were included in an almost equal ratio. Next, other cyclic hydrocarbon solvents

(cyclopentane, cycloheptane and cyclooctane) were used as co-solvents with chloroform.

Not so surprisingly, mixed solvents containing cylcopentane or cycloheptane yielded crystal Form 3 while Form 1 was observed from the cyclooctane mixture solvent.

Failure to include cyclooctane can be accounted for since cyclooctane is too large to occupy the channel formed by the host molecules.

As a polar cyclic molecule, THF was also tested as a co-solvent with chloroform.

Interestingly, this mixture produced the inclusion crystal Form 3 (P21/c) rather than previous Form 4 (Cc). As seen in Figure 2.19, two significant differences between these two structures are the orientation of the THF molecules and the host-guest interactions.

The THF molecules in Form 3 are orientated with their plane nearly perpendicular to the cross-section of the channel, while the THF plane is parallel to the channel cross-section in Form 4. In addition, the THF molecules in Form 3 are less disordered and employ much stronger host-O-H..O-guest interactions while THF only utilises dispersion forces in Form 4.

Figure 2.19 Part of the structure of (15)2·(THF) (Form 3) viewed down the channel

(projected on the ac plane) where THF is disordered over two positions, and the hydrogen atoms are omitted for clarity.

Based on all the observations mentioned above, the scope of solvent inclusion was considerably extended. Other small but polar solvent molecules were utilised as co- 60 solvents with cyclic hydrocarbons. A experimental matrix containing all combinations of small polar solvents and cyclic hydrocarbons was set up, as shown in Table 2.2.

As shown in the first row and first column, single pure solvents were used for crystallisation and solvent-free Form 1 was produced exclusively. In the methanol column, mixturex with cylcohexane or cycloheptane yielded inclusion Form 3 and the rest failed. In acetone and acetonitrile mixtures, only one mixture worked to give inclusion in each column (cyclohexane and cycloheptane, respectively). The results of chloroform mixture have already been described.

The most remarkable result came from mixed solvents with dichloromethane. In mixtures containing cyclopentane, cycloheptane or cyclooctane, only dichloromethane was included as guest and it was situated in the host channel without any disorder.

Weak host-guest interactions such as CH…Cl and C=O…Cl were present to stabilise the guest molecule (Figure 2.20).

Figure 2.20 Dichloromethane is preferred over other partner solvents. It has high occupancy and is anchored perfectly in the channel.

Table 2.2 The summary of crystallisation results of 15 using mixed solvents

solvent A none methanol acetone chloroform dicholoromethane acetonitrile solvent B None Form 1 Form 1 Form 1 Form 1 Form 1

CHCl3 CH2Cl2 cyclopentane Form 1 Form 1 Form 1 Form 1 5:1 1:1

cyclohexane C6H12 C3H6O+C6H12 CHCl3+C6H12 CH2Cl2+C6H12 Form 1 Form 1 2:1 2:1:1 2:1:1 2:1:1

C7H14 CHCl3+C7H14 CH2Cl2 C7H14 cycloheptane Form 1 Form 1 2:1 4:1:1 1:1 2:1

CH2Cl2 cyclooctane Form 1 Form 1 Form 1 Form 1 Form 1 1:1

N.B. Pink or green colours indicate the apohost form 1 or inclusion form 3, respectively. Molecular formulae in each cell signify the guest included in that particular case. Ratio of two digits stands for host/guest and the three digits ratio means host/guest A/guest B.

What is even more surprising is that there seems to be a critical concentration of the combination of chloroform and cyclohexane for the formation of inclusion. The last experiment that gave us the inclusion Form 3 was obtained when the ratio of chloroform is lowered to 5% (v/v). (5mg tetraester and 0.4 mL mixture solvent were used in this experiment). No inclusion compound was ever observed, and instead crystal Form 1 was once again produced, when the chloroform ratio was below 5%.

As aforementioned, the tetraester 15 conformation in crystal Forms 1 and 3 is notably different as regards the orientation of one of the four carbomethoxy groups. It is well known that the solvation-desolvation process is one of the key factors in crystallisation.

In solution, a complex of two components in the mixture solvent could be formed through weak forces. The host molecules in this solution are surrounded by this type of solvent complexation. It is possible that the combination of two solvents displaces the

62 solution conformational equilibria in favour of Form 3. In this way that the channel started to be constructed.

Alternatively, a binary complex of the two solvents may have the optimum size to stabilise, and then occupy, the host cavity spaces of Form 3. This could possibly explain why dichloromethane is situated so perfectly in the channel in the mixture solvent case whereas it is not included when just pure dichloromethane is used.

Due to the differences in binding strength of different solvents to the host molecules in the channel, some might stay in the channel and some may escape, thus resulting in a different host-guest ratio.

Typical examples of the different inclusion compounds obtained from these mixture solvent studies are shown in Figure 2.21 and 2.22.

Figure 2.21 Acetone and cyclohexane can both be included when this combination was used as the solvent for crystallisation.

Figure 2.22 Cycloheptane is trapped in the cavity when host compound 15 was crystallised from a mixture solvent of acetonitrile and cycloheptane.

A combination of three different polar solvents (methanol+acetone+chloroform, 1:1:1 v/v) was also tested for recrystallization and this just gave the apohost crystal Form 1.

2.4 Conclusions

The published structure of Form 1 involves an awkwardly shaped concave face to concave face unit, which led us to investigate the possibility of alternative crystal forms.

Our views were vindicated by discovery of a new apohost polymorph (Form 2) and a large group of essentially isostructural inclusion compounds (Form 3). These results support our design theory that awkward molecules would have high probability of adopting multiple crystal forms. A second inclusion structure (Form 4) was also produced from tetrahydrofuran (THF) solution.

Apart from being a molecule yielding different crystal forms, the tetraester 15 also amazed us with its unprecedented crystallisation behaviour. Mixture solvents made the inclusion Form 3 possible for several cases where the pure single component only produced apohost crystals. This observation has little precedent and has revealed an aspect of inclusion chemistry that deserves further investigation in the future.

CHAPTER 3

Methyl Derivatives of the Tetraester

3.1 Introduction

As discussed in the last chapter, the racemic compound 2,4,6,8- tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene-3,7-diol 15 has been revealed to adopt more than one crystal form, namely two solvent-free polymorphs and a big family of essentially isostructural lattice inclusion compounds (solvates) and a unique THF solvate, in which weak C-H…O and orthogonal C=O…C=O interactions prevail. Apart from acting as a versatile compound with multiple crystal forms, it also shows distinctively unique properties by which normally excluded solvents can then be included when solvent mixture were applied for crystal growth.

With all these in mind, we intended next to fine-tune the crystal engineering properties of the tetraester 15 by exerting minimum change on its chemical structure. Of a large number of potential substituent groups, the methyl group is about the smallest one, but one that sometimes plays a surprisingly important role in supramolecular chemistry. It will not alter the molecular shape and volume drastically, but in the meantime it is likely to result in extra findings. The next benefit that the methyl group provides is that it will not be involved in energetically strong supramolecular interactions. Hence, its properties will not dominate the weak interactions such as C-H…O and orthogonal

C=O…C=O in its new crystal structures. We were anxious to understand how these minimal chemical changes will influence the crystal engineering characteristics of the

66 original tetraester 15. Therefore, the methyl group was chosen to be incorporated into the tetraester structure.

3.2 Synthesis

Regarding the number of active sites on the bicyclic core, up to four methyl groups can be attached. Methyl iodide was used as a methylation reagent to synthesize methyl derivatives of tetraester through nucleophilic substitution. The five potential products are referred as the monomethyl-, trans- and cis-dimethyl-, trimethyl- and tetramethyl tetraester, respectively.

18 19 20

Monomethyl tetraester trans- and cis- Dimethyl tetraester

21 22

Trimethyl tetraester Tetramethyl tetraester

As we initially imagined in Scheme 3.1, the number of methyl groups attached to the core would be simply controlled by adjusting the number of equivalents of methyl iodide used. Thus, mono-, di-, tri- and tetramethyl derivatives would be obtained by adding one, two, three or four equivalents of methyl iodide to each reaction. The disodium salt 23 of tetraester was used as a reagent instead of the tetraester 15 itself

68 because of its stronger nucleophilic potency. In all the trial reactions, the reaction temperature was kept at room temperature and water was added as co-solvent with methanol to solubilise the disodium salt due to its poor solubility in pure organic solvents.

Scheme 3.1 Initially proposed synthetic route.

The reactions were all monitored by TLC which showed that some unreacted tetraester

15 always remained even with the reaction time as long as 4 days. The crude reaction mixture dissolved in methanol was left to evaporate at room temperature after standard workup. Needle-like crystals were always isolated no matter how many equivalents of methyl iodide had been added to the reaction as long as the reaction time was more than

12 hours. These needle-like crystals were later characterised to be the pure trimethyl tetraester product 21.

Based on the observations accumulated, it appeared that the trimethyl derivative 21 is the most stable product under the trial reaction conditions. Apparently, a relatively fast three-step reaction process takes place, giving the trimethyl compound as the major product in all the trial reactions. It was possible to isolate very small quantities of the monomethyl 18 and cis-dimethyl tetraester 20 from these trial reactions. However, the trans-dimethyl compound could not be detected at all. Sufficient cis-dimethyl tetraester

20 was obtained for crystallisation studies.

Only one of these methylated compounds is described in the literature, and so preparations of the four unknown derivatives are required. The tetramethyl tetraester 22 was described by O’Hare in 2007.[180] This was obtained very simply by reacting the tetraester 15 with excess methyl iodide and potassium carbonate in refluxing acetone.

Its crystal structure was also reported.

15 22

Scheme 3.2 The reported method of synthesizing tetramethyl tetraester 22.[180]

Examination of the literature provided a potential means of obtaining the trans-dimethyl tetraester. Sieburth and Santos had reported that tetraester 15 underwent concomitant formation of the bis(enol ether) derivatives and also dimethylation to 24 using methyl iodide and a basic pyrrolidinone catalyst 27.[181] Cleavage of the bis(enol ether) groups using boron tribromide should then afford the required trans-dimethyl tetraester

(Scheme 3.3 and 3.4). This conversion was carried out successfully.

Scheme 3.3 Synthesis of the trans-dimethyl tetraester 19.[181]

Scheme 3.4 Synthesis of catalyst 27.[182,183]

With the successful syntheses of four methyl derivatives of the tetraester 15, the acquisition of adequate amounts of the pure monomethyl tetraester still remained a problem. It is so reactive at room temperature that it reacts with a second molecule of methyl iodide faster than the unmethylated tetraester. A strong base like the pyrrolidinone tetrabutyl ammonium salt 27 would be beneficial in two ways: first, it is a strong base allowing rapid deprotonation of the tetraester 15. Secondly, it leaves limited space around the tetraester 15 molecules due to the bulky ammonium cation. In addition, the reaction temperature was reduced to -78Ԩ.

Scheme 3.5 Synthesis of the monomethyl tetraester 18.

Base was added extremely slowly to the tetraester 15 solution in THF while the reaction mixture was maintained at -78 Ԩ. By doing so, we expected that the majority of the tetraester 15 would be mono-deprotonated and that this would react immediately with the same amount of methyl iodide to achieve the desired product. The result proved our hypothesis correct by giving us good quantities of the long-awaited monomethyl tetraester.

In all the preparations of methylated tetraester products, only exo-methyl products were detected. The bicyclo[3.3.0]octane ring skeleton has a V-shape and therefore methylation occurs preferentially on the more exposed face. It is also worth noting that all of the methylated tetraester derivatives are chiral molecules with the exception of the tetramethyl compound. Hence, the first four derivatives were obtained as racemic compounds.

In conclusion, we succeeded in synthesizing all five methyl derivatives of the tetraester as proposed, which paved the way for their crystal engineering investigation.

3.3 Crystal Structures of the Methylated Compounds

The five methyl derivatives of the tetraester 15 have been systematically screened and exhibit completely different properties from the mother compound, since none of these inherited the ability of including guest molecules.

Monomethyl tetraester 18 was found to form two solvent-free polymorphs (apohost) at room temperature and pressure. The trans-Dimethyl 19, cis-diemthyl 20 and trimethyl tetraesters 21 stubbornly produce only one crystal form for each of them. The derivative with the most methyl groups, the tetramethyl tetraester 22, is very versatile as it was found to form three solvent-free polymorphs in addition to the one published.

Numerical details of the solution and refinement of these crystal structures from all five methyl derivatives are presented in Table 3.1 and Table 3.2.

Table 3.1 Numerical details of the crystal structures of 18, 19 and 20.

apohost apohost crystal form apohost apohost polymorph 1 polymorph 2

compound 18 18 19 20

formula C17H20O10 C17H20O10 C18H22O10 (C18H22O10 formula mass 384.33 384.33 398.36 398.36

crystal system, Orthorhombic, Monoclinic, Orthorhombic Triclinic, P-1 space group P21/c P21/n Pca21 temperature (K) 150 150 293 154

6.3111 (4), 11.2299 (4), 18.930 (4), 9.0707 (14),

a, b, c (Å) 15.9491 (8), 9.6321 (3), 10.747 (2), 9.5912 (14), 17.4620 (9) 17.0593 (5) 17.976 (4) 11.5863 (18)

90 90 90 84.215 (8),

α, β, γ (°) 90 96.844 (2) 90 75.785 (8),

90 90 90 72.699 (7)

V (Å3) 1757.66 (17) 1832.11 (10) 3657.1 (13) 932.5 (2)

Z 3 4 8 2

Synchrotron, λ Radiation type Mo Kα Mo Kα Mo Kα = 0.71073 Å

μ (mm−1) 0.12 0.12 0.12 0.12

0.25 × 0.22 × 0.21 × 0.18 × 0.17 × 0.02 × 0.29 × 0.14 × crystal size (mm) 0.18 0.16 0.02 0.07

Tmin, Tmax 0.970, 0.979 0.976, 0.982 0.967, 0.992 No. of measured, 6889, 3049, 12136, 3181, 44794, 6361, 11352, 3224, independent and observed 2741 2635 6187 2372 [I > 2σ(I)] reflections

Rint 0.035 0.037 0.042 0.053

R [F2 > 2σ(F2)], wR(F2), 0.038, 0.109, 0.049, 0.129, 0.033, 0.091, 0.047, 0.132,

S 1.06 1.05 1.27 1.04

no. of reflections 3049 3181 6361 3224

no. of parameters 257 251 520 260 no. of restraints 0 0 1 0

−3 Δρmax, Δρmin (e Å ) 0.27, −0.20 0.38, −0.20 0.32, −0.19 0.21, −0.26

Table 3.2 Numerical details of the crystal structures of 21 and 22.

apohost apohost apohost apohost crystal form apohost polymorph 1 polymorph 2 polymorph 3 polymorph 4

compound 21 22[180] 22 22 22

formula C19H24O10 C20H26O10 C20H26O10 (C20H26O10 C20H26O10 formula mass 412.38 426.41 426.41 426.41 426.41

crystal system, Monoclinic Orthorhombic Triclinic Triclinic Monolinic

space group P21/c P212121 P-1 P-1 P21/c temperature (K) 150 150 150 150 293

10.862 (5), 11.6929 (2), 8.6454 (2), 14.3729(12), 14.300 (4),

a, b, c (Å) 17.277 (8), 11.9874 (2), 14.6909 (4), 16.9165(16), 30.828 (4), 12.120 (5) 14.3447 (3) 16.4880 (5) 18.7126 (17) 23.516 (3)

90 90 97.580 (2), 75.006 (3), 90,

α, β, γ (°) 116.62 90 90.271 (1), 89.962 (4), 127.451 (9),

90 90 97.418 (1) 71.053 (3) 90

V (Å3) 2033.4 (15) 2010.66 2057.94 (10) 4139.4 (6) 8230 (3)

Z 4 4 4 8 4

Radiation type Mo Kα Mo Kα Mo Kα Mo Kα Mo Kα

μ (mm−1) 0.11 0.11 0.11 0.11

0.44 × 0.07 0.41 × 0.36 0.50 × 0.27 0.39 × 0.22 crystal size (mm) × 0.06 × 0.22 × 0.22 × 0.13

Tmin, Tmax 0.953, 0.994 0.956, 0.976 0.947, 0.976 No. of measured,

independent and 13614, 29243, 61761, 27927,

observed [I > 2σ(I)] 3520, 1169 7204, 5750 14482, 9749 11949, 4928

reflections

Rint 0.197 0.060 0.084 0.062

R [F2 > 2σ(F2)], 0.058, 0.040, 0.113, 0.053,

wR(F2), S 0.182, 0.66 0.109, 1.01 0.309, 1.13 0.121, 1.05

no. of reflections 3520 7204 14482 11949 no. of parameters 269 557 1113 1113

no. of restraints 0 0 0 0

−3 Δρmax, Δρmin (e Å ) 0.26, −0.24 0.36, −0.39 0.78, −0.49 0.26, −0.29 75

3.3.1 Polymorph 1 of Monomethyl Tetraester 18

The crystallisation of racemic monomethyl tetraester 18 from the solvents methanol, tetrahydrofuran (THF), toluene, acetone and ethyl acetate gave polymorph 1 in monoclinic space group P21/c. Single crystal X-ray diffractometry was used to confirm that the crystal structures were identical in all cases. The calculated density is 1.452 g cm-3. The compound 18 adopts two cyclic intramolecular hydrogen bonds, between each enol hydroxy group and the carbonyl oxygen of its adjacent conjugated ester groups. We were surprised by the large length difference of these two hydrogen bonds,

1.901 Հ and 2.146 Հ, respectively (Figure 3.1). These motifs are dominant in the structure even though polar solvents like methanol had been used for crystal growth. It should be noted that the hydrogen bond near the introduced methyl group is longer than the other. The overall crystal engineering properties are affected with resulting change in molecular shape, electron density and orientation of the ester groups.

With two conjugated ester groups involved in hydrogen bonding, the remaining two are able to enjoy rotational freedom in solution. However, in the solid state these non- conjugated ester groups are orientated differently to each other. The one proximal to the methyl group is oriented inwards towards the bicyclic core and the remaining ester group does the opposite.

1.901Հ

2.146Հ

Figure 3.1 The molecular conformation adopted by monomethyl derivative 18 in polymorph 1. Hydrogen bonding is indicated by dashed lines. Atom code: C green. O red. H grey.

Polymorph 1 contains homochiral layers in the ab plane. Molecules are linked into infinite chains along b by means of hydroxy group hydrogen bonding. The linking motif comprises the original intramolecular association in combination with two intermolecular interactions. Adjacent chains are repeated along a to complete the homochiral layer (Figure 3.2).

Figure 3.2 Part of a homochiral layer of monomethyl tetraester 18 polymorph 1 with molecules projected on the ab plane. Hydrogens are omitted for the purpose of clarity.

Layers of opposite chirality alternate along the c axis and are connected by means of weak C-H…O and C-H…C=O interactions where the hydrogens are donated from the methyl group of the protruding ester group. Due to disturbance caused by both the protruding methyl and ester groups in each molecule, off-set concave to concave face or convex to convex face stacking is preferred instead of the layers stacking directly on top of each other in order to achieve more efficient packing. The positioning of molecules in the layers can be seen more clearly from the side view (Figure 3.4).

Figure 3.3 Packing of 18 projected on the bc plane showing the layers of alternating handedness along the c axis. Each layer is stabilised by C-H…O (black dots) and C-

H…C=O Pi (blue dots) weak interactions.

Figure 3.4 Side view of two layers stacking in an off-set concave to convex manner in the monomethyl tetraester 18 polymorph 1 structure.

3.3.2 Polymorph 2 of Monomethyl Tetraester 18

Polymorph 2 of the monomethyl tetraester was produced only once from methanol. All attempts to reproduce this polymorphic crystal form turned out to be in vain.

Disappearing polymorphs have harassed many chemists both in university research groups and industry laboratories. The loss in control over the reproducibility is disturbing and can incur the loss of time, money and other resources. As chemists, we would like to believe that all our results are reproducible if all the conditions can be repeated in exactly the same way. Unfortunately, there are too many factors, known or unknown, that affect the whole process of crystal growth and some of these are still beyond our comprehension.

Polymorph 2 crystallised in the monoclinic space group P21/n with the significantly smaller density of 1.393 g cm-3 compared to polymorph 1. Homochiral molecules along the b axis form a hydrogen bonded chain by using a cyclic (OH)2(C=O)2 motif that combines two intramolecular hydrogen bonds and two intermolecular links. Molecules along the c axis have alternating handedness and associate by C-H…O interaction as shown in Figure 3.5. Each hydroxy hydrogen atom behaves as a donor to two carbonyl oxygens and each carbonyl oxygen acts as an acceptor for two hydroxy hydrogens. The intramolecular hydrogen bonds are of nearly the same length, (2.057 Հ and 2.080 Հሻǡ while the two intermolecular hydrogen bonds are 2.223 Հ and 2.304 Հ. A further difference from the polymorph 1 structure is that in each hydrogen bonded chain, all molecules have the same orientation.

Figure 3.5 Part of a layer of molecule 18 projected on the bc plane in the polymorph 2 structure. The O-H…O and C-H…O hydrogen bonds are indicated as black dashed lines.

Figure 3.6 C-H…O weak interactions in polymorph 2. Upper: view of molecular packing down the b axis. Lower: view of a layer down the c axis.

Apart from O-H…O hydrogen bonding, the only evident interaction in this structure is

C-H…O weak interaction that prevails to arrange the hydrogen bonded chains into 82 layers and then the layers into three dimensional packing. Interestingly, the protruding ester group merely provides its ester carbonyl as an acceptor for C-H…O interaction, with the methyl group uninvolved this time, as shown in Figure 3.6.

3.3.3 Discussion on Polymorphs 1 and 2

All the test crystallisation solvents yielded polymorph 1, except that methanol also gave polymorph 2 once. These experiments were conducted at the same room temperature and pressure. Although there are multiple conditions of T and P that could be tested aiming to produce polymorph 2 once again, this would be a major undertaking. Hence, the polymorph 2 can be regarded as a disappearing polymorph. As we are all aware there is a variety of conditions that control crystallisation. For any crystallisation system it is indeed difficult to single out a particular factor that dominates the formation of a particular polymorph. It is the holistic fine balance of a large number of parameters such as solvent, temperature, degree of supersaturation, impurities, additives, cooling speed and so on, just to name a few, that determines the occurrence of a desired polymorph. In such a situation, it is almost impossible to maintain all parameters exactly the same, and whose slight change could lead to the destruction of the fragile balance on which formation of the particular polymorph depends.

However, one test that was not carried out is seeding. Seeding is a common practice that is applied to both milligram scale crystallisation in research facilities and large scale product purification in industry. Of course, this depends on having previously obtained crystals of the various crystal forms.

The two polymorphs of 18 involve different ester group conformations. Such conformation change is a common means for a molecule achieving alternative crystal forms. Details of conformational polymorphs have been discussed in the introduction chapter. The conformations observed for 18 in polymorphs 1 and 2 are generally similar apart from the orientation of the protruding ester group. This has the carbonyl pointing

84 inward in polymorph 1, while it faces outward in polymorph 2 if the ester group rotates around C-C bond by 180°. Conformational differences can directly be viewed from overlapped structures below as shown in Figure 3.7.

Figure 3.7 Overlapped structures for the two polymorphs. Polymorph 1: red.

Polymorph 2: blue.

It seems unscientific to comment on the stability of these two polymorphs without doing any free energy calculation or any other experimental tests such as DSC (differential scanning calorimetry) or TGA (thermal gravimetric analysis). We presume that polymorph 1 is a more stable form than polymorph 2 in terms of its crystal density

(1.452 g cm-3 for polymorph 1 and 1.393 g cm-3 for polymorph 2) and reproducibility.

Empirically speaking, a stable crystal form is always the one that can be reproduced under different conditions. A general principle proposed by Kitaigorodskii and others is that the more stable form should be expected to have more efficient packing and a correspondingly higher density.[184] This is a general rule that has frequent exceptions 85 when strong and directional bonding (such as hydrogen bonding) dominates the packing and results in void space and lower density. The ultimate determination of stability of these two polymorphs requires more work both experimentally and theoretically.

3.3.4 Crystal Structure of trans-Dimethyl Tetraester 19

Good quality crystals of the racemic trans-dimethyl tetraester 19 in space group Pca21 can be obtained from diethyl ether, acetone, benzene, chloroform, acetonitrile, p-xylene and toluene. Crystals from each solvent were again screened by single crystal X-ray diffractometry to confirm they had the same structure. No other crystal forms were found under our experimental conditions. Although there exists a popular notion that the number of polymorphs known for a given compound is proportional to the time and money devoted to that compound, compounds like naphthalene and sucrose remain loyal to themselves no matter how hard scientists have tried. In this work, only laboratory temperature and pressure were utilised.

trans-Dimethyl tetraester 19 has C2-symmetry and is racemic. The molecules form hydrogen bonded chains along a using the cyclic (OH)2(CO)2 motif that employs two intramolecular hydrogen bonds (2.305 Հ and 2.068 Հ) and two intermolecular hydrogen bonds (2.186 Հ 2.335 Հሻ. The molecules alternate in chirality and also orientation along the chain. This hydrogen bonding motif also exists in polymorph 2 of monomethyl tetraester 18. It can be seen clearly as shown below in Figure 3.8 that the methyl hydrogen from one of the conjugated ester groups acts as a donor to the enol oxygen atom of the neighbouring molecule.

Figure 3.8 Part of a hydrogen bonded chain along the a axis in the structure of the trans-dimethyl tetraester. O-H…O and C-H…O interactions are indicated as black dashed lines.

Two types of flat layers (type 1 and type 2) lie in the ac plane and are constructed from parallel hydrogen bonded chains as seen in Figure 3.9 and Figure 3.10, respectively. In both layers, the hydrogen bonded chains share high similarity except that there is a C-

H…O interaction in the type 1 layer of 2.626 Հ while the type 2 layer has the longer distance of 2.795 Հ.

What really distinguishes the layers is the style of arranging the hydrogen bonded chains into the two-dimensional layers. In the type 1 layer, molecules of the same handedness and opposite orientation in each chain are connected along c by C-H…O interactions which combine a methyl hydrogen from the conjugated ester group and carbonyl oxygen of the protruding ester group (Figure 3.9). In the type 2 layer, molecules alternate in both handedness and orientation in the hydrogen boned chain.

Extension along the c axis involves just dispersion forces, mainly from the methyl moiety of the protruding ester group. In this pattern along the c axis, molecules of alternating handedness but the same orientation are linked (Figure 3.10) 88

Figure 3.9 Part structure of the type 1 layer projected on the ac plane. The two enantiomers are indicated as light green and dark green.

Figure 3.10 Part structure of the type 2 layer projected on the ac plane. The methyl

H…H contacts are coloured.

The three dimensional crystal structure of 19 can therefore be generated by assembling two types of molecular layers using a quantity of weak interactions such as C-H…O, C-

H…C and C-H…O=C. An undulating layered structure viewed along the c axis is shown in Figure 3.11. Numerous weak interactions are omitted here for the purpose of clarity.

Figure 3.11 Part of the structure of the trans-dimethyl tetraester 19 projected on the ab plane.

3.3.5 Crystal Structure of cis-Dimethyl Tetraester 20

Crystals of racemic 20 were obtained unexpectedly from the crude product of the reaction set up for synthesizing monomethyl tetraester 18. Unlike its isomer 19, it has one enol group at C3 and one carbonyl group at C7. The only strong hydrogen bonding in this structure is intramolecular hydrogen bonding (d=1.983 Հ) formed between the enol hydroxyl group and the carbonyl group of an ester group, as shown in Figure 3.12.

Figure 3.12 A molecule of cis-dimethyl tetraester 20 emphasizing the single intramolecular bond formed between an enol hydroxyl group and an ester carbonyl group.

There is no intermolecular O-H…O interaction but C-H…O interactions dominate the structure by forming a hexagonal shaped interaction motif together with intramolecular

O-H…O interactions. Two O-H…O and four C-H…O interactions are involved in this cyclic hexagonal motif which is employed as the basic repeat unit in the structure

(Figure 3.13)

A double molecular strand along b is formed by combining two homochiral strands using the hexagonal motifs. These two homochiral single strands differ in their chirality.

Within each single strand, C-H…Pi (C=O) interactions are also observed to further link the homochiral molecules (Figure 3.14).

Figure 3.13 The basic hexagonal repeat unit motif in the crystal structure of 20.

The double strands are linked in parallel following the diagonal direction of the ac plane by means of C-H…O interactions to generate a molecular layer. In these molecular layers, each single strand alternates in its handedness. Molecular layers are then stacked on top of each other using C-H…O interactions to complete the full structure, as shown in Figure 3.15.

Figure 3.14 Part of the two double strands of 20 extending along the b axis.

Figure 3.15 Part of the structure of 20 formed by stacking molecular layers on each other along the indicated diagonal direction. 94

3.3.6 Crystal Structure of Trimethyl Tetraester 21

Crystallisation of racemic trimethyl tetraester 21 from the solvents, diethyl ether, ethyl acetate, toluene, chlorobenzene, benzene, chloroform and acetone yielded needle-like crystals in space group P21/c. Once again, single crystal X-ray diffractometry was used to confirm that all crystal structures from different solvents were identical.

In this structure, the carbonyl form is adopted in preference to the enol form. With the introduction of three methyl groups into the tetraester, we finally eradicated the strong hydrogen bond donor since all enol hydroxy groups were now turned into carbonyl groups. Would it be possible to obtain multiple crystal forms with the loss of this strong interaction? Would these additional carbonyl groups revive the dipolar C=O…C=O interaction seen in the parent tetraester crystal?

The trimethyl tetraester 21, like the trans-dimethyl tetraester 19, was found to produce only one crystal form. This is particularly distinguishable since it consistently forms its characteristic needle-like crystals under most experimental conditions.

No dipolar C=O…C=O interactions were observed in this crystal structure. It contains more C-H…O interactions instead, some of which are more robust than those in the trans-dimethyl tetraetster 19 structure. These C-H…O interactions have distances, as short as 3.34 Հ compared to the earlier examples in the range of 3.5-4.0 ՀǤ The structure is simply the repeat of one basic unit three-dimensionally as depicted in Figure 3.16.

There are four molecules in the repeat unit, in which molecules of opposite chirality are connected by C-H…O interactions. No interactions among these units are apparent as

95 the unit is repeated along the b axis. It is another story when the units are repeated along either the a or c axis, where additional linking C-H…O interactions are present.

Figure 3.16 The repeat unit of in the crystal structure of the trimethyl tetraester 21. The two enantiomers are coloured light or dark green, and C-H…O interactions are indicated by dashed lines.

Figure 3.17 Part of the crystal structure of 21 projected on the bc plane. 96

As shown in Figure 3.17 above, compensation for loss of O-H…O bonds has been successfully made by increasing the number of C-H…O interactions. Although C-H…O bonding is much weaker than O-H…O individually, the overall efficacy of C-H…O interaction in stabilising the structure is due to its overwhelming advantage in quantity.

That is probably the reason underlying the observation that trimethyl tetraester 21 embraces its choice of fostering only one crystal form at room temperature and pressure.

3.3.7 Polymorph 1 of Tetramethyl Tetraester 22

Polymorph 1 is a published structure by Ashley et al.[180] However, it is a structure that we were unable to reproduce in the way they described or other methods that we attempted. As noted in section 3.3.2, the repetition of polymorph structures can often be problematical. As reported, crystals of polymorph 1 were grown from methanol at -10 Ԩ and it was found to have a structure in the chiral space group P212121.

It is evident that polymorph 1 employs helical packing of the achiral molecules in its structure. As shown in Figure 3.18, molecules surround a crystallographic 21 screw axis and form a helical strand along the a axis as part of the chiral packing of the whole structure. Another reason that could lead to the chiral space group of polymorph 1 is that it only adopts one conformational isomer which is shown in Figure 3.19. The compound 22 having a single conformational isomer in this structure is accordingly crystallised out as a chiral space group, in a similar manner to the way that an enantiomerically pure compound behaves.

Figure 3.18 A helical strand of tetramethyl tetraester 22 molecules surrounding a 21 screw axis in crystals of polymorph 1.[180]

Figure 3.19 The only conformational isomer present in polymorph 1.[180]

Figure 3.20 Part of the structure of the polymorph 1 projected on the bc plane.[180]

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3.3.8 Polymorph 2 of Tetramethyl Tetraester 22

As the second of the four polymorphs of the termethyl tetraester 22, crystals of the new polymorph 2 which has the space group P-1 were grown from the solvents pentane, diethyl ether, dichloromethane, benzene, chloroform and acetonitrile. Single crystal X- ray diffractometry was used in all these cases to ensure that all these structures were identical to the original one.

As aforementioned, tetramethyl tetraester 22 is an achiral molecule because of its two formal mirror planes. However, due to restraints in free rotation of the ester groups in the solid state, two conformational isomers which are mirror images of each other exist in the crystal as shown in Figure 3.21. If the molecules are viewed down the endo face of the backbone, two types of molecules with different orientation of their ester groups can be found. The first one, we named the left-handed conformational isomer, has two diagonal carbonyls in an anti-parallel position. The other molecule which is the mirror image is designated as the right-handed conformational isomer.

Figure 3.21 Left-handed and right-handed conformational isomers in the polymorph 2 crystal structure of 22.

The basic packing unit of this structure is a dimer formed by two left-handed or two right-handed conformational isomers, respectively (Figure 3.22). Within each dimer,

101 there are two pairs of C-H…O interactions to form two cyclic motifs. The C-H…O interactions within each dimer are generated between the ester groups. Two such dimers, of opposite handedness, are again linked by means of two C-H…O interactions (Figure

3.22). These two weak interactions are constructed between the introduced substituent methyl groups and ester carbonyl groups.

Right-handed dimer Left-handed dimer

Figure 3.22 Two linked dimers each formed by two handed conformational isomers.

These are constructed using C-H…O interactions.

Dimers alternating in handedness form an infinite chain along the indicated direction in

Figure 3.23. A layer structure is then generated by cross-linking the parallel infinite chains also by C-H…O interactions. The complete crystal structure is finally obtained by stacking layers on top of each other along c axis. All the interactions that construct the structure over three dimensions are only of the C-H…O interaction type (Figure

3.24).

102

Figure 3.23 Part of the structure of tetramethyl tetraester 22 polymorph 2 projected on the bc plane.

103

Figure 3.24 Part of the structure of tetramethyl tetraester 22 polymorph 2 projected on the ac plane.

104

3.3.9 Polymorph 3 of Tetramethyl Tetraester 22

The third polymorph of tetramethyl tetraester 22, which also shares the same space group P-1 with polymorph 2, was obtained by crystallisation of the compound from trifluoromethylbenzene, toluene, chlorobenzene, p-xylene and m-xylene. Single crystal

X-ray diffractometry was used in all these cases to ensure that all crystal were identical.

As illustrated in Figure 3.25, Polymorph 3 shows many similarities in structure with polymorph 2. The crystal structure of polymorph 3 is also constructed from alternating pair of left-handed and two right-handed conformational isomers linked into infinite chains. However, in polymorph 3, only two C-H…O interactions are present within the right-handed dimer, compared to the left handed dimer where four such interactions are present.

Left-handed dimer Right-handed dimer

Figure 3.25 The left and right-handed dimers in the structure of polymorph 3 and the C-

H…O interactions that connect them.

These infinite chains run along the direction indicated in Figure 3.26, and pack parallel to each other to form a layer in the ac plane. Once again, the chains are joined by C-

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H…O interactions. Stacking of layers along b then generates the full crystal structure

(Figure 3.27 and 3.28).

Figure 3.26 Part structure of a layer in polymorph 3 projected on the ac plane.

106

Figure 3.27 Part of the structure of polymorph 3 projected on the bc plane.

107

Figure 3.28 Part structure of polymorph 3 projected on the ab plane.

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3.3.10 Polymorph 4 of Tetramethyl Tetraester 22

Crystallisation of tetramethyl tetraester 22 from 1,4-dioxane, acetone, tetrahydrofuran

(THF), water, ethyl acetate, methanol and fluorobenzene yielded polymorph 4 in the different space group P21/c. Single crystal X-ray diffractometry was used to ensure that all crystals were identical.

Polymorph 4 once again demonstrates a very similar structure to the previous two cases.

A significant change continues to progress from polymorph 2 to polymorph 4. It is observed clearly that disappearance of two C-H…O interactions in the right-handed dimer of polymorph 3 now happens to both dimers in polymorph 4, but in an alternating mode. This only happens to either the left-handed dimer or right-handed dimer in a given layer structure, which means that it switches to the other dimer in the adjacent layer. More interestingly, molecules try to compensate for the loss of two C-H…O interactions by building one more C-H…O interaction in unaffected dimers in an alternating mode among layers. All the details can be seen in Figure 3.29.

Left-handed dimer Right-handed dimer

New C-H…O interaction

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New C-H…O interaction

Right-handed dimer Left-handed dimer

Figure 3.29 The structure of the left and right-handed dimers in the crystal structure of polymorph 4.

The crystal has a highly similar packing style to the previous polymorphs when viewed down the a axis. (Figure 3.30)

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Figure 3.30 Part of the structure of polymorph 4 projected on the bc plane.

Layers are formed in a similar way using the dimers described above. In the first layer, as shown in Figure 3.31 below, all left-handed dimers have lost two C-H…O interactions whereas all right-handed dimers have gained one extra C-H…O interaction.

In the layer beneath that, it is the turn for left-handed dimers to gain one C-H…O and right-handed dimers to lose two. This game is then played alternatively, so on and so forth.

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Two C-H…O interactions are missing in the left-handed dimer in this layer

Two C-H…O interactions are missing in the right-handed dimer in this layer

Figure 3.31 Part of the structure of polymorph 4 projected on the bc plane.

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3.3.11 Discussion on the Polymorphs of Tetramethyl Tetraester 22

The tetramethyltetraester 22 is proved to be the most productive molecule on account of the three new polymorphs we discovered under similar conditions to those used for other methyl derivatives of tetraester 15. The three polymorphs are highly similar in their packing and have surprisingly similar molecular conformations. The overlapped molecules from the three polymorphs 2-4 are shown in Figure 3.32.

Figure 3.32 Conformational comparison of the bicyclo[3.3.0]octane ring from three polymorphs of tetramethyl tetraester 22. Colour code: red polymorph 2, blue polymorph

3, yellow polymorph 4.

With the introduction of methyl groups to the original tetraester 15, all resulting compounds lost the inclusion properties shown by their precursor. Strong hydrogen bonding completely disappeared in the trimethyl and tetramethyl analogs and C-H…O interaction started to take control. The C=O…C=O dipolar interactions of tetraester 15 were no longer observed in these methyl derivatives. We cannot explain convincingly

113 why tetramethyl tetraester 22 produced four polymorphs while trimethyl tetraester 21 just has one. At this stage, we can only hypothesize that molecular shape, size and how the C-H…O interactions are utilised in the structure are three of many factors for the differences in their crystal engineering behaviours.

Molecules are prone to packing efficiently to achieve higher density and low energy in accord with Kitaigorodskii’s principle of close packing. First of all, trimethyl tetraester

21 is not fully methylated which results in less crowding on both the exo and endo faces compared to the tetramethyl tetraester 22. It therefore has more space for other molecules to come closer so that it can establish more C-H…O interactions and then build stronger interactions. If the packing mode is kinetically or thermodynamically easy to attain under certain conditions, then molecules are able to pack closely which results in formation of only one crystal form. Secondly, the tetramethyl tetraester 22 is a slightly larger molecule than trimethyl tetraester 21. Very often larger molecules will have more options for packing. This can be simplified by envisaging that pebbles in a bottle can be shaken rather easily to restack them differently, but it is not possible to do so using sand. Thirdly, it is the lack of strong interactions that gives rise to polymorphism in the tetramethyl tetraester 22 where only C-H…O interactions are present. C-H…O interactions are weak but are ubiquitous. Here they are determinant in crystal packing. Weak C-H…O interactions are apt to be disconnected and rearranged more easily than stronger forces and this possibility gives us the chance to manipulate the crystal structures.

What forces or factors could do that? It must be emphasized here again that all new polymorphs came out from different solvent systems, as summarized in Table 3.3.

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Table 3.3 Polymorphs of compound 22 and their corresponding solvents.

Polymorph No. Solvents

1 methanol at -10 Ԩ

2 pentane, diethyl ether, dichloromethane, benzene, chloroform,

acetonitrile

3 trifluoromethylbenzene, toluene, chlorobenzene, p-xylene, m-xylene

4 1,4-dioxane, acetone, tetrahydrofuran (THF), water, ethyl acetate,

methanol, fluorobenzene

N.B. Polymorphs 2, 3 and 4 were obtained at ambient temperature and pressure.

It seems confusing to just look into the relation between polymorph 2 and its group of solvents. However, it is self-evident that correlations like cause-and-effect can be easily recognized for the other polymorphs. Aromatic solvents produced polymorph 3 and solvents with excellent hydrogen bond acceptors produced polymorph 4, which means that polymorphism can be controlled here to some degree by simply using different types of solvent. Solvation is an important factor that should always be taken in account in crystallisation. In solution, the solute molecules are surrounded by large number of solvent molecules, but how exactly these different solvents induced the different polymorphs is beyond our current level of understanding.

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3.4 Conclusions

Five mono-, di-, tri- and tetramethyl tetraester derivatives have been successfully synthesized, which means that extent of methylation of the original tetraester 15 can indeed be controlled by using different synthetic methods. However, none of these derivatives display the property of inclusion.

The mono- 18 and trans-dimethyl tetraester 19 preserve O-H…O hydrogen bonding which allows formation of hydrogen bonded chains as the core of the crystal structure.

As for the monomethyl tetraester 18, its two polymorphs show different conformations of one ester group. Flexible groups like ester groups are prone to yielding polymorphs because of their many potential conformations. cis-Dimethyl tetraester 20 employs only intramolecular hydrogen bonding and utilises a complete new hexagonal packing motif containing two hydrogen bonds and four C-H..O interactions. Trimethyl- 21 and tetramethyl tetraester 22 had lost their hydroxy group. As a consequence, the C-H…O interaction dominates their crystal structures. However, this is a weaker interaction and more prone to adopting alternative arrangements.

Regarding the solvents used for crystallisation and the corresponding polymorphs obtained, control of formation of the polymorphs by using distinctive solvent systems has been shown to be possible. The relation between the solvent and formation of polymorphs in the crystallization process requires further investigation. Finally, all these experiments were conducted at laboratory temperature and pressure. It is remarkable that so many polymorphs were obtained just under these unique conditions.

Future experiments conducted over a range of temperature and pressure values are likely to reveal even more possibilities.

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CHAPTER4

Bicyclo[3.3.0]octane Diols with Aromatic Substituents

4.1 Introduction

Generally, awkwardly shaped molecules tend to yield more than one crystal form in order to minimise packing difficulties, and these structural alternatives may involve polymorph, solvate, hydrate and/or hydrogen bonded co-crystal arrangements. This awkward shape principle has long been applied in the deliberate design of new host molecules or other crystal forms. Our studies on various packing modes adopted by alicyclic diols manifest the versatility of this concept.

Recently we have published that rather simply structured bicyclo[3.3.0]octane diols

(tetraester 15, dimethyl diol 5, diphenyl diol 6), the bicyclic backbone of which has a shape like a shallow dish, yielded multiple crystal forms when crystallised from different solvents under ambient temperature and pressure. Racemic tetraester 15 forms two solvent-free polymorphs and also two different solvates as described in Chapter 2.

Dimethyl diol 5 gave three different crystal forms: a hemihydrate, a hydrate and a solvate containing benzene.[138] Diphenyl diol 6 was found to be more versatile in its crystallisation performance. A number of types of crystal forms from the diphenyl compound 6 have been discovered including a solvent-free material, two solvates and several hydrogen bonded co-crystals.[139]

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These results demonstrate unambiguously that simple molecules with appropriate molecular structures have a strong tendency to produce multiple crystal forms.

Structurally related molecules therefore will help us further explore the crystallisation behaviour of additional derivatives from the bicyclo[3.3.0]octane diol family and also the structural limits associated with their potential inclusion capability. Five analogues

28, 29, 30, 31, 32 were selected for this study. These simple achiral compounds were chosen in order to provide a range of substituents of differing size, flexibility and functionality.

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4.2 Synthesis

As outlined in Scheme 4.1, the preparation of dithienyl diol 32, dibenzyl diol 29 and dinaphthyl diol 30[185] were carried out using standard Grignard methods. Reaction of dione 33 with Grignard reagents prepared from each aromatic halide gave the three desired products. The bicyclo[3.3.0]octane framework has a V-shape and therefore alkylation is preferred on the exo-face. The pure isomers illustrated were obtained after just one crystallisation of the crude products.

Scheme 4.1 Synthesis of dibenzyl diol 29, dinaphthyl diol 30 and dithienyl diol 32.

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Dipyridyl diol 31 and di-n-butyl diol 28 were synthesized using alkyl lithium methodology, shown in Scheme 4.2.

Scheme 4.2 Synthesis of dipyridyl diol 31 and di-n-butyl diol 28.

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4.3 Crystal Structures of Bicyclo[3.3.0]octane Diols

Each diol was dissolved in a range of test solvents with warming and crystals were allowed to grow by slow evaporation under ambient laboratory temperature and pressure. The crystals obtained were then characterised using single crystal X-ray diffractometry.

Di-n-butyl diol 28, dibenzyl diol 29 and dinaphthyl diol 30 only crystallised as solvent- free structure from various solvents, but crystals of the dibenzyl diol 29 assembled into a chiral space group. In contrast, dipyridyl diol 31 and dithienyl diol 32 were found to behave very differently. Dithienyl diol 32 produced three closely-related isostructural hydrogen bonded co-crystals and one solvent-free form. Dipyridyl diol31 adopted five different structures comprising two hydrate polymorphs, two solvent- free polymorphs and one solvate.

Numerical details of the solution and refinement of these crystal structures from all five diols are presented in Table 4.1 and Table 4.2

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Table 4.1 Numerical details of crystal structures of 28, 29, 30 and 32.

ethanol crystal form solvent free solvent free solvent free solvent free co-crystal

compound 28 29 30 32 (32)·(ethanol)

(C16H18O2S2)· formula C16H30O2 C22H26O2 C28H26O2 C16H18O2S2 (C2H6O)

formula mass 254.40 322.43 394.49 306.42 352.49

crystal system, Triclinic Orthorhombic Monoclinic Monoclinic Triclinic

space group P-1 P212121 P21/c P21/n P-1

temperature (K) 154 150 150 155 151

9.8213 (10), 6.1401 (6), 15.811 (2), 5.7978 (2), 6.3545 (5),

a, b, c (Å) 10.428 (1), 9.9528 (9), 11.0456 (12), 11.2970 (4), 10.7726 (9),

12.3093 (12) 28.312 (3) 12.0271 (16) 21.8346 (9) 12.9505 (11)

109.989 (3), 90 90 90 84.473 (4),

α, β, γ (°) 113.504 (3), 90 107.179 (4) 90.648 (2) 87.757 (4),

118.100 (3) 90 90 90 81.410 (4)

V (Å3) 770.78 (13) 1730.2 (3) 2006.7 (4) 1430.03 (9) 872.22 (12)

Z 2 4 4 4 2

Radiation type Mo Kα Mo Kα Mo Kα Mo Kα Mo Kα

μ (mm−1) 0.07 0.08 0.08 0.37 0.32

0.31 × 0.05 × 0.45 × 0.40 × 0.23 × 0.20 × 0.25 × 0.22 × 0.40 × 0.10 × crystal size (mm) 0.03 0.15 0.06 0.08 0.05

Tmin, Tmax 0.966, 0.989 0.982, 0.995 0.915, 0.970 0.884, 0.983

No. of measured,

independent and 10064, 7059, 14577, 11160, 12537,

observed [I> 2σ(I)] 2657, 2161 2928, 2416 3521, 1897 3083, 2855 3713, 2800

reflections

Rint 0.036 0.042 0.102 0.030 0.030

R [F2 > 2σ(F2)], 0.048, 0.169, 0.039, 0.085, 0.055, 0.103, 0.041, 0.115, 0.045, 0.128,

wR(F2), S 0.94 1.05 1.09 0.97 1.05

no. of reflections 2657 2928 3521 3083 3713

no. of parameters 171 225 279 226 212

no. of restraints 4 0 0 45 0

−3 Δρmax, Δρmin (e Å ) 0.28, −0.65 0.14, −0.17 0.20, −0.25 0.69, −0.59 0.45, −0.41 122

Table 4.2 Numerical details of crystal structures of 31.

benzene crystal form apohost apohost hydrate hydrate clathrate

compound 31 31 (31)·(water) (31)·(water) (31)·(benzene)

(C18H21N2O)· (C18H21N2O)· (C18H21N2O)· formula C18H21N2O2 C18H21N2O2 (H2O) (H2O) (C6H6) formula mass 297.37 297.37 314.38 314.38 374.47

crystal system, Monoclinic Orthorhombic Monoclinic Monoclinic Monoclinic

space group C2/c Pna21 P21/c P21/n P21/c temperature (K) 155 160 155 155 155

22.8627(10), 19.7275 (18), 12.5839 (6), 14.208 (6), 19.0145 (9), a, b, c (Å) 7.3486 (3), 7.6198 (5), 6.0146 (3), 7.401 (3), 9.8544 (4), 19.1526 (10) 9.9770 (9) 21.2073 (11) 15.291 (6)) 10.6615 (4)

90 90 90 90 90 α, β, γ (°) 111.435 (4) 90 101.632 (2) 98.77 (2) 98.419 (2) 90 90 90 90 90 V (Å3) 2995.2 (2) 1499.7 (2) 1572.15 (14) 1589.1 (11) 1976.19 (14)

Z 8 4 4 4 4 Radiation type Mo Kα Mo Kα Mo Kα Mo Kα Mo Kα

μ (mm−1) 0.09 0.09 0.09 0.09 0.08 0.39 × 0.27 × 0.19 × 0.15 × 0.39 × 0.35 × 0.17 × 0.10 × 0.41 × 0.27 × crystal size (mm) 0.22 0.12 0.17 0.06 0.17

Tmin, Tmax 0.967, 0.981 0.984, 0.990 0.966, 0.985 0.985, 0.994 0.968, 0.986 No. of measured, independent and 20326, 2639, 6083, 2825, 12788, 3399, 7829, 2690, 15365, 4293, observed 2508 2278 3038 1160 3308 [I>2σ(I)] reflections Rint 0.036 0.034 0.027 0.170 0.037

R [F2 > 2σ(F2)], 0.068, 0.145, 0.039, 0.087, 0.036, 0.099, 0.062, 0.129, 0.054, 0.149,

wR(F2), S 1.25 1.01 1.02 0.92 1.04

no. of reflections 2639 2825 3399 2690 4293 no. of parameters 207 207 218 224 255

no. of restraints 2 1 0 0 0

Δρmax, Δρmin (e 0.36, −0.45 0.14, −0.17 0.35, −0.19 0.29, −0.24 0.54, −0.58 Å−3)

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4.3.1 Crystal Structure of Di-n-butyl Diol 28

Crystallisation of di-n-butyl diol 28 gave the same solvent-free crystals in space group

P-1 from methanol, ethyl acetate, acetone, dichloromethane and benzene. Single crystal

X-ray diffractometry was used to confirm that these crystal structures were all identical.

This crystal structure is relatively simple, not only in its packing style but also the intermolecular interactions employed in stabilising the whole structure. As a molecule with longer, but also more floppy, alkyl chains compared to the dimethyl diol 5, it consistently yielded just one crystal structure. The awkwardness of the bicyclic backbone has been to some extent overwhelmed since the floppy alkyl chain is so flexible in bending or rotation.

As shown in Figure 4.1, intermolecular O-H…O interactions are used to link the molecules into double stranded chains. Inter and intramolecular O-H…O together form an infinite hydrogen bonding chain. Each hydroxy group is hydrogen bonded to two others by an intramolecular hydrogen bond and an intermolecular hydrogen bond. The intra and intermolecular O…O distances are 2.686, 2.660 and 2.711 Հ, respectivelyǤ The diol molecules in the two strands are joined as centrosymmetric pairs which are oriented in an out of phase concave face to concave face manner.

The packing viewed down the a, b and c axes can be seen in Figures 4.2, 4.3 and 4.4.

The double stranded chains pack parallel to each other. Apart from the strong O-H…O interactions, the only other interactions that exist are very weak C-H…C and C-H...H-C dispersion forces with the C…H distance as long as 2.964 Հ.

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Figure 4.1 Part of a double strand of diol 28 molecules associated by O-H…O interactions. Hydrogen bonds are indicated by dashed lines. Hydrogen atoms are omitted for clarity. Green C, red O.

Figure 4.2 Part of the structure of diol 28 projected on the bc plane.

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Figure 4.3 Part of the structure of diol 28 projected on the ac plane.

Figure 4.4 Part of the structure of diol 28 projected on the ab plane.

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4.3.2 Crystal Structure of Dibenzyl Diol 29

Different from the other achiral compounds in this group, the dibenzyldiol29 crystallised into chiral space group P212121 from all the solvents tested: ethyl acetate, dichloromethane, diethyl ether, acetone, fluorobenzene, carbon disulfide, toluene, acetonitrile, chloroform, methanol, mesitylene, triethylamine, tetrahydrofuran (THF) and pyridine. Single crystal X-ray diffractometry was used to confirm that all these crystal structures were identical.

In this chiral but extremely simple structure, molecules of dibenzyl diol 29 are arranged around a 21 screw axis so that a helical hydrogen bond chain is formed along the a direction. Each hydroxyl group in the molecule is hydrogen bonded to another two hydroxyl groups by one intramolecular and one intermolecular hydrogen bond. The

O…O distances of intra- and intermolecular interaction are 2.638 Հ and 2.744 Հ, respectively (Figure 4.5).

Figure 4.5 One of the helical hydrogen bonding units in crystalline 29.

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Whereas helical hydrogen bonding dominates the packing along the a axis, it is the C-

H…Pi interaction’s world when molecules pack along b and c. Along the c direction, molecules are linked using the C-H…Pi interaction. One of the benzyl rings of a molecule participates as an acceptor, and the other ring as a donor, in two C-H…Pi interactions, as shown in Figure 4.6. The distances are the same: d=2.885 Հ.

Figure 4.6 Part of the structure of 29 projected on the bc plane.

There is no convincing explanation for the fact that achiral dibenzyl diol 29 consistently crystallises with a chiral space group. We do believe that the flexibility of the benzyl group compared to the more rigid phenyl ring in diphenyl diol 29 is one of the main reasons underlying its unique crystallisation behaviour. In other words, less awkwardness results in fewer crystal forms.

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4.3.3 Crystal Structure of Dinaphthyl Diol 30

The crystallisation of dinaphthyl diol 30 from benzene, methanol, chloroform, acetone and toluene produced the same solvent-free crystals in space group P21/c.

The dimer as shown in Figure 4.7 is the smallest motif in this structure. Two molecules are connected in a concave face to concave face manner by two intermolecular hydrogen bonds which share the same O…O distance of 2.757 Հ. Interestingly, no intramolecular hydrogen bond is present as seen in the previous two cases. In this dimer, one hydroxy hydrogen atom in each molecule is not hydrogen bonded and therefore forms instead an O-H…Pi interaction with a naphthyl ring from an adjacent molecule.

Figure 4.7 Two molecules of 30 are linked by two intermolecular hydrogen bonds to form a dimer.

As illustrated in Figure 4.8, dimers associate primarily by means of O-H…Pi and C-

H…Pi interactions running along both b and c directions to form a layer. However,

129 there is no significant interaction between layers due to the fact that the aromatic rings in a layer are oriented nearly parallel to other rings in the neighbouring layers and thus are unable to provide their Pi rings as C-H…Pi acceptors for each other, as shown in

Figure 4.9. Certainly, there are other types of weaker interactions and van der Waals forces to unite the layers.

Figure 4.8 The O-H…Pi and C-H…Pi interactions that link the dimers.

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Figure 4.9 Part of the layered structure of dinaphthyl diol 30 projected on the ac plane.

With a larger, pure hydrocarbon aromatic substituent on its bicyclic core, dinaphthyl diol 30 yields only one solvent-free crystal form, despite the molecules of dinaphthyl diol 30 being packed in an awkward concave face to concave face mode. Each naphthyl ring rotates to a certain position to achieve a most efficient C-H…Pi establishment whereby it leaves insufficient space between the dimers. Hence, dinaphthyl diol 30 molecules pack efficiently with no inclusion potential.

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4.3.4 Apohost Polymorph 1 of Dipyridyl Diol 31

Crystallisation of dipyridyl diol 31 from pyridine, acetone, toluene, dry tetrahydrofuran

(THF), diethyl ether, p-xylene, m-xylene gave solvent-free polymorph 1 in space group

C2/c. Single crystal X-ray diffractometry was used to confirm that crystal structures from all other solvents were identical.

There is no intramolecular O-H…O hydrogen bonding present in this structure except weaker intramolecular associations such as Ar-H…O, alkyl C-H…O and C-H…N, as shown in Figure 4.10.

Figure 4.10 Weak interactions employed within a single molecule of 31 in the structure of apohost polymorph 1. Colour code: C green, N blue, O red. H grey.

The crystal structure is relatively simple and uses intermolecular O-H…O hydrogen bonding to link the molecules into double stranded chains running along the b axis. As illustrated in Figure 4.11, the diol molecules in the two strands are oriented in an out of phase concave face to concave face manner and are connected as centrosymmetric dimers, with neighbouring dimers being linked by additional hydroxy group hydrogen bonding. The O…O distances of hydrogen bonding within the dimer and between the dimer are 2.858 Հ and 2.779 Հ, respectively. Adjacent double chains pack in a herringbone arrangement (Figure 4.12). In this packing mode, one of the pyridyl rings 132 of 31 interacts with a molecule in the same chain using a double alkyl-H…Pi interaction

(blue), while the other pyridyl ring participates in a triple Ar-H…Pi interaction (black) with a pyridyl ring from the neighbouring chain.

Figure 4.11 Part of a double stranded chain of diol 31 molecules running along b in the structure of apohost polymorph 1. All hydrogen atoms are omitted for clarity. O-H…O hydrogen bonds are indicated by dashed lines.

Figure 4.12 Adjacent chains pack in a herringbone arrangement in the apohost polymorph 1 structure of 31 on the ac plane after rotated 90 ° around the b axis.

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A layer is then formed by simply arranging the double stranded chain using Ar-H…Pi interactions along the c direction. Each layer is joined together by Ar-H…N-Ar weak hydrogen bonding, the distance of which is 2.710 Հ (Figure 4.13).

Figure 4.13 Part of the structure of apohost polymorph 1 projected on the ac plane.

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4.3.5 Apohost Polymorph 2 of Dipyridyl Diol 31

Dipyridyl diol 31 gave a second solvent-free structure, apohost polymorph 2 in space group Pna21 when crystallised from a solvent mixture of acetone and water. No other pure solvents or solvent mixtures were found that yielded the same structure.

The only strong hydrogen bonding present in this structure is intramolecular O-H…O interaction, the O…O distance of which is 2.744 Հ. Each molecule of 31 forms an internal hydrogen bond, while the hydrogen from the other hydroxy group interacts with one of the pyridyl rings forming an intramolecular hydrogen bond. Other weak interactions within the molecule, seen also in apohost polymorph 1, include alkyl C-

H…N, Ar-H…O interactions (Figure 4.14). This group of weak attractions imparts significant conformational rigidity to the diol 31 framework.

Figure 4.14 Weak interactions employed within a single molecule of 31 in the structure of apohost polymorph 2.

Despite the absence of intermolecular O-H...O hydrogen bonding, polymorph 2 shares some degree of similarity in its packing mode with polymorph 1, as shown in Figure

4.15. Molecules of dipyridyl diol 31 associate nearly orthogonally into zigzag chains along a by means of Ar-H…Pi interactions. A hydrogen atom from one of the pyridyl

135 rings serves as the donor for the Ar-H…Pi interaction, while the other ring in the same molecule behaves as the acceptor for another Ar-H…Pi interaction. Adjacent chains running along the c direction are linked by C-H…O and C-H…N interactions shown in

Figure 4.16 and 4.17.

Figure 4.15 Part of a zigzag chain of dipyridyl diol 31 molecules in the structure of apohost polymorph 2.

Figure 4.16 Zigzig chains are connected along the c axis by C-H…O and C-H…N interactions.

136

Figure 4.17 Part of the structure of apohost polymorph 2 projected on the ac plane.

137

4.3.6 Monohydrate Polymorph 1 of Dipyridyl Diol 31

Dipyridyl diol 31 yielded a hydrate crystal structure in space group P21/c from damp solvents such as tetrahydrofuran (THF), methanol and ethanol by slow evaporation at room temperature and pressure. The ratio of water and molecule 31 in this hydrate is 1:1.

Single crystal X-ray diffractometry was used to confirm that crystal structures from those solvents were identical.

As shown in Figure 4.18, intermolecular O-H…O hydrogen bonding links centrosymmetric pairs of diol molecules in a concave face to concave face manner. A water molecule is located near each outer face of this diol pair. Two pyridyl rings in the molecule of 31 in hydrate polymorph 1 adopt very different conformations compared with those in the previous two solvent-free polymorphs, which results in free space between the dimer. The resulting space within the dimer then facilitates the inclusion of small molecules. This results in diol and water molecules forming two O-H…O-H…O-

H hydrogen bonded chains along the b axis. In projection, Figure 4.18, there are two triangle-like helical chains, which are identical except for their opposite handedness. In a given chain, one of the water hydroxy groups forms a donor hydrogen bond to a diol and its oxygen atom acts as a hydrogen bond acceptor with another diol molecule. In addition, the second hydroxy group of the water molecule forms an O-H…N hydrogen bond with one the diol pyridyl rings.

The resulting twin helical units pack parallel to each other by translating the twin helical units along the a axis and repeating the units with alternating handedness along the c axis. The units running along the c direction are connected by C-H…N, C-H…Pi weak interactions.

138

Figure 4.18 Part of the structure of hydrate polymorph 1 projected on the ac plane.

Figure 4.19 depicts the weak attractions between two helical units along a. One of the pyridyl rings is involved in two C-H…O interactions both with water and diol hydroxy groups from an adjacent helical unit along a. C-H…Pi interactions are also observed between neighbouring units.

Figure 4.19 Two adjacent helical units along the a axis, emphasising the interactions and in-phase relationship between them.

139

4.3.7 Monohydrate Polymorph 2 of Dipyridyl Diol 31

Dipyridyl diol 31 adopts a second hydrate structure in space group P21/n when crystallised from damp acetonitrile. The ratio of water and molecule 31 in this hydrate is also 1:1.

Pairs of diol 31 molecules are once again oriented concave face to concave face, but are displaced out- of-phase with respect to each other. Molecules of 31 are no longer directly hydrogen bonded in hydrate polymorph 2. The new outcome is a single but more complicated diol-water combination than that in the hydrate polymorph 1. This consists of O-H…O-H infinite hydrogen bonding surrounding a 21 screw axis along the b direction, which is shown in Figure 4.20. In this helical unit, one hydrogen atom and the oxygen atom of one water molecule act as donor and acceptor respectively, to link the two separate diol molecules groups O…O distances 2.718 Հ and 2.834 Հ. The remaining water hydroxy group is used to connect a third diol molecule (O…O distance

2.766 Հሻ.

140

Figure 4.20 The helical hydrogen bonding arrangement formed between water and diol molecules in the hydrate polymorph 2.

As illustrated in Figure 4.21, these helical hydrogen bonding units appear as a rectangular shape when projected on the ac plane. They are further linked along a by means of O-H…N and Ar-H…O interactions that involve the same oxygen atom, as shown in Figure 4.22. These associations create two five-membered cyclic interactions

(black) surrounding an inversion centre. There is very little interaction between helical units in the other directions. No C-H…Pi or Pi…Pi interactions are present, but there is a cyclic six-membered interaction (blue) involving two Ar-H…N attractions (Figure

4.22).

141

Figure 4.21 Part of the structure of hydrate polymorph 2 projected on the ac plane.

Figure 4.22 Helical units projected on the ac plane and showing the weak interactions between them.

142

4.3.8 Solvate Structure of Dipyridyl Diol 31

A solvate structure (31)∙(benzene) was obtained in space group P21/c when diol 31 was crystallised from benzene solution.

Single molecules of 31 have an extraordinarily similar conformation to that found in the apohost polymorph 2 structure. The only strong interaction here is an intramolecular O-

H…O hydrogen bond (O…O 2.634 Հሻ. This intramolecular hydrogen bond has become somewhat stronger at the expense of the O-H…N interaction compared with its value in the apohost polymorph 2 structure (O...O 2.744 Հ). The alkyl C-H…O interaction has vanished, but alkyl C-H…C and alkyl C-H…N interactions are preserved. This arises because the two pyridyl rings are even closer to co-planarity in the solvate compound.

Figure 4.23 The intramolecular interactions present within a single molecule of 31 in the structure of (31)∙(benzene).

The guest benzene molecule is sandwiched between two host molecules by means of

Ar-H…Pi interactions, as seen in Figure 4.24. Extension of this pattern along a produces a chain structure. In this interaction motif, one aryl hydrogen atom is provided by the N1 pyridyl ring and other belongs to the N2 pyridyl ring. Parallel chains associate on one face by a bifurcated O-H…O motif that utilises both oxygen atoms as

143 acceptors from the host molecule. The hydrogen donor is the C1-H1 of the bicyclic backbone.

Figure 4.24 Part of two parallel chains of the solvate showing sandwiched benzene molecules and interactions between adjacent chains.

Figure 4.25 Four adjacent chains, showing the O-H...N and bifurcated C-H...O interactions.

The other face of parallel chains involves more weak interactions. Both oxygen atoms once again participate in a bifurcated C-H…O assembly with an aryl hydrogen (Figure

4.25). The structure along the b axis is simply constructed by using chains with inverted

144 orientation and displacing them along the a direction. These centrosymmetric chains are further linked by means of O-H…N attractions (Figure 4.26).

Figure 4.26 The parallel chains in the benzene solvate structure associate in a centrosymmetric manner.

Figure 4.27 Part of the solvate structure of (31)∙(benzene) projected on the ab plane.

145

4.3.9 Discussion of the Dipyridyl Diol 31 Crystal Structures

Once again, our principle that awkward shaped molecules are inclined to produce more than one crystal form, proved to be successful. The dipyridyl diol 31 was indeed found to yield alternative crystal forms when crystallized from different solvents at ambient temperature and pressure. However, its manner of achieving multiple crystal forms is very different from its close diphenyl relative 6. When the phenyl ring is replaced by the pyridyl ring, diol 31 became more prone to yielding polymorphs and hydrates rather than organic co-crystal structures. This can be accounted for by the pyridyl group providing a good hydrogen bond acceptor for water molecules with the introduction of nitrogen atoms into the molecules. Despite the subtle change we made to the molecule, the differences in its crystallisation behaviour are enormous. Figure 4.28 compares the conformations of diol 31 in the five crystal structures obtained. This overlapped diagram clearly reveals the two cases where its two hydroxy groups are proximal due to their intramolecular hydrogen bonding, and the three examples in which this interaction is absent. The latter structures are those in which concave face to concave face packing manner is favoured. It is also shown clearly that the orientations of the pyridyl ring of

31 in the latter group of three conformations are distinct.

146

Figure 4.28 The comparison of conformations in five crystal structures of 31. Colour code: apohost polymorph 1 (red) and polymorph 2 (purple), hydrate polymorph 1

(yellow) and polymorph 2 (blue), benzene solvate (green).

The diol configurations of apohost polymorphs 1 and 2 share almost no similarities.

Apohost polymorph 1 has a rather conventional structure, in being constructed from O-

H…O hydrogen bonded double strands that pack in parallel. It should be noted, however, that this hydrogen bonding only extends over three consecutive bonds and does not form an infinite O-H...O chain as is usually the case for alcohol compounds.

Further, the hydrogen bonded links between the diol dimers are disordered. Attractions between adjacent helices involve only weak forces and the nitrogen atoms play a minor role. These various characteristics make it easier for alternative structural behaviour to occur.

Interestingly, the apohost polymorph 2 was obtained from aqueous acetone solution while two hydrate polymorphs were formed from common solvents containing traces of water. Here, the diol 31 has a crystal structure totally unlike any previously observed for its close analogue 6. Its configuration initially appears to be an unusual choice, since the strong intermolecular O-H…O hydrogen bonding of polymorph 1 has been abandoned

147 in favour of intramolecular attractions. Both the nitrogen atoms and C-H...Pi interactions now participate more prominently in its crystal structure.

However, as shown in Figure 4.12, apohost polymorph 1 adopts a herringbone packing on the ac plane, which has some degree of similarity to the packing style shown in

Figure 4.16. We described structural arrangement as zigzag packing in apohost polymorph 2. It can also be viewed as a herringbone packing by taking every second zigzag chains into account.

The (31)·(benzene) solvate shares nearly identical configuration of bicyclic ring to that present in the apohost polymorph 2. Minor changes result from the central bicyclo[3.3.0]octane ring being more eclipsed, which causes loss of the weak intramolecular C-H...O interaction and the two pyridyl substituents to become almost coplanar. The benzene guest molecules are efficiently sandwiched between these aromatic groups using Ar-H...Pi interactions and thereby linking the hosts and guests into chains. Adjacent chains pack in parallel utilising clusters of weak molecular attractions (Figure 4.24 and 4.25).

The hydrate polymorphs 1 and 2 are closely related in structure, and also share packing similarity with the apohost polymorph 1 since the diol 31 molecules are oriented concave face to concave face in all three cases. The conformations adopted by 31 in these crystals are shown in Figure 4.29. This comparison reveals that all employ intramolecular C-H...N and C-H...O attractions, with the latter motifs replacing the intramolecular O-H...O hydrogen bond in the apohost polymorph 2 and benzene clathrate structures.

148

Figure 4.29 Comparison of the conformations and intramolecular attractions adopted by diol 31 in the three concave face to concave face crystals: apohost polymorph 1 (upper), hydrate polymorph 1 (centre), and hydrate polymorph 2 (lower).

In hydrate polymorph 1 (P21/c) the diol pairs are positioned in-phase with respect to each other. This results in two enantiomeric diol-water helices giving a twin helical unit of triangular cross-section (Figure 4.18). In the hydrate polymorph 2 (P21/n) the diol 31 molecules are positioned out-of-phase, resulting in just one diol-water helix of a more complex nature. This results in an elongated parallelogram cross-section (Figure 4.21). 149

A further significant difference lies in the organisation of the water molecules within their helical units. The P21/c structure contains water molecules oriented along the +b direction in one helix and along –b in the other helix, as illustrated in Figure 4.30. In contrast, each helical unit in the P21/n structure contains only one hydrogen bonded helix with unidirectional water orientations (Figure 4.31). However, the opposite helical sense (and hence water orientation) is present in adjacent units, thereby providing the overall achiral crystal.

150

Figure 4.30 One twin helical unit of the hydrate polymorph 1 structure emphasising the organisation of its water molecules. Upper: Projection of the unit onto the ac plane.

Lower: The unit running along the b direction (vertical) showing the opposing water orientations present in its two hydrogen bonded helices and O-H…O interactions in the twin helices are coloured blue and purple, respectively.

151

Figure 4.31 One helical unit of the hydrate polymorph 2 structure emphasising the organisation of its water molecules. Upper: Projection of the unit onto the ac plane.

Lower: The unit running along the b direction (vertical direction) shows the unidirectional water molecules present in its single hydrogen bonded helix.

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4.3.10 Apohost Structure of Dithienyl Diol 32

An apohost structure in space groupP21/n was obtained when 32 crystallised from a large number of solvents including ethyl acetate, benzene, dichloromethane, chloroform, diethyl ether, carbon disulfide, tetrahydrofuran (THF), acetone, acetonitrile, toluene, hexafluorobenzene, trifluoromethylbenzene and p-xylene. Single crystal X-ray diffractometry was used to confirm that these crystal structures were identical.

One of the thienyl rings is disordered over two positions due to its free rotation. As shown in Figure 4.32, only intermolecular O-H…O hydrogen bonding exists and the two hydroxyl groups connect two different neighbours, one group acting as a donor and the other as acceptor. This results in a double stranded chain where the remaining hydrogen atom from one hydroxy group forms an O-H…Pi interaction as a donor. This attraction was also observed in the dinaphthyl diol 30 structure. In addition, Ar-H…Pi and S…Pi attractions also help stabilise the chain.

There is very little interaction between chains in the a and c directions. The attractions appear just to be dispersion forces (Figure 4.33).

153

Figure 4.32 Part of the apohost structure of the dithienyl diol 32 projected on the bc plane. The other disorder position is omitted for clarity. Colour code: C green, O red, S yellow, H grey.

Figure 4.33 Part of the apohost structure of the dithienyl diol 32 projected on the ac plane. The hydrogen atoms and other disordered position are omitted for clarity.

154

4.3.11 Alcohol Co-crystals of Dithienyl Diol 32

Our definition of a co-crystal used here refers to molecules that are hydrogen bonded to each other. Three isostructural co-crystals of 32 with methanol, ethanol and butan-2-ol were produced by using these three alcoholic solvents separately for crystal growth.

These experiments were all conducted at room temperature and pressure. Since these structures are nearly identical, only the ethanol co-crystal structure will be discussed in detail here. A further reason for choosing this structure is that both the methanol and butan-2-ol are disordered with respect to one of their thiophene rings.

All three co-crystals share the same triclinic space group P-1. Interestingly, the c dimension of the unit cell grows larger from methanol to butan-2-ol while the other two dimensions remain nearly unchanged. This trend fits perfectly with the growing size from methanol to butan-2-ol.

The structure of the ethanol co-crystal of 32 shares remarkable similarity with hydrate polymorph 1 of dipyridyl diol 31, as shown in Figure 4.34. Pairs of both dithienyl diol

32 and dipyridyl diol 31 are oriented concave face to concave face around an inversion centre using intermolecular O-H…O hydrogen bonding. Two ethanol molecules are inserted into the dimer and form helical O-H…O-H…O-H hydrogen bonded chains with diol molecules along the a axis. These helices have a triangular shape in cross- section. The ethanol molecules also provide alkyl hydrogen atoms that form C-H…Pi interactions with the thiophene rings.

There is little interaction between helical units running along both the b and c directions.

A pair of alkyl C-H…Pi interactions along b and a pair of Ar-H…Pi interactions along c are utilised to stabilise the helical units in these two directions. What differs notably

155 from hydrate polymorph 1 of dipyridyl diol 31 in this structure is that helical units along care not positioned in a mutually in-phase manner.

Figure 4.34 Part of the ethanol co-crystal structure projected on the bc plane. Hdrogen atoms are omitted for clarity.

It is shown in Figure 4.35 that the only conformational difference of the two diol molecules lies in the orientation of one thiophene ring. It is evident that molecules in this co-crystal structure cannot adopt the ring orientation of the apohost molecules as this orientation would significantly reduce the interior space within the dimer and this is required to the accommodation of two alcohol molecules.

156

Figure 4.35 Conformational comparison of two molecules of 32 from the apohost and the ethanol co-crystal structures, respectively. Colour code: apohost: blue, co-crystal: purple.

157

4.4 Conclusions

In general, molecules of awkward shape are inclined to produce alternative crystal forms. Size, flexibility and also functionality of peripheral substituents on the bicyclic backbone influence the crystallisation behaviour substantially. As a substituent, the naphthyl ring is too big, while benzyl groups and n-butyl chains are overly flexible so that no second crystal form was obtained. There may be a tipping point in both size and flexibility where molecules with even larger or more flexible substituents would regain their productivity of producing more than one crystal form.

Despite their extremely simple achiral molecular structure, both dipyridyl diol 31 and dithienyl diol 32 yielded a number of different crystal forms when crystallised from different solvents under ambient conditions. Bearing nearly the same size of substituent as diphenyldiol6, the dipyridyl diol 31 showed marked crystal engineering differences in forming hydrates instead of organic co-crystals, and in yielding both solvent-free and hydrate polymorphic crystalline compounds. Dithienyl diol 32 exhibits a different characteristic in its crystallisation properties. With its smaller sized five-membered thiophene ring, diol 32 produced a solvent-free crystal form persistently from all non- alcohol solvents and it somewhat selectively chooses small molecular sized alcohols as co-crystal partners.

Prediction of the likelihood of forming multiple crystal forms, even for simple achiral molecules such as dipyridyl diol 31 and dithienyl diol 32can be made with confidence in this area. However, to predict which type of crystal form will be obtained and how exactly this will be achieved, still remains elusive.

158

CHAPTER 5

Diquinoline Derivatives of Bicyclo[3.3.0]octane

5.1 Introduction

V-shaped molecular frameworks with C2-symmetry have proved to be versatile building blocks for the construction of host molecules. As pointed out by Bishop[57], three modular construction units shown in Figure 1.11, all of which are playing a crucial role in the function of the host, are essential for the deliberate design of diquinoline based host molecules. First, two aromatic wings are needed to provide planar surfaces for interacting with guests or other host molecules using C-H…Pi and/or Pi…Pi interactions. Second, a central alicyclic linker is a must for connecting aromatic wings, imparting C2-symmetry and certain degree of conformational flexibility. Third, substituent groups confer awkwardness on the molecule which results in the guest inclusion. Diquinoline derivatives with the bicyclo[3.3.0]octane linker 40, 10[146], 41[186],

12[147] were synthesized according to the theories above and the three halogenated compounds proved to be highly successful in incorporating small guest molecules.

159

In probing the extent of packing prediction, the positional isomers 43, 44, 45, 46 were now synthesized. What differences in crystal engineering properties would come to the surface from these closely-related positional isomers? In addition, it was also planned to further explore how the weak interactions dominate the crystal structures when there is no directional strong hydrogen bonding or coordination complexation present. These hosts are designed to purposely avoid strong intermolecular attractions, and merely weak interactions like C-H…Pi, Pi…Pi, C-H…N, halogen bond or halogen…Pi are possible.

In this work, we hoped also to gain more understanding of design of host molecules and also to investigate systematically the weaker and less familiar supramolecular synthons.

160

5.2 Synthesis

As described in Scheme 5.1, the family of positional isomers can be prepared using the synthetic approach which is similar to the method for synthesizing their earlier isomeric compounds.

Scheme 5.1 Syntheses of potential host molecules 44-46 which are positional isomers of the host compounds 10, 41 and 12.

161

Diquinoline 43 was synthesized by means of Friedländer condensation using two equivalents of 2-aminobenzaldehyde 42 and one equivalent of bicyclo[3.3.0]octane-3,7- dione 33. In principle, reaction between dione 33 and 42 could generate two diquinoline condensation products resulting from two different enolisation directions of the two ketone groups. Interestingly, only 43 was observed in practice. This is because double bonds formed at the 2, 6 positions of the bicyclic ring are less strained than for the alternative 2,7 positional isomer, as shown in Figure 5.1.

Figure 5.1 Two possible positions where double bonds could be formed in Friedländer condensation

Dibromodiquinoline 44 and hexabromodiquinoline 46 can be made with high regio- and stereo-selectivity through free radical benzylic bromination. Tetrabromodiquinoline 45 was synthesized by electrophilic substitution on the aromatic wings. Further details of the selectivity of the radical bromination can be obtained in a paper written by Marjo and Bishop[187].

All these diquinoline derivatives were synthesized in racemic form. Scheme 5.1 shows only one of the enantiomers for clarity. Compared to the original four isomers, all four of the new diquinoline derivatives were all obtained in relatively poorer yields as shown in the experimental chapter. This is due in part to their poorer solubility.

162

5.3 Crystal Structures of Diquinoline Derivatives

The three halogenated diquinoline derivatives have been systematically screened and behave very differently from their corresponding isomers in terms of their inclusion behaviour.

Dibromodiquinoline 44 proved to be a very productive host molecule forming a large number of inclusion compounds when crystallised from a wide range of solvents. The solvent-free crystal form was also obtained from other solvents.

Tetrabromodiquinoline 45 produced no crystals of quality suitable for single crysal X- ray diffractometry due to its extremely low solubility in most solvents.

Hexabromodiquinoline 46 was shown to yield two inclusion compounds from different solvents. However, it lost the selectivity of trapping just the aromatic solvents shown by its positional isomer 12.

Numerical details of the solution and refinement of crystal structures from all four new diquinoline derivatives are presented in Tables 5.1, 5.2 and 5.3.

163

Table 5.1 Numerical details of five structures of dibromodiquinoline 44.

carbon benzene toluene 1,4-dioxane crystal form apohost tetrachloride clathrate clathrate clathrate clathrate

(44)2· (44)2· (44)2· compound 44 (44)·(CCl4) (benzene) (toluene) (1,4-dioxane)

(C22H14Br2N2)· (C22H14Br2N2)2· (C22H14Br2N2)2· (C22H14Br2N2)2· formula C22H14Br2N2 (CCl4) (C6H6) (C7H8) (C4H8O2) formula mass 466.17 619.98 505.23 512.24 496.20 crystal system, Monoclinic Monoclinic Triclinic, P-1 Triclinic, P-1 Triclinic, P-1 space group P21/n P21/n temperature (K) 293 293 155 156 155 10.492 (2), 14.314 (3), 12.5942 (5), 9.9506 (4), 12.3747 (5), a, b, c (Å) 16.047 (3), 9.915 (2), 13.5889 (6), 10.5554 (5), 13.7223 (6), 11.558 (2) 16.588 (3) 14.8893 (6) 11.3107 (5) 14.8147 (6) 90 90 67.192 (1), 64.444 (2), 67.994 (2), α, β, γ (°) 109.30 (3) 90.73 (3) 66.617 (1), 82.355 (2), 67.049 (2), 90 90 65.880 (1) 80.173 (2) 67.298 (2) V (Å3) 1836.6 (6) 2354.0 (8) 2055.93 (15) 1053.68 (8) 2061.28 (15) Z 4 4 4 2 4 Synchrotron, Synchrotron, λ Radiation type Mo Kα Mo Kα Mo Kα λ = 0.71073 Å = 0.71073 Å μ (mm−1) 4.42 3.91 3.96 3.86 3.95 crystal size 0.20 × 0.02 × 0.20 × 0.02 × 0.22 × 0.19 × 0.11 × 0.10 × 0.31 × 0.13 × (mm) 0.02 0.02 0.11 0.06 0.11

Tmin, Tmax 0.476, 0.679 0.667, 0.793 0.371, 0.668 No. of measured, independent and 21584, 3187, 24423, 4122, 29405, 7203, 15308, 3709, 28334, 7046, observed [I > 3105 3012 6106 3056 5862 2σ(I)] reflections Rint 0.055 0.198 0.043 0.039 0.032 R [F2 > 2σ(F2)], 0.032, 0.095, 0.090, 0.256, 0.035, 0.090, 0.030, 0.125, 0.042, 0.112, wR(F2), S 0.78 1.03 1.01 0.97 1.28 no. of 3187 4122 7203 3709 7046 reflections no. of 235 280 569 269 523 parameters no. of restraints 0 28 114 18 72

Δρmax, Δρmin (e 0.54, −1.20 2.52, −1.53 0.57, −0.82 0.96, −0.46 2.36, −0.60 Å−3)

164

Table 5.2 Numerical details of five structures of dibromodiquinoline 44.

1,1,1- Pyridine dichloromethane acetone crystal form trichloroethane ethanol clathrate clathrate clathrate clathrate clathrate

(44)· (44)·(1,1,1- (44)2· (44)2· (44)2· compound (pyridine) trichloroethane) (dichloromethane) (acetone) (ethanol)

(C22H14Br2N2) (C22H14Br2N2)· (C22H14Br2N2)2· (C22H14Br2N2)2· (C22H14Br2N2)· formula ·(C5H5N) (C2H3Cl3) (CH2Cl2) (C3H6O) (C2H6O) formula mass 545.27 599.57 508.64 503.21 512.24 crystal system, Triclinic, P-1 Triclinic, P-1 Triclinic, P-1 Triclinic, P-1 Triclinic, P-1 space group temperature (K) 155 293 155 156 159

9.8181 (15), 9.5190 (19), 9.9358 (4), 10.6761 (16), 10.1015 (5),

a, b, c (Å) 10.1226 (16), 10.053 (2), 10.6243 (5), 12.871 (2), 10.5844 (5), 11.6978 (16) 12.126 (2) 11.6026 (4) 14.494 (2) 11.1951 (5) 88.169 (6), 90.64 (3), 62.773 (1), 98.026 (6), 64.088 (2),

α, β, γ (°) 85.214 (6), 92.02 (3), 83.438 (1), 95.161 (6), 81.867 (2), 89.213 (7) 96.93 (3) 62.827 (1) 95.760 (6) 78.545 (2) V (Å3) 1157.9 (3) 1151.1 (4) 961.92 (7) 1951.3 (5) 1053.15 (9)

Z 2 2 2 2 2 Synchrotron, λ = Radiation type Mo Kα Mo Kα Mo Kα Mo Kα 0.71073 Å

μ (mm−1) 3.52 3.89 4.36 4.17 3.87 0.32 × 0.24 × 0.12 × 0.02 × 0.23 × 0.10 × 0.12 × 0.09 × 0.22 × 0.14 × crystal size (mm) 0.18 0.02 0.04 0.07 0.10

Tmin, Tmax 0.399, 0.570 0.435, 0.852 0.646, 0.773 0.483, 0.689 No. of measured,

independent and 14588, 3870, 13443, 3645, 13642, 3371, 33995, 6765, 16941, 4598, observed [I > 2879 3081 3038 4847 4117 2σ(I)] reflections Rint 0.044 0.138 0.033 0.054 0.032

R [F2 > 2σ(F2)], 0.042, 0.190, 0.092, 0.250, 0.029, 0.117, 0.039, 0.141, 0.023, 0.101, wR(F2), S 1.03 1.36 0.98 1.20 0.83

no. of reflections 3870 3645 3371 6765 4598 no. of parameters 289 281 262 507 275 no. of restraints 0 0 6 0 0

Δρmax, Δρmin (e 0.73, −1.06 2.90, −1.48 0.63, −0.72 0.76, −0.68 0.47, −0.50 Å−3)

165

Table 5.3 Numerical details of the structure of 43 and two structures of 46.

benzene diethyl ether crystal form Solvent-free clathrate clathrate

(46)2· compound 43 (46)2·(benzene) (diethyl ether)

C22H16N2 (C22H10Br6N2)2· (C22H10Br6N2)2· formula (C6H6) (C4H10O)

formula mass 308.37 1642.29 1638.36

crystal system, Monoclinic, Triclinic, P-1 Triclinic, P-1 space group C2/c

temperature (K) 100 160 151

26.063 (5), 11.6218 (7), 16.3697 (10),

a, b, c (Å) 4.759 (1), 11.7853 (6), 19.9241 (12),

12.411 (3) 21.3674 (11) 21.9754 (14)

90, 93.323 (3), 92.455 (2),

α, β, γ (°) 107.28 (3), 101.156 (3), 109.740 (2),

90 112.958 (3) 111.926 (2)

V (Å3) 1469.9 (5) 2614.9 (2) 6139.9 (7)

Z 4 4 8

Synchrotron, Radiation type Mo Kα Mo Kα λ = 0.71073 Å

μ (mm−1) 0.08 9.22 7.95

0.02 × 0.02 × 0.16 × 0.13 × 0.12 × 0.11 × crystal size (mm) 0.02 0.11 0.07

Tmin, Tmax 0.329, 0.430 0.444, 0.591

No. of measured, independent and 8688, 1243, 34214, 10188, 81153, 21454,

observed [I > 2σ(I)] reflections 1076 7458 13030

Rint 0.099 0.052 0.061

0.064, 0.177, 0.072, 0.260, 0.080, 0.259, R [F2 > 2σ(F2)], wR(F2), S 1.08 1.71 1.53

no. of reflections 1243 10188 21454

no. of parameters 109 622 1176

no. of restraints 0 0 0

−3 Δρmax, Δρmin (e Å ) 0.38, −0.38 1.64, −0.92 5.89, −2.79

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5.3.1 Crystal Structure of Diquinoline 43

Diquinoline 43 has extremely low solubility in most solvents and it tends to form needle-like micro-crystals or even powders. It was therefore impossible to solve the structure using our home X-ray source. A decent sized crystal was obtained from dimethyl disulfide (DMSO) and the structure was resolved using the much powerful X- ray source at the Australian Synchrotron. The material crystallised solvent-free in space group C2/c.

Racemic molecules of diquinoline 43 pack in a concave face to convex face mode which allows molecules with such a shape to achieve close packing and low energy. A molecular layer is formed with the molecules packing along both a and b directions, as shown in Figure 5.2. Molecules stacked on top of each other along the b axis in the concave face to convex manner using C-H…Pi interactions. The donors in this weak interaction are the two hydrogen atoms at the bridgehead position of the bicyclic core.

Each stack of molecules is linked along a also using C-H…Pi interactions, but where the hydrogen is donated from the aromatic ring.

Figure 5.2 Part of the structure of 43 projected on the ab plane. Colour code: C green,

N blue, H grey. The b axis is vertical, and a is horizontal, in this figure. 167

Each layer is composed of molecules with the same chirality. Molecular layers, alternating in handedness, are linked by means of bifurcated C-H…N interactions along the c direction. It also can be noted that adjacent molecular stacks from neighbouring layers are connected by C-H…N interactions face in the opposite direction (Figure 5.3).

Although these interactions are only weak intermolecular attractions, this assembly is highly efficient and compound 43 has the remarkably high melting point of 352-354 Ԩ.

Figure 5.3 Part of the structure of 43 projected on the ac plane.

168

5.3.2 Apohost Structure of Dibromodiquinoline 44

The crystallisation of racemic dibromodiquinoline 44 from methanol, chloroform, trifluoromethylbenzene, p-xylene and ethyl acetate gave a solvent-free structure in the monoclinic space group P21/n. Single crystal X-ray diffractometry was used to confirm that these crystal structures were identical in all cases.

Pairs of 44 with opposite handedness associate in an endo, endo-facial manner by using both Pi…Pi and C-H…Pi interactions. This type of dimer is a parallel fourfold aromatic embrace (P4AE) using the description of Dance and Scudder.[144,145] It is a highly efficient means for V-shaped molecules to pair up and form an effective repeat unit, as shown in Figure 5.4.

Figure 5.4 The dimeric repeat unit in the crystal structure of 44. This is a P4AE embrace that assembles using two C-H…Pi interactions.

Adjacent dimers interact by means of exo, exo-facial Pi…Pi interactions to produce a layer structure (Figure 5.5). Layers stack on each other in a laterally displaced mode.

Each is stabilised by four pairs of C-H…N interactions, as shown in Figure 5.6. In addition to these, four halogen…Pi interactions are also contributing to its stability. In both of these two associations, the PA4E unit acts as both donor and acceptor in equal numbers.

169

Figure 5.5 Part of one layer in the apohost crystal structure of 44.

Figure 5.6 Interactions between layers in the apohost structure of 44. 170

5.3.3 Crystal Structure of (44)·(CCl4)

A 1:1 inclusion compound in space group P21/n was obtained when 44 was crystallised from carbon tetrachloride solvent. Once again pairs of 44 molecules form a P4AE embrace (Figure 5.7) and this constitutes the host repeat unit in the crystal. Compared to the P4AE formed in apohost structure, it employs not only C-H…Pi interactions but also a Pi…Pi interaction (around 3.4 Հ) between the endo-faces of the two host molecules.

Figure 5.7 The repeat host unit in the structure of the carbon tetrachloride solvate.

Colour code: C green, N blue, Br brown, H grey.

The structure of the carbon tetrachloride solvate is simple although it looks more complicated at first sight. Groups of four host dimers assemble in the ac plane thereby leaving a cavity between them (Figure 5.8). Stacking along b provides a channel for guest inclusion. The four host molecules associate by means of means of Ar-H…Pi and

Ar-H…Br interactions. A clear perspective of the positioning of these host molecules and the interactions utilised among them can be seen in Figure 5.9. The host molecules are linked to their guests through Ar-H…Cl attractions.

171

Figure 5.8 Cross-section view of a channel in the structure of (44)·(CCl4) projected on the ac plane. Colour code: C green, N dark blue, Br brown, Cl sky blue, H grey.

Figure 5.9 Mutually perpendicular positioning of four host molecules in (44)·(CCl4)

172

Channels are therefore created along the b direction by the perpendicular association of host molecules. The length of each channel for hosting guest molecules is extended simply by repeating four pairs of the host dimer along the b direction and linking them using a pair of bifurcated alkyl-H…N interactions (Figure 5.10).

Figure 5.10 The C-H…N interactions that link the host molecules along the b axis.

173

5.3.4 Crystal Structure of (44)2·(benzene)

Crystallisation of the racemic dibromodiquinoline 44 from benzene gave crystals of

(44)2·(benzene) in space group P-1. It once again forms a dimeric P4AE unit assembled using two different enantiomeric molecules. The distances of the H…Pi and Pi…Pi interactions used are 2.856 and 3.360 Հ, respectively (Figure 5.11).

Figure 5.11 The dimeric host unit in the structure of (44)2·(benzene).

Benzene molecules, which are disordered over two positions, are enclosed between two of these dimeric units. As illustrated in Figure 5.12, the two dimers are linked by two

Ar-H…Br interactions, and the space between them is then occupied by a benzene molecule which is stabilised by multiple C-H…Pi interactions. A layer is formed by repeating this packing mode along both the a and c directions. The resulting layers are then connected by numerous Ar-H…Br, Ar-H…N and alkyl-H….N interactions, as shown in Figure 5.13. Nonetheless, adjacent layers are not stacked directly on top of each other but in a laterally displaced pattern so that guest molecules are confined securely within cage-like enclosures.

174

Figure 5.12 Part of the structure of (44)2·(benzene) projected on the ac plane.

Disordered benzene molecules are designated as light and dark green colours.

Figure 5.13 Part of the structure of (44)2·(benzene) projected on the ab plane whereby the typical interactions between layers are emphasized.

175

5.3.5 Crystal Structure of (44)2·(toluene)

An inclusion compound also in space group P-1 was obtained when dibromodiquinoline

44 crystallised from pure toluene under ambient conditions. Similar to the benzene solvate, the structure of (44)2·(toluene) still adopts the P4AE dimer as its fundamental host packing unit. The values of H…Pi and Pi…Pi interactions in this unit are 2.580 and

3.478 Հ. The toluene guest molecule behaves in a more disordered style. Four distinctive positions were observed in the structure, as seen in Figure 5.14.

Figure 5.14 Fourfold-disordered toluene guest molecules indicated by four different colours. Hydrogen atoms are omitted for clarity.

Once again, each guest molecule is sandwiched between two dimeric units but this time by using Pi…Pi interactions. The distance between host and guest is around 3.392 Հ. As shown in Figure 5.15, the molecular sandwiches are stacked directly on top of each other to create a molecular column, in which toluene acts as a bridging molecule connecting each host unit. Part of three columns, made of molecular sandwiches, is shown in Figure 5.16. There is no evident interaction between adjacent molecular columns in the same layer, as can be seen from the cross-section of molecular column in

Figure 5.17. Pairs of two neighbouring molecular columns in the same layer are bridged

176 by another molecular column in an adjacent layer, since the layers are laterally displaced. These interactions among layers are mainly C-H…N associations.

Figure 5.15 A toluene molecule sandwiched between two dimeric host P4AE units.

Figure 5.16 Part of the structure of (44)2·(toluene) projected on the bc plane.

177

Figure 5.17 Cross-section view of molecular columns projected on the ac plane.

178

5.3.6 Crystal Structure of (44)2·(1,4-dioxane)

The structure of (44)2·(1,4-dioxane), in space group P-1, also employs the dimeric

P4AE host unit in its packing. Here the Ar-H…Pi value is 2.850 Հ and the Pi…Pi distance is 3.869 Հ. This structure has many similarities to that of (45)2·(benzene). The

1,4-dioxane guest molecule is disordered over two positions and is sandwiched between two pairs of dimeric units using C-H…Pi interactions.

These molecular sandwiches are stacked on top of each other along the a axis by means of Ar-H…Br interactions to build up a molecular column, which is then linked to adjacent columns along the c direction to form a molecular layer. The complete three dimensional crystal structure is accomplished by placing layers on top of each other in a laterally displaced manner (Figure 5.18). The attractions prevailing among layers are C-

H…N and C-H…Br interactions. The caged guest 1,4-dioxane molecules are further stabilised by forming Ar-H…O interactions with both molecules above and beneath them, as depicted in Figure 5.19.

179

Figure 5.18 Part of the structure of (44)2·(1,4-dioxane) projected on the ac plane.

Figure 5.19 Interactions between the layers in (44)2·(1,4-dioxane).

180

5.3.7 Crystal Structure of (44)·(pyridine)

Crystallisation of dibromodiquinoline 44 from pyridine resulted in formation of the solvate (44)·(pyridine) in triclinic space group P-1. Once again, pairs of opposite host enantiomers form P4AE dimers. The H…Pi distance is 2.618 Հ and Pi…Pi distance is

3.838 Հ. Two molecules of pyridine are enclosed between a pair of these dimeric units.

The host dimers are in a slightly displaced position this time, so that more space is created in between to accommodate the additional guest molecule. Consequently, each pyridine molecule now is stabilised by a Pi…Pi and a C-H…Pi interaction. There is no direct linkage between these two host dimers. However, alkyl-H…Br attractions are tilised to connect adjacent host dimers. By extending the packing in this way, a layer is produced. Subsequent layer stacking completes the whole structure, as seen in Figure

5.20.

Figure 5.20 Part of a layer in the structure of (44)·(pyridine).

181

C-H…N interactions are once again playing an important role in joining neighbouring layers. In addition, C-H…N interaction between the non-bridgehead alkyl-H and pyridine nitrogen atom also helps further stabilise the guest molecules.

Figure 5.21 Two layers in the structure of (44)·(pyridine) viewed from a different angle.

182

5.3.8 Crystal Structure of (44)2·(1,1,1-trichloroethane)

The inclusion compound of (44)2·(1,1,1-trichloroethane) not only has the same space group but also very similar packing to the crystal structure of (44)·(pyridine). A further similarity between these two structures is the manner in which C-H…N interactions are applied to join the layers. No further detailed description of this structure is therefore necessary and only two diagrams will be presented for review.

Figure 5.22 Part of a layer in the structure of (44)·(1,1,1-trichloroethane).

183

Figure 5.23 Two layers stacked on top of each other by means of C-H…N interactions in the (44)·(1,1,1-trichloroethane) structure.

184

5.3.9 Crystal structures of (44)2·(acetone) and (44)2·(dichloromethane)

Crystallisation of diquinoline dibromide 44 from acetone gave inclusion crystals of

(44)2·(acetone) in the triclinic space group P-1. Likewise, crystals of

(44)2·(dichloromethane) with the same space group were formed when dichloromethane was used as crystallisation solvent. These two inclusion compounds share a highly similar packing style in their crystal structures, despite the distinctive differences in molecular shape, size and functionality of these two solvents. Therefore, only the structure of (44)2·(acetone) will be discussed here in detail, and only some diagrams of

(44)2·(dichloromethane) will be provided for comparison.

This time, a molecular pen structure was formed. This was the only type of structure that was produced by the earlier isomeric dibromodiquinoline compound 10. In both cases, two host molecules of opposite handedness wrap around a molecule of guest to create the penannular structure illustrated in Figure 5.24. Each molecular pen is assembled from two molecules of opposite handedness through C-H…Pi interactions

(H…Pi are 2.868 and 2.968 Հ). The space within the pen, having the cross-section of

10.43ՀX7.29Հ, is occupied by the acetone guest molecule is anchored by four C-H...Pi interactions and one aryl Pi… O=C Pi interaction.

185

Figure 5.24 A molecular pen unit in (44)2·(acetone) where the host-host and host-guest interactions are presented.

As shown in Figure 5.25, a layer-like structure is formed where each molecular pen links to neighbouring units by various weak interactions. At the corner of the molecular pen, where the bromine atom resides, dimeric C-H….Br interactions are employed so that each pen is chained diagonally. In addition, each pen associates laterally with surrounding units by means of rather weak Pi…Pi attractions and a second type of C-

H…Br interaction.

Figure 5.25 Part of a layer structure projected on the ac plane in (44)2·(acetone).

186

Similar to previous pen structures, a layer comprising molecular pens is connected to its adjacent layers in an offset manner by two types of C-H…N interactions, namely, bifurcated C-H…N and dimeric C-H…N as shown in Figure 5.26. With such offset packing, no channel is formed and the guest molecule is caged separately in each pen.

Furthermore, the acetone molecule is stabilised by O…Br halogen bonding formed between a guest and a host molecule from the adjacent layer.

Figure 5.26 Interactions between layers of molecular pens in (44)2·(acetone).

As shown below in Figure 5.27 the structure of (44)2·(dichloromethane) highly resembles that of (44)2·(acetone). However, the guest dichloromethane molecule is disordered over two centrosymmetric positions. The two structures are so similar that only Figure 5.27 is shown for illustration.

187

Figure 5.27 Part of a layer in the structure of (44)2·(dichloromethane) which shares high similarity with that of (44)2·(acetone).

188

5.3.10 Crystal Structure of (44)2·(ethanol)

The crystal structure of (44)2·(ethanol) shares a certain amount of similarity with the previous structure but also exhibits its own characteristics. In Figure 5.28, two molecules of ethanol are located in the rather narrow space between two pairs of dimers with the help of C-H…O interactions. As a strong hydrogen bond donor, it is not surprising to observe that strong hydrogen bonding exists to link the molecular layers, in addition to C-H…N interactions, as shown in Figure 5.29.

Figure 5.28 Part of the layer structure in (44)2·(ethanol).

189

Figure 5.29 Included ethanol molecules help connect molecular layers.

190

5.3.11 Crystal Structure of (46)2·(benzene)

Hexabromodiquinoline 46 was synthesized via the intermediate tetrabromodiquinoline

45 as outlined in Scheme 5.1. In the first place, tetrabromodiquinoline 45 was tested by using different solvents to determine which would be suitable for its crystallisation.

Unfortunately, no solvents tested proved to be a suitable choice due to the extremely poor solubility of 45. Consequently, no crystal structure of tetrabromodiquinoline 45 was able to be obtained.

Hexabromodiquinoline 46 has slightly improved solubility with the introduction of two further bromine atoms on the aliphatic rings. Solvate crystals in space group of P-1 were obtained when 46 was crystallised from benzene and diethyl ether.

A dimer, comprising two homochiral 46 molecules, is formed by means of an endo, endo-facial swivel interaction, together with dimeric C-H…N (d=2.823 Հ) and Br…Br interaction (d=3.680 Հ). As observed by Bishop, V-shaped diquinoline derivatives are often involved in a centrosymmetric motif, such as P4AE (parallel fourfold aryl embrace interaction) and PHD (Pi…halogen dimer), where two aromatic wings are oriented parallel to each other. In other situations, as shown in Figure 5.30, molecules are rotated in some degree around the axes of the interacting aromatic wings. The interfacial association resulting in this directional change the of aromatic wings is described as a swivel interaction.[188]

191

Figure 5.30 A dimer arising from swivel interaction in the structure of (46)2·(benzene).

The swivel dimers of the same chirality stack on top of each other along the a direction using Ar-H…Br-Alkyl interactions to form a molecular column. Within the molecular column, the space between dimers is occupied by a benzene molecule (Figure 5.31). A layer is then formed by molecular columns of the same handedness along the b direction using C-H…Br and Br…Br interactions.

The molecular layers alternate in chirality along c and channels are generated between four molecular columns every two layers (Figure 5.32). Benzene molecules are trapped in the channel with their plane parallel to the channel, which is perpendicular to the orientation of the benzene within the column.

192

Figure 5.31 Two molecular columns where guest benzene molecules are trapped in the space between two swivel dimers.

193

Figure 5.32 Part of the structure of the (46)2·(benzene) emphasizing that layers alternate in chirality and that channels are formed between every pair of layers.

Molecules of the opposite handedness are coloured light and dark green.

194

5.3.12 Crystal Structure of (46)2·(diethyl ether)

Hexabromodiquinoline 46 also crystallised in space group P-1 when diethyl ether was used as the crystal growth solvent. Dimers arising from swivel interactions are present again, but with a difference the relative position of the two molecules. These also have the same handedness and swivel such that their aliphatic parts become closer. This different orientation causes stronger dimeric C-H…N interactions (D=3.630 Հ), but weakens Br…Pi attraction (d=3.716 Հ).

Figure 5.33 A swivel dimer in the structure of (46)2·(diethyl ether).

As shown in Figure 5.34, there are four crystallographically independent host molecules and two independent diethyl ether molecules in the asymmetric unit: each molecule is coloured in different colour. Four host molecules are associated by swivel interactions to form two swivel dimers. One of the diethyl ether molecules in the unit is disordered.

The two different swivel dimers are connected by two C-H…Br interactions.

195

Figure 5.34 The unit cell projected on the ab plane contains four independent 46 molecules (host) and two independent diethyl ether molecules (guest). Molecules coloured green and blue make one swivel pair, and the red and yellow molecules make the other.

It can be seen clearly from the colours that the two types of swivel dimer extend along both a, b and a, c directions respectively to create an interconnected network in which channels are formed along the a axis. Disordered diethyl ether molecules are located in the periphery of the channel so that a large void space is present in the middle of the channel (Figure 5.35). When observed from other directions, further channels along different directions can also be seen. Figure 5.36 shows a view along this new type of channel where ordered diethyl ether molecules are trapped. In such channels, two centrosymmetric guest molecules are present. In a word, the crystal structure of

(46)2·(diethyl ether) has relatively high porosity compared to other structures from earlier V-shaped systems. This is the first time such a phenomenon has been observed in

196 the derivatives of the bicyclo[3.3.0]octane system. As a porous network made of pure organic molecule using weak interactions, such crystals are less stable compared to inorganic or organometallic newworks.

Figure 5.35 Part of the structure projected on the bc plane showing the largest channel.

197

Figure 5.36 Image viewed from a direction emphasizing a different channel where ordered diethyl ether molecules (light blue) are located.

198

5.4 Conclusions

Compounds 44 and 46 are the nineteenth and twentieth potential diquinoline hosts synthesized in the Bishop group. Both showed inclusion-forming properties as planned.

The success rate is now 19/20 which is remarkable for systems involving only weak forces. The dibrodiquinoline positional isomer 10 only produced molecular pen structures and the hexabromodiquinoline isomer 12 included small aromatic molecules.

Our newly designed isomers behave very differently in both cases.

This inclusion host design has been highly successfully, but little prediction of the exact packing in potential inclusion compounds is possible. Therefore, prediction of inclusion formation has been maximised by paying the price of minimising packing prediction.

199

CHAPTER 6

Experimental

6.1 General Conditions and Instrumentation

The compounds synthesized are presented in order according to the chapter in which they first appear. All NMR data were recorded using a Bruker DPX300 instrument as solutions at 25 Ԩ. Mass spectra were recorded using a Thermo Finnigan LCQ DecaXP instrument at the University of New South Wales. Melting points were recorded with a uncalibrated Kofler device. All X-ray single crystals were grown by dissolving the compound in a small volume of solvent and allowing slow evaporation to occur at ambient temperature and pressure, unless otherwise specified.

The 1H NMR spectra of the compounds synthesized, and the crystallographic information files (CIF) of the solved X-ray structures, are presented as Supplementary

Material on the Compact Disk at the end of the Thesis.

200

6.2 X-Ray Diffraction and Crystallography

Single crystal structure determinations were conducted by Dr Mohan Bhadbhade using a Bruker Kappa Apex single crystal diffractometer, while a polarizing microscope

(Leica M165Z) was used to help single crystal selection. The low temperature during data collection was maintained using an Oxford Cryostream 700 system. Structures of ultra-thin or extremely tiny crystals were determined using the Macromolecular

Crystallography (MX) beamline at the Australian Synchrotron.

The data integration and reduction with the multi-scan absorption correction method was carried out using APEX2 suite software. The structure was solved by direct methods using SHELXS-97 and was refined by the full-matrix least–squares refinement program SHELXL to the final R value. Data collected at the Australian Synchrotron were refined at a wavelength of 0.71072 Հ.

201

6.3 Synthetic Procedures

2,exo-4,6,exo-8-Tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene-3,7-diol (15)

Under nitrogen, dimethyl 1,3-acetonedicarboxylate (20 mL, 0.115 mmol) was added dropwise to a solution of NaOH (5.64 g, 0.141 mmol) in methanol (100 mL) using a dropping funnel. The resulting viscous mixture was heated to reflux until the solution turned clear. Aqueous 40% glyoxal (10 mL, 0.087 mmol) was then added dropwise over

20 minutes and the reaction mixture was kept refluxing for another 10 minutes. The mixture was then cooled down to room temperature.

The red-brown precipitate (disodium salt) was filtered and washed with methanol several times until the filter cake became yellow-white. The cake was then dissolved in a solvent mixture of chloroform (100 mL) and water (100 mL) and stirred vigorously while aqueous HCl (1 M, 150 mL) was added. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and then filtered. The solvent was removed under reduced pressure to give the crude product 15 as waxy solid which can be further purified by recrystallization from n-hexane/ethyl acetate.

Yield: 21.3 g, 48%; Lit.[179]56%

1 H NMR (300 MHz, CDCl3) δ: 3.62 (m, 2H), 3.76 (s, 6H), 3.78 (s, 6H), 3.85 (m, 2H),

10.31 (br, 2OH).

202

13 C NMR (75MHz, CDCl3) δ: 43.8 (CH), 51.7 (CH3), 52.7 (CH3), 55.3 (CH), 103.9 (C),

169.1 (C), 170.6 (C), 170.9 (C)

4-exo-Methyl-2,4,6,exo-8-tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene-3,7-diol

(18)

A round bottom flask was purged with argon for 10 minutes before tetraester 15 (0.5 g,

1.35 mmol) and dry THF (200 mL) were added to it and the mixture cooled in a dry ice- acetone bath. Freshly prepared catalyst 27 (0.51 g, 1.49 mmol) dissolved in dry THF

(20 mL) was then added dropwise through a syringe to the mixture over 30 minutes.

The reaction mixture was left stirring in the bath for another 2 hours before methyl iodide (93 μL, 1.49 mmol) was slowly added. The cooling bath was removed and the reaction mixture stirred at room temperature overnight.

Solvent was removed under vacuum and the residue was washed with brine followed by extraction with ethyl acetate. The extract was then dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel to give the product 18 as a white solid.

Yield: 0.29 g, 56%;

Melting point: 126-129 Ԩ (from methanol) 203

1 H NMR (300 MHz, CDCl3) δ: 1.55 (s, 3H), 3.44-3.48 (dd, 1H), 3.57 (s, 3H), 3.66-3.69

(dd, 1H), 3.76 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.80-3.84 (dd, 1H), 10.17 (br, OH),

10.50 (br, OH)

13 C NMR (75MHz, CDCl3) δ:21.2 (CH3), 44.3 (CH), 51.6 (CH3), 51.7 (CH), 52.4 (CH3),

52.7 (CH3), 52.8 (CH3), 56.2 (CH), 58.5 (C), 102.1 (C), 103.4 (C), 169.3 (C), 169.6 (C),

171.6 (C=O), 171.9 (C=O), 172.8 (C=O), 175.3 (C=O).

+ HRMS m/z: found 407.0941; calcd. for (C17H20O10Na) : 407.0948.

exo-4,exo-8-Dimethyl-2,4,6,8-tetracarbomethoxybicyclo[3.3.0]octa-2,6-diene3,7- diol (19)

The dimethoxytetraester 24 (0.5 g, 1.17 mmol) was added under protection of argon to dichloromethane (15 mL) in a round bottom flask cooled by an ice bath. Boron tribromide (0.76 mL, 7.04 mmol) was added to the solution and the reaction mixture was stirred at 0 Ԩor 30 minutes before being left at room temperature overnight.

Methanol was added to quench the unconsumed boron tribromide, followed by the addition of water. Dichloromethane was added for extraction. The organic extracts were combined, dried (Na2SO4), filtered and evaporated. The residue was purified by flash

204 chromatography on silica gel using an eluent of ethyl acetate and n-hexane (1:1) to give the product 19 as a white powder.

Yield: 0.35 g, 66%;

Melting point: 130-134 Ԩ (from methanol)

1 H NMR (300 MHz, CDCl3) δ: 1.55 (s, 6H), 3.37 (s, 2H), 3.58 (s, 6H), 3.81 (s, 6H),

10.47 (br, 2H).

13 C NMR (75MHz, CDCl3) δ: 23.5 (CH), 51.5 (CH3), 51.9 (CH3), 52.3 (CH3), 57.8

(CH3), 101.8 (C), 170.2 (C), 172.1 (C), 174.9 (C).

+ HRMS m/z: 399.1281; calcd. for (C18H22O10+H) : 399.1286.

exo-4,exo-6-Dimethyl-7-keto-2,4,6,exo-8-tetracarbomethoxybicyclo[3.3.0]oct-2-en-

3-ol (20) cis-Dimethyl tetraester was obtained unexpectedly. Since the reaction was set up for synthesizing the monomethyl tetraester 18. To a precooled solution of tetraester 15 (0.5,

1.35 mmol) in MeOH/H2O (10 mL, 9:1) was added methyl iodide (101 μL, 1.62 mmol).

The reaction was kept at 0 Ԩ using ice bath for 2 hours and was stirred for another 24 hours. 205

The reaction mixture was extracted with ethyl acetate. Combined extracts were dried over Na2SO4 and solvent was removed under reduced pressure. A brown sticky oil was obtained and methanol (2 mL) was added to redissolve it. The solution was left evaporating on the bench and block-like crystals formed. These proved to be the cis- dimethyl tetraester 20, together with other methylated products remaining in solution.

1 H NMR (300 MHz, CDCl3) δ: 1.54 (s, 3H), 1.61 (s, 3H), 2.73-2.76 (d, 1H), 3.45-3.48

(d, 1H), 3.53 (s, 3H), 3.67 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H), 3.89-3.95 (t, 1H), 10.08 (br,

1OH).

13 C NMR (75MHz, CDCl3) δ: 23.0 (CH3), 25.1 (CH3), 41.3 (CH), 51.9 (CH3), 52.4

(CH3), 52.5 (CH3), 52.9 (CH3), 56.9 (CH3), 57.4 (C), 59.1 (C), 60.0 (CH), 103.9 (C),

169.3 (C), 170.2 (C=O), 170.3 (C=O), 171.4 (C=O), 174.4 (C=O), and ketone carbonyl not observed.

+ HRMS m/z: found 421.1095; calcd. for (C18H22O10Na) : 421.1105.

206 exo-2,exo-4,exo-8-Trimethyl-2,4,exo-6,8-tetracarbomethoxybicyclo[3.3.0]octane-

3,7-dione (21)

Disodium salt of tetraester 23 (1.0 g, 2.42 mmol) and methyl iodide (0.90 mL, 14.5 mmol) were added to a mixture of solvent (20 mL) of methanol/water (3:1 v/v).This reaction mixture was then stirred at room temperature for two days.

The reaction mixture was extracted with dichloromethane three times and organic extracts was combined. The extracts were concentrated under vacuum to give a brown oil. This was then redissolved in small amount of methanol and solvent allowed to evaporate under ambient conditions to yield needle-like colourless crystals of 21.

Yield: 0.60 g, 60%;

Melting point: 149-150 Ԩ (from a mixture of n-hexane and ethyl acetate)

1 H NMR (300 MHz, CDCl3) δ: 1.57 (s, 6H), 1.67 (s, 3H), 2.91 (q, 1H), 3.40 (q, 1H),

3.57 (s, 3H), 3.68 (d, 6H), 3.77 (s, 3H), 3.94 (d, 1H).

13 C NMR (75MHz, CDCl3) δ: 23.9 (CH3), 25.2 (CH3), 26.9 (CH3), 47.2 (CH), 52.8

(CH3), 53.1 (CH3), 53.4 (CH3), 55.0 (CH), 56.5 (CH3), 59.1 (CH), 60.12 (C), 60.19 (C),

169.4 (C), 169.9 (C), 170.5 (C), 170.6 (C), 202.3 (C), 210.5 (C)

+ HRMS m/z: found 435.1255; calcd. for (C19H24O10Na) : 435.1262.

207 exo-2,exo-4,exo-6,exo-8-Tetramethyl-2,4,6,8- tetracarbomethoxybicyclo[3.3.0]octane-3,7-dione (22)

To a round bottom flask were added tetraester15 (1.0 g, 2.70 mmol), K2CO3 (3.0 g, 21.6 mmol ), methyl iodide (1.34 mL, 21.6 mmol) and acetone (20 mL). The mixture was allowed to reflux overnight.

The solid was filtered off from the cooled mixture and washed with acetone. The solvent was removed and the residue was redissolved in dichloromethane. The solution was then filtered again to remove insoluble material. Solvent was removed under vacuum to yield the product 22 as a white solid.

Yield: 1.04 g, 90%; Lit.[180]98%

Melting point: 170-174 Ԩ

1 H NMR (300 MHz, CDCl3) δ: 1.72 (s, 12H), 2.86 (s, 2H), 3.60 (s, 12H).

13 C NMR (75MHz, CDCl3) δ: 26.7 (CH3), 29.5 (CH3), 52.3 (CH3), 53.0 (C), 58.1 (CH),

171.0 (C), 204.3 (C=O).

3,7-Dimethoxy-exo-4,exo-8-dimethyl-2,4,6,8-tetracarbomethoxybicyclo[3.3.0]octa-

2,6-diene (24) 208

To a solution of tetraester 15 (1 g, 2.70 mmol) in dry THF (20 mL) was added a DMF solution of catalyst 27 (5.60 g, 16.2 mmol) and then the solution was stirred for 30 minutes at room temperature. Methyl iodide (0.42 mL, 6.75 mmol) was added to the mixture, which was stirred overnight.

The reaction mixture was poured into a saturated aqueous solution of NH4Cl and extracted with diethyl ether. The combined extracts were then dried over anhydrous

Na2SO4, filtered and concentrated. The residue was columned on silica to give the white solid product 24 as a white solid.

Yield: 0.35 g, 30%; Lit.[181]37%

1 H NMR (300 MHz, CDCl3) δ: 1.46 (s, 6H), 3.45 (s, 2H), 3.59 (s, 6H), 3.68 (s, 6H),

3.94 (s, 6H).

13 C NMR (75MHz, CDCl3) δ: 24.3 (CH3), 51.1 (C), 51.8 (CH3), 52.4 (CH3), 60.5 (CH3),

62.8 (CH3), 108.2 (C), 164.4 (C), 170.6 (C), 172.6 (C).

1-(Trimethylsilyl)-2-pyrrolidinone (26)

To a solution of 2-pyrrolidinone (10 g, 0.12 mol), and triethylamine (14.9 g, 0.15 mol) in toluene (100 mL) was added trimethylsilyl chloride (16.4 mL, 0.13 mol) under argon.

The mixture was stirred at 40 Ԩ for 4 hours before being cooled down to 0 Ԩ and

209 diluted with 100 mL n-hexane-ether (1:1).The diluted solution was then filtered through

Celite and the filtrate was concentrated. The residue was distilled (80 Ԩ) under reduced pressure to give 26 colourless, peach scented oil.

Yield: 15.0 g, 80%; Lit.[183]95%

1 H NMR (300 MHz, CDCl3) δ: 0.16 (s, 9H), 1.90 (m, 2H), 2.24 (t, 2H), 3.26 (t, 2H).

13 C NMR (75MHz, CDCl3) δ: -1.8 (CH3), 21.0 (CH2), 32.1 (CH2), 45.8 (CH2), 182.5

(C=O).

(Tetra-n-butyl)ammonium 2-pyrrolidinone-1-ide (27)

To a solution of n-Bu4NF in dry DMF (15 mL) under argon was added a solution of 1-

(trimethylsilyl)-2-pyrrolidinone in dry DMF (5 mL) at room temperature. The mixture was stirred for 15 minutes before trimethylsilyl fluoride (b.p. 16 Ԩ) was removed under reduced pressure. The flask was then purged with argon and the catalyst solution 27 was ready for use.

210

3,7-Di-n-butylbicyclo[3.3.0]octane-endo-3,endo-7-diol (28)

The compound was obtained from a failed experiment aimed at synthesizing an adamantyl derivative of bicyclo[3.3.0]octane. The procedure is similar to that of 3,7- di(2-pyridyl)bicyclo[3.3.0]octane-endo-3,endo-7-diol 31. Diketone 33 (0.38 g, 2.76 mmol) and n-butyl lithium solution (4.4 mL, 6.9 mmol) were added in this reaction. The white powder-like product 28 was precipitated out from the reaction mixture when treated with a small amount of cold methanol.

Yield: 0.35 g, 50%

Melting point: 113-117 Ԩ (from methanol)

1 H NMR (300 MHz, CDCl3) δ: 0.87 (t, 6H), 1.36 (m, 8H), 1.48 (t, 4H), 1.76 (dd, 4H),

1.94 (q, 4H), 2.63 (m, 2H), 3.39 (br, 2OH).

13 C NMR (75MHz, CDCl3) δ: 14.2 (CH3), 23.4 (CH2), 26.9 (CH2), 41.9 (CH2), 42.8

(CH2), 47.6 (CH), 84.7 (C).

+ HRMS m/z: found 277.2131; calcd. for (C16H30O2Na) : 277.2138.

3,7-Dibenzylbicyclo[3.3.0]octane-endo-3,endo-7-diol (29)

211

Dry magnesium turnings (0.57 g) and a grain of iodine were added under argon to a solution of benzyl chloride (1.00 g, 7.91 mmol) in dry THF (15 mL) in an oven-dried two-neck round bottom flask. Gentle heat was applied to initiate the reaction. Once the vigorous reflux started, heating was stopped and reflux was allowed to continue. The reaction flask was cooled down in an ice bath before a solution of diketone 33 (0.36 g,

2.63mmol) in dry THF (15 mL) was added dropwise through a syringe. After addition over 30 minutes, the reaction mixture was heated using an oil bath and was allowed to reflux overnight.

Saturated aqueous ammonium chloride solution (20 mL) was added slowly to the cooled mixture and stirring continued for another 10 minutes. THF was then removed under reduced pressure. The reaction product was extracted with ethyl acetate three times. The combined organic extracts were dried with anhydrous sodium sulfate, then filtered and the solvent was evaporated under reduced pressure to give crude product 29.

This was columned on silica gel using an eluent of ethyl acetate and n-hexane (3:1) to give the pure desired product as white solid.

Yield: 0.31 g, 45%

Melting point: 151-152 Ԩ (from ethyl acetate)

1 H NMR (300 MHz, CDCl3) δ: 1.66-1.72 (dd, 4H), 1.82 (s, 2OH), 1.97-2.05 (dd, 4H),

2.69 (m, 2H), 2.80 (s, 4H), 7.20-7.30 (m, 10H).

13 C NMR (75MHz, CDCl3) δ: 41.6 (CH2), 46.4 (CH2), 46.9 (CH), 84.0 (C), 126.6 (CH),

128.4 (CH), 130.3 (CH), 138.1 (C).

+ HRMS m/z: found 345.1817; calcd. for (C22H26O2Na) : 345.1825.

212

3,7-Di(1-naphthyl)bicyclo[3.3.0]octane-endo-3,endo-7-diol (30)

Reaction procedures are similar to those used for synthesis of 3,7- dibenzylbicyclo[3.3.0]octane-endo-3,endo-7-diol 29.

Magnesium turnings (0.50 g) and a grain of iodine were added under argon to a solution of 1-naphthyl bromide (1.35 g, 6.52 mmol) in dry THF (20 mL) in an oven-dried two- neck round bottom flask. Gentle heat was applied to initiate the reaction. Once the vigorous reflux started, heating was stopped and reflux was allowed to continue. The reaction flask was cooled down in an ice bath before a solution of diketone 33 (0.30 g,

2.17 mmol) in dry THF (15 mL) was added dropwise through a syringe. The reaction mixture was then heated in an oil bath and was allowed to reflux overnight.

Saturated aqueous ammonium chloride solution (20 mL) was added slowly to the cooled mixture and stirring continued for another 10 minutes. All insoluble solid was removed by filtration. THF was then removed under reduced pressure. The reaction product was extracted with ethyl acetate three times. The combined organic extracts were dried with anhydrous sodium sulfate, then filtered and the solvent was evaporated under reduced pressure to give crude product 30.This was columned on silica gel using an eluent of ethyl acetate and n-hexane (2:1) to give the pure desired product as a white powder.

Yield: 0.34 g, 40%, Lit.[185]73 %

213

Melting point: 209-213Ԩ (from ethyl acetate), Lit.[185]211-213 Ԩ

1 H NMR (300 MHz, CDCl3) δ: 2.32 (dd, 4H), 2.58 (d, 4H), 3.13 (m, 2H), 7.34 (m, 4H),

7.40 (dd, 2H), 7.61 (dd, 2H), 7.75 (q, 4H), 8.82 (m, 2H).

13 C NMR (75MHz, CDCl3) δ: 36.5 (CH2), 47.1 (CH), 87.2 (C), 123.5 (CH), 124.9 (CH),

125.2 (CH), 125.3 (CH), 127.6 (CH), 128.5 (CH), 128.8 (CH), 132.2 (C), 134.5 (C),

138.3 (C).

+ HRMS m/z: found 417.1818; calcd. for (C28H26O2Na) : 417.1825.

3,7-Di(2-pyridyl)bicyclo[3.3.0]octane-endo-3,endo-7-diol (31)

A dry and round bottom flask was purged with argon for 10 minutes. Under an argon atmosphere, 2-chloropyridine (1.2 mL, 14.5 mmol) was injected into pre-cooled dry

THF (10 mL) in a two-neck round bottom flask cooled by a dry ice-acetone bath (-

77 Ԩ). The mixture was stirred gently and n-butyl lithium solution (9 mL, 14.5 mmol)was added slowly through a syringe. After stirring for 30 minutes, the cooling bath was removed and diketone 33 (0.5 g, 3.62 mmol) solution in dry THF (20 mL) was transferred into the reaction mixture. After 30 minutes, the reaction mixture was heated up to reflux and left refluxing overnight.

214

Saturated aqueous ammonium chloride solution (20 mL) was added slowly to the cooled mixture and stirring continued for another 10 minutes. THF was then removed under reduced pressure. The reaction mixture was extracted with dichloromethane three times. The combined organic extracts were dried with anhydrous sodium sulfate, then filtered and the solvent was evaporated under reduced pressure to give crude product as a black sticky oil. This was columned on silica gel using an eluent of dichloromethane and methanol (1:5) to give the pure product 31 as a white powder.

Yield: 0.35 g, 33%

Melting point: 125-126 Ԩ (from a mixture of ethyl acetate and n-hexane)

1 H NMR (300 MHz, CDCl3) δ: 2.22 (d, 4H), 2.63 (dd, 4H), 3.19 (m, 2H), 6.61 (s, 2OH),

7.17 (m, 2H), 7.61 (m, 2H), 7.71 (m, 2H), 8.55 (m, 2H).

13 C NMR (75MHz, CDCl3) δ: 45.2 (CH2), 50.5 (CH), 85.8 (C), 119.5 (CH), 121.7 (CH),

136.9 (CH), 147.8 (CH), 165.1 (C).

+ HRMS m/z: found 319.141; calcd. for (C18H20O2N2Na) : 319.1417.

3,7-Di(2-thienyl)bicyclo[3.3.0]octane-endo-3,endo-7-diol (32)

215

Reaction procedures are similar to that for synthesis of 3,7- dibenzylbicyclo[3.3.0]octane-endo-3,endo-7-diol.

Magnesium turnings (0.50 g) and a grain of iodine were added under argon to a solution of 1-chlorothiophene (1.1 g, 11.6 mmol) in dry THF (10 mL) in an oven-dried two-neck round bottom flask. Gentle heating was supplied to initiate the reaction. Once the vigorous reflux started, heating was stopped and reflux was allowed to continue. The reaction flask was cooled down in an ice bath before a solution of diketone 33 (0.40 g,

2.90 mmol) in dry THF (20 mL) was added dropwise through a syringe. The reaction mixture was then heated using an oil bath and was allowed to reflux overnight.

Saturated aqueous ammonium chloride solution (20 mL) was added slowly to the cooled mixture and stirring continued for another 10 minutes. All insoluble solid was removed by filtration. THF was then removed under reduced pressure. The reaction product was extracted with ethyl acetate three times. The combined organic extracts were dried with anhydrous sodium sulfate, then filtered and the solvent was evaporated under reduced pressure to give crude product as a dark brown oil. This was columned on silica gel using an eluent of ethyl acetate and n-hexane (1:2) to give the pure desired product 32 as a white powder.

Yield: 0.36 g, 41%

Melting point: 148-149Ԩ (from acetonitrile)

1 H NMR (300 MHz, CDCl3) δ: 2.29 (dd, 4H), 2.47 (d, 4H), 2.84 (m, 2H), 3.08 (s, 2OH),

6.93 (q, 2H), 6.98 (dd, 2H), 7.20 (dd, 2H).

13 C NMR (75MHz, CDCl3) δ: 41.9 (CH2), 49.3 (CH), 83.4 (C), 122.6 (CH), 124.3 (CH),

126.7 (CH), 152.1 (C).

216

+ HRMS m/z: found 329.0634; calcd. for (C16H18O2S2Na) : 329.0640.

Bicyclo[3.3.0]octane-3,7-dione (33)

Tetraester 15 (63 g, 0.17 mol) was added to a mixture of glacial acid (31 mL) and aqueous HCl (1 M, 280 mL) under vigorous stirring and the mixture was then refluxed for 2.5 hours. The reaction mixture was cooled down using an ice bath and then extracted with chloroform.

The chloroform and acid were removed under reduced pressure and the residue was redissolved in chloroform, followed by neutralisation with saturated NaHCO3 solution.

The organic layer was separated, dried over anhydrous Na2SO4 and then filtered. The solvent was evaporated under vacuum to yield the crude product 33 as a pale yellow solid. Pure material was obtained by recrystallization from methanol.

Yield: 20.0 g, 85%; Lit.[189]90%

Melting point: 84-86 Ԩ; Lit.[189]85-86 Ԩ.

1 H NMR (300 MHz, CDCl3) δ: 2.13 (dd, 4H), 2.55 (dd, 4H), 3.03 (m, 2H).

13 C NMR (75MHz, CDCl3) δ: 36.3 (CH), 43.5 (CH2), 217.8 (C=O).

217

2-Aminobenzaldehyde (42)

Iron powder (22.2 g, 0.4 mol) and concd. HCl (ca. 200 mg) were added to a solution of

2-nitrobenzaldehyde in ethanol (120 mL) and water (30 mL). The mixture was refluxed for 1.5 hours. The mixture was then extracted with ethyl acetate. The organic extracts were dried over anhydrous Na2SO4 and then filtered. Solvent was removed and the residue was purified by flash chromatography on silica gel to yield the desired product

42 as pale yellow semi-solid.

Yield: 4.20 g, 87%; Lit.[190]87%

1 H NMR (300 MHz, CDCl3) δ: 6.18 (br, NH), 6.65 (d, 1H), 6.71 (q, 1H), 7.31 (q, 1H),

7.46 (d, 2H), 9.86 (d, 1H).

13 C NMR (75MHz, CDCl3) δ: 116.1 (CH), 116.3 (CH), 118.8 (C), 135.2 (CH), 135.7

(CH), 150.0 (C), 194.1 (CHO).

6,6aα,13,13aα-Tetrahydropentaleno[1,2-b:4, 5-b’]diquinoline (43)

218

To a precooled solution of 2-aminoebenzaldehyde 42 (3.2 g, 26.4 mmol), and diketone

33 (1.73 g, 12.5 mmol) in methanol (20 mL) using an ice bath were added a couple of drops of aqueous NaOH solution (2M). After stirring mixture for 30 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature overnight. The precipitate was filtered and washed with methanol to give the product 43 as a highly insoluble pale yellow powder.

Yield: 2.51 g, 65%;

Melting point: 352-354Ԩ (after washing with methanol)

1 H NMR (300 MHz, CDCl3) δ: 3.54-3.60 (d, 2H), 3.81-3.84 (dd, 2H), 4.32 (d, 2H),

7.41-7.46 (m, 2H), 7.56-7.62 (m, 2H), 7.75 (d, 2H), 7.95 (d, 2H), 8.07 (s, 2H).

13 C NMR (75MHz, CDCl3) δ: 40.8 (CH2), 45.3 (CH), 126.0 (C), 127.7 (C), 127.8 (C),

128.6 (C), 129.2 (C), 132.1 (C), 137.5 (C), 148.0 (C), 165.7 (C).

6α,13α-Dibromo-6,6aα,13,13aα-tetrahydropentaleno[1,2-b:4, 5-b’]diquinoline (44)

Under argon atmosphere, diquinoline 43 (1.5 g, 4.9 mmol), N-bromosuccinimide (2.25 g, 12.6 mmol) and solvent CCl4 (100 mL) were added to a round bottom flask. The mixture was heated to reflux and kept refluxing overnight. 219

Insoluble solid was filtered off from the cooled mixture and washed with dichloromethane. The filtrate was concentrated under vacuum to give dark brown solid which was columned on silica gel using dichloromethane to give the product 44 as a pale white powder.

Yield: 0.61 g, 27%;

Melting point: decomposed at 200 Ԩ (from methanol)

1 H NMR (300 MHz, CDCl3) δ: 4.86 (s, 2H), 5.86 (s, 2H), 7.53 (q, 2H), 7.68 (q, 2H),

7.80 (d, 2H), 8.01 (d, 2H), 8.26 (s, 2H).

13 C NMR (75MHz, CDCl3) δ: 52.7 (CH), 55.4 (CH), 127.8 (CH), 128.2 (CH), 128.4 (C),

129.8 (C), 130.5 (CH), 131.1 (C), 134.1 (CH), 149.3 (C), 163.2 (C),

81 + HRMS m/z: found 466.9564; calcd. for (C22H14N2 Br2+H) : 466.9556

1,4,8,11-Tetrabromo-6,6aα,13,13aα-tetrahydropentaleno[1,2-b:4, 5-b’]diquinoline

(45)

Diquinoline 43 (1 g, 3.25 mmol) and silver sulfate (2.7 g, 8.66 mmol) were dissolved in concd. sulfuric acid (11 mL) in a round bottom flask. Light was excluded using

220 aluminium foil, bromine (5 mL) was then added slowly to the mixture, and this was stirred at room temperature for another 10 hours.

The reaction mixture was poured into aqueous NaOH solution (2 M), followed by the addition of sodium sulfite until the brown colour of the solution had disappeared.

Chloroform was added to extract the mixture (five times 5Χ60 mL). The combined extracts were dried over anhydrous Na2SO4 and then filtered. Solvent was removed under reduced pressure to give the pale yellow powder 45 which was recrystallised from toluene give white needle crystals.

Yield: 1.00g, 50%;

Melting point: slowly decomposed when temperature was above 260 Ԩ (from toluene)

1 H NMR (300 MHz, CDCl3) δ: 3.76 (s, 1H), 3.82 (s, 1H), 3.93 (dd, 1H), 3.99 (dd, 1H),

4.42 (dd, 2H), 7.58 (d, 2H), 7.79 (d, 2H), 8.47 (d, 2H)

13 C NMR (75MHz, CDCl3) δ: 40.8 (CH2), 45.4 (CH), 121.7 (C), 124.1 (C), 128.3 (C),

130.1 (CH), 132.3 (CH), 132.8 (CH), 139.7 (C), 146.3 (C), 167.7 (C).

79 81 + HRMS m/z: 624.7757; calcd. for (C22H12N2 Br2 Br2+H) : 624.7767

221

1,4,6α,8,11,13α-Hexabeomo-6,6aα,13,13aα-tetrahydropentaleno[1,2-b:4, 5- b’]diquinoline (46)

Under an argon atmosphere, dibromodiquinoline 55 (1.0 g, 1.6 mmol), newly recrystallised N-bromosuccinimide (1.32 g, 9.6mmol) and CCl4 (60 mL) were added to a round bottom flask. The mixture was heated to reflux and kept refluxing overnight.

Insoluble solid was filtered off from the cooled mixture and washed with dichloromethane. The filtrate was concentrated under vacuum to give a dark brown solid which was columned on silica gel using dichloromethane to give the product 46 as a white powder.

Yield: 0.31 g, 25%;

Melting point: decomposed at 210Ԩ (from methanol)

1 H NMR (300 MHz, CDCl3) δ: 4.91 (s, 2H), 6.0 (s, 2H), 7.65 (d, 2H), 7.85 (s, 2H), 8.65

(s, 2H).

13 C NMR (300MHz, CDCl3) δ: 50.9 (CH), 55.1 (CH), 121.7 (C), 124.8 (C), 128.8 (C),

131.5 (CH), 134.0 (CH), 134.5 (CH), 134.8 (C), 147.0 (C), 164.7 (C).

79 81 + HRMS m/z: found 782.5946; calcd. for (C22H10N2 Br3 Br3+H) : 782.5957.

222

Publications and Conference Papers

Journal Publications

1. Different Crystal Forms of a Rich Hydrogen Bond Acceptor Compound Resulting from Alternative C-H…O and Orthogonal C=O…C=O Molecular Interaction Patterns

(Resolutions and Polymorphs – Part 8).

J. Gao, M. M. Bhadbhade and R. Bishop

CrystEngComm, 14, 138-146 (2012). http://dx.doi.org/10.1039/c1ce05728f

2. Polymorphic Crystals Formed by an Achiral Diol under Ambient Conditions

(Resolutions and Polymorphs – Part 9).

J. Gao, M. M. Bhadbhade and R. Bishop

Cryst. Growth Des., 12, 5746-5756 (2012). http://dx.doi.org/10.1021/cg301259f

See also: Virtual special issue in honour of Prof. G. R. Desiraju on the occasion of his 60th birthday.

3. A Clathrate Uncertainty Principle

R. Bishop, J. Gao, D. Djaidi and M. M. Bhadbhade

Transactions of the American Crystallographic Association, 43, 34-44 (2012). http://www.amercrystalassn.org/content/pages/main-transactions

‘Transformations and Structural Oddities in Molecular Crystals: In Honor of Bruce M. Foxman’

Editors: K. Wheeler, M. Hickey and G. Diaz de Delgado

223

Conference Presentations

1. Can a Molecule have More Than One Crystal Structure? J. Gao, M. M. Bhadbhade and R. Bishop, RACI Division of Organic Chemistry, NSW Branch 31st Annual One-day Symposium, University of Wollongong, 1 December 2010.

2. Non-positive Definite Atomic Displacement Parameters From Micro Crystals of Small Molecules Using Synchrotron Data: Investigation Into Possible Sources and Recommendation For Data Collection Strategies, Isa Chan, Muhammad Arif Nadeem, J. Gao, M. M. Bhadbhade, T. Caradoc-Davies and R. Williamson, Australian Synchrotron User Meeting 2010.

3. Awkward Shape and the Prediction of Potential Host Molecules? R. Bishop, J. Gao, M. M. Bhadbhade, 13th International Seminar on Inclusion Compounds (ISIC 13), Gierloz, Poland, 11-16 September 2011.

4. What makes a better host? J. Gao, M. M. Bhadbhade and R. Bishop ,7th International Symposium on Macrocyclic and Supramolecular Chemistry (ISMC-7), University of Otago, Dunedin, New Zealand, 29 January – 2 February 2012.

5. A Clathrate Uncertainty Principle, R. Bishop, J. Gao, D. Djaidi and M. M. Bhadbhade, Meeting of the American Crystallographic Association, Boston, USA, 28 July – 1 August 2012.

6. Bicyclo[3.3.0]octane Diols: A Rich Source of Competing Polymorph, Co-crystal, olvate and Apohost Crystal Forms, J. Gao, M. M. Bhadbhade and R. Bishop, Crystal & Graphene Science Symposium – 2012, Boston, USA, 5-6 September 2012.

7. United We Stand, Divided We Fall: Structures of Double Guest Inclusions of a Compound where a Single Guest Fails to Include, J. Gao, M. M. Bhadbhade and R. Bishop, Conference of the Asian Crystallographic Association (AsCA ’12) — Crystal 28 2012, Adelaide, 2 – 5 December 2012.

224

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