Synthesis of 4-(4-Alkylphenyl) and 4-(4-Alkyloxyphenyl)Cyclopent-3-ene-1,2-Diones and Formation of Metal Complexes that have

Potential as Metal-Centered Liquid Crystals

Theodore James Hester

University of Central Lancashire

Submitted for the Degree of MChem

Supervisors – R. W. McCabe and Janine McGuire

2014-2015

Master of Chemistry in Chemistry

i

I confirm that this report is all my own work and that all references and quotations from

both primary and secondary sources have been fully identified and properly acknowledged

in footnotes and bibliography.

Signed.............................................................. Date......................................

ii

Acknowledgements

First and foremostly I would like to acknowledge and thank Dr. Richard W. McCabe for his

guidance, support and everlasting patience throughout both this project and the course in

general here at UCLan. Without his influence I would never have managed to achieve as

much, or learn as much about this fascinating subject as I have done during my stay here,

and for that I am forever grateful. I hope that this document stands as testament to the

dedication and hard work that we have both put towards this project, and I look forward to

exploring any future collaborations and research opportunities that may come about as a

result of this work, in the years to come. My gratitude also extends to Tamar Garcia-

Sorribes, Jim Donnelly, Hannah Kinvig and Patrick Cookson for their tireless efforts in

helping me to analyse my compounds. I hope I brought them as many smiles and laughs as

they have brought me whilst working with them. I would like to thank all my friends on

the course, in particular Jonny, Hussein, Roksana, Sarah, and Sean, as well as the organic

research team and others, for their quality advice, support and company whilst studying

here. It’s been one hell of a ride guys, and we’ve made it, together! I would like to

acknowledge and thank Sal Tracey for supporting me and my peers in the lab this year

and the three preceding this one, and for, generally, being the glue which has held this

course and the department together over the last few years… I would like to say a big

thank you those of my family who have kept in contact with me, and supported my

transition into adult life and professionalism over the last 4 years, It has meant so much to

me. I acknowledge and thank my mother who, despite our disagreements, gave me a roof

over my head and kept me fed even when times were very hard. You encouraged the

budding philosopher within me to pursue a career in science, and I will forever be grateful

for your teachings of philosophy and critical thinking which have stirred within me a

seemingly never-quenchable thirst for knowledge and finding reason in the world. I

dedicate this work to you, and hope it makes you proud to call me your son. Lastly, and

perhaps most importantly, I would like to thank my girl, Gwendoline. Without her infinite

patience and love, I most certainly would not have been strong enough to endure the

iii

stress and fatigue that has come with uni life. I am forever grateful to you, my darling, and I

will never forget all you have done for me…

Contents

Synthesis of 4-(4-Alkylphenyl) and 4-(4-Alkyloxyphenyl)Cyclopent-3-ene-1,2-Diones and

Formation of Metal Complexes that have Potential as Metal-Centered Liquid Crystals......i

Acknowledgements................................................................................................................ iii

Aims and Objectives............................................................................................................... 2

Chapter 1................................................................................................................................3

Introduction............................................................................................................................3

Cyclopent-3-ene-1,2-dione.................................................................................................4

Enolic forms of cyclopent-3-ene-1,2-dione.........................................................................5

Formation of metal complexes with diones.......................................................................6

Aromatic substituted cyclopent-3-ene-1,2-diones.............................................................7

Liquid Crystals.....................................................................................................................8

The “Normal” States of Matter...........................................................................................9

The Solid Phase...............................................................................................................9

The Liquid Phase.............................................................................................................9

The Gas Phase...............................................................................................................10

The Liquid Crystal Mesophases.........................................................................................10

The Thermotropic Mesophases........................................................................................10

Orientational and Positional Order of the Thermotropic Liquid Crystalline Phases..........12

The Lyotropic Liquid Crystalline Phases............................................................................16

The Determination of the Liquid Crystalline Mesophase..................................................17

Applications of Liquid Crystals..........................................................................................22

iv

Metallomesogens.............................................................................................................22

Proposed Work.................................................................................................................26

Chapter 2..............................................................................................................................27

Results and Discussion..........................................................................................................27

Synthetic Routes to 4-alkyl or 4-alkoxyphenyl Substituted Cyclopent-3-ene-1,2-diones. 34

Route 1: Friedel-Crafts alkylation, bromination, dehydrobromination and oxidations.34

Route 2: Grignard-1,4-addition, bromination, dehydrobromination and oxidations....46

Route 3: Friedel-Crafts acylation, aldol cyclisation and oxidations...............................49

Chapter 3..............................................................................................................................67

Conclusions and Future Work...............................................................................................67

Chapter 4..............................................................................................................................69

Experimental.........................................................................................................................69

General............................................................................................................................. 70

References............................................................................................................................77

v

List of Figures

Fig. 1.1 Schematic representation of the molecular arrangement in: (a) a smectic phase,

(b) a nematic phase and (c) a cholesteric or chiral nematic phase.......................13

Fig. 1.2 A schematic representation of molecules in the smectic C phase........................14

Fig. 1.3 Schematic representation of the main columnar mesophases, the disordered (a),

ordered (b), tilted (c), hexagonal (d) and tetragonal (e) phases...........................16

Fig. 1.4. Phase diagram highlighting the lyotropic mesophases and how they form with

respect to changes in temperature and concentration of mesogen....................17

Fig. 1.5 Simplified schematic of a hot stage polarising microscope (HSPM).....................18

Fig 1.6 Example of the Schlieren texture observed for the nematic mesophase (a) and the

“finger-print” texture of the chiral nematic phase (b) under the HSPM..............19

Fig. 1.7 The focal conic texture of the SmA mesophase (a) and the Schlieren texture of

the SmC mesophase (b) under the HSPM............................................................19

Fig. 1.8 DSC trace showing crystal-to-crystal transitions as well as the formation of the

SmC mesophase...................................................................................................20

Fig. 1.9 A schematic representation of an X-ray diffraction apparatus.............................21

Fig. 1.10 Schematic representation of the scattering pattern produced by unaligned (a)

and aligned (b) SmA liquid crystals.......................................................................21

Fig. 2.1 1H NMR spectrum of the product of the aqueous selenium dioxide oxidation. The

spectrum appeared to match that of the starting material..................................29

Fig. 2.2 1H NMR spectrum of the product of the week long selenium dioxide oxidation.

Again, the clear peaks of the spectrum appeared to match those of the starting

material, 4. The other peaks were difficult to assign accurately..........................30

Fig. 2.3 1H NMR spectrum of the “product” of second selenium dioxide oxidation..........31

Fig. 2.4 1H NMR spectrum of the third Riley oxidation reaction mixture..........................32

Fig. 2.5 GC-MS of the of the third Riley oxidation reaction mixture. The MS is super-

imposed onto the chromatogram for ease of viewing. The expected mass of 96

was seen for the small peak seen at 0.59 minutes on the GC..............................33

vi

Fig. 2.6 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 25 using AlCl3

as catalyst.............................................................................................................35

Fig. 2.8 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 26 using Al-

ZSM-5 as catalyst..................................................................................................37

Fig. 2.9 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 25 using

Al-ZSM-5 as catalyst. A strange splitting pattern is observed in the aromatic

region...................................................................................................................38

Fig. 2.10 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 25 using

H-ZSM-5 as catalyst..............................................................................................39

Fig. 2.11 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 26 using

H-ZSM-5 as catalyst..............................................................................................40

Fig. 2.12 Gas chromatogram of the product of the Friedel-Crafts alkylation of 26 which

used H-ZSM-5 as catalyst......................................................................................41

Fig. 2.13 1H NMR spectrum of the product of the direct bromination of 27 (R = OCH 3). The

spectrum showed that unwanted bromination of the aromatic ring had occurred

instead..................................................................................................................43

Fig. 2.14 1H NMR spectrum of the product of the bromination of 27 (R = OCH3) using 34 as

a source of bromine radicals................................................................................45

Fig. 2.15 1H NMR spectrum of the product of the Grignard 1,4-addition of 36 to cyclopent-

3-en-1-one 4.........................................................................................................47

Fig. 2.16 1H NMR spectrum of the product of the Grignard 1,4-addition of 36 to cyclopent-

3-en-1-one 4.........................................................................................................48

Fig. 2.17 1H NMR spectrum of methyl levulinate 48, the two CH3 and two CH2

environments are clearly evidenced....................................................................52

Fig. 2.18 1H NMR spectrum of the product mixture from the Friedel-Crafts acylation

reaction of 26 with 44..........................................................................................53

Fig. 2.19 Gas chromatogram (a) and mass spectrum (b) of the product mixture from the

Friedel-Crafts acylation reaction of 26 with 44.....................................................53

vii

Fig. 2.20 1H NMR spectrum of the purified para-isomer product of the Friedel-Crafts

acylation reaction.................................................................................................55

Fig. 2.21 1H NMR spectrum of the purified para-isomer product of the Friedel-Crafts

acylation reaction. The second spectrum shows the same sample ran with a few

drops of D2O added to the NMR tube..................................................................56

Fig. 2.22 FTIR spectrum of the purified para-isomer product of the Friedel-Crafts acylation

reaction................................................................................................................57

Fig. 2.23 13C NMR analysis of the para-isomer product of the Friedel-Crafts acylation

reaction................................................................................................................58

Fig. 2.24 DEPT 45 13C NMR analysis of the purified para-isomer product of the Friedel-

Crafts acylation reaction.......................................................................................59

Fig. 2.25 DEPT 90 13C analysis of the purified para-isomer product of the Friedel-Crafts

acylation reaction.................................................................................................59

Fig. 2.26 DEPT 135 13C NMR spectrum of the purified para-isomer product of the Friedel-

Crafts acylation. Two CH2 groups are clearly evidenced, appearing as negative on

the spectrum........................................................................................................60

Fig. 2.27 2D COSY NMR spectrum of the purified para-isomer product of the Friedel-Crafts

acylation, showing the homo-nuclear (1H) spin couplings....................................61

Fig. 2.28 2D NOESY NMR spectrum of the purified para-isomer product of the Friedel-

Crafts acylation, evidencing no homo-nuclear (1H) spin couplings through space,

as expected..........................................................................................................62

Fig. 2.29 2D HSQC NMR spectrum of the purified para-isomer product of the Friedel-Crafts

acylation, showing the hetero-nuclear (1H-13C) spin couplings.............................63

Fig. 2.30 2D HMBC NMR spectrum of the purified para-isomer product of the Friedel-

Crafts acylation, showing the heteronuclear spin couplings through multiple

bonds....................................................................................................................64

Fig. 2.31 Proposed structure with nuclear environments labelled A-J, for producing a

correlation table...................................................................................................64

viii

List of Schemes

Scheme 1.1 Maignan’s synthesis of cyclopent-3-ene-1,2-dione 1......................................4

Scheme 1.2 Wanzlick and Sucrow’s synthesis of cyclopent-3-ene-1,2-dione 1...................4

Scheme 1.3 Keto-enol tautomerisation of cyclopent-3-ene-1,2-dione 1............................5

Scheme 1.4 Proposed deprotonation of dione 1 to form the keto-enolate species ).........5

Scheme 1.5 General synthesis of salicylatometal complexes..............................................6

Scheme 1.6 General synthesis of metalacetylacetonates...................................................6

Scheme 1.6 Keto-enol tautomerisation of dibenzoylmethane 7.........................................7

Scheme 1.7 Mesophase sequences with respect to the isotropic liquid state (l) and the

solid crystalline state (K)................................................................................15

Scheme 1.8 An illustration of (a) enantiotropic and (b) monotropic phase sequences……

15

Scheme 1.9 General synthesis of N-methylidenearoylhydrazinatonickel(II) complexes

(23)................................................................................................................25

Scheme 2.1 Proposed synthesis of 3-cyclopent-3-ene-1,2-dione 1...................................28

Scheme 2.2 Initially proposed synthetic route for 32, where R = CH2CH3 or R = OCH3......34

Fig. 2.7 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 26 using

AlCl3 as catalyst..............................................................................................36

Scheme 2.3 Preparation of diethyl bromomalonate (34) and it’s use as a source of

bromine radicals for the bromination of 27..................................................44

Scheme 2.4 Second proposed synthesis route..................................................................46

Scheme 2.5 Proposed synthetic route to 32 (R = OCH3)....................................................49

Scheme 2.6 Reaction mechanism for the proposed intramolecular aldol-cyclisation

reaction.........................................................................................................50

Scheme 2.7 Alternative dione synthesis............................................................................50

Scheme 2.8 Introduction of the long chain-tails required for mesophase formation, via

de-methylation of the methoxy group followed by Williamson ether

ix

synthesis with the corresponding alkyl halides to form 10(a-t).....................51

Scheme 2.9 First proposed mechanism for formation of 50.............................................66

Scheme 2.10 Second proposed mechanism for formation of 50........................................66

List of Tables

Table 2.1 HMBC correlation table, using the labelled structure (50) as reference………………………………………………………………………………………….……....65

Glossary

Abbreviation Meaning

NMR Nuclear Magnetic Resonance

HSPM Hot Stage Polarising Microscope

DSC Differential Scanning calorimetry

GC-MS Gas chromatography-Mass spectrometry

FT-IR Fourier-Transformed Infra Red

DCM Dichloromethane

NBS N-Bromosuccinimi

x

Abstract

The attempted syntheses of cyclopent-3-ene-1,2-dione and 4-(4-ethylphenyl)- and (4-(4-

methoxyphenyl)-cyclopent-3-ene-1,2-diones, as potential model ligands, are reported

herein. Qualitative evidence supported the successful synthesis of cyclopent-3-ene-1,2-

dione, however, due to the difficult separation requirements for work-up, which were not

fully discerned within the time-frame of the project, it was not possible to produce sufficient

quantities of the compound for further study. In the case of the extended ligand

compounds, difficulties in synthesis arose relating to the differences in relative reactivities of

the representative starting materials, ethylbenzene and anisole, as well as to

selectivity/regiospecificity considerations of the reactions attempted, as discussed in the

following chapters. Despite not being able to synthesise the target compounds, several

successes were reported. These included: the, apparently, successful synthesis of cyclopent-

3-ene-1,2-dione, despite low yields/purity; and the discovery of a new route to chiral

aromatic-substituted lactones by a one-pot aluminium chloride catalysed aromatic

acylation/ring-closure/methyl migration sequence, from anisole and levulinoyl chloride. This

novel reaction could lead to publishable synthetic work in the future. Also reported are

some novel Friedel-Crafts type reactions which used clay minerals/zeolites as catalysts for

highly regiospecific electrophilic aromatic substitution reactions, although these too

produced poor yields. It was unfortunate that the desired long-chained final compounds

were not obtained as we wished to explore their potential as mesomorphic materials;

however, this work lays the ground for future research in this field and because of this,

having an empirical understanding of the synthetic drawbacks surrounding the preparation

of these compounds is certainly not a deplorable result.

1

Aims and Objectives

The overall aim of this project was to design and synthesise a variety of novel 4-(4-

alkylphenyl)- and 4-(4-alkyloxyphenyl)-cyclopent-3-ene-1,2-dione ligands. These ligands

would then be used to produce coordination complexes that have potential as novel metal-

centred liquid crystals.

The ultimate objectives of the project are as follows:

1. To synthesise cyclopent-3-ene-1,2-dione and determine whether it can form

complexes with transition metals such as nickel(II) or copper(II).

2. To synthesise and characterise novel 4-(4-alkylphenyl) and 4-(4-

alkyloxyphenyl)cyclopent-3-ene-1,2-diones and determine whether their aromatic

substituents stabilise metal complex formation.

3. To vary the alkyl chain length of these ligands/metal complexes and to determine

whether these materials can demonstrate mesophasic properties, using hot stage polarising

microscopy, differential scanning calorimetry and possibly X-Ray diffraction techniques.

4. To deprotonate these 4-(4-alkylphenyl) and 4-(4-alkyloxyphenyl)cyclopent-3-ene-1,2-

diones at the -ketone position, forming a pseudo aromatic enol species that carries a

resonance stabilised negative charge

5. To assess the potential lyotropic mesophasic properties of these charged species.

Obviously, these objectives are very wide ranging and could easily form the basis of a PhD

project, however, our aims are to attempt to synthesise representative compounds that

would prove the validity of examining these materials for these purposes.

2

Chapter 1

Introduction

3

Cyclopent-3-ene-1,2-dione

The apparent synthesis of cyclopent-3-ene-1,2-dione 1 has been reported in the literature

only three times.1,2,3

Maignan reports two of these syntheses, both involving the bromination of (5-

oxocyclopenten-1-yl) acetate 2 using NBS to form (3-bromo-5-oxo-cyclopenten-1-yl) acetate

3, which was then hydrolysed in water to form dione 1 (Scheme 1.1).1,2

Scheme 1.1 Maignan’s synthesis of cyclopent-3-ene-1,2-dione 1.1,2

This is a two-step method that requires the enol acetate 2 as starting material, which,

apparently, is unavailable from chemical suppliers. The other method, which seems much

simpler, was reported by Wanzlick and Sucrow.3 This involves an aqueous selenium dioxide

oxidation of the α-keto position of cyclopent-2-ene-1-one 4, forming cyclopent-3-ene-1,2-

dione 1 in one step (Scheme 1.2).

Scheme 1.2 Wanzlick and Sucrow’s synthesis of cyclopent-3-ene-1,2-dione 1.3

1

O O

4

The starting material 4 is readily available from SigmaAldrich, therefore, this synthesis will

be attempted.

Enolic forms of cyclopent-3-ene-1,2-dione

Cyclopent-3-ene-1,2-dione 1, as well as having the enone functionality, also contains a

saturated α-ketone group. All ketones of this type can exist in equilibrium with their enolic

tautomers, in this case 5 (Scheme 1.3):

Scheme 1.3 Keto-enol tautomerisation of cyclopent-3-ene-1,2-dione 1.

The ketone tautomer is usually more stable, however, other factors such as hydrogen

bonding and resonance can affect the position of equilibrium. As a result of the extensive

resonance in tautomer 5, the α-hydrogens of dione 1 will have relatively low pKa’s and be

removed easily by a base. Dione 1 should therefore deprotonate readily at the saturated

keto α-position, forming the resonance stabilised keto-enolate species 6 (Scheme 1.4)

Scheme 1.4 Proposed deprotonation of dione 1 to form the keto-enolate species 6.

5

This deprotonated structure 6 would be expected to be highly stabilised by enolate

resonance and since the two resonance forms are identical it should produce a pseudo-

aromatic 5-ring that carries a resonance stabilised negative charge between the two oxygen

head groups.

- OO

6

This deprotonated, ionic form 6 and its chemistry is of paramount importance to the project

as it could act as the charged head group of two of the target materials: the lyotropic liquid

crystals and the metal-containing liquid crystals, via coordinating this species to a suitable

metal centre.

Formation of metal complexes with diones

Dioxo compounds, especially those that exist in enolic forms, have been shown in the

literature to form stable transition metal complexes. Typical examples would be salicylate 4

or acetylacetonate (acac)5 metal complexes, both of which are synthesised easily by treating

the starting compound with a suitable metal salt (Schemes 1.5 & 1.6).

Mx+ + x(salicyl.H) M(salicyl.)x + xH+

Scheme 1.5 General synthesis of salicylatometal complexes.4

Mx+ + x(acacH) M(acac)x + xH+

Scheme 1.6 General synthesis of metalacetylacetonates.5

For both series of complexes coordination occurs through two oxygen centres to the metal,

forming six-membered rings that are stabilised by both resonance and the chelate effect.

Square planar, octahedral and square pyramidal geometries are all possible.

6

Base catalyses the reaction via proton abstraction, but the stabilisation gained from

resonance and the chelate effect upon complexation can sometimes be enough to carry the

reactions forward without additional catalysts. The geometry of the complex formed is, as

expected, largely dependent on the central metal cation and consideration of this factor is

crucial to designing successful metal-centred liquid crystals, as these would normally require

a flat and rigid core. Previous work at this institution has found Cu(II) and Ni(II) to be very

suitable metal centres for liquid crystal formation, as they form thermally-stable, flat,

square-planar complexes with bidentate sulphur6 and nitrogen/oxygen7 donor ligands. We

expect enolate 6 to behave as an oxygen-donating bidentate ligand that should form

thermally-stable square-planar transition-metal complexes with the appropriate

substituents and metal centres.

Aromatic substituted cyclopent-3-ene-1,2-diones

The equilibrium between α-saturated ketones and their enolic forms usually favours the

keto-form. For liquid acetone at room temperature, the proportion is around 99.9% acetone

to 0.1% propen-2-ol.8 This is because the keto-form is more thermodynamically stable under

normal conditions and, in this case, there are no other electronic factors influencing the

molecule. However, in the case of dibenzoylmethane 7, a 1,3-diketone with 1,3-phenyl

substituents, the enol-form 8 is more favoured (80-98%),9 particularly in non-polar solvents

(Scheme 1.6), due to hydrogen bonding and resonance stabilisation with the phenyl rings.10

87

O O OH

O

Scheme 1.6 Keto-enol tautomerisation of dibenzoylmethane (7).

It was these factors that ultimately helped design the final target ligand compounds, 9(a-t)

and 10(a-t).

7

These have a phenyl substituent at the 4-position of the 5-ring that is π-conjugated with the

enone. We theorised that this additional aromatic substituent would stabilise the enol forms

of 9 and 10 further, holding these charged polar head groups in a conjugated, planar

conformation, which would, hopefully, aid the formation of the metal-centred liquid

crystalline materials that were of ultimate interest to the project.

Liquid Crystals

The liquid crystalline state, or "mesophase" describes a state of matter that exists between

the liquid and the solid; materials in this state exhibit some properties typical of liquids

(fluidity, formation of droplets which coalesce and an inability to support shear) and some

properties more usually attributed to solids (directionally dependant optical, magnetic and

electrical properties, regular arrangement of molecules in one spatial direction, etc.) A liquid

crystalline substance was first observed by the physician Rudolf Virchow10 in the 19th century

when he examined his new discovery myelin,11 the material which nerve cells in the body.

Up until this point, a direct phase transition (melting) on heating from the solid to the

isotropic liquid state and vice versa on cooling was assumed to be the correct general model

applied to all matter; however, Virchow noticed an unusual double melting behaviour.

Similar observations were made in 1888 when botanist Friedrich Reinitzer carried out

melting experiments with cholesteryl benzoate, 11, under a hot stage polarising microscope.

8

The compound appeared to have two melting points, one which produced a cloudy liquid

and one which yielded a clear isotropic liquid. Similar transitions were also observed upon

cooling the substance. Reinitzer wrote to a colleague, Otto Lehmann, who first described

this newly discovered state perhaps somewhat misleadingly in terms of "flowing" or "liquid

crystals".12 This work was controversial at the time, as it proposed the existence of a liquid

substance that could exhibit anisotropic optical properties.

The “Normal” States of Matter

Classical theory tells us that there are three states of matter; the solid, liquid and gaseous

states.10 The main thing distinguishing these states is the different levels of order they

possess.

The Solid Phase

In the solid state, molecules are held together in a more or less rigid structure. They occupy

a specific position and orientation and, apart from some vibration, will remain this way

unless a large enough external force or heat is applied to them. This occurs because of the

very strong forces of attraction acting between molecules in this state, which induce a high

degree of order in solid state materials.

The Liquid Phase

The forces of attraction between molecules in the liquid phase are much stronger than

between those in the gaseous phase, but less so than between molecules in the solid phase.

The liquid phase is therefore much less ordered than the solid phase, but more so than the

9

gaseous. In the liquid phase molecules move around each other freely, but maintain an

average specific distance from one another. This explains why a liquid will take the shape of

any vessel which contains it. Because molecules in this state are still relatively close to each

other liquids are typically difficult to compress, which makes them useful in hydraulic and

pump systems.

The Gas Phase

In the gaseous state, molecules have very weak forces of attraction between them, such

that the molecules move over one another in a very disordered and energetic fashion,

maintaining a large distance between one another at all times. This explains why gasses

diffuse out to fill their container, regardless of the size or shape of the container, and

concordantly why we can compress gasses fairly easily to an extent. In addition, average

intermolecular distances can be calculated just from the number of molecules present and

the size of the container. These properties have found gasses various applications, such as in

aerosols, pistons, measuring devices, fuels, etc.

The Liquid Crystal Mesophases

As discussed, the main distinguishing physical feature of each of the three "normal" states

of matter is the different amounts of order they possess. The liquid crystalline state or

"mesophase" is viewed as either a partially ordered liquid or partially disordered solid,

though aesthetically they appear as liquids. Materials that exhibit liquid crystalline

properties are known generally as mesogens. There are two broad categories of mesogens,

thermotropic and lyotropic.13

The Thermotropic Mesophases

Thermotropic liquid crystals are typically pure materials, and change phase upon heating

and cooling or by changes in pressure. Thermotropic mesogens are further sub-categorised

into those which derive from rod-like molecules such as 12,14 which form "calamitic"

mesophases and those derived from disc-like molecules such as 13,15 which form "discotic"

mesophases.

10

Where R = CnH2n+1

One of the first mesogens extensively studied was cholesteryl myristate10 14, similar in

structure to 11.10,13 14 melts at 71°C forming a cloudy liquid, but then at 85°C the cloudy

liquid “clears” and becomes a true isotropic liquid. The cloudy liquid phase is the mesophase

of 14.

Specific molecular attributes are required for a material to exhibit liquid crystallinity. The

molecules must be anisotropic and possess a rigid core (a moiety with few or no degrees of

freedom), with long mobile substituents attached to it (typically alkyl/alkoxy chains).

Anything from benzene 15, cyclohexane 16, adamantane 17 and even cubane 18 can be

used to provide the core, or mesogenic centre.16

11

HH

H

H

15 16 17 18

The long chains joined to the core provide fluidity17 and an axial polar group such as a nitrile,

carboxylic acid or an ester group18 allow the molecule to exhibit liquid crystalline behaviour.

Orientational and Positional Order of the Thermotropic Liquid Crystalline Phases

There are several different molecular arrangements that mesogens can adopt, defined by

the long-range intermolecular order the materials possess.

Three degrees of long-range positional order exist in the solid crystal, i.e. the x, y and z

directions of the crystal lattice. Conversely, there is no long-range positional order present

in any dimension of the isotropic liquid phase. When a solid melts, both orientational and

positional order are lost and the forces of attraction between the molecules are reduced

greatly.

Thermotropic liquid crystals in the mesophase exhibit order in only one or two dimensions.

The long axes of calamitic molecules or the faces of discotic molecules align in parallel to

one another over relatively large distances, and though positional order is lost upon melting,

some orientational order remains. The term “director” (symbol n) is used to measure this

order, and denotes the average direction of the long axes of calamitic mesogens or the

perpendicular to the faces of discotic mesogens.

The formation of one mesophase over another depends largely on the structure and dipole

moments of the molecules, as well as the temperature. Three classes of thermotropic

mesophase exist, depending on the degree of order the materials possess. These are the

smectic (a), nematic (b) and the chiral nematic (or cholesteric) (c) phases, (Figure 1.1).

12

n

(a) (b)

(c)

n

n

n

n

n

Fig. 1.1 Schematic representation of the molecular arrangement in: (a) a smectic phase, (b) a nematic phase and (c) a cholesteric or chiral nematic phase.

The nematic phase has the least order; the molecules only correlate orientationally so that

within local domains of molecules there is a mean alignment in only one dimension,

indicated by the director n.

The chiral nematic (or cholesteric) phase describes molecules lying in planes which are

twisted slightly in respect to one another. These molecules are typically chiral, or nematic

molecules with chiral dopants added to them.19 Upon translation through the cholesteric

medium in a direction perpendicular to the planes, a left or right handed helix is traced out

by the director. If the period of this helix is of the order of the wavelengths of visible light,

colours may be observed which shift as the period of the helix changes with temperature.

Materials of this type have therefore been utilised for thermometric devices.20,21

The smectic phases possess greater order; orientational and some positional ordering of the

molecules into layers is observed. Because of this, the smectic phase will always occur at a

13

lower temperature than the nematic or cholesteric phase.10 Smectic phases are sub-

categorised depending upon the degree and type of order present in the system.16

The smectic A (SmA) phase describes the long axis of the molecules being (on average)

oriented in the same direction, with the molecules loosely associating themselves into layers

and the director npointing perpendicular to the layer normal. The smectic C (SmC)

mesophase also forms layers, however the molecules of each layer are tilted slightly in the

same direction (Figure 1.2).

Fig. 1.2 A schematic representation of molecules in the smectic C phase.

Often with many long alkyl chain containing liquid crystals, the smectic phases (namely SmA)

are the only ones observed. Conversely, long alkyloxy-chains prefer to adopt the SmC

phase.7,8

The much rarer SmB, SmF, SmI and SmE mesophases are more ordered, hexagonal-variants

of the SmA and SmC phases.22 Chiral modifications of the SmC, SmI and SmF mesophases are

also possible; named the SmC*, SmI* and SmF* phases respectively.14

The phases SmA, SmB, SmC, SmF and SmB are all distinct smectic phases. The

thermodynamic sequence of mesophases with respect to the isotropic liquid phase (I) and

the solid crystalline phase (K) is illustrated below (Scheme 1.7).10,14

14

KI N SmA SmC SmI SmF SmB

Scheme 1.7 Mesophase sequences with respect to the isotropic liquid state (l) and the solid crystalline state (K).

Most transitions between mesophases are fully reversible upon heating and cooling

(enantiotropic transitions, (a)), however some mesophases may only occur upon cooling

(monotropic or metastable mesophases, (b)) (Scheme 1.8).18

Scheme 1.8 An illustration of (a) enantiotropic and (b) monotropic phase sequences.18

Disc-shaped molecules have also been found to exhibit mesomorphic properties 23 and the

first family of organic discogens, (the hexa-n-alkanoates of benzene 13), were discovered in

1997.15

Two distinct classes of mesophase exist for disc-like molecules, the columnar (canonic)

phases and the discotic nematic phases.15 In the columnar phases the molecules line up face-

to-face, forming columns, which assemble themselves into tilted, hexagonal or tetragonal

arrangements. In contrast the positions of the discs in the discotic nematic mesophase are

random, but their faces all point in approximately the same direction (Figure 1.3).

Cholesteric phases can

also be formed from

discogens.

(a) (b) (c)

(d) (e)

(a)

(b)

K SmA N I

K I

SmA N

15

Fig. 1.3 Schematic representation of the main columnar mesophases, the disordered (a), ordered (b), tilted (c), hexagonal (d) and tetragonal (e) phases.

The Lyotropic Liquid Crystalline Phases

The other broad class of mesophase already mentioned is the lyotropic liquid crystal, and

this occurs in certain materials via the addition of a solvent, usually water. Historically

“lyotropic” described amphiphilic compounds; those comprised of a hydrophilic head group,

either ionic (e.g. polyethylene glycol) or non-ionic (e.g quaternary ammonium salts) in

nature, attached to a hydrophobic tail group, typically a long alkyl chain.

When mixed with water, these compounds aggregate via a self-assembly mechanism driven

by the hydrophobic effect.24 These aggregates are characterised by the structures they form

in their effort to shield the hydrophobic tail groups from the surrounding water molecules

using their hydrophilic head groups. This self-assembly occurs when the concentration of

the amphiphile exceeds a certain value, known as the critical micelle concentration (CMC).

The lyotropic mesophases occur in the following order as amphiphile concentration

increases and are named: the micellar cubic (I1), hexagonal phase (Hl) and the lammelar

phase (Lα). A complex bicontinuous cubic phase (V1) can also sometimes form at

concentrations between those

required for the hexagonal and

lammelar phases (Figure 1.4).

16

Fig. 1.4 Phase diagram highlighting the lyotropic mesophases and how they form with respect to changes in temperature and concentration of mesogen.25

The Determination of the Liquid Crystalline Mesophase

Hot Stage Polarising Microscopy is one of the most powerful and cost-effective techniques

still used today to classify mesophases according to their textures when viewed under a hot-

stage polarising microscope (HSPM). A sample is loaded between a glass slide and a cover

slip, fitted onto the special heating stage of the microscope (Figure 1.5).

17

Fig. 1.5 Simplified schematic of a hot stage polarising microscope (HSPM).

If a liquid crystalline mesophase exists between the polariser and analyser (a second

polariser, positioned at 90° to the first), then the polarised light falling onto the sample is

split into ordinary and extraordinary beams. These beams can interfere and some colours

will therefore be obliterated whilst others remain or even get enhanced, which explains the

different colours and textures of light seen through the eyepiece, characteristic to each

liquid crystalline mesophase.26

Placing a nematic liquid crystal under the HSPM, the image will appear dark where the

molecules are aligned in the direction of one of the polarisers (Figure 1.6 (a)). The chiral

nematic phase produces a fingerprint pattern (b).

18

(a) (b)

Fig 1.6 Example of the Schlieren texture observed for the nematic mesophase (a) and the “finger-print” texture of the chiral nematic phase (b) under the HSPM.

The typical focal-conic texture of the SmA phase is clearly discernible; the regions which

appear black occur when the polarised light passes down the molecular axis in regions

where the molecules are aligned homeotropically (axis perpendicular to the glass substrate)

(Figure 1.7 (a)).

(a) (b)

Fig. 1.7 The focal conic texture of the SmA mesophase (a) and the Schlieren texture of the SmC mesophase (b) under the HSPM.

This focal conic fan texture is also observed for the SmC mesophase, however the SmA

texture first forms bâtonnets (rods) upon cooling from the nematic or the isotropic phase,

which then develop into the fans.27 Because of the similarity between the focal conic

textures of both the SmA and SmC mesophases, characterisation and distinction of these

mesophases is difficult using polarising microscopy alone. Schlieren textures can also be

19

observed for SmC (Figure 1.7 (b)), similarly to the nematic mesophase, however because of

its lamellar structure the SmC texture exhibits only a four-brush Schlieren texture. In

contrast, the nematic phase exhibits two- or four-brush textures.

These different textures result from the different ordering of the molecules in their

respective phases.28 However, optical analysis should not constitute the only method of

mesophase classification. Differential Scanning Calorimetry (DSC) (Figure 1.8)29 has become a

widely used complimentary technique to optical microscopy.

117.8oC

155oC

133oC

Smectic C

Solid Phase

Solid Phase

Smectic CIsotropic Phase

Cooling

Heating

K-K 1 123oC

Fig. 1.8 DSC trace showing crystal-to-crystal transitions as well as the formation of the SmC mesophase.30

This method is particularly useful for studying crystal-crystal phase changes rather than

crystal-liquid transitions. The change in heat capacity of a sample is measured as a function

of temperature change, giving the enthalpy change (ΔH) accompanying a phase transition.

However, the different mesophases themselves cannot be differentiated properly by this

technique alone. In order to distinguish between mesophases, which are optically or

calorimetrically similar, another technique, X-ray diffraction is used. (Figure 1.9).

20

Fig. 1.9 A schematic representation of an X-ray diffraction apparatus.

This method measures the long-range order present in a system; the more and better

defined the order the sharper the scattering produced. The SmA phase (which has well

defined layer spacing) produces a sharp inner ring in the scattering pattern, however

because the intra-layer separation is not well defined (i.e. liquid like) a broad diffuse outer

ring is also seen in the pattern, (Figure 1.10 (a)).31 When aligned in a magnetic field, the SmA

pattern reduces to a pair of mutually perpendicular arcs (Figure 1.10 (b)).

Fig. 1.10 Schematic representation of the scattering pattern produced by unaligned (a) and aligned (b) SmA liquid crystals.

21

Similar to the diffuse ring seen for the smectic mesophases, the nematic phase too produces

a diffuse ring diffraction pattern. When oriented with a magnetic field, this ring is reduced to

a pair of diffuse arcs which are perpendicular to the magnetic field. The pattern produced by

a non-aligned SmC mesophase is identical to that of a non-aligned SmA mesophase.

However, when the SmC is aligned with a magnetic field the two arcs produced are twisted

towards one another slightly by the tilt angles of the molecules relative to the layers. These

differences in scattering patterns are what make XRD a useful technique for differentiating

between similar mesophases.

Miscibility studies can also help to classify mesophases. A sample is mixed with a compound

for which the mesophase type is known and if the sample is completely miscible with the

known mesophase then the two mesophases of each material are identical and they belong

to the same miscibility group.32

Applications of Liquid Crystals

Over the last 60 years several uses and applications of these materials have been

discovered, with Williams33 in the 1960's and later Heilmeyer34 realising that the anisotropic

physical properties of liquid crystals could be utilised in flat optical displays through the use

of dynamic scattering (scattering of transmitted or reflected light). In the 1970’s Gray

managed to synthesise materials with the properties required for use in commercial

applications, such as in liquid crystal displays (LCD's).35 These compounds had a biphenyl

central moiety, which provided the thermal stability and rigid core required for the

mesophase to form.35 This work solved one of the biggest problems associated with the

development and production of high quality LCD’s, and since then the world has seen the

rapid commercialisation and distribution of LCD television, computer and phone screens

which most people now own at least one of. Liquid crystals have some other applications,

including thermometric devices/thermometers, as well as in optical imaging and mechanical

stress testing, however by far the most common and industrially lucrative application is in

LCD’s.

22

Metallomesogens

In 1910 the mesogenic properties of some alkali metal carboxylic acid salts were reported by

Vorlander, and these would constitute the first known metal-containing liquid crystals or

“metallomesogens”.36 In the 1970’s Giroud and Mueller-Westerhoff first reported

mesomorphic properties in some dithiolene complexes of nickel(II).37,38 This work was

extended by our group and several similar mesomorphic complexes with branched chains

and fluorine groups attached to the aromatic rings 19 were synthesised and characterised.39

This research showed it was possible to incorporate ligands with mesophasic properties into

the co-ordination sphere of a transition metal. Due to the relative weakness of the metal-

ligand coordinative bond,13 many metallomesogens decompose when approaching their

isotropic liquid phase melting point.,40,41 To counter this, metal centres which are less

reactive such as copper, nickel and palladium are used, in order to increase the

thermodynamic stability of the materials. Ni(II), Cu(II) and Pd(II), (as well as Au(III), Pt(II),

Zn(II), Ir(I) and Rh(I)) all form complexes with stable d8-d10 configurations,36,42 and typically

adopt the linear or square planar geometry43 required for the mesogenic centre.

The transition metal provides ligands with high electron density and therefore increased

polarizability. This increases the refractive index and induces birefringence,

hyperpolarisability and useful dielectric properties in the mesomorphic materials.40

Additionally, due to the low energy d-d electronic transitions which can occur in transition

metal complexes, colours may also be introduced via the central transition metal cation.

Pleiochroism is observed in some metallomesogens, whereby vivid colours are observed

perpendicular to the plane of the molecule but the material appears colourless within the

plane.10 This phenomena allows for high contrast colour switching of the mesophase and

has seen many applications in industry for fast switching display devices.

23

The ferrocene Schiff bases (20) were the first metallomesogens with octahedral geometry44

and many other mesomorphic derivatives of 20 have been reported by Deschenaux.45,46

20

FeOC

O

CN R

H

NC O C

O

H

R

Bruce47,48 found that these complexes could become liquid crystalline if the mesogenic

centre was made long enough. More recently, chiral columnar metallomesogens with

octahedral geometry have been reported49,50 which exhibit ferroelectricity,51 exceptional

second-order nonlinear optical susceptibilities52 as well as high birefringence.53

Many varieties of donor ligand sets can and have been used to form metal complexes with

mesomorphic properties, including monodentate organoisonitriles,54 substituted pyridines,55

acetylides56 and thiolates,57 as well as bidentate dithiolenes,58,59 dithiobenzoates,60,61

salicylaldimates,62,63 α-diimines64,65 and β-diketonates. The β-diketonate class of ligands are of

particular interest due to their structural similarities to the proposed compounds. The first

to recognise β-diketonates as potential donor ligands for making mesomorphic complexes

were Bulkin, Rose and Santoro, who in 1977 synthesised the palladium complex 21 shown

below.66

24

Several longer chain derivatives of 21 were produced by Ohta67 and Giroud-Godquin and

Billard68 in 1980-1981, which replaced Pd(II) with Cu(II). In 1986 a copper β-diketonate which

was both nematic and paramagnetic was reported. The calimitic69 molecules were confirmed

to correlate in an anti-parallel fashion.70,71

Further work at this institute has involved synthesising metallomesogens based on the

N-alkylideneacylhydrazine ligand 22.72 The N-Methylidene-aroylhydrazinatonickel(II)

complexes 23 had even-chain lengths ranging from C4H9 to C22H45,8,29,48,73,74,75,76 and this

research found copper and nickel to be highly suitable metal centres for mesophase

formation. The nickel and copper acetate starting materials were found to be basic enough

to deprotonate the ligands themselves, producing the metal complexes via a simple reflux in

ethanol (Scheme 1.9). The product complex is stabilised via the chelate effect, much like in

the synthesis of metal acetylacetonantes and it is hoped that the proposed ligand

compounds will also complex easily due to this additional chelate stabilisation.

2 Ni(O2CMe)2 4H2O.EtOH

Reflux

2322

HC

H

NNH

O

R

O

O

Ni

NN

CH H

O

NN

CHH

O

R

O

R

Scheme 1.9 General synthesis of N-methylidenearoylhydrazinatonickel(II) complexes 23.8

These findings altogether would suggest that oxygen based donor ligands are suitable for

metallomesogen formation and that use of nickel(II) and paramagnetic copper(II) as the

metal centres can produce thermally and chemically stable mesogenic compounds which

potentially have highly exploitable electromagnetic properties. The mesomorphic properties

of the β-diketonate class of ligand have been explored further and developed in the

literature in the last few decades77,78,79,80,81,82,83 and although similar, the structures proposed

25

by us are unique and cannot be found in the literature. This offers an opportunity to

produce a new and novel family of ligands and subsequent potential metallomesogens, with

the aim of determining their mesomorphic properties (if any).

Proposed Work

This project aims to extend the research done at this institution by synthesising a new class

of donor ligands based around the cyclopent-3-ene-1,2-dione functionality. These ligands

may then be deprotonated and coordinated to a metal centre such as Cu(II) or Ni(II),

potentially forming a new class of thermodynamically stable metallomesogens with

interesting paramagnetic electrochemical switching properties. Alternatively, the charged

head group may be balanced with a small alkali metal ion such as Na+, Cs+ or Ca2+, generating

potentially lyotropic mesomorphic systems when in water.

Since this project will probably form the basis of future PhD work, it will focus primarily on

synthesis, with the aim of determining which structural variations are conducive to

mesophase formation within the novel class of metal complexes that can be derived from

this new class of ligand. We intend first to synthesise the core moiety 1, along with

representative ligand compounds 9 and 10 (R=CH3), to assess the ease of complex

formation. We then intend to synthesise and study the mesomorphic properties of the long

chain derivatives. We also aim to determine how the mesomorphic properties of the

complexes vary with the length of alkyl/alkyloxy chain and to this end, ultimately, we wish

to synthesise odd and even chain length analogues of the simple alkyl- and alkyloxy- ligands

in order to determine whether the “two tailed” complexes that result from them show odd-

even effects.

26

27

Chapter 2

Results and Discussion

28

Synthesis of Cyclopent-3-ene-1,2-dione (1).

One of the core objectives of the project was to synthesise the cyclopent-3-ene-1,2-dione 1

moiety, to see if it could be de-protonated to form the stable, highly conjugated keto-

enolate species 6 and to determine whether 6 could form a stable metal complex upon

reaction with the corresponding metal acetate. The chemistry of 1 would be crucial to

forming the core of the desired metal-centred liquid crystals, so it was an obvious target for

the project.

The simplest route to moiety 1 in the literature3 seemed to be a Riley oxidation of

2-cyclopent-3-ene-1-one 4, furnishing the desired compound in one step (Scheme 2.1).

Scheme 2.1 Proposed synthesis of 3-cyclopent-3-ene-1,2-dione 1.

This reaction came with it some apparent limitations, such as competing allylic oxidation at

the 4-position of the ring of 4, forming undesired 4-hydroxycyclopent-2-en-1-one 24. The

low yield and the difficult separation steps reported to have been required for purification

of the desired product made this reaction seem less than ideal. However it was unclear from

the literature3 how effective the reaction would be at forming the desired compound over

the undesired one(s), so it was decided to simply try it and see what compounds were

obtained and in what ratios.

The reaction was attempted (in water initially) according to the method found, 3 the only

alteration being that dichloromethane was used to extract the product not chloroform.

Unfortunately, the isolated product gave 1H NMR and GC-MS data that correlated to starting

material 4 (Figure 2.1)

29

Fig. 2.1 1H NMR spectrum of the product of the aqueous selenium dioxide oxidation. The spectrum appeared to match that of the starting material, (4).

It was possible that the lower polarity of dichloromethane compared to chloroform and the

increased polarity of the product compared to the starting material meant that the product

was remaining in the more polar aqueous phase. Analysis of the aqueous layer of the

reaction, however, also showed mostly starting material, indicating the reaction was far

from complete. The reaction was repeated again on the same scale, but left for over week

to stir at room temperature. 1H NMR analysis of this reaction showed mainly starting

material together with a large number of indistinguishable products and it was difficult to

assign peaks confidently to the desired product (Figure 2.2).

30

Fig. 2.2 1H NMR spectrum of the product of the week long selenium dioxide oxidation. Again, the clear peaks of the spectrum appeared to match those of the starting material, 4. The other peaks were difficult to assign accurately.

It appeared as though no reaction had taken place. The paper upon which the reaction was

based was examined further, and it was found they reported very low yields (1%) and did

not provide any spectroscopic evidence to support that they had in fact produced 1. Since

no real analytical data was provided by the authors to support their claims, this source of

experimental method was deemed untrustworthy.

Further literature searching found similar reactions, but on larger molecules that used 1,4-

dioxane as solvent instead of water and this work quoted much better results.84 The authors

of this paper even stated that following the literature aqueous procedure, nothing but

starting material or decomposition products were obtained. The reaction was attempted

again according to this new literature84 method,85 however, again problems arose. When

working up the first attempt, the mixture was diluted with water according to the method,

however, extraction into ether and subsequent removal of solvent under reduced pressure

failed to yield any product! It was realised later that this was probably due to the literature

reactions being carried out with much larger, less polar molecules that could be extracted

easily from water into an organic solvent. The reaction attempted here used the small and

much more polar 4 and so, if formed, the product 1 was likely remaining in the more polar

31

aqueous phase which unfortunately had been discarded. Upon repetition of the reaction,

however, isolation of the product now became an issue, since both starting material and the

product were both small in molecular size and very polar and since difficult to remove

micro-particles of elemental selenium were produced in the mixture as a by-product of the

oxidation. To remove the selenium, filtration through silica gel was carried out; however,

once again no product was found, as evidenced by analytical data (Figure 2.3).

Fig. 2.3 1H NMR spectrum of the “product” of second selenium dioxide oxidation.

It was realised that 1, again due to its size and polar nature, may be adsorbed strongly onto

the silica used to filter the selenium out of the mixture. This presented a large problem as all

attempts to elute the possible product also brought selenium off the silica gel. A centrifuge

was found to be effective at separating most of the solid selenium from the reaction

mixtures, however some still remained in solution which precipitated out if removal of

solvent under vacuum was attempted. Without a viable extraction method, separating the

selenium completely from the mixture seemed an impossible task.

32

Several further attempts were made and each time product isolation presented a large

problem, however analytical data did in some attempts show evidence for the desired

product being produced (Figure 2.4).

Fig. 2.4 1H NMR spectrum of the third Riley oxidation reaction mixture.

Zooming the spectrum up from the baseline revealed several small peaks, most of which

corresponded to starting material 4. However, the remaining peaks (8.1 ppm, 6.24 ppm and

3.12 ppm) showed the expected shifts, integrals and splitting patterns for the desired

product 1. Comparing the integrals of these peaks with those representing starting material,

we found that around 50% of the material present was unreacted 4, and 50% was the

oxidised 1, evidencing a reasonable conversion. GC-MS data also showed a component with

the expected product mass of 96, however the relative area of this peak was extremely

small i.e. < 1% (Figure 2.5)

33

Fig. 2.5 GC-MS of the of the third Riley oxidation reaction mixture. The MS is super-imposed onto the chromatogram for ease of viewing. The expected mass of 96 was seen for the small peak seen at 0.59 minutes on the GC.

These results showed that it was possible to produce 1 from 4 via this method, however

yields were seemingly poor and isolation of 1 was so difficult that it seemed to be an

unsuitable method for producing usable amounts of 1. However, fair to good yields were

reported in the literature syntheses of the larger diones, which the reaction was based

upon,82,83 and it was hoped that this method would be put to better use synthesising the

dione functionality of the larger final compounds 9 and 10. However, before optimisation of

the reaction conditions (in order to generate better yields) could be carried out, the project

ran out of time as these reactions were done towards and right up until the end of the

project. Future work will include optimising the reaction conditions, and finding an effective

isolation method for the small compound 1.

In parallel with the attempted synthesis of 1, we were trying to synthesise the 4-alkyl or 4-

alkyloxyphenyl substituted cyclopent-3-ene-1,2-diones 9 and 10 that would be required for

34

construction of a mesogenic molecule. As model compounds for the final long-chain

molecules we used ethylbenzene (25) and anisole (26).

O

25 26

These simple starting materials have, assumingly, analogous chemistry to and are relatively

cheaper and more available than, the more expensive longer-chain p-alkyl- or p-alkoxy-

materials required for the final products.

Synthetic Routes to 4-alkyl or 4-alkyloxyphenyl Substituted Cyclopent-3-ene-1,2-diones

Route 1: Friedel-Crafts alkylation, bromination, dehydrobromination and

oxidations.

The synthetic plan proposed initially for the project is outlined in Scheme 2.2:

27 28

303132

Or 26 (R = OCH3)29

25 (R = C2H5)

SeO2

K2Cr2O7

Or Mn(OAc)3,

then H3O+ and [O]

hv

SeO2

AlCl3

Br2 KOH

R

Cl

R R

Br

R

OH

R

O

R

O O

R

Scheme 2.2 Initially proposed synthetic route for 32, where R = CH2CH3 or R = OCH3 .

35

It was thought that this route, if successful, would provide a simple pathway to the desired

1,2-dione moiety of the final product, as the regiospecificity of each step would, hopefully,

give the desired compound as the major product. However, most of these reactions do have

certain limitations, the main ones being a low degree of selectivity for reaction at the

desired position and as such it was expected that several isomers would be produced at

each stage and we would need to either minimise this or separate the desired product from

its other isomers once formed. The use of 25 (R = C2H5) or 26 (R = OCH3) as the initial starting

materials would provide differing challenges for the synthetic plan due to their differing

reactivities to electrophilic reaction conditions.

Initially, a Friedel-Crafts alkylation was attempted, in accordance with step one of Scheme

2.2, with chlorocyclopentane as the alkylating agent, AlCl3 as the Lewis-acid catalyst and

ethylbenzene (25) and anisole (26) as both reactant and solvent. However, the reactions

proved to be too non-regiospecific with all three ring isomers, as well as di-substituted

products, being produced in each case. This was evidenced by the complex splitting pattern

seen in the aromatic region (Figure 2.6 and 2.7)

Fig. 2.6 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 25 using AlCl3 as catalyst.

36

Fig. 2.7 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 26 using AlCl3 as catalyst.

An alternative alkylation method was therefore proposed in order to try and increase the

ratio of the desired para-substituted products. Clay minerals and zeolites are known to act

as Lewis acid catalysts for Friedel Craft alkylation reactions.86,87,88,89 Reactions in the interlayer

space of the clay mineral or the pore of the zeolite may provide the steric constraint

required to alkylate the para-positions of the rings selectively. Fulacolor, an acid activated

clay with known Lewis acid characteristics,14 was tried first. However, this catalyst failed to

yield very much product, most likely due to the low degree of Lewis acidity within the

interlayer of this clay catalyst at the reflux temperatures of the reactants/solvents.

Previously, the Lewis acid properties of this mineral were exploited at temperatures in

excess of 200-300C.90

Based on rough computational spatial/energy predictions (Chem 3D) and evidence in the

literature on the alkylation of toluene and isomerisation of xylene,91 it was envisaged that

performing the reaction inside the sterically constricted pore system of zeolite ZSM-5

37

(approximately 5 Å wide pore-channel system)92 would increase the regiospecificity of the

reaction. In the synthesis of p-xylene, the regiospecificity of the alkylation reaction is

thought to be observed due to diffusional effects as well as the sterically altered intrinsic

kinetics of the system, both of which favour the formation of the para-isomer, p-xylene.90

This concept formed the basic rationale for the following Friedel-Crafts reactions. The ZSM-

5 zeolite was cation exchanged with Al3+ in order to create Lewis acid catalytic sites

throughout the zeolite structure and an excess of starting materials 25 and 26 were used

once again to try and minimise the formation of unwanted isomers and di-substituted

products. However, analysis of the products showed that all three isomers of both products

were still being produced to some extent, as well as some di-alkylation occurring.

For example, the expanded region of spectrum for the alkylation product of 26 (Figure 2.8)

showed peaks representing the methoxy groups of at least three different isomers as well as

starting material (3.81-3.86 ppm), indicating the reaction was still largely non-regiospecific.

Fig. 2.8 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 26 using Al-ZSM-5 as catalyst.

38

However, evidence for the formation of the desired para-isomer appeared in the aromatic

region of the spectrum (6.5 – 8 ppm), where a pair of doublets with identical splitting could

be clearly distinguished. The alkylation of 25 was less successful, as evidenced by the 1H

NMR analysis (Figure 2.9). The pair of doublets expected in the aromatic region were not

clearly visible and the complex pattern of peaks seen in this region suggested that multiple

isomers had been produced.

Fig. 2.9 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 25 using Al-ZSM-5 as catalyst. A strange splitting pattern is observed in the aromatic region.

These results suggested that the reactions were taking place on the outside of the zeolite

structure (where some of the Al3+ ions would be sitting), as well as inside the zeolite pores.

The reactions were attempted a few more times at differing temperatures and lengths of

reaction times, to see if results could be improved with different conditions, however no

real improvements in isomer ratios were observed.

In order to try to circumvent the problem of the reaction occurring on the outside of the

zeolite structure, it was decided to replace the Lewis acid catalyst Al-ZSM-5 with the protic

39

catalyst H-ZSM-5 (where the catalytic proton sites sit further within the pore structure) and

to use cyclopentene as the alkylating agent instead of chlorocyclopentane. Cyclopentene is

smaller in breadth than chlorocyclopentane and it was expected that upon protonation, this

material would occupy the catalytic sites within the pores of the zeolite more readily. H-

ZSM-5 was prepared by heating commercial NH4-ZSM-5 in a boiling tube over a Bunsen

burner for ten minutes until all of the water/ammonia were visibly removed from the zeolite

(a HCl fume test was used to confirm this).

The reactions were carried out in a similar manner to previously, under dry and inert

conditions and at around 150C. This method seemed to work reasonably well for the more

reactive anisole (26), but failed to produce very much product using the poorly activated

ethylbenzene (25) (Figure 2.10).

Fig. 2.10 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 25 using H-ZSM-5 as catalyst.

The spectrum shows very little reaction has taken place, with all clear peaks corresponding

to unreacted 25.

40

It was assumed that the more electronically activated aromatic ring of 26 was the reason for

this. The reaction was therefore optimised using just 26 and eventually gave a good

proportion of the desired para-isomer (Figure 2.11), in this case approximately 95 % of the

product formed; indicated largely by the pair of doublets in the aromatic region. GC-MS

data also corroborated these results (Fig. 2.12).

Fig. 2.11 1H NMR spectrum of the product of the Friedel-Crafts alkylation of 26 using H-ZSM-5 as catalyst.

The other clearly visible methoxy peak (3.85 ppm) is too high in shift to be representative of

unreacted 26 (the OCH3 peak of anisole appears in chloroform at around 3.76 ppm,) leading

us to assume that this peak represented the ortho-isomer. These results were still very

41

encouraging, showing that through optimising the method the selectivity could be improved

and the ratio of desired isomer increased to as high as 95%!

Fig. 2.12 Gas chromatogram of the product of the Friedel-Crafts alkylation of 26 which used H-ZSM-5 as catalyst.

The large peak represents the desired para-isomer, whilst the other two much smaller peaks

represent the ortho- and meta-isomers.

However, the consistently poor yields of this reaction (~5-10%) meant that this method

would, most likely, be an unsuitable first step for producing the desired ligand compounds,

as these would require expensive long-chained starting materials for the alkyl products or

extra de-protection and alkylation steps for the alkoxy products. The poor yields were

probably due to unwanted polymerisation reactions occurring on the surface of the catalyst,

indicated by browning of the catalyst after the reaction had taken place. Another possible

complication was the extreme volatility of the cyclopentene starting material. The high

temperatures and long times required for this reaction meant that the volatile starting

material could have been escaping from the flask and out the top of the condenser. Many

42

attempts were made to improve the yields by varying temperatures and altering the

proportions of catalyst and reactants. A double-jacket glass coil condenser set-up was also

used, to try to minimise the escape of the volatile starting material, but still yields were

never >10%.

It was decided to test the next reaction in the proposed scheme with a small amount of the

isolated p-isomer 27 (where R = OCH3) to see if it was worth pursuing this route any further.

This step was a direct bromination of 27 to form a tertiary bromide 28; which should then E-

eliminate readily in the presence of a base to form the desired conjugated cyclopentene 29.

It was expected that the radical bromination would occur preferentially at the tertiary

carbon as this reaction should occur via the most stable radical intermediate. Similarly, the

E-elimination reaction should occur preferentially at the aryl carbon of the cyclopentane

ring, as this would form the most inductively and resonance stabilised carbocation that is

required for this SN1 type reaction.

A small scale photochemical bromination was carried out on isolated 27 (R = OCH3) in

dichloromethane, using an equimolar amount of pure bromine as the brominating agent. A

40W artificial daylight lamp bulb was used to illuminate the reaction mixture, generating the

required bromine radicals for the reaction. The reaction seemed to go well, with the brown

colouration of the bromine in the mixture disappearing as the reaction proceeded. The

isolated product was analysed via GC-MS, which showed the expected molecular weight of

254/256.

Unfortunately, upon analysis of the 1H NMR data it became obvious from the changes in the

splitting pattern/integrations of the aromatic region and the persistence of the peak at 2.93

ppm, (which represented the aryl CH group of the starting material,) that bromination had

occurred at the ortho-position of the aromatic ring, rather than the aryl-CH position of the

cyclopentane ring (Figure 2.13).

43

Fig. 2.13 1H NMR spectrum of the product of the direct bromination of 27 (R = OCH3). The spectrum showed that unwanted bromination of the aromatic ring had occurred instead.

Had the reaction proceeded as intended, this peak (2.93 ppm) would have disappeared with

the aromatic region remaining as a pair of doublets. It was possible that bromine radicals

were forming relatively large amounts of HBr in solution, which in turn was acting as a

Lewis-acid, catalysing the ring bromination of the reactive anisole. To circumvent this

problem, a source of bromine radicals was required which did not produce large quantities

of hydrogen bromide.

Diethyl bromomalonate (34) has been reported as a good source of bromine radicals for

photo-induced benzylic hydrogen abstraction and subsequent bromination93 and this work

formed a rational basis for the following reactions (Scheme 2.3). Using 34 instead of pure

bromine would avoid the complication of large amounts of HBr being produced in situ and

would hopefully provide a good enough source of bromine radicals for the reaction to take

place.

44

33 34

27 28

34

hν

hν

Br2

O

O

O

O O

O

O

Br

O

O O

Br

Scheme 2.3 Preparation of diethyl bromomalonate (34) and it’s use as a source of bromine radicals for the bromination of 27.

Diethyl malonate (33) was reacted with equimolar Br2 in dichloromethane under a 40W

artificial daylight lamp,94 forming the desired diethyl-2-bromomolaonate (34) in good yield.

The structure of the product was confirmed via 1H NMR and GC-MS and a small scale

reaction of 27 with 34 in dichloromethane was carried out under the 40W artificial daylight

lamp at 70C. After 24 hours an aliquot of the mixture was taken and analysed, but

unfortunately the spectroscopic data (Figure. 2.14) indicated that no reaction had occurred.

The integral of the Ph-CH peak (2.95 ppm) had not reduced, as would be expected upon

abstraction of this hydrogen atom.

45

Fig. 2.14 1H NMR spectrum of the product of the bromination of 27 (R = OCH 3) using 34 as a source of bromine radicals.

The reaction was left at 70C for a further 7 days, but even after this time the spectrum

showed the same result. It was theorized that the additional steric bulk of the cyclopentane

ring coupled with the already bulky brominating material was the reason for this, as the

authors of the literature did comment that slow rates were observed even for the less

hindered benzylic hydrogens (e.g. those of toluene.) There was no real way to work around

this problem without using a different brominating material such as n-bromosuccinimide,

which was initially considered. However, upon reviewing the time already spent on this

route compared with its success, and considering the lack of starting material to work with

due to the very low yields of the first step, it was decided to abandon this synthetic route in

favour of another, potentially more favourable one.

Unfortunately, a lot of the lab time allocated to project work had already been used up

through repetition of the Friedel-Crafts alkylation reactions, so some success with the

second route was required If the final products were to be made and characterised in time.

It was unfortunate that the Friedel-Crafts reaction could not be optimised to produce

decent yields, as the regiospecificity of these reactions made them novel and potentially

publishable. Future research may include further optimisations and a look at this reaction in

greater detail, in order to fully discern its synthetic potential along with its full limitations.

46

Route 2: Grignard-1,4-addition, bromination, dehydrobromination and

oxidations.

Another synthesis was proposed, which if successful would find another use for the 2-

cyclopenten-1-one 4 bought in to test the Riley oxidation (Scheme 2.4)

40

35

41 39

36

38

37

Mg, Et2O

Cu(I)Br(1,4-nucleophillic addition)

Br2/diethyl bromomalonate

SeO2

Br MgBrO

O

O

Br

O

Br

OO

O

+

Scheme 2.4 Second proposed synthesis route.

The Grignard reagent 36 would be formed from bromobenzene 35. A 1,4-nucleophilic

addition to cyclopent-2-en-1-one 4 using copper(I) bromide as catalyst95 should then form 3-

phenylcyclopentan-1-one 37. This might then be brominated to form 38 or 39, both of

which should prefer to eliminate HBr to give the desired phenyl-substituted ene-one 40.

Oxidation using selenium dioxide or another appropriate oxidising agent would then be

used to produce the desired cyclopent-3-ene-4-phenyl-1,2-dione 41.

Bromobenzene 35 was used as a substitute for 4-bromoanisole or 4-bromoalkylbenzene and

Cu(I)Br used instead of Cu(I)Cl, as these materials were available immediately and we

wished to test the feasibility of this first step before ordering materials for the route.

Unfortunately, GC-MS analysis of the first attempt showed several impurities and the 1H

NMR spectrum showed only starting material 35 in the worked-up product (Figure 2.15).

47

Fig. 2.15 1H NMR spectrum of the product of the Grignard 1,4-addition of 36 to cyclopent-3-en-1-one 4.

The reaction was attempted again more carefully and, this time, an aliquot was taken of the

Grignard reagent once formed. This was added to some acetone to test whether the

Grignard reagent had indeed been formed and 1H NMR analysis of this test did show

evidence for formation of the 1,2-additon product 2-phenylpropan-2-ol. The 1,4-addition

reaction was attempted again, however, 1H NMR spectroscopic analysis of the product was

not clear and peaks were difficult to assign confidently (Figure 2.16).

48

Fig. 2.16 1H NMR spectrum of the product of the Grignard 1,4-addition of 36 to cyclopent-3-en-1-one 4.

The spectrum was difficult to analyse and showed that little or no desired reaction had

occurred. Due to the apparent lack of success of the 1,4-addition reaction, coupled with its

complex set-up requirements, it was decided that this route be abandoned in favour of

another.

49

Route 3: Friedel-Crafts acylation, aldol cyclisation and oxidations.

It was thought originally that the route proposed first would provide the simplest way of

furnishing the desired compound 32 (R = OCH3), however, the failure of the initial steps

made it seem much less favourable. Instead, a route that would involve a ring-closure to

form the phenyl-substituted cyclopent-3-en-1-one ring was proposed (Scheme 2.5).

43 44 45

31 32

SOCl2DCM

AnisoleAlCl3

10% KOH

Or Mn(OAc)3,

then H3O+ and [O]

SeO2

OH

O

O O

O

Cl

O

OO

O

O

O

O

O

Scheme 2.5 Proposed synthetic route to 32 (R = OCH3).

Levulinoyl chloride 44 would be generated from levulinic acid 43 and thionyl chloride and it

was hoped that a Friedel-Crafts acylation reaction with anisole would furnish the desired

para-substituted diketone 45. It was envisaged that the diketone 45, in the presence of a

strong enough base, would be able to overcome the slightly disfavoured 5-enolendo-exo-trig

ring closure mechanism and undergo an intramolecular aldol-type cyclisation, with

subsequent elimination of water to furnish the cyclopent-3-en-1-one moiety of 31 in a

smooth step (Scheme 2.6).

50

B:

B

31

:O

O

O HHH

O

O –

O HHO

O H

OH

H

O –

O H

O

O

O

Scheme 2.6 Reaction mechanism for the proposed intramolecular aldol-cyclisation reaction.

Enone 31 could then be reacted with selenium dioxide in the Riley oxidation,3 hopefully,

producing the desired cyclopent-3-en-1,2-dione 32.

An alternative α-oxidation of 31 using manganese(III) acetate,96 could form the enol acetate

46, which would then be hydrolysed and oxidised to form the desired cyclopent-3-en-1,2-

dione functionality of 32 (Scheme 2.7).

i. H3O+

ii. [O]

46

Mn(OAc)3,

31 32

O

O

O

O

OO

O

O

O

Scheme 2.7 Alternative dione synthesis.

The final steps to a potentially liquid crystalline compound would involve the de-

methylation of the methoxy group of 32 using boron tribromide97 or iodotrimethylsilane98 to

form the phenol 47. The phenol could then be reacted in the standard way with varying

51

chain-length alkyl halides to form one of the two ranges of potentially liquid crystalline

ligands that were of ultimate interest to the project, 10a-t (Scheme 2.8).

BBr3

Or ISiMe3

NaOH, Reflux

32 47 10(a-t)

BrR

O

O O

O H

O O

O

O O

R

Scheme 2.8 Introduction of the long chain-tails required for mesophase formation, via de-methylation of the methoxy group followed by Williamson ether synthesis with the corresponding alkyl halides to form 10(a-t).

On reflection this route seemed more favourable than the previous ones as it reduced the

number of steps required to reach the desired ene-dione functionality. Also, since the long-

chains could be introduced onto 47 towards the end of the synthesis, this offered a cheaper

and less risky route since anisole, 26, (a cheap and readily available product) could be used

as starting material for every alkyloxy-derivative, avoiding the need to use the more

expensive longer chained alkyloxy-benzene derivatives as starting materials.

First then, levulinic acid (43) was reacted with an excess of thionyl chloride to form the acid

chloride 44. Initially this was done with thionyl chloride as solvent, however, issues with

darkening of the product and the lack of temperature control using basic hot plates

prompted the use of dichloromethane as solvent in later syntheses. Proof that the acid

chloride 44 had formed was given by mixing an aliquot of the reaction mixture with

methanol to give the ester, methyl levulinate 48.

48

O

O

O

52

This structure was confirmed by 1H NMR spectroscopy; a clear methyl ester group is

evidenced by a singlet peak at 3.68 ppm (Figure 2.17).

Fig. 2.17 1H NMR spectrum of methyl levulinate 48, the two CH3 and two CH2

environments are clearly evidenced.

Excess thionyl chloride was removed under vacuum at 40°C and 44 was added immediately

to a stirring mixture of anisole and aluminium chloride in dichloromethane at around 0°C.

The reaction mixture was worked-up 12 hours later by decomposition of the aluminium

chloride complex with strong hydrochloric acid, separating the dichloromethane solution

and washing with water before drying and evaporation of the dichloromethane to yield a

deep, orange oil. 1H NMR spectroscopic analysis of the product showed some evidence for a

successful reaction (Figure 2.18), as did gc/ms analysis (Figure 2.19), which showed two

isomers with the correct molecular mass of 206.

53

Fig. 2.18 1H NMR spectrum of the product mixture from the Friedel-Crafts acylation reaction of 26 with 44.

(a) (b)

54

Fig. 2.19 Gas chromatogram (a) and mass spectrum (b) of the product mixture from the Friedel-Crafts acylation reaction of 26 with 44.

The gc-ms shows a mixture of two isomers in a ratio of approximately 1:4, while the 1H NMR

spectrum showed the desired para-isomer as a pair of doublets in the aromatic region,

overlapping with the peaks of what appears to be the ortho-isomer.

The pair of doublets seen in the 1H NMR spectrum (7.31 and 6.91 ppm) indicated the

presence of a para-di-substituted benzene ring, however, there was certainly evidence for

the ortho-isomer also being formed; ortho-substitution splitting pattern overlapping with

the pair of doublets in the aromatic region and two large methoxy CH3 peaks, rather than

one. Most interestingly, in the 2-3 ppm region the splitting pattern of the peaks here

seemed overly complex for what should simply be two triplets, each representing the

adjacent CH2 groups of the middle of the acylated chain (like those seen in the spectrum of

48, Figure 2.17). Initially, it was thought that overlap of the CH2 environments of the two

isomers may explain this, but purification and subsequent analysis later would refute this

assumption. Also of note, the methyl singlet (1.72 ppm) seemed too low to be

representative of a methyl group adjacent to a carbonyl, expected at around 2-2.2 ppm. The

position of this peak pointed to a methyl group one carbon away from a singly bonded

oxygen, such as in an ether or alcohol. However, an ether group was not expected and no

alcohol peaks were immediately obvious from the spectrum. Although the peak integral

ratio in the 1H NMR spectrum fitted with the expected product, all of the anomalies together

suggested that something unexpected had been formed.

In order to progress any further, the structure of this para-product needed to be proven.

TLC developed an appropriate solvent system (50/50 hexane/diethyl ether) for separating

the isomers and some time was spent purifying the desired para-isomer using a

chromatotron. Once pure, full spectroscopic analysis was carried out on the para-compound

(FTIR, 13C, 1H, DEPT 45, DEPT 90 and DEPT 135 NMR and 2 dimensional COSY, NOESY, HSQC

and HMBC NMR analysis) and under the understanding that the ortho-isomer would have

similar spectroscopic properties and its structure could be inferred from that of the para-

isomer. The 1H NMR spectrum of the pure para-compound showed the same complicated

splitting pattern in the 2-3 ppm region, ruling out that this pattern was caused by the

overlap of multiple isomers (Figure 2.20).

55

Fig. 2.20 1H NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation reaction.

Since, during the reaction, the aluminium chloride catalyst would be expected to coordinate

to the lone pairs of both ketone groups of 44, as well as the methoxy group of 26, it was

originally thought that the expected product might be undergoing the intramolecular aldol-

cyclisation of the next step in-situ via a Lewis-acid catalysed mechanism. However, if this

were the case, the product should contain either an alcohol or the dehydrated alkene

moiety, neither of which were evidenced by NMR, (GC-MS also disputed the dehydration

product as this would have given a molecular mass of 188 not 206).

In an attempt to confirm, via 1H NMR spectroscopy, whether the ring-closed alcohol had

been formed, an exchange experiment with D2O was carried out on the purified compound,

but this only produced a reduction in the water peak at 1.59 ppm (Figure 2.21).

56

Fig. 2.21 1H NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation reaction. The second spectrum shows the same sample ran with a few drops of D2O added to the NMR tube.

A reduction in the water peak was observed (1.59 ppm) and no deuterated alcohol peak

disappeared from the spectrum (the peak appearing at 4.8 represents HOD in chloroform.)

The FTIR spectrum (Figure 2.22) showed an intense uniformly-shaped peak at 1763.87 cm -1,

indicating the presence of one carbonyl group only.

57

Fig. 2.22 FTIR spectrum of the purified para-isomer product of the Friedel-Crafts acylation reaction.

However, the position of this peak indicated a carbonyl either within a strained ring, or one

otherwise altered in such a way that increased its carbonyl electron density. The expected

CH stretch peak (2975.75 cm-1) and C-O stretch peak (1244.16 cm-1) were also clearly visible.

Interestingly, the IR data also helped rule out the existence of an alcohol group (no peak

seen above 3000 cm-1) proving the aldol-cyclisation could not have occurred since this would

result in either an alcohol or a dehydrated alkene group, neither of which were evidenced

by any of the spectra. Furthermore, the mass spectrum (figure 2.19) showed a base peak at

M-43+ peak, suggesting that a CH3CO group might be present. Originally, this observation

led us to the suggested structure 49, which fitted, with some assumption of through-space

electronic effects, the 1H NMR spectrum, especially the fact that the CH2 groups were

diastereotopic and not simple CH2 triplets.

O

OO

49

58

It would be necessary to obtain a full 13C NMR analysis and 2D correlations to prove the

unknown structure.

The 13C spectrum (Figure 2.23) showed 10 carbon environments as expected, one of which

appeared to be an ester carbonyl C due to its relatively low (for a carbonyl) shift value

(176.42 ppm). This was the only carbonyl peak observed and this correlated with the data so

far, but again suggested that neither the expected product 45 nor the proposed structure 49

had been formed, as the former would have two ketone groups and the latter would have

had one non-ester carbonyl.

Fig. 2.23 13C NMR analysis of the para-isomer product of the Friedel-Crafts acylation reaction.

DEPT 45 13C NMR analysis (Figure 2.24) showed the carbon environments with hydrogen

substituents and this data made sense as the two aromatic CH’s, two CH2 groups and two

methyl groups were all visible, whilst the expected quaternary/carbonyl carbons were

absent.

59

Fig. 2.24 DEPT 45 13C NMR analysis of the purified para-isomer product of the Friedel-Crafts acylation reaction.

DEPT 90 13C NMR analysis (Figure 2.25) showed evidence for only two CH environments, as

expected (CH groups of the para-di-substituted aromatic ring).

Fig. 2.25 DEPT 90 13C analysis of the purified para-isomer product of the Friedel-Crafts acylation reaction.

60

DEPT-135 analysis (Figure 2.26) evidenced two CH2 groups (29.02 and 36.14 ppm), which

corroborated with the expected product 45. However, 45 would not have produced such a

complex (obviously diastereotopic) pattern in the 2-3 ppm CH2 region of the 1H NMR

spectrum, so structure 45 could not be correct.

Fig. 2.26 DEPT 135 13C NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation. Two CH2 groups are clearly evidenced, appearing as negative on the spectrum.

The fact that GC-MS confirmed a mass of 206 meant that the expected empirical formulae

must have been correct. However, spectroscopic analysis ruled out the presence of an

alcohol group and confirmed only one electronically dense or ring-strained ester carbonyl

group. Two CH2 groups were also confirmed, however the complex splitting pattern of these

protons on the 1H NMR spectrum suggested they sat within a ring containing at least one

chiral centre. After further consideration, the structure 50 was proposed, structure 49 being

eliminated as not being in agreement with the 13C NMR C=O chemical shift (~178 ppm).

61

50

Structure 50 fitted well with the analytical data, as it included:

A mass of 206 (three oxygens), but no alcohol group.

A chiral centre within a strained ring.

One ester carbonyl group within a strained ring.

Adjacent diastereomeric CH2 groups, both in a small ring as their coupling constants

were low.

A methyl group one C away from a singly bonded oxygen.

This particular arrangement of atoms would also explain the unusually low methyl peak at

1.7 ppm on the 1H NMR spectrum, which for a typical carbonyl methyl group should have

been around 2-2.5 ppm. The only piece of data structure 50 did not appear to fit was the

mass spectrum (Figure 2.19), which showed a M-43+ peak, suggesting that a CH3CO group

might be present.

In order to prove whether structure 50 was correct, 2-dimensional NMR analysis was carried

out. First, the COSY spectrum (Figure 2.27) that shows which H environments are coupled to

each other.

62

Fig. 2.27 2D COSY NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation, showing the homo-nuclear (1H) spin couplings.

This correlated with the proposed structure 50 as it showed a clear “box” in the aromatic

region, indicating the coupled aromatic proton environments, and a less clear “mess” of

correlating peaks in the 2-3 ppm region that showed that the compound had two adjacent

CH2 groups within a ring, one of which sits next to a chiral centre. This means that all four of

these hydrogens should be magnetically non-equivalent, each coupling to each other at a

different frequency and as a result, producing a very complicated correllation pattern in the

2-3 ppm region, such as the one evidenced here and on the 1D spectrum.

Next, 2D NOESY NMR analysis (Figure 2.28) showed which hydrogen environments were

coupled through space.

Fig. 2.28 2D NOESY NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation, evidencing no homo-nuclear (1H) spin couplings through space, as expected.

63

This showed that no hydrogen environments were coupling through space, as would be

expected for a relatively small and constrained molecule.

The HSQC analysis (Figure 2.29) showed which hydrogen environments were bonded to

which carbons, helping to assign the different carbon environments accurately on the 13C

NMR spectrum.

Fig. 2.29 2D HSQC NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation, showing the hetero-nuclear (1H-13C) spin couplings.

Finally, and perhaps most importantly, the HMBC analysis (Figure 2.30) showed which

nuclear spins were coupling through several bonds. This technique is particularly useful, as it

clarifies which environments are bonded to which, thereby helping to elucidate the true

structure.

64

Fig. 2.30 2D HMBC NMR spectrum of the purified para-isomer product of the Friedel-Crafts acylation, showing the heteronuclear spin couplings through multiple bonds.

Labelling the proposed structure’s carbon and carbon/hydrogen environments A-J (Figure

2.31), a table of heteronuclear multiple-bond correlations can be produced:

50

Fig. 2.31 Proposed structure with nuclear environments labelled A-J, for producing a correlation table.

65

Table 2.1 HMBC correlation table, using the labelled structure (Figure 2.28) as reference.

1H NMR environment Coupled to the following 13C environments,

as shown on HMBC spectrum

A B

C B, D and E

D B, C, D and G

F E, G and H

H E, F, G and J

I G, H, and J

This fits with what would be expected if structure 50 were correct, (e.g. the chiral methyl

coupled through 2-3 bonds to quaternary aromatic E, quaternary non-aromatic G and the

C(H2) group H etc.). If either structure 45 or 49 were correct we would not see these

correlations and since all HMBC correlations match with what would be expected for 50 we

could now state that the actual product of step 1 of route 3 was in fact 50. The only

analytical data which disagreed with this result again was the mass spectrum, which showed

a M-43+ bass peak. This fragmentation suggested that a CH3CO group was present, which

would correlate with the expected product 45 or the initially proposed structure 49 but not

50. However, loss of a methyl was also clearly evident on the MS, which would agree with

our compound as loss of the chiral methyl of 50 would leave behind a stable tertiary

carbocation. Also, all other spectroscopic data pointed to 50 being the correct structure and

so it was assumed that perhaps some re-organisation of atoms/electrons upon ionisation

might explain the persistence of the bass peak (M-43+).

A literature search was carried out to find this structure or reactions similar to the one

described, which turned up several syntheses for 50,99,100,101,102,103 however, none of these

matched the conditions that we had used to prepare 50. It was thought that either the

expected acylation had occurred, followed by an unexpected 1,3-sigmatropic

rearrangement, catalysed by the AlCl3 (Scheme 2.9), or perhaps a strange arylation reaction,

similarly catalysed by this powerful Lewis-acid catalyst (Scheme 2.10).

66

Scheme 2.9 First proposed mechanism for formation of 50.

Scheme 2.10 Second proposed mechanism for formation of 50.

This result was very interesting, as it could potentially mark the discovery of a new reaction,

or at least a new synthetic route to Ar-substituted cyclic esters that has previously never

been found! Unfortunately, no further lab work could be carried out to examine this

compound or the reaction which created it in any more detail, as the time allocated for

project labs had ran out by the time this structure was solved.

67

Chapter 3

Conclusions and Future Work

68

Unfortunately, the final ligand compounds 9(a-t) and 10(a-t) could not be prepared in time,

and this can be put down to the limited lab time given to the project compared with the

work necessary to complete it. Obviously, as stated at the beginning, this work forms the

basis for future research and, despite not completing the main objectives of the project,

several positive results have been discovered. Namely, a potentially new type of

reaction/route to synthesising Ar-substituted lactones, which will certainly be developed in

future work, has been discovered. Also, despite low yields, excellent regiospecificity was

observed for the Friedel Crafts alkylation reactions involving H-ZSM-5 catalyst, and this

reaction will also be looked at in greater detail for future research. It can also be seen as a

positive that the reactions attempted in the lab which failed to generate good results can

now be removed from the synthetic plan, as this rules out the possibility of wasted time for

future researchers. To conclude, despite not completing the main objectives of the initially

outlined project, several interesting discoveries were made which could potentially open up

brand new routes of synthetic research. The reactions attempted were difficult and not

always fruitful, however, novel results were obtained in some cases and all of the work

reported contributes positively towards a greater body of on-going synthetic research and

development.

69

Chapter 4

Experimental

70

General

1H and 13C NMR spectra were measured on either a Bruker Avance-III 300MHz or a Bruker

Avance 400MHz spectrometer at ambient temperature using tetramethylsiliane (TMS) as

the internal standard for 1H NMR with deuteriochloroform (CDCl3, 77.23 ppm) and

deuteriodimethylsulfoxide (d6-DMSO, 39.52 ppm) for 13C NMR, unless otherwise stated. All

chemical shifts are quoted in δ (ppm) and coupling constants in Hertz (Hz) using the high-

frequency positive convention. The abbreviations used for the multiplicity of the NMR

signals are: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, sex = sextet, m =

multiplet, dd = doublet of doublet, td = triplet of doublets, dm = doublet of multiplets, br s =

broad singlet, etc. GC/mass spectra were recorded on a Perkin Elmer Auto System XL Gas

Chromatograph and Perkin Elmer Turbomass Mass Spectrometer. Infrared spectra were

recorded on a Thermo Scientific Nicolet IR200 FT-IR spectrometer with a He/Ne-633 nm

laser using a Specac ATR attachment. Thin layer chromatography was carried out on

Machery-Nagel polygram Sil/G/UV254 pre-coated plates. All chemicals were obtained from

SigmaAldrich or Alfa Aesar and used without further purification.

Cyclopent-3-ene-1,2-dione 1 (Aqueous method)

2-Cyclopenten-1-one (0.5 g, 6 mmol) and selenium dioxide (0.66 g, 6 mmol) were added to

de-ionised water (5 ml). The reaction was stirred at room temperature for 10 days, forming

an orange solution. The mixture was filtered over ammonium sulphate, extracted into DCM,

washed with water (4 x 20 ml) and dried over ammonium sulphate. The DCM solvent was

removed carefully using a gentle flow of N2 gas, leaving a yellow oil (0.104 g, 17.8%).

Analysis showed this to be starting material: 1H NMR (300 MHz, Deuterium Oxide) δ 7.88

(dt, J = 5.4, 2.6 Hz, 1H, CH), 6.09 (dt, J = 5.6, 2.1 Hz, 1H, CH), 2.61 (m, J = 4.2, 2.3 Hz, 2H, CH2),

2.28 (m, 2H, CH2). ESI-MS: m/z 82 (M+., 66%).

Cyclopent-3-ene-1,2-dione 1 (1,4-dioxane method)

2-Cyclopenten-1-one (47 mg, 0.57 mmol) and selenium dioxide (251 mg, 2.26 mmol) were

added to 1,4-dioxane (6 ml) and heated under reflux for 18 h. The cooled solution was

centrifuged at 4000 rpm and decanted to yield a brown/red solution, which still

71

unfortunately contained some dissolved elemental selenium. 1,4-Dioxane was removed

carefully under reduced pressure at 25°C, yielding a small amount of the title compound 1

along with elemental selenium red. 1H NMR (300 MHz, Chloroform-d) δ 8.10 (dt, J = 7.5, 2.5

Hz, 1H, O=C-CH=CH), 6.24 (dt, J = 5.7, 2.0 Hz, 1H, O=C-CH=CH), 3.13 (dd, J = 2.5 Hz, 2H, O=C-

CH2). ESI-MS: m/z 96 (M+., 28%) M-28 ( – C=O).

1-Cyclopentyl-4-ethyl-benzene 27 (AlCl 3 method)

A slight excess of ethylbenzene (1.1:1) (1.062 g, 10 mmol) was added to chlorocyclopentane

(0.941 g, 9 mmol) and a catalytic amount of anhydrous AlCl3 (0.267 g, 2 mmol) in dry DCM

(10 ml). The reaction was warmed at 25°C with continuous stirring for 5 hours, forming a

dark orange/black solution. The reaction was quenched in ice water and the organic layer

extracted with diethyl ether (20 ml), washed with deionised water (2 x 20 ml) and dried over

sodium sulphate. Ether was removed in air, yielding the title compound 27 as a dark black

oil (0.871 g, 55.6%). 1H NMR (300 MHz, Chloroform-d) δ 7.22-6.78 (m, 4H, Ar-H), 2.61 (q, J =

14.4, 9.7, 5.2 Hz, 2H, Ar-CH2), 2.26 (quin, J = 17.5, 8.3, 7.8, 5.0 HZ, 1H, Ar-CH), 2.15 – 1.96 (m,

2H, CH2), 1.93 – 1.49 (m, 6H, CH2), 1.23 (t, 3H, CH3). (Peaks not clearly defined, mixture of

isomers produced).

1-Cyclopentyl-4-methoxybenzene 28 (AlCl 3 method)

A slight excess of anisole (1.1:1) (1.081 g, 10 mmol) was added to chlorocyclopentane (0.941

g, 9 mmol) and a catalytic amount of AlCl3 (0.267 g, 2 mmol) in dry DCM (10 ml). The

reaction was warmed at 25°C with continuous stirring for 5 hours, forming a pink/orange

solution. The reaction was quenched in ice water and the organic layer extracted with

diethyl ether (20 ml), washed with deionised water (2 x 20 ml) and dried over sodium

sulphate. Ether was removed in air, yielding the title compound 28 as a dark pink oil (1.015

g, 64.1%). 1H NMR (300 MHz, Chloroform-d) δ 7.35-7.09 (m, 2H, Ar-H), 7.01-6.79 (m, 2H, Ar-

H), 3.83 (s, 3H, OCH3), 3.30 (quin, 1H, Ar-CH), 2.14 – 1.92 (m, 2H, CH2), 1.91 – 1.44 (m, 6H,

CH2). (Peaks not clearly defined, mixture of isomers produced).

72

1-Cyclopentyl-4-ethyl-benzene 27 (Fulacolor TM clay method)

Chlorocyclopentane (2 g, 20 mmol) was added to an excess of ethylbenzene (2:1) (4.33 g, 41

mmol) and a catalytic amount of FulacolorTM clay (0.5 g). The reaction was heated at 100°C

with continuous stirring for 3 hours, forming a dark orange/black solution. After 3 hours, the

reaction was cooled and filtered, yielding a dark brown oil (2.540 g, 73.0%). 1H NMR (300

MHz, Chloroform-d) δ 7.27 (m, (overlap with ethylbenzene) 2H, Ar-H), 7.14 (m, (overlap with

ethylbenzene) 2H, Ar-H), 2.96 (quin, 1H, Ar-CH), 2.64 (q, (overlap with CH2 of ethylbenzene)

2H, CH2), 2.04 (m, 2H, CH2) 1.75 (m, 6H, CH2), 1.23, (t, (overlap with CH3 of ethylbenzene) 3H,

CH3).

1-Cyclopentyl-4-methoxy-benzene 28 (Fulacolor TM clay method)

Chlorocyclopentane (2 g, 20 mmol) was added to an excess of anisole (2:1) (5 g, 46 mmol)

and a catalytic amount of FulacolorTM clay (0.5 g). The reaction was heated at 100°C with

continuous stirring for 3 hours, forming a pink/orange solution. After 3 hours the reaction

was cooled and filtered, yielding a dark purple oil (2.754 g, 78.2%). 1H NMR (300 MHz,

Chloroform-d) δ 7.15 (m, 2H, Ar-H), 6.82 (m, 2H, Ar-H), 3.79 (s, 3H, Ar-OCH3), 2.92 (quin, 1H,

Ar-CH), 2.16 – 1.86 (m, 8H, CH2).

1-Cyclopentyl-4-ethyl-benzene 27 (Al-ZSM-5 method)

N.B. The following reaction was carried out a number of times using a range of reaction

times (2-48 hours), temperatures (100-150°C) and varying amounts of catalyst (0.5-3 g), to

try and optimise results. The best results were seen for the following procedure:

Chlorocyclopentane (2 g, 20 mmol), was added to an excess of ethylbenzene (2:1) (4.33 g,

41 mmol) and Al-ZSM-5 (3 g). The reaction was heated at 150°C with continuous stirring for

48 hours, forming a dark brown solution. After 48 hours the reaction was cooled, filtered

and concentrated under reduced pressure to yield the title compound 27 as a dark brown oil

(0.121 g, 3.5%). 1H NMR (300 MHz, Chloroform-d) δ 7.18 (dd, 4H, Ar-H), 2.98 (tt, J = 9.2, 7.2

Hz, 1H, Ar-CH), 2.64 (q, J = 3.7 Hz, 2H, Ar-CH2), 2.17 – 1.99 (m, 2H, CH2), 1.77 – 1.47 (m, 6H,

CH2), 1.26 (t, 3H, CH3). ESI-MS: m/z 174 (M+., 42%), M-29 (-C2H5).

73

1-Cyclopentyl-4-methoxy-benzene 28 (Al-ZSM-5 method)

N.B. The following reaction was carried out a number of times using a range of reaction

times (2-48 hours), temperatures (100-150°C) and varying amounts of catalyst (0.5-3 g), to

try and optimise results. The best results were seen for the following procedure:

Chlorocyclopentane (2 g, 20 mmol) was added to an excess of anisole (2:1) (5 g, 46 mmol)

and Al-ZSM-5 (3 g). The reaction was heated at 150°C with continuous stirring for 48 hours,

forming a dark pink/purple solution. After 48 hours the reaction was cooled, filtered and

concentrated under reduced pressure to yield the target compound 28 as a dark purple oil

(1.024 g, 29.1%). 1H NMR (300 MHz, Chloroform-d) δ 7.20 (d, 2H, Ar-H), 6.87 (d, 2H, Ar-H),

3.82 (s, 3H, OCH3 ,)2.97 (tt, 1H, Ar-CH), 2.17 – 1.94 (m, 4H, CH2), 1.93 – 1.76 (m, 4H, CH2).

ESI-MS: m/z 176 (M+., 98%) M-29 (-C2H5).

1-Cyclopentyl-4-ethyl-benzene 27 (H-ZSM-5 method)

Cyclopentene (1.36 g, 20 mmol) was added to an excess of ethylbenzene (2:1) (4.33 g, 41

mmol) and H-ZSM-5 (1 g). The reaction was heated at 150°C with continuous stirring for 48

hours, forming a brown solution. After 48 hours the reaction was cooled, filtered and

concentrated under reduced pressure to yield the title compound 27 as a brown oil (0.0712

g, 2.1%). 1H NMR spectra showed mostly starting material. ESI-MS: m/z 174 (M+., 40%) M-29

(-C2H5).

Reaction not taken forward due to poor results

1-Cyclopentyl-4-methoxy-benzene 28 (H-ZSM-5 method)

N.B. The following reaction was carried out a number of times using a range of reaction

times (48 hours to 10 days), temperatures (100-200°C) and varying amounts of catalyst (0.5-

3 g), to try and optimise results. The best results were seen for the following procedure:

Cyclopentene (3.13 g, 46 mmol) was added to anisole (5 g, 41 mmol) and H-ZSM-5 (3.5 g).

The reaction was heated at 180°C with continuous stirring for 7 days, forming a brown

solution. After 7 days the reaction was cooled, filtered and concentrated under reduced

pressure to yield the title compound 28 as a brown oil (0.513 g, 6.3%). 1H NMR (300 MHz,

Chloroform-d) δ 7.19 (d, 2H, Ar-H), 6.86 (d, 2H, Ar-H), 3.81 (s, 3H, Ar-O-CH3), 2.96 (tt, J = 9.6,

74

7.4 Hz, 1H, Ar-CH), 2.16 – 1.97 (m, 2H, CH2), 1.86 – 1.51 (m, 6H, CH2). ESI-MS: m/z 176 (M+,

56%), M-29 (-C2H5).

1-(1-Bromocyclopentyl)-4-methoxy-benzene 29 (R=OCH 3) (Direct bromination)

4-Cyclopentylanisole (0.4 g, 2.3 mmoles) was dissolved in DCM (10 ml) and a solution of Br 2

(0.37 g, 0.12 ml, 2.3 mmoles) in DCM (10 ml) was added slowly whilst a 40W low energy

artificial daylight lamp bulb illuminated the solution. The solution of bromine was added

slowly, drop-wise and in portions, with each portion added only after the brown colour in

the reaction mixture had disappeared. Addition was continued until this colouration

remained in the reaction mixture, indicating the reaction had gone to completion. A small

aliquot was taken for qualitative analysis. Data correlated to benzene ring bromination: 1H

NMR (300 MHz, Chloroform-d) δ 7.42 (d, 1H, Ar-H), 7.15 (dd, J = 8.5, 2.2 Hz, 1H, Ar-H), 6.84

(d, J = 8.4 Hz, 1H, Ar-H), 3.89 (s, 3H, ArOCH3), 2.93 (tt, J = 9.7, 7.4 Hz, 1H, Ar-CH), 2.05

(ddddd, J = 11.1, 7.6, 6.3, 3.7, 1.5 Hz, 2H CH2), 1.89 – 1.52 (m, (overlapping) 6H, CH2). m/z

254/256 (M+., 52%) M-79/81 (-Br), M-108 (-BrC2H4).

Diethyl bromomalonate 34

A two-necked flask fitted with a reflux condenser and dropping funnel was purged with N 2

for approximately five minutes. A solution of bromine (15.32 g, 4.91 ml, 95.86 mmol) in

DCM (30 ml) was added dropwise to a stirred mixture of diethyl malonate (15 g, 14.29 mL

94.65 mmol) and DCM (20 ml). After six drops of the bromine solution had been added, the

reaction was initiated by irradiating the flask with an incandescent bulb. The remaining

bromine solution was added over 15 minutes to maintain an orange-red colour in the

reaction mixture. The reaction mixture was then heated under reflux for 1 h, diluted with an

equal volume of DCM, washed with 5% NaHCO3 (2 x 10 mL), dried over anhydrous MgSO4,

and evaporated in vacuo to yield the title compound 34 (19.55 g, 86.4%). 1H NMR (300 MHz,

Chloroform-d) δ 4.84 (s, 1H, O=C-CBrH-C=O), 4.30 (q, J = 7.1 Hz, 4H, O=C-CH2), 1.32 (t, J = 7.1

Hz, 6H, O=C-CH2CH3). m/z 210/212 (M+. - CH2CH3, 71%).

75

1-(1-Bromocyclopentyl)-4-methoxy-benzene 29 (R=OCH 3) (bromomalonate bromination)

A two-necked 10 ml flask fitted with a reflux condenser and dropping funnel was purged

with N2 for approximately five minutes. A solution of diethyl 2-bromomalonate (0.15 g, 0.63

mmol) in DCM (3 mL) was added dropwise to a stirred mixture of 4-cyclopentylanisole (0.1

g, 0.57 mmol) and DCM (2 mL). After six drops of the malonate solution had been added,

the reaction was initiated by irradiating the flask with a incandescent bulb. The remaining

malonate solution was added over 15 minutes. The reaction mixture was heated under

reflux at 70°C for a week. A small aliquot was taken and qualitative analysis carried out. Data

showed only starting material: 1H NMR (300 MHz, Chloroform-d) δ 7.18 (d, 2H, Ar-H), 6.85

(d, 2H, Ar-H), 3.80 (s, 3H, O-CH3), 2.95 (tt, 1H, CH), 2.15 – 1.97 (m, 2H, CH2), 1.83 – 1.56 (m,

6H, CH2).

Route abandoned due to lack of success.

3-Phenylcyclopentanone 37 (Grignard 1,4-addition)

Magnesium turnings (0.078 g, 3.2 mmol) was added to a purged, dry flask and

bromobenzene (0.5 g, 3.2 mmol) dissolved in 10 ml of dry ether was added slowly, at such a

rate as to maintain a vigorous reflux, along with a crystal of iodine. The mixture was heated

under reflux for 1 hour until all the magnesium had dissolved. Cu(I)Br (4.6 mg, 1 mol%) was

added and the flask cooled to approximately 5°C in an ice bath. 2-Cyclopenten-1-one (0.263

g, 3.2 mmol) in ether (5 ml) was added dropwise over the course of an hour, producing a

white precipitate. The mixture was again heated under reflux for a further hour at

approximately 50°C. The cooled reaction mixture was then poured onto ice (5 g) and glacial

acetic acid (5 ml), the ether layer separated and the aqueous layer extracted two times with

ether (10 ml). The organic layers were combined, washed with sodium carbonate solution

and water and dried over sodium sulphate. The solvent was removed under reduced

pressure to yield a yellow oil (0.177, 34.6%). 1H NMR analysis failed, could not assign peaks.

ESI-MS: m/z 160 (M+, 78%).

1-(4-methoxyphenyl)pentane-1,4-dione 45

A two-necked quick-fit 150 ml Erlenmeyer flask was purged with N2 for an hour. Levulinic

acid (10 g, 86 mmol, 8.7 ml) was added to the flask and the second neck sealed with a

76

rubber septum. SOCl2 (30.75 g, 258 mmol, 18.7 ml) was added via a syringe. The mixture

was stirred at 20°C for 2 hours, then transferred to a weighed and N2-purged round

bottomed flask and rotoevaporated for 20 minutes to remove any excess SOCl2. A reflux

condenser was attached and anisole (9.3 g, 86 mmol, 9.3 ml), 40 mol% of AlCl3 (4.7 g, 35.5

mmol) and DCM (50 ml) added to the flask. The mixture was stirred in an ice bath overnight,

then quenched with ice water/HCl and the organic layer separated. The product was

extracted into ether, washed 3 times with water and concentrated under reduced pressure

to yield a sticky orange oil (3.68g, 81.2%). The para-isomer was separated using a

chromatotron and subsequent 2D NMR analysis would reveal the product to be 5-(4-

methoxyphenyl)-5-methyl-tetrahydrofuran-2-one 50: 1H NMR (400 MHz, Chloroform-d) δ

7.32 – 7.26 (d, 2H, Ar-H), 6.92 – 6.87 (d, 2H, Ar-H), 3.80 (s, J = 0.8 Hz, 3H, ArOCH3), 2.68 –

2.31 (m, 4H, O=COCH2CH2), 1.70 (s, J = 0.7 Hz, 3H, O-CCH3). 13C NMR (101 MHz, CDCl3) δ

176.42 (O=COR), 159.05 (Ar-C), 136.38 (Ar-C), 125.36 (Ar-CH), 113.95 (Ar-CH), 86.84 (Ar-

CCH3COCO), 55.28 (Ar-OCH3), 36.14 (O=CCH2), 29.42 (Ar-CCH3COCO), 29.03 (O=CCH2CH2R).

FT-IR (Cm-1): 2975.75 (CH stretch), 1244.16 (C-O stretch), 1763.87 (cyclic C=O stretch). m/z

206 (M+. 71%), M-15 (-CH3).

Ortho-isomer: 1H NMR (300 MHz, Chloroform-d) δ 7.49 (dd, J = 7.7, 1.8 Hz, 1H, Ar-H), 7.32

(dd, J = 7.7, 1.7 Hz, 1H, Ar-H), 7.02 – 6.91 (m, 2H, Ar-H), 3.87 (s, 3H, ArOCH3), 2.69 – 2.40 (m,

4H, O=COCH2CH2C), 1.77 (s, 3H, O-CCH3).

77

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